Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
This study combines canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) monoclonal antibody (mAb), and spartalizumab (PDR001), a mAb directed against human Programmed Death-1 (PD-1), with the chemotherapy combination of gemcitabine and nab-paclitaxel. This study will confirm for this 4-drug combination the tolerable doses, the acceptable safety profile, and the dose to be used for a Phase II combination treatment regimen.

Detailed description:
This is an open-label multi-center phase Ib study to confirm the recommended phase II/III dose of canakinumab and spartalizumab in combination with nab-paclitaxel and gemcitabine.

The study will recruit patients with metastatic pancreatic adenocarcinoma treated in the first line setting. The starting dose level of canakinumab explored will be 250 mg Q4W ("starting dose level"). In case of unacceptable toxicity of the starting dose level of canakinumab, the dose of canakinumab will be de-escalated to the "-1 dose level" administered as 250 mg Q8W, while other components of the combination stay at the same dose as the starting dose level.

Patients will be observed for dose limiting toxicities (DLTs) for a minimum duration of 56 days (8 weeks). To achieve study objectives and to ensure the adequate number of DLT evaluable patients, the study will recruit approximately ten patients to have at least 6 evaluable patients per dose level of canakinumab. Additional approximately ten patients (to have at least 6 additional evaluable patients) may be enrolled at lower dose level in case a dose de-escalation is necessary.

Dose confirmation will be guided by an adaptive Bayesian logistic regression model (BLRM) based on any DLTs observed for two cycles of treatment (i.e. 56 days, or 8 weeks). The adaptive BLRM will be guided by the Escalation with Overdose Control (EWOC) principle to control the probability of DLT in future patients on the study. BLRM is a well-established and widely used method to estimate the recommended dose for expansion (RDE) or maximal tolerable dose (MTD) in clinical trials in patients with cancer with small sample size. The use of Bayesian response adaptive models for small datasets has been endorsed by academic publications (Babb et al. 1998, Neuenschwander et al. 2008, Neuenschwander et al. 2010, Natanegara et al. 2014), by the European Medicines Agency (Guideline on Clinical Trials in Small Populations, 2007) and it constitutes an important aspect of the FDA's Critical Path Initiative (Clinical Path White Paper, FDA, 2004). The Bayesian analysis incorporates prior toxicity data of single agent and drugs combinations together with the currently available data to predict the probability of DLT and excessive toxicity of a dose level of interest.

The Bayesian method is be based on a Meta-Analytical-Combined (MAC) approach (Spiegelhalter 2004, Neuenschwander 2016) to combine all historical and concurrent data. Prior toxicity information included in the BLRM model was obtained from three studies with canakinumab as a single agent and combination of canakinumab and spartalizumab (PDR001X2101, ACZ885I2202, PRD001X2103) and from a phase I/II study of nab-paclitaxel + gemcitabine (Von Hoff D, et.al., 2011). Simulation was used to illustrate the recommendation from BLRM under a set of hypothetical scenarios with assumed number of evaluable patients and DLTs.

The decisions on a recommended dose will be made by the Investigators and the Sponsor in a Safety Review meeting when at least 6 DLT evaluable patients per dose level will be observed for DLTs for a minimum duration of 56 days (8 weeks). Safety review will be based upon the review of all relevant data available including treatment tolerability and safety information together with the BLRM summaries of DLT probability, PK, PD, and preliminary activity information (if available) at the time of the meeting.

Patients will be treated until disease progression per RECIST 1.1, unacceptable toxicity, or until the patient or treating physician decides to stop treatment.

Pharmacokinetic (PK) and immunogenicity (IG) samples will be collected at specific time points throughout treatment. Each treatment cycle is 4 weeks. All patients must be followed for safety up to 150 days after the last dose of spartalizumab or canakinumab, or 30 days after the last dose of the combination chemotherapy, whichever the later. After the end of safety follow-up, patients will be followed for disease progression if discontinuation of treatment is due to reason other than progression, and for survival (via telephone call or onsite visit if a patient happens to be visiting the site) until the end of study The study completion is defined as when the last patient has completed the study treatment, safety follow up, and completed survival follow up period up to 1 year from first treatment, whichever is later or in the event of an early study termination decision, the date of that decision.

Arms:
arm 1: Spartalizumab (PDR001),IV infusion, 400 mg, D1 of each 28-day cycle; Canakinumab (ACZ885), s.c. injection, 250 mg, Day 1 of each 28- day cycle; Gemcitabine, IV Infusion, 1000 mg/m2, Days 1, 8, 15 of each 28-day cycle; Nab-paclitaxel, IV Infusion, 125 mg/m2, Days 1, 8, 15 of each 28-day cycle.

Interventions: intervention 1: Canakinumab injection; spartalizumab, nab-paclitaxel, gemcitabine
Intervention descriptions: intervention 1: Canakinumab 250 mg s.c. injection; Spartalizumab 400 mg IV infusion, nab-paclitaxel 125 mg/m2 IV infusion, gemcitabine 1000 mg/m2 IV infusion

Protocol document:
Prot_SAP_000.pdf: 
Phase 1b Safety Run-In Study  
 
Pancreatic Cancer Action Network 
Confidential and Proprietary 
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A PHASE 1B  STUDY TO DETERMINE THE SAFETY 
AND TOLERABILITY AND CONFIRM THE DOSE OF 
CANAKINUMAB AND SPARTALIZUMAB IN 
COMBINATION WITH NAB-PACLITAXEL AND 
GEMCITABINE FOR PATIENTS WITH METASTATIC 
PANCREATIC CANCER 
 
 
DESCRIPTION/CATEGORY: 
Phase 1b Safety Run-In Study 
DATE FINAL: 
22 July 2020 
IND NUMBER: 
 
PROTOCOL NUMBER: 
PanCAN-SR1 
PROTOCOL VERSION: 
1.2 
PRINCIPAL INVESTIGATORS:  
 
 
 
 
 
 
 
 
 
 
 
SPONSOR NAME/ADDRESS:  
Pancreatic Cancer Action Network 
 
1500 Rosecrans Avenue, Suite 200 
 
Manhattan Beach, CA 90266 
 
 
 
 
CONFIDENTIAL 
This protocol is provided to you as an Investigator, potential Investigator, or consultant for 
review by you, your staff, and ethics committee/institutional review board. The information 
contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless such disclosure is 
required by law or regulations. Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 


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GLOSSARY AND LIST OF ABBREVIATIONS 
 
AE  
 
Adverse Event 
ALK  
Anaplastic large cell lymphoma 
ALP 
 
Alkaline phosphatase 
ALT (SGPT) Alanine Aminotransferase 
ANC  
Absolute neutrophil count 
AST (SGOT) Aspartate aminotransferase 
β-hCG  
β-human chorionic gonadotropin 
BUN  
Blood urea nitrogen 
CANTOS 
the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study  
Ca 
 
Cancer; carcinoma 
Ca 
 
Calcium 
CAPS  
Cryopyrin Associated Periodic Syndromes 
CA 19-9 
Carbohydrate antigen 19-9 
CBC  
Complete blood count  
CLIA  
Clinical Laboratory Improvement Amendments 
CR 
 
Complete remission / complete response 
CRP 
 
C-reactive protein 
CRF/eCRF 
Case Report Form/electronic Case Report Forms 
CRF 
 
Chronic renal failure 
CRO   
Clinical Research Organization 
CT 
 
Computerized tomography (scan) 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte Antigen-4  
dL 
 
Deciliter 
DSMB  
Data and Safety Monitoring Board 
ECG  
12-lead electrocardiogram (ECG) 
ECOG  
Eastern Cooperative Oncology Group   
EDC  
Electronic Data Collection tool 
EDTA  
Lavender top tubes 


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FMF  
Familial Mediterranean Fever 
FDA   
Food and Drug Administration 
FFPE  
Formalin-fixed paraffin-embedded  
FSH 
 
Follicle-stimulating hormone 
FWA  
Federal-wide Assurance 
GA 
 
Gemcitabine + nab-paclitaxel 
mGPS  
modified Glasgow Prognostic Score 
GCP   
Good Clinical Practice 
g 
 
Gram (unit) 
Hgb 
 
Hemoglobin 
HIDS  
Hyperimmunoglobulin D Syndrome  
IgG1/κ  
Immunoglobulin G1/κ isotype subclass 
ICF  
 
Informed Consent Form 
ICH GCP  
International Conference on Harmonisation - Good Clinical Practice 
IL-1 
 
Interleukin-1 cytokine 
IL-1α  
Interleukin-1α cytokine 
IL-1β  
Interleukin-1β cytokine 
IL-1R  
Interleukin-1 Receptor 
IL-1Ra  
Interleukin-1 Receptor agonist 
IL-6 
 
Interleukin-6 cytokine  
IB  
 
Investigator Brochure 
IND   
Investigational New Drug 
IRB  
 
Institutional Review Board 
IV 
 
Intravenous 
LD 
 
Longest diameter 
LLN 
 
lower limit of normal 
mg 
 
milligram 
m2 
 
meter square 
mm 
 
millimeter 
MRI 
 
Magnetic Resonance Imaging 
MKD  
Mevalonate Kinase Deficiency 


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MMR-D 
Mismatch repair deficient state 
MDSCs 
Myeloid-derived suppressor cells 
NCI   
National Cancer Institute 
NGS  
Next-generation sequencing 
NIH   
National Institutes of Health 
ORR  
Overall Response Rate 
OS 
 
Overall Survival 
PanCAN 
Pancreatic Cancer Action Network 
PD 
 
Progressive disease 
PDAC  
Pancreatic adenocarcinoma 
PET 
 
Positron Emission Tomography 
PFS 
 
Progression free Survival 
PI  
 
Principal Investigator 
PK 
Pharmacokinetic 
PO 
 
Oral administration/by mouth 
PR 
 
Partial Response  
PD-1  
Programmed cell Death protein-1 
PD-L1  
Programmed cell Death ligand-1 
PD-L2  
Programmed cell Death ligand-2 
PT 
 
Prothrombin time 
PTT 
 
Partial thromboplastin time 
RBC  
Red blood cell / red blood count 
RECIST  
Response Evaluation Criteria in Solid Tumors 
SAE   
Serious adverse event 
SJIA  
Systemic Juvenile Idiopathic Arthritis 
SD 
 
Stable disease 
SOC 
 
Standard of Care 
SOP   
Standard operating procedures 
TLR 
 
Toll-like receptors 
TGFβ  
Transforming growth factor-β 
TRAPS 
Tumor Necrosis Factor Receptor Associated Periodic Syndrome  


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TAMs  
Tumor associated microphages 
TAN  
Tumor associated neutrophils 
ULN  
Upper limit of normal 
WBC  
White blood cell count 
WCC  
White cell count 
WOCBP 
Women of child-bearing potential


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TABLE OF CONTENTS 
1.0 
INTRODUCTION ............................................................................................................ 14 
1.1 
Background ...................................................................................................................... 14 
1.1.1 Prevalence and outcomes in pancreatic adenocarcinoma 
14 
1.1.2 Prognosis and staging ....................................................................................................... 14 
1.1.3 Current treatment landscape ............................................................................................. 14 
1.1.4 Challenges in pancreatic cancer drug development ........................................................... 15 
1.2 
Study overview................................................................................................................. 15 
1.3 
 Overview of IL-1β ........................................................................................................... 16 
1.3.1 IL-1β in cancer ................................................................................................................. 17 
1.3.2 IL-1β in pancreatic cancer ................................................................................................ 18 
1.3.3 Anti-IL-1β therapy effect on cancer in CANTOS.............................................................. 19 
1.3.4 Immunotherapy in pancreatic cancer................................................................................. 19 
1.3.5 Inflammation in pancreatic cancer and rationale to combine with a IL-1β inhibitor ........... 21 
1.4 
Overview of canakinumab ................................................................................................ 21 
1.4.1 Non-clinical experience with canakinumab ....................................................................... 22 
1.4.2 Clinical experience with canakinumab in cancer ............................................................... 22 
1.5 
Overview of spartalizumab ............................................................................................... 23 
1.5.1 Non-clinical experience with spartalizumab ...................................................................... 24 
1.5.2 Clinical experience with spartalizumab ............................................................................. 24 
1.6 
Rationale for the dosing regimen of canakinumab............................................................. 26 
1.7 
Rationale for the Study Regimen ...................................................................................... 28 
2.0 
OBJECTIVES AND ENDPOINTS................................................................................... 29 
2.1 
Overview .......................................................................................................................... 29 
2.2 Study Design ....................................................................................................................... 31 
3.0 
STUDY POPULATION ................................................................................................... 32 
3.1  Study Duration ................................................................................................................. 32 
3.2 
Inclusion Criteria .............................................................................................................. 33 
3.3 
Exclusion Criteria ............................................................................................................. 34 
4.0 
STUDY TREATMENT AND DOSE MODIFICATION .................................................. 38 
4.1 
Administration and Dosing ............................................................................................... 38 
4.1.1 Gemcitabine and nab-paclitaxel ........................................................................................ 39 
4.1.2 Canakinumab ................................................................................................................... 39 
4.1.3 Spartalizumab................................................................................................................... 40 
4.1.4 Initial Dosing Schedule 
40 


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4.1.5 Dose Recommendation Guideline for Study Cohort 
41 
4.1.5.1 Definitions of Dose Limiting Toxicities (DLTs) 
42 
4.2 Dose Modifications 
44 
4.2.1 Dose Modifications of Gemcitabine and Nab-Paclitaxel 
44 
4.2.2 Dose modification and dose interruption of spartalizumab and canakinumab 
47 
4.2.3 Dose Modification Guidelines for Canakinumab 
48 
4.2.4 Dose modification and Dose Interruption for spartalizumab 
51 
4.2.4.1 General dose modification instructions for spartalizumab 
52 
4.2.5 Dose modification and Management Requirements for Potential Immune-Mediated 
Adverse Events (irAEs) 
52 
4.2.5.1 Guidance for Corticosteroids Tapering for Management of Immune-Related AEs 
65 
4.2.6 Permanent discontinuation of spartalizumab 
65 
4.3 Follow-up for toxicities 
66 
4.3.1 Follow-up of Immune-Related AEs 
66 
4.3.2 Follow-up of Potential Drug-Induced Liver Injury (DILI) Cases 
66 
4.3.3 Follow-up for Infections 
68 
4.4 
Concomitant Medications ................................................................................................. 68 
4.4.1 Permitted Concomitant Therapy 
69 
4.4.2 Permitted concomitant therapy requiring caution and/or action 
70 
4.4.3 Prohibited concomitant therapy 
71 
4.4.3.1 Prohibited concomitant therapy for spartalizumab 
72 
4.4.3.2 Prohibited concomitant therapy for canakinumab 
72 
4.5 
Overdose .......................................................................................................................... 73 
4.6 
Investigational Product Accountability and Disposal ........................................................ 73 
4.7 
Investigational Product Compliance ................................................................................. 73 
5.0 
STUDY ASSESSMENTS ................................................................................................ 74 
5.1 
Study Schedule ................................................................................................................. 75 
5.2 
Baseline Procedures ......................................................................................................... 79 
5.3 
Treatment Procedures ....................................................................................................... 81 
5.4 
Study Treatments.............................................................................................................. 83 
5.4.1 Study Treatment Beyond Disease Progression 
85 
5.4.2 Study Treatment Duration ................................................................................................ 85 
5.5 
End of Treatment Procedures ............................................................................................ 86 
5.6 
Pharmacokinetic (PK)
 Blood Draw Schedules.......................... 88 
5.7 
As Needed Assessments ................................................................................................... 90 


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5.8 
Safety Follow Up (30-day, 60-day, 90-day, 120-day and 150-day Assessments) ............... 91 
5.9 
Post Treatment Efficacy Follow Up .................................................................................. 92 
5.10 Survival Follow Up .......................................................................................................... 93 
5.11 Patient Discontinuations ................................................................................................... 93 
 
 
 
 
 
7.0 
SAFETY ASSESSMENTS............................................................................................... 97 
7.1 
Definition of Adverse Event ............................................................................................. 97 
7.2 
Definition of a Serious Adverse Event .............................................................................. 98 
7.3 
Monitoring ....................................................................................................................... 98 
7.4 
Reporting ......................................................................................................................... 99 
7.4.1 Adverse Events................................................................................................................. 99 
7.4.2  
Severity of AEs .......................................................................................................... 100 
7.4.3 Causality of AEs ............................................................................................................ 101 
7.4.4 Adverse Events of Special Interest .................................................................................. 101 
7.4.5 Serious Adverse Events .................................................................................................. 102 
7.4.6 Manufacturer Communications ....................................................................................... 103 
7.4.7 End of Treatment safety Follow-up................................................................................. 103 
8.0 
RESPONSE ASSESSMENT .......................................................................................... 103 
8.1 
Methods for Evaluation of Measurable Disease .............................................................. 104 
8.1.1 Imaging Requirements .................................................................................................... 104 
8.1.2 Tumor Marker Requirements .......................................................................................... 104 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................ 105 
9.1 
Analysis Sets .................................................................................................................. 105 
9.1.1 Full Analysis Set ............................................................................................................ 105 
9.1.2 Safety Set ....................................................................................................................... 105 
9.1.3 Dose-Determining Analysis Set (DDS) ........................................................................... 105 
9.1.4 Pharmacokinetic Analysis Set ......................................................................................... 105 
9.2 
Subject Demographics and Other Baseline Characteristics.............................................. 106 
9.3 
Study Treatment and Dose Exposure .............................................................................. 106 
9.4 
Study Primary Objective................................................................................................. 106 




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12.0 RECORD KEEPING/QUALITY CONTROL ................................................................ 121 
12.1   Inspection ...................................................................................................................... 121 
12.2 Record Retention ............................................................................................................ 122 
13.0 CONFIDENTIALITY .................................................................................................... 123 
14.0 REFERENCES ............................................................................................................... 124 
15.0 APPENDICES ............................................................................................................... 132 
APPENDIX A ......................................................................................................................... 132 
APPENDIX B ......................................................................................................................... 133 
1 
Statistical model for triple combination .......................................................................... 133 
1.1 
Single agent parts ........................................................................................................... 133 
1.2 
Interaction ...................................................................................................................... 133 
1.3 
Meta-analytic framework ................................................................................................ 134 
1.3.1 Single agent part 
134 
1.3.2 Interaction 
134 
1.4 
Reference doses for spartalizumab, canakinumab and chemotherapy .............................. 134 
1.5 
Prior specification .......................................................................................................... 135 
1.5.1 Single agent 
135 
1.6 
Interactions between spartalizumab, canakinumab, and chemothereapy .......................... 136 
1.7 
Historical data ................................................................................................................ 137 
1.8 
Summary of prior distribution of DLT rates .................................................................... 139 
APPENDIX C ......................................................................................................................... 140 
 
 
 


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TABLES AND FIGURES 
 
Figure 1. Involvement of IL-1 in Cancer ................................................................................... 17 
Table 1-1. Steady State PK Parameters of canakinumab ............................................................ 26 
Table 2-1. Study Objectives and Endpoint Summary ................................................................. 29 
Table 4-1. Initial Dose and Treatment Schedule ........................................................................ 39 
Table 4-2. Provisional Dose Levels for canakinumab with fixed dosages of spartalizumab, 
gemcitabine and nab-paclitaxel ......................................................................................... 41 
Table 4-3. Criteria for Defining Dose-Limiting Toxicities ......................................................... 42 
Table 4-4. Dose Modifications for Gemcitabine and Nab-paclitaxel .......................................... 44 
Table 4-5. Dose Modifications for Neutropenia and Thrombocytopenia at the Start of a Cycle or 
Within a Cycle ................................................................................................................. 45 
Table 4-6. Dose Modifications for Other Clinically Significant Non-Hematological Toxicities . 46 
Table 4-7. Criteria for Dose Interruption and Re-Initiation of Canakinumab for Adverse Events 
at least possibly related to canakinumab treatment ………………………………………..47 
Table 4-8. Mandatory Dose Modification Requirements for Potential Immune-Related Diarrhea 
or Colitis at least possibly related to spartalizumab treatment ........................................... 53 
Table 4-9. Mandatory Dose Modification Requirements for Immune-Related Liver Laboratory 
Alterations at least possibly related to spartalizumab treatment ......................................... 54 
Table 4-10. Mandatory Dose Modification Requirements for Immune-Related Skin Events at 
least possibly related to spartalizumab treatment............................................................... 57 
Table 4-11. Mandatory Dose Modification Requirements for Immune-Related Nephritis at least 
possibly related to spartalizumab treatment....................................................................... 58 
Table 4-12. Mandatory Dose Modification Requirements for Immune-Related Pneumonitis at 
least possibly related to spartalizumab treatment............................................................... 59 
Table 4-13. Mandatory Dose Modification Requirements for Immune-Related Endocrine Events 
at least possibly related to spartalizumab treatment ........................................................... 60 
Table 4-14. Mandatory Dose Modification Requirements for “Other” Immune-Related Potential 
AEs at least possibly related to spartalizumab treatment ................................................... 61 
Table 4-15. Mandatory Dose Modification Requirements for Immune-Related Infusion-Related 
Reactions or Injection Site Reactions at least possibly related to spartalizumab treatment . 63 
Table 4-16. Guidance for Specific Clinical and Diagnostic Assessments ................................... 67 
Table 5-1. Schedule of Assessments .......................................................................................... 74 
Table 5-2. ECOG Performance Status ....................................................................................... 80 
Table 5-3. Pharmacokinetic and 
Blood Draw Log for Canakinumab .................. 87 
Table 5-4. Pharmacokinetic and 
Blood Draw Log for Spartalizumab ................. 88 
Table 5-5. Pharmacokinetic Blood Draws for Gemcitabine ....................................................... 88 
Table 5-6. Pharmacokinetic Blood Draws for Nab-paclitaxel .................................................... 89 


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Table 7-1. AE Severity and Intensity ....................................................................................... 100 
Table 7-2. AE Causeality Assessments .................................................................................... 100  
Table 9-1. Hypothetical Dose Escalation Scenarios ................................................................. 107 


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1.0 
INTRODUCTION 
1.1 
Background 
1.1.1 Prevalence and outcomes in pancreatic adenocarcinoma 
Pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States 
and is projected to become the fourth leading cause of cancer death by 2020 (Siegal et al. 2020, 
Amer Cancer Society Facts and Figures 2017). While the incidence and death rates from cancer 
are declining overall, these rates for pancreatic cancer are on the rise. Pancreatic cancer has the 
highest incidence-to-mortality ratio of any solid tumour (Bray et al. 2018).  An estimated 56,770 
people in the US will be diagnosed with pancreatic cancer in 2019, and 45,750 are expected to 
die from their disease (Howlander et al. 2017). 
 
1.1.2 Prognosis and staging 
The majority of patients (52%) are initially diagnosed with advanced disease that is inoperable. 
Median survival for untreated Stage IV disease (metastatic) is only 4.5 months with 5-year 
survival for these patients estimated at  less than 3% (Amer. Cancer Society Facts and Figures 
2017, Howlander et al. 2017, Malvezzi et al. 2013). 
 
For 15 to 20% of newly diagnosed patients, long-term survival can be achieved with treatment by 
surgical resection followed by adjuvant therapy (Bray et al. 2018). However, recurrence is 
common, even in cases where optimal resection is achieved. For patients who present with locally 
advanced disease, treatment consists of chemotherapy with or without radiation.  For patients with 
more advanced disease, including metastatic disease, treatment usually consists of investigational 
agents, chemotherapy alone, and/or supportive care.  
 
1.1.3 Current treatment landscape 
Gemcitabine monotherapy was considered a standard therapy in metastatic disease for many years 
but provided only a marginal improvement in survival. The addition of erlotinib or capecitabine 
to gemcitabine have shown small incremental improvements in survival (Moore et al. 2007). 
More recently, the use of combination therapies such as gemcitabine plus nab-paclitaxel (Von 
Hoff et al. 2013) and FOLFIRINOX regimen (5-fluouracil, leucovorin, oxaliplatin and irinotecan) 
(Conroy et al. 2011) have become standard-of-care for patients with PDAC; however, impact on 


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survival remains modest with median overall survival less than 12 months and the 2-year survival 
rate less than 7%.  
 
1.1.4 Challenges in pancreatic cancer drug development 
Drug development in pancreatic cancer has been challenged by a number of factors hindering 
pharmaceutical interest in this space. Advanced stage at diagnosis and high patient morbidity are 
major challenges in improving disease outcomes, specially within this naturally described older 
patient population.  
 
The desmoplastic tumor microenvironment is known to limit drug penetration and contributes to 
chemoresistance and, more recently described, immunoresistance (Clinical Dev Success Rates 
2006-2015, Mahadevan et al. 2007, Minchinton et al. 2006). Though critical histopathologic 
aspects of the disease are defined, its molecular underpinnings require further elucidation 
(Whatcott et al. 2015).  Driver mutations in KRAS, p53 and p16 are widely characterized, but 
large-scale “druggable” targets that effect response remain unknown (Jones et al. 2008). This 
leads to challenges in identifying rationale and biologically driven therapeutic combinations 
needed to have a greater impact on patients with advanced disease.  
 
 
1.2 
Study overview  
This study combines canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) 
monoclonal antibody (mAb), and spartalizumab (PDR001), a mAb directed against human 
Programmed Death-1 (PD-1), with the chemotherapy combination of gemcitabine and nab-
paclitaxel. This study will confirm for this 4-drug combination the tolerable doses, the acceptable 
safety profile, and the  dose to be used for a Phase II combination treatment regimen. The 
description of the two investigational agents and their potential activity in pancreatic cancer are 
described in Section 1.3 below.  
We hypothesize that blockade of IL-1β and PD-1 will result in alterations in myeloid, lymphoid, 
and fibroblast subsets within the pancreatic cancer microenvironment. We further predict that 
circulating monocytes and neutrophils, whose production and mobilization from the bone marrow 
is augmented in PDAC patients, will decline upon treatment with IL-1β and PD-1 blockade.  


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This study offers a unique window to collect rich datasets on a small number of patients before 
and after perturbation of a biological pathway of interest. To this end, we propose to collect pre- 
and on treatment blood and tumor tissue from trial patients. These samples will be used to expand 
our knowledge of IL-1β signaling in human PDAC and will generate rich datasets for evaluation 
of biomarkers of response and understanding of immune regulatory pathways that may contribute 
to drug resistance. A full description of the samples collected in this study for this analysis is 
described in Section 6.0 and is listed in the Schedule of Events Table in Section 5.0. 
 
1.3 
 Overview of IL-1β 
IL-1 (interleukin-1) is a pro-inflammatory cytokine secreted by a number of different cells, 
including monocytes and macrophages. The IL-1 gene family consists of cytokines IL-1α and IL-
1β, and the natural receptor antagonist (IL-1Ra). Pro-IL-1α is functionally active and, because of 
a lack of the leader peptide, it remains in the cytoplasm. Pro-IL-1β is inactive and is secreted after 
cleavage by a specific intracellular protease abundant in hematopoietic cells. While IL-1β is most 
commonly found in circulation, detection of IL-1α is rare as it is released only in severe disease 
states as a consequence of cell death (Dinarello 1996, Garlanda et al 2013). 
IL-1β binds the IL-1 receptor (IL-1R) inducing a conformational change that allows binding of the 
accessory protein (IL-1RAcP) to the IL-1β/IL-1R complex. Activated IL-1R, which is found on 
almost all nucleated cell types, induces intracellular signaling cascade involving MAPK, JNK, 
ERK and NF-κB that control gene expression of multiple transcription factors, growth factors and 
cytokines involved in cell functional activation and cell survival responses (Dinarello 1996, 
Arranz et al 2017). When released as part of inflammatory reaction, IL-1β produces a range of 
biological effects, including through the induction of other inflammatory mediators such as 
corticotrophin, platelet factor-4, prostaglandins, IL-6, and IL-8. Circulating IL-1β and IL-6 
promote synthesis of C-reactive protein (CRP) in hepatocytes. CRP has a role in clearance of 
microorganisms and dead cells by the immune system and serves as a sensitive indicator of 
inflammation and IL-1β secretion. In addition, it is commonly used as a marker of IL-1β inhibition 
(Ridker 2016). IL-1β modulates hematopoietic stem cell function and contributes to bone marrow 
regeneration after myeloablation and transplantation. Inhibition of IL-1β signaling reduces bone 
marrow colony formation in vivo and suppresses cell cycle in bone marrow while reducing 


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numbers of leucocytes and platelets in peripheral blood (Zhang et al 2009). Being a pleiotropic 
cytokine, IL-1β has roles in other body systems, like bone and cartilage, where it facilitates bone 
resorption and cartilage destruction (Gowen et al 1983); it promotes vasodilation and leucocytes 
migration (Koch et al 1992), elevates body core temperature and increases cortisol levels 
(Garlanda et al 2013), and modulates sensitivity to pain via direct and indirect activation of pain 
nerve receptors (Sommer and Kress 2004). In addition, IL-1 orchestrates the differentiation and 
function of innate and adaptive lymphoid cells thus directly contributing to the immune response 
(Garlanda et al 2013). 
1.3.1 IL-1β in cancer 
IL-1 expression is elevated in human pancreatic, skin, and other cancers. Patients with IL-1 
producing tumors have poor prognosis (Lewis et al 2006). Due to the pleiotropic nature of IL-1, 
there are several likely mechanisms by which IL-1 promotes tumor growth and metastasis 
(Figure 1). Preclinical data has demonstrated that IL-1β is involved in all phases of the malignant 
process, including tumorigenesis, tumor invasiveness, angiogenesis, progression, as well as in 
activation/suppression of anti-tumor immunity (Apte et al 2006, Becker 2006, Lewis et al 2006, 
Krelin et al 2007, Zitvogel et al 2013, Wu et al 2016). IL-1β is one of the most abundant and 
influential cytokines in the tumor microenvironment, and is produced by tumor cells, stromal 
cellular elements, and infiltrating leukocytes. Furthermore, IL-1β signaling induces a cascade of 
several pro-metastatic proteins such as matrix metalloproteinases and endothelial adhesion 
molecules as well as VEGF, transforming growth factor-β (TGFβ), and other chemokines and 
growth factors thus creating microenvironment that promotes tumor initiation, growth and 
progression. IL-1β plays major role in later stages of tumor progression by driving angiogenesis, 
promoting 
cancer 
“stemness” 
and 
“epithelial 
to 
mesenchymal 
transition” 
(Mora and Weigert 2016). In addition, IL-1β is capable of suppressing local anti-tumor immunity 
by promoting the infiltration of immunosuppressive cells into the tumor, including myeloid-
derived suppressor cells (MDSCs) and tumor associated microphages (TAMs) (Guo et al 2016). 


