A Phase Ib/II Trial of Siltuximab and Spartalizumab in Metastatic Pancreatic Cancer
Phase: PHASE1
Conditions: Metastatic Pancreatic Adenocarcinoma, Stage IV Pancreatic Cancer AJCC v8
Sponsor: Emory University

Protocol Study No:  Winship4463-18
Product:   Siltuximab plus Spartalizumab
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Protocol/Version No.: 5, Date December 15, 2022
Winship Cancer Institute
Emory University
Phase Ib/II trial of Siltuximab and Spartalizumab in Metastatic 
Pancreatic Cancer
Principal Investigators
Olatunji Alese (Clinical PI) 
olatunji.alese@emory.edu
Gregory Lesinski (Translational co-PI)
gregory.b.lesinski@emory.edu
1365 Clifton Rd NE
Atlanta, GA 30322
Co-Investigators
Maria Diab, MD
Sujata Kane, PA
Olumide Gbolahan, MD
Biostatistician
Jeffrey Switchenko, PhD
Study Coordinator
Katie Coleman
SPONSOR: Olatunji Alese. MD
Research support: Novartis/ EUSA Pharmacovigilance EUSA Pharma 
IND NUMBER: 146523

Protocol Study No:  Winship4463-18
Product:   Siltuximab plus Spartalizumab
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Protocol/Version No.: 5, Date December 15, 2022
TABLE OF CONTENTS
2.1
Trial Diagram: Figure 1. Study schema.................................................................................8
3.0
OBJECTIVE(S) & HYPOTHESES...........................................................................8
3.1
Primary Objective & Hypothesis...........................................................................................8
3.2
Secondary Objectives & Hypotheses.....................................................................................8
3.3
Exploratory Objective............................................................................................................9
4.0
BACKGROUND & RATIONALE ............................................................................9
4.1
Background............................................................................................................................9
4.1.1
Pharmaceutical and Therapeutic Background- spartalizumab ..........................................9
4.1.2
Pharmaceutical and Therapeutic Background - Siltuximab ............................................11
5.0
Rationale.....................................................................................................................19
5.1
Study rationale and purpose.................................................................................................19
5.2
Rationale for the study design .............................................................................................21
5.3
Rationale for dose and regimen selection for spartalizumab:..............................................22
5.4
Risks and benefits................................................................................................................22
5.4.1
Rationale for Endpoints...................................................................................................23
6.0
METHODOLOGY ....................................................................................................25
6.1
Entry Criteria .......................................................................................................................25
6.1.1
Diagnosis/Condition for Entry into the Trial...................................................................25
6.1.2
Subject Inclusion Criteria ................................................................................................25
6.1.3
Subject Exclusion Criteria...............................................................................................27
6.2
Trial Treatments...................................................................................................................28
6.2.1
Siltuximab dose levels.....................................................................................................29
6.2.2
Dose Escalation ...............................................................................................................29
6.3
Dose Modification: ..............................................................................................................31
6.3.1
Dose modification and dose interruption.........................................................................31
6.3.2
Dose modification and dose interruption for spartalizumab ...........................................32
6.3.3
Dose modifications Siltuximab .......................................................................................50

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Protocol/Version No.: 5, Date December 15, 2022
6.3.4
Timing of Dose Administration.......................................................................................51
6.3.5
Trial Blinding/Masking ...................................................................................................51
6.4
Concomitant Medications/Vaccinations (allowed & prohibited)........................................51
6.4.1
Acceptable Concomitant Medications.............................................................................51
6.4.2
Prohibited Concomitant Medications ..............................................................................52
6.5
Rescue Medications & Supportive Care..............................................................................53
6.5.1
Supportive Care Guidelines.............................................................................................53
6.6
Study drug preparation and dispensation.............................................................................56
6.6.1
Spartalizumab ..................................................................................................................56
6.6.2
Siltuximab........................................................................................................................56
6.6.3
Study treatment packaging and labeling..........................................................................57
6.6.4
Drug supply and storage..................................................................................................57
6.6.5
Study drug compliance and accountability......................................................................57
6.6.6
Disposal and destruction..................................................................................................58
6.7
Subject Withdrawal/Discontinuation Criteria......................................................................58
6.7.1
Replacement policy .........................................................................................................58
6.7.2
Withdrawal of consent.....................................................................................................59
6.7.3
Follow up for safety evaluations .....................................................................................59
6.7.4
Follow-up for efficacy evaluations..................................................................................59
6.7.5
Survival follow-up...........................................................................................................60
6.7.6
Lost to follow-up .............................................................................................................60
6.7.7
Discontinuation of Study Therapy after CR....................................................................60
7.0
TRIAL FLOW CHART............................................................................................61
7.1
Study Flow Chart.................................................................................................................61
8.0
TRIAL PROCEDURES ............................................................................................64
8.1
Trial Procedures...................................................................................................................64
8.1.1
Tumor Tissue Collection and Correlative Studies Blood Sampling................................64

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Product:   Siltuximab plus Spartalizumab
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Protocol/Version No.: 5, Date December 15, 2022
8.1.2
Screening .........................................................................................................................68
8.1.3
Treatment period..............................................................................................................69
9.0
Safety monitoring and reporting-Novartis..............................................................72
9.1
Adverse events.....................................................................................................................72
9.1.1
Definitions and reporting.................................................................................................72
9.1.2
Laboratory test abnormalities ..........................................................................................74
9.1.3
Adverse events of special interest ...................................................................................74
9.2
Serious adverse events.........................................................................................................75
9.2.1
Definitions .......................................................................................................................75
9.2.2
Reporting .........................................................................................................................75
9.3
Pregnancies..........................................................................................................................76
9.4
Warnings and precautions....................................................................................................77
10.0
Safety monitoring and reporting-EUSA PHARMA...............................................77
10.1
Overview..............................................................................................................................77
10.2
Management of Safety Data ................................................................................................77
10.3
Definitions ...........................................................................................................................77
10.3.1 Adverse Event (AE).........................................................................................................77
10.3.2 Adverse Events of Special Interest..................................................................................78
10.4
Individual Case Safety Report (ICSR).................................................................................78
10.5
Product Quality Complaint (PQC).......................................................................................79
10.6
Serious Adverse Event (SAE)..............................................................................................79
10.6.1 Hospitalization.................................................................................................................80
10.6.2 Life-Threatening Conditions ...........................................................................................80
10.7
Unlisted (Unexpected) Adverse Event/Reference Safety Information................................80
10.8
Special Reporting Situations................................................................................................80
10.9
Pregnancy.............................................................................................................................81
10.10
Maintenance of Safety Information.....................................................................................82
10.11
Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
EUSA Pharma Medicinal Products to EUSA Pharmacovigilance ......................................82
10.12
SAEs and Special Reporting Situations...............................................................................82
10.13
Non-Serious AEs .................................................................................................................83
10.14
Product Quality Complaint Reporting.................................................................................83
10.15
Reporting Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Non-EUSA Medicinal Products........................................................................84
10.16
Transmission Methods.........................................................................................................84

Protocol Study No:  Winship4463-18
Product:   Siltuximab plus Spartalizumab
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Protocol/Version No.: 5, Date December 15, 2022
11.0
Data Monitoring Committee.....................................................................................84
12.0
STATISTICAL ANALYSIS PLAN .........................................................................85
12.1
Determination of Sample Size.............................................................................................85
12.2
Statistical and Analytical Plans............................................................................................86
12.3
Analysis Sets........................................................................................................................86
12.4
Subject Disposition and Baseline Characteristics................................................................86
12.5
Safety Analysis ....................................................................................................................87
13.0
ADMINISTRATIVE AND REGULATORY DETAILS .......................................87
13.1
Compliance with Trial Registration and Results Posting Requirements.............................87
13.2
Prestudy Documentation......................................................................................................87
13.3
Protocol Adherence..............................................................................................................88
13.4
Retention of Study Documents............................................................................................88
14.0
APPENDICES............................................................................................................89
14.1
ECOG Performance Status ..................................................................................................89
14.2
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)..................................90
14.3
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................................91
Efficacy assessments ....................................................................................................................91
References.........................................................................................................................................94

Protocol Study No:  Winship4463-18
Product:   Siltuximab plus Spartalizumab
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Protocol/Version No.: 5, Date December 15, 2022
1.0 TRIAL SUMMARY
Title 
A Phase Ib/II trial of Siltuximab and Spartalizumab in Metastatic 
Pancreatic Cancer
Abbreviated Title
Siltuximab/ Spartalizumab 
Trial Phase
Phase Ib/II
Clinical Indication
Stage IV pancreas cancer
Trial Type
Single arm dose escalation
Type of control
None
Route of administration
IV 
Purpose and Rationale 
Purpose of the study is to evaluate the safety and biologic activity of the 
combination of spartalizumab and siltuximab in patients with advanced 
stage pancreatic cancer. The rationale is based on preclinical experiments 
(in vivo and in vitro) conducted by our group demonstrating that inhibition 
of IL-6 facilitates migration of lymphocytes into pancreatic tumor. 
Furthermore, combining IL-6 and PD-1 inhibitor was more effective in 
controlling tumor growth than either agent alone using syngeneic and 
genetically engineered mouse models. 
Primary objectives 
Primary objective of part 1 to determine RP2D of spartalizumab and 
siltuximab in advanced pancreatic CA.  
Secondary objective to determine the safety profile of the RP2D of 
spartalizumab and siltuximab in advanced pancreatic CA 
Secondary Objectives
Objective 1. To evaluate the activity of siltuximab and spartalizumab 
Objective 2. Evaluate the effect of the combination on the immune profile 
in the serum and in tumor biopsies
Treatment Groups
Spartalizumab and siltuximab
Treatment cohorts
No of pts
Cohort
Siltuximab
SPARTALIZUMAB
3 to 6
1
6 mg/KG IV every 3 weeks
300 mg every 3 weeks
3 to 6
2
11 mg/Kg every 3 weeks
300 mg every 3 weeks
3 to 6
2a
9 mg/Kg every 3 weeks 
300 mg every 3 weeks
Dose level 2a will only be tested if we observe 2 DLT’s on dose level 2.
Selected Inclusion criteria
1.
Patients with stage IV adenocarcinoma of the pancreas
2.
Patients must have failed at least one prior line of therapy
3.
ECOG PS 0 or 1
4.
Adequate liver, hematologic and renal functions
Selected Exclusion criteria 
1.
Pancreatic neuroendocrine tumor
2.
Prior PD-1, PDL-1 inhibitor
3.
Active autoimmune disease that has required immunosuppressive 
systemic treatment in the past 2 years. Replacement therapy (e.g., 

Protocol Study No:  Winship4463-18
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physiologic corticosteroid replacement therapy for adrenal or other 
hormone replacements) is allowed.
4.
Diagnosis of immunodeficiency including systemic steroid 
therapy or any other form of immunosuppressive therapy within 7 days 
prior to the first dose of trial treatment.
5.
Active infection
Number of trial subjects
The total number of patients who will undergo treatment will range from 
27 to 42 patients. In order to have 42 patients undergo treatment, we plan 
to enroll up to 70 patients to account for screen failures.  
Estimated enrollment period
12 Months
Estimated duration of trial
2 years
Duration of Participation
6 months
Estimated average length of 
treatment per patient
6 months
2.0 TRIAL DESIGN
Open label phase I trial. Primary objective is to determine the recommended phase 2 dose 
(RP2D) of the combination of spartalizumab and siltuximab.  The design is 3+3 with 3 dose 
levels of siltuximab. Maximal Tolerated Dose (MTD )is defined as the dose at which less than 
one-third of the subjects experience a DLT in the first 6 weeks of treatment. 
After determining the RP2D, an additional 24 patients with pancreatic cancer will be enrolled 
in an expansion phase to confirm toxicity profile and obtain paired biopsies. Paired biopsy 
performed on all patients in each group. Patient must have a primary or metastatic non-bone 

Protocol Study No:  Winship4463-18
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site that is amenable to safe biopsy.  Bone only lesions are not suitable for biopsy.  Investigators 
will discuss with radiologist each case to ensure safety of biopsy procedure.
2.1
Trial Diagram: Figure 1. Study schema
3.0 OBJECTIVE(S) & HYPOTHESES
3.1
Primary Objective & Hypothesis

Objective: Determine the recommended phase II dose for the combination of 
spartalizumab and siltuximab
Hypothesis:  The combination of a PD-1 inhibitor with IL-6 inhibitor is safe with no 
added toxicity.
3.2
Secondary Objectives & Hypotheses
(1) Objective:  
A. Define the toxicity profile of the combination of the recommended phase II dose 
of spartalizumab and siltuximab. The additional patients enrolled on the expansion 
cohorts will help confirm the toxicity profile.
Hypothesis:  The combination of a PD-1 inhibitor with IL-6 inhibitor is safe with no 
added toxicity.

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Product:   Siltuximab plus Spartalizumab
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Protocol/Version No.: 5, Date December 15, 2022
B. Evaluate the activity of the combination of spartalizumab and siltuximab in 
previously treated patients with pancreatic cancer. Specifically, we will measure 
overall response rate (PR +CR), response duration and progression free survival. 
This will only be preliminary data since this is a secondary objective. 
Hypothesis:  The combination of a PD-1 inhibitor with IL-6 inhibitor will be active 
against pancreatic cancer resulting in tumor shrinkage.
3.3
Exploratory Objective
Objective: Evaluate the effect of the combination on the immune profile in the serum and 
in tumor biopsies.
Hypothesis:  The IL-6 inhibitor will change the micro-environment to favor an immune 
response to the PD-1 inhibitor. 
4.0 BACKGROUND & RATIONALE
4.1
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on spartalizumab and siltuximab. Neither siltuximab nor spartalizumab are 
approved in pancreatic cancer. The combination of both agents is also investigational. 
4.1.1
Pharmaceutical and Therapeutic Background- spartalizumab 
Spartalizumab is a high-affinity, ligand-blocking, humanized IgG4 antibody directed against 
Programmed Death-1 (PD-1) receptor that blocks the binding of PD-L1 and PD-L2.  PD-1 is 
a critical immune-checkpoint receptor that is expressed on CD4 and CD8 T cells upon 
activation (Freeman, 2008).  Engagement of PD-1 by its ligands, PD-L1 and PD-L2, transduces 
a signal that inhibits T-cell proliferation, cytokine production, and cytolytic function (Riley, 
2009). Monoclonal antibody (mAb) inhibitors of immunological checkpoints, including PD-1 
and PD-L1, have demonstrated significant antitumor activity in patients with various solid 
tumors. For further details, please refer to the latest spartalizumab (PDR0001) Investigator’s 
Brochure.  
4.1.1.1
Non-clinical experience of spartalizumab
Spartalizumab binds specifically and with high affinity to human PD-1 and enhances 
interleukin-2 production in ex-vivo lymphocyte stimulation assays. It does not cross react with 
rodent PD-1; therefore, toxicology studies were performed only in cynomolgus monkeys 
where there was acceptable cross reactivity with monkey PD-1. Repeat administration of 
spartalizumab to monkeys was tolerated at all doses tested up to 100 mg/kg/week for 5 weeks 

Protocol Study No:  Winship4463-18
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in the GLP toxicology single-agent study. No test article-related in-life, mortality, organ weight 
changes, or macroscopic findings were noted. There were no spartalizumab -related effects 
seen in any of the safety pharmacology endpoints assessed (cardiovascular, neurobehavioral, 
and respiratory). Macrophage infiltrates into the splenic white pulp were observed in animals 
given 100 mg/kg/week and mononuclear cell infiltrates, often associated with fibrosis, around 
the injection site blood vessel (saphenous vein) in a few animals given ≥25 mg/kg/week. These 
spartalizumab -related microscopic changes were fully reversible after an eight-week recovery. 
Additionally, mostly low grade mononuclear infiltrates in the vascular and perivascular space 
in several tissues of main and recovery treated animals and in recovery controls were observed 
but with a slightly higher incidence in treated animals. No evidence of parenchymal damage 
was associated with the vascular/perivascular changes in any of the organs examined and the 
changes were not associated with any frank tissue injury. Dose-proportional exposure to 
spartalizumab in each dose group was confirmed. Anti-drug antibodies (ADA) to 
spartalizumab were observed in some spartalizumab treated cynomolgus monkeys. A trend of 
reduced drug exposure was observed in these ADA-positive animals. Based on the toxicology 
studies with spartalizumab as a single-agent, the Highest Non-Severely Toxic Dose (HNSTD) 
dose is 100 mg/kg. For further details, please refer to the latest spartalizumab [Investigator’s 
Brochure].
4.1.1.2
Clinical experience of spartalizumab
As of 23-Jan-2017, 9 Novartis-sponsored clinical studies have treated patients with 
Spartalizumab.  A total of 210 patients were exposed to spartalizumab single agent on an every 
2 weeks (Q2W), every three weeks (Q3W) or every 4 weeks (Q4W) schedule, and 160 patients 
were exposed to spartalizumab in combination with other agents. Three studies have treated 
patients with spartalizumab as a single agent. These include the first-in-human phase I/II 
CPDR01X2101 study (160 patients of which 101 patients were treated at 400 mg Q4W), the 
CPDR001X1101 phase I study in Japanese patients (18 patients, Q2W), and the 
CPDR001X2201 phase II study in patients with nasopharyngeal carcinoma (32 patients, 400 
mg Q4W). These studies have preliminarily identified safety risks associated with 
spartalizumab that are characteristic of agents that inhibit the PD-1 receptor (please refer also 
to approved drug labels of nivolumab and pembrolizumab).
In the dose escalation phase of study CPDR001X2101 in patients with advanced solid tumors, 
no Dose Limiting Toxicities (DLTs) were reported in any of the tested doses and regimens (1, 
3, 10 mg/kg Q2W and 3 and 5 mg/kg Q4W). Based on the available PK and safety data, two 
recommended phase 2 doses (RP2Ds) for spartalizumab have been declared: 400 mg Q4W or 
300 mg Q3W, with the choice between these two regimens determined by scheduling 
convenience, for example in combination settings.
Adverse events (AEs; all grades, regardless of relationship to study drug) were reported in 147 
out of the 160 patients (91.9%) enrolled in study CPDR001X2101. The most frequent AEs (≥ 
10% of patients) were nausea, fatigue, anemia, dyspnea, decreased appetite, cough, 
constipation, vomiting, abdominal pain, diarrhea, pyrexia, pleural effusion, dizziness, asthenia, 
increased aspartate aminotransferase and peripheral edema, which are consistent with the AEs 
reported in studies with other PD-1 inhibitors and with the AEs commonly reported for patients 

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with advanced solid malignancies. Eighty-four patients (52.5%) experienced Grade 3 or Grade 
4 AEs regardless of relationship to study drug. Seventy-nine patients (49.4%) experienced AEs 
(all grades) suspected to be related to study treatment. Serious adverse events (SAEs; all 
grades, regardless of relationship to study drug) were reported in 61 (38.1%) patients. Five 
patients had SAEs suspected to be related to study treatment (colitis and pneumonitis, hepatitis, 
nausea and vomiting, dyspnea, vomiting). The safety was similar across the different dose and 
disease groups.
For further details on clinical experience with spartalizumab, please refer to the latest version 
of the spartalizumab [Investigator’s Brochure].
4.1.2
Pharmaceutical and Therapeutic Background - Siltuximab 
Siltuximab is a chimeric monoclonal antibody against interleukin-6 (IL-6) indicated for the 
treatment of patients with multicentric Castleman’s disease (MCD) who are human 
immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. 
[Package Insert]
4.1.2.1
Clinical experience with siltuximab
Study CNTO328MCD2001 (referred to as Study 1) (NCT01024036) was a Phase 2, multinational, 
randomized (2:1) double blind, placebo controlled study to evaluate the clinical efficacy and safety 
of SYLVANT for the treatment of patients with MCD. In this study 53 patients were randomized 
to Best Supportive Care (BSC) and SYLVANT at a dose of 11 mg/kg every 3 weeks and 26 patients 
were randomized to BSC and placebo. The median age was 48 years (range 20 to 78), 66% male, 
48% Asian, 39% White, 4% Black or African American, 7% other. The histological subtype of 
MCD was similar in both treatment arms, with 33% hyaline vascular subtype, 23% plasmacytic 
subtype and 44% mixed subtype. Treatment was continued until treatment failure (defined as 
disease progression based on increase in symptoms, radiologic progression or deterioration in 
performance status) or unacceptable toxicity.
The major efficacy outcome of the study was durable tumor and symptomatic response, defined as 
tumor response (PR and CR based on modified International Working Group response criteria for 
malignant lymphoma) assessed by independent review and complete resolution or stabilization of 
MCD symptoms. Thirty-four MCD related signs and symptoms prospectively identified were 
collected and graded according to the NCI-CTCAE v 4, by investigators. A durable response was 
defined as tumor and symptomatic response that persisted for a minimum of 18 weeks without 
treatment failure. The durable tumor and symptomatic response in the SYLVANT arm was 34% 
compared to 0% in the placebo arm (95% CI: 11.1, 54.8; p=0.0012).
Other analyses included tumor response, time to treatment failure and an increase in hemoglobin 
of 1.5 g/dL or more, in patients who were anemic at time of study entry, at week 13. The results 
are summarized in Table 4.