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Figure 1. Involvement of IL-1 in cancer  
 
Based on [Mantovani et al 2018].  
Abbreviations: MDSC – myeloid-derived suppressor cells; TAM – tumor-associated 
macrophages; TAN - tumor-associated neutrophils; TLR – toll-like receptors 
 
1.3.2 IL-1β in pancreatic cancer 
IL-1β plays an important role in pancreatic cancer development and progression. High IL-1β 
concentration in serum and in the tumor correlate with tumor fibrosis, resistance to chemotherapy 
and poor survival (Maker et al 2011; Zhang et al 2018). In mouse models, IL-1β  was shown to 
promote obesity-induced (a well-established risk factor for pancreatic cancer) pancreatic 
carcinogenesis and drug resistance (Incio et al 2016). In addition, NLRP3 pathway that controls 
IL-1β production was shown to support pancreatic cancer progression by increasing population of 
intratumoral immune-suppressive macrophages and Treg and thus promoting intratumoral 
immune tolerance (Daley et al 2017). Das et al showed that IL-1β expression is upregulated in 
patients-derived pancreatic cancer tumors relative to normal pancreatic tissue both in ductal 
epithelium and in the stroma. This group also showed in the tumor mice model that tumor-derived 
IL-1β promoted activation of dormant pancreatic stellate cells (important step for carcinogenesis 
and progression) and induced immunosuppressive tumor microenvironment through increase in 
immunosuppressive M2 macrophages, MDSC and other cell populations. Elimination of tumor 
IL-1β signaling was associated with increase in cytotoxic T-cells, attenuation of tumor growth 
which resulted improved survival of mice (Das et al 2020). All these support the role of IL-1β in 
pancreatic cancer and identify it as an attractive target for future development.   


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1.3.3 Anti-IL-1β therapy effect on cancer in CANTOS 
The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was a 
randomized, double blind, placebo-controlled phase III trial of 10,061 subjects who were stable 
after a myocardial infarction (Ridker et al 2017). The study was designed primarily to assess 
whether canakinumab, a human mAb targeting IL-1β, can prevent recurrent cardiovascular events 
among men and women who have a persistent proinflammatory response defined by the presence 
of high-sensitivity CRP (hs-CRP) ≥2 mg/L. Subjects were randomized to three canakinumab doses 
(50 mg, 150 mg, and 300 mg administered subcutaneously every 3 months), or placebo. The 
primary endpoint was reducing the risk of recurrent major cardiovascular events.  All participants 
in CANTOS had to be free of previously diagnosed cancer at trial entry, and subjects were 
followed prospectively for incident AEs (including cancer, except for basal cell carcinoma) for up 
to 5 years. During the median follow-up of 3.7 years, canakinumab administration was associated 
with dose-dependent reductions in concentrations of hs-CRP and IL-6 vs placebo. Total cancer 
mortality (n=196) was lower in the pooled canakinumab group than in the placebo group, the 
incidence rate of cancer mortality per 100 person-years was 0.64 in the placebo group, 0.55 in the 
50 mg group, 0.50 in the 150 mg, and 0.31 in the 300 mg group. The association of canakinumab 
with a dose-dependent reduction of the incidence cancer mortality rate was prominent with lung 
cancers. Incidence of fatal non-lung cancers showed a reduction with canakinumab, although the 
number of these cancers in general was low (Ridker et al 2017). Taken together, these hypothesis-
generating data from pre-specified safety analysis of CANTOS suggest the possibility that 
inhibition of the IL-1β pathway may have a role in the treatment of cancers characterized by an 
activated IL-1β pathway. 
1.3.4 Immunotherapy in pancreatic cancer 
Immunotherapy and the use of immune checkpoint inhibitors such as anti-Programmed cell Death 
protein 1 (PD-1), PD ligand 1 (PDL-1) or cytotoxic T-lymphocyte Antigen 4 (CTLA-4), have been 
demonstrated to be effective agents for treatment of several key solid tumors. PD-1 is a critical co-
inhibitory receptor that is upregulated on T cells upon activation (Freeman et al. 2008). It is also 
expressed by B cells, NK cells, dendritic cells, and activated monocytes. The ligands for PD-1, 
programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), are expressed by 
macrophages and monocytes, and can be induced on numerous cell types (T cells, endothelial cells, 
and tumor cells) during inflammation (Keir et al. 2008). Engagement of PD-1 by its ligands 


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transduces a signal that inhibits T-cell proliferation, cytokine production, and cytolytic function 
(Pu et al. 2019). During tumorigenesis, cancer cells from a wide range of tumor types exploit 
immune checkpoint pathways, such as PD-1, to avoid detection by the adaptive immune system 
(Fox et al. 2011). Blockade of the PD-1 pathway has been shown to lead to both accumulation and 
increased activity of antitumor effector T cells and reduced numbers of regulatory T cells (Tregs) 
at the tumor site (Wang et al. 2009;  Mangsbo et al. 2010; Mkrtichyan et al. 2011; Rosenblatt et 
al. 2011). Results of a phase I/II study of pembrolizumab with gemcitabine + nab-paclitaxel in 
PDAC  showed 3 partial responses (27%) and 100% disease control rate among 11 evaluable 
chemotherapy naive patients with an overall survival of 15 months (Weiss et al. 2018). 
Unfortunately, for the majority of patients, single agent immune checkpoint inhibitors have failed 
to improve survival in PDAC (Brahmer et al. 2012; Royal et al. 2010). A putative explanation is 
that PDACs have a low mutation burden and have an immune suppressive tumor 
microenvironment in comparison to other solid cancers, leading to a less immunogenic profile 
(Biankin et al. 2012). Strategies to overcome this problem include combinations with other 
checkpoint inhibitors, vaccines, or cytotoxic therapy. Nonetheless, there is a small subgroup of 
patients with a mismatch repair deficient (MMR-D) state, which represent approximately 1-3% of 
PDACs (Hu et al. 2018). These patients typically occur in the setting of Lynch syndrome in PDAC, 
where there is a rationale to use checkpoint inhibitors. These patients present with a significantly 
higher burden of mutations that may encode proteins recognized by the immune system. This 
hypothesis was validated in a phase II study of MMR proficient and deficient solid tumors, as 
significant response to pembrolizumab was seen only in MMR-D patients (Le et al. 2015). Of the 
8 patients with metastatic pancreatic cancer enrolled, there were 5 responders (2 complete 
response, 3 partial response) for an overall response rate of 62%. Median PFS and OS had not been 
reached (Le et al. 2017). These results have recently led to the FDA approval of pembrolizumab 
in MMR-D patients with solid tumors agnostic of the specific underlying malignancy (please refer 
to 
the 
Keytruda 
USPI: 
https://www.accessdata.fda.gov/ 
drugsatfda_docs/label/2019/125514Orig1s054lbl.pdf).  
Adding chemotherapy to immunotherapy and canakinumab may contribute to increased efficacy 
of immunotherapy by improving immunogenicity of the tumor by causing tumor cells to emit 


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“danger” signal, by stimulating anticancer immune effector cells and  suppressing 
immunosuppressive cells (Zitvogel et al. 2013, Zitvogel et al. 2011).   
1.3.5 Inflammation in pancreatic cancer and rationale to combine with a IL-1β 
inhibitor  
The presence of stromal desmoplasia is a characteristic of pancreatic cancer that leads to a unique 
tumor microenvironment that comprises of several cell types that includes fibroblasts that deposit 
fibronectin and collagen and inflammatory cells and macrophages that releases cytokines. These 
proinflammatory cytokines such as IL1β and IL-6 have been implicated for the adverse outcomes 
of pancreatic cancer (Lesina et al. 2011; Ebrahimi et al 2004). This systemic inflammatory 
response has been associated with a more pronounced symptom burden, including cachexia 
syndrome, and poorer survival outcomes (Tan CR et.al. 2014). Consequently, elevated levels of 
CRP, weight loss and low serum albumin concentrations (hypoalbuminemia) are recognized as 
poor prognostic markers which is thought to be part of the systemic inflammatory response 
(Salmiheimo A et al 2016). The modified Glasgow Prognostic Score (mGPS) is a risk-stratification 
tool that evaluates systemic inflammation by incorporating CRP and albumin values into a score 
to predict clinical outcomes in patients with cancer (McMillan DC. 2013) and is extensively 
reported in retrospective analyses of pancreatic cancer. Moreover, preclinical models have 
demonstrated that enhancing IL-1 signaling in pancreatic cancer cells leads to enhanced 
proliferation of the tumor cells.  
It is therefore hypothesized that addition of a IL-1β inhibitor to the combination of inhibitors of 
immune checkpoint blockade and standard of care chemotherapy would lead to salutary effect on 
the efficacy of pancreatic cancer by altering the tumor microenvironment as described in Section 
1.3.2 to facilitate the activity of the antitumor immune cells and inhibition of the cancer. Recent 
preclinical data (Das et al 2020) demonstrated an improved tumor growth suppression when 
blocking antibodies against IL-1β and PD-1 were combined in the KPC pancreatic cancer mouse 
model, which is supportive of this hypothesis. 
1.4 
Overview of canakinumab 
Canakinumab (ACZ885) is a high-affinity human anti-interleukin-1β (IL-1β) monoclonal antibody 
that belongs to the Immunoglobulin G1 (IgG1)/κ isotype subclass. Canakinumab is manufactured 
in a murine SP2/0 cell line. Currently canakinumab is approved and marketed as Ilaris® in more 


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than 70 countries for the treatment of IL-1β driven auto-inflammatory diseases: gouty arthritis, 
Still's disease, Cryopyrin Associated Periodic Syndromes (CAPS), Systemic Juvenile Idiopathic 
Arthritis (SJIA), Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), 
Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), Familial 
Mediterranean Fever (FMF). For additional details please refer to the canakinumab Investigator’s 
Brochure.  
1.4.1 Non-clinical experience with canakinumab 
Canakinumab neutralizes the bioactivity of human IL-1β by preventing its binding to the IL-1β 
receptor. Canakinumab specifically binds human IL-1β with a Kd of 40-60 picomolar and has no 
cross-reactivity with other members of the IL-1 family (e.g. IL-1α IL-1Ra etc). Canakinumab is 
selective for human and marmoset IL-1β but does not bind to mouse, rat, rabbit, rhesus, or 
cynomolgus monkey IL-1β. An extensive program of toxicology studies was performed with 
canakinumab. The marmoset monkey was characterized as an appropriate model to predict human 
safety. Following IV or SC administration, canakinumab was well tolerated in marmosets at all 
dose levels without any relevant adverse findings. No anti-drug antibodies were detected. No 
significant treatment-related effects were observed with respect to male or female fertility in a 
mouse model using a murine analog of canakinumab. For further details, please refer to the 
canakinumab Investigator’s Brochure. 
1.4.2 Clinical experience with canakinumab in cancer 
As of June 2019, approximately 13,111 patients were exposed to canakinumab in Novartis-
sponsored clinical studies at various doses. Canakinumab is being studied in NSCLC in a number 
of settings: as single-agent adjuvant therapy (CACZ885T2301), in combination with 
chemotherapy and immunotherapy in the first line setting (CACZ885U2301 and 
CPDR001C2101), and in combination with chemotherapy in the second-line treatment setting 
(CACZ885V2301). These trials are ongoing. 
In the open-label safety run-in part of a phase 3 study CACZ885U2301 (CANOPY-1), 
canakinumab (200 mg SC Q3W) was administered to 30 patients with Stage IIIB/C/IV NSCLC in 
combination with pembrolizumab and chemotherapy regimens: carboplatin+ pemetrexed (Cohort 
A; 10 patients), cisplatin+pemetrexed (Cohort B; 11 patients), or carboplatin+paclitaxel (Cohort 
C; 9 patients). Only 1 dose-limiting toxicity (DLT) was reported with these combinations (in 


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Cohort C only; hepatitis, considered to be related to pembrolizumab), and 12 SAEs reported in 8 
patients, none considered to be related to canakinumab by the investigators. There was no common 
pattern for SAEs except for infections (two events of pneumonia in two patients, urinary tract 
infection, lower respiratory tract infection). The dose level review team meeting concluded that 
the regimen evaluated in all three cohorts in the safety run-in (canakinumab 200 mg Q3W) is 
tolerable and considered safe to be used in combination with pembrolizumab and chemotherapy 
in the randomized phase 3 part of the study. The phase 3 part of the study is ongoing.  
Study CACZ885T2301 (CANOPY-A) is a phase III randomized double-blind placebo-controlled 
study exploring canakinumab (200 mg SC every three weeks, up to 18 cycles) as adjuvant therapy 
in patients with completely resected Stages II-IIIA/IIIB (T>5cmN2) NSCLC. The safety of study 
treatment in first 56 subjects has been reviewied by DMC that recommended to continue the study.  
Study CACZ885T2301 (CANOPY-2) is a phase III randomized double-blind placebo-controlled 
study exploring canakinumab (200 mg SC every three weeks, up to 18 cycles) evaluating 
canakinumab (200 mg SC every three weeks) with docetaxel (75 mg/m2 every three weeks) in 
patients with metastatic NSCLC previously treated with PD-1 or PD-L1 inhibitors and platinum-
based chemotherapy. In the open-label safety run-in part of the study in 8 patients, one DLT of 
pneumocococcal pneumonia was reported (considered by the investigator related to combination 
of canakinumab and docetaxel) in the DLT observation period of the first 42 days of study 
treatment and 6 SAEs in 3 patients. None of these SAEs were considered related to canakinumab 
per investigators assessment. The dose level review team concluded that the regimen evaluated in 
the safety run-in is tolerable and is safe to be used in combination with docetaxel in the randomized 
phase 3 part of the study. The randomized part of the study is ongoing.  
For additional information on studies of canakinumab in patients with oncology indications 
(including studies in metastatic melanoma, triple-negative breast and colorectal cancer) refer to 
the last canakinumab Investigator’s Brochure. Information on studies exploring canakinumab in 
combination with PD-1 inhibitor spartalizumab (PDR001) is provided in Section 1.5 
1.5 
Overview of spartalizumab 
Spartalizumab (PDR001) is a mAb directed against human Programmed Death-1 (PD-1). PD-1 is 
a critical immune-checkpoint receptor that is expressed on CD4 and CD8 T cells upon activation.  


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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. During tumorigenesis, cancer cells from 
a wide range of tumor types exploit immune checkpoint pathways, such as PD-1/PD-L1, to avoid 
detection by the adaptive immune system. Inhibitors of immunological checkpoints, including PD-
1 and PD-L1 mAb’s, have demonstrated significant antitumor activity in patients with various 
solid tumors.  
1.5.1 Non-clinical experience with spartalizumab 
Spartalizumab binds specifically and with high affinity to human PD-1 and enhances IL-2 
production in lymphocyte stimulation assays in vitro. Spartalizumab does not cross react with 
rodent PD-1. However, toxicology studies performed in cynomolgus monkeys showed acceptable 
cross reactivity with monkey PD-1. Repeat administration of spartalizumab to cynomolgus 
monkeys was tolerated at all doses tested up to 100 mg/kg/week for 5 weeks in the GLP toxicology 
single-agent study. No drug-related changes in life, mortality, organ weight changes, or 
macroscopic findings were noted. For further details, please refer to the spartalizumab 
Investigator’s Brochure. 
 
1.5.2 Clinical experience with spartalizumab 
As of 26-March-2020, a total of 1702 patients have received spartalizumab in Novartis-sponsored 
clinical studies as a single agent (562 patients), or in combination with other agents (1140 patients) 
in multiple tumor types. In these studies spartalizumab was administered every two weeks (Q2W), 
Q3W or every four weeks (Q4W).  
Safety profiles of spartalizumab in clinical studies across different tumor types and regimen/dose 
groups were similar and consistent with and characteristic of other agents that inhibit the PD-1 
receptor. Severe immune-related adverse events (irAEs) were rare and typically manageable with 
dose interruption and use of immunosuppressive treatment or other supportive therapy as clinically 
indicated; discontinuations due to irAEs were rare. For additional details on safety of 
spartalizumab please refer to the spartalizumab Investigator’s Brochure. 
Based on the available PK and safety data, two recommended phase two doses (RP2D) for 
spartalizumab single-agent have been declared: spartalizumab 400 mg Q4W or 300 mg 
spartalizumab Q3W.  


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Clinical experience of administering spartalizumab with chemotherapy or canakinumab include 
phase I/II studies CPDR001C2101, CPDR001X2103 and CPDR001J2201.  
- 
In CPDR001C2101, spartalizumab (300 mg Q3W) was administered in combination with 
platinum-based regiments (gemcitabine + cisplatin; pemetrexed + cisplatin; paclitaxel + 
carboplatin) to patients with advanced and metastatic NSCLC. As of January 2019, a total 
of 33 adults were treated in this study. The safety profile observed was characterized mostly 
by toxicities attributed to chemotherapy regimens (e.g. bone marrow suppression, nausea, 
and asthenia/fatigue). AEs attributed to spartalizumab were manageable and in-line with 
the existing safety profile of spartalizumab. In addition, the study confirmed spartalizumab 
recommended dose for subsequent NSCLC trials as 300 mg IV Q3W. 
- 
In CPDR001X2103, spartalizumab was administered to patients with advanced/metastatic 
colorectal cancer, triple-negative breast cancer or NSCLC in combinations with 
canakinumab or other immunomodulatory agents or tyrosine kinases inhibitors. One 
hundred and seven patients were treated with spartalizumab (400 mg Q4W) and 
canakinumab combination at doses 100 mg (6 patients), 300 mg (13 patients) and 600 mg 
(88 patients) (all Q8W SC). In the spartalizumab + canakinumab group, 104 patients (97.2 
%) had permanently discontinued study treatment, 3 (2.8 %) due to an AE, 93 (86.9 %) 
due to progression of disease, 5 (4.7 %) due to physician decision and 3 (2.8 %) due to 
subject/guardian decision. The most frequent AEs (≥20%) in this group regardless of 
relationship to study drug, were dyspnoea (30.8%), decreased appetite (28.0%), fatigue and 
nausea (24.3% each) and vomiting (22.4%).  
- 
In CPDR001J2201, spartalizumab was administered to patients with previously treated 
unresectable or metastatic melanoma in combinations with canakinumab or other 
immunomodulatory agents or small molecules. As of interim analysis data cutoff date of 
07-Oct-2019, 36 patients have been administered spartalizumab 400 mg every 4 weeks and 
canakinumab 300 mg every 4 weeks. The most frequent AEs (>10%) in the spartalizumab 
+ canakinumab group, regardless of relationship to study drug, were dyspnoea (17.1%), 
constipation (14.3%), abdominal pain (14.3%), decreased appetite (14.3%), anemia 
(14.3%), asthenia (14.3%), fatigue (11.4%) and weight decreased (11.4%). Grade >3 AEs 
reported more than once include anemia (three), fatigue, decreased appetite, tumour pain, 
lipase and amylase increased (twice each). The most frequent treatment-related AEs, 


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reported in at least 3 (>8%) subjects include pruritus (8.6%) and eosinophilia (8.6%). 
Treatment related events were grade >3 gastrointestinal pain, gastroesophageal reflux, 
lipase increased and peripheral ischaemia (once each). At the interim analysis with a cutoff 
date of 07-Oct-2019, spartalizumab + canakinumab arm crossed the efficacy futility 
threshold and will not be further expanded. 
For additional details on CPDR001X2103, CPDR001C2101 and CPDR001J2201 please refer to 
the last edition of the spartalizumab Investigator’s Brochure.  
1.6 
Rationale for the dosing regimen of canakinumab 
 
As described in Section 1.3.3, administration of canakinumab (50 mg, 150 mg, and 300 mg SC 
every three months) in CANTOS resulted in a dose dependent decrease in hs-CRP and was 
associated with a reduction of lung cancer cumulative incidence and mortality, compared to 
placebo, in a dose-dependent manner and with no plateau observed at the highest dose 
administered (300 mg every 3 months), suggesting that higher doses of canakinumab could be 
associated with a greater decrease in risk of lung cancer incidence rate and mortality (Ridker et al 
2017a). Importantly, the median hs-CRP at baseline in subjects who were subsequently diagnosed 
with cancer was higher compared to those patients who were not diagnosed with cancer (median 
6.0 mg/L versus 4.2 mg/L). Moreover, for subjects with higher baseline hs-CRP, the proportion of 
subjects whose hs-CRP normalized to a post-treatment target level of 2.3 mg/L was less than in 
subjects with lower baseline hs-CRP. All these suggest that increasing the exposure of 
canakinumab beyond the maximal dose explored in CANTOS may result in an improved control 
of inflammation in subjects with higher baseline hs-CRP which may lead to a greater antitumor 
efficacy of canakinumab. Based on this assumption, a dose of canakinumab 200 mg administered 
SC every 3 weeks (Q3W), which results in higher steady-state exposure compared to the maximal 
exposure achieved in CANTOS, was selected for studies exploring anti-tumor effect of 
canakinumab in NSCLC (Section 1.4.2). In these studies canakinumab is being explored in patients 
with NSCLC as monotherapy, or in combination with chemotherapy, or with chemotherapy and 
PD-1 blockers. Rationale for this dose was based on the PK properties of canakinumab, the drug’s 
ability to suppress hs-CRP for at least 1 month across a wide range of doses and indications, 
efficacy observed in the CANTOS study, safety considerations, and schedule of administration of 


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a standard of care backbone treatment (i.e. chemotherapy) in NSCLC. Ability of Q3W dosing 
schedule of canakinumab to suppress hs-CRP for at least 1 month was also demonstrated in two 
single-dose phase II studies with dose ranges of 0.03 to 10 mg/kg IV ([CACZ885A2213] in 
diabetes) and 25 to 300 mg SC ([CACZ885H2251] in gouty arthritis). 
In this study, the backbone regimen of chemotherapy of gemcitabine and nab-paclitaxel is 
administered as 4-weeks cycles. To align with the dosing regimen of chemotherapy, the every four 
week regimen of 250 mg canakinumab SC as starting dose was selected. This decision was based 
on population PK analysis, where a 250 mg Q4W SC dosing schedule resulted in comparable PK 
at steady state to the 200 mg Q3W SC, the regimen used in NSCLC studies (Table 1-1). This 
dosing is also supported by a long, 26-days half-life of canakinumab.  
 
 
Table 1-1: Steady State PK parameters of canakinumab 
 
Dose Regimen 
Cmin ug/mL 
(95% PI) 
Cmax ug/mL 
(95% PI) 
 
 
AUC0-tau 
ug*day/mL 
(95% PI) 
Cave ug/mL 
(95% PI) 
 
 
200 mg Q3W S.C. 
22.44 
(9.16, 50.31) 
35.21 
(16.03, 75.42) 
 
AUC21-24week 
625.67 
(278.36, 
1334.69) 
29.79 (13.26, 
63.56) 
 
 
250 mg Q4W S.C. 
18.28 
(7.50, 43.51) 
35.65 
(16.31, 76.64) 
 
 
AUC20-24week 
771.81 
(348.12, 
1705.89) 
27.56 
(12.43, 60.92) 
 
 
 
As described in the canakinumab Investigator’s Brochure, safety of canakinumab doses equivalent 
to or higher than selected for this study dose (250 mg Q4W) has been confirmed in several 
completed and ongoing studies exploring canakinumab, including in combinations with 
chemotherapy and/or immunotherapy. In Study CACZ885A2204, canakinumab was given at a 
dose of 600 mg IV Q4W along with methotrexate. In studies CACZ885G2301 and 
CACZ885G2301E1 (extension of the former study), canakinumab was administered at a dose of 
4 mg/kg up to maximum 300 mg SC Q4W to patients with systemic juvenile idiopathic arthritis 
for a total median duration of exposure of more than 2 years.  As described in Section 1.4.2, 
canakinumab dose of 200 mg SC Q3W is being explored currently as monotherapy or in 
combination with chemotherapy or  chemoimmunotherapy in multiple studies in NSCLC. In a 


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phase 1b study CADPT01A12101C, 600 mg Q8W canakinumab was adminsitered in combination 
with spartalizumab and LAG25 to patients with metastatic triple negative breast cancer.  
In summary, based on evidence of efficacy from the CANTOS, PK and PD properties of 
canakinumab and the well-established safety profile of canakinumab at wide dose ranges, a dose 
of 250 mg SC Q4W has been selected for this study.   
 
 
1.7 
Rationale for the Study Regimen 
As described in Section 1.3.4, checkpoint inhibitor monotherapy has not demonstrated outstanding 
efficacy in pancreatic cancer. This is possibly due to the immune suppressive tumor 
microenvironment with stromal infiltration of myeloid-derived suppressor cells (MDSC), tumor-
associated macrophages and/or overall low mutational load. IL-1β plays an important role in 
pancreatic cancer development and progression via activation of dormant pancreatic stellate cells 
and increasing population of intratumoral immune-suppressive macrophages M2, Treg and MDSC 
(Section 1.3.2). Recent preclinical data in pancreas cancer animal models showed improved tumor 
growth suppression with concurrent blockage of antibodies against IL-1β and PD-1 (Das et al 
2020). Similarly, in an animal model of breast cancer, treatment with antibodies against IL-1β 
caused regression of the tumor due to decrease in intratumoral immunosuppressive macrophages 
and improvement of antitumor immunity via an increase in dendritic cell function and activated 
cytotoxic CD8+ lymphocytes (Kaplanov et al 2019). In the same model, where treatment with anti-
PD-1 had moderate effect on tumor growth, combination of anti-IL1β and anti-PD-1 abrogated the 
tumors completely. Combined, this data provide a strong preclinical rationale for a clinical trial 
investigating a combination of anti-IL1β and anti-PD-1 agents in the treatment of advanced 
pancreatic cancer.  
In this trial, anti-IL-1β antibody canakinumab will be combined with an anti-PD-1 antibody 
spartalizumab and chemotherapy regimen of gemcitabine and nab-paclitaxel. As described in 
Section 1.1.3, gemcitabine and nab-paclitaxel is a standard treatment regimen for metastatic 
pancreatic cancer. It is expected, that combining anti-IL1β and anti-PD-1 agents with standard 
chemotherapy will have more than an additive effect: chemotherapy may increase the amount of 
neoantigens in the tumor and contribute to improved response to immune checkpoint inhibition. 
As an evidence, it was shown in preclinical models of pancreatic cancer that combining 


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gemcitabine with either anti-PD-1 or anti-PD-L1 antibody enhanced tumor infiltration with CD8+ 
T cells and resulted in complete responses (uncommon in pancreatric cancer models) in the treated 
animals (Nomi et al 2007). In this trial, approved doses of gemcitabine and nab-paclitaxel will be 
used (Section 4.1.1).  
Spartalizumab will be administered at the recommended dose for phase II of 400 mg Q4W 
(Section 1.5.2). As described in Section 1.5.2, the combination of chemotherapy and 
spartalizumab is feasible, with the safety profile mostly attributed to chemotherapy regimens; AEs 
attributed to spartalizumab were manageable and in-line with the existing safety profile of 
spartalizumab. 
The first dose level explored of canakinumab will be 250 mg Q4W (Section 1.6), that is expected 
to be equivalent to the dose explored in multiple ongoing phase III clinical trials in NSCLC and 
phase I/II clinical trials in other cancers where no outstanding safety signals as a result of 
combination with chemotherapy administered in approved doses (and checkpoint inhibitors, where 
applicable) with canakinumab have been observed, and the combination was feasible and tolerable, 
no overlapping toxicities were observed (Canakinumab IB).  
Canakinumab and spartalizumab are monoclonal antibodies and not metabolized by Cytochrome 
P450 (CYP450) enzymes or transported by P-glycoprotein (PgP) or related ABC membrane 
transporters. Therefore, the risk of DDI between canakinumab, spartalizumab and chemotherapy 
agents is expected to be low. However, as canakinumab is a cytokine modulator, the risk of DDI 
between canakinumab and chemotherapy agents that are metabolized by CYP enzymes (e.g. 
paclitaxel) cannot be completely excluded. In addition, when canakinumab was administered 
together with paclitaxel in the safety run-in of study CACZ885U2301, no additional toxicities or 
DLT were observed (Section 1.4.2). Therefore, the PK of chemotherapy agent that is metabolized 
by CYP enzymes (nab-paclitaxel) will also be characterized in this study to explore the DDI 
between canakinumab and spartalizumab and nab-paclitaxel, if any. 
 
2.0 OBJECTIVES AND ENDPOINTS 
2.1 
Overview 
This is an open-label multi-center phase Ib study to confirm the recommended phase II/III dose of 
canakinumab and spartalizumab in combination with nab-paclitaxel and gemcitabine  as first-line 
therapy for patients with metastatic pancreatic cancer.  






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The Bayesian analysis incorporates prior toxicity data of single agent and drugs combinations 
together with the currently available data to  predict the probability of DLT and excessive toxicity 
of a dose level of interest.   
The Bayesian method is be based on a Meta-Analytical-Combined (MAC) approach (Spiegelhalter 
2004, Neuenschwander 2016) to combine all historical and concurrent data. Prior toxicity 
information included in the BLRM model was obtained from three studies with canakinumab as a 
single agent and combination of canakinumab and spartalizumab (PDR001X2101,  ACZ885I2202, 
PRD001X2103) and from a phase I/II study of  nab-paclitaxel + gemcitabine (Von Hoff D, et.al., 
2011).  Simulation was used to illustrate the recommendation from BLRM under a set of 
hypothetical scenarios with assumed number of evaulable patients and DLTs (See Table 9-1). Full 
details on the model, prior toxicity information from clinical trials in patients and assessment of 
DLT probability using the BLRM model are provided in Section 9.4 and Appendix B. 
The decisions on a recommended dose will be made by the Investigators and the Sponsor in a 
Safety Review meeting when at least 6 DLT evaluable patients per dose level will be observed for 
DLTs for a minimum duration of 56 days (8 weeks). Safety review will be based upon the review 
of all relevant data available including treatment tolerability and safety information together with  
the BLRM summaries of DLT probability, PK, PD, and preliminary activity information (if 
available) at the time of the meeting (Section 4.1.5). 
 
3.0 
STUDY POPULATION 
The study population is treatment naïve metastatic pancreatic ductal adenocarcinoma patients.  
 
3.1  
Study Duration 
Patients will be treated until disease progression per RECIST 1.1, unacceptable toxicity, or until 
the patient or treating physician decides to stop treatment.  
All patients must be followed for safety up to 150 days after the last dose of spartalizumab or 
canakinumab, or 30 days after the last dose of the combination chemotherapy, whichever the later. 
After the end of safety follow-up, patients will be followed for disease progression if 
discontinuation of treatment is due to reason other than progression, and for survival (via 
telephone call or onsite visit if a patient happens to be visiting the site) until the end of study  


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The study completion is defined as when the last patient has completed the study treatment, safety 
follow up,  and completed survival follow up period up to 1 year from first treatment, whichever 
is later or in the event of an early study termination decision, the date of that decision.  
  
3.2 
Inclusion Criteria 
A patient will be eligible to participate in this study if all of the inclusion criteria below are met: 
• Age > 18 years at the time of informed consent 
• Histologically or cytologically confirmed pancreatic ductal adenocarcinoma (PDAC) 
(determined by a local laboratory) with metastatic spread of disease (adenosquamous is 
also allowed).  
• Patients must have not received previous anti-cancer therapy for the treatment of metastatic 
pancreatic ductal adenocarcinoma.  
• Patients who received previous neo-/adjuvant systemic therapy for non-metastatic PDAC 
≥12 months from the last treatment to study enrollment date are allowed unless this therapy 
included immunotherapy and/or IL-1 inhibitors.   
• Radiographically measurable disease of at least one site by computed tomography (CT) 
scan (or magnetic resonance imaging, if allergic to CT contrast media) as defined by 
Response Evaluation Criteria In Solid Tumors (RECIST 1.1). Primary lesion is allowed as 
long as it is measurable (per RECIST 1.1) and has not been previously irradiated. Imaging 
results must be obtained within the 28-day screening window.  
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.  
• Adequate organ function (laboratory results must be obtained within the 28-day screening 
window) 
o Absolute neutrophil count > 1500/mm3 
o Hemoglobin > 9 g/dL 
o Platelets > 100,000/mm3 
o Serum creatinine < 1.5 x upper limit normal (ULN), or calculated creatinine 
clearance > 60 mL/min (Cockcroft Gault) 
o Albumin > 3.0 g/dL 


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o Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase 
(SGOT) and/or alanine aminotransferase (ALT) serum glutamic pyruvic 
transaminase (SGPT) < 3.0 x ULN (< 5 x ULN in presence of liver metastasis).  
In patients with elevated ALT or AST, the values must be stable for at least 2 weeks  
and with no evidence of biliary obstruction on imaging  
o Total bilirubin ≤ 1.5 X ULN 
o INR ≤ 1.5 x ULN 
• Consent to provide protocol-mandated tissue and blood samples for diagnostic, PK, and 
research purposes 
• Able to adhere to study visit schedule and other protocol requirements 
 
3.3 
Exclusion Criteria 
A patient will not be eligible to participate in this study if any of the following criteria below are 
met: 
• Diagnosis of pancreatic neuroendocrine carcinoma or pancreatic acinar cell carcinoma 
• Previous immunotherapy (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, 
or any other antibody or drug specifically targeting T-cell co-stimulation or immune 
checkpoint pathways). 
• Known microsatellite instability-high (MSI-H) or mismatch repair-deficient pancreatic 
cancer  
• Prior treatment with canakinumab or drugs of a similar mechanism of action (IL-1 
inhibitor). 
• History of known hypersensitivity to any of the drugs used in this study or any of their 
excipients, or patient has contraindication to any of the study drugs as outlined in the local 
prescribing information (e.g. United States Prescribing Information [USPI]) 
• Active autoimmune disease that has required systemic treatment in the past 2 years prior  
to enrollment i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs. Control of the disorder with replacement therapy (e.g., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is permitted. 


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• Patient with suspected or proven immunocompromised state or infections, including: 
- 
Evidence of active or latent tuberculosis (TB) as determined by locally approved 
screening methods. If the results of the screening per local treatment guidelines or 
clinical practice require treatment, then the patient is not eligible. 
- 
Chronic or active hepatitis B or C 
- 
Known history of testing positive for Human Immunodeficiency Virus (HIV) 
infections.  
- 
Any other medical condition (such as active infection, treated or untreated), which in 
the opinion of the investigator places the patient at an unacceptable risk for 
participation in immunomodulatory therapy. 
Note: Patients with localized condition unlikely to lead to a systemic infection e.g. chronic 
nail fungal infection are eligible. 
• Allogeneic bone marrow or solid organ transplant 
• Treatment with any immune modulating agent in doses with systemic effects e.g.: 
- 
Systemic treatment with prednisone > 10 mg (or equivalent) for >14 days within 4 
weeks prior to the first dose of study treatment.   
- 
Equivalent dose of methotrexate > 15 mg weekly 
- 
Patient receiving any biologic drugs targeting the immune system (for example, TNF 
blockers, anakinra, rituximab, abatacept, or tocilizumab). 
- 
Note: Daily glucocorticoid-replacement for conditions such as adrenal or pituitary 
insufficiency is allowed. 
- 
Note: Topical, inhaled, or local steroid use in doses that are not considered to cause 
systemic effects are permitted (based on investigator’s discretion and consultation with 
the Medical Monitor if needed). 
• Patient has concurrent malignancy other than the disease under investigation, with 
exception of malignancy that was treated curatively and has not recurred within 2 years 
prior to the date of screening. Fully resected basal or squamous cell skin cancers, and any 
carcinoma in situ are eligible.  
• Uncontrolled or severe cardiac disease (history of unstable angina, myocardial infarction, 
coronary stenting, or bypass surgery within the prior 6 months), symptomatic congestive 


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heart failure, serious uncontrolled cardiac arrhythmia [including atrial flutter/fibrillation], 
requirement for inotropic support or use of devices for cardiac conditions 
[pacemakers/defibrillators]), uncontrolled hypertension defined by a systolic blood 
pressure =>160 mg and/or diastolic blood pressure =>100 mg Hg 
• Pre-existing peripheral neuropathy > Grade 1 (CTCAE V 5.0)  
• Receipt of live vaccines within 3 months prior to the first dose of study treatment or while 
on active treatment within the trial (examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral vaccine). Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are permitted. However, intranasal influenza vaccines (e.g. Flu-mist) are live 
attenuated vaccines and are not permitted.  
• Patient has had major surgery within 14 days prior to enrollment  
• Patient has symptomatic brain metastases, or brain metastases that require directed therapy 
(such as focal radiotherapy or surgery). Patients with treated brain metastases have to be 
neurologically stable and not using systemic steroids for at least 4 weeks prior to the study 
drug administration.  
• Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are willing to use highly effective methods of 
contraception during treatment with study drugs (canakinumab, spartalizumab, 
gemcitabine and nab-paclitaxel). 
• Highly effective contraception methods are required while on treatment and for 150 days 
after stopping spartalizumab. No contraception is required after treatment with 
canakinumab is stopped. Contraception use after chemotherapy is stopped should be 
followed per the local drug label requirements.  
 
Highly effective contraception methods include: 
- 
Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (i.e., calendar, ovulation, symptothermal, postovulation methods) 
and withdrawal are not acceptable methods of contraception 
- 
Female sterilization (have had bilateral surgical oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before 


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taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 
- 
Male sterilization (at least 6 months prior to screening). The vasectomized male partner 
should be the sole partner for that patient.  
- 
Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Note: Women of non-childbearing potential is defined as women who are physiologically 
and/or anatomically incapable of becoming pregnant, as now further described: 
- 
They are post-menopausal as evidenced by 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (i.e., age appropriate history of 
vasomotor symptoms). 
- 
They have had bilateral surgical oophorectomy (with or without hysterectomy), 
total hysterectomy or bilateral tubal ligation at least six weeks prior. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of 
childbearing potential. 
Note: Sexually active male patients and their partners who are women of childbearing 
potential should follow the contraception recommendations and any other precautionary 
measures as required by the local prescribing information for the SOC anti-cancer. 
• Any significant medical condition, laboratory abnormality or psychiatric condition that would 
constitute unacceptable safety risks to the patients, contraindicate patient participation in the 
clinical study, limit the patient’s ability to comply with study requirements, or compromise 
patient’s compliance with the protocol and all requirements of the study as stated in the 
Informed Consent Form. Significant medical conditions include but are not limited to known 
history or current interstitial lung disease or non-infectious pneumonitis, medical history or 
current diagnosis of myocarditis, chronic active hepatitis, liver cirrhosis or any other 


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significant liver disease with moderate to severe hepatic impairment (Child-Pugh B or C), 
serious non-healing wound/ulcer/bone fracture, uncompensated/symptomatic hypothyroidism, 
or requirement for hemodialysis or peritoneal dialysis. 
• Unwillingness or unable to comply with all requirement of the study as stated in the Informed 
Consent Form 
 
 
 
4.0 
STUDY TREATMENT AND DOSE MODIFICATION 
4.1 
Administration and Dosing 
For this study, the investigational drugs (INDs) are spartalizumab (PDR001) and canakinumab 
(ACZ885). The study treatment is defined as spartalizumab with canakinumab in combination with 
gemcitabine and nab-paclitaxel. Below are details of the dosing regimen and administration 
instructions for the four-drug combination. On days of combination therapy canakinumab will be 
administered first, followed by 30 min observation period. After the end of the observation period, 
spartalizumab will be administered. After spartalizumab infusion, patients should be closely 
observed for potential infusion-related reactions for at least 2 hours after the first two 
spartalizumab infusions (before administration of chemotherapy). The same may apply for the 
subsequent spartalizumab infusions if medically indicated. Observation for a specific period of 
time after for the 3rd and subsequent infusions is not necessary (unless medically indicated) but 
subjects should be provided instructions to notify the study personnel if symptoms of infusion 
reaction occur after any spartlizumab infusion. Any pre-medication for the chemotherapies should 
be administered at least 30 minutes after the end of the infusion of spartalizumab (for additional 
detials see Section 5.4).  
For the non-investigational drugs (gemcitabine and nab-paclitaxel), prescribing information and 
local institutional practice are to be followed. All dosages prescribed and dispensed to the patient 
and all dose changes during the study must be recorded on the appropriate eCRF page. 


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4.1.1 Gemcitabine and nab-paclitaxel 
Gemcitabine and nab-paclitaxel are FDA approved therapies for metastatic pancreatic cancer and 
will be supplied or obtained according to local clinical study agreements and in accordance with 
local guidelines. Additional information may be included on the label as needed or applicable.  
The following are recommended parameters for infusion timing and sequence of gemcitabine and 
nab-paclitaxel, although institutional variation in the administration of the regimen are permitted 
as long as drug dosing and modification guidelines are followed. 
• Nab-paclitaxel is infused at an initial dose of 125 mg/m2 over 30-40 min on days 1, 8, 15 
of each 28-day cycle. 
• Gemcitabine is infused at an initial dose of 1000 mg/m2 over 30 min, immediately after 
completion of nab-paclitaxel infusion, on days 1, 8, 15 of each 28-day cycle 
Doses should be re-adjusted if the patient’s BSA changes by +/- >10%. If the patient’s BSA 
changes by <10%, no adjustment is necessary unless the site has a standard procedure to adjust 
doses based upon current BSA according to institutional guidelines.  
Specifics on dosing and toxicity modifications for gemcitabine and nab-paclitaxel can be found in 
their Package Inserts (Appendix A).  
 
4.1.2 Canakinumab 
Canakinumab is provided as ready-to use pre-filled syringes to be administered by study center 
personnel.  Two strengths of solution for injection will be supplied: 
• Canakinumab 50 mg/ 0.5 mL 
• Canakinumab 200 mg/ 1.33 mL  
 
The starting dose of canakinumab will be 250 mg, administer subcutaneously (SC) in the abdomen, 
upper outer thigh or upper outer arm once every 4 weeks. To administer a target dose of 
canakinumab of 250 mg, two separate subcutaneous injections (one of 200 mg and one of 50 mg)  
must be administered to the patient at a visit. Pre-medication to prevent injection reaction before 
the first administration of canakinumab is not recommended. For additional guidance refer to 
canakinumab (ACZ885) Instructions for Use/ and to the canakinumab Investigators Brochure.  


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4.1.3 Spartalizumab 
Spartalizumab will be supplied in a liquid solution. The starting dose of spartalizumab is 400 mg 
(prepared by reconstituting four vials with sterile water for injection (SWFI) and diluted in a 5% 
dextrose infusion bag before use) administered via intravenous infusion over 30 minutes (up to 2 
hours, if clinically indicated) once every 4 weeks. Infusion of spartalizumab 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.  
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 2 hours after the first two 
spartalizumab infusions (before administration of chemotherapy).  Observation for a specified 
period of time for the 3rd and subsequent infusions is not necessary (unless medically indicated) 
but subjects should be provided instructions to notify the study personnel if symptoms of infusion 
reaction occur after any spartalizumab infusion. Patients should not receive pre-medication to 
prevent infusion reaction before the first infusion of study treatment. If a patient experiences an 
infusion reaction, he/she may receive premedication on subsequent dosing days. The pre-
medication should be chosen per institutional standard of care, at the discretion of the investigator. 
Please refer to Table 4-15 below for additional details.  The same may apply for the subsequent 
spartalizumab infusions if medically indicated. 
For additional guidance refer to Spartalizumab (PDR001) Pharmacy Manual and to the 
spartalizumab Investigator’s Brochure. 
4.1.4 Initial Dosing Schedule 
Table 4-1. Initial Dose and Treatment Schedule  
Study 
treatments 
Pharmaceutical 
form and route of 
administration 
Strength  
Starting 
Frequency and/or 
Regimen 
Dose 
Administered 
Spartalizumab 
(PDR001) 
Concentrate 
for 
solution 
for 
IV 
infusion 
 4 x 100 mg 
vials 
Day 1 of each 28-
day cycle 
 
400 mg  
 


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Study 
treatments 
Pharmaceutical 
form and route of 
administration 
Strength  
Starting 
Frequency and/or 
Regimen 
Dose 
Administered 
Canakinumab 
(ACZ885) 
Solution 
for 
s.c. 
injection  
in prefilled syringe 
200 
mg/1.33 
mL AND 1 x  
50 mg/0.5 mL 
Day 1 of each 28-
day cycle  
250 mg 
Gemcitabine 
IV 
 
Days 1, 8, 15 of  
each 28-day cycle    
1000 mg/m2 
Nab-paclitaxel 
IV 
 
Days 1, 8, 15 of  
each 28-day cycle    
125 mg/m2 
 
 
4.1.5 Dose Recommendation Guideline for Study Cohort 
Approximately ten patients will be enrolled initially to have at least 6 evaluable patients per dose 
level (additional patients maybe enrolled as needed in order to have 6 evaluable patients). The 
evaluable criteria are defined in Dose Determining Set (DDS) , and the evaluable patients will be 
included in the Dose-Determining set. Patients must complete a minimum of 56 days (8 weeks) of 
dosing of study treatment with the minimum safety evaluation and drug exposure or have had a 
DLT within the first 56 days of study treatment to be considered evaluable for recommended dose 
decisions (Please refer to Section 9.1.3 for further details). Additional approximately ten patients 
(to have at least 6 additional evaluable patients) may be enrolled at lower dose level in case a dose 
de-escalation is necessary.   
 
Table 4-1 defines the starting dose level.  In case of unaccepatable toxicility of the starting dose 
devel,  the enrollment to the current dose level will be stopped and a lower dose (-1 dose level) 
will be used.  At the -1 dose level,  canakinumab is adminstered at 250 mg s.c Q8W while other 
components of the combination stay the same as the starting dose level.  Table 4-2 below describes 
the starting dose and the -1 dose level in case the starting dose has unacceptable toxicity.   
  


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Table 4-2: Provisional dose levels for the canakimumab with fixed dosage of spartalizumab, 
Gemcitabine and nab-paclitaxel  
Dose level 
Proposed dose of canakinumab 
 
 
 
 
1 (starting dose) 
250 mg s.c. Q4W Canakinumab 
 
-1* 
250 mg s.c Q8W  Canakinumab 
 
Spartlizumab:  400 mg s.c. Q4W;  Gemcitabine: 1000 mg/m2+ nab-paclitaxel 125 mg/m2 (on day 1, 8, and 15 of 
every cycle). 
  
*Dose level -1 represents the treatment dose for patients requiring a dose reduction from the starting dose level.  
 
As the starting dose is the highest provisional dose level, this dose may be declared the 
recommended dose. This could occur if a minimum of 6 evaluable patients has been treated and 
deemed evaluable at this dose, and the dose is considered safe by BLRM and it is the dose 
recommended for patients after the review of all clinical databy investigators and Novartis. At the 
Dose Confirmation Meeting the Safety Review Team (composed at least of a clinician, patient 
safety representative and biostatistician) would review all available toxicity information (including 
adverse events and laboratory abnormalities that are not DLTs) and the available PK information. 
 
The decision on dose tolerability will be based on all relevant data from the ongoing study and a 
review of safety data from the first 8 weeks. A Bayesian logistic regression model (BLRM) for 
combinations using the escalation with overdose control (EWOC) criterion to evaluate the risk of 
DLT will guide the decision.  The details of the BLRM are provided in Section 9.4 and Appendix 
B.   The adaptive Bayesian methodology provides an estimate of all dose levels of the combination 
and incorporates all DLT information at all dose levels for this estimation. To limit the patient 
exposure to DLT,  if 2 or more patients in the starting dose level (or -1 dose level) experienced a 
DLT, Novartis should be notified and the BLRM will be updated with this new information. 
Additional patients may be continued into the current dose cohort only if the combination still 
meets the EWOC criteria and as agreed by Investigators and Novartis personnel.  
 
4.1.5.1 
Definitions of Dose Limiting Toxicities (DLTs) 
A dose-limiting toxicity (DLT) is defined as an adverse event (AE) or abnormal laboratory value 
assessed as unrelated to disease, disease progression, inter-current illness, or concomitant 
medications that occurs within the first 8 weeks of study treatment and at least possibly related to 


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the study drugs. The investigator must notify the sponsor immediately (within 24 hours of the 
treating physician’s knowledge) of any unexpected CTCAE grade ≥ 3 AEs or laboratory 
abnormalities. NCI CTCAE v5.0 will be used for all grading. 
Table 4-3:   Criteria for Defining Dose-Limiting Toxicities 
TOXICITY 
DLT CRITERIA (NCI CTCAE v5.0 will be used for grading) 
Cardiac 
• Grade ≥ 3 cardiac events 
Cutaneous 
reactions 
• Grade ≥ 3 
Gastrointestinal 
• Grade 3 nausea and vomiting for > 3 days despite optimal anti-emetic 
therapy 
• Grade 3 diarrhea for > 5 days despite optimal antidiarrheal treatment 
(which could include steroids) 
• Grade 4 vomiting or diarrhea 
Hematological 
• Grade 4 neutropenia for > 7 consecutive days, or grade 4 febrile 
neutropenia 
• Grade 4 anemia 
• Grade 3 thrombocytopenia with clinically significant bleeding (i.e. life 
threatening and invasive intervention indicated) regardless of duration 
or requirement for transfusion, or grade 4 thrombocytopenia 
(<25,000/mm3)  
Hepatobiliary 
• Grade 4 bilirubin elevation 
• For patients with normal baseline AST, ALT and bilirubin values: 
- 
AST or ALT > 8.0 × ULN; OR 
- 
AST or ALT > 5.0 × ULN for more than 2 weeks; OR 
- 
AST or ALT > 3.0 × ULN combined with total bilirubin > 2.0 × 
ULN without evidence of cholestasis 
• For patients with abnormal baseline AST or ALT or abnormal baseline 
bilirubin value: 
- 
ALT or AST > 3.0 x baseline value; OR 
- 
ALT or AST > 3.0 x baseline (or > 8.0 x ULN), whichever is lower, 
combined with total bilirubin > 2.0 x baseline and > 2.0 x ULN 
without evidence of cholestasis  
Immune-related 
toxicities 
(except 
pneumonitis) 
• Grade 3 immune-related toxicities that persist > 14 days with same 
severity despite treatment with corticosteroids. 
• Grade 4 immune related toxicities of any duration 
• Grade ≥ 3 infusion related reaction 
Infections 
• Grade 4 
Hypertension 
• Grade 3 hypertension if it persists > 7 days despite optimal anti-
hypertensive treatment 
• Grade 4 hypertension of any duration 


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Pancreatitis 
• Symptomatic serum amylase or lipase elevation, medical intervention 
required 
• Grade ≥ 3 pancreatitis 
Peripheral 
neuropathy 
• Grade ≥ 3 
Pneumonitis  
• Grade 2 pneumonitis if it persists > 7 days despite treatment with 
corticosteroids 
• Grade ≥ 3 pneumonitis of any duration 
Other AEs 
Other clinically significant AEs: 
• grade ≥ 3 AEs that have not been previously identified for canakinumab 
or spartalizumab or grade 4 AEs that have not been previously identified 
for gemcitabine and nab-paclitaxel 
• grade ≥ 3 AEs that are known to occur with canakinumab or 
spartalizumab, or grade 4 AEs that are known to occur with gemcitabine 
and nab-paclitaxel, but cannot be controlled using the recommended 
product-specific management guidelines (per local prescribing 
information), or leads to ˂50% of planned exposure of study 
medications 
• Other clinically-significant AEs, including a single event or multiple 
occurrences of the same event that lead to a dosing delay of > 8 weeks 
should be considered as DLTs by the Investigators and the sponsor, 
even if not grade 3 or higher 
 
Events which will NOT be considered as DLT for the purpose of this protocol: 
• Clinically insignificant laboratory values ≤ grade 2.  
• For electrolyte abnormalities ≥ grade 3, the maximum allowable time limit for correction  
to ≤ grade 1 is 72 hours. 
 
4.2 Dose Modifications 
4.2.1 Dose Modifications of Gemcitabine and Nab-Paclitaxel 
Toxicities for gemcitabine and nab-paclitaxel are graded based on Tables 4-4 and 4-5 below 
(according to CTCAE v5.0). Dose adjustments are to be made according to the system showing 
the greatest degree of toxicity. Please refer to the gemcitabine and nab-paclitaxel package inserts 
(Appendix A).  








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please see Section 4.2.3 and Tables 4-6 and 4-7 below.  For dose modifications of spartalizumab 
please see Sections 4.2.4 and 4.2.5 below.  
If canakinumab is interrupted for more than 12 weeks or a subject misses more than two doses of 
canakinumab due to canakinumab-related toxicities (whichever is longer), canakinumab must be 
permanently discontinued. If the chemotherapy drugs need to be interrupted due to chemotherapy-
related toxicity, canakinumab and spartalizumab can be continued if a patient is clinically 
benefitting from the treatment until disease progression per RECIST 1.1, intolerable toxicity, or 
any other conditions specified in Section 5.4.2. 
If spartalizumab and chemotherapy drugs are permanently discontinued due to toxicity, the 
investigator can continue canakinumab until disease progression per RECIST 1.1 or any other 
conditions for treatment discontinuation as defined Section 5.4.2, whichever is earlier. 
4.2.3 Dose Modification Guidelines for Canakinumab 
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions are 
permitted in order to allow patients to continue the study treatment. There are no canakinumab 
dose reductions allowed. However, if required, dose regimen modification by adjusting the interval 
between doses can be allowed (from Q4W to Q8W). 
Table 4-7.  Criteria for Dose Interruption and Re-Initiation of Canakinumab for Adverse 
Events at least possibly related to canakinumab treatment 
 
Worst toxicity 
(CTCAE v5.0) during a 
cycle of therapy 
Mandatory dose schedule modifications for canakinumab 
General guidance for adverse drug reaction (to be followed whenever no other specific guidance is 
described in this table) 
Grade 1/ Grade 2 
Maintain dose level 
Grade 3 
Interrupt dose until resolved to ≤ grade 2, then increase canakinumab 
dosing intervala 
Grade 4 
Permanently discontinue canakinumab 
Exceptions to the above general guidanceb 
Infections 


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Worst toxicity 
(CTCAE v5.0) during a 
cycle of therapy 
Mandatory dose schedule modifications for canakinumab 
Grade 2 
Maintain dose level.  
For an infection that requires medical intervention, if it persists for >14  
days despite appropriate treatment, then interrupt dose until infection 
resolves to <grade 2; then resume treatment and maintain dose 
Grade 3 
Omit dose until resolved to <grade 2, then maintain dose and schedule 
Neutropenia (ANC) 
Grade 2  
Interrupt until ≤ grade 1, then maintain dose 
Grade 3 
Interrupt until resolved to ≤ grade 1, then: 
• For subjects receiving chemotherapy, maintain canakinumab dosing 
interval, only delay canakinumab dose to match chemotherapy dosing 
• After permanent discontinuation of chemotherapy, increase 
canakinumab dosing intervala 
Grade 4  
• If ≤7 consecutive days, omit dose until resolved to ≤ grade 1, then 
maintain dose and schedule 
• If >7 consecutive days,  permanently discontinue canakinumab 
Febrile neutropenia 
Grade 3 
Omit dose until resolved, then maintain dose and schedule 
Grade 4 
Permanently discontinue canakinumab 
Thrombocytopenia 
Grade 3 
Interrupt dose until resolved to ≤ grade 1, then: 
• If resolved in ≤ 7 days, then maintain dose level 
• If resolved in > 7 - increase canakinumab dosing intervala 
• With clinically significant bleeding (i.e. life threatening or invasive 
intervention indicated) - increase canakinumab dosing intervala 
Serum creatinine 
Grade 2 
• Maintain dose level; monitor other renal functions (e.g. creatinine 
clearance, glomerular filtration rate/GFR, blood urea nitrogen/BUN, 
urinalysis).  
• If elevated creatinine level persists at grade 2 for >14 days despite 
appropriate management for other underlying contributing factors, 
interrupt the dose until resolved to <grade 2 or baseline, then resume 
treatment and increase dosing interval of canakinumab  
Grade 3 
• 1st occurrence: Omit dose until resolved to ≤ grade 1 or baseline, then 
maintain dose and schedule  
• 2nd occurrence: Permanently discontinue treatment 
Isolated total bilirubin elevation* 
Any elevation > ULN  
 
Fractionate bilirubin, evaluate for cholestatic liver injury (ALP) or 
alternative causes of bilirubin elevation (e.g. disease progression 
[imaging]). Treat alternative causes according to local institutional 
guidelines 
Grade 2: > 1.5 - 3.0 x ULN 
• Maintain treatment.  
• Repeat LFTs within 48-72 hours, then monitor LFTs weekly until 
resolution to ≤ grade 1 or to baseline 
• If isolated bilirubin remains stable at grade 2, continue treatment with 
canakinumab at the same dosing interval  


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Worst toxicity 
(CTCAE v5.0) during a 
cycle of therapy 
Mandatory dose schedule modifications for canakinumab 
Grade 3: >3.0 – 10 ULN 
Interrupt treatment.   
Repeat LFTs within 48-72 hours, monitor LFTs weekly until resolution to 
≤ grade 1 or to baseline. 
 
If resolved in ≤ 14 days, maintain dose regimen; if not resolved in 14 
days, permanently discontinue canakinumab. (Please see foot-note 
regarding alternative cause/s of bilirubin elevation). 
Grade 4: > 10 x ULN 
See footnote* - otherwise permanently discontinue treatment 
 
If alternative cause/s is identified and managed, and bilirubin resolves to 
≤ grade 1 or to baseline, resume canakinumab at the same dose 
regimen. 
* An isolated bilirubin elevation is not typical for DILI. Bilirubin can be elevated either as part of a “Hy’s law” 
constellation with a preceding elevation of ALT/AST, or as part of a cholestatic reaction with simultaneous elevation 
of other cholestatic parameters (ALP, GGT). Isolated bilirubin can be seen in conjunction with drugs that inhibit 
bilirubin conjugation or excretion, but both scenarios do not typically represent liver injury. Alternative causes of 
bilirubin elevation should therefore, be ruled out before basing dose modification decisions on bilirubin values alone. 
Isolated AST or ALT elevation 
Grade 1, 2 
May continue canakinumab treatment 
Grade 3: >5 - 20 x ULN* 
 
With normal baseline: 
 
AST or ALT >5.0 –  10.0 x 
ULN 
Interrupt treatment. Repeat LFTs within 48-72 hours, then monitor LFTs 
weekly until recovery to grade ≤1 or to baseline.  
If resolved in ≤ 14 days, maintain dose level; if resolved in > 14 days, 
reduce by 1 dose level. 
AST or ALT >10.0 – 20.0 x 
ULN 
Interrupt treatment. Repeat LFTs within 48-72 hours, then monitor LFTs 
weekly until recovery to grade ≤1 or to baseline.  
Then reduce by 1 dose level. 
With abnormal baseline ALT/AST (up to grade 2: ≤  5.0 ULN): 
ALT/AST > 2.0 x baseline 
AND > 5.0 x ULN  
 
Interrupt treatment. Repeat LFTs within 48-72 hours, then monitor LFTs 
weekly until recovery to baseline. If resolved in ≤ 14 days, maintain dose 
level; if resolved in > 14 days, reduce by 1 dose level 
ALT/AST > 3.0 x baseline 
AND >10 x ULN 
Interrupt treatment. Repeat LFTs within 48-72 hours, then monitor weekly 
until resolved to baseline, then reduce by 1 dose level 
Grade 4: >20 x ULN* 
Permanently discontinue treatment 
Combined elevations of AST or ALT and total bilirubin  
With normal baseline LFTs: 
Grade 2 ALT/AST ( >3.0 x 
ULN) 
with bilirubin > 2.0 x ULN 
(unless Gilbert's syndrome) 
Interrupt study treatment. Assess if case is true DILI.*     
• If DILI confirmed - Permanently discontinue. 
• If Not DILI – interrupt treatment. Treat the identified                                 
cause according to institutional guidelines. Repeat LFTs within 48-72 
hours, then monitor weekly, till enzyme levels resolve to ≤Grade 1 or 
Baseline.                                                                                                    
With abnormal baseline LFTs: 
ALT or AST >3.0  x baseline  
After recovery, re-administration of study treatment could be considered 
only if Investigator assesses benefit to outweigh the risk. Any decision 


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Worst toxicity 
(CTCAE v5.0) during a 
cycle of therapy 
Mandatory dose schedule modifications for canakinumab 
OR  ALT or AST >8.0 x ULN 
[which ever is lower) 
combined with total 
bilirubin >2.0 x baseline 
AND >2.0 x ULN                      
regarding re-administration of study drug/s and dose regimen should be 
discussed with the Sponsor.                                                                           
* For additional information on follow-up of potential drug induced liver injury cases, refer to section 4.3.2 
Pancreatitis  
Grade 3 
Permanently discontinue canakinumab 
Hypertension 
Grade 3 
• Interrupt dose until resolved ≤ grade 1, if resolved within ≤7 days then 
maintain dose level 
• if it persists > 7 days despite optimal anti-hypertensive treatment -  
then increase canakinumab dosing interval 
Diarrhea - institute appropriate anti-diarrheal treatment and follow general guidelines 
Rash/photosensitivity - initiate/institute appropriate skin toxicity therapy (such as antihistamines and/or 
topical corticosteroids) and follow general guidelines. 
Grade 3  
Omit dose until resolved to grade ≤1 
• if resolved ≤7 days – increase canakinumab dosing interval 
• if resolved >7 days despite optimal therapy – permanently discontinue 
canakinumab 
Steven Johnson Syndrome, Toxic epidermal necrolysis 
• 
Permanently discontinue canakinumab 
Tuberculosis or reactivation of hepatitis 
• 
Permanently discontinue canakinumab 
Asymptomatic laboratory abnormalities-   
• 
If clinically significant, follow general guidelines 
DILI – drug-induced liver injury; LFTs- Liver function Tests 
a Canakinumab dosing interval can be increased from Q4W to Q8W. 
b If relatedness to canakinumab can be excluded with certainty and there is no risk for the patient, the dose 
modification for canakinumab is not mandatory 
 
4.2.4 Dose modification and Dose Interruption for spartalizumab 
The following sections address the specific instructions for mandatory and recommended dose 
modifications and recommended management for adverse events considered suspected to be 
related to spartalizumab. These modifications/interruptions must be recorded on the Dosage 
Administration Record CRF. 