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Table 4:
Efficacy Endpoints From Study 1
Efficacy Endpoint
SYLVANT
n=53
Placebo
n=26
p-valuea
Durable tumor and symptomatic 
response (independent review)
34%
0
0.0012
Tumor response
38%
4%
<0.05
Median time to treatment failure 
(days)
NRb
134
<0.05
≥1.5 g/dL increase in hemoglobin
61% (19/31)
0% (0/11)
<0.05
a
Adjusted for corticosteroid use at randomization
b
NR=“Not Reached” 
A consistent treatment effect was confirmed on subgroup analysis for all parameters evaluated with 
the exception of the hyaline vascular histological subtype. There were no patients with hyaline 
vascular histology who demonstrated a durable tumor and symptomatic response. However, 
activity was suggested in this subtype based on change in hemoglobin and median time to treatment 
failure.
At the time of the analysis, overall survival data were not mature. One year survival rate was 100% 
in the SYLVANT arm and 92% in the placebo arm.
Subgroup analyses:
Analyses for both primary and secondary endpoints on various subgroups including age (<65 
years and ≥65 years); race (White and non-White); region (North America, EMEA, and Asia 
Pacific); baseline corticosteroid use (yes and no); prior therapy (yes and no); and MCD 
histology (plasmatic and mixed histology) consistently showed that the treatment effect 
favored the siltuximab arm except for the hyaline vascular subgroup. A consistent treatment 
effect favoring siltuximab treated patients across all major secondary endpoints was shown in 
the hyaline vascular subgroup. Select efficacy results from Study 1 in the hyaline vascular 
subgroup are summarized in Table 2.
Table 2.0: Select Efficacy Endpoints for Hyaline Vascular Subgroup from Study 1

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Efficacy endpoints
SILTUXIMAB+BSC
Placebo+BSC
95% CIa
Primary efficacy endpoint
Durable tumor & symptomatic 
response (independent review)
0/18 (0%)
0/8 (0%)
(N/A; N/A)b
Secondary efficacy endpoints
Durable tumor & symptomatic 
response (investigator review)
3/18 (16.7%)
0/8 (0%)
(-25.7; 55.9)
Best tumor response (independent 
review)
1/18 (5.6%)
1/8 (12.5%)
(-46.7; 35.3)
Best tumor response (investigator 
assessment)
4/18 (22.2%)
0/8 (0%)
(-20.3; 60.6)
Time to treatment failure
206 days
70 days
(0.17; 1.13)c
Hemoglobin increase > 15 g/L at 
Week 13/hemoglobin response-
evaluable population
3/7 (42.9%)
0/4 (0%)
(-22.7; 83.7)
Durable complete symptomatic 
responsed
3/18 (16.7%)
0/8 (0%)
(-25.7; 55.9)
a
95% confidence interval  for the difference in proportions b
N/A = “Not applicable”, there were no responders therefore 95% CI is 
not applicable c
95% confidence interval for the hazard ratio
dComplete symptomatic response is defined as a 100% reduction in the baseline MCD overall symptom score sustained for at 
least
18 weeks prior to treatment failure
Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in the clinical trials of a drug cannot be directly compared to rates in the 
clinical trials of another drug and may not reflect the rates observed in clinical practice.
Study 1, in MCD, was an international, multicenter, randomized Phase 2 study of every 
3 week infusions comparing SYLVANT and best supportive care (BSC) to placebo and 
BSC. There were 53 patients randomized to the SYLVANT arm at a dosage of 11 
mg/kg and 26 patients randomized to the placebo arm. Of the 26 placebo-treated 

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patients, 13 patients subsequently crossed-over to receive SYLVANT. The median age 
was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African 
American, 7% other.  The patients randomized to SYLVANT received a median of 19 
infusions (range 1 to 50) compared to patients randomized to placebo who received a 
median of 8 infusions (range 2 to 32). To control for disparate exposure between arms, 
Table 3 reports the per patient incidence of adverse reactions that occurred during the 
first 8 infusions.  Adverse reactions that occurred >3% in the SYLVANT arm are 
presented.
The most common adverse reactions (> 10% compared to placebo) during treatment 
with SYLVANT in the MCD clinical trial were rash, pruritus, upper respiratory tract 
infection, increased weight, and hyperuricemia.
Table 3:
Per Patient Incidence of Common Adverse Reactions in Study 1 During 
Initial 8 Infusions
Body System/Adverse Reactions
SYLVANT+BSC
a
n=53
Placebo+BSC
n=26
All 
Grad
es
Grad
es 3-
4
All 
Grad
es
Grad
es 3-
4
Skin disorders
Rash (rash, rash generalized, rash 
maculo-papular, rash popular and 
rash pruritic)
15 
(28
%)
1 
(2%)
3 
(12
%)
0
Pruritus
15 
(28
%)
0
2 
(8%)
0
Skin hyperpigmentation
2 
(4%)
0
0
0
Eczema
2 
(4%)
0
0
0

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Table 3:
Per Patient Incidence of Common Adverse Reactions in Study 1 During 
Initial 8 Infusions
Body System/Adverse Reactions
SYLVANT+BSC
a
n=53
Placebo+BSC
n=26
Psoriasis
2 
(4%)
0
0
0
Dry skin
2 
(4%)
0
0
0
Infections
Lower respiratory tract
4 
(8%)
2 
(4%)
1 
(4%)
1 
(4%)
Upper respiratory tract
14 
(26
%)
1 
(2%)
4 
(15
%)
1 
(4%)
Blood 
and 
lymphatic 
system 
disorders
Thrombocytopenia
5 
(9%)
2 
(4%)
1 
(4%)
1 
(4%)
General disorders
Edema (general and localized)
14 
(26
%)
4 
(8%)
7 
(27
%)
0
Gastrointestinal disorders
Constipation
4 
(8%)
0
1 
(4%)
0
Metabolism

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Table 3:
Per Patient Incidence of Common Adverse Reactions in Study 1 During 
Initial 8 Infusions
Body System/Adverse Reactions
SYLVANT+BSC
a
n=53
Placebo+BSC
n=26
Hypertriglyceridemia
4 
(8%)
0
0
0
Hypercholesterolemia
2 
(4%)
0
0
0
Hyperuricemia
6 
(11
%)
1 
(2%)
0
0
Respiratory, 
thoracic 
and 
mediastinal disorders
Oropharyngeal pain
4 
(8%)
0
1 
(4%)
0
Renal and urinary disorders
Renal impairment
4 
(8%)
0
0
0
Nervous system disorders
Headache
4 
(8%)
0
1 
(4%)
0
Investigations
Weight increased
10 
(19
%)
1 
(2%)
0
0
Vascular disorders

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Table 3:
Per Patient Incidence of Common Adverse Reactions in Study 1 During 
Initial 8 Infusions
Body System/Adverse Reactions
SYLVANT+BSC
a
n=53
Placebo+BSC
n=26
Hypotension
2 
(4%)
1 
(2%)
b
0
0
a
Best Supportive Care
b
Anaphylactic reaction
Study CNTO328MCD2002 (referred to as Study 2) (NCT01400503) was an open label, 
long term extension study of patients with MCD treated on prior trials. The median 
duration of siltuximab treatment was 5.52 years (range: 0.8 to 10.8 years); more than 
50% of patients received siltuximab treatment for ≥5 years. The rate of serious or Grade 
≥3 adverse events did not increase over time as a function of cumulative exposure.
Other important adverse reactions reported in MCD clinical studies, all of which were 
very common, were:
Infections and infestations: nasopharyngitis, urinary tract infection
Blood and lymphatic system disorders: neutropenia
Nervous system disorders: dizziness
Vascular disorders: hypertension
Gastrointestinal 
disorders: 
nausea, 
abdominal 
pain, 
vomiting, 
diarrhea, 
gastroesophageal reflux disease, mouth ulceration
Anaphylaxis and Infusion Related Reactions 

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During IV infusion of siltuximab, mild to moderate infusion reactions may improve following 
slowing of or stopping the infusion. Upon resolution of the reaction, reinitiating the infusion at a 
lower infusion rate and therapeutic administration of antihistamines, acetaminophen, and 
corticosteroids may be considered. For patients who do not tolerate the infusion following these 
interventions, siltuximab should be discontinued. During or following infusion, treatment with 
siltuximab should be discontinued in patients who have severe infusion related hypersensitivity 
reactions (e.g. anaphylaxis). The management of severe infusion reactions should be dictated by 
the signs and symptoms of the reaction. Appropriate personnel and medication should be available 
to treat anaphylaxis if it occurs.
Immunogenicity
 Immunogenicity data are highly dependent on the sensitivity and specificity of the test 
methods used. Additionally, the observed incidence of a positive result in a test method may 
be influenced by several factors, including sample handling, timing of sample collection, drug 
interference, concomitant medication and the underlying disease. Therefore, comparison of the 
incidence of antibodies to SYLVANT with the incidence of antibodies to other products may 
be misleading. The clinical significance of anti-siltuximab antibodies following treatment with 
SYLVANT is not known.
The immunogenicity of siltuximab has been evaluated using antigen-bridging enzyme 
immunoassay (EIA) and electrochemiluminescence-based immunoassay (ECLIA) methods. A 
total of 432 patients across the clinical studies were evaluated at multiple time points for 
anti-therapeutic antibody (ATA) responses to siltuximab after treatment with SYLVANT. 
Following SYLVANT dosing, 0/243 (0%) patients tested positive for anti-siltuximab 
antibodies by EIA and 4/189 (2%) patients tested positive by ECLIA. Further immunogenicity 
analyses were conducted for all positive samples from the 4 patients with detectable anti-
siltuximab antibodies. None of these patients had neutralizing antibodies.
4.1.2.2
Non-Clinical experience with Siltuximab
No carcinogenicity or genotoxicity studies have been conducted with siltuximab. 
Two fertility studies were conducted. In one study, drug-treated male mice were mated with 
untreated females and in the second study drug-treated female mice were mated with untreated 
males. A murine analog of siltuximab was administered subcutaneously at doses up to 100 
mg/kg/week for a total of 7 doses in both studies. There was no effect on male or female 
fertility parameters. In addition, siltuximab did not produce any toxicity in the reproductive 
organs in cynomolgus monkeys in the 6-month repeat-dose toxicology study at doses up to 46 
mg/kg (approximately 7 times) the systemic exposure in patients at the recommended dose.

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5.0 RATIONALE
5.1
Study rationale and purpose
A. IL-6 orchestrates pancreatic carcinogenesis, immune suppression and is a poor 
prognostic indicator.  Signaling downstream of IL-6 is important in PDAC genesis and 
progression. (Zhang et al., 2013, Lesina et al., 2011) This pleiotropic cytokine binds membrane 
receptor complexes containing the common signal transducing receptor chain gp130 
(glycoprotein 130)(Rose-John, 2006) thereby initiating a complex series of signaling events 
that include the Jak/STAT, MAPK and PI3K pathways.(Fisher et al., 2014, Scheller et al., 
2011) In particular, STAT3 is activated via phosphorylation at Tyr705 in most human PDAC 
specimens and cooperates with activated Kras to drive initiation and progression of PDAC in 
murine models. (Corcoran et al., 2011, Scholz et al., 2003)Recent studies using an inducible 
Kras-mediated PDAC mouse model further showed that IL-6 was instrumental for PDAC 
progression. (Zhang et al., 2013, Goumas et al., 2015) In fact, lack of IL-6 completely 
ablated cancer progression even in the presence of oncogenic Kras.(Zhang et al., 2013) 
In addition to its impact on tumor cells, the IL-6/STAT3 axis is instrumental for regulating 
immune phenotype and function. This pathway facilitates the expansion of CD4+ T cell subsets 
(i.e. Th17), which limit antitumor immune responses when present in the tumor 
microenvironment.(Amedei et al., 2013, He et al., 2011, Liyanage et al., 2002, McAllister et 
al., 2014, Viehl et al., 2006) This pathway can also simultaneously promote the expansion of 
immunosuppressive cells. Among the most notable of these subsets are MDSCs and T 
regulatory cells (T regs). Our group and others have shown that these cells are expanded, and 
are poor prognostic indicators in patients with advanced GI cancer.(Gabitass et al., 2011, 
Markowitz et al., 2015, Mundy-Bosse et al., 2011) In this manner, IL-6 can cooperate with 
other cytokines either systemically or in the tumor microenvironment to further amplify 
immune changes in patients. In agreement with these data, recent results from our group 
showed that systemic IL-6 had a strong inverse relationship (p=0.0007) with overall survival 
in metastatic PDAC patients(Farren et al., 2016). Further studies by our group confirm 
abundant secretion of IL-6 by stromal cells derived from human PDAC tumors, and that 
this cytokine is a key factor that allows pancreatic stroma to promote expansion of 
myeloid-derived suppressor cells (MDSC) .(Mace et al., 2013) 
B. IL-6 blockade improves the efficacy of immune checkpoint blockade in pre-clinical 
models of pancreatic cancer. Blockade of T cell checkpoint receptors with Ab has emerged 
as a promising immunotherapeutic approach.(Jiang et al., 2013, Chen and Han, 2015) 
Programmed death-1-ligand 1 (PD-L1), also known as B7-H1, is a cell surface protein and one 
of 2 ligands for program death receptor 1 (PD-1), a costimulatory molecule that negatively 
regulates T cell responses.(Freeman, 2008, Goldberg et al., 2007) Ligation of PD-L1 on cancer 
cells to PD-1 expressed on T cells suppresses T cell activation, proliferation, and induces 

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apoptosis. PD-1/PD-L1 blockade has antitumor activity in preclinical models, while 
intratumoral expression of PD-L1 correlates with poor prognosis in patients with PDAC. (Jiang 
et al., 2013, Topalian et al., 2012)Indeed, increased PD-L1 expression by cancer cells or the 
stroma is a fundamental escape mechanism from host immunity. In theory, IL-6 blockade will 
downregulate immune suppressive features of PDAC in both the systemic circulation and 
the tumor stroma, thereby enhancing antitumor activity of antibodies directed against 
immune checkpoint blockades. Fortunately, IL-6 blocking Ab like Siltuximab are FDA-
approved for other indications. These data suggest blocking IL-6 and downstream pathways 
could enhance the efficacy of immunotherapy regimens.
Recently published work from our laboratory demonstrates that in vivo administration of 
antibodies (Ab) targeting interleukin-6 (IL-6) and PD-L1 limit tumor progression in 
subcutaneous, orthotopic and autochthonous, mutant KRas-driven models of PDAC (Fig. 1A-
C and data not shown; (Mace et al., 2018)). We also demonstrate this treatment combination 
results in increased infiltration of effector T cells into pancreatic tumors, and reduced levels of 
activated pancreatic stellate cells within these same tumors. The efficacy of this treatment 
regimen was dependent upon CD8+ T cells, and an increase in circulating cells with Th1 
phenotypic characteristics was observed.
Finally, our data using an aggressive, genetically engineered model of PDAC indicates 
that combined inhibition of IL-6 and PD-L1 leads to significant prolongation of survival 
as compared to mice treated with isotype control antibodies (Figure 2A-C and data not 
shown; (Mace et al., 2018)).  
Figure 2.  IL-6 and PD-L1 antibody blockade combination therapy decreases PDAC tumor progression and 
increases the percentage of intratumoral effector T cells. A) MT5 and B) Panc02 murine pancreatic tumor cells 
were subcutaneously injected into C57BL/6 mice with treatment beginning when tumors reached 50-100mm
3.  Mice 
were treated with 200mg (intraperitoneal injection 3 times/week) with isotype control, anti-IL-6 and/or anti-PD-L1 
antibodies (n=5-6 mice/group) until mice met pre-specified IACUC-approved early removal criteria. Geometric means 
± SD; *p<0.01 compared to Isotype;
 †p<0.03 compared to PD-L1; 
‡p<0.05 compared to IL-6. C) Panc02 tumors were 
dissociated using Collagenase II and the Miltenyi Biotec gentleMACS dissociator to obtain a single cell suspension.  
Cells were stained and analyzed by flow cytometry for activation markers for CD8
+ T cell subsets (n=3/group).  Naïve 
(CD62L
+CD44
-), Effector Memory (CD62L
-CD44
+), and Central Memory (CD62L
+CD44
+). Means ± SD; *p<0.002 
compared to Isotype; 
†p<0.01 compared to PD-L1; 
‡p<0.02 compared to IL-6.  
A
B
C

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Together, our data suggest that IL-6 blockade will modulate immunologic features of 
PDAC both systemically and in the tumor microenvironment, thereby enhancing the 
efficacy of immune checkpoint inhibitors. 
5.2
Rationale for the study design
Because this is a new combination, the first part of the study is focused on safety of the 
combination and determining the recommended phase II dose. The expansion cohort will 
confirm the safety profile plus provide preliminary response data regarding activity.
Figure 3.  IL-6 and PD-L1 antibody blockade combination therapy decreases PDAC tumor progression and 
a-SMA
+ cells in the pancreata from KPC-Brca2 mice. A highly aggressive, autochthonous model of spontaneously 
arising PDAC driven by mutant Kras, Trp53 and Brca2 (KPC-Brca2) was used to recapitulate a clinically relevant tumor 
model.  KPC-Brca2 mice were treated at 5-6 weeks of age with 200mg (intraperitoneal injection 3 times/week) of 
isotype control, anti-IL-6R and/or anti-PD-L1 antibodies for 2 weeks (n=5 mice/group).  A cohort of mice treated with 
anti-IL-6R and PD-L1 antibodies were also depleted for CD8
+ T cells. A) Quantification of the H&E stained slides was 
conducted by a board certified pathologist. Data revealed a statistically significant shift in the proportion of low grade 
PanIN lesions, with fewer PanIN3 or foci of adenocarcinoma in mice treated with antibodies targeting PD-L1 and IL-
6R, as compared to animals treated with isotype control Ab; Means ± SD; *p<0.005 compared to Isotype; 
†p=0.01) 
compared to PD-L1; B) Pancreatic tissue was stained for alpha-SMA
+ stromal cells (red) by IHC and quantified at 20x 
magnification. Means ± SD; *p=0.0545 compared to Isotype. C) KPC-Brca2 beginning at 5 weeks of age (100% 
penetrance of adenocarcinoma) mice were treated with isotype control antibodies or antibodies targeting IL-6 and PD-
L1 (200µg/each) until mice were moribund and met pre-specified IACUC-approved early removal criteria.  Kaplan-
Meier survival curves with log-rank test for significance between isotype control and IL-6/PD-L1 antibodies (p=0.0012).
A
B
C

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In addition, the trial will include serial blood collections and tumor biopsies which will enable 
us to evaluate the biologic effect of the combination on tumor microenvironment and 
lymphocytes in the tumor and in circulation. 
5.3
Rationale for dose and regimen selection for spartalizumab: 
In study [CPDR001X2101], spartalizumab single-agent was administered as an intravenous 
infusion over 30 minutes at doses ranging from 1 to 10 mg/kg on every 2 weeks (Q2W) 
schedule or at 3 and 5 mg/kg every 4 weeks (Q4W) schedules. Approximately dose-
proportional increase in exposure (C1D1 AUC0-336) was observed with doses from 1 to 10 
mg/kg and no DLTs were observed. Accumulation of approximately 2.1-3.4-fold was observed 
with Q2W dosing and 1.6-2.2-fold with Q4W dosing. Population PK analysis indicated that 
weight-adjusted or flat dosing lead to similar exposure range Therefore, a flat dosing scheme 
was selected which has the added advantage of convenience and less risk for medication errors. 
Two recommended dosing regimens have been established: 300 mg Q3W and 400 mg Q4W 
flat dosing schedules. A flat dose of 400 mg Q4W or 300 mg Q3W is expected to achieve a 
mean steady-state C trough value higher than the ex vivo EC50 for antigen-stimulated IL-2 
production, a translational biomarker for PD-1 blockade (Patnaik et al, 2015). Based on the 
safety profile observed in study [CPDR001X2101] and the expected Ctrough values, 400 mg 
Q4W is expected to be a safe and efficacious dose. 
The use of the Q3W regimen is intended to align the administration of Siltuximab and 
spartalizumab every 3 weeks.   
5.4
Risks and benefits 
Spartalizumab is a humanized IgG4 monoclonal antibody which belongs to a class of agents 
known as immune-checkpoint inhibitors, specifically anti-PD-1. This class of compounds has 
demonstrated significant improvement in efficacy combined with a tolerable and manageable 
safety profile, supporting regulatory approvals in various indications..
Immune-checkpoint inhibitors of this class may be associated with the occurrence of immune-
mediated adverse events (irAE). In general, irAE can potentially involve every organ system 
but gastrointestinal (e.g. colitis), dermatologic (e.g. rash, pruritus), hepatic (e.g. hepatitis), 
pulmonary (e.g. pneumonitis), renal (e.g. nephritis) and endocrine toxicities (e.g. 
hypothyroidism, hyperthyroidism, type I diabetes, hypophysitis including hypopituitarism and 
adrenal insufficiency) being typically the most frequent. Other immune-mediated AEs may 
rarely include the nervous system (e.g. encephalitis, Guillain-Barre syndrome, myasthenia 
gravis), eye (e.g. uveitis), musculo-skeletal system (e.g. myositis, arthritis), cardio-vascular 
system (e.g. vasculitis, myocarditis) or blood system (e.g. anemia, cytopenias), and severe skin 
reactions such as toxic epidermonecrolysis or Steven Johnson syndrome. Furthermore, 
complications in patients with bone marrow or solid organ transplant have been reported (e.g. 
organ rejection, severe graft-versus-host disease). These side effects are generally manageable 
and reversible with dose interruption and administration of corticosteroids and/or other 
immunosuppressants. However, fatal events have been reported in some cases with checkpoint 
inhibitors; furthermore, some events like endocrinopathies may require life-long hormonal 

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replacement. While most irAEs are expected to occur during the treatment with spartalizumab, 
onset may be delayed and irAEs may also occur after discontinuation of study treatment 
(Eggermont, 2015 #13Champiat, 2016 #14; Hofmann, 2016 #).  
In addition, monoclonal antibodies can be associated with infusion-related reactions some of 
which can be severe; these are often immediate and usually occur within minutes of the 
exposure to the study drug. Therefore, infusions must take place in a facility with appropriate 
resuscitation equipment available at the bedside and a physician readily available, and patients 
monitored for respective signs and symptoms. Patients who experience severe or life-
threatening irAEs or infusion reactions may need to permanently discontinue spartalizumab 
(see Section 6.3.1 for further guidance).
It is expected that spartalizumab would have a similar safety profile as other immune 
checkpoint inhibitors with the above mentioned side effects possibly occurring in patients 
treated  in the present study (for most common adverse reactions observed in clinical studies 
with spartalizumab, please refer to the latest version of the Investigator’s Brochure). It is 
therefore important to be vigilant and carefully identify events that may be suggestive of 
potential immune-mediated AEs, as their appearance may be sub-clinical (for example an 
asymptomatic laboratory abnormality), and early diagnosis is critical for appropriate 
management and possibly prevent complications. Serological, immunological and histological 
assessments (such as biopsy of the affected tissue) should be performed as deemed appropriate 
by the investigator to verify the potential immune-mediated nature of the AE and to exclude 
alternative diagnoses or disease progression.  The protocol includes specific eligibility criteria 
(Section 5), DLT definitions, monitoring visits and assessments, dose modification and 
stopping rules as well as recommended guidelines for prophylactic or supportive treatment of 
expected toxicities, including identification and management of study-drug induced adverse 
events.  The risks to patients in this trial may be minimized by compliance with the eligibility 
criteria and study procedures as well as, close clinical monitoring. There may be unforeseen 
risks with which could be serious. 
Refer also to preclinical toxicity and or clinical data found in the latest [Investigator’s 
Brochure].  Side effect of siltuximab reviewed in section 1.2.
The patient population selected for this trial advanced pancreatic cancer with at least one prior 
line of therapy, have very limited effective therapeutic options. The disease has uniform 
mortality. The treatment proposed in this trial has the potential to impact outcome based on the 
pre-clinical data. The study is designed to lower risks for participants through dose escalation 
to select the appropriate dose, strict eligibility criteria, and frequent monitoring on trial for side 
effects. 
5.4.1
Rationale for Endpoints
5.4.1.1
Efficacy Endpoints: This is a phase I trial. The primary endpoint is still toxicity. The 
plan is to evaluate the response rate, response duration, and progression free survival 

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of the patients on the trial. These endpoints will provide preliminary data in advanced 
pancreatic cancer.
5.4.1.2
Biomarker Research: We intend in all patients to evaluate the effects of the 
combination on T-cell population in peripheral blood. In addition, we plan to evaluate 
the effects of the combination versus spartalizumab alone in paired biopsy samples. 
These samples will be analyzed for tumor infiltrating lymphocytes, stromal/tumor 
markers and expression immune inhibitory molecules (PD-L1, PD-L2, PD1, etc). We 
anticipate to see a difference between the groups treated with the combination versus 
the group treated with spartalizumab alone.
Table 4.0 Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Section 6.2
Evaluate the safety profile of the 
combination of siltuximab and 
spartalizumab
Determine the recommended phase II dose 
of siltuximab that can be combined with 
spartalizumab
Key secondary
Section 14.3
To evaluate the activity of 
siltuximab and spartalizumab 
Overall response rate (CR+ PR) in 
patients treated with siltuximab and 
spartalizumab
Other secondary
Section 14.3
To 
evaluate 
the 
response 
duration, 
progression 
free 
survival and overall survival of 
patients with pancreatic cancer 
receiving 
siltuximab 
and 
spartalizumab
Response duration. progression free 
survival and overall survival time from 
treatment start until progression or death
Exploratory
Section 7.1
Evaluate 
the 
effect 
of 
the 
combination on the immune 
profile in the serum and in tumor 
biopsies.
Characterization 
of 
immune 
cell 
phenotypes in serum and tissue pre and 
post treatment.  
Characterization of the effects of the 
combination 
on 
immune 
inhibitory 
pathways 

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6.0 METHODOLOGY
6.1
Entry Criteria
6.1.1
Diagnosis/Condition for Entry into the Trial
Patients must have a cytological or histologic diagnosis and metastatic pancreatic 
adenocarcinoma disease that has failed at least one standard regimen. In the expansion phase, 
patients will participate in the paired biopsy studies. Patient selected for biopsy must have a 
primary or metastatic non-bone site that is amenable to safe biopsy.  Bone only lesions are not 
suitable for biopsy. These patients will provide informed consent for the paired biopsy study.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
6.1.2
Subject Inclusion Criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Cytological or histologic diagnosis and metastatic pancreatic adenocarcinoma disease that 
has failed at least one standard regimen such as gemcitabine nab-paclitaxel or 
FOLFIRINOX.
2. Be  18 years of age on day of signing informed consent.
3. Patient must meet the following laboratory values at the screening visit:

Absolute Neutrophil Count ≥1.5 x 109/L

Platelets ≥75 x 109/L

Hemoglobin (Hgb) ≥9 g/dL 

Serum creatinine <1.5 mg/dL OR Creatinine Clearance ≥ 45 mL/min using 
Cockcroft-Gault formula 

Total bilirubin ≤1.5 x ULN 

Aspartate transaminase (AST) ≤ 2.5 x ULN, except for patients with liver 
metastasis, who may only be included if AST ≤5.0 x ULN 

Alanine transaminase (ALT) ≤ 2.5 x ULN, except for patients with liver 
metastasis, who may only be included if ALT ≤5.0 x ULN 
4. Presence of measurable disease by RECIST criteria
5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-
2.(Appendix 1)
6. Written informed consent must be obtained prior to any screening procedures.
7. Normal ECG defined as the following:

Resting heart rate 50-90 bpm

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
QTcF at screening <450 ms (male patients), <460 ms (female patients) 
8. Before enrollment, a woman must be either:
a.
Not of childbearing potential: postmenopausal (>45 years of age with amenorrhea 
for at least 12 months or any age with amenorrhea for at least 6 months and a serum 
follicle stimulating hormone (FSH) level >40 IU/mL); permanently sterilized (eg, 
tubal occlusion, hysterectomy, bilateral salpingectomy); or otherwise be incapable 
of pregnancy
b. Of childbearing potential and practicing (during the study and for 150 days after 
receiving the last dose of study agent) a highly effective method of birth control 
consistent with local regulations regarding the use of birth control methods for 
subjects participating in clinical studies: eg, established use of oral, injected or 
implanted hormonal methods of contraception; placement of an intrauterine device 
(IUD) or intrauterine system (IUS); barrier methods: condom with spermicidal 
foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization 
(the vasectomized partner should be the sole partner for that subject); true 
abstinence (when this is in line with the preferred and usual lifestyle of the subject)
c.
Note: If the childbearing potential changes after start of the study (eg, woman who 
is not heterosexually active becomes active) a woman must begin a highly effective 
method of birth control, as described above.
9. A woman of childbearing potential must have a negative serum (β-human chorionic 
gonadotropin [β-hCG]) or urine pregnancy test at screening
10. During the study and for 150 days after receiving the last dose of study agent, a woman 
must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction
11. A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must 
also not donate sperm during the study and for 150 days after receiving the last dose of 
study drug 
12. Sign an informed consent document indicating that they understand the purpose of and 
procedures required for the study, are willing to participate in the study, and are willing 
and able to adhere to the prohibitions and restrictions specified in this protocol. Informed 
consent must be obtained before performing any study specific procedures. 

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6.1.3
Subject Exclusion Criteria
Patients eligible for this study must not meet any of the following criteria:
1. Prior exposure to agents targeting PD-1, PD-L1, IL-6 or the IL-6 receptor. Prior 
chemotherapy is allowed as long as adequate washout period of ≥ 4 weeks. 
2. Any untreated central nervous system (CNS) lesion. However, patients are eligible if: a) 
all known CNS lesions have been treated with radiotherapy or surgery and b) patient 
remained without evidence of CNS disease progression ≥ 4 weeks after treatment and c) 
patients must be off corticosteroid therapy for ≥ 2 weeks. 
3. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study 
treatment
4. Systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any 
immunosuppressive therapy 7 days prior to planned date of first dose of study treatment. 
Note: Topical, inhaled, nasal and ophthalmic steroids are allowed.
5. Active, known or suspected autoimmune disease or a documented history of autoimmune 
disease Note: Patients with vitiligo, controlled type I diabetes mellitus on stable insulin 
dose, residual autoimmune-related hypothyroidism only requiring hormone replacement 
or psoriasis not requiring systemic treatment are permitted).
6. Allogenic bone marrow or solid organ transplant
7. History of severe hypersensitivity reactions to other monoclonal antibodies, which in the 
opinion of the investigator may pose an increased risk of serious infusion reaction
8. Known history or current interstitial lung disease or non-infectious pneumonitis
9. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred 
within 2 years prior to study treatment; completely resected basal cell and squamous cell 
skin cancers and any completely resected carcinoma in situ 
10. Clinically significant infection, including known HIV or hepatitis C infection, or known
      hepatitis B surface antigen positivity 
11. Clinically significant ongoing infection
12. Received an investigational drug (including investigational vaccines) or used an invasive 
investigational medical device within 14 days or 5 half-lives before enrollment (whichever 
is longer) or is currently enrolled in the treatment stage of an investigational study
13. A woman who is pregnant or breast-feeding, or a woman who is planning to become 
pregnant or a man who plans to father a child while enrolled in this study or within 150 
days after the last dose of study agent

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14. Had hospitalization for infection or major surgery (eg, requiring general anesthesia) within 
2 weeks before enrollment or have not fully recovered from surgery. Note: subjects with 
surgical procedures conducted under local anesthesia may participate
15. History or current diagnosis of cardiac disease indicating significant risk of safety for 
patients participating in the study such as uncontrolled or significant cardiac disease, 
including any of the following:
a.
recent myocardial infarction (within last 6 months), 
b. uncontrolled congestive heart failure, 
c.
unstable angina (within last 6 months),
d. clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained 
ventricular tachycardia, and clinically significant second or third degree AV block 
without a pacemaker).
6.1.4 Screen Failures
Minimal data for subjects who fail screening will be collected such as demographic 
information and the reason for screen failure. Such subjects may be re-screened at the 
discretion of the investigator after approval by the Data and Safety Monitoring Committee 
(DSMC). The reason for the need to re-screen a subject will be documented in the subject’s 
source documents. 
6.2
Trial Treatments
The treatment to be used in this trial is outlined below in Table 
Table 5.  Trial Treatment
Siltuximab will be infused first. Patients will be observed for at least 1 hour post infusion of 
siltuximab. 
Spartalizumab will be administered via intravenous infusion over 30 minutes (up to 2 hours, if 
clinically indicated) once every 3 weeks. The dose may be interrupted for up to 12 weeks. The 
safety assessments should be performed according to the actual day of infusion.
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment Period
Spartalizumab
300 mg 
  Q3W
IV infusion
  Day 1 of each 3 week cycle
Siltuximab
As Below
Q 3W
IV Infusion
Day 1 of each 3 week cycle

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Patients should be closely observed for potential infusion-related reactions including rigors, 
chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever, and vital signs 
monitored more frequently if clinically indicated, during and for at least 4 hours after the first 
two spartalizumab infusions. The same may apply for the subsequent spartalizumab infusions 
if medically indicated. Patients should be further provided instructions to notify study 
personnel if symptoms of infusion reaction occur after any spartalizumab infusion.
6.2.1
Siltuximab dose levels
Open label phase I trial. Primary objective is to determine the recommended phase 2 dose 
(RP2D) of the combination of siltuximab plus spartalizumab in a pancreatic cancer.  The 
design is 3+3 with 3 dose levels of siltuximab. 
Table 6. Dose escalation for siltuximab
No of pts
Cohort Level
Siltuximab
Spartalizumab
3 to 6
1
6 mg/Kg IV every 3 weeks
300 mg every 3 weeks
3 to 6
2
11 mg/Kg every 3 weeks
300 mg every 3 weeks
3 to 6
2a
9 mg/Kg every 3 weeks 
300 mg every 3 weeks
Dose level 2a will only be tested if we observe 2 DLT’s on dose level 2.
6.2.2
Dose Escalation
For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled 
patients who will be treated at the specified dose level. The first cohort will be treated with the 
starting dose of 300 mg of spartalizumab and 6 mg/Kg of Siltuximab.
Patient will be considered evaluable for dose escalation decision if patients have received at 
least 2 infusions of both study drugs (spartalizumab and siltuximab) and had safety assessments 
for a minimum of 6 weeks or have had a DLT during the first 6 weeks. Dose escalation 
decisions will occur when the cohort of patients has met these criteria. All patients within a 
dosing cohort must have completed the DLT evaluation period and have been evaluated for 
DLT prior to dose escalation.
If 1 of the first 3 patients develops a DLT, then enroll up to 3 additional patients at the same 
dose level. If 2 or more patients in any dose cohort of 6 or fewer patients have a DLT, then the 
MTD of the combination is exceeded. If there are no DLTs in the first 3 patients at dose level 
1 or 1 of 6 patients in dose level 1 has a DLT, enroll 3 patients into the 11 mg/Kg dose level. 
If 2 or more patients in this dose cohort have a DLT, reduce dose to 9 mg/Kg and enroll 3 more 
patients. If an acceptable dose is identified, then start the expansion phase. Prior to dose 
escalation, we will obtain approval from the Data Safety and Monitoring Committee (DSMC) 
for implementation of dose escalation decisions.

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6.2.3 Dose limiting toxicity (DLT) 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as at least possibly related to study treatment that occurs within the first 6 weeks and 
meets any of the criteria included in Table 7. National Cancer Institute Common Terminology 
Criteria for Adverse events (NCI CTCAE) version 4.03 will be used for all grading. 
The investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, 
CTCAE grade ≥ 2 adverse events will be reviewed for all patients at the current dose level.
 