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4.2.4.1 General dose modification instructions for spartalizumab 
No dose reductions of spartalizumab are allowed. Dose interruption for spartalizumab includes 
delaying or withholding the treatment for any reason as well as an interruption of treatment. 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 study 
treatment as outlined in Section 4.2.5 below.  
 
4.2.5 Dose modification and Management Requirements for Potential Immune-
Mediated Adverse Events (irAEs) 
Adverse events of a potential immune-mediated etiology (irAE) can be associated with 
spartalizumab treatment. 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. Collaboration with disease-specific subspecialties is 
encouraged; corticosteroids are the mainstay of treatment for most irAEs.  
An irAE may be of low grade and self-limited, most frequently involving the GI tract (e.g. 
diarrhea/colitis), skin (e.g. rashes, pruritus), liver (e.g. hepatitis), lung (e.g. pneumonitis), kidneys 
(e.g. nephritis) and endocrine systems (e.g. hypothyroidism, hyperthyroidism, type I diabetes, 
hypophysitis including hypopituitarism and adrenal insufficiency). Other immune-mediated AEs 
may rarely include the nervous system (e.g. encephalitis, Guillain-Barre syndrome, myasthenia 
gravis), eye (e.g. uveitis, vision changes), musculo-skeletal system (e.g. myositis, arthritis), 
pancreas (e.g. pancreatitis), cardio-vascular system (e.g. vasculitis, myocarditis) or blood system 
(e.g. anemia, cytopenias), and severe skin reactions such as toxic epidermal necrolysis (TEN) or 
Steven Johnson syndrome (SJS). Furthermore, complications in patients with bone marrow or solid 
organ transplant have been reported (e.g. organ rejection, severe graft-versus-host disease). 
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.  


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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 (TNFα) 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 immunosuppressants. Some events like endocrinopathies may 
require life-long hormonal replacement.  
Tapering of steroids should not be too rapid (i.e. >4 weeks) 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 clinical experience and published guidelines on the management of irAEs in patients 
treated with immune checkpoint inhibitors (Brahmer et al, 2018, Haanen et al, 2017, NCCN 2018), 
instructions have been developed how to manage irAEs that may occur in patients receiving 
spartalizumab with canakinumab. Dose modification requirements and AE management 
guidelines for the potential irAEs are provided in the following tables: diarrhea/colitis (Table 4-
8), hepatitis (liver laboratory alterations) (Table 4-9), skin toxicity (Table 4-10), nephritis (Table 
4-11), pneumonitis (Table 4-12), endocrinopathies (Table 4-13), and other potential immune-
related AEs (Table 4-14). In addition, guidance for management of spartalizumab infusion-related 
reactions is provided in (Table 4-15). 
Investigators are encouraged to contact the Medical Monitor/ Sponsor as needed to discuss cases 
that warrant separate discussion outside of the scope of the current instructions.  


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The dosing modification requirements are mandatory or recommended depending on AE, 
however, the AE management guidelines are recommendations and can be modified according to 
the local practices.  
 
Table 4-8. Mandatory dose modification requirements and recommended clinical 
management guidelines for potential immune-related diarrhea/colitis at least 
possibly related to spartalizumab treatment 
 
 
Diarrhea and/or Colitis  
Grade  
Recommended adverse event 
management guidelines 
Mandatory dose 
modification 
requirements (unless 
specified otherwise) 
Grade 1 diarrhea: < 4 stools 
per day over baseline 
 
Grade 1 colitis: 
asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated 
• Symptomatic treatment  (hydration, diet) 
• Monitor closely 
May continue treatment 
(recommendation) 
Grade 2 diarrhea: 4-6 stools 
per day over baseline  
 
Grade 2 colitis: abdominal 
pain; mucus or blood in stool 
• Consult with GI specialist 
• Stool evaluation, imaging and endoscopy 
as clinically indicated 
• Symptomatic treatment (hydration, diet) 
• Commence steroids (0.5-1 mg/kg/d 
prednisone or IV equivalent) until 
recovery to grade 1, particularly in case 
of persisting/worsening symptoms, 
ulcerations or bleeding seen on 
endoscopy, or blood in stool. If no 
improvement within few days, manage as 
per Grade 3. 
• Slowly taper steroids once symptoms 
improve to Grade 1 (i.e. over 4-6 weeks) 
• Interrupt treatment 
until diarrhea/colitis 
recover to grade ≤1 
or baseline 
Grade 3 diarrhea: increase of 
≥7 stools per day over 
baseline; incontinence; 
hospitalization indicated; 
limiting self-care ADL 
 
Grade 3 colitis: severe 
abdominal pain; peritoneal 
signs 
 
• Consider hospitalization; rule out bowel 
perforation and initiate IV hydration as 
needed 
• Consultation with GI specialist; consider 
endoscopy and biopsy  
• In addition to symptomatic treatment, 
initiate treatment with IV steroids (1 to 2 
mg/kg/d of methylprednisolone or 
equivalent) 
• Consider antibiotics as appropriate 
• Interrupt treatment 
until diarrhea/colitis 
recover to grade ≤1 
or baseline 
 


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Diarrhea and/or Colitis  
Grade  
Recommended adverse event 
management guidelines 
Mandatory dose 
modification 
requirements (unless 
specified otherwise) 
• If no improvement in 2-3 days: consider 
initiating infliximab 5 mg/kg and continue 
steroids. (infliximab is contraindicated in 
patients with sepsis/perforation) 
• Slowly taper steroids once symptoms 
improve to grade 1 (4 to 6 weeks) 
• If symptoms worsen during steroid 
reduction, re-escalate as needed 
followed by more prolonged taper and 
consider infliximab 
Grade 4 diarrhea or colitis: 
life-threatening 
consequences; urgent 
intervention indicated 
Same as for grade 3 
Permanently 
discontinue treatment 
 
 
 
Table 4-9. Mandatory dose modification requirements and recommended clinical 
management guidelines for potential immune-related liver laboratory alterations 
at least possibly related to spartalizumab treatment 
  
 
Abnormal liver function tests 
Severity 
Recommended 
adverse event 
management 
guidelines 
Mandatory dose modification requirements  
Isolated AST and/or ALT elevation 
With normal AST and ALT at baseline: 
Grade 3: AST or ALT 
(>5.0 – 20.0) x ULN: 
AST or ALT >5.0 –  10.0 
x ULN 
Start oral prednisolone 
1 mg/kg 
 
 
Interrupt treatment.  
Repeat LFTs within 48-72 hours, then monitor 
LFTs weekly until recovery to grade ≤1 or to 
baseline; then resume same dose  
AST or ALT >10.0 – 20.0 
x ULN 
Start I.V. (methyl) 
prednisolone 1-2 
mg/kg 
Permanently  discontinue study treatment. 
Monitor LFTs within 48-72 hours, then monitor 
LFTs weekly until recovery to grade ≤1 or to 
baseline.  
Grade 4: AST or ALT 
(>20 x ULN) 
Start I.V. (methyl) 
prednisolone 2 mg/kg 
 
Permanently discontinue treatment 
 


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Abnormal liver function tests 
Severity 
Recommended 
adverse event 
management 
guidelines 
Mandatory dose modification requirements  
Isolated AST and/or ALT elevation 
With abnormal ALT/AST (up to grade 2 -  ≤ 5.0 x ULN) at baseline: 
ALT/AST > 2.0 x baseline 
AND > 5.0 x ULN  
If rising ALT/AST when 
re-checked, start oral 
prednisolone 1 mg/kg 
Interrupt treatment.  
Repeat LFTs within 48-72 hours, then monitor 
LFTs weekly until recovery to baseline; then 
resume same dose.  
• 
 
ALT/AST > 3.0 x baseline 
AND >10 x ULN 
Start oral prednisone/ 
prednisolone 1-2 mg/kg 
Interrupt treatment.  
Repeat LFTs within 48-72 hours, then monitor 
weekly until resolved to baseline, then resume 
same dose.  
 
AST or ALT >20 x ULN 
(grade 4) 
Start I.V. (methyl) 
prednisolone 1-2 mg/kg 
Permanently discontinue treatment. 
Concomitant elevation of AST and/or ALT and total bilirubin 
With normal AST/ALT and bilirubin at baseline:  
Grade 2 ALT and/or 
AST elevation ( >3.0 x 
ULN) with bilirubin > 
2.0 x ULN (unless 
Gilbert's syndrome)        
Start I.V. (methyl) 
prednisolone 1-2 
mg/kg 
Interrupt treatment. Assess if case is drug induced 
liver injury (DILI) -      
• If DILI confirmed, permanently discontinue study 
treatment. For additional information on follow-up 
of potential drug induced liver injury cases, refer 
to section 4.3.2. If no DILI confirmed, interrupt 
treatment, treat the identified cause according to 
institutional                                                 
guidelines. 
Repeat LFTs within 48-72 hours, then monitor 
weekly, till enzyme levels resolve to ≤grade 1 or 
baseline.                                                                          
After recovery, re-administration of study treatment 
could be considered only if Investigator assesses 
benefit to outweigh the risk. Any decision regarding 
re-administration of study drugs and dose regimen 
should be discussed with the Medical Monitor.               
With abnormal ALT/AST at baseline: 
ALT or AST >3.0  x 
baseline OR  ALT or 
AST >8.0 x ULN             
[whichever is lower]        
combined with total 
bilirubin >2.0 x 
baseline AND >2.0 x 
ULN                                   
Start oral 
prednisone/ 
prednisolone 1-2 
mg/kgf 
Same as above 


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Isolated total bilirubin elevation 
Any elevation > ULN 
 
Fractionate bilirubin, evaluate for cholestatic liver 
injury (e.g. by testing ALP) or alternative causes of 
bilirubin elevation (e.g. disease progression 
[imaging]). Treat alternative causes according to 
institutional guidelines 
Grade 2 (>1.5 - 3.0 
ULN) 
 
Maintain treatment.  
Repeat LFTs within 48-72 hours, then monitor LFTs 
weekly until resolution to ≤ grade 1 or to baseline. 
If isolated bilirubin remains stable at Grade 2, 
continue treatment with spartalizumab at the same 
dose regimen. 
Grade 3 (>3.0 – 10 
ULN) 
 
 
Interrupt treatment.  
Repeat LFTs within 48-72 hours, then monitor LFTs 
weekly until resolution to ≤ Grade 1 or to baseline.  
Grade 4 (> 10 x ULN) 
 
See footnote*- otherwise discontinue treatment 
Foot note:  an isolated bilirubin elevation is not typical for DILI. Bilirubin can be elevated either as part of a “Hy’s 
law” constellation with a preceding elevation of ALT/AST, or as part of a cholestatic reaction with simultaneous 
elevation of other cholestatic parameters (ALP, GGT). Isolated bilirubin can be seen in conjunction with drugs that 
inhibit bilirubin conjugation or excretion, but both scenarios do not typically represent liver injury. Alternative 
causes of bilirubin elevation should therefore, be ruled out before basing dose modification decisions on bilirubin 
values alone. 


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Table 4-10. Mandatory dose modification requirements and recommended clinical  
                    management 
guidelines 
for 
potential 
immune-related 
skin 
events                        
at least possibly related to spartalizumab treatment 
Skin Events  
Grade  
Recommended adverse event 
management guidelines 
Mandatory dose 
modification requirements 
(unless specified 
otherwise) 
Grade 1 (e.g. rash, pruritus) 
• Initiate prophylactic and 
symptomatic treatment 
• Consider mild/moderate potency 
topical steroids or urea containing 
creams in combination with oral 
antipruritics 
• Reassess after 2 weeks 
May continue treatment 
(recommendation) 
 
Grade 2 (e.g. rash, pruritus) 
• Consider initiating systemic 
steroids (e.g. oral prednisolone 
0.5-1mg/kg daily).  
• In addition, treat with topical 
emollients, oral antihistamines, 
and medium/high-potency topical 
steroids 
• If symptoms persist or recur 
consider skin biopsy 
• 
Consider dose 
interruption 
(recommendation) 
• 
In case of bullous 
dermatitis, acute 
generalized 
exanthematous 
pustulosis or DRESS, 
interrupt spartalizumab 
until recovery to grade ≤1 
or baseline (mandatory) 
Grade 3 (e.g. rash, pruritus 
and other severe cutaneous 
adverse reactions, bullous 
dermatitis) 
• Consult with dermatologist and 
consider skin biopsy.  
• Initiate systemic steroids (1 
mg/kg/d prednisone or IV 
equivalent); consider increasing if 
no improvement 
• High-potency topical steroids  
• Topical emollients, oral 
antihistamines as indicated 
• Consider GABA agonists or 
aprepitant in case of severe 
pruritus 
• Interrupt treatment until 
recovery to grade ≤1 or 
baseline 
• For patients with severe 
cutaneous adverse 
reaction or bullous 
dermatitis, risk/benefit 
before resuming treatment 
should be carefully 
considered.  
Grade 4: life-threatening 
• 
Urgent dermatologic consultation 
and additional measures as per 
local guidelines  
Permanently discontinue 
treatment 
Stevens-Johnson syndrome, 
toxic epidermal necrolysis 
• Hospitalization and urgent 
dermatology consultation 
• Institute supportive care 
immediately as per institutional 
guidelines 
Permanently discontinue 
treatment  
 


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Table 4-11. Mandatory dose modification requirements and recommended clinical  
                    management guidelines for potential immune-related nephritis at least possibly  
                    related to spartalizumab treatment 
 
Nephritis 
Creatinine increased 
Recommended adverse event 
management guidelines 
Mandatory dose 
modification 
requirements (unless 
specified otherwise) 
Creatinine >ULN  to ≤1.5x 
ULN; >1 to ≤1.5x baseline 
• 
Monitor creatinine weekly 
• 
Rule-out other causes (e.g. fluids, 
medications, IV contrast) 
• 
Promote hydration and consider 
cessation of nephrotoxic drugs 
May continue treatment 
(recommendation) 
 
Creatinine >1.5 to ≤3 x 
ULN; >1.5 to ≤3 x baseline 
• Monitor creatinine every 2 to 3 days and 
consult with nephrologist 
• Rule-out other causes (e.g. fluids, 
medications, IV contrast) 
• Initiate 0.5 to 1 mg/kg/d prednisone or 
equivalents if other causes are ruled-out 
• If worsening or no improvement: 1 to 2 
mg/kg/d prednisone or equivalents 
• Promote hydration and cessation of 
nephrotoxic drugs 
• Consider renal biopsy 
Interrupt treatment until 
serum creatinine 
recovers to ≤ grade 1 or 
baseline.  
 
Creatinine >3.0 ULN 
• Monitor creatinine every 1 to 2 days and 
consider hospitalization 
• Consult with nephrologist and consider 
renal biopsy 
• Start 1 to 2 mg/kg/d prednisone or 
equivalents 
• Once event improves to grade ≤1, 
slowly taper steroids over at least 4-6 
weeks 
Permanently 
discontinue treatment 
 
 
 


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Table 4-12. Mandatory dose modification requirements and recommended clinical  
                    management guidelines for potential immune-related pneumonitis                                
                    at least possibly related to spartalizumab treatment 
 
Pneumonitis   
Grade  
Recommended adverse event 
management guidelines 
Mandatory dose 
modification 
requirements (unless 
specified otherwise) 
Grade 1: asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not indicated  
 
• Confirm diagnosis by appropriate 
investigations (CT scan) and rule out 
other causes e.g. infection.  
• Chest imaging/CT scan; repeat imaging 
in 3-4 weeks or as clinically indicated 
• Monitor symptoms every 2-3 days; 
clinical evaluation and laboratory work-up 
for infection: pulse oximetry 
• Consultation with pulmonologist 
recommended 
Consider treatment 
interruption 
(recommendation) 
 
Grade 2: symptomatic; 
medical intervention 
indicated; limits 
instrumental ADLs  
• Chest imaging/CT scan; repeat imaging 
in 3-4 weeks or as clinically indicated 
• Monitor symptoms daily, consider 
hospitalization 
• Clinical evaluation and laboratory work 
up for infection, pulse oximetry 
• Consult pulmonologist 
• Pulmonary function tests  
• Bronchoscopy with biopsy and/or BAL to 
rule out infection and/or disease 
progression/lung infiltration 
• Initiate steroids (1 to 2 mg/kg/d 
prednisone or equivalent) 
• Consider empirical antibiotics 
• If no improvement within 2-3 days, or 
worsening, treat as grade 3 
• Interrupt treatment 
until recovery to 
grade ≤1 or 
baseline 
• 
Permanently 
discontinue 
treatment in case 
of recurring grade 
2 pneumonitis 
Grade 3: severe 
symptoms; limits self-care 
ADLs; oxygen indicated 
 
Grade 4: life- threatening 
respiratory compromise; 
urgent intervention 
required (e.g. tracheotomy 
or intubation) 
• Same as grade 2; in addition: 
• Hospitalization and pulmonary and 
infectious disease consultation 
• Methylprednisolone (1-2 mg/kg/d or 
equivalent) until symptoms improve to 
Grade ≤1, then slow taper over ≥4-6 
weeks 
• If no improvement within 48 hours, 
consider infliximab and/or other immune-
suppressive therapy, or IVIG as per local 
guidelines 
• Consider empiric antibiotic therapy 
Permanently 
discontinue treatment 
 


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Table 4-13.  Mandatory dose modification requirements and recommended clinical  
                        management guidelines for potential immune-related endocrine events                    
                        at least possibly related to spartalizumab treatment 
 
Endocrine events  
Grade  
Recommended adverse 
event management 
guidelines 
Mandatory dose modification 
requirements (unless 
specified otherwise) 
Grade 1: e.g. asymptomatic or 
mild symptoms, clinical or 
diagnostic observations only, 
intervention not indicated   
• Consider endocrinologist 
consult 
• If hypophysitis is suspected, 
consider pituitary gland 
imaging (MRIs with 
gadolinium and sellar cuts); 
evaluate hormone levels as 
clinically indicated 
• Repeat labs in 1 to 3 
weeks/MRI in 1 month if 
laboratory abnormalities 
persist but normal 
lab/pituitary scan 
• 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 
May continue treatment 
(recommendation) 
 
Grade 2: moderately 
symptomatic endocrinopathy 
(e.g., hypophysitis, adrenal 
insufficiency, hypothyroidism, 
hyperthyroidism), or minimal, 
local or noninvasive 
intervention indicated; limiting 
age-appropriate instrumental 
ADL  
 
 
• Endocrinology consultation 
• Rule out infection/sepsis and 
other alternative causes with 
appropriate cultures/imaging 
• Evaluate hormone levels 
(e.g. ACTH, cortisol, 
FSH/FH, TSH, free T4, 
testosterone/estrogen), 
metabolic panel (e.g. Na, K, 
CO2, glucose), and imaging 
(e.g. brain MRI) as clinically 
indicated 
• Initiate hormone replacement 
therapy as appropriate  
• Consider steroids 
(methylprednisolone 1 to 2 
mg/kg/d or equivalent) in 
case of severe hypophysitis 
or thyrotoxicosis 
• Consider beta-blocker in 
case of severe 
hyperthyroidism 
• Consider hospitalization 
(e.g. in case of severe 
• 
Interrupt treatment until 
recovery to mild or no 
symptoms, and controlled 
with hormone replacement 
therapy. Hypothyroidism 
may be managed with 
replacement therapy 
without treatment 
interruption (unless life-
threatening) 
(recommendation) 
• 
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. 
 


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Endocrine events  
Grade  
Recommended adverse 
event management 
guidelines 
Mandatory dose modification 
requirements (unless 
specified otherwise) 
adrenal insufficiency/crisis), 
fluid replacement, and 
other supportive measures 
as clinically indicated 
Autoimmune diabetes 
(grade 3 hyperglycemia, or 
symptomatic hyperglycemia) 
 
 
Autoimmune diabetes 
(grade 4 hyperglycemia, or life-
threatening complications) 
• Initiate anti-glycemic therapy 
(i.e. insulin) as medically 
indicated and monitor 
glucose levels regularly until 
metabolic control is achieved 
• Evaluate for ketoacidosis as 
medically indicated 
• Consultation with 
endocrinologist 
• Consider hospitalization (e.g. 
in case of ketoacidosis) 
• 
Interrupt treatment until 
recovery to grade 1 or 
baseline 
• 
Permanently discontinue 
treatment in case of 
recurring severe/life-
threatening events not 
controlled by anti-glycemic 
therapy. 
 
 
Table 4-14. Mandatory dose modification requirements and recommended clinical  
                    management 
guidelines 
for 
“other” 
potential 
immune-related 
AEs                        
at least possibly related to spartalizumab treatment 
 
Other (e.g. autoimmune neuropathy, demyelinating polyneuropathy, Guillain-Barre syndrome, 
myasthenia gravis-like syndrome, encephalitis, non-infectious myocarditis, pericarditis, 
pancreatitis, grade 3 fatigue with rapid onset in absence of disease progression, etc.)  
Grade  
Recommended Adverse Event 
management guidelines 
Mandatory dose 
modification requirements 
(unless specified otherwise) 
Grade 1: mild 
• Provide symptomatic treatment 
evaluate/monitor adequately 
May continue treatment 
(recommendation) 
Grade 2: 
moderate 
• Ensure adequate evaluation to confirm 
etiology or exclude other causes 
• Provide symptomatic treatment 
• Systemic corticosteroids may be indicated 
• Consider biopsy or additional tests for 
confirmation of diagnosis 
• A specialist should be consulted 
Consider interruption of 
treatment until recovery to ≤ 
grade 1 or baseline 
(recommendation) 
 
 
Grade 3: severe 
• Initiate systemic corticosteroids (prednisone 
at a dose of 1-2 mg/kg/d or equivalent) and 
other therapies as appropriate 
• Monitor closely and consult with a specialist 
 
• 
Interrupt treatment until 
recovery to ≤ grade 1 or 
baseline.  
• 
May restart treatment at 
the same dose and 
schedule taking into 
account the risks and 
benefits 
Grade 4: life-
threatening 
• Hospitalization and consult with specialist 
Permanently discontinue 
treatment 


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Other (e.g. autoimmune neuropathy, demyelinating polyneuropathy, Guillain-Barre syndrome, 
myasthenia gravis-like syndrome, encephalitis, non-infectious myocarditis, pericarditis, 
pancreatitis, grade 3 fatigue with rapid onset in absence of disease progression, etc.)  
Grade  
Recommended Adverse Event 
management guidelines 
Mandatory dose 
modification requirements 
(unless specified otherwise) 
• Initiate systemic corticosteroids (prednisone 
a dose of 1-2 mg/kg/d or equivalent) and 
other therapies as appropriate 
Encephalitis or 
aseptic meningitis  
• 
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 
treatment 
Guillain-Barre, 
neuropathy 
(motor, sensory or 
autonomic) OR , 
or transverse 
myelitis 
(grade 3: severe 
symptoms; limiting 
self-care and 
ADL)  
• 
Hospitalization and consult with specialist 
Permanently discontinue 
treatment 
Myasthenia gravis 
 
• 
Consult with specialist 
• 
Consider pyridostigmine and systemic 
corticosteroids (prednisone or equivalent) 
at a dose of 1-2 mg/kg/d; other therapies 
as appropriate (e.g. IVIG) 
• 
Hospitalization in case of severe cases 
Grade 2: Interrupt treatment 
until recovery to ≤ grade 1 or 
baseline  
Grade ≥3: Permanently 
discontinue treatment 
Myocarditis grade 
≥2 or cardiac 
event grade ≥3 
• Initiate systemic corticosteroids (prednisone 
or equivalent) at a dose of 1-2 mg/kg/d 
• Consult with specialist; hospitalization as 
indicated 
Permanently discontinue 
treatment 
Pancreatitis/serum 
amylase/lipase 
increase 
 
Grade ≥2  
 
 
• Evaluate for pancreatitis (clinical 
assessment, abdominal imaging and/or 
MRCP as appropriate) 
• Initiate steroids in case of ≥ grade 2 acute 
pancreatitis  
• Treatment may be continued in case of 
asymptomatic, isolated enzyme elevations 
without evidence for pancreatitis 
Grade 2: interrupt treatment 
until recovery to ≤ grade 1 or 
baseline  
 
Grade≥3: permanently 
discontinue treatment 
Autoimmune 
hemolytic anemia, 
hemolytic uremic 
syndrome, or 
acquired 
hemophilia, grade 
≥3 
• 
Consult with specialist 
• 
Consider systemic corticosteroids and 
other therapies as appropriate (e.g. 
transfusion) per local institutional 
guidelines 
• Permanently discontinue 
treatment 


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Other (e.g. autoimmune neuropathy, demyelinating polyneuropathy, Guillain-Barre syndrome, 
myasthenia gravis-like syndrome, encephalitis, non-infectious myocarditis, pericarditis, 
pancreatitis, grade 3 fatigue with rapid onset in absence of disease progression, etc.)  
Grade  
Recommended Adverse Event 
management guidelines 
Mandatory dose 
modification requirements 
(unless specified otherwise) 
Ocular events 
• 
Consult with ophthalmologist 
• Grade 2: interrupt treatment 
until recovery to ≤ grade 1 or 
baseline 
• Grade 3 and 4: permanently 
discontinue treatment 
 
Table 4-15. Mandatory dose modification requirements and recommended clinical  
                    management guidelines for potential infusion-related reactions or injection site  
                    reaction at least possibly related to spartalizumab treatment 
 
Infusion reaction  
Grade  
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements (unless 
specified otherwise) 
Grade 1: mild reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
• Increase monitoring of vital 
signs/pulse oximetry as 
medically indicated until patient 
is deemed medically stable 
• Consider slowing infusion rate 
until recovery of symptoms 
May continue treatment 
(recommendation) 
Grade 2: requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
• 
Additional medical therapy as 
per local institutional guidelines 
that may include : 
o IV fluids 
o Antihistamines 
o NSAIDS, acetaminophen 
o Narcotics 
o Oxygen and corticosteroids 
as indicated 
• 
Increase monitoring of vital 
signs/pulse oximetry as 
medically indicated until patient 
is deemed medically stable  
• 
If symptoms resolve, the 
infusion may be restarted at 
50% of the original infusion rate  
• 
Pre-medicate patients 
approximately 1.5 hours prior 
to next infusion with: 
o Diphenhydramine (50 mg PO 
or equivalent) 
• 
Stop infusion and keep line 
open 
• Permanently discontinue 
treatment in case of 
recurring infusion reaction 
despite adequate 
premedication and 
prolonged infusion/slow 
infusion rate 


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Infusion reaction  
Grade  
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements (unless 
specified otherwise) 
o Acetaminophen (500-1000 
mg PO or equivalent) 
o Or as per local institutional 
guidelines  
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 
other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
 
Grade 4: life-threatening; 
pressor or ventilatory 
support indicated 
• Stop Infusion 
• 
Additional medical therapy as 
per local institutional guidelines 
that may include: 
o IV fluids 
o Antihistamines 
o NSAIDS, acetaminophen 
o Narcotics 
o Oxygen 
o Corticosteroids 
o Epinephrine 
• 
Close monitoring of vital signs, 
pulse oximetry and ECG as 
medically indicated until the 
patient is deemed medically 
stable 
• 
Hospitalization as indicated 
Permanently discontinue 
treatment 
 
4.2.5.1 Guidance for Corticosteroids Tapering for Management of Immune-Related 
AEs  
Consultation with disease-specific experts is recommended. Steroids should be tapered slowly and 
based on response/recovery of clinical symptoms. Consider complete tapering over a period of at 
least 4 weeks (sometime 6-8 weeks or longer) to present recurrent irAEs. Slower tapering or re-
escalation of corticosteroids therapy may be needed if the adverse event is not showing 
improvement. Once corticosteroid tapering is achieved at a level of 10 mg of prednisone/day (or 
equivalent) or less, spartalizumab can be restarted as indicated in the dose modification tables. 
4.2.6 Permanent discontinuation of spartalizumab  
In general, spartalizumab must be permanently discontinued in case of: 
• Any grade 4 (life-threatening) adverse reactions (excluding endocrinopathies controlled 
with hormone replacement therapy) 


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• Persistent grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to ≤ grade 1 within 12 weeks  
• Inability to reduce the dose of steroids (for the management of irAE) to 10 mg/day or less 
of prednisone or equivalent within 12 weeks* 
• Any severe or grade 3 recurring adverse event that is at least possibly related to 
spartalizumab 
*The 12 week timeframe will begin from the time the irAE reaches a grade that leads to 
spartalizumab interruption. 
4.3 Follow-up for toxicities 
4.3.1  Follow-up of Immune-Related AEs 
 
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. All patients must be followed-up for 
irAEs for 150 days following the last dose of spartalizumab . If SAEs suspected to be related to 
study medication occur beyond Day 150, information should also be collected. 
4.3.2 Follow-up of Potential Drug-Induced Liver Injury (DILI) Cases 
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potentially severe DILI (including immune-related DILI), and should be considered 


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as clinically important events and should be assessed appropriately to establish diagnosis. The 
required clinical information, as detailed below, should be sought to obtain the medical diagnosis 
of the most likely cause of the observed laboratory abnormalities. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL value 
(please see Table 5-1); patients meeting any of the following criteria will require further follow-
up and assessments 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 > 3.0  x 
baseline ] or 8.0x ULN, whichever is lower, combined with [TBIL > 2.0 x baseline AND > 2.0 
x ULN]  
NOTE: As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests 
should be considered and their role clarified before the diagnosis of DILI is confirmed. 
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. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, 
GLDH, prothrombin time (PT)/INR, alkaline phosphatase, albumin, and creatine kinase.  
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion with CT, MRI, 
duplex sonography.  
Perform relevant examinations (Ultrasound or MRI, ERCP) as appropriate, to rule out if LFTs are 
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). 
Table 4-16 provides guidance on specific clinical and diagnostic assessments to be (OR which can 
be) performed to rule out possible alternative causes of the observed LFT abnormalities.  