Table 7
Criteria for defining dose-limiting toxicities
TOXICITY
DLT CRITERIA
Thrombocytopenia Grade 3 with clinically significant 
bleeding
Thrombocytopenia Grade 4
Neutropenia Grade 4 lasting more than 8 days
Blood and lymphatic 
system disorders
Febrile neutropenia CTCAE Grade ≥ 3
Diarrhea CTCAE Grade ≥ 3 ≥ 72 hrs., despite the use 
of anti-diarrhea therapy
Nausea/ vomiting CTCAE Grade ≥ 3 ≥ 72 hrs., despite 
the use of anti-emetic therapy
Gastrointestinal 
disorders
Pneumonitis (interstitial 
lung disease)

CTCAE Grade 2 pneumonitis if it persists > 7 days despite 
treatment with corticosteroids. 

Second episode of grade 2 pneumonitis of any duration

Grade 3-4 pneumonitis of any duration
Immune-related 
toxicities 
(except 
pneumonitis)

CTCAE Grade 3 immune-related toxicities that persist > 14 
days with same severity despite treatment with corticosteroids. 

Immune-related toxicities CTCAE Grade 4 of any duration
Other Adverse Events

Grade 3-4 infusion reaction 

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
Other non-hematologic treatment-related toxicity at Grade 3 or 
higher

Any AE that leads to permanent discontinuation of siltuximab 
or spartalizumab 

Death 
6.2.4 Dose expansion 24 patients will be treated on the dose expansion at the RP2D dose.
6.2.5 Duration of therapy: Subjects may withdraw consent at any time for any reason or be 
dropped from the trial at the discretion of the investigator should any untoward effect occur.  
In addition, a subject may be withdrawn by the investigator if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  A 
subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

Confirmed radiographic disease progression
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved.

Unacceptable adverse experiences 

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Completed 24 months of uninterrupted treatment.
Note: 24 months of study medication is calculated from the date of first dose. 
Subjects who stop after 24 months may be eligible for up to one year of additional 
study treatment if they progress after stopping study treatment.

Administrative reasons

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6.3
Dose Modification: 
6.3.1
Dose modification and dose interruption
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions are 
mandated in order to allow the patient to continue the study treatment. Dose interruption for 
spartalizumab and/or siltuximab includes delaying or withholding the treatment for any reason 
as well as an interruption of treatment during an infusion.
The following sections addresses the specific instructions for mandatory dose modifications 
and recommended management for adverse events considered suspected to be related to 
spartalizumab and/or siltuximab. These modifications/interruptions must be recorded on the 
Dosage Administration Record CRF.
6.3.2
Dose modification and dose interruption for spartalizumab and siltuximab 
General dose modification instructions:
Siltuximab and spartalizumab have class-specific safety profiles based on their mechanism of 
action but may also cause AEs that overlap. For management of AEs which can be clearly 
attributed to siltuximab or spartalizumab, independent dose modification for either agent is 
allowed. For AEs without clear attribution to either study treatment, management of toxicity 
should include dose modifications of both agents.
Overall AEs are to be graded according to NCI-CTCAE v4.03 (http://ctep.cancer.gov). All 
dose interruptions and the reason for the dose interruption must be documented in the eCRF.  
Overall, patients with AEs suspected to be related to spartalizumab including those of potential 
immune-mediated etiology (irAE) may need to interrupt or permanently discontinue 
spartalizumab as outlined in Section 6.3.2. In general, study treatment with spartalizumab must 
be permanently discontinued in case of:

Any life-threatening adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy)

Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to <= Grade 1 within 12 weeks after 
last dose of study treatment 

Inability to reduce the dose of steroids (for the management of irAE) to 10 mg/day or 
less of prednisone or equivalent (or as indicated in the tables below) within 12 weeks

Any severe or Grade 3 recurring treatment-related adverse reaction  
The 12 weeks’ timeframe will begin from the time the irAE reaches a grade that leads to 
spartalizumab interruption.
Overall, patients with AEs suspected to be related to siltuximab include pruritus, increased 
weight (edema), rash, hyperuricemia, neutropenia, and upper respiratory tract infection. Rare 
side effects include gastrointestinal perforation. Toxicities may require interruption of therapy, 

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dose reduction or permanent discontinuation from trial as detailed in section 6.3 and Tables 
8-8 and 8-9. In general study treatment with siltuximab must be discontinued for:

Gastrointestinal perforation

Grade 4 weight gain

Grade 4 upper respiratory tract infection

Recurrent or severe grade 3 treatment-related adverse events.

Life threatening adverse events

Interruption of therapy for longer than 12 weeks 
If either study drug (siltuximab or spartalizumab) is on temporary hold, therapy with the other 
agent will continue. Cross sectional imaging will be performed every 3rd cycle as per protocol. 
If there is disease progression, the subject should be removed from the study. The only 
exception is siltuximab may be continued as a single agent to control immune-related adverse 
events (irAEs) attributed to spartalizumab, but siltuximab therapy must be stopped after the 
irAEs can be adequately controlled with corticosteroids therapy.
If either study drug (siltuximab or spartalizumab) is being permanently discontinued, the 
remaining study drug should also be permanently discontinued given that either drug alone is 
unlikely to have adequate anti-tumor activity to justify its continuation for a prolonged period 
of time with the following exceptions:
1. In subjects who are demonstrating objective benefit from treatment (radiologic CR, PR 
or SD), a discussion regarding continuing single agent therapy will be conducted with 
PI and patient. Subject will be informed single agent activity of either agent is unlikely 
in pancreatic cancer. If the subject is agreeable, single agent therapy may continue until 
progression. No single agent therapy beyond progression will be offered. 
2. Siltuximab may be continued as a single agent to control immune-related adverse 
events (irAEs) attributed to spartalizumab, but siltuximab therapy must be stopped after 
the irAEs can be adequately controlled with corticosteroids therapy.
6.3.2.1
Dose Modification requirements for potential immune- mediated adverse 
events 
6.3.2.1.1 Identification of and management requirements for AEs of potential 
immune-mediated etiology (irAE)
Adverse events of special interest (AESI) include AEs of a potential immune-mediated 
etiology (irAE) that are associated with spartalizumab treatment. An irAE may be experienced 
by patients treated with spartalizumab due to its mechanism of action and predicted based on 
the reported experience with other immunotherapies that have a similar mechanism of action.  

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Investigators must be vigilant and carefully identify AEs that may be suggestive of potential 
irAEs as their appearance may be sub-clinical and early diagnosis is critical for its adequate 
management and resolution. 
An irAE may be of low grade and self-limited, most frequently involving the GI tract (i.e. 
diarrhea/colitis), skin (i.e. rashes), liver (i.e. hepatitis), lung (i.e. pneumonitis), kidneys (i.e. 
nephritis) and endocrine systems (a variety of endocrinopathies) and rarely CNS (i.e. 
encephalitis), however, nearly all organs can be affected by immune-mediated toxicities. irAEs 
often occur relatively early (mostly within weeks to 3 months after treatment initiation), 
however, may develop at any time during treatment (even after several months), and may also 
occur after the treatment discontinuation. Serological, immunological and histological 
assessments should be performed as deemed appropriate by the investigator, to verify the 
potential immune-related nature of the AE, and exclude a neoplastic, infectious or metabolic 
origin of the AE. 
Severe grade or persistent lower grade irAEs typically require interrupting or permanently 
discontinuing treatment and administration of systemic steroids, and sometimes other 
immunosuppressive medications (i.e. tumor necrosis factor alpha (TNFa) antagonists, 
mycophenolate or tacrolimus, etc.). Early recognition and work-up of irAEs and initiation of 
treatment are critical to reduce the risk of complications, since the majority of irAEs are 
reversible with the use of steroids and other immune suppressants. Some events like 
endocrinopathies may require life-long hormonal replacement. Tapering of steroids should not 
be too rapid to avoid recurrence or worsening of irAEs. The management of irAEs may further 
include initiation of antibiotics for prophylaxis against opportunistic infections.
Patients should be instructed to return to the study site as soon as possible (instead of waiting 
for their next scheduled visit) if they experience symptoms consistent with an irAE. Patients 
who experience a new or worsening irAE should be contacted and/or evaluated by the study 
site more frequently. 
Based on experience from compounds with similar mechanism of action of spartalizumab and 
published guidelines (Haanen, 2017), instructions have been developed regarding how to 
identify, assess severity and manage irAEs that may occur in patients receiving spartalizumab. 
Dose modification requirements and AE management guidelines for the potential irAEs are 
provided in the following tables: diarrhea/colitis (Table 8-0), hepatitis (liver laboratory 
alterations) (Table 8-1), skin (rash) (Table 8-2), nephritis (Table 8-3), pneumonitis (Table 8-
4), endocrinopathies (Table 8-5), and other potential immune-related AEs (Table 8-6). Any 
Grade 4 irAE must result in permanent discontinuation of spartalizumab. In addition, guidance 
for management of spartalizumab -infusion reaction & cytokine release syndrome is provided 
in (Table 8-7).  
Under the category of OTHERS (Table 8-9) are included several irAE of interest that must be 
managed specifically and for which no specific guidance are provided in the table below.  
OTHERS include (but is not restricted to)  the following events : Autoimmune neuropathy, 
demyelinating polyneuropathy, Guillain-Barre, myasthenia Gravis-like syndrome, non-
infectious myocarditis, non-infectious pericarditis, pancreatitis, encephalitis, and, rapid onset 
of Grade 3 fatigue in the absence of disease progression.

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Patients receiving spartalizumab, may experience other irAEs than those listed in this 
document, therefore, all AEs of unknown etiology associated with drug exposure should be 
evaluated to determine if it is possibly immune-related. In cases where the specific irAE is not 
listed in the tables below, the investigator should follow the dose modification requirements in 
section 6.3.2 which details the measures to be taken for suspected (could be potentially 
immune-related or non-immune-related) AEs. Investigators are encouraged to contact the 
Sponsor as needed to discuss cases that warrant separate discussion outside of the scope of the 
current instructions. 
The dosing modification requirements are mandatory, however, the AE management 
guidelines are recommendations and can be modified according to the local practices.   
Table 8.0 Mandatory dose modification requirements and recommended 
clinical 
management 
guidelines 
for 
potential 
immune-related 
diarrhea/colitis
Diarrhea/Colitis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
Grade 1 (< 4 bowel actions per 
day over baseline) mild
Grade 2 (4-6 bowel actions per 
day over baseline) and / or 
abdominal pain/ blood in stool.
Diet
Hydration
Loperamide: initially 4 mg, 
followed by 2 mg every four 
hours or after every unformed 
stool; maximum 16 mg/day. 
Continue until diarrhea free for 
12 hours;
Diarrhea > 24h: loperamide 2 
mg every two hours; 
maximum 16 mg/day. 
Consider adding oral 
antibiotics.
Diarrhea > 48hrs: loperamide 
2 mg every two hours; 
maximum 16 mg/day. 
Consider  other second-line 
therapies for diarrhea (e.g: 
(octreotide, oral 
diphenoxylate) and oral 
antibiotics
If Grade 2 and no 
improvement in 5 days may 
require oral steroids
If Grade 2 diarrhea 
persists >1 week consider GI 
consultation and endoscopy to 
evaluate for colitis.
Continue spartalizumab  
treatment
If diarrhea is Grade 2, 
despite loperamide at 2 mg 
every two hours for > 48hrs:
o
Interrupt 
spartalizumab until 
diarrhea recovers to 
Grade ≤1 and then 
restart 
spartalizumab 
treatment at the 
same dose and 
schedule.

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Diarrhea/Colitis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
If Grade 2 persists for 5 days 
and worsening of symptoms 
or diffuse ulcerations and 
bleeding seen on endoscopy , 
commence steroids at a dose 
of 0.5-1mg/kg per day of 
prednisone (or IV  equivalent) 
and continue until symptoms 
improve to Grade 1. If no 
improvement occurs, manage 
as per Grade 3. Steroids can 
be tapered as per section 
6.3.1.2.2.
Sigmoidoscopy and biopsy 
can be considered and may 
assist in determining the 
duration of steroid taper 
based on the evidence of 
macroscopic and microscopic 
inflammation.
Grade 3 Diarrhea: Increase of 
≥7 stools per day over baseline; 
incontinence; hospitalization 
indicated; limiting self-care ADL;
Grade 3 Colitis: Severe 
abdominal pain; change in 
bowel habits; medical 
intervention indicated; 
peritoneal signs

Clinical evaluation and 
hospitalization indicated; 
rule out bowel perforation 
and intravenous hydration.

Consider consultation with 
gastroenterologist and 
confirmation biopsy with 
endoscopy.

In addition to symptomatic 
treatment (diet, hydration, 
loperamide, antibiotics if 
indicated); initiate 
immediate treatment with 
intravenous steroids 
(methylprednisolone 125 
mg) followed by high dose 
oral steroids (prednisone 1 
to 2 mg/kg once per day or 
dexamethasone 4 mg every 
4 hours) is recommended. 

When symptoms improve to 
≤Grade 1, steroid taper 
should be done as per 
section 6.3.1.1.2.

Taper over 6 to 8 weeks in 
patients with diffuse and 
1st occurrence: 

Interrupt  spartalizumab until 
diarrhea/colitis recovers to 
Grade ≤1 or baseline
o Once recovered restart 
spartalizumab treatment 
at the same dose and 
schedule and after 
appropriate steroid 
tapering (if initiated).
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 12 weeks since a 
Grade 3 event has been 
identified, otherwise 
spartalizumab must be 
permanently discontinued
2nd occurrence:
Permanently discontinue 
spartalizumab 

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Diarrhea/Colitis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
severe ulceration and/or 
bleeding.

If no improvement in 2-3 
days: consider initiating 
infliximab 5mg/kg and 
continue steroids. 
(Infliximab is 
contraindicated in patients 
with sepsis or a 
perforation). Upon 
symptomatic relief initiate a 
prolonged steroid taper over 
45 to 60 days. 

If symptoms worsen during 
steroid reduction, initiate a 
re-tapering of steroids 
starting at a higher dose of 
80 or 100 mg followed by a 
more prolonged taper and 
administer infliximab.

If symptoms persist despite 
the above treatment a 
surgical consult should be 
obtained.
Grade 4: Life-threatening 
consequences; urgent 
intervention indicated
Same as Grade 3
Permanently discontinue 
spartalizumab
Table 8-1 Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related liver laboratory 
alterations
Abnormal liver function tests
Severity
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Grade 2: 
AST or ALT > 3x ULN to ≤ 
5.0x ULN and/or 
bilirubin > 1.5x ULN to 
≤ 3x ULN (if patient 
meets criteria for Hy’s 
law refer to section 
6.5)
Monitor hepatic laboratory tests 
more frequently (every 2-3 
days) until returned to baseline 
values

Interrupt spartalizumab 
treatment until recovery to 
Grade ≤1 or baseline
o Once recovered restart 
spartalizumab treatment 
at the same dose and 
schedule 

Patients with baseline grade 
2 AST/ALT value (>3.0-5.0 
ULN) may continue 
spartalizumab treatment

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Abnormal liver function tests
Severity
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Grade 3 or 4: AST or 
ALT >5.0xULN and/or bilirubin > 
3.0x ULN 
Monitor hepatic laboratory 
tests more frequently (every 2-
3 days) until returned to 
baseline values. 
Consider  viral serology (i.e. 
hepatitis A/B/C, CMV, and rule 
out other potential cause of 
liver injury such as conmeds 
or alcohol),  consultation with 
hepatologist and liver biopsy 
to establish etiology of hepatic 
injury
If after 2-3 days new liver 
assessment shows worsening 
of laboratory test consider to 
initiate treatment with steroids 
prednisone 1-2 mg/kg/day or 
IV equivalents.
Add prophylactic antibiotics for 
opportunistic infections as 
appropriate
When symptoms/liver function 
tests improve to Grade ≤1, 
taper steroids over at least 4 
weeks.
If serum transaminase levels 
or bilirubin do not decrease 48 
hours after initiation of 
systemic steroids, oral 
mycophenolate mofetil 500 mg 
every 12 hours may be given 
as per local treatment 
guidance.
Infliximab is not recommended 
due to its potential for 
hepatotoxicity  

Permanently discontinue 
spartalizumab

Patients with baseline grade 
2 AST/ALT value (>3.0-5.0 
ULN) will discontinue 
spartalizumab treatment if 
value increased to grade 3 
with increase >=2x baseline

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Table 8-2 Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related skin events
Rash Events (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
Grade 1: Rash covering < 10% 
Body Surface Area (BSA)

Initiate prophylactic and 
symptomatic treatment 
measures.

Consider use of topical 
corticosteroids or urea 
containing creams in 
combination with oral 
antipruritics or moderate 
strength topical steroid 
(hydrocortisone 2.5% cream 
or fluticasone propionate 
0.5% cream)

Reassess after 2 weeks.
Continue spartalizumab 
treatment
Grade 2: 10-30% of BSA

If tolerable, treat as per 
Grade 1; 

If intolerable, initiate 
systemic steroids (e.g. oral 
prednisolone 0.5-1mg/kg 
daily) and consider dose 
interruption until tolerable or 
recovery to grade <=1 or 
baseline; once recovered 
resume spartalizumab 
treatment at the same dose 
and schedule. 

If symptoms persist or recur 
consider skin biopsy.
Continue spartalizumab 
treatment
o
AE resolution to ≤1 or baseline 
must occur within a period of 12 
weeks since Grade 2 event has 
been identified, otherwise 
spartalizumab must be 
permanently discontinued.
Grade 3: More than 30% of 
BSA

Obtain a skin biopsy and 
dermatology consult. 

Initiate systemic steroids 
with 1mg/kg of 
prednisolone or IV 
equivalent. 
1st occurrence: 

Interrupt spartalizumab until 
rash recovers to Grade ≤1 
or baseline
o Once recovered restart 
spartalizumab treatment 
at the same dose and 
schedule  
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 12 weeks since Grade 
3 event has been identified. 

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Rash Events (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
Otherwise, spartalizumab must 
be permanently discontinued
2nd occurrence: 
Permanently discontinue 
spartalizumab
Grade 4: Life-threatening
Same as Grade 3; additional 
measures as per local 
institutional guidelines 
Permanently discontinue 
spartalizumab
Other skin events
Stevens-Johnson syndrome, 
toxic epidermal necrolysis and 
other serious or life-threatening 
skin reactions 
Institute supportive care 
immediately as per institutional 
guidelines
Permanently discontinue 
spartalizumab
Table 8-3
Mandatory dose modification requirements and recommended clinical 
management guidelines for potential immune-related nephritis
Nephritis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
Grade 1:  Creatinine >ULN  to 
≤1.5x ULN)

Monitor creatinine weekly

If creatinine return to 
baseline resume routine 
creatinine monitoring per 
protocol

Promote hydration and 
cessation of nephrotoxic 
drugs
Continue spartalizumab
Grade 2: Creatinine >1.5 to ≤3 
x ULN

Monitor creatinine every 2 to 
3 days

Initiate 0.5 to 1 mg/kg/day 
prednisone or equivalents

If worsening or no 
improvement: 1 to 2 
mg/kg/day prednisone or 
equivalents 

Promote hydration and 
cessation of nephrotoxic 
drugs

Consult with specialist and 
consider renal biopsy  

Interrupt spartalizumab until 
serum creatinine recovers 
to ≤ Grade 1 or baseline. 
o Once recovered restart 
spartalizumab at the 
same dose and schedule 
  
AE resolution to ≤ Grade 1 
must occur within a period of 
12 weeks since Grade 2  event 
has been identified, otherwise 
spartalizumab must be 
permanently discontinued.

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Nephritis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
Grade 3: Creatinine >3.0 to <6 
x ULN

Monitor creatinine every 1 
to 2 days

Start 1 to 2 mg/kg/day 
prednisone or equivalents 

Consult with nephrologist 
and consider renal biopsy 
1st occurrence: 

Interrupt spartalizumab until 
serum creatinine recovers 
to ≤Grade 1 or baseline. 
o Once recovered restart 
spartalizumab treatment 
at the same dose and 
schedule
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 12 weeks since the 
Grade 3 event has been 
identified, otherwise 
spartalizumab must be 
permanently discontinued
2nd occurrence: 
Permanently discontinue 
spartalizumab.   
Grade 4: Creatinine >6x ULN

Monitor creatinine daily

Initiate steroids  with 1 to 2 
mg/kg/day prednisone or 
equivalent

Consult with nephrologist 
and consider renal biopsy
Permanently discontinue 
spartalizumab
Table 8-4 Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related pneumonitis
Pneumonitis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
Grade 1: Radiographic 
changes only- Asymptomatic

CT scan (high-resolution 
with lung windows) 
recommended, with serial 
imaging to monitor for 
resolution or progression- 
re-image at least every 3 
weeks

Monitor for symptoms every 
2-3 days - Clinical 
 

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Pneumonitis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
evaluation and laboratory 
work-up for infection

Monitoring of oxygenation 
via pulse oximetry 
recommended

Consultation of 
pulmonologist 
recommended
Grade 2: Symptomatic-medical 
intervention indicated; limits 
instrumental ADLs

CT scan (high-resolution 
with lung windows)

Monitor symptoms daily, 
consider hospitalization

Clinical evaluation and 
laboratory work up for 
infection

Consult pulmonologist

Pulmonary function tests - if 
normal at baseline, repeat 
every 8 weeks 

Bronchoscopy with biopsy 
and/or BAL recommended

Symptomatic therapy 
including corticosteroids if 
clinically indicated (1 to 2 
mg/kg/day prednisone or 
equivalent as clinically 
indicated).
1st occurrence:

Interrupt  spartalizumab 
until recovery to Grade ≤1 
or baseline
o
Once recovered restart 
spartalizumab treatment 
at the same dose and 
schedule
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 12 weeks since 
Grade 2 event has been 
identified, otherwise 
spartalizumab must be 
permanently discontinued.
If worsens treat as Grade 3 or 
4
2nd occurrence:
Permanently discontinue 
spartalizumab 
Grade 3: Severe symptoms; 
limits self-care ADLs; oxygen 
indicated
Grade 4: Life- threatening 
respiratory compromise; urgent 
intervention required

CT scan (high-resolution 
with lung windows)

Clinical evaluation and 
laboratory work-up for 
infection

Consult pulmonologist

Pulmonary function tests-if 
< normal, repeat every 8 
weeks until ≥ normal

Bronchoscopy with biopsy 
and/or BAL if possible

Treat with IV steroids 
(methylprednisolone 125 
mg) as indicated. When 
Permanently discontinue 
spartalizumab 

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Pneumonitis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
symptoms improve to ≤ 
Grade 1, a high dose oral 
steroid (prednisone 1 to 2 
mg/kg once per day or 
dexamethasone 4 mg every 
4 hours).

If IV steroids followed by 
high dose oral steroids 
does not reduce initial 
symptoms within 48 to 72 
hours, consider non-
corticosteroid 
immunosuppressive 
medication 
Table 8-5 Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related endocrine events
Endocrine events (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
Asymptomatic, intervention not 
indicated (e.g. hyperthyroidism 
or hypothyroidism)
If TSH <0.5x LLN, or 
TSH >2x ULN, or 
consistently out of range in 2 
subsequent measurements, 
include free T4 at 
subsequent cycles as 
clinically indicated
Consider endocrinologist 
consult
If hypophysitis is considered, 
pituitary gland imaging 
should be considered (MRIs 
with gadolinium and 
selective cuts of the pituitary 
can show enlargement or 
heterogeneity and confirm 
the diagnosis)
Repeat labs in 1 to 3 
weeks/MRI in 1 month if 
laboratory abnormalities 
persist but normal 
lab/pituitary scan
Continue spartalizumab

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Endocrine events (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
Symptomatic endocrinopathy 
(e.g., hypophysitis, adrenal 
insufficiency, hypothyroidism, 
hyperthyroidism)
Consider Endocrinology 
consultation
Rule out infection/sepsis and 
other alternative causes with 
appropriate cultures and 
imaging
Treat with an initial dose of 
methylprednisolone 1 to 2 
mg/kg intravenously followed 
by oral prednisone 1 to 2 
mg/kg per day. (only for life-
threatening 
endocrinopathies)
Replacement of appropriate 
hormones may be required 
as the steroid dose is 
tapered
Hypophysitis with clinically 
significant adrenal 
insufficiency and 
hypotension, dehydration, 
and electrolyte abnormalities 
(such as hyponatremia and 
hyperkalemia) constitutes 
adrenal crisis
Consider hospitalization and 
intravenous 
methylprednisolone should 
be initiated.

Interrupt spartalizumab until 
recovery to mild or no 
symptoms, and controlled 
with hormone replacement 
therapy
o Once recovered or 
controlled with hormone 
replacement, restart 
spartalizumab at the 
same dose and 
schedule
o
Hypothyroidism may be 
managed with 
replacement therapy 
without treatment 
interruption (unless life-
threatening) 
Permanently discontinue 
spartalizumab for life-
threatening endocrinopathies 
(i.e. hyperthyroidism, adrenal 
insufficiency, hypophysitis) or 
recurring severe/life-
threatening events not 
controlled by hormone 
replacement therapy.
Autoimmune diabetes
(Grade 3 or symptomatic 
hyperglycemia)
Initiate anti-glycemic therapy 
(i.e. insulin) as medically 
indicated and monitor 
glucose levels regularly until 
metabolic control is achieved

Interrupt spartalizumab until 
recovery to grade 1 or 
baseline
o
Once recovered, 
restart spartalizumab 
treatment at the 
same dose and 
schedule 

Second occurrence: 
permanently discontinue
Autoimmune diabetes
(Grade 4 hyperglycemia or life-
threatening complications)
Same as Grade 3
Permanently discontinue 
spartalizumab
Management for immune-related: 

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a.
For non-life-threatening immune-related endocrinopathy, the administration of 
corticosteroids can be omitted, and the patient can be treated with physiologic 
replacement of the deficient hormone (e.g. provide levothyroxine for immune-
related hypothyroidism, and omit administration of corticosteroids).
b. Use corticosteroids only used if endocrinopathy is life-threatening or as physiologic 
replacement for primary or secondary adrenal insufficiency.
Table 8-6 Mandatory dose modification requirements and recommended 
clinical management guidelines for “other” potential immune-related AEs of 
special interest
Other(e.g. Autoimmune neuropathy, Demyelinating polyneuropathy, Guillain Barre, 
Myasthenia Gravis-like syndrome, Non-infectious myocarditis, pericarditis, pancreatitis, 
encephalitis, and Grade 3 Fatigue with rapid onset in absence of disease progression) 
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Mild (Grade 1)
Provide symptomatic treatment
Continue spartalizumab
Moderate (Grade 2)

Consider interruption of 
spartalizumab until recovery to ≤ 
Grade 1 or baseline. 

Ensure adequate evaluation to 
confirm etiology or exclude other 
causes

Provide symptomatic treatment

Systemic corticosteroids may be 
indicated

Consider biopsy for confirmation of 
diagnosis

A specialist should be consulted
Severe (Grade 3)

Initiate systemic corticosteroids 
(prednisone or equivalent) at a 
dose of 1-2 mg/kg QD and other 
therapies as appropriate

Monitor closely and consult with a 
specialist
1st occurrence: 

Interrupt spartalizumab until 
recovery to ≤ Grade 1 or 
baseline 
o May restart spartalizumab 
treatment at the same dose 
and schedule
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
maximum period of 12 weeks since 

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Other(e.g. Autoimmune neuropathy, Demyelinating polyneuropathy, Guillain Barre, 
Myasthenia Gravis-like syndrome, Non-infectious myocarditis, pericarditis, pancreatitis, 
encephalitis, and Grade 3 Fatigue with rapid onset in absence of disease progression) 
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
a Grade 3 event has been 
identified, otherwise spartalizumab 
must be permanently discontinued.
2nd occurrence: 
Permanently discontinue 
spartalizumab 
Grade 4
Refer to management of severe AEs
Permanently discontinue 
spartalizumab
Encephalitis (any 
grade) 

Rule out infectious or other 
causes of moderate to severe 
neurologic deterioration, and 
consult with specialist.

If other etiologies are ruled out, 
administer corticosteroids at a 
dose of 1 to 2 mg/kg/day 
prednisone equivalents.
Permanently discontinue 
spartalizumab
Myocarditis or cardiac 
event grade>=3
Initiate systemic corticosteroids 
(prednisone or equivalent) at a dose 
of 1-2 mg/kg QD, and consult with 
specialist.
Permanently discontinue 
spartalizumab
Table 8-7 Mandatory dose modification requirements and recommended 
clinical management guidelines for infusion reaction events and cytokine 
release syndrome 
Infusion reaction (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital 
signs as medically indicated 
until the patient is deemed 
medically stable in the opinion 
of the investigator.
Continue spartalizumab
Grade 2
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 

Stop Infusion

Additional appropriate 
medical therapy may 
include but is not limited to:
o IV fluids
spartalizumab may continue 
with close monitoring and 
premedication as per local 
institutional guidelines for 
prophylaxis of infusion reaction

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Infusion reaction (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs
o Antihistamines
o NSAIDS
o Acetaminophen
o Narcotics

Increase monitoring of vital 
signs as medically 
indicated until the patient is 
deemed medically stable in 
the opinion of the 
investigator.

If symptoms resolve within 
one hour of stopping drug 
infusion, the infusion may 
be restarted at 50% of the 
original infusion rate (e.g. 
from 100 mL/hr to 50 
mL/hr). Otherwise dosing 
will be held until symptoms 
resolve and the patient 
should be re-premedicated 
for the next scheduled 
dose.

Patient may be 
premedicated 1.5hr (± 30 
minutes) prior to infusion of 
spartalizumab with:
o Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine).
o Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic).

Consider discontinuation of 
spartalizumab in case of 
recurring infusion reaction 
despite premedication and 
prolonged infusion
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of  infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 

Stop Infusion

Additional appropriate 
medical therapy may 
include but is not limited to:
o IV fluids
o Antihistamines
o NSAIDS
Permanently discontinue 
spartalizumab

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Infusion reaction (NCI-CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
o Acetaminophen
o Narcotics
o Oxygen
o Pressors
o Corticosteroids
o Epinephrine

Increase monitoring of vital 
signs as medically 
indicated until the patient is 
deemed medically stable in 
the opinion of the 
investigator. Hospitalization 
may be indicated.
2nd occurrence of grade 2 irAE (including colitis/diarrhea, LFT abnormalities, 
rash, nephritis and other AEs as listed in table 8-6) or for  grade 2 irAE lasting  
more than 12 weeks. Permanently discontinue spartalizumab. 
6.3.2.1.2 Guidance for corticosteroids tapering for management of immune-related 
AEs:
Steroids should be tapered slowly and based on response/recovery of clinical symptoms. 
Consider to complete tapering over a period of at least 4 weeks. Slower tapering of 
corticosteroids therapy may be recommended if the adverse event is not showing improvement. 

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Once corticosteroid tapering is achieved at a level of 10 mg of prednisone/day (or equivalent), 
spartalizumab can be restarted as indicated in the dose modification tables.
6.3.2.2
Dose modification requirements for adverse events suspected to be related to 
study treatment
The required dose modification and management of adverse events that are considered to be 
related to study medication and do not have specific management requirements noted 
elsewhere in the protocol are provided in Table 8-8 & Table 8-9. 
Table 8-8 Mandatory dose modification requirements and recommended 
clinical management guidelines for hematologic adverse events suspected to 
study treatment
Hematologic suspected AEs (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Neutropenia
Grades 1, 2
NA
Continue spartalizumab and 
siltuximab
Grade 3, 4
Monitoring blood test more frequently 
(every 7 days for grade 3, and 3-5 
days for grade 4)
Consider consulting with a specialist, 
initiation of corticosteroids or other 
therapies as medically appropriate and 
as per institutional guidelines.
1st occurrence: 

Interrupt spartalizumab and 
siltuximab until toxicity recovers 
to Grade ≤2 or baseline.
o Once recovered restart 
spartalizumab and siltuximab 
treatment at the same dose 
and schedule
o Grade 4 febrile neutropenia or 
thrombocytopenia should lead 
to permanent discontinuation 
of spartalizumab and 
siltuximab
2nd occurrence: 

Interrupt spartalizumab and 
siltuximab until toxicity recovers 
to Grade ≤2 or baseline
o Once recovered restart 
spartalizumab and siltuximab 
treatment at the same dose 
and schedule
AE resolution to ≤ Grade 2 or 
baseline must occur within a 
maximum period of 12 weeks since 
Grade 3 or 4 event has been 
identified, otherwise spartalizumab 

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Hematologic suspected AEs (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
and siltuximab  must be permanently 
discontinued 
3rd  occurrence: 
Permanently discontinue 
spartalizumab and siltuximab 
Febrile 
Neutropenia
Apply Institutional guidelines
Follow- neutropenia Grade 4 
requirements (above)
Thrombocytopenia (NCI-CTCAE v4.03)
Grade 1, 2, 3 
without clinical 
significant 
bleeding
Grade 3: monitoring blood test more 
frequently (every 7 days)
Continue spartalizumab and 
siltuximab
Grade 3 with 
clinical significant 
bleeding OR 
Grade 4
Monitoring blood test more frequently 
(every 3-5 days)
Consider consulting with a specialist, 
initiation of corticosteroids or other 
therapies as medically appropriate and 
as per institutional guidelines.
1st occurrence:

Interrupt  spartalizumab and 
siltuximab until toxicity resolves 
to Grade ≤2 or baseline. 
o Once recovered restart 
spartalizumab and siltuximab 
at the same dose and 
schedule
2nd occurrence: 

Interrupt spartalizumab and 
siltuximab until toxicity resolves 
to Grade ≤2 or baseline 
o Once recovered restart 
spartalizumab and siltuximab 
at the same dose and 
schedule
AE resolution to ≤ Grade 2 or 
baseline must occur within a 
maximum period of 12 weeks since 
Grade 3 with clinically significant 
bleeding or Grade 4 event has been 
identified, otherwise spartalizumab 
and siltuximab must be permanently 
discontinued.  
3rd occurrence: 
permanently discontinue 
spartalizumab and siltuximab

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Table 8-9 Mandatory dose modification requirements and recommended 
clinical management guidelines for non-hematologic adverse events suspected 
related to study treatment (excluding alopecia, grade 2 fatigue and irAE)
Non-Hematologic suspected AEs (except Grade 2 alopecia, Grade 2 fatigue, irAE) (NCI-
CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
Grade 1-2 tolerable

Monitor closely

Provide supportive care 
according to institutional 
standards
Continue spartalizumab and 
siltuximab treatment at the 
same dose and schedule
Grade 2 intolerable or
Grade 3

Monitor closely

Provide supportive care 
according to institutional 
standards

Consider consulting with a 
specialist, initiation of 
corticosteroids or other 
therapies as medically 
appropriate and as per 
institutional guidelines.
1st or 2nd occurrence:

Interrupt spartalizumab and 
siltuximab until toxicity 
recovers to Grade ≤1 or 
baseline.
o Once recovered restart 
spartalizumab and 
siltuximab at the same 
dose and schedule
AE resolution to Grade ≤1 or 
baseline must occur within a   
maximum period of 12 weeks 
since intolerable Grade 2 or 
Grade 3 event has been 
identified, otherwise 
spartalizumab and siltuximab 
must be permanently 
discontinued.  
3rd occurrence: 
Permanently discontinue 
spartalizumab and siltuximab
Grade 4

Monitor closely

Provide supportive care 
according to institutional 
standards

Consider consulting with a 
specialist, initiation of 
corticosteroids or other 
therapies as medically 
appropriate and as per 
institutional guidelines.
1st occurrence:

Interrupt  spartalizumab and 
siltuximab
o Consider permanently 
discontinuing 
spartalizumab. If benefit 
risk assessment support 
treatment continuation, 
restart spartalizumab and 
siltuximab at the same 
dose and schedule. 

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Non-Hematologic suspected AEs (except Grade 2 alopecia, Grade 2 fatigue, irAE) (NCI-
CTCAE v4.03)
Grade 
Recommended Adverse 
Event management 
guidelines
Mandatory Dose Modification 
requirements
2nd occurrence: 
Permanently discontinue 
spartalizumab and siltuximab
 
6.3.3
Dose modifications Siltuximab 
Table 9.
Dose reduction steps for siltuximab
Overall, patients with AEs suspected to be related to siltuximab include pruritus, increased 
weight (edema), rash, hyperuricemia, and upper respiratory tract infection. Rare side effects 
include gastrointestinal perforation. 
Each patient can receive a maximum of 2 dose reductions of siltuximab prior to 
permanent discontinuation of siltuximab.
Siltuximab can be held for a maximum of  12 weeks, if no resolution of toxicity to grade 
1 or less, then siltuximab will be permanently discontinued. 
Dose reduction*
Starting dose level – 0
Dose level - 1
Dose level – 2
Siltuximab
11 mg/kg
9 mg/kg
6 mg/kg **
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.
**Dose reduction below 6 mg/Kg is not allowed.
1. Weight gain due to edema grade 1 or 2 manage symptomatically with diuretics. 
Patients with grade 3 hold siltuximab treat symptomatically resume at one dose 
level lower once grade 1. Patients with grade 4 hold siltuximab and treat 
symptomatically. Permanently discontinue siltuximab for first occurrence of 
grade 4 weight gain.
2. Hyperuricemia grade 1 or 2 continue treatment with siltuximab and monitor. 
Grade 3 start therapy for hyperuricemia (allopurinol) and hold siltuximab until it 
resolves to grade 1. Resume at a lower dose level. Grade 4 hold siltuximab 
permanently, treat hyperuricemia (rasburicase). 