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Table 4-16.      Guidance for specific clinical and diagnostic assessments 
Disease 
Assessment 
Hepatitis A, B, C, E 
• IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, 
HCV RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
• IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune hepatitis 
• ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
• Ethanol history, γGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
• Ultrasound or MRI 
Hypoxic/ischemic hepatitis 
• Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
• Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 yrs old) 
• Ceruloplasmin 
Hemochromatosis 
• Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• Alpha-1-antitrypsin 
 
 
Other causes should also be considered based upon patients medical history (hyperthyroidism / 
thyrotoxic hepatitis – T3, T4, TSH; CVD / ischemic hepatitis – ECG, prior hypotensive episodes; 
T1D / glycogenic hepatitis). 
Obtain PK sample to determine exposure to study drug and metabolites. 
Following appropriate causality assessments, as outlined above, the causality of the drug is 
estimated as “probable” i.e. >50% likely, if it appears greater than all other causes combined. The 
term “drug-induced” indicates probably caused by the drug, not by something else, and only such 
a case can be considered DILI case and should be reported as an SAE. 
4.3.3 Follow-up for Infections 
Patients should be followed closely for any signs or symptoms of infection and receive prompt 
appropriate treatment for any suspected infection. 
4.4 Concomitant Medications 
 
A detailed list of a patient’s current medications will be gathered at consent and assessed against 
the list of concerning or prohibited concomitant medications listed below, as appropriate. Any 
required medication adjustments or wash outs will be documented on an individual basis. Once on 
study, newly prescribed concomitant medications will be added and similarly reviewed to ensure 
patient safety and compliance. 
 


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4.4.1 
Permitted Concomitant Therapy 
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 except those prohibited in 
Section 4.4.3 and Appendix A (Package Inserts for gemcitabine and nab-paclitaxel). 
• 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 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. 
Caution is advised for radiation that include lung tissue or heart. 
• 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 
are permitted at least > 2 weeks before the start of study treatment; in case of anemia, 
thrombocytopenia or neutropenia, potential immune-mediated etiology should be ruled out 
before administration of these agents 
• 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 blood 
transfusions) administered during the study must be listed on the Concomitant Medications. 
 


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4.4.2 
Permitted concomitant therapy requiring caution and/or action 
If a patient is using erythropoiesis stimulating agents (ESAs) prior to enrollment (at least > 2 weeks 
before start of study treatment), he/she may continue the treatment. 
Anticoagulation and anti-aggregation agents are permitted if the patients are already at stable doses 
for > 2 weeks at time of first dose and International Normalized Ratio (INR) should be monitored 
as clinically indicated per investigator’s discretion. However, ongoing anticoagulant therapy 
should be temporarily discontinued to allow tumor sample according to the institutional guidelines. 
In cases of isolated brain progression or other local progression, patients may receive palliative 
radiotherapy or surgery. In addition, localized, palliative radiotherapy for pre-existing bone/liver 
metastases is permitted. Spartalizumab should be held for ≥1 week prior to radiotherapy or surgery. 
Spartalizumab may be resumed ≥2 weeks after radiation or surgery, provided the patient has 
recovered from radiation or surgery related toxicity. If palliative radiotherapy or surgery is initiated 
after start of study treatment, the reason for its use must be clearly documented and progression as 
per RECIST 1.1 must be assessed and documented (Patients must not continue study treatment 
beyond disease progression per RECIST 1.1 [see Section 5.4.1]). 
Since the metabolism of nab-paclitaxel is catalyzed by CYP2C8 and CYP3A4, caution should be 
exercised when administering paclitaxel/nab-paclitaxel concomitantly with medicines known to 
inhibit or induce either CYP2C8 or CYP3A4.  
Cytochrome P450 (CYP450) enzymes are suppressed by increased levels of cytokines (e.g.,IL-1) 
during chronic inflammation. CYP450 expression may be normalized when potent cytokine 
inhibitory therapy, such as canakinumab, is introduced. This is clinically relevant for CYP450 
substrates with a narrow therapeutic index. Caution should be exercised when administering these 
agents  concomitantly with canakinumab. Given the potential DDI via cytokine modulation by 
canakinumab, subjects who are on warfarin or warfarin-like treatment with narrow therapeutic 
index, should have their international normalized ratio (INR) measured locally and warfarin or 
warfarin-like treatment dose adjusted accordingly within one month from starting study treatment. 
 
 


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4.4.3 
Prohibited concomitant therapy 
 
There are no prohibited or required concomitant medications for combination of gemcitabine and 
nab-paclitaxel. Other antineoplastic agents or investigational drugs, other than what is specified in 
this protocol, are prohibited.  
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the patients, including side effects from study treatments or disease recurrence. 
Supportive care, including but not limited to antiemetic medications, may be administered at the 
discretion of the Investigator, consistent with institutional guidelines. 
For information regarding other drugs that may interact with either nab-paclitaxel or gemcitabine 
and affect their metabolism, pharmacokinetics, or excretion, see the nab-paclitaxel and 
gemcitabine package inserts (refer to Prescribing Information), Appendix A. 
Treatment with the following agents is not permitted within ≤ 2 weeks prior start of study 
treatment: 
• hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), or 
• thrombopoietin mimetics, or 
• erythroid stimulating agents. 
If erythroid stimulating agents were initiated more than 2 weeks prior to the first dose of study 
treatment and the patient is on a stable dose, they can be maintained. In addition, hematopoietic 
colony-stimulating growth factors and thrombopoietin mimetics may be used to treat treatment 
emergent cytopenias during the course of the study. 
During the course of the study, patients must not receive other additional investigational drugs, 
devices, chemotherapy, or any other therapies that may be active against cancer or modulate the 
immune responses. However, limited-volume palliative radiotherapy may be allowed as 
concomitant therapy. Such local therapies administered during the study treatment must be 
documented. Additionally, no other therapeutic systemic antineoplastic agents and no 
immunosuppressive medication may be administered while on this study unless given for the 
management of immune toxicity or circumstances where there is further discussion with the 
Medical Monitor . 


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4.4.3.1 Prohibited concomitant therapy for spartalizumab 
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed except for 
use as pre-medication for chemotherapy (when needed), the treatment of infusion reaction, irAEs, 
treatment for brain metastasis, and for prophylaxis against imaging contrast dye allergy 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 for ≤ 3 weeks. 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 within 12 weeks from irAE 
cause delay dosing then spartalizumab must be discontinued. 
The use of live vaccines is not allowed through the whole duration of the study. Inactivated 
vaccines are allowed. 
There are no spartalizumab-specific prohibited therapies during the post-treatment follow-up 
period. 
4.4.3.2  Prohibited concomitant therapy for canakinumab 
Due to the potential risk of serious infections and increased risk of neutropenia, caution should be 
excised when administering canakinumab in combination with immuno-suppressive medications. 
The use of below is not allowed after the start of study treatment and for at least 130 days after 
discontinuation of canakinumab unless medically indicated for the management of immune related 
AEs or other serious conditions. In these cases patients should be closely monitored for infection 
and the dose modification guidelines should be followed. 
• Any systemic antiretroviral agents and / or any biologic drugs targeting the immune system 
(e.g. TNF-alpha blockers, anakinra, rituximab, abatacept, tocilizumab) 
• Live vaccines. All immunizations should be completed at least 3 months prior to initiating 
canakinumab. Patients should discontinue canakinumab if administered any live vaccine 
during the course of the study. Inactivated vaccines are allowed.  


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4.5 Overdose 
 
Overdose, as defined for this protocol, refers to the medications included in the therapeutic 
regimens to which patients are randomized (the agents being given to treat pancreatic cancer). On 
a per dose basis, an overdose is defined as 10% over the protocol-specified dose given to a patient, 
regardless of any associated AEs or sequelae. On a schedule or frequency basis, an overdose is 
defined as anything more frequent than the protocol-required schedule or frequency. Complete 
data about drug administration, including any overdose, regardless of whether the overdose was 
accidental or intentional, should be reported in the eCRF. 
4.6 Investigational Product Accountability and Disposal 
 
Investigational product (IP) should be disposed of in accordance with institutional/regional 
requirements. Disposition should be recorded on the investigational drug accountability forms. 
The Investigator, or designee, shall record the dispensing of IP to patients in the IP accountability 
record. The IP record will be made available to authorized sponsor-designated monitoring 
personnel, for the purpose of accounting for the IP supply. 
 
Inspections of the IP supply for inventory purposes and assurance of proper storage will be 
conducted as necessary. Any significant discrepancy will be recorded and reported to the sponsor 
designee and a plan for resolution will be documented. 
 
Investigational product will not be loaned or dispensed by the Investigator to another 
Investigator or site.  
4.7 Investigational Product Compliance 
 
Accurate recording of all IP administration will be made in the appropriate section of the patient’s 
eCRF and source documents. The Investigator or designee is responsible for the accountability for 
all study-specific IP either administered or in their custody during the course of the study. 
 
 
 


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5.0 
STUDY ASSESSMENTS 
All patients will undergo uniform assessments and procedures defined below in Section 5.1. For 
ease of review, the procedures are described below: 1) Screening/ Baseline, 2) Study Treatment 
Assessments, 3) End of Treatment, 4) As Needed Assessments, 5) Safety Follow-Up, 6) Post 
Treatment Efficacy Follow Up, and 7) Survival Follow-Up.  
 
 
 








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Table 5-1:  Schedule of Events (Continued) 
Footnotes:             
 ***A cycle is at defined as 4 weeks***  
 
 
1       Treatment ICF must be signed by patient prior to the initiation of treatment 
2       Tuberculosis screening is performed per local and  institutional guidelines 
3       Only study treatment-related AEs will be reported after the start of new anti-cancer therapy and until the end of the Safety Follow-Up period;  
4       Only study treatment-related SAEs will be reported after the end of safety f/u or after the start of new anti-cancer therapy, whichever is the earliest, until the end of survival  f/u;   
         After the Safety Follow-up Period, and in the post-treatment efficacy follow-up period, report only treatment-related SAEs until the start of a new anti-neoplastic therapy; 
5       The specific Pharmacokinetic and 
blood collection for canakinumab, spartalizumab, gemcitabine and nab-paclitaxel is outlined in Section 5.6 below. Blood  
draws for canakinumab and spartalizumab will be performed on Days 1,8, and 15 of Cycle 1, and Day 1 of Cycles 2-5 (pre-dose); Blood draws for gemcitabine and nab-paclitaxel  
will be performed on Day 1 of Cycles 1 and 2 (pre-dose);  
6      Concomitant medications should be recorded from 28 days prior to starting study treatment (during screening period) until end of safety follow up or start of new antineoplastic 
medications, whichever is sooner. After starting a new antineoplastic medication, only report medications related to study treatment-related AEs/SAEs  
7       Concomitant medications must be collected at any visit when AEs are collected; No need to report conmeds after the end of safety f/u or at the start of new anti-cancer therapy; 
8       Thyroid panel should be performed on Day 1 of the first two cycles, and Day 1 of every second cycle (cycles 4,6, etc.) 
9       CA 19-9 should be evaluated every 4 weeks from C1D1 of treatment (every Cycle) 
10    HIV testing during screening period to be conducted only if there is a known history of HIV documented in clinical notes or if patient is currently receiving treatment for HIV. HIV  
testing is not required in the absence of clinical suspicion (i.e. this test is NOT mandatory). 
11     HBV/HCV during screening period to be conducted only if there is an active infection of HBV and/or HCV. Patients who have tested positive for antibody (due to exposure) with no 
history of active infection do not need a HBV/HCV test during screening period 
12    Procedures completed within 14 days of last study treatment can be used for End of Treatment values when appropriate; Reason for stopping treatment will be recorded in EDC;  
13  
 
  
14    CT or MRI of chest, abdomen, pelvis, and Tumor evaluation per RECIST 1.1 is performed Every 8 weeks (every 2 cycles) starting from C1D1 of study treatment.  
15    If brain lesions are documented at baseline, follow same schedule as CT/MRI of chest, abdomen, and pelvis. 
16    Only for lesions on whole body scan that are not visible on the chest, abdomen and pelvis scans. If bone lesions were documented at screening, follow same schedule as  
         CT/MRI of the chest, abdomen, and pelvis.  
17     Post Treatment Efficacy Follow-up visit is for those patients who discontinue treatment due to reasons other than disease progression, and therefore could have these assessments  
         performed to show possible disease progression during the follow-up period. The frequency of assessment for patients in post-treatment efficacy follow-up is the same  
         as during the treatment period. 
18    This test will only occur prior to the two biopsies on the Screening/ Day 1 visit and the Cycle 3 Day 1 treatment (after 8 weeks of treatment).   
19    Gemcitabine and nab-paclitaxel will be administered on days 1, 8, and 15 of each 28-day cycle.  
  


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5.2 
Baseline Procedures 
Patients will have the following procedures conducted within 28 days of Day 1 of Study treatment.  
Questions regarding eligibility should be directed to the Medical Monitor or his/her authorized 
designee. 
 
The following procedures will be performed within 28 days prior to Cycle 1 Day 1 treatment 
(Baseline): 
• Informed consent 
• Medical History, Family History, Demographics, and Cancer History (including 
specifically previous PDAC treatments) 
• Tuberculosis Status Assessment 
• Hepatitis Status Assessment 
• Vital signs (including blood pressure, temperature, and heart rate) 
• Physical examination (including height and weight) 
• Clinical assessment of neuropathy performed according to local practice 
• 12-lead electrocardiogram (ECG) 
• Adverse Event and Serious Adverse Event assessment  
• List of prior and concomitant medications going back over the last 6 months 
• ECOG Performance Status (see Table 5-2 below) 
• Laboratory blood tests (collected and assessed locally) 
• Complete blood count (CBC) with differential (absolute), including but not limited to: 
o Red blood cell (RBC) count 
o Hemoglobin 
o Hematocrit 
o Differential White blood cell (WBC) count 
o Absolute neutrophil count (ANC)  
o Platelet count 
• Chemistry panel including, but not limited to: 
o Sodium 
o Potassium 


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o Calcium 
o Chloride 
o Uric Acid 
o Blood urea nitrogen (BUN) 
o Creatinine 
o Glucose 
o Aspartate 
aminotransferase/serum 
glutamic 
oxaloacetic 
transaminase 
(AST/SGOT) 
o Alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) 
o LDH 
o Serum Lipase 
o Alkaline phosphatase 
o Bilirubin (total and direct) 
 
• Coagulation tests including (only performed prior to the two biopsies per patient—
please see Section 5.7 below (As Needed Assessments)): 
o Prothrombin time (PT) and international normalized ratio (INR) 
o Partial thromboplastin time (PTT) 
• Thyroid Panel (free T3, free T4, and TSH) 
• Pregnancy test (serum) is required for WOCBP and will be performed within 14 days 
of Day 1 of study treatment.  
• Urinalysis  
• CA 19-9 (as defined by local practice) 
• HIV test (if there is a known history of HIV in clinical notes or if patient is currently 
receiving treatment for HIV; HIV testing is not required in the absence of clinical 
suspicion (this is NOT mandatory));  
• Laboratory Assessments for active viral infections: Hepatitis B surface antigen (HBV 
sAG) and Hepatitis C antibody (HCV Ab) or Hepatitis C RNA (HCV RNA) 
• 
 
• 
 




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The following procedures will be performed at Day 1 of every cycle, prior to any study 
treatment administration, unless otherwise specified below: 
• Vital signs (including blood pressure, temperature, and heart rate) (also performed on Day 
8 of Cycle 1 only); 
• Physical examination; 
• Clinical assessment of neuropathy performed according to local practice; 
• Adverse Event and Serious Adverse Event assessment (performed on Days 1,8, and 15 of 
every treatment cycle) 
• Pharmacokinetics (PK) and
 blood draws performed on Days 1, 8, and 15 
of Cycle 1, and Day 1 of Cycles 2-5 (pre-dose); (See Section 5.6 below for details on 
specific days and times for PK and 
draws) 
• New concomitant medications since last visit; 
• ECOG Performance Status (see Table 5-2 above) 
• Weight 
• Laboratory blood test (collected and assessed locally) 
o Complete blood count (CBC) with differential (absolute) to be performed on Days 1 
and 15 of Cycles 1 and 2, and Day 1 only of Cycle 3 and thereafter, including but not 
limited to: 
 Red blood cell (RBC) count 
 Hemoglobin 
 Hematocrit 
 Differential White blood cell (WBC) count 
  Absolute neutrophil count (ANC)  
  Platelet count 
o Chemistry panel to be performed on Days 1 and 15 of Cycles 1 and 2, and Day 1 only 
of Cycle 3 and thereafter including, but not limited to: 
 Sodium 
 Potassium 
 Calcium 
 Chloride 


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 Uric Acid 
 Blood urea nitrogen (BUN) 
 Creatinine 
 Glucose 
 Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(AST/SGOT) 
 Alanine aminotransferase (ALT/SGPT) 
 Alkaline phosphatase 
 LDH 
 Serum Lipase 
 Bilirubin (total and direct) 
• Thyroid Panel (free T3, free T4, and TSH) 
• Pregnancy test (urine) is required for WOCBP   
• Urinalysis  
• CA 19-9 (as defined by local practice) (to be performed on Day 1 Cycle 1 and every 
cycle thereafter (every 4 weeks)) 
• 
 
 
 
5.4 
Study Treatments  
Please also refer to Section 4.0 for complete study drug administration information, and for dose 
modification and toxicity information.   
 
Canakinumab 
Canakinumab is provided as ready-to use pre-filled syringes to be administered by study center 
personnel.  Two strengths of solution for injection will be supplied: 
• Canakinumab 50 mg/ 0.5 mL 
• Canakinumab 200 mg/ 1.33 mL  
 


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The starting dose of canakinumab will be 250 mg, administer subcutaneously (SC) in the abdomen, 
upper outer thigh or upper outer arm once every 4 weeks (on Day 1 of each treatment cycle). To 
administer a target dose of canakinumab of 250 mg, two separate subcutaneous injections  must 
be administered to the patient at a visit and should not be injected in the same site (e.g. if first 
injection was done in the thigh, the second injection should be done in the opposite thigh). 
Alternate injection sites should be used throughout the study. 
If this initial dose level (DL1) of 250 mg Q4W is not tolerated, the next reduced dose level -1 (DL 
-1) will be explored. DL -1 aims to reduce canakinumab exposure by increasing the dosing interval 
of 250 mg dose from Q4W to Q8W without change in actual dose strength. 
 
 For additional guidance refer to canakinumab (ACZ885) Instructions for Use/Pharmacy Manual 
and to the canakinumab Investigator’s Brochure.  
 
Spartalizumab  
Spartalizumab will be supplied in a liquid solution. The starting dose of spartalizumab is 400 mg 
(prepared by reconstituting four vials with sterile water for injection (SWFI) and diluted in a 5% 
dextrose infusion bag before use) administered via intravenous infusion over 30 minutes (up to 2 
hours, if clinically indicated) once every 4 weeks (on Day 1 of every cycle). For additional 
guidance refer to spartalizumab Instructions for Use/Pharmacy Manual and to the spartalizumab 
Investigator’s Brochure.  
On days of combination therapy canakinumab will be injected first followed by 30 min observation 
period and then by spartalizumab infusion.  After spartalizumab infusion, 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 2 hours after the first two spartalizumab 
infusions (before administration of chemotherapy). The same may apply for the subsequent 
spartalizumab infusions if medically indicated.  
 
 


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Gemcitabine/Nab-paclitaxel  
• Nab-paclitaxel is infused at an initial dose of 125 mg/m2 over 30-40 min on days 1, 8, 15 
of each 28-day cycle. 
• Gemcitabine is infused at an initial dose of 1000 mg/m2 over 30 min, immediately after 
completion of nab-paclitaxel infusion, on days 1, 8, 15 of each 28-day cycle 
If one of the chemotherapy medications is held, the other study medications may be given. 
Doses should be re-adjusted if the patient’s BSA changes by +/- >10%. If the patient’s BSA 
changes by <10%, no adjustment is necessary unless the site has a standard procedure to adjust 
doses based upon current BSA according to institutional guidelines.  
On days of combination therapy, chemotherapy will be administered at least 30 minutes after the 
end of spartalizumab infusion. Any pre-medication for the chemotherapies, if required, should be 
administered at least 30 minutes after the end of the infusion of spartalizumab. 
Specifics on dosing and toxicity modifications for gemcitabine and nab-paclitaxel can be found in 
their Package Inserts (Appendix A).  
 
5.4.1 Study Treatment Beyond Disease Progression  
Patients will not continue study treatment beyond PD per RECIST 1.1, since progression prior to 
response has not been reported in pancreatic cancer treated with immunotherapy and was 
associated with grade 3/4 AEs when treatment continued beyond progression (Parseghian et al 
2018). Therefore, the overall risk-benefit for continuing the study treatment beyond disease 
progression is considered as not favorable.  
5.4.2 Study Treatment Duration  
Patients will continue to receive study treatment until one of the following events occur: 
• disease progression per RECIST 1.1 is radiologically documented by investigator 
assessment;  
• unacceptable toxicity that precludes further treatment;  
• treatment is discontinued at the discretion of the investigator;  
• patient withdrawal of consent;  


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• pregnancy;  
• patient is lost to follow-up;  
• death 
If study chemotherapy drugs are permanently discontinued because of chemotherapy-related 
intolerable toxicities, the investigator can continue spartalizumab with canakinumab until RECIST 
1.1 disease progression as per investigator assessment, as long as:  
• The patient is continuing to benefit from investigational drug treatment as assessed by the 
investigator, and 
• The patient is tolerating the treatment and clearly understands the risks associated with 
continuing treatment with canakinumab. 
If spartalizumab and/or canakinumab have been discontinued because of treatment-related 
toxicity, treatment with chemotherapy may continue as long as the patient is continuing to benefit 
from chemotherapy continuation as assessed by the investigator. 
 
 
5.5 
End of Treatment Procedures 
 
All the procedures outlined below need to be completed within 14 days of last dose of study 
treatment, or otherwise repeated.   
• Vital signs (including blood pressure, temperature, and heart rate); 
• Physical examination; 
• Clinical assessment of neuropathy performed according to local practice; 
• Adverse Event and Serious Adverse Event assessment; 
• New concomitant medications since last visit; 
• ECOG Performance Status (see Table 5-2 below); 
• Pharmacokinetics (PK) and
 blood draws performed during the End of 
Treatment Visit; (See Section 5.6 below for details on specific days and times for PK and 
 draws) 
• Weight;  
• Laboratory blood test (collected and assessed locally); 
o Complete blood count (CBC) with differential (absolute), including but not limited to: 


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 Red blood cell (RBC) count 
 Hemoglobin 
 Hematocrit 
 Differential White blood cell (WBC) count 
  Absolute neutrophil count (ANC)  
  Platelet count 
o Chemistry panel including, but not limited to: 
 Sodium 
 Potassium 
 Calcium 
 Chloride 
 Uric Acid 
 Blood urea nitrogen (BUN) 
 Creatinine 
 Glucose 
 Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(AST/SGOT) 
 Alanine aminotransferase (ALT/SGPT) 
 Alkaline phosphatase 
 LDH 
 Serum Lipase 
 Bilirubin (total and direct) 
• Thyroid Panel (free T3, free T4, and TSH) 
• Pregnancy test (Serum) is required for WOCBP   
• Urinalysis  
• CA 19-9 (as defined by local practice); 
• 
 
 
 




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Table 5-4: 
Pharmacokinetic 
 Blood Collection Log for 
Spartalizumab (PDR001) 
Cycle 
Day 
Scheduled Time Point (hr) 
PK 
 
1 
1 
Pre-dose Cycle 1  
Spartalizumab PK 
1 
1  
End of infusion (within 5  
min) 
Spartalizumab PK 
1 
8 
168 hr post-dose (±8 hr) 
Spartalizumab PK 
 
1 
15 
336 hr post-dose (±24 hr) 
Spartalizumab PK 
 
2 
1 
Pre-dose Cycle 2 
Spartalizumab PK 
 
3 
1 
Pre-dose Cycle 3 
Spartalizumab PK 
 
4 
1 
Pre-dose Cycle 4 
Spartalizumab PK 
 
5 
1 
Pre-dose Cycle 5 
Spartalizumab PK 
 
5 
1 
End of infusion within 5 
min ) 
Spartalizumab PK 
 
6 
1 
Pre-dose Cycle 6 
Spartalizumab PK 
EOT 
 
Anytime 
Spartalizumab PK 
 
Unscheduled 
 
Anytime 
Spartalizumab PK 
 
Table 5-5: 
Pharmacokinetic draws for Gemcitabine  
Cycle 
Day 
Scheduled Time Point (hr) 
1 
1 
Pre-infusion 
1 
1  
EOI (within 5 minutes) 
1 
1 
0.5 hr (±10 minutes) post-EOI 
1 
1 
1 hr (±10 minutes) post-EOI 
1 
1 
2 hr (±10 minutes) post-EOI 
1 
1 
4 hr (±10 minutes) post-EOI 
2 
1 
Pre-infusion 
2 
1 
EOI (within 5 minutes) 
2 
1 
0.5 hr (±10 minutes) post-EOI 
2 
1 
1 hr (±10 minutes) post-EOI 
2 
1 
2 hr (±10 minutes) post-EOI 
2 
1 
4 hr (±10 minutes) post-EOI 
Unscheduled 
 
Anytime 
EOI- end of infusion 


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Table 5-6: 
Pharmacokinetic draws of nab-paclitaxel 
Cycle 
Day 
Scheduled Time Point (hr) 
1 
1 
Pre-infusion 
1 
1  
EOI (within 5 min) 
1 
1 
4 hr (±10 minutes) post-EOI 
1 
1 
6 hr  (± 1 hour) post-EOI 
1 
2 
24  hr (±1 hour minutes) post-EOI 
2 
1 
Pre-infusion 
2 
1 
EOI (within 5 min) 
2 
1 
4 hr (±10 minutes) post-EOI 
2 
1 
6 hr  (± 1 hour) post-EOI 
2 
2 
24  hr (±1 hour minutes) post-EOI 
Unscheduled 
 
Anytime 
EOI- end of infusion 
 
 
5.7 
As Needed Assessments 
• 
 
 
• After every 8 weeks of study treatment, a Computerized tomography (CT) scans (with PO 
and IV contrast) of the chest, abdomen, and pelvis will be performed.  In the case of CT 
contrast agent allergy, Magnetic Resonance Imaging (MRI) of the abdomen and pelvis 
(with IV contrast) along with CT scan of the chest is acceptable. Scans will be reviewed 
and interpreted at each site per standard a protocol detailed in the Study Manual/ Imaging 
Guidelines. 
Note: the imaging modality chosen at baseline should remain the same throughout the duration 
of this study. 
• Coagulation tests including (to be performed prior to each biopsy at the Screening Visit 
and prior to the biopsy after 8 weeks of treatment (prior to Cycle 3 Day 1)): 
o Prothrombin time (PT) and international normalized ratio (INR) 
o Partial thromboplastin time (PTT) 
• Re-assessment of Tuberculosis Status at any time during Study treatment, if clinically 
indicated;  


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• Re-assessment of Hepatitis Status at any time during Study treatment, if clinically 
indicated;  
• 12-lead ECG at any time during Study treatment, if clinically indicated;  
• Re-assessment of HIV Status at any time during Study treatment, if clinically indicated;  
• Brain CT or MRI at any time during Study treatment, if clinically indicated;  
• Whole Body bone scan at any time during Study treatment, if clinically indicated;  
• Localized bone CT, MRI or X-Ray at any time during Study treatment, if clinically 
indicated;  
 
5.8       Safety Follow Up (30-day, 60-day, 90-day, 120-day and 150-day Assessments) 
The following assessments below will occur at 30 days after the last study treatment, (and 
at 60-days, 90-days, 120-days and 150-days after treatment, when indicated). All patients 
will be followed for safety assessment 150 days following the last dose of spartalizumab 
and canakinumab or 30 days after the last dose of the combination chemotherapy, 
whichever is later.  
• Vital signs (including blood pressure, temperature, and heart rate); 
• Physical examination; 
• Adverse Event and Serious Adverse Event assessment (at 30-day,60-day, 90-day, 120-day 
and 150- day after last study treatment (suspected AEs and SAEs), until resolution to Grade 
1/baseline levels;  unsuspected AEs or SAEs are followed up to the 150-day follow-up 
visit, or until the initiation of a new anti-cancer therapy (whichever is sooner)); 
• New concomitant medications since last visit (at 30-day,60-day, 90-day, 120-day and 150- 
day after last study treatment, or until the start of new anti-neoplastic medications;  
• ECOG Performance Status (see Table 5-2 above); 
• Weight;  
• Laboratory blood test (collected and assessed locally); 
o Complete blood count (CBC) with differential (absolute), including but not limited to: 
 Red blood cell (RBC) count 
 Hemoglobin 
 Hematocrit 
 Differential White blood cell (WBC) count 


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  Absolute neutrophil count (ANC)  
  Platelet count 
o Chemistry panel including, but not limited to: 
 Sodium 
 Potassium 
 Calcium 
 Chloride 
 Uric Acid 
 Blood urea nitrogen (BUN) 
 Creatinine 
 Glucose 
 Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(AST/SGOT) 
 Alanine aminotransferase (ALT/SGPT) 
 Alkaline phosphatase 
 LDH 
 Serum Lipase 
 Bilirubin (total and direct) 
• Thyroid Panel (free T3, free T4, and TSH) 
• Pregnancy test (Serum) is required for WOCBP at 30-day follow up only;  
• Pregnancy test (Urine) is required for WOCBP at 60-day, 90-day, 120-day and 150-
day follow-up visits; 
• Urinalysis is required at 30-day and 150-day follow up visits;  
• Recording of anti-neoplastic therapies since the discontinuation of the study treatment 
is required at 30-day, 60-day, 90-day, 120-day and 150-day follow-up visits;  
 
5.9 Post Treatment Efficacy Follow Up 
Post treatment efficacy follow-up is for those patients who discontinue treatment due to reasons 
other than disease progression, e.g. adverse event. Patients will be followed until disease 
progression, withdrawal of consent, or lost to follow-up, whichever comes first. The frequency of 


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tumor response assessments and Ca-19-9 measurements for patients in post-treatment efficacy 
follow-up is the same as during the treatment period. 
5.10 
Survival Follow Up 
After the end of the Safety Follow-Up and Post Treatment Efficacy Follow Up periods above 
(where applicable), all patients will be followed for overall survival every three months (+/- 14 
days) until death, withdrawal of consent, or lost to follow-up, whichever comes first.  Survival 
follow-up will continue until the end of study, death, or withdrawal of consent by the patient.  
If a patient starts a new anti-cancer therapy prior to disease progression during the follow-up 
period, those patients will continue to be followed for post treatment efficacy and overall survival. 
This data should be captured in the EDC.  
The following procedures will be performed during the efficacy and survival follow-up period: 
•
Overall survival assessment (phone call every 3 months after the 150-day safety follow-up
period);
•
Documentation of new anti-cancer therapy if applicable;
•
CT/MRI for response assessment, if applicable. For patients that discontinue study
treatment in the absence of disease progression (unacceptable toxicity or
patient/investigator discretion), CT/MRI scans should be performed accordingly to
standard practice to assess efficacy status.
5.11 
Patient Discontinuations 
The reason for study discontinuation should be recorded in the eCRF and in the source documents. 
The decision to discontinue a patient remains the responsibility of the treating physician. However, 
prior to discontinuing a patient, the Investigator may contact the Medical Monitor with the decision 
to discontinue/withdraw a patient due to an AE (any unacceptable toxicity) and forward 
appropriate supporting documents for review and discussion. Every attempt should be made to 
collect all survival information, unless the patient has specifically withdrawn consent from further 
follow-up. The Investigator should make every effort to obtain minimal information regarding the 
patient’s survival status before determining the patient is lost to follow-up.  