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3. Upper respiratory tract infection grade 1 and 2 treat infection and continue 
siltuximab. Grade 3 or 4 hold siltuximab treat infection. First occurrence of grade 
4 upper respiratory tract infection will lead to permanent discontinuation of 
siltuximab. For Grade 3,  resume after infection treated no dose reduction for first 
occurrence. Dose reduce by one dose level for second occurrence. Hold 
permanently for third occurrence. 
4. Pruritus grade 1 and 2 treat symptomatically and continue siltuximab. Grade 3 
hold siltuximab, treat symptomatically, resume siltuximab after symptoms resolve.  
5. Gastrointestinal perforation any grade permanently hold siltuximab.
6. Dose modifications of siltuximab for hematologic and non-hematologic toxicities 
also review 6.3.2.2.
6.3.4
Timing of Dose Administration
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed.  Trial treatment may be administered up to 3 days before or 
after the scheduled Day 1 of each cycle due to administrative reasons.
All trial treatments will be administered on an outpatient basis.
Spartalizumab 300 mg will be administered as a 30 minute IV infusion every 3 weeks.  Given 
the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min).
Siltuximab will be administered IV infusion over a period of 1 hour on day 1 of every 3-week 
cycle. Given the variability of infusion pumps, a window of -10 minutes and +10 minutes is 
permitted (i.e., infusion time is 60 minutes: -10 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the spartalizumab 
and siltuximab infusion fluid and administration of infusion solution.
6.3.5
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
6.4
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 

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vaccination may be required.  The investigator should discuss any questions regarding this 
with the PI.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician. 
6.4.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded.
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the patient are allowed.

Medications to prevent or treat nausea or vomiting.

Anti-diarrheal medications (e.g., loperamide) for patients who develop diarrhea.

Pain medication to allow the patient to be as comfortable as possible.

Treatment with bisphosphonates or denosumab for pre-existing, painful bone/liver 
metastases, and limited-field palliative radiotherapy or surgery is permitted. Patients 
requiring initiation of such treatment during the course of the study must be evaluated for 
disease progression; radiotherapy like any concomitant medication must be listed on the 
CRF. Spartalizumab and siltuximab should be held for ≥1 week prior to radiotherapy or 
surgery, and be resumed ≥2 weeks after radiation or surgery, provided the patient has 
recovered from radiation or surgery related toxicity.

Immunosuppressive agents to treat suspected irAEs

Hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), 
thrombopoietin mimetics or erythroid stimulating agents as per local or published 
guidelines; in case of anemia, thrombocytopenia or neutropenia, potential immune-
mediated etiology should be ruled out

Nutritional support or appetite stimulants (e.g. megestrol).

Oxygen therapy and blood products or transfusions.

Inactivated vaccines. 

The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy, herbal/natural medications and 

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blood transfusions) administered during the study must be listed on the Concomitant 
Medications.
6.4.2
Prohibited Concomitant Medications
During the course of the study, patients must not receive other antineoplastic therapies (e.g. 
investigational drugs, devices, chemotherapy, immunotherapies) or any other therapies that 
may be active against cancer or modulate the immune responses.  However, limited-field 
palliative radiotherapy may be allowed as concomitant therapy (see above). 
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed except 
for the treatment of infusion reaction, irAEs, and for prophylaxis against imaging contrast dye 
allergy, standard pre-medication for chemotherapy or replacement-dose steroids in the setting 
of adrenal insufficiency (providing this is < 10 mg/day prednisone or equivalent), or transient 
exacerbations of other underlying diseases such as COPD requiring treatment. If systemic 
corticosteroids are required for the control of infusion reactions or irAEs, it must be tapered 
and be at non-immunosuppressive doses (< 10 mg/day of prednisone or equivalent) before the 
next administration of study treatment. If the dose of prednisone or equivalent cannot be 
reduced to less than 10 mg/day before the administration of next dose of study treatment then 
spartalizumab or siltuximab must be discontinued (note: next dose can be delayed up to 12 
weeks).
The use of live vaccines is not allowed through the whole duration of the study. Inactivated 
vaccines are allowed.
There are no prohibited therapies during the post-treatment follow-up period except for live 
vaccines within 4 weeks of last administration of siltuximab.
6.5
Rescue Medications & Supportive Care
6.5.1
Supportive Care Guidelines
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrists etc. should be consulted as deemed necessary.  All patients must 
be followed up for adverse events and serious adverse events until start of new antineoplastic 
medication or 150 days after discontinuation of siltuximab and spartalizumab, whichever is 
sooner. If the patient begins post treatment antineoplastic medications before the 150-Day 
safety follow-up, only suspected AEs and suspected SAEs will be collected thereafter up to 
the 150 days following the last dose of siltuximab or spartalizumab.  Suspected SAEs will 
continue to be collected beyond the 150-Day safety visit. This will be done by return clinic 
visits, laboratory checks, and phone calls .  

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The emergence of Immune-Related AE (irAE) may be anticipated based on the mechanism of 
action of immunomodulatory therapies.
Serologic, histologic (tumor sample) and immunological assessments should be performed as 
deemed appropriate by the Investigator to verify the immune-related nature of the AE and to 
exclude alternative explanations. Recommendations have been developed to assist 
investigators in assessing and managing the most frequently occurring irAEs.
Patients whose treatment is interrupted or permanently discontinued due to an irAE, AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 30 days, and 
subsequently at approximately 30-day intervals (or more frequently if required by institutional 
practices, or if clinically indicated), until resolution or stabilization of the event, whichever 
comes first. Appropriate clinical experts should be consulted as deemed necessary.
If an AE is suspected to be immune-related the relevant immunological assessments (e.g. 
rheumatoid factor, anti-DNA Ab, etc.) should be performed. If cytokine release syndrome is 
suspected, the assessments outlined below must be performed. All patients must be followed-
up for AEs and SAEs for 150 days following the last dose of spartalizumab or siltuximab.  
However, if the patient begins post treatment antineoplastic medication before the 150-Day 
safety visit the collection of new SAEs and AEs unrelated to study medication will stop and 
thereafter only suspected SAEs and suspected AEs will continue to be collected to Day 150.  
If SAEs suspected to be related to study medication occur beyond Day 150, information should 
also be collected. This will be done by return clinic visits, laboratory checks, and phone calls 
until SAE resolves. 
6.5.1.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 
x baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).

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In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2 . A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
6.5.1.2
Infusion Reactions
Spartalizumab: If a patient experiences an infusion reaction, he/she may receive pre-
medication on subsequent dosing days. The pre-medication should be chosen per institutional 
standard of care, at the discretion of the treating physician.
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status.
If a patient experiences a Grade 3 infusion or anaphylactic/anaphylactoid reaction, the patient 
will discontinue spartalizumab treatment. Further guidelines on management of spartalizumab 
infusion reactions are provided in Section 6.3.2.
The CTCAE category of “Infusion related reaction” should be used to describe study treatment 
related infusion reactions, unless the investigator considers another category, such as “Allergic 
reaction”, “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a specific 
situation.
Siltuximab (infusion reactions) 

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During IV infusion of siltuximab, mild to moderate infusion reactions may improve following 
slowing of or stopping the infusion. Upon resolution of the reaction, reinitiating the infusion 
at a lower infusion rate and therapeutic administration of antihistamines, acetaminophen, and 
corticosteroids may be considered. For patients who do not tolerate the infusion following 
these interventions, siltuximab should be discontinued. During or following infusion, treatment 
with siltuximab should be discontinued in patients who have severe infusion related 
hypersensitivity reactions (e.g. anaphylaxis). The management of severe infusion reactions 
should be dictated by the signs and symptoms of the reaction. Appropriate personnel and 
medication should be available to treat anaphylaxis if it occurs.
If a patient experiences an infusion reaction with signs of anaphylaxis, stop the infusion of 
siltuximab. Discontinue further therapy with siltuximab. 
If the patient develops a mild to moderate infusion reactions, stop the infusion. If the reaction 
resolves, the siltuximab infusion may be restarted at a lower infusion rate. Consider medication 
with antihistamines, acetaminophen, and corticosteroids. Discontinue siltuximab if the patient 
does not tolerate the infusion following these interventions.
6.6
Study drug preparation and dispensation
6.6.1
Spartalizumab
Spartalizumab will be provided as global clinical supply and will be packed and labeled under 
the responsibility of Novartis, Drug Supply Management.
Spartalizumab will be administered intravenously as a 30 minute infusion (up to 2 hours, if 
clinically indicated). Infusion must take place in a facility with appropriate resuscitation 
equipment available at the bedside and a physician readily available during the period of drug 
administration.  Clinical monitoring during and post infusion should be performed according 
to local practice and institutional guidelines, and as outlined in Section 6.1. Further instructions 
for the preparation and dispensation of spartalizumab are described in the [Study Pharmacy 
Manual].
6.6.2
Siltuximab
Use aseptic technique for reconstitution and preparation of dosing solution. 
1.
Calculate the dose (mg), total volume (mL) of reconstituted siltuximab solution 
required and the number of vials needed. A 21-gauge 1-½ inch needle is recommended for 
preparation. Infusion bags (250 mL) must contain Dextrose 5% in Water and must be made of 
Polyvinyl chloride (PVC) with Di-{2-ethylhexyl}phthalate (DEHP), or Polyolefin (PO). 
2.
Allow the vial(s) of siltuximab to come to room temperature over approximately 30 
minutes. Siltuximab should remain at room temperature for the duration of the preparation. 
3.
Aseptically reconstitute each siltuximab vial as instructed in Table 2. 

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Gently swirl the reconstituted vials to aid the dissolution of the lyophilized powder. DO NOT 
SHAKE or SWIRL VIGOROUSLY. Do not remove the contents until all of the solids have 
been completely dissolved. The lyophilized powder should dissolve in less than 60 minutes.
Once reconstituted, and prior to further dilution, inspect the vials for particulates and 
discoloration. Do not use if particles or solution discoloration are present or if visibly opaque. 
The reconstituted product should be kept for no more than two hours prior to addition into the 
infusion bag.
4.
Dilute the reconstituted siltuximab solution dose to 250 mL with sterile Dextrose 5% 
in Water by withdrawing a volume equal to the total calculated volume of reconstituted 
siltuximab from the Dextrose 5% in Water, 250 mL bag. Slowly add the total calculated 
volume (mL) of reconstituted siltuximab solution to the Dextrose 5% in Water infusion bag. 
Gently invert the bag to mix the solution.
5.
Administer the diluted siltuximab solution in 5% Dextrose in Water 250 mL by 
intravenous infusion over a period of 1 hour using administration sets lined with polyvinyl 
chloride (PVC) with di-{2-ethylhexyl}phthalate (DEHP) or polyurethane (PU), containing a 
0.2micron inline polyethersulfone (PES) filter. The infusion should be completed within 4 
hours of the dilution of the reconstituted solution to the infusion bag. 
6.
Do not infuse siltuximab concomitantly in the same intravenous line with other agents. 
7.
Do not store any unused portion of the reconstituted product or of the infusion solution. 
Waste material should be disposed of in accordance with local requirements. 
6.6.3
Study treatment packaging and labeling
Study treatment, spartalizumab, will be provided as global clinical open supply and will be 
packed and labeled under the responsibility of Novartis, Drug Supply Management. 
Study treatment, Siltuximab, will be provided by EUSA Pharmac (UK) Ltd.  
6.6.4
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels and in the latest Investigator’s 
Brochure. 

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6.6.5
Study drug compliance and accountability
6.6.5.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.  Dose changes and interruptions of spartalizumab and/or siltuximab must be specifically 
documented in the patient source documents and eCRF.
6.6.5.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
6.6.6
Disposal and destruction
The study drug supply will be disposed of as per Winship’s Investigational Pharmacy SOP.
6.7
Subject Withdrawal/Discontinuation Criteria
Patients may voluntarily discontinue from the siltuximab or spartalizumab for any reason at 
any time. If a patient decides to discontinue from the investigational treatment, the 
investigator should make a  r e a s o n a b l e  effort (e.g. telephone, e-mail, letter) to 
understand the primary reason for this decision and record this information in the patient’s 
chart and on the appropriate CRF pages.  They may be considered withdrawn if they state an 
intention to withdraw, fail to return for visits, or become lost to follow-up for any other reason.
The investigator may discontinue siltuximab or/and spartalizumab for a given patient if, he/she 
believes that continuation would be detrimental to the patient’s well-being.
In addition to mandatory spartalizumab and siltuximab must also be discontinued under the 
following circumstances:
a.
Pregnancy
b. Any other protocol deviation that results in a significant risk to the patient’s safety
Patients who discontinue either spartalizumab or siltuximab should NOT be considered 
withdrawn from the study. They should return for the assessments indicated in Section 14.3. 
If they fail to return for these assessments for unknown reasons, every effort (e.g. telephone, 
email, letter) should be made to contact them as specified in Section 6.7.6.
For patients who discontinue treatment for reasons other than documented disease progression 
per RECIST 1.1, death, lost to follow-up, or withdrawal of consent, clinical and tumor 
assessments must continue to be performed every 9 weeks (+/- 1 week) until documented 
disease progression per RECIST 1.1, death, lost to follow-up, or withdrawal of consent.

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In some circumstances patients may be allowed to continue to receive study treatment beyond 
disease progression as per RECIST 1.1 criteria (Section 14.3). These patients will continue 
assessments, and will complete the EOT visit only after permanent discontinuation of study 
treatment. 
6.7.1
Replacement policy 
Escalation part:
Patients will not be replaced on study. However, if a patient is considered as non-evaluable for 
the DDS, enrollment of a new patient to the current cohort will be considered if there is less 
than the required number of evaluable patients. Enrollment of new patients may be considered 
until at least the minimum number (1 or 3) or at most the maximum number (3 or 6) of 
evaluable patients is achieved within the cohort. Minimum and maximum numbers of 
evaluable patients per cohort are defined in Section 6.2.2.
    Expansion part:
During the dose expansion part, no replacements will be needed.
6.7.2
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation.  All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone, 
e-mail, letter) to understand the primary reason for this decision and record this information.
Spartalizumab and siltuximab must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
6.7.3
Follow up for safety evaluations
All patients must be followed for safety up to 150 days after the last dose of spartalizumab or 
siltuximab. After the 30-day onsite safety follow-up visit, patients will be followed (via 
telephone call or onsite visit if patient happens to be visiting the site) at 60, 90, 120 and 150 
days after the last dose of spartalizumab and or siltuximab. All safety assessments should be 
completed as per Section 7.0.  However, if the patient begins post treatment antineoplastic 
medication before the 150-Day safety follow-up visit the collection of new SAEs and AEs 
unrelated to study medication will stop and thereafter only suspected AEs and suspected SAEs 
will continue to be collected up to Day 150. All irAE will collected till the end of the safety 

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monitoring period (i.e. 150 days as stated in the protocol). Suspected SAEs will continue to be 
collected beyond the 150-Day safety visit. Data collected should be added to the appropriate 
eCRF pages. For female patients of child bearing potential, a pregnancy test will be performed 
at the time points listed in Section 7.0.
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF.
6.7.4
Follow-up for efficacy evaluations
Patients who discontinue study treatment for reasons other than disease progression as per 
RECIST 1.1, should continue tumor assessment until disease progression as per RECIST 1.1, 
withdrawal of consent, lost to follow up, or death irrespective of start of new anti-neoplastic 
therapy at the same intervals as per Section 7.0.
6.7.5
  Survival follow-up
Patients will enter the survival follow-up period once they complete the safety follow-up and 
efficacy follow-up after treatment discontinuation (whichever is longer).  Patients will then be 
contacted by telephone every 12 weeks to follow-up on their survival status. Any new 
antineoplastic therapies that have been started since the last contact date will also be collected 
during these phone calls along with the start/end date and date of disease progression (clinical 
or radiological) on subsequent therapies to assess time to progression on next-line therapy 
(PFS2).
6.7.6
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
6.7.7
Discontinuation of Study Therapy after CR 
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with spartalizumab and siltuximab and had at 
least two treatments with spartalizumab and siltuximab beyond the date when the initial CR 
was declared.  Subjects who then experience radiographic disease progression may be eligible 
for additional treatment with spartalizumab and siltuximab via the Second Course Phase at the 
discretion of the investigator as detailed in Section 6.7.

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7.0 TRIAL FLOW CHART
7.1
Study Flow Chart
Trial Period:
Treatment Cycles a
End of 
Treatment
Post-Treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Main 
Study 
Screening 
(Visit 2)
1
2 
3
4
5
6
7
8
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
discon
Every 
12 
weeks 
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics and Medical History
X
X
X
X
X
X
X
X
X
X
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration c
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
X
X
X
X
X
X
X
Directed Physical Examination
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
Xd
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test – Urine or Serum -HCGe
X
PT/INR and aPTT
X

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Trial Period:
Treatment Cycles a
End of 
Treatment
Post-Treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Main 
Study 
Screening 
(Visit 2)
1
2 
3
4
5
6
7
8
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
discon
Every 
12 
weeks 
CBC with Differential
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry Panel
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis screening f
X
Urinalysis
X
X
T3, FT4 and TSH
X
X
X
X
X
X
ECG
X
Uric Acid
X
X
X
X
Tumor Imaging
Xg
Xg
Xg
Archival or Newly Obtained Tissue 
Collection i
X
X
Correlative Studies Blood Collection j
X
X
X
X
X
a.
Treatment cycles are 3 weeks
b. Only for patients with ongoing treatment related toxicities. Details of required follow up visit are given in section 6.5.1 and 
6.7. 
c.
Siltuximab and spartalizumab given day 1 of each cycle except cycle 1 in the expansion phase
d. ECOG performance status should be done within 10 days or less from day 1 of cycle 1 
e.
Pregnancy test once a month women of child bearing potential

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f.
HBV-DNA, Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), Hepatitis B surface antibody (HBsAb), 
HCV RNA- PCR
g. Baseline imaging with 8 weeks of day 1 is acceptable
h. Scans will be done every 3 cycles between day 15 and day 21 of that cycle
i.
Paired biopsies will only be obtained from patients on the dose expansion cohort at baseline and between days 14 and 21 of 
cycle 1. Archival tissue will be tested for MSI status. 
j.
Samples will be collected at baseline, cycle1 days 1,8,15, cycle 2 day 1 and cycle 3 day 1. Blood will also be collected at EOT 
and disease progression. Analysis will include proportion of T, B, NK, memory and effector T cell subsets and expression of 
PD-1, PD-L1 and B7 family members.

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8.0 TRIAL PROCEDURES
8.1
Trial Procedures
The Trial Flow Chart - Section 7.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator.
8.1.1
Tumor Tissue Collection and Correlative Studies Blood Sampling
 Biomarker analyses will be used to investigate the effect of the spartalizumab and siltuximab 
at the molecular and cellular level as well as to determine how changes in the markers may 
relate to exposure and clinical outcomes.  In addition, potential predictive markers of efficacy, 
as well as mechanisms of resistance to spartalizumab and siltuximab treatment will also be 
explored.
While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or not perform or 
discontinue an analysis due to either practical or strategic reasons (e.g., inadequate sample 
number, issues related to the quality of the sample or issues related to the assay that preclude 
analysis, impossibility to perform correlative analyses, etc.). Therefore, depending on the 
results obtained during the study, sample collection analysis may be omitted at the discretion 
of the PI. 
The sample collection information must be entered on the appropriate sample collection log 
eCRF page(s) and requisition form(s). Detailed instructions for the collection, handling, and 
shipment of tumor samples are outlined in the laboratory manual for the study.
Samples collected for research purposes include blood and tissue. Blood is not optional. The 
samples will be used to evaluate correlative markers for this study and will be stored and may 
be used for other research in the future. Tissue biopsies performed as part of the trial will only 
be done in a subset of patients and are optional. Tissue biopsies will only be performed during 
the expansion phase. Tissue will used to evaluate correlative markers for this study and will be 
stored and may be used for other research in the future. 
All correlative samples will be de-identified. A study specific subject number will used to 
identify the samples. The study specific subject number will be linked to the patient 
information only in our HIPPA compliant electronic CRF. 
Samples will be handled and stored in Dr. Lesinski’s lab (Winship Bldg. C 3rd floor). 
During the study, both blood and tumor samples will be collected to perform exploratory 
biomarker assessments. These are summarized in Table 10

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Table  10 Biomarker sample collection plan
Sample type
Volume
Visit
Time point
Optional:
Paired biopsies pre and post treatment for patients 
on the expansion phase
 Core, 
excisional 
and 
incisional 
biopsies 
are 
acceptable. 
Pretreatment
And days 14-21 
of cycle 1
pretreatment 
days 14 to 21 of 
cycle 1
Blood samples as detailed in study calendar 
8.1.1.1
Biomarker assessments in tumor samples
Pre- and post- treatment tumor biopsies will be obtained from 24 patients enrolled on the 
expansion phase. Patients will sign the optional biopsy consent prior to starting treatment and 
will be assigned to either start spartalizumab or spartalizumab / siltuximab for the first cycle. 
Biopsies will be obtained within 4 weeks prior to the first dose of study therapy (biopsy #1) 
and then during the third week between Day 14 and Day 20.  At least three core biopsies will 
be obtained at the time of the biopsy (unless limited for technical/safety reasons). The obtained 
tissues will be handled in the following way: 
1) RNAlater for RNA stabilization and tissue storage 
2) Formalin-fixed paraffin block with one cut H&E stained slide 
3) Liquid nitrogen frozen tissue in cryo-preservation vials
All collected tissues are stabilized and stored in -80°C freezers (RNAlater stabilized, OCT 
embedded, short term storage) or the vapor phase of a liquid nitrogen freezer (long term 
storage) in single use aliquots.   All FFPE tissue blocks are stored in a climate controlled 
storage room that is temperature (less than 27ºC) and humidity controlled.
Tissue will be evaluated using IHC for CD3, CD4, CD8, CD163, PD-1, PD-2, PDL-1, MIF, 
TAM and stromal/ vascular markers. Tissue will also be dissociated and flow cytometry will 
be used to determine the characteristics of macrophages and lymphocytes. Genomic 
(transcriptome) profiling will be performed on tissue and lymphocytes.
8.1.1.2
Biomarker assessments in plasma
All patients participating in the study will be requested to provide a mandatory whole blood 
samples (approximately 20 mL each), collected at study treatment baseline (Pre-dose) and at 
specific time points during treatment (Table 7.6).  The plasma will be used to measure 
cytokines levels (and/or other circulating markers) to correlate with antitumor activity of 
spartalizumab. The changes of cytokines (or other markers) related to immune response will 

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be assessed to explore spartalizumab activity (e.g. assessing interferon gamma response 
cytokines).
Approximately 20 mL of peripheral blood samples will be collected prior to initiation of study 
therapy, on day 1 of the first 3 cycles. The peripheral blood mononuclear cells will be isolated 
from these samples and stored in -80°C freezers until analysis. Samples will be evaluated for:
i.
Determine whether there is an increase in expression of T-cell co-stimulatory markers 
in PBMCs after treatment. Samples will be collected at baseline and every other week for the 
first 9 weeks. Analysis will include proportion of T, B, NK, memory and effector T cell subsets 
and expression of PD-1, PD-L1 and B7 family members.
ii.
Determine whether changes in ex vivo functional assays for PBMCs post treatment 
correlate with response. Samples will be collected at baseline and on weeks 6 and 9. This will 
be performed using interferon- gamma and CD107.
8.1.1.3
Biomarker Germline DNA analysis
A mandatory blood sample will be obtained from all patients participating in the study. One 
whole blood (6mL) sample will be collected at any time during screening. The 6mL sample 
will be used for germline DNA analysis.  The germline DNA will be used to compare with 
genetic sequences found in tumor DNA of the same patients that differ from reference genes 
sequences; the goal is to determine if any difference of tumor DNA, from reference gene 
sequences is of somatic or germline origin. In addition eventual polymorphism of PD1, PD-L1 
and PD-L2 may be assessed in germline DNA.

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8.1.2
Screening
A patient who has a laboratory test result(s) that does not satisfy the entrance criteria may have 
the test(s) repeated. These test(s) may be repeated as soon as the investigator believes the re-
test result(s) is/are likely to be within the acceptable range to satisfy the entrance criteria, but 
should be completed within approximately 3 weeks of the original screening visit date. In this 
case, the subject will not be required to sign another ICF, and the original patient ID number 
assigned by the investigator will be used. In the event that the laboratory test(s) cannot be 
performed within 3 weeks of the original screening visit, or the re-test(s) do not meet the 
entrance criteria, or other eligibility criteria have changed and are not met anymore, the patient 
is considered a screen failure, and must be discontinued from the study.
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed, however, the patient ID number will remain the same.  All required 
screening activities must be performed when the patient is re-screened for participation in the 
study. An individual patient may only be re-screened once for the study. Once the number of 
patients screened and enrolled is likely to ensure target enrollment, the Sponsor may close the 
study to further screening.  In this case, the patients who screen failed will not be permitted to 
re-screen.
All subjects must sign an informed consent document prior to the initiation of any study related 
procedures. The informed consent document must be signed within 28 days of Cycle 1 Day 1. 
Screening procedures (with the exception of the scans) are to be conducted within 28 days of 
Cycle 1 Day 1.

Review of study eligibility criteria

Medical History

Record concomitant medications taken up to 28 days prior to day 1 cycle 1

Vitals [temperature, heart rate (HR), blood pressure (BP) and respiratory rate (RR)]

Physical Examination, including height and weight

ECOG Performance Status evaluation (within 10 days or less of cycle 1 day 1)

Laboratory Assessments
o
Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential and platelet count
o
Serum chemistry: sodium, potassium, chloride, bicarbonate, magnesium, 
calcium, phosphorus, blood urea nitrogen, creatinine, total bilirubin, LDH, 
total protein, ALP, ALT, AST, uric acid and albumin. Fasting glucose.
o
Serum or urine pregnancy test for women of childbearing potential
o
Prothrombin time (PT) and activated partial thromboplastin time (aPTT)
o
Urinalysis
o
Tumor markers(when applicable such as known elevated tumor markers): 
CA19-9 

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o
T3, FT4, TSH
o
HBV-DNA, Hepatitis B surface antigen (HBsAg), Hepatitis B core 
antibody (HBcAb), Hepatitis B surface antibody (HBsAb), HCV RNA- 
PCR
o
HIV, if clinically indicated

12-lead ECG

Radiologic imaging studies to evaluate tumor status. contrast computed 
tomography (CT) or magnetic resonance imaging (MRI) of the chest and abdomen 
and pelvis. Additional imaging may be obtained as clinically indicated. Baseline 
scans may be done within 8 weeks prior to cycle 1 day 1.

Baseline fresh biopsy (in selected group) will be obtained with 28 days of day1 
cycle 1 and after consent is signed.
8.1.2.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered in 
the patient’s electronic research records. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). 
8.1.2.2
Patient demographics and other baseline characteristics
Baseline demographic data will be collected on all patients include: gender, race, and age. Past 
medical history, concomitant medications, family history and prior treatments for pancreatic 
cancer will be collected at baseline. 
8.1.3
Treatment period
Day 1 (+3 days) of each cycle

Record concomitant medications

Vitals (temperature, HR, BP and RR) 

History and physical exam

ECOG performance status

Toxicity assessment

Laboratory Assessments 
o
Hematology hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential and platelet count

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o
Chemistry sodium, potassium, chloride, bicarbonate, magnesium, calcium, 
phosphorus, blood urea nitrogen, creatinine, glucose (random), total 
bilirubin, LDH, total protein, ALP, ALT, AST,  and albumin 
o
Tumor markers - when applicable
o
T3, FT4, TSH cycle 2 and then after every 3 cycle
o
Uric acid every other cycle
o
For the cycle1 day 1 labs, blood samples from the screening tests maybe 
used if completed within 1 week of day 1

Blood sample 20 cc for correlative work (only cycle  1, 2, 3)

Spartalizumab and siltuximab will be administered as IV infusion every 3 weeks.  
Given the variability of infusion pumps, a window of -5 minutes and +10 minutes 
is permitted.

In selected case in patients receiving paired biopsies siltuximab maybe held in 
cycle 1
 Days 8 and 15 (+1 day) in cycle 1 and 2 ONLY

Record concomitant medications

Vitals (temperature, HR, BP and RR) 

History and physical exam

ECOG performance status

Toxicity assessment

Blood sample 20 cc for correlative work (only cycle1)

Laboratory Assessments 
o
Chemistry sodium, potassium, chloride, bicarbonate, magnesium, calcium, 
phosphorus, blood urea nitrogen, creatinine, glucose (random), total 
bilirubin, LDH, total protein, ALP, ALT, AST,  and albumin 
Between days 14-21 cycle 1

Repeat biopsy in selected cases.
Every Month

Pregnancy test for women of child bearing potential 

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Every 3 cycles between day 15 and 21

Repeat cross sectional imaging (CT or MRI)
End of treatment visit

Vitals (temperature, HR, BP and RR) 

History and physical exam

ECOG performance status

Toxicity assessment

Laboratory Assessments 
o
Hematology hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential and platelet count
o
Chemistry sodium, potassium, chloride, bicarbonate, magnesium, calcium, 
phosphorus, blood urea nitrogen, creatinine, glucose (random), total 
bilirubin, LDH, total protein, ALP, ALT, AST,  and albumin 
o
Tumor markers - when applicable
o
T3, FT4, TSH cycle 2 and then after every 3 cycle
o
Blood sample 20 cc for correlative work
8.1.3.1
Second Course Phase (Retreatment Period)
Subjects who stop siltuximab and spartalizumab with SD or better may be eligible for up to 
one year of additional siltuximab and spartalizumab therapy if they progress after stopping 
study treatment.  This retreatment is termed the Second Course Phase of this study and is only 
available if the study remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with siltuximab and spartalizumab after attaining an 
investigator-determined confirmed CR according to RECIST 1.1, and

Was treated for at least 24 weeks with siltuximab and spartalizumab before 
discontinuing therapy

Received at least two treatments with siltuximab and spartalizumab beyond 
the date when the initial CR was declared
OR
o
Had SD, PR or CR and stopped siltuximab and spartalizumab treatment after 24 
months of study therapy for reasons other than disease progression or intolerability

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AND

Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with siltuximab and spartalizumab

Did not receive any anti-cancer treatment since the last dose of siltuximab and 
spartalizumab

Has a performance status of 0 or 1 on the ECOG Performance Scale

Patients should not be restarted on the study treatments if urgent treatment of the 
tumor(s) is needed to avoid risk to organ function or physical function (e.g. visceral 
crisis or spinal cord compression).

Meet all the eligibility criteria as detailed in Section 6.1
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received siltuximab and spartalizumab.  Treatment will be administered for up to one 
additional year.
Visit requirements are outlined in Section 7.0 – Trial Flow Chart.
9.0
SAFETY MONITORING AND REPORTING-NOVARTIS 
9.1
Adverse events
9.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. Abnormal laboratory values or test results occurring after informed consent 
constitute adverse events only if they induce clinical signs or symptoms, are considered 
clinically significant, require therapy (e.g., hematologic abnormality that requires transfusion 
or hematological stem cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least: 

150 days following the last dose of spartalizumab (or all patients in a double blind study) 
OR

until the start of a new post treatment antineoplastic medication if sooner than the 150 
days mentioned above.  If a patient starts a post treatment antineoplastic therapy, then 

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only adverse events suspected to be related to study treatment should be collected out 
to 150 days after discontinuation of spartalizumab. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event.
Adverse events will be assessed and graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version
Grade 1 to 5 will be used to characterize the severity of the Adverse Event.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will 
be used. Information about any deaths (related to an Adverse Event or not) will also be 
collected through a Death form (or EOT/SEC/Survival Information in NOVDD).
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(patient) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(patient) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1. The severity grade (CTCAE Grade 1-5)
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
or
Its relationship to the study treatment (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 9.2 and 
which seriousness criteria have been met (include for NCDS trials)
Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 

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to a lower grade is determined a new entry for this event should be reported in the CRF noting 
the start date when the event improved from having been Grade 3 or Grade 4.  
For phase I studies any AE that constitutes a DLT should be reported like a grade 3 and 4 
adverse event. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a 
serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
9.1.2
Laboratory test abnormalities
9.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required 
by the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
9.1.3
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 

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appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the latest Investigator Brochure for spartalizumab are: 

Endocrinopathies (Hypothyroidism, hyperthyroidism, diabetes, hypophysitis and 
hypopituitarism, adrenal insufficiency)

Pneumonitis

Colitis 

Hepatitis

Nephritis

Encephalitis

Rash

Other immune-mediated events

Infusion reactions
9.2
Serious adverse events
9.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given 
above is not a serious adverse event

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9.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent must be reported to Novartis within 24 hours of learning 
of its occurrence and until:

at least 150 days following the last dose of spartalizumab (or all patients in a double 
blind study) OR

the start of a new post treatment antineoplastic medication if sooner than the 150 days 
mentioned above.
If a patient starts a post treatment antineoplastic therapy, then only SAEs suspected to be 
related to study treatment should be collected out to 150 days after discontinuation of 
spartalizumab. SAEs suspected to be related to spartalizumab will continue to be collected 
beyond the 150-Day safety visit.
Any additional information for the SAE including complications, progression of the initial 
SAE, and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one should 
be reported separately as a new event.
Any SAEs experienced after the reporting period described above should only be reported to 
Novartis if the investigator suspects a causal relationship to the study treatment.  
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis.  Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site
Follow-up information is submitted in the same way as the original SAE Report.  Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported 
by Dr Alese as sponsor to the FDA and to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
9.3
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 

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the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office, and Patient Safety (CMO&PS).   
 Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the investigational study treatment any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form.
The newborn will be followed up at birth only. Further advice on the length of post-natal follow 
up will be sought from Novartis Pediatric Advisory Group.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
9.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
10.0 SAFETY MONITORING AND REPORTING-EUSA PHARMA
10.1 Overview
As the sponsor of the Study, the SPONSOR INVESTIGATOR (SI) shall be solely responsible 
for complying, within the required timelines, any safety reporting obligation to competent 
Health Authorities, IRB/ECs and any participating (co or sub) investigators, as defined in 
applicable laws and regulations.  For the purposes of this section, safety data includes adverse 
events, product quality complaints (PQCs), and special situations including pregnancies.
The SI will provide safety information to EUSA Pharmacovigilance on adverse events, special 
situations including pregnancies and product quality complaints as defined within this section.
10.2 Management of Safety Data
This Study has been designated as an interventional study.  As such, all adverse events 
regardless of causality and special situations excluding those from subjects not exposed to a 
EUSA Pharma Medicinal Product and product quality complaints with or without an adverse 
event as described in this section will be reported from the time a subject has signed and dated 
an Informed Consent Form (ICF) until completion of the subject’s last study-related procedure 
(which may include contact for follow-up safety).  Serious adverse events will be reported for 
30 days after the last dose of study drug.

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For the purposes of this study, the EUSA Pharma medicinal product is: SILTUXIMAB™ 
(Siltuximab) 
10.3 Definitions
10.3.1 Adverse Event (AE)
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 [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
10.3.2 Adverse Events of Special Interest 
Adverse events of special interest are events that EUSA Pharmacovigilance is actively 
monitoring as a result of a previously identified signal (even if non-serious). These adverse 
events are:  

All-Grade Infections and Infestations

Hepatotoxicity 

Gastrointestinal Perforations

Hemoglobin Increases above the ULN

QT Interval Prolongation
Any Adverse Event of Special Interest that is to be reported to EUSA medicinal product 
should be recorded on a Serious Adverse Event Report Form and be reported to EUSA 
Pharmacovigilance within 24 hours of knowledge of the event.
10.4 Individual Case Safety Report (ICSR)
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements.
Instructions (Remove Instruction Box prior to finalization)
Include this text where applicable, to clarify for which Janssen medicinal product(s) adverse even
reporting is solicited
Instructions (Remove Instruction Box prior to finalization)
Include this text where applicable, to clarify for which Janssen medicinal product(s) adverse even
reporting is solicited

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
an identifiable subject (but not disclosing personal information such 
as the subject’s name, initials or address)

an identifiable reporter (investigational site)

a EUSA Pharma medicinal product

an adverse event, outcome, or certain special situations

The minimum information required is:

suspected EUSA medicinal product (doses, indication)

date of therapy (start and end date, if available)

batch or lot number, if available

subject details (subject ID and country)

gender

age at AE onset

reporter ID

adverse event detail (AE verbatim in English), onset date, relatedness, 
causality, action taken, outcome, (if available)

protocol ID
10.5 Product Quality Complaint (PQC)
A product quality compliant is defined as any suspicion of a product defect related to a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product, or delivery system.  Not all PQCs involve a 
subject.  Lot and batch numbers are of high significance and need to be collected whenever 
available.
Examples of PQC include but not limited to:

Functional Problem: e.g., altered delivery rate in a controlled release product

Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules

Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, 
needle detaching from syringe

Suspected Contamination

Suspected Counterfeit
10.6 Serious Adverse Event (SAE)
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

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
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

Is a congenital anomaly/birth defect

Is medically important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is also appropriate in other situations, such as important medical events that 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 other outcomes listed in the definition above. 
These should usually be considered serious.
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS 
ADVERSE EVENT.
10.6.1 Hospitalization
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. Any event requiring 
hospitalization or prolongation of hospitalization that occurs during the study must be reported 
as a serious adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (e.g., 
social reasons such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study. [Note: 
Hospitalizations that were planned before the start of data collection and where 
the underlying condition for which the hospitalization was planned has not 
worsened will not be considered serious adverse events. Any adverse event that 
results in a prolongation of the originally planned hospitalization is to be 
reported as a new serious adverse event.]
 
10.6.2 Life-Threatening Conditions
The cause of death of a subject in a study within 30 days of the last dose of study drug, whether 
or not the event is expected or associated with the study drug, is considered a serious adverse 
event.