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6.0 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
6.1 
Tumor Biomarker Collection 
Unlike other solid tumors, where traditional imaging modalities provide an accurate and reliable 
means to assess tumor size and response, pancreatic cancer poses difficulties in lesion 
measurements. Due to the desmoplastic component of its lesions, unequivocal measurements are 
challenging (Brand et al. 1998). For this reason, there is increasing interest in identifying 
correlative endpoints by which to evaluate the effectiveness of therapy.  Carbohydrate antigen 
19-9 (CA 19-9), a tumor marker widely used in clinical practice in the assessment of patients with 
pancreatic cancer, has prognostic significance in overall survival and response to treatment in 
patients with metastatic PDAC (Maisey et al. 2005, Ko et al. 2005, Boeck et al. 2006). Although 
CA 19-9 is not detectable in 15% of metastatic pancreatic cancer patients, the opportunity for 
serial CA 19-9 measurements across a variety of novel therapeutic evaluations, including 


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immunotherapy, stromal disruption and DNA damage pathways, makes this an interesting target 
for further surrogate development (Poruk et al. 2013, Chiorean et al. 2016). 
 
6.2 
Specimen Collection Overview 
 
 
 
 
 
  
.  
 
6.2.1 
 
 
  
 
 
 
 
   
 
   
 
 
 
  
 
  




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7.0 
SAFETY ASSESSMENTS 
All patients will be uniformly monitored for safety and tolerability. Patient safety assessments will 
be performed based as outlined in the Schedule of Events in Section 5.1.  
Toxicity will be evaluated according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) v 5.0 criteria and assessed by a qualified clinician. 
 
7.1 
Definition of Adverse Event 
An Adverse Event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a patient during their study participation.  
An AE can therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not, considered related to the medicinal product. 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition), except as if related to tumor progression. 
• Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant treatment 
or discontinuation from study drug. 


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• AEs that are related to a protocol-mandated intervention, including those that occur prior 
to assignment of study treatment (e.g., screening invasive procedures such as biopsies). 
 
7.2 
Definition of a Serious Adverse Event 
A serious adverse event (SAE) is any adverse event that meets any of the following criteria:  
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to perform 
normal life functions 
• A congenital anomaly or birth defect 
• Important medical events that may not be immediately life-threatening or resulting in death 
or hospitalization should also be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require intervention to prevent one of 
the other outcomes. 
 
 
Events not considered to be SAEs are hospitalizations for: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment not related to the condition being studied 
• Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
• Respite/hospice care 
 
7.3 
Monitoring 
Patients will be monitored for S/AEs during the trial.   All S/AEs will be recorded from the time 
the patient signs the Informed Consent Form (ICF) through study treatment. During the 150- day 
(5 months) period after the last dose of study treatment of canakinumab or spartalizumab (due to 
the half-life of this drug), only treatment-related S/AEs will be recorded.   
Assessments may include monitoring of any or all the following parameters: 


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• Patients’ clinical symptoms, laboratory, pathological, radiological or surgical findings 
• Physical examination finding 
• Findings from other tests and/or procedures 
 
7.4 
Reporting 
All AEs and SAEs will be coded using MedDRA for reporting to the FDA, and Institutional 
Review Boards (IRBs), as required. All reportable adverse events should be recorded in the 
Electronic Data Capture (EDC) system.  
 
7.4.1 Adverse Events  
Pre-specified AEs that occur after signing the ICF through the completion of the Treatment Phase 
related or not to the study assessments, must be entered in the EDC.  Refer to the detailed Data 
Plan with these definitions and specific data entry instructions. Adverse Event assessment will 
occur until there is a resolution to Grade 1/baseline levels, stabilization, or the initiation of new 
anti-cancer therapies.  
 
For each reportable AE, the treating clinician will evaluate and report the following: 
• Event onset date and event ended date  
• AE verbatim term  
• Severity grade  
• Attribution to study agent (relatedness) with rationale for causality assessment 
• Whether or not the event was reported as an SAE (if SAE, criterion/a for seriousness) 
• Action taken with study drugs and any treatment given for the AE 
• Outcome of the event  
• Whether or not the patient discontinued study treatment due to AE  
• If treatment was temporarily interrupted, date and dose of re-administration   
 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate method 
(for example, as per RECIST 1.1 criteria) should not be reported as an AE or SAE except if the 
investigator considers that progression of malignancy is related to study treatment.               


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AEs separate from the progression of malignancy (example, i.e. 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 study 
drug/s. 
Conditions that were already present at the time of informed consent should be recorded as the 
medical history. Condition/s which developed or worsened after signing informed consent 
(including during the screening period) should be recorded as AE. 
 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded as a S/AE.  If the abnormality was not a part of a diagnosis or 
syndrome, then the laboratory abnormality should be recorded as the AE.  
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least one 
of the following criteria:  
• they induce clinical signs or symptoms  
• they are considered clinically significant  
• they require therapy 
 
7.4.2  Severity of AEs 
It is important to distinguish between serious and severe AEs.  An AE of severe intensity may not 
necessarily be considered serious and vice versa. See definition of SAEs in Section 7.2. 
 
Severity is a measure of intensity which will be graded by using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v 5.0 criteria. These are based on the general guidelines 
described in Table 7-1 below and should be used to assess severity for AE terms not listed in the 
CTCAE v 5.0.  
 
 
 
 
 
 




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Adverse events of special interest are defined on the basis of an ongoing review of the safety data. 
 
Based upon the available safety information from  spartalizumab and canakinumab oncology  
clinical  development programs and known mechanism of action of these drugs and potential 
overlapping toxicity of all combination drugs, following adverse events are considered of special 
interest in this trial population:  
• Infections (severe infections and opportunistic infections), including sepsis 
• Neutropenia CTCAE Grade >3 
• Febrile neutropenia  
• Peripheral/Sensory neuropathy CTCAE  Grade >3 
• Thrombocytopenia CTCAE  Grade >3  
• In addition, the potential immune-related AEs considered to be AESIs include, 
endocrinopathies, colitis, skin reactions, hepatitis, nephritis, pneumonitis and infusion 
reaction.  
 
Details regarding these adverse events are provided in the spartalizumab and canakinumab 
Investigator’s Brochures. Potential emergent new AEs will be monitored during the course of the 
study. 
 
7.4.5 
Serious Adverse Events  
Any AE that meets any criterion for a SAE requires the completion of a SAE Report Form in 
addition to being recorded in the EDC.  All SAEs must be reported to Sponsor or his/her authorized 
designee immediately, but no later than within 24 hours of the awareness of the event, via phone 
or e-mail, along with the SAE report form completed . The Investigator is required to ensure that 
the data on these forms is accurate and consistent. SAEs must be followed until resolved.  
 
Complete information is important to assess the SAE, but at least the following information needs 
to be provided within initial 24-hour notification, and additional information may be collected in 
follow-up contacts: 
• Date and time of SAE 
• Name of reporter 


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• Institution Name 
• Protocol number/title 
• Description of SAE, including reason of seriousness and causality to study treatment 
The Medical Monitor and safety/regulatory staff of the Pancreatic Cancer Action Network 
(PanCAN) or his/her designee will determine which SAEs require expedited FDA submission as 
safety reports.  
All institutions will comply with applicable regulatory requirements related to reporting SAEs to 
the IRB. The Investigator must keep copies of all SAE information on file including 
correspondence with Sponsor or his/her authorized designee and the IRB.  
 
7.4.6 Manufacturer Communications 
SAEs and AEs will be communicated to the relevant agent manufacturer per their individual safety 
reporting requirements regarding timing, frequency, and format. 
 
7.4.7 End of Treatment safety Follow-up 
All S/AEs, including any laboratory abnormalities, that fit the reportable criteria described in 
Section 7.4.1,  will be recorded from the time the patient signs the Informed Consent Form (ICF) 
until 150 days (5 months) after the last dose of study treatment of canakinumab or spartalizumab 
(due to the half-life of these  drugs), or 30 days after the last dose of the combination chemotherapy, 
whichever is later. 
 
 
For SAEs, Investigator (or sub-investigator) and/or their research staff should submit follow-up 
reports when additional information is available or requested by Sponsor or his/her authorized 
designee.  
 
8.0 
RESPONSE ASSESSMENT 
Response assessments (tumor evaluations) should be performed radiographically (CT/MRI) at 
screening (within a 28-day window prior to Day 1 of treatment), every 8 weeks (± 7 days) until 
disease progression, at suspected progression if off cycle for evaluation, or withdrawal of consent. 
CT is the imaging modality of choice for all patient evaluations, although MRI is permitted if CT 


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contrast allergies occur. Tumor/Response evaluations will be conducted according to RECIST 1.1 
guidelines. RECIST evaluations at baseline must be performed at the treating institution.  
The primary evaluation of response should be performed using RECIST 1.1 guidelines, by 
clinician assessment. The same modality (CT/ or MRI) chosen at screening should be used 
throughout the study. Please refer to Appendix C and Section 9.6 below for full details on the 
RECIST 1.1 Guidelines to follow for this study.  
 
8.1 
Methods for Evaluation of Measurable Disease 
 
8.1.1 Imaging Requirements 
Response assessments will be evaluated by imaging (either CT or MRI if CT contrast allergies 
occur).  PET scans are not permissible.  The regions to be imaged are the chest and abdomen/pelvis, 
as well as any other sites that in the opinion of the clinician and medical monitor required tumor 
imaging. The same mode of imaging for lesion evaluation at pretreatment must be used 
consistently throughout the study. Adherence to the planned imaging schedule is critical regardless 
of dose delays, unscheduled or missed assessments.  
The CT imaging should include contrast unless medically contraindicated. 
 
8.1.2 Tumor Marker Requirements 
Tumor marker response assessments will be evaluated by measuring serum 19-9 (CA19-9) levels 
at the beginning of each cycle, including at the time of every CT/MRI scan assessment (+/- every 
4 weeks).  Measurements will be analyzed according to local practice. If feasible, the same assay 
should be used serially for each patient. Tumor marker levels will be recorded with response, 
although not included as official response criteria.  
Please refer to Appendix C and Section 9.6 below for full details on the RECIST 1.1 Guidelines 
to follow for this study.  
 


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9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Analysis Sets 
9.1.1 Full Analysis Set 
The Full Analysis Set (FAS) and Safety set are defined in the same way and comprise all patients 
who received at least one dose of study treatment.  
9.1.2 Safety Set 
See definition of Full Analysis Set (FAS) in Section 9.1.1 above. 
 
9.1.3 Dose-Determining Analysis Set (DDS) 
The Dose-Determining Set (DDS) includes all patients from the safety set who meet the minimum 
exposure criterion and have sufficient safety evaluations, or experienced a dose limiting toxicity 
(DLT) during the first two cycles (8 weeks) of dosing. 
A patient meets the minimum exposure criterion if the patient received:   
• 2 doses of canakinumab (for Q4W dosing regimen cohort) or 1 dose of canakinumab (for Q8W 
dosing regimen cohort in case the canakinumab dose is de-escalated) and 2 infusions of 
spartalizumab (full dose) within the first 56 days (8 weeks) of study treatment 
• Takes at least 75% of planned doses of gemcitabine plus nab-paclitaxel chemotherapy within 
the first 56 days (8 weeks) of study treatment 
If the patient did not  receive the planned number of doses due to DLT, the patient will be 
considered as meeting the minimum exposure criterion. Patients who do not experience a DLT 
during the first 56 days (8 weeks) are considered to have sufficient safety evaluations if they have 
been observed for ≥ 56 days (8 weeks) following the first dose, and are considered by the dose 
level review team (DLRT) to have sufficient safety data to conclude that a DLT did not occur. 
9.1.4 Pharmacokinetic Analysis Set 
 
The Pharmacokinetic Analysis Set (PAS) consists of all subjects who received at least one dose 
of study drug and have at least one evaluable pharmacokinetic (PK) sample. The definition of 
an evaluable PK blood sample will be further specified in the statistical analysis plan (SAP). 
PAS will be defined for canakinumab, spartalizumab, nab-paclitaxel, and gemcitabine separately. 


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9.2 
Subject Demographics and Other Baseline Characteristics  
 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term.  
9.3            Study Treatment and Dose Exposure  
The duration of exposure in months as well as the dose intensity (computed as the ratio of actual 
cumulative dose received and actual duration of exposure) and the relative dose intensity 
(computed as the ratio of dose intensity and planned dose intensity) will be summarized by means 
of descriptive statistics using the safety set. 
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group; and all dosing data will 
be listed. The reason for discontinuation from treatment will be summarized and listed, along with 
dates of first and last dose of study drug. 
Concomitant medications and significant non-drug therapies prior to and after the start of the study 
treatment will be listed and summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system by dose level.  
9.4             Study Primary Objective  
The primary objective is to confirmation of the recommended dose for Phase II/III study.    The 
primary endpoint is the incidence of dose limiting toxicities (DLT) in the first 56 days (8 weeks) 
of the study treatment. 
9.4.1 Statistical Model, Hypothesis, and Method of Analysis  
For the dose confirmation of canakinumab and spartalizumab in combination with nab-paclitaxel 
and gemcitabine, a Bayesian hierarchical logistic regression model (BLRM) will be applied to 
estimate the relationship between dose and the probability of a patient experiencing a dose limiting 
toxicity (DLT).    Some dose-limiting toxicity data are available from previous studies on single 
agent and combination of canakinumab and spartalizumab (PDR001X2101,  ACZ885I2202, 
PRD001X2103) and a phase I/II study of  nab-paclitaxel + gemcitabine (Von Hoff D, et.al., 2011).  


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These data will be incorporated into BLRM model using a meta-analytic-predictive (MAC) 
approach (Neuenschwander et al 2016). The details of the historical study and the data are provided 
in Appendix B.   
 
The decision on dose tolerability for will be based on the totality of all relevant data from the 
ongoing study and a review of safety data from during the DLT evaluation period (the first 8 
weeks). A Bayesian logistic regression model (BLRM) for combinations using the escalation with 
overdose control (EWOC) criterion to evaluate the risk of DLT will guide the decision.   
 
Additional information on the BLRM statistical model is located in Appendix B.  
9.4.2 Assessment of Patient Risk 
Dose recommendations will be based on summaries of the posterior distribution of DLT rates for 
each dose level of the respective combination therapy. After each cohort of patients, the posterior 
distribution for the risk of DLT for new patients at combination doses of interest will be evaluated. 
The posterior distributions will be summarized to provide the posterior probability that the risk of 
DLT for each dose regimen lies within the following intervals:  
• Under-dosing: [0 , 0.16) 
• Targeted toxicity: [0.16 , 0.33) 
• Excessive toxicity: [0.33 , 1] 
 
Dosing regimen decisions are guided by the escalation with overdose control (EWOC) principle 
(Rogatko et al 2007).   The possibility of excessive toxicity is of interest in this study as the 
objective is to confirm the safety of the proposed dose regimen.  A dosing regimen may only be 
used for newly enrolled patients if the risk of excessive toxicity (within the interval [0.33, 1]) at 
that dosing regimen is less than 25%. 
 
 
 
 


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Hypothetical on-study scenarios 
To illustrate the performance of the BLRM model used to guide dose escalation, hypothetical dose 
escalations scenarios are presented in Table 9-1 .  In each scenario, the table displays the next dose 
level with the mean expected probability of dose limited toxicity P(DLT) and the probability of 
having excessive toxicity  P(excessive toxicity) at that dose level.  Note that next dose level could 
be the same dose level.  If P(excessive toxicity) is ≥ 25%, then the next dose level does not meet 
EWOC and no more patients should be enrolled at this dose level and a new cohort should be 
opened at a lower dose level. The hypothetical scenarios considered various cases with 10 
evaluable patients or 6 evaluable patients.   Scenario 1, 5,  and 6 are cases such that the starting 
dose is considered safe to proceed (meet EWOC),  while scenario 2, and 7 are cases such that 
starting dose is not considered safe (do not meet EWOC).  In those cases, cohort 2 will be opened 
at a lower dose level (scenario 3, 4, 8, and 9).  If cohort 2 is considered unsafe to proceed, no more 
cohort will be opened.     
Table 9-1 
Hypothetical Dose Escalation Scenarios  
Scenario 
Cohort 
Canakinumab 
dose Schedule* 
Number of  
 
Next dose level 
Evaluable 
patients 
DLTs 
 
Canakinumab 
dose schedule* 
Median 
P(DLT) 
P(excessive 
toxicity) 
1 
Cohort 1 
Q4W 
10 
2 
 
Q4W 
0.152 
0.081 
2 
Cohort 1 
Q4W 
10 
3 
 
Q4W 
0.239 
0.257 
3 
Cohort 1 
Q4W 
10 
3 
 
 
 
 
 
Cohort 2 
Q8W 
10 
1 
 
Q8W 
0.126 
0.019 
4 
Cohort 1 
Q4W 
10 
3 
 
 
 
 
 
Cohort 2 
Q8W 
10 
2 
 
Q8W 
0.172 
0.071 
5 
Cohort 1 
Q4W 
6 
0 
 
Q4W 
0.038 
0.008 
6 
Cohort 1 
Q4W 
6 
1 
 
Q4W 
0.119 
0.075 
7 
Cohort 1 
Q4W 
6 
2 
 
Q4W 
0.240 
0.301 
8 
Cohort 1 
Q4W 
6 
2 
 
 
 
 
 
Cohort 2 
Q8W 
6 
1 
 
Q8W 
0.150 
0.074 
9 
Cohort 1 
Q4W 
6 
2 
 
 
 
 
 
Cohort 2 
Q8W 
6 
2 
 
Q8W 
0.226 
0.234 
* Canakinumab 250 mg Q4W or Q8W in combination with fixed dose of  spartalizumab 400mg Q4W + nab-
paclitaxel 125 mg/m2  + gemcitabine 1000 mg/m2 (Day 1, 8 ,15 of each cycle) 
 
 
 


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Listing/ summary of DLTs 
DLTs will be listed and their incidence summarized by primary system organ class, worst grade 
based on the CTCAE version 5.0, type of adverse event, and by treatment group in the dose 
escalation. The dose-determining set will be used for these summaries. 
 
9.5 
Secondary Safety Objective 
 
Safety summaries will use the Safety Analysis Set. 
The overall observation period will be divided into three mutually exclusive segments: 
• Pre-treatment period: from day of subject’s informed consent to the day before first dose of 
study treatment 
• On-treatment period: from day of first dose of study medication to 30 days after last dose of 
study treatment 
• Post-treatment period: starting at day 30+1 after last dose of study treatment 
 
9.5.1 Adverse Events 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided.   Summary tables for adverse events (AEs) will include AEs 
with onset date during the on-treatment period, the treatment-emergent AEs. The incidence of 
treatment-emergent adverse events will be summarized by system organ class and or preferred 
term, severity (based on CTCAE 5.0  grades), type of adverse event, and relation to study 
treatment.  All AEs, deaths and serious adverse events (including those from the pre and post-
treatment periods) will be listed and those starting during the pre-treatment and post-treatment 
period will be flagged. 
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI) 
during the on-treatment period will be tabulated. AESIs will be defined based on the current case 


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retrieval strategy (CRS). All reported deaths (on-treatment and post-treatment) will be 
summarized.  
9.5.2 Clinical laboratory evaluations 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0  the study’s biostatistical and reporting team will grade laboratory data accordingly. 
For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-missing values not 
graded as 1 or higher. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following by-treatment/patient group summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests: 
Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 
Listing of all clinically relevant laboratory data with values flagged to show the corresponding 
CTCAE grades and the classifications relative to the laboratory normal ranges. 
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might be 
specified in the SAP. 
9.5.3 Other safety data 
Other safety data, include vital signs and ECGs will be listed by dose level and subject, and 
visit/time and if ranges are available, abnormalities (and relevant orthostatic changes) will be 
flagged. Summary statistics will be provided by treatment and visit/time. 
 
9.6 Secondary Efficacy and PK Objective(s) 
 
9.6.1  Secondary Efficacy Objective(s) 
 
• Analysis of efficacy endpoints will be performed on the Full Analysis Set.  
• Tumor response will be determined per local investigators’ assessment.  
• Response related efficacy assessments will be defined and analyzed based on RECIST 1.1 
(primary).  ORR and DCR will be estimated, and the exact binomial 95% CI will be 


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reported.  Time to event efficacy endpoints using Kaplan-Meier method and the median 
along with 95% confidence intervals. 
 
Overall response rate (ORR)  
ORR is defined as the proportion of subjects with best overall response (BOR) of complete 
response (CR) or partial response (PR), according to RECIST 1.1. ORR will be calculated based 
on the FAS. ORR and its 95% exact confidence interval will be presented  
Duration of response (DOR)  
DOR only applies to subjects in FAS whose BOR is CR or PR according to RECIST 1.1. The start 
date is the date of first documented response of CR or PR (i.e., the start date of response, not the 
date when response was confirmed), and the end date is defined as the date of the first documented 
progression or death due to underlying cancer. Subjects continuing without progression or death 
due to underlying cancer will be censored at the date of their last adequate tumor assessment.   
Kaplan-Meier method will be used to estimate median PFS and 95% confidence intervals will be 
presented by dose level in FAS (by investigator assessment). 
Disease Control Rate (DCR)  
DCR is defined as the proportion of subjects with a BOR of CR, PR, or SD, according to RECIST 
1.1.  DCR will be calculated based on the FAS. DCR and its exact 95% confidence interval will 
be presented. 
Progression Free Survival (PFS)  
PFS is defined as the time from the date of first dose  to the date of the first documented disease 
progression based on local investigator assessment as per RECIST 1.1 (assessed by investigator) 
or death due to any cause.   Kaplan-Meier method will be used to estimate median PFS and 95% 
confidence intervals will be presented by dose level in FAS (by investigator assessment). 
 
Time to response (TTR) 
Time to response (TTR) is defined as the time from the date of first doseto the date of first 


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documented response (CR or PR, which must be confirmed subsequently). Summary statistics will 
be presented.  
Overall survival (OS)  
OS is defined as the time from date of first dose of study treatment to date of death due to any 
cause. If a subject is not known to have died, then OS will be censored at the latest date the subject 
was known to be alive (on or before the cut-off date). 
OS will be analyzed in the FAS population. The OS distribution will beestimated using the Kaplan-
Meier method, and the Kaplan-Meier medians and 95% confidence intervals of the medians will 
be presented.  
9.6.2 Secondary PK Objective(s) 
 
PAS will be used in the pharmacokinetic data analysis.. Descriptive statistics (n, m (number of 
non-zero concentrations), mean, coefficient of variation CV%, SD, median, geometric mean, 
geometric CV%, minimum and maximum) for each analyte (canakinumab, spartalizumab, nab-
paclitaxel and gemitabine) will be presented separately at each scheduled timepoint. 
All concentration data for canakinumab, spartalizumab, nab-paclitaxel and gemitabine vs. time 
profiles will be displayed graphically. 
The descriptive statistics (n, mean, CV%, standard deviation (SD), median, geometric mean, 
geometric CV%, minimum and maximum) will be presented for PK parameters as well, except 
Tmax, where only n, median, minimum and maximum will be presented, when applicable. PK 
parameters (e.g. AUC, Cmin, Cmax, Tmax, T1/2) will be estimated and reported at appropriate 
timepoints, when derivation of selective PK parameters is feasible. 
 
9.7 Exploratory Objectives 
 
9.7.1 Biomarkers 
This clinical trial is not designed to address specific biomarkers-related exploratory objectives, 
the analysis of the data should be viewed as hypotheses generating. 
There may be circumstances when a decision is made to stop a collection, or not to perform or 
discontinue the analysis of samples due to either practical or strategic reasons. Under such 


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circumstances, the sample size number may be too small or the quality of the data not sufficient to 
perform any data analysis and the available data will be only listed. 
Additional analyses that may be performed after the completion of the end-of-study CSR will be 
documented in separate reports. These analyses may include but are not limited to the meta-
analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database lock 
and completion of the CSR. The data analysis will be described in an addendum of the Statistical 
Analysis Plan or in a stand-alone analysis plan document, as appropriate. 
Data transformations, such as base 2 logarithms, may be used to summarize and adequately 
analyze the data and will be described in detail in the statistical analysis plans. 
 
9.7.2 Data Handling Principles 
 
Analysis sets 
 
Unless otherwise mentioned, the Full Analysis Set is used to describe biomarkers; Safety Set is 
used to assess the relationship between biomarkers and selected safety endpoints, while the PK 
Set is used to assess the relationship between PK parameters and biomarkers. Since no 
imputation is usually planned, the number of subjects included in a given analysis will reflect the 
number of subjects in the chosen analysis set which have valid biomarker assessments. 
 
Basic tables, figures and listings 
 
Unless otherwise specified, analysis will be performed by dose groups (if more than one dose) 
 
will be summarized using means, medians, standard deviations, minimums, and maximums, by 
visit. Both level and change from baseline levels (absolute, percent and fold changes) will be 
summarized for biomarker that also have assessments at post-baseline visits. 
 
 will be summarized using frequency counts and percentages. 


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If sample size is limited then the biomarker data will be listed. For large panels, selected sets of 
relevant markers will be selected for the listing. 
 
9.7.3 
 
 
 
 
 
 
 
9.8 
Handling of Missing Values/ Censoring/ Discontinuations 
 
Patients who are ineligible for the DDS will be excluded from the primary analysis (assessment of 
recommended dose using incidence of DLT during first 56 days of treatment with canakinumab in 
combination with spartalizumab, nab-paclitaxel and gemcitabine), although their data will be used 
for all remaining analyses.  
Continuing events (e.g. AEs, concomitant medication, etc.) will be summarized using the data cut-
off date as the date of completion, with an indication within listings that the event is 
continuing. For patients who discontinue the study with ongoing events, the discontinuation 
date will be used as the completion date of the event with the appropriate censoring as described 
in the above paragraph. 
 
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study drug treatment, duration of exposure to study drug treatment and date of 
discontinuation for each patient. Other missing data will simply be noted as missing on appropriate 
tables/listings.  
A subject whose disease has not progressed or died by the date of the analysis cut-off will have 
their PFS censored at the time of the last adequate tumor evaluation performed on or before the 
cut-off date. Clinical deterioration will not be considered as documented disease progression. 
Censoring rules for PFS follow the RECIST 1.1 guidelines and will be further detailed in the 
SAP. 


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A subject who has not died by the date of the analysis cut-off date will have their OS censored 
at the last known date the subject is alive. 
 
9.9            Sample size  
 
Approximately 10 patients will be enrolled to the starting dose level to have at least 6 evaluable 
patients.  If the starting dose level is considered unsafe,  the dose will be de-escalated to dose level 
-1 and  approximatley 10 patients will be enrolled to achieve at least 6 evalulable patients.  For 
further elaboration of safety and pharmacokinetic parameters, additional patients may be enrolled 
if considered neccessary by Novarits and PIs. Appendix B provided hypothetical scenarios to 
illustrate the dose recommedation by BLRM.   
 
 
10.0 STUDY OVERSIGHT 
 
10.1  Investigator Responsibilities  
The Investigator will conduct all aspects of this study in accordance with applicable national, state, 
and local laws of the pertinent regulatory authorities.  
 
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in the 
local regulations. PanCAN Chief Medical Officer or an authorized representative will evaluate and 
approve all Investigators who in turn will select their staff.  
 
The Investigator should ensure that all persons assisting with the study at his or her site are 
adequately informed about the protocol, amendments, study treatments, as well as study-related 
duties and functions, including obligations of confidentiality. 
 
The Investigator should maintain a list of sub-Investigators and other appropriately qualified 
persons to whom he/she has delegated authority to perform significant study-related duties.  
The Investigator is responsible for keeping a record of all patients who sign an ICF document and 
are screened for entry into the study. Patients who fail screening must have the reason(s) recorded 
in the patient’s source documents.  


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The Investigator must ensure that a patient’s records and documents pertaining to the conduct of 
the study and the distribution of the investigational agent are complete, accurate, filed and retained.  
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to patient records. The 
Investigator must ensure timely and accurate completion of electronic Case Report Forms (eCRF) 
and queries.  
 
10.2 
Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the sponsor, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International Conference 
on Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles 
outlined in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities. 
 
10.3 
Data Management 
The Investigator must ensure that the records and documents pertaining to the conduct of the study 
and the distribution of the IP are complete, accurate, filed and retained. Examples of source 
documents include: hospital records; clinic and office charts; laboratory notes; memoranda; 
patient’s diaries or evaluation checklists; dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; x-ray film 
and reports; and records kept at the pharmacy, and the laboratories, as well as copies of CRFs or 
CD-ROM. 
 
Data will be entered into the RAVE-X electronic data capture (EDC) platform by study staff. This 
data will be electronically verified through the use of programmed edit checks specified by 
Covance. Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary. Resolutions to these issues will be reflected in the 
database. An audit trail within the system will track all changes made to the data. 


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10.4 
Data Monitoring 
This study focuses data collection on critical and essential variables to ensure important efficacy 
and safety information are captured.  The Data Plan specifies the variables collected and those that 
are not. The Data Plan also details the process (and systems) for data collection, cleaning, and 
verification in Precision PromiseSM. The objective is to decrease data quality issues, improve site 
compliance and data completeness, control operational bias and ultimately improve patient 
management and safety.  
 
10.5 
Study Monitoring 
PanCAN or its authorized designee will ensure that appropriate monitoring procedures are 
performed before, during and after the study. All aspects of the study, including review the 
protocol, eCRFs, ICF documents and procedures for obtaining and withdrawing informed consent, 
record keeping, and reporting of AEs/SAEs, are reviewed with the Principal Investigator, sub-
investigators and the study research staff at a study initiation visit and/or at an Investigator meeting.  
Monitoring will include remote and on-site visits with the Investigator, sub-investigators, and 
study research staff as well as any appropriate communications by mail, email, fax, or telephone. 
During monitoring visits, the facilities, investigational agent storage area, eCRFs, patients’ source 
documents, and all other study documentation will be inspected/reviewed by PanCAN or its 
authorized designee(s) in accordance with the Study Monitoring Plan.  
 
10.6 
Audits and Inspections 
PanCAN or its authorized designee(s), local IRB or the FDA may conduct audits of clinical 
research activities to evaluate compliance with Good Clinical Practice guidelines and regulations.  
 
The Investigator is required to permit direct access to the facilities where the study takes place, 
source documents, eCRFs and applicable supporting records of study participation for audits and 
inspections by IRBs, FDA and PanCAN or his/her authorized designees. The Investigator should 
make every effort to be available for the audits and/or inspections. If the Investigator is contacted 
by any regulatory authority regarding an inspection, he/she should contact PanCAN or his/her 
authorized designee immediately.  


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10.7 
Pharmaceutical Agreements 
Investigational agents are provided under a contract between Agent Manufacturer and PanCAN. 
They may not be used outside of the study protocol. 
 
11.0 ETHICAL AND REGULATORY CONSIDERATIONS 
11.1  Good Clinical Practice 
This protocol describes procedures pertaining to conduct, evaluation, and documentation to ensure 
that PanCAN, its authorized designee(s), and the study Investigators, sub-investigators and site 
staff abide by Good Clinical Practice (GCP), as described in International Conference on 
Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki.  
 
11.2  Record Keeping 
Study sites selected for participation in this study will be responsible for submitting essential 
regulatory documents to PanCAN or its authorized designee. 
  
The collection of regulatory documents will take place in accordance with applicable ICH GCP 
guidelines, state and federal regulations. Regulatory documents must be maintained per all 
applicable institutional and federal regulations.  All questions related to regulatory document 
submission should be directed to the attention of PanCAN or his/her authorized designee. The 
following documents comprise the essential regulatory document packet required. 
 
11.2.1 Form FDA 1572  
The Investigator will provide an original signed Form FDA 1572 stating that the study will be 
conducted in compliance with regulations for clinical investigations and listing all the sub-
investigators at that institution that will participate in the protocol prior to study initiation.  
 
11.2.2 Other Required Documents 
• CV/Biosketch for the Investigator and all sub-investigators listed on Form FDA 1572  
• Current professional licenses (where applicable) for the Investigator and all sub-


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investigators listed on Form FDA 1572  
• Financial Disclosure Form for the Investigator and all sub-investigators listed on Form 
FDA 1572  
• Certification of Human Subjects Protection Training (NIH or institution-based training 
program certificate) for the Investigator and all sub-investigators listed on Form FDA 1572  
• Delegation of Responsibilities Log signed by the Investigator.  This document lists the 
names and responsibilities of all study staff, including all sub-investigators listed on Form 
FDA 1572  
• Lab certifications (CLIA and CAP) and lab normal ranges for all labs listed on each site’s 
Form FDA 1572. 
• Documentation of Federal wide Assurance (FWA). A print-out of the institutional FWA 
number 
may 
be 
accessed 
via 
the 
OHRP 
website 
as 
follows: 
http://ohrp.cit.nih.gov/search/fwasearch.aspx?styp=bsc. (Click the button for FWAs [FWA 
number]) 
• Investigator’s Brochure (IB) Acknowledgment Form signed by the Investigator for 
each IB received 
• IRB approval for all PanCAN-approved Protocol versions, ICFs, IB versions (if 
applicable) and patient educational and recruitment materials 
 
11.2.3 Submission of Required Documents  
All required documents may be transmitted via email with the exception of the following 
documents for which signed originals must be sent via traceable courier:  1) Form FDA 1572 2) 
Financial Disclosure Form. 
 
11.3 
Patient Information and Informed Consent 
The investigator or his/her authorized designee must obtain informed consent of a patient and/or a 
patient’s legal representative prior to any study-related procedures.  
 
Documentation that informed consent occurred prior to the patient’s entry into the study and of 
the informed consent process should be recorded in the study patient’s source documents including 
the date. The original ICF documents signed and dated by the patient and by the person consenting 


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the patient prior to the patient’s entry into the study, must be maintained in the Investigator’s study 
files and a copy given to the study patient.  
In addition, when the protocol is amended and the information changes patient risk, the ICF 
document will be revised. Study patients who are active in the study when the updated relevant 
informed consent is implemented must be re-consented with the revised version of the appropriate 
ICF. Those patients that are on active treatment must be re-consented only to the treatment phase 
ICF and investigational arm ICF, if appropriate. If the Screening ICF is updated once a patient 
proceeds to the Treatment Phase, re-consenting to the Screening ICF is not required.  The revised 
ICF document signed and dated by the study patient and by the person re-consenting the study 
patient must be maintained in the Investigator’s study files and a copy given to the study patient.  
 
11.3.1 Informed Consent Form(s) Review and Approval Process 
Prior to study initiation, the ICF documents must be reviewed and approved by PanCAN or his/her 
authorized designee, and the IRB at each institution at which the protocol will be implemented. 
Any subsequent changes to the ICF document(s) must be approved by PanCAN or his/her 
authorized designee, and then submitted to each institution’s IRB for approval prior to initiation.  
 
11.4 
Institutional Review Board (IRB) Approval 
Prior to initiating the study and receiving the investigational agent(s), written approval to conduct 
the study from the appropriate IRB must be obtained. As changes to the study become necessary, 
protocol amendments will be submitted to PanCAN according to Amendment Guidelines. 
PanCAN-approved amended protocol must be approved by the IRB prior to implementation.  
As investigational arms move in and out of the trial, protocol amendments will be issued. 
  
11.4.1 IRB Approval Timeline Guidelines 
Participating institutions will be notified of the allowable timeframe permitted to get each 
amendment approved by their institutional IRB.  
• Major Modification: Participating institutions have 60 calendar days to submit and obtain 
IRB approval. If an institution’s IRB approval letter is not received by PanCAN or his/her 
authorized designee ≤ 60 calendar days, accrual at that institution may be placed on hold 
until IRB approval is obtained and approval letters have been received and processed by 


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PanCAN or his/her authorized designee.  
• Minor Modification (not including administrative amendments): Participating 
institutions have 30 calendar days to submit and obtain IRB approval. If an institution’s 
IRB approval letters are not received by PanCAN or his/her authorized designee ≤30 
calendar days, accrual at that institution may be placed on hold until institutional IRB 
approval is obtained, and approval letters have been received and processed by PanCAN 
or his/her authorized designee. 
• Administrative Amendments: Amendments that are administrative in nature do not 
require IRB approval will be submitted to the IRB for information purposes.  
 
11.5  Joint Safety Committee and Dose Confirmation Meeting  
Decisions for confirmation of dose or to assess a different dose level will be made jointly by 
Investigators and study personnel that will include at least Medical Monitor and a biostatistician. 
Decisions will be based on a synthesis of all relevant data available from all dose levels evaluated 
in the ongoing study including safety information, DLTs, all CTCAE Grade ≥ 2 toxicity data 
during the first two cycles, and PK data from evaluable patients. The recommended dose for the 
next cohort of patients will be guided by the BLRM.  
 
11.6 
Study Termination 
The Sponsor (PanCAN) or FDA can terminate the trial at any time. Appropriate measures would 
be made to try to ensure support and continuance of patient care. 
 
12.0 RECORD KEEPING/QUALITY CONTROL 
12.1   Inspection 
PanCAN or its authorized designee must be allowed to conduct site visits for monitoring any 
aspects of the study.   Source data/documents must be available for inspection for PanCAN, its 
authorized designee or any Regulatory Authority.  Monitoring can include inspection of drug 
storage area, study drug stocks, drug accountability records, patient medical records and study 
source documents, and other records related to study conduct. 
  


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12.2 
Record Retention 
In accordance with applicable regulatory requirements, following closure of the trial, the 
Investigator will maintain a copy of all essential documents in a safe and secure location. Essential 
documents must be retained by the Investigator according to the period of time outlined in the 
Clinical Trial Agreement.  
 
Documents included in this retention policy include but is not limited to: 
• Signed ICF’s for all patients 
• Pre-screening and screening logs and enrollment logs  
• Record of all communication with Investigator and IRB 
• Composition of IRB or confirmation statement that the IRB is composition is in accordance 
with GCP, if composition may not be disclosed. 
• Communication between Investigator and Sponsor and authorized designees 
• Delegation of Responsibility Log 
• Access to eCRFs 
• Study treatment accountability records 
• Record of and body fluid or samples retained 
• All other source documents listed in Section 8 of ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) 
 
PanCAN or his/her authorized designee must be notified, in writing, if the Investigator wishes to 
assign the study records to another party or move them to another location or destroy any 
documents.  Institutions/Investigators should take measured to prevent accidental or premature 
destruction of these documents.  
 
 
 
 
 
 


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13.0 CONFIDENTIALITY 
The information contained in this Study Protocol (except for the information provided by PanCAN 
in public scientific presentations and publications, public websites or through press releases) is 
considered PanCAN confidential information. Only information that is previously disclosed by 
PanCAN in public scientific presentations and publications, public websites or through press 
releases may be freely disclosed by the Investigator, his/her sub-investigators, study staff or 
institution, or as outlined in the Clinical Trial Agreement. This Study Protocol is not to be made 
publicly available (for example on the Investigator’s or his/her institution’s website) without 
written approval from PanCAN.  
 


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Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To 
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Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for 
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15.0 APPENDICES 
 
APPENDIX A 
Gemcitabine and Nab-paclitaxel Package Inserts  
 
Gemzar USPI 2019 http://uspl.lilly.com/gemzar/gemzar.html 
 
Abraxane USPI 2019 https://media2.celgene.com/content/uploads/abraxane-pi.pdf 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
BLRM Statistical Model 
This appendix provides details of the statistical model used for each treatment arm, the derivation 
of prior distributions, and the results of the Bayesian analyses and respective dosing decisions for 
some hypothetical data scenarios. 
1 Statistical model for triple combination 
For each treatment arm, the statistical model comprises single-agent toxicity parts, which allow 
the incorporation of single-agent toxicity information, and interaction parts to describe two-way 
drug safety interactions. The proposed statistical model uses a meta-analytic framework 
(Neuenschwander 2016) to combine all historical and concurrent data.  
 
1.1 
Single agent parts 
Let 𝜋𝜋𝑖𝑖(𝑑𝑑𝑖𝑖) be the risk of DLT for compound i given as a single agent at dose 𝑑𝑑𝑖𝑖 (i=1, 2, 3).  The 
single agent dose-DLT models are logistic: 
logit൫𝜋𝜋i(𝑑𝑑𝑖𝑖)൯ =  log(𝛼𝛼𝑖𝑖) + 𝛽𝛽i log(𝑑𝑑i 𝑑𝑑i
∗
⁄
) i=1, 2, 3 
(1) 
where 𝑑𝑑𝑖𝑖
∗ , the reference dose, is used to scale the doses of each compound. The reference doses 
are defined in the appropriate model specification sections.  
Hence, 𝛼𝛼𝑖𝑖 (>0) is the single-agent odds of a DLT at 𝑑𝑑𝑖𝑖
∗ and  𝛽𝛽𝑖𝑖 (>0) is the increase in the log-odds 
of a DLT by a unit increase in log-dose. 
 
1.2 
Interaction  
Under no interaction, the risk of a DLT for combination dose (𝑑𝑑1, 𝑑𝑑2, 𝑑𝑑3) is: 
𝜋𝜋123
0 (𝑑𝑑1, 𝑑𝑑2, 𝑑𝑑3) = 1 − ൫1 −𝜋𝜋1(𝑑𝑑1)൯൫1 −𝜋𝜋2(𝑑𝑑2)൯൫1 −𝜋𝜋3(𝑑𝑑3)൯ 
To allow for interaction between each pair of compounds, odds multipliers, 𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23 
are introduced. 
The risk of DLT for combination dose (𝑑𝑑1, 𝑑𝑑2, 𝑑𝑑3) is then given by: 
odds൫𝜋𝜋123(𝑑𝑑1, 𝑑𝑑2, 𝑑𝑑3)൯= exp ቆ𝜂𝜂12
𝑑𝑑1𝑑𝑑2
𝑑𝑑1
∗𝑑𝑑2
∗+ 𝜂𝜂13
𝑑𝑑1𝑑𝑑3
𝑑𝑑1
∗𝑑𝑑3
∗+ 𝜂𝜂23
𝑑𝑑2𝑑𝑑3
𝑑𝑑2
∗𝑑𝑑3
∗ቇ× odds൫𝜋𝜋123
0 (𝑑𝑑1, 𝑑𝑑2, 𝑑𝑑3)൯ 
Where, 
 odds(𝜋𝜋) = 𝜋𝜋(1 −𝜋𝜋)
⁄
; 
 𝜂𝜂𝑖𝑖𝑖𝑖 is the log of the odds ratio  between the interaction and no interaction model at dose 𝑑𝑑i
∗ and 𝑑𝑑j
∗ 
for treatments i and j and a zero dose of the third treatment;  
𝜂𝜂. = 𝜂𝜂12 + 𝜂𝜂23 + 𝜂𝜂32 is the log of the odds ratio between the interaction and no interaction model 
at dose 𝑑𝑑1
∗, 𝑑𝑑2
∗ and 𝑑𝑑3
∗ for all three treatments. Here 𝜂𝜂. = 0 corresponds to no overall interaction, 
with 𝜂𝜂. > 0 and 𝜂𝜂. < 0 representing overall synergistic and antagonistic toxicity respectively. 














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APPENDIX C 
RECIST Guidelines 1.1  
 
 
 
 
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Statistical Analysis Plan 
 
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PanCAN-SR1 
 
 
Labcorp Drug Development Study ID: 000000203412 
Document Version: 1.0 
Document Date: 16Sep2022 
 
 
 
 
 
 
 
Labcorp Drug Development 
 
 
Table of Contents 
1. 
Source Documents ................................................................................. 8 
2. 
Protocol Details ..................................................................................... 8 
2.1 
Study Objectives................................................................................. 8 
2.1.1 
Study Primary Objective........................................................................................................ 8 
2.1.2 
Study Secondary Objectives .................................................................................................. 8 
2.1.3 
Study Exploratory Objectives ................................................................................................ 8 
2.2 
Overall Study Design ........................................................................... 8 
2.3 
Sample Size and Power ..................................................................... 11 
3. 
Efficacy and Safety Variables................................................................. 11 


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3.1 
Primary Safety Endpoint .................................................................... 11 
3.2 
Secondary Efficacy Endpoints ............................................................. 11 
3.2.1 
Derivation of RECIST Visit Responses .................................................................................. 12 
3.2.2 
Overall response rate (ORR) ............................................................................................... 17 
3.2.3 
Duration of response (DOR) ................................................................................................ 18 
3.2.4 
Disease control rate (DCR) .................................................................................................. 18 
3.2.5 
Progression free survival (PFS) ............................................................................................ 18 
3.2.6 
Time to response (TTR) ....................................................................................................... 19 
3.2.7 
Overall survival (OS) ............................................................................................................ 19 
3.3 
Safety Variables................................................................................ 20 
3.3.1 
Secondary Safety Endpoints................................................................................................ 20 
3.3.2 
Other safety variables ......................................................................................................... 26 
3.4 
Exploratory Endpoints ....................................................................... 29 
4. 
Secondary Pharmacokinetic  (PK) endpoint ............................................. 30 
5. 
Analysis populations ............................................................................. 31 
5.1 
All Screened ..................................................................................... 31 
5.2 
Safety Analysis Set (SAF) .................................................................. 31 
5.3 
Full Analysis Set (FAS) ...................................................................... 31 
5.4 
Dose-Determining Analysis Set (DDS) ................................................. 31 
5.5 
Pharmacokinetic Analysis Set (PAS) .................................................... 31 
5.6 
Important Protocol Deviations ............................................................ 32 
6. 
DATA Handling .................................................................................... 33 
6.1 
Time points and Visit Windows ........................................................... 33 
6.2 
Handling of Dropouts, Missing Data, and Outliers .................................. 34 
7. 
Statistical Methods ............................................................................... 34 
7.1 
General Principles ............................................................................. 34 
7.2 
Patient Disposition and Data Sets Analyzed .......................................... 36 
7.3 
Protocol Deviations ........................................................................... 37 
7.4 
Demographics and Other Baseline Characteristics ................................. 37 
7.4.1 
Medical History ................................................................................................................... 39 
7.4.2 
Previous and Concomitant Medications ............................................................................. 39 


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7.5 
Efficacy ............................................................................................ 39 
7.5.1 
Primary Efficacy Analysis ..................................................................................................... 39 
7.5.2 
Secondary Efficacy Analysis ................................................................................................ 41 
7.5.3 
Secondary Pharmacokinetic Analysis .................................................................................. 42 
7.6 
Exploratory  Analysis ......................................................................... 44 
7.7 
Safety ............................................................................................. 45 
7.7.1 
Secondary Safety Analysis ................................................................................................... 45 
7.7.2 
Other Safety Variables ........................................................................................................ 50 
7.8 
Interim Analysis................................................................................ 51 
8. 
Changes in Planned Analysis ................................................................. 52 
9. 
.Data Issues........................................................................................ 52 
10. 
References .......................................................................................... 52 
11. 
Appendices ......................................................................................... 53 
Appendix 1: Document History ............................................................ 53 
 
 
 






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OS 
Overall Survival 
PAS 
Pharmacokinetic analysis set 
PD 
Progressive disease 
PDAC 
Pancreatic adenocarcinoma 
PK 
Pharmacokinetic 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred Term 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAF 
Safety  
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
SoC 
Standard of Care 
tlast 
Time of the last quantifiable concentration 
tmax 
Time to reach maximum plasma concentration  
TTR 
Time to response 
TFLs 
Tables, figures, and listings 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
 
 


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STATISTICAL ANALYSIS PLAN AMENDMENT 1 
 
This section is not required at this time, but may be populated in a future approved 
version of this document. 
 
 




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This is an open-label multi-center phase Ib study to confirm the recommended 
phase II/III dose of canakinumab  and spartalizumab in combination with 
nab-paclitaxel and gemcitabine as first-line therapy for patients with metastatic 
pancreatic cancer.  
Patients will be treated until disease progression per RECIST 1.1, unacceptable 
toxicity, or until the patient or treating physician decides to stop treatment. 
Pharmacokinetic (PK) 
 samples will be collected at specific 
time points throughout treatment. Each treatment cycle is 4 weeks. 
The study population is treatment naïve patients with metastatic PDAC.  
All patients must be followed for safety up to 150 days after the last dose of 
spartalizumab or canakinumab, or 30 days after the last dose of the combination 
chemotherapy, whichever the later. 
After the end of safety follow-up, patients will be followed for disease progression if 
discontinuation of treatment is due to any reason other than progression, and for 
survival until the end of study. The study completion is defined as when the last 
patient has completed the study treatment, safety follow-up,  and completed 
survival follow up period up to 1 year from first treatment, whichever is later or in 
the event of an early study termination decision, the date of that decision.  
For this study, the investigational drugs (INDs) are spartalizumab (PDR001) and 
canakinumab (ACZ885) while the non-investigational drugs are gemcitabine and 
nab-paclitaxel. The study treatment is defined as canakinumab in combination with 
spartalizumab, gemcitabine and nab-paclitaxel. 
Table 1 defines the starting dose level.  In case of unacceptable toxicity of the 
starting dose level, the enrollment to the current dose level will be stopped and a 
lower dose (-1 dose level) will be used.   
Table 1 Initial Dose and Treatment Schedule 
Study 
treatments 
Pharmaceutical 
form and route of 
administration 
Strength  
Starting 
Frequency 
and/or Regimen 
Dose 
Administered 
Spartalizumab 
(PDR001) 
Concentrate 
for 
solution 
for 
IV 
infusion 
 4 x 100 mg 
vials 
Day 1 of each 28-
day cycle 
 
400 mg  
 
Canakinumab 
(ACZ885) 
Solution 
for 
SC. 
injection  
in prefilled syringe 
200 mg/1.33 
mL AND 1 x  
50 mg/0.5 mL 
Day 1 of each 28-
day cycle  
250 mg 


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Study 
treatments 
Pharmaceutical 
form and route of 
administration 
Strength  
Starting 
Frequency 
and/or Regimen 
Dose 
Administered 
Gemcitabine 
IV 
 
Days 1, 8, 15 of  
each 28-day cycle   
1000 mg/m2 
Nab-paclitaxel 
IV 
 
Days 1, 8, 15 of  
each 28-day cycle   
125 mg/m2 
IV = intravenous; SC = subcutaneous 
 
Table 2 below describes the starting dose and the -1 dose level in case the starting 
dose has unacceptable toxicity. 
Table 2 Provisional dose levels for the canakinumab with fixed dosage of 
spartalizumab, Gemcitabine and nab-paclitaxel 
Dose level 
Proposed dose of canakinumab 
 
 
1 (starting dose) 
250 mg SC Q4W Canakinumab 
-1* 
250 mg SC Q8W  Canakinumab 
SC = subcutaneous Q4W= every 4 weeks Q8W= every 8 weeks 
Spartalizumab: 400 mg SC. Q4W; Gemcitabine: 1000 mg/m2+ nab-paclitaxel 125 mg/m2 
(on day 1, 8, and 15 of every cycle). 
  
*Dose level -1 represents the treatment dose for patients requiring a dose reduction from 
the starting dose level.  
 
Approximately 10 patients will be enrolled initially to have at least 6 evaluable 
patients per dose level (additional patients may be enrolled as needed in order to 
have 6 evaluable patients). Patients must complete a minimum of 56 days (8 
weeks) of dosing of study treatment with the minimum safety evaluation and drug 
exposure or have had a DLT within the first 56 days of study treatment to be 
considered evaluable for recommended dose decisions. Additionally, approximately 
ten patients (to have at least 6 additional evaluable patients) may be enrolled at 
lower dose level in case a dose de-escalation is necessary.  This could occur if a 
minimum of 6 evaluable patients has been treated and deemed evaluable at this 
dose and unacceptable toxicity is observed at that dose. 
The decision on dose tolerability will be based on all relevant data from the ongoing 
study and a review of safety data from the first 8 weeks (see section 4.1.5 of CSP). 


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2.3 Sample Size and Power 
 
Approximately 10 patients will be enrolled to the starting dose level to have at least 
6 evaluable patients.  If the starting dose level is considered unsafe, the dose will be 
de-escalated to dose level -1 and approximately 10 patients will be enrolled to 
achieve at least 6 evaluable patients. For further elaboration of safety and PK 
parameters, additional patients may be enrolled if considered necessary by Novartis 
and Principal Investigators. Appendix B of the clinical study protocol (CSP) provided 
hypothetical scenarios to illustrate the dose recommendation by Bayesian hierarchical 
logistic regression model (BLRM). 
3. Efficacy and Safety Variables 
3.1 Primary Safety Endpoint 
 
The primary endpoint is the incidence of dose limiting toxicities (DLT) in the first 56 
days (8 weeks) of the study treatment.  
See Section 4.1.5.1 of the CSP for the definition of DLTs.  
A dose-limiting toxicity (DLT) is defined as an adverse event (AE) or abnormal 
laboratory value assessed as unrelated to disease, disease progression, inter-
current illness, or concomitant medications that occurs within the first 8 weeks of 
study treatment and at least possibly related to the study drug. The investigator 
must notify the sponsor immediately (within 24 hours of the treating physician’s 
knowledge) of any unexpected CTCAE grade ≥ 3 AEs or laboratory abnormalities. 
National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) v5.0 
will be used for all grading as per Table 4-3 of CSP. 
Events which will NOT be considered as DLT are: 
 
Clinically insignificant laboratory values ≤ grade 2.  
 
For electrolyte abnormalities ≥ grade 3, the maximum allowable time limit 
for correction to ≤ grade 1 is 72 hours. 
 
3.2 Secondary Efficacy Endpoints 
 


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3.2.1 Derivation of RECIST Visit Responses 
 
For all patients, the Response Evaluation Criteria in Solid Tumors (RECIST) tumor 
response data will be used to determine each patient’s visit response according to 
RECIST Version 1.1 It will also be used to determine if and when a patient has 
progressed in accordance with RECIST and their best overall response (BOR) to 
study treatment.   
Baseline tumor evaluations are to be performed radiographically (computed 
tomography [CT] or magnetic resonance imaging [MRI]) no more than 28 days 
before the administration of first dose of study medication and ideally as close as 
possible to the start of study treatment (prior to Day 1 of treatment). Tumor 
assessments are then performed every 8 weeks (±7 days) from the date of study 
treatment until either disease progression, at suspected progression if off cycle for 
evaluation, or withdrawal of consent.  
From the investigator’s review of the imaging scans, the RECIST tumor response 
data will be used to determine each patient’s visit response according to RECIST 
Version 1.1. At each visit, patients will be assigned a RECIST 1.1 visit response of 
complete response (CR), partial response (PR), stable disease (SD) or progressive 
disease (PD), using the information from target lesions (TLs), non-target lesions 
(NTLs) and new lesions, and dependent upon the status of their disease compared 
with baseline and previous assessments. If a patient has had a tumor assessment 
that cannot be evaluated then the patient will be assigned a visit response of not 
evaluable (NE), (unless there is evidence of progression in which case the response 
will be assigned as PD). 
Please refer to section 3.2.1.2 for the full definitions of CR, PR, SD and PD.  
RECIST outcomes (progression free survival (PFS), overall response rate (ORR), 
disease control rate (DCR), and duration of response (DOR), time to response 
(TTR)) and overall survival (OS) will be calculated programmatically for the site 
investigator data (see sections 3.2.2 and onwards) from the overall visit responses.  
 
3.2.1.1 
Target lesions (TLs) – site investigator data 
Measurable disease is defined as having at least one measurable lesion, not 
previously irradiated, which is ≥10 mm in the longest diameter (LD), (except lymph 
nodes which must have short axis ≥15 mm) with CT or MRI and which is suitable 
for accurate repeated measurements. A patient can have a maximum of 5 
measurable lesions recorded at baseline with a maximum of 2 lesions per organ 


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(representative of all lesions involved and suitable for accurate repeated 
measurement) and these are referred to as target lesions (TLs).  If more than 1 
baseline scan is recorded, then measurements from the one that is closest and prior 
to first dose/administration of study treatment will be used to define the baseline 
sum of TLs. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement. In which circumstance the next largest lesion, 
which can be measured reproducibly, should be selected. 
All other lesions (or sites of disease) pathological lymph nodes not recorded as TL 
should be identified as non-target lesions (NTLs) at baseline.  Measurements are 
not required for these lesions, but their status (present or absent or unequivocal 
progression) should be followed at subsequent visits. 
 
 
Table 3 TL Visit Responses (RECIST 1.1) 
Visit Responses 
Description 
Complete response (CR) 
Disappearance of all TLs.  Any pathological lymph nodes 
(whether target or non-target)  selected as TLs must have a 
reduction in short axis to <10mm. 
Partial response (PR) 
At least a 30% decrease in the sum of diameters of TLs, 
taking as reference the baseline sum of diameters as long as 
criteria for PD are not met. 
Progressive disease (PD) 
A ≥20% increase in the sum of diameters of TLs and an 
absolute increase of ≥5mm, taking as reference the smallest 
sum of diameters since treatment started including the 
baseline sum of diameters. Note: the appearance of one or 
more new lesions is also considered progression 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
Not evaluable (NE) 
Only relevant in certain situations (i.e. if any of the TLs were 
not assessed or not evaluable or had a lesion intervention at 
this visit; and scaling up could not be performed for lesions 
with interventions – see ‘Scaling’ later in this section). Note: If 
the sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL response. 
 
Missing TL data  
If all TL measurements are missing, then the TL visit response is NE.  Overall visit 
response will also be NE, unless there is a progression of non-TLs or new lesions, in 
which case the response will be PD. 
 


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Lymph nodes 
 
For lymph nodes, if the size reduces to <10mm then these are considered non-
pathological. However, a size will still be given and this size should still be used to 
determine the TL visit response as normal.  In the special case where all lymph 
nodes are <10mm and all other TLs are 0mm then although the sum may be 
>0mm the calculation of TL response should be over-written as a CR.  
 
TL visit responses subsequent to CR 
Only CR, PD or NE can follow a CR.  If a CR has occurred, then the following rules 
at the subsequent visits must be applied: 
 
Step 1:  If all lesions meet the CR criteria (ie 0mm  or <10mm for lymph 
nodes) then response will be set to CR irrespective of whether the criteria 
for PD of TL is also met i.e. if a lymph node LD increases by 20% but 
remains <10mm.  
 
Step 2:  If some lesion measurements are missing but all other lesions 
meet the CR criteria (i.e. 0mm or <10mm for lymph nodes) then response 
will be set to NE irrespective of whether, when referencing the sum of TL 
diameters, the criteria for PD are also met.  
 
Step 3:  If not all lesions meet the CR criteria  (i.e. a pathological lymph 
node selected as TL has short axis >10mm or the reappearance of 
previously disappeared lesion) or a new lesion appears, then response will 
be set to PD 
 
Step 4:  If after steps 1 – 3 a response can still not be determined the 
response will be set to remain as CR 
 
3.2.1.2 
Non-target lesions (NTLs) and new lesions – site 
investigator data 
3.2.1.2.1 
Non-target lesions (NTLs) 
 
At each visit, the investigator should record an overall assessment of the NTL 
response. This section provides the definitions of the criteria used to determine and 
record overall response for NTL at the investigational site at each visit. 