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10.7 Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For a medicinal product(s) with a marketing 
authorization, the expectedness of an adverse event will be determined by whether or not it is 
listed in the applicable product information. 
http://www.siltuximab.com/shared/product/siltuximab/siltuximab-prescribing-
information.pdf
10.8 Special Reporting Situations 
Safety events of interest for a medicinal product that require expediting reporting and/or safety 
evaluation include, but are not limited to:

Drug exposure during pregnancy (maternal and paternal)

Overdose of a EUSA medicinal product 

Exposure to a EUSA medicinal product from breastfeeding 

Suspected abuse/misuse of a EUSA medicinal product

Inadvertent or accidental exposure to a EUSA medicinal product 

Any failure of expected pharmacological action (i.e., lack of effect) of 
an EUSA medicinal product

Medication error involving a EUSA medicinal product (with or 
without patient exposure to the EUSA medicinal product, e.g., name 
confusion)

Suspected transmission of any infectious agent via administration of a 
medicinal product

Unexpected therapeutic or clinical benefit from use of a EUSA 
medicinal product
These safety events may not meet the definition of an adverse event; however, from a EUSA 
Pharmacovigilance perspective, they are treated in the same manner as adverse events. Special 
situations should be recorded on the Adverse Event page of the CRF.
Any special situation that meets the criteria of a serious adverse event should be recorded on a 
Serious Adverse Event Report Form and be reported to EUSA Pharmacovigilance within 24 
hours of becoming aware of the event.
10.9 Pregnancy 
All initial reports of pregnancy must be reported to EUSA Pharmacovigilance by the SI within 
24 hours of their knowledge of the event using the Serious Adverse Event Form. Abnormal 
pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomaly, 
ectopic pregnancy) are considered serious adverse events and must be reported using the 
Serious Adverse Event Form. 

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If a subject becomes pregnant during the study, a determination regarding study drug 
discontinuation must be made by the investigator in consultation with the reference safety 
information. 
Because the effect of the EUSA medicinal product on sperm is unknown, pregnancies in 
partners of male subjects exposed to a EUSA medicinal product will be reported by the SI  
within 24 hours of their knowledge of the event using the Serious Adverse Event Form.  
Depending on local legislation this may require prior consent of the partner.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required.
10.10 Maintenance of Safety Information
All safety data should be maintained in a clinical database in a retrievable format. The 
PRINCIPAL INVESTIGATOR shall provide all adverse events, both serious and non-serious, 
in report format. However, in certain circumstances more frequent provision of safety data may 
be necessary, e.g. to fulfill a regulatory request, and as such the data shall be made available 
within a reasonable timeframe at EUSA Pharmacovigilance request.
10.11 Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
EUSA Medicinal Products to EUSA Pharmacovigilance
All adverse events and special situations, whether serious or non-serious, related or not related, 
following exposure to a EUSA medicinal product are to be documented by the investigator and 
recorded in the CRF and in the subject’s source records. Investigators must record in the CRF 
their opinion concerning the relationship of the adverse event to a EUSA medicinal product. 
All (serious and non-serious) adverse events reported for a EUSA medicinal product should be 
followed-up in accordance with clinical practice.
10.12 SAEs and Special Reporting Situations
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, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct

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
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 SI will transmit all SAEs and special situations following exposure to a EUSA Pharma 
product under study in a form provided by EUSA Pharmacovigilance in accordance with 
Section 10.16, Transmission Methods, in English within 24-hours of becoming aware of the 
event(s).
In the event the study is blinded, the SI will submit an unblinded SAE or pregnancy exposure 
report to EUSA Pharmacovigilance.
All follow-up information for serious adverse events that are not resolved at the end of the 
study or by the time of patient withdrawal must be reported directly by the SPONSOR 
INVESTIGATOR (SI), within 24 hours becoming aware, to EUSA Pharmacovigilance. 
using EUSA’s Serious Adverse Event Report 
All available clinical information relevant to the evaluation of a related SAE, serious ADR or 
special situation is required.

The SI is responsible for ensuring that these cases are complete and if not are 
promptly followed-up. A safety report is not considered complete until all clinical 
details needed to interpret the case are received. Reporting of follow-up information 
should follow the same timeline as initial reports.

Copies of any and all relevant correspondences with regulatory authorities and 
ethics committees regarding any and all serious adverse events, irrespective of 
association with the EUSA Product under study, are to be provided to EUSA 
Pharmacovigilance using a transmission method in Section 10.16 within 24 hours 
of such report or correspondence being sent to applicable health authorities.
10.13 Non-Serious AEs
All non-serious adverse events where causality cannot be excluded should be reported to 
EUSA Pharmacovigilance within 10 days of becoming aware.
10.14 Product Quality Complaint Reporting
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the protection 
of patients, investigators, and EUSA Pharmacovigilance, and are mandated by regulatory 
agencies worldwide. EUSA Pharmacovigilance has established procedures in conformity with 

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regulatory requirements worldwide to ensure appropriate reporting of PQC information. Lot 
and/or Batch #s shall be collected or any reports failure of expected pharmacological action 
(i.e., lack of effect). The product should be quarantined immediately and if possible, take a 
picture.
All initial PQCs involving a EUSA medicinal product under study must be reported to EUSA 
Pharmacovigilance by the SI  within 24 hours after being made aware of the event. The 
EUSA contact will provide additional information/form to be completed.
If the defect for a EUSA medicinal product under study is combined with either a serious 
adverse event or non-serious adverse event, the SI  must report the PQC to EUSA 
Pharmacovigilance according to the serious adverse event reporting timelines.  A sample of 
the suspected product should be maintained for further investigation if requested by EUSA 
Pharmacovigilance.
10.15 Reporting Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Non-EUSA Medicinal Products 
For SAEs, special reporting situations and PQCs following exposure to a non-EUSA medicinal 
product under study, the SI should notify the appropriate regulatory/competent authority or the 
manufacturer of that medicinal product (in the absence of appropriate local legislation) as soon 
as possible.
10.16 Transmission Methods
The following methods are acceptable for transmission of safety information to EUSA 
Pharmacovigilance:

Electronically via Email service (preferred)
 safety@eusapharma.com

For business continuity purposes, if SECURE Email is non-functional:
o
Facsimile (fax), receipt of which is evidenced in a successful fax 
transmission report on Fax +44 (0) 33 0500 1167

Telephone (if fax is non-functional) +1 888 255 9029.
Please use the contact information and process information provided by EUSA 
Pharmacovigilance.
11.0 DATA MONITORING COMMITTEE 
 The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study.  The DSMC functions independently within 
Winship Cancer Institute to conduct internal monitoring functions to ensure that research being 

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conducted by Winship Cancer Institute Investigators produces high-quality scientific data in a 
manner consistent with good clinical practice (GCP) and appropriate regulations that govern 
clinical research.    Depending on the risk level of the protocol, the DSMC review may occur 
every 6 months or annually.  For studies deemed High Risk, initial study monitoring will occur 
within 6 months from the date of the first subject accrued, with 2 of the first 5 subjects being 
reviewed.  For studies deemed Moderate Risk, initial study monitoring will occur within 1 year 
from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed.  
Subsequent monitoring will occur in routine intervals per the Winship Data and Safety 
Monitoring Plan (DSMP). 
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute 
Internal Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, 
accuracy and availability of source documents, AEs/SAEs, and essential regulatory documents.  
Following the monitoring review, monitors will provide a preliminary report of monitoring 
findings to the PI and other pertinent individuals involved in the conduct of the study.  The PI 
is required to address and respond to all the deficiencies noted in the preliminary report.  Prior 
to the completion of the final summary report, monitors will discuss the preliminary report 
responses with the PI and other team members (when appropriate).  A final monitoring 
summary report will then be prepared by the monitor.  Final DSMC review will include the 
final monitoring summary report with corresponding PI response, submitted CAPA (when 
applicable), PI Summary statement, and available aggregate toxicity and safety data.  
The DSMC will render a recommendation and rating based on the overall trial conduct.  The 
PI is responsible for ensuring that instances of egregious data insufficiencies are reported to 
the IRB.  Continuing Review submissions will include the DSMC recommendation letter.  
Should any revisions be made to the protocol-specific monitoring plan after initial DSMC 
approval, the PI will be responsible for notifying the DSMC of such changes.  The Committee 
reserves the right to conduct additional audits if necessary. 
Dose escalation decisions will be done at the GI working group. The PI or designee must obtain 
approval from the DSMC for dose escalation. The PI will provide an update on all relevant 
safety data of patients entered to a dose level to the DSMC when dose escalation is planned. 
Dr. Alese and the investigators, the clinical research coordinator and the regulatory affairs 
coordinator will meet to review and discuss study data to ensure subject safety. During the 
meetings the PI or co-I will review the eligibility criteria for each new patient. In addition, 
during these meeting the group will review all the toxicity (AE/SAE) logs, random checks of 
case report form completion and roadmap for each patient on the trial. All study personnel will 
be trained on the protocol by the PI or co-I. Study personnel will sign training log prior to being 
included on delegation of authority log. All AE and SAE will be handled according to Section 
7.2 which provides detailed instructions on reporting requirements.
Written IND safety reports will be submitted to the FDA by the IND sponsor, for serious, 
unexpected suspected adverse reactions within 15 calendar days of learning of its occurrence. 
If the event is fatal or is deemed to be life threatening, the report will be made within 7 calendar 

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days.  The IND sponsor will also make an assessment of whether the event constitutes an 
unanticipated problem posing risks to subjects or others (UP). This assessment will be provided 
to the Emory University IRB, copied to EUSA Pharmacovigilance.  The Emory University 
IRB will make a final determination.  If the Emory IRB determines an event is a UP it will 
notify the appropriate regulatory agencies and institutional officials.
12.0STATISTICAL ANALYSIS PLAN
12.1
Determination of Sample Size
 This is a 3+3 standard phase I trial design. The plan is to evaluate two dose cohorts- 6 mg/Kg 
and 11 mg/Kg of siltuximab. An intermediate dose cohort (9 mg/Kg) will be evaluated only if 
we observe 2 or more DLT’s in the 3 or 6 patients enrolled on the 11 mg/kg dose. If we observe 
2 dose limiting toxicities on dose level 1, then the study will be completed with three patients 
(minimal number of patients).  If we observe two DLT in the first three patients on dose level 
1, the study will stop and the principal investigator will discuss at that point whether a lower 
dose level of siltuximab should be tested. If we do not observe any dose limiting toxicities the 
study will require 9 patients. If we observe one dose limiting toxicity per dose level (maximum 
number of patient), then the study would require 18 patients.  Therefore the phase part sample 
size can range from 3 to 18 patients. 
Expansion phase will be started once the recommended phase II dose (RP2D) is determined. 
Given minimal activity of checkpoint inhibitors in pancreatic cancer (Response rate less than 
5%) , an overall response rate of the combination of PD-1 plus IL-6 inhibitor of 20% would be 
considered clinically significant. With an alpha of 0.1, and power of 90% a total of 24 patients 
should be sufficient to make this determination. We will also obtain biologic endpoints with 
the paired biopsy samples that can help further develop the combination and understand its 
role in pancreatic cancers. We plan to enroll 24 patients on the RP2D level. Patients in the 
expansion phase will be assigned to treatment arms by PI (spartalizumab or spartalizumab plus 
siltuximab). After the first 3 weeks all patients will receive the combination therapy. There is 
no planned comparison between the two arms. The aim of the expansion phase is to confirm 
the safety profile and tolerability of the regimen in patients with pancreatic cancer.
Early stopping for safety:  If we observe more than 3 dose limiting toxicities as defined in 
Section 6.3.2 and Table 7 (excluding death since a single death will fulfil the stopping rule) 
during the first 8 weeks of treatment in the first 12 patients in the expansion cohort, study 
enrollment be halted pending a safety review by the safety monitoring committee for a single 
death. Consideration for lower dose regimen will be discussed with DSMC and sponsors. If 
the plan is to test additional dose levels, the protocol and informed consent will be amended 
and re-submitted for review by the IRB. 
The total number of patients who will undergo treatment will range from 27 to 42 patients. In 
order to have 42 patients undergo treatment, we plan to enroll up to 70 patients to account for 
screen failures.  

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12.2
Statistical and Analytical Plans
Summary statistics will be presented for all safety, efficacy and biomarker parameter analyses. 
The purpose of these analyses is hypothesis generating and therefore, formal statistical testing 
will not be performed. Various exploratory statistical tests may be applied to data generated 
from this trial to generate hypotheses to be tested in subsequent trials. In general, data for 
continuous parameters will be presented using descriptive statistics including sample size, 
mean, and median; standard deviation; and minimum and maximum. Categorical parameters 
(such as pathologic response rate) will be displayed using counts and percentages. Toxicities 
will be presented as worst toxicity per patient and will be reported as percent toxicity. 
12.3
Analysis Sets
All subjects who receive any amount of study drug will be included in the evaluation of safety 
and efficacy, except for patients who take less than 80% of their prescribed dose of siltuximab 
and spartalizumab since they will be considered in-evaluable for the primary endpoint of 
toxicity. 
12.4
Subject Disposition and Baseline Characteristics
The number and percentage of subjects who enrolled, were treated, and who discontinued will 
be tabulated. The reasons for treatment and study discontinuation will be presented. 
Demographic and other baseline characteristics will be summarized using descriptive statistics 
or counts and percentages, as appropriate.
12.5
Safety Analysis
12.5.1.1
Adverse Events 
Adverse events will be classified using MedDRA System Organ Classes and Preferred Terms. 
Furthermore, SAEs, AEs with a severity grade of 3 or above using NCI CTCAE version 4.0, 
AEs deemed related to study drug, AEs leading to discontinuation of study drug, and AEs 
leading to death will also be summarized in preferred term by system organ class and listed on 
an individual subject basis. 
12.5.1.2
Laboratory Data
Descriptive statistics for worst grade of each laboratory parameter by the NCI CTCAE scale 
version4.0 at baseline and follow-up will be presented along with change from Baseline. 
Additionally, laboratory values ≥ Grade 3 severity will be tabulated and listed on an individual 
subject basis.
12.5.1.3
Dose Modifications and Reasons
The number of subjects with skipped doses, dose delays and dose reductions as well as major 
reasons for dose modifications will be summarized.

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13.0 ADMINISTRATIVE AND REGULATORY DETAILS
13.1 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.    
13.2
Prestudy Documentation
The Sponsor-Investigator must provide EUSA Pharma, and Novartis with the following 
documents prior to the enrollment of any subjects:

Copy of the IRB/IEC approval letter for protocol, informed consent, Investigator and 
site

Signed and dated current curricula vitae of the investigator

Copy of approved informed consent document

Copy of the FDA letter and IND receipt and number assignment

Signed Clinical Trial Agreement
13.3
Protocol Adherence
By signing the Form FDA 1572, the Investigator agrees to conduct the study according to the 
protocol and the FDA regulations set forth in 21 CFR Parts 50, 54, 56, and 312.
13.4
Retention of Study Documents
All documentation of adverse events, records of study drug receipt and dispensation, and all 
IRB correspondence will be maintained for at least 2 years after the investigation is completed.

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14.0 APPENDICES
14.1 ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair.

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14.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)

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14.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors
Efficacy assessments
Tumor response is the primary efficacy endpoint. Please refer to RECIST 1.1 criteria.

Radiologic assessment will be performed at baseline and until disease progression or 
withdrawal of consent as defined in section 8.1.2 and study calendar (section 7).

Patients who discontinue study treatment for reasons other than disease progression as 
per RECIST 1.1 should continue tumor assessment until disease progression as per 
RECIST 1.1.

Each lesion that is measured at baseline must be measured by the same method (either 
same radiologic/nuclear method or by physical exam) throughout the study so that the 
comparison is consistent. The same is true for any new lesions that occur after start of 
treatment.  They should be imaged using the same modality at each subsequent time 
point.  Criteria required for determining partial or complete response should be present 
for at least 4 weeks. 
 If treatment beyond initial disease progression as per RECIST 1.1 criteria (or other 
criteria) is planned, patients should continue to have imaging every 9 weeks after 
continuation of study treatment beyond PD. Patients who develop progressive disease 
after cessation of study treatments should not be restarted on the study treatments if 
urgent treatment of the tumor(s) is needed to avoid risk to organ function or physical 
function (e.g. visceral crisis or spinal cord compression).

Local imaging radiology evaluations will be used for endpoints determination.

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Table 7-2
Imaging Assessment Collection Plan.  
Procedure
Screening/Baseline
During Treatment/Follow-up
Chest, abdomen and pelvis CT or 
MRI(with 
intravenous 
contrast 
enhancement) 
Mandated
Mandated, every 3 cycles between 
day 15 and 21
 
Brain CT or MRI
If clinically indicated
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis
Whole body bone scan
If clinically indicated
If clinically indicated
Localized bone CT, MRI or x-ray
For any lesions identified on the whole 
body bone scan that are not visible on the 
chest, abdomen and pelvis CT or MRI
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis
CT or MRI of other metastatic sites 
(e.g., neck)
If clinically indicated
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis
Baseline imaging assessments
Imaging assessments will be performed at screening/baseline within 8 weeks of start of 
treatment (prior to Cycle 1 Day 1).
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. The following assessments are required at 
screening/baseline:

Chest, abdomen and pelvis CT or MRI 

Brain CT or MRI, if clinically indicated

Whole body bone scan, if clinically indicated

Localized bone CT, MRI or x-ray, for any lesions identified on the whole body bone scan 
that are not visible on the chest, abdomen and pelvis CT or MRI

CT or MRI of other metastatic sites (e.g., neck), if clinically indicated
If a patient is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed.

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If brain metastases are suspected at baseline, brain MRI or CT must be completed. Contrast 
enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then MRI 
without contrast or CT with/without contrast is acceptable.
If clinically indicated, a whole body bone scan Fluorodeoxyglucose positron emission 
tomography (FDG-PET) will be performed. Localized CT, MRI or X-rays must be acquired 
for all skeletal lesions identified on the screening whole body bone scan, which are not visible 
on the chest, abdomen and pelvis CT/MRI.
If clinically indicated, CT or MRI of other areas (e.g., neck) of disease as appropriate should 
be performed.
Any potentially measurable lesion that has been previously treated with radiotherapy should 
be considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a 
measurable lesion.
Chest x-rays and ultrasound should not be used to measure tumor lesions.
Post-baseline imaging assessments
Imaging assessments as described in Table 7-2 should be performed at the time points specified 
using the same imaging modality used at baseline, irrespective of study treatment interruption 
or actual dosing (see Table 7-1).  Imaging assessments for response evaluation will be 
performed every 3 cycles between days 15 and 21  until disease progression per RECIST 1.1 ,  
death, lost to follow-up or withdrawal of consent. 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a patient, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment.
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same 
local radiologist/physician throughout the study so that the comparison is consistent. The same 
is true for any new lesions that occur after start of treatment.  They should be imaged using the 
same modality at each subsequent time point.  If an off-schedule imaging assessment is 
performed because progression is suspected, subsequent imaging assessments should be 
performed in accordance with the original imaging schedule.

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