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NTL response will be derived based on the investigator’s overall assessment of NTLs 
as follows:   
Table 4 NTL Visit Responses 
Visit Responses 
Description 
Complete response (CR) 
Disappearance of all NTLs present at baseline with 
all lymph nodes non-pathological in size (<10 mm 
short axis and normalization of tumour marker 
level). 
Progressive disease (PD) 
Unequivocal progression of existing NTLs. 
Unequivocal progression may be due to an 
important progression in one lesion only or in 
several lesions. In all cases, the progression MUST 
be clinically significant for the physician to 
consider changing (or stopping) therapy. 
Non-CR/Non-PD 
Persistence of one or more NTLs with no evidence 
of progression and/or maintenance of tumour 
marker level above the normal limits. 
Not evaluable (NE) 
Only relevant when one or some of the NTLs were 
not assessed and, in the investigator's opinion, 
they are not able to provide an evaluable overall 
NTL assessment at this visit. 
Note: For patients without TLs at baseline, this is 
relevant if any of the NTLs were not assessed at 
this visit and the progression criteria have not 
been met. 
Not applicable (NA) 
Only relevant if there are no NTLs at baseline. 
 
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall 
level of substantial worsening in non-target disease such that, even in the presence 
of SD or PR in TLs, the overall tumor burden has increased sufficiently to merit a 
determination of disease progression.  A modest ‘increase’ in the size of one or 
more NTLs is usually not sufficient to qualify for unequivocal progression status. 
3.2.1.2.2 
New Lesions 
 
Details of any new lesions will also be recorded with the date of assessment.  The 
presence of one or more new lesions is assessed as progression. 


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The finding of a new lesion should be unequivocal: i.e. not attributable to 
differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor. 
A lesion identified at a follow up assessment in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease 
progression. 
New lesions will be identified via a Yes/No tick box. The absence and presence of 
new lesions at each visit should be listed alongside the TL and NTL visit responses. 
A new lesion indicates progression so the overall visit response will be PD 
irrespective of the TL and NTL response. 
Symptomatic progression is not a descriptor for progression of NTLs: it is a reason 
for stopping study therapy and will not be included in any assessment of NTLs. 
Patients with ‘symptomatic progression’ requiring discontinuation of treatment 
without objective evidence of disease progression at that time should continue to 
undergo tumor assessments where possible until objective disease progression is 
observed. 
 
3.2.1.3 
Overall visit response – site investigator data 
 
Table 5 defines how the previously defined TL and NTL visit responses will be 
combined with new lesion information to give an overall visit response.  
Table 5 Overall visit responses 
TARGET 
NON-TARGET 
NEW LESIONS 
OVERALL VISIT 
RESPONSE 
CR 
CR or NA 
No (or NE) 
CR 
CR 
Non-CR/Non-PD or 
NE 
No (or NE) 
PR 
PR 
Non-PD or NE 
No (or NE) 
PR 
SD 
Non-PD or NE 
No (or NE) 
SD 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
NE 
Not PD 
No (or NE) 
NE 


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3.2.2 Overall response rate (ORR) 
 
ORR is defined as the proportion of patients with best overall response (BOR) of 
complete response (CR) or partial response (PR), according to RECIST 1.1. and will 
be based on a subset of all treated patients with measurable disease at baseline per 
the site investigator. 
BOR is calculated based on the overall visit responses from each RECIST 
assessment, described in section 3.1. It is the best response a patient has had 
following the first day of study treatment, but prior to starting any subsequent 
cancer therapy and up to and including RECIST progression or the last evaluable 
assessment in the absence of RECIST progression. Categorization of BOR will be 
based on RECIST using the following response categories: CR, PR, SD, PD and NE. 
Overall visit responses of CR or PR must be confirmed for the purpose of BOR 
assignment. A confirmed response of CR/PR means that a response of CR/PR 
recorded at 1 visit requires confirmation by repeat imaging not less than 4 weeks 
after the visit when the response was first observed, with no evidence of 
progression between the initial and CR/PR confirmation visit. 
For determination of a best response of SD, the earliest of the dates contributing 
towards a particular overall visit assessment will be used. SD should be recorded at 
least 8 weeks minus 1 week, i.e. at least 49 days (to allow for an early assessment 
within the assessment window), after first dose of study treatment.  For CR/PR, the 
initial overall visit assessment that showed a response will use the latest of the 
dates contributing towards a particular overall visit assessment. 
BOR will be determined programmatically based on RECIST from the overall visit 
response using all site investigator data up until the first progression event.   
For patients whose progression event is death, BOR will be calculated based upon 
all evaluable RECIST assessments prior to death. 
For patients who die with no evaluable RECIST assessments, if the death occurs 
≤17 weeks (i.e. 2x8 weeks + 1 week to allow for a late assessment within the 
assessment window) after first dose of study treatment, then BOR will be assigned 
to the progression (PD) category.  For patients who die with no evaluable RECIST 
assessments, if the death occurs >17 weeks after first dose of study treatment then 
BOR will be assigned to the NE category. 


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A patient will be classified as a responder if the RECIST criteria for a CR or PR are 
satisfied at any time following first dose of study treatment, prior to RECIST 
progression and prior to starting any subsequent cancer therapy. 
 
3.2.3 Duration of response (DOR) 
 
DOR is defined for patients whose BOR is either CR or PR and is calculated as the 
time from the date of first documented response of CR or PR (which is subsequently 
confirmed, i.e., the start date of response, not the date when response was 
confirmed) until the date of the first documented progression or death due to 
underlying cancer in the absence of disease progression (i.e. date of PFS event or 
censoring – date of first response + 1).   
Patients continuing without progression or death due to underlying cancer, will be 
censored at the date of their last adequate tumor assessment. However, patients 
who progress or die immediately after two or more consecutive missed visits will be 
censored at the time of the latest evaluable assessment prior to the two missed 
visits (note that an overall visit response of NE is not considered as a missed visit). 
 
3.2.4 Disease control rate (DCR) 
 
DCR is defined as the proportion of patients with a BOR of CR, PR, or SD (without 
subsequent cancer therapy) for at least 7 weeks after start of treatment (to allow 
for an early assessment within the assessment window) according to RECIST 1.1. 
 
3.2.5 Progression free survival (PFS) 
 
PFS is defined as the time from the date of first dose  to the date of the first 
documented disease progression based on local investigator assessment as per 
RECIST 1.1 (assessed by investigator) or death (due to any cause in the absence of 
progression) (i.e. date of PFS event or censoring – date of first dose of study 
treatment + 1). Patients who have not progressed or died by the date of the analysis 
cut-off will be censored at the time of the latest date of assessment from their last 
evaluable RECIST assessment (on or before the cut-off date). Clinical deterioration 
will not be considered as documented disease progression. However, if the patient 
progresses or dies immediately after two or more consecutive missed visits, they will 


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be censored at the time of the latest evaluable RECIST 1.1 assessment prior to the 
two missed visits (Note: NE visit is not considered as missed visit).   
The PFS time will always be derived based on scan/assessment dates not visit 
dates. 
RECIST assessments/scans contributing towards a particular visit may be 
performed on different dates.  The following rules will be applied: 
 
The date of progression will be determined based on the earliest of the 
dates of the component that triggered the progression. 
 
When censoring a patient for PFS the patient will be censored at the latest 
of the dates contributing to a particular overall visit assessment.  
Note: for TLs only the latest scan date is recorded out of all scans performed at that 
assessment for the TLs and similarly for NTLs only the latest scan date is recorded 
out of all scans performed at that assessment for the NTLs. 
3.2.6 Time to response (TTR) 
 
TTR is defined as the time from the date of first dose to the date of first 
documented response (CR or PR, which must be confirmed subsequently). The date 
of first documented response should coincide with that used for the DOR endpoint. 
Time to response will not be defined for those patients who do not have a 
documented response which is subsequently confirmed.   
3.2.7 Overall survival (OS) 
 
OS is defined as the time from the date of first dose of study treatment to the date 
of death due to any cause (i.e., date of death or censoring – date of first dose of 
study treatment + 1). If a patient is not known to have died, then OS will be 
censored at the latest date the patient was known to be alive (on or before the cut-
off date). If a patient is confirmed to be alive or if the death date is post the data 
cut-off date, then this patient will be censored at the date of data cut-off. 
 
If a patient is known to have died where only a partial death date is available then 
the date of death will be imputed as the latest of the last date known to be alive +1 
from the database and the death date using the available information provided: 
a) For Missing day only – using the 1st of the month  
b) For Missing day and Month – using the 1st of January 


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If there is evidence of death but the date is entirely missing, it will be treated as 
missing, i.e. censored at the last known alive date. 
 
3.3 Safety Variables 
3.3.1 Secondary Safety Endpoints 
3.3.1.1 
Adverse events 
 
All AEs and SAEs, including any laboratory abnormalities, that fit the reportable 
criteria described in Section 7.4.1 of CSP, will be recorded from the time the patient 
signs the Informed Consent Form until 150 days (5 months) after the last dose of 
study treatment of canakinumab or spartalizumab (due to the half-life of these  
drugs), or 30 days after the last dose of the combination chemotherapy, whichever 
is later. 
Events will be defined as treatment emergent if they onset or worsen (by investigator 
report of a change in severity) during the treatment period as defined in the CSP. 
More specifically, 
 
when the start times of adverse events are not available: 
 
treatment-emergent AEs (TEAEs) are events with a start date on or after the first 
dose date of canakinumab or spartalizumab up until the last dose date of 
canakinumab or spartalizumab plus 30 days. TEAEs are also events with a start 
date prior to the first dose date of any of the canakinumab or spartalizumab whose 
severity worsens on or after the earliest first dose date of any of the canakinumab 
or spartalizumab Events with an onset date during the on-treatment period will be 
considered as TEAEs. Ongoing events with a start date as described above will be 
considered as ongoing TEAEs. 
 
when the start times of adverse events are available: 
 
TEAEs are events with a start date-time on or after the first dose date-time of 
canakinumab or spartalizumab up until the last dose date of canakinumab or 
spartalizumab plus 30 days. TEAEs are also events with a start date-time prior to the 
first dose date-time of any of the canakinumab or spartalizumab whose severity 
worsens on or after the earliest first dose date-time of any of the canakinumab or 
spartalizumab Events with an onset date-time during the on-treatment period will be 
considered as TEAEs. Ongoing events with a start date-time as described above will 
be considered as ongoing TEAEs. 


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The Medical Dictionary for Regulatory Activities (MedDRA) (using the latest effective 
MedDRA version) will be used to code the AEs.  AEs will be graded according to the 
NCI-CTCAE for AEs (using the CTCAE version 5.0). 
 
AEs of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-
serious) which are of scientific and medical concern specific to the sponsor’s program, 
for which ongoing monitoring and rapid communication by the investigator to the 
sponsor may be 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. 
An adverse event of special interest (AESI) is a grouping of AEs that are of scientific 
and medical concern specific to compound canakinumab. 
These groupings are defined using MedDRA terms, SMQs (standardized MedDRA 
queries), high level group terms, high level terms, and PTs. Customized SMQs 
(Novartis MedDRA queries, NMQ) may also be used. An NMQ is a customized group 
of search terms which defines a medical concept for which there is no official SMQ 
available or the available SMQ does not completely fit the need. It may include a 
combination of single terms and/or an existing SMQ, narrow or broad. For each 
specified AESI, number and percentage of participants with at least one event of the 
AESI occurring during on-treatment period will be summarized. As more safety data 
and AE/SAE data are collected, we may identify different risks and change the list of 
AESI. 
A non-exhaustive list of AESI is provided below for investigational drug. This may 
change as further data becomes available. 
 
Renal toxicity/serum creatinine ≥ Grade 2 
 
Neutropenia ≥ Grade3 
 
Febrile neutropenia 
 
Immunogenicity/Hypersensitivity reactions ≥ Grade3 
 
Infusion reactions ≥ Grade3 
 
Diarrhea ≥ Grade3 
 
Hypertension ≥ Grade3 
 
Haemorrhage ≥ Grade3 
 
Cardiac valvulopathy (symptomatic) ≥ Grade3 


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 
Skin reactions ≥ Grade3 
 
Eyelid abnormality (≥ Grade 2) 
 
In addition, following health authority requests the following will also be assessed 
as AESIs: 
 
Covid-19 / SARs-CoV2 positive cases, irrespective of causality 
 
Covid-19 vaccination status in study subjects & subsequent infection 
incidence 
 
Summaries of these AESI will be provided by treatment arms (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose interruption, 
hospitalization, death etc.). A listing of all grouping levels down to the MedDRA PTs 
used to define each AESI will be generated.  
 
The CRS will be used to determine the MedDRA search criteria to be used to identify 
events of special interest. 
 
Based upon the available safety information from spartalizumab and canakinumab 
oncology clinical  development programs and known mechanism of action of these 
drugs and potential overlapping toxicity of all combination drugs, following adverse 
events are considered of special interest in this trial population:  
 
Infections (severe infections and opportunistic infections), including sepsis 
 
Neutropenia CTCAE Grade >3 
 
Febrile neutropenia  
 
Peripheral/Sensory neuropathy CTCAE Grade >3 
 
Thrombocytopenia CTCAE Grade >3  
 
In addition, the potential immune-related AEs considered to be AESIs include, 
endocrinopathies, colitis, skin reactions, hepatitis, nephritis, pneumonitis and 
infusion reaction.  
Details regarding these adverse events are provided in the spartalizumab and 
canakinumab Investigator’s Brochures.. 
3.3.1.2 
12-lead electrocardiogram (ECG) 
 


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Twelve-lead electrocardiograms (ECGs) will be performed  and assessed at the 
scheduled time points according to the Schedule of Events Table 5-1 of the CSP.  
An overall Investigator assessment of ECG will be provided (categories <“normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant”>). 
The following quantitative 12-lead ECG measurements will be taken during the study: 
 
heart rate (beats/min); 
 
RR interval (ms); 
 
PR interval (ms); 
 
QRS interval (ms); 
 
QT interval (ms); 
 
Bazett corrected QT (QTcB) interval (ms)  
 
Fridericia corrected QT (QTcF) interval (ms)  
 
3.3.1.3 
Clinical laboratory evaluations 
 
Laboratory blood tests will be collected  at the scheduled time points according to 
the Schedule of Events Table 5-1 of the CSP and assessed locally. The protocol 
required laboratory parameters are: 
 
Complete blood count (CBC) including but not limited to: 
o Red blood cell (RBC) count 
o Hemoglobin 
o Hematocrit 
o Platelet count 
o White blood cells (WBC) total Count 
o Neutrophils absolute count 
o Lymphocytes absolute count 
o Monocytes absolute count 
o Eosinophils absolute count 
o Basophils absolute count 
o Neutrophils % 
o Lymphocytes % 
o Monocytes % 


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o Eosinophils % 
o Basophils % 
 
 
Chemistry panel including, but not limited to: 
o Total Bilirubin 
o Direct Bilirubin  
o Alkaline Phosphatase 
o ALT (SGPT) 
o AST (SGOT) 
o Albumin  
o Total Protein 
o Serum Creatinine 
o Blood Urea Nitrogen (BUN) 
o Sodium 
o Potassium 
o Calcium 
o Chloride 
o Glucose 
o C-reactive protein 
o Pre-Albumin 
 
 
Thyroid Panel  
o TSH 
o T3FREE 
o T4FREE 
 
 
Coagulation 
o INR 
o Prothrombin Time (PT) 
o Activated Partial Thromboplastin Time (APTT) 
 
 
Urinalysis 


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o Gravity 
o pH 
o Color 
o Viscosity 
o Appearance (Clear, Cloudy, Not Done, Other) 
o Turbidity (Negative, Trace 1+, 2+, 3+_, 4+) 
o Ketones (Negative, Trace 1+, 2+, 3+_, 4+, Not Done, Other) 
o Bilirubin ((Negative, Trace 1+, 2+, 3+_, 4+ Not Done, Other) 
o Blood (Negative, Trace 1+, 2+, 3+_, 4+ Not Done, Other) 
o Glucose (Negative, Trace 1+, 2+, 3+_, 4+ Not Done, Other) 
o Protein (Negative, Trace 1+, 2+, 3+_, 4+ Not Done, Other)  
o Nitrites (Negative, Trace 1+, 2+, 3+_, 4+ Not Done, Other) 
o Urobilinogen (Negative, Trace 1+, 2+, 3+_, 4+ Not Done, Other) 
o Leukocyte Esterases (Negative, Trace 1+, 2+, 3+_, 4+ Not Done, 
Other) 
o Urine Microscopy 
o Red blood Cells 
o White blood cells 
o Epithelial cells 
o Bacteria 
o Crystals 
o Casts 
 
For laboratory tests covered by the CTCAE version 5.0, the study’s biostatistical and 
reporting team will grade laboratory data accordingly. For laboratory tests covered 
by CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or 
higher. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded 
by the low/normal/high classifications based on local laboratory normal ranges. 
Laboratory test with any clinically significant results will also be collected. 
 


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3.3.2 Other safety variables 
 
3.3.2.1 
Duration of exposure 
 
The duration of (total or intendedexposure (in months) will be calculated separately 
for each study drug. 
The duration of (total or intended) exposure (in months), to any drug will also be 
calculated. 
Exposure will be defined as follows: 
For canakinumab: 
 
(Total or intended) duration of exposure (months) = ((date of last dose where 
dose >0 [units]– date of first dose where dose >0 [units]) + length of dose 
frequency)/ (365.25 / 12).  
Where length of dose frequency = 28 if last dose is given on Q4W and 56 if 
last dose is given on Q8W 
For spartalizumab: 
 
(Total or intended) duration of exposure (months) = ((date of last dose where 
dose >0 [units]– date of first dose where dose >0 [units]) + 28)/ (365.25 / 
12).  
For nab-paclitaxel or gemcitabine: 
 
(Total or intended) duration of exposure (days) = ((date of last dose where 
dose >0 [units]– date of first dose where dose >0 [units]) + i)) / (365.25 / 
12). 
 
Where i =7 if last dose is given on cycle day 1 or 8, i =14 if last dose is given 
on cycle day 15 
For Any Drug: 
 
(Total or intended) duration of exposure (days) = ((date of last dose where 
dose >0 [units]– date of first dose where dose >0 [units]+x) / (365.25 / 12). 
Where x is: 
 
the length of dose frequency when the date of last dose is the last dose date 
of canakinumab 


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 
28 for date of last dose of spartalizumab 
 
x = i =7 if last dose of nab-paclitaxel or gemcitabin is given on cycle day 1 or 
8 
 
x= i =14 if last dose nab-paclitaxel or gemcitabin is given on cycle day 15 
 
3.3.2.2 
Dose intensity 
 
The actual dose intensity and the relative dose intensity (RDI) will be summarized 
for each study drug component nested within the groups as defined for the 
cumulative dose (i.e. total dose given during the study drug exposure ) by 
descriptive statistics. In addition, categorical summary of RDI for each study drug 
will be presented. The number of administrations (or treatment cycles) of each 
study drug component of the study treatment nested within the treatment groups 
as defined for the cumulative dose will be summarized by frequencies and 
descriptive statistics. 
The actual dose intensity (DI) is defined as: 
DI=actual cumulative dose / number of cycles on treatment, for subjects with non-
zero duration of exposure. For subjects who did not take the drug, the DI is by 
definition equal to zero. 
Number of cycles on treatment are defined as: 
 
For canakinumab 
 
Number of cycles on treatment = (last date of administration of study drug - first 
date of administration of study drug + length of dose frequency)/28 
 
For spartalizumab 
 
Number of cycles on treatment = (last date of administration of study drug - first 
date of administration of study drug + 28)/28 
 
For nab-paclitaxel or gemcitabine 
 
scheduled for Day 1, 8 and 15 of every 28-day cycle, with the last non-zero 
administration of nab-paclitaxel or gemcitabine at Cycle u Day v: 


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If v=1, number of cycles on treatment = (u-1)+1/3 
If v=8, number of cycles on treatment = (u-1)+2/3 
If v=15, number of cycles on treatment = u 
 
PDI (dosing unit/unit of time) = planned dose intensity 
PDI is the assigned dose by unit of time planned to be given to subjects as per 
protocol in the same dose unit and unit of time as that of the dose intensity.  
PDI and relative dose intensity (RDI) is defined as: 
 
For canakinumab: 
- 
PDI is the planned dose as per protocol in mg (i.e. 250 mg Q4W) 
- 
RDI (%) = DI (mg/cycle) / PDI (mg/cycle) * 100 
For spartilizumab: 
- 
PDI is the planned dose as per protocol in mg (i.e. 400 mg Q4W) 
- 
RDI (%) = DI (mg/cycle) / PDI (mg/cycle) * 100 
For chemotherapy: 
- 
nab-paclitaxel 
o 
PDI is the planned dose as per protocol in mg/m2 (i.e. 375 mg/m2/cycle) 
o 
RDI (%) = DI (mg/m2/cycle) / PDI (mg/m2/cycle) * 100 
- 
gemcitabine 
o 
PDI is the planned dose as per protocol in mg/m2 (i.e. 1000 mg/m2/cycle) 
o 
RDI (%) = DI (mg/m2/cycle) / PDI (mg/m2/cycle) * 100 
 
3.3.2.3 
Vital signs 
 
Vital signs will be performed and assessed at the scheduled time points according 
to the Schedule of Events Table 5-1 of the CSP. Vital signs include temperature 
(°C), heart rate (beats per minute), systolic and diastolic blood pressure (mmHg). 
Results will be graded by the low/normal/high classifications based on normal 
ranges CTCAE will be used to define low/high classification. 


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3.3.2.4 
Physical examination 
 
A complete physical examination will be performed at the scheduled time points  
indicated in Schedule of Events Table 5-1 of the CSP and will include an assessment 
of the following: general appearance, cardiovascular, abdomen, skin, neck, lymph 
nodes, HEENT, thorax/lungs, musculoskeletal, neurological and other. 
An overall Investigator assessment of physical examination will be provided 
(categories <“normal”, “abnormal, not clinically significant” and “abnormal, 
clinically significant”>) 
 
3.3.2.5 
Previous and Concomitant medications 
 
Medications and significant non-drug therapies received prior to, concomitantly (after 
the start of the study treatment) or post-treatment will be coded by Covance using 
the WHODrug Dictionary Version B3 (or a later version if updated during the study)], 
Anatomical Therapeutic Chemical (ATC) Classification codes.  
Prior medications and concomitant medications are defined as follows: 
Prior medications are those taken prior to study treatment with a stop date prior to 
the first dose date of study treatment (i.e. the earliest first dose of any of the 
canakinumab or spartalizumab). 
Concomitant medications are those with a start date  on or after the first dose date 
of study treatment, or those with a start date before the first dose date of study 
treatment and a stop date on or after the first dose date  of study treatment or 
ongoing end of study. 
Post-treatment medications are those with a start date after the last dose date of 
study treatment. 
If a medication cannot be classified as “prior” or “concomitant” after applying 
imputation rules for missing/incomplete dates, it will be classified as concomitant. 
Missing coding terms should be listed and summarized as "Not coded". 
 
 
 
 


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 
 
  
 
4. Secondary Pharmacokinetic  (PK) endpoint  
The secondary PK endpoint comprises PK concentrations and parameters of 
canakinumab, spartalizumab, gemcitabine and nab-paclitaxel. 
The specific Pharmacokinetic blood collection for canakinumab, spartalizumab, 
gemcitabine and nab-paclitaxel is outlined in Section 5.6 of CSP.  
Blood draws for canakinumab and spartalizumab will be performed on Days 1,8, 
and 15 of Cycle 1, and Day 1 of Cycles 2-6 (pre-dose), (8 days post dose of Cycle 5 
for canakinumab  and spartalizumab) and at End of Treatment. PK draws for both 
gemcitabine and nab-paclitaxel will be performed on Day 1 of Cycles 1 and 2.  
All PK samples collected will be sent to Novartis. 
The merging of PK concentration data for canakinumab, spartalizumab, gemcitabine 
and nab-paclitaxel with  eCRF data, i.e actual PK sampling times and actual doses 
or infusion duration will be performed by Covance Clinical and Periapproval Services 
Limited, UK, who will also be responsible for the summaries, figures, and data 
listings. 
The non-compartmental analysis  will be carried out by the Covance Clinical 
Pharmacokinetic Alliance (CPKA). Pharmacokinetic parameters will be derived using 
non-compartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. 
The PK parameters to be reported are: AUClast Cmin, Cmax, tmax, and tlast. Half-life 
(t1/2) may be estimated for nab-paclitaxel and gemitabine if data allow. 
 
The actual sampling times will be used in the final plasma PK parameter 
calculations. If actual times are missing, nominal times may be used. 
Plasam concentration below assay lower limited of quantitation (BLQ) will be 
treated as zero if it occurs prior to the first quantifiable concentration; thereafter, 
any BLQs will be treated as missing for PK parameters calculation. 
Cmax, Cmin, tmax, and tlast are observed values based on concentration-time profile. 
AUClast will be calculated using linear up-log down trapezoidal method. 


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5. Analysis populations 
5.1 All Screened 
 
All patients who consent to participate in the study and who undergo screening will 
be included in the All Screened population.  
5.2 Safety Analysis Set (SAF) 
All patients treated with at least one dose of any of the constituent study 
treatments will be included in the safety population.  
5.3 Full Analysis Set (FAS) 
The full analysis set FAS is defined in the same way as the SAF in section 5.2 and 
will comprise all patients who received at least one dose of any of the constituent 
study treatments. 
5.4 Dose-Determining Analysis Set (DDS) 
The dose determining set (DDS) includes all patients from the SAF who meet the 
minimum exposure criterion and have sufficient safety evaluations, or experienced 
a dose limiting toxicity (DLT) during the first two cycles (8 weeks) of dosing. 
A patient meets the minimum exposure criterion if the patient received:   
 
2 doses of canakinumab (for Q4W dosing regimen cohort) or 1 dose of 
canakinumab (for Q8W dosing regimen cohort in case the canakinumab dose is 
de-escalated) and 2 infusions of spartalizumab (full dose) within the first 56 days 
(8 weeks) of study treatment 
 
Takes at least 75% of planned doses of gemcitabine plus nab-paclitaxel 
chemotherapy within the first 56 days (8 weeks) of study treatment. 
If the patient did not receive the planned number of doses due to DLT, the patient 
will be considered as meeting the minimum exposure criterion. Patients who do not 
experience a DLT during the first 56 days (8 weeks) are considered to have 
sufficient safety evaluations if they have been observed for ≥56 days (8 weeks) 
following the first dose, and are considered by the dose level review team (DLRT) to 
have sufficient safety data to conclude that a DLT did not occur. 
5.5 Pharmacokinetic Analysis Set (PAS) 
 
The Pharmacokinetic Analysis Set (PAS) is defined for canakinumab, spartalizumab, 
nab-paclitaxel, and gemcitabine separately. 




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study they will be documented in a SAP amendment and included in all relevant 
protocol deviation reviews and approvals. 
6. DATA Handling 
6.1 Time points and Visit Windows 
 
Day 1 is defined as the day of first dose of study treatment. Relative days after Day 
1 are calculated as (assessment date – Day 1 date) + 1. Relative days prior to Day 
1 are calculated as (assessment date – Day 1 date).  
The day prior to Day 1 is Day -1.  
The following visit windows will be used for the by-visit analyses of laboratory, ECG 
and vital sign data. All other analysis will use the nominal study visit as defined in 
the Study Schedule and eCRF. 
Table 1 
Definition of visit windows 
Visit 
Acceptable visit window 
Screening 
Cycle 1 Day -28 to -3 
Cycle 1 Day 1 
Cycle 1 Day -2 to 4 (Day 1±3 days) 
Cycle 1 Day 8 
Cycle 1 Day 5 to 11 (Day 8±3 days) 
Cycle 1 Day 15 
Cycle 1 Day 12 to 18 (Day 15±3 days) 
Cycle 2 Day 1 
Cycle 2 Day -1 to 3 (Day 1±2 days) 
Cycle 2 Day 8 
Cycle 2 Day 6 to 10 (Day 8±2 days) 
Cycle 2 Day 15 
Cycle 2 Day 13 to 16 (Day 15±2 days) 
For Cycles > 2 
 
Cycle X Day 1 
Cycle X Day -1 to 3 (Cycle X Day 1±2 days) 
EOT 
-7 days to +14 days of date of last dose or decision to 
discontinue study treatment (whichever date comes later) 
30 Day Safety Follow-up 
EoT + 23 to EoT + 37 (EoT +30 ±7 days) 
60 Day Safety Follow-up 
EoT + 53 to EoT + 67 (EoT +60 ±7 days) 
90 Day Safety Follow-up 
EoT + 83 to EoT + 97 (EoT +90 ±7 days) 
120 Day Safety Follow-up 
EoT + 113 to EoT + 127 (EoT +120 ±7 days) 
150 Day Safety Follow-up 
EoT + 143 to EoT + 157 (EoT +150 ±7 days) 
 
 
NA = not applicable; EoT = Date of last dose;  
 
Multiple visits within the same window will be dealt with as follows: 
 
If both scheduled and unscheduled visits fall within the same visit window, the 
scheduled visit will be used for analysis. 
 
If multiple scheduled visits occur within a single visit window, then the visit 
closest to the target day of the visit window will be used in the analysis.  If there 
is a tie, the later visit will be used in the analysis.> 


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 
If multiple unscheduled visits occur within a single visit window (with no 
scheduled visit within the window) then the unscheduled visit closest to the 
target day of the visit window will be used in the analysis.  If there is a tie, the 
later unscheduled visit will be used in the analysis. 
6.2 Handling of Dropouts, Missing Data, and Outliers 
 
No rules for outlier detection are planned. 
Missing safety data will generally not be imputed. However, safety assessment values 
of the form of “<x” (i.e. below the lower limit of quantification) or “>x” (i.e. above 
the upper limit of quantification) will be imputed as “x” in the calculation of summary 
statistics but displayed as “<x” or “>x” in the listings. Additionally, adverse events 
that have missing causality (after data querying) will be assumed to be related to 
study drug. 
For missing start AE dates, the following will be applied: 
 
Missing day – impute the 1st of the month unless month is same as month of 
first dose of study drug then impute first dose date. 
 
Missing day and month – impute 1st January unless year is the same as first 
dose date then impute first dose date. 
 
Completely missing – impute first dose date unless the end date suggests it 
could have started prior to this in which case impute the 1st January of the 
same year as the end date. 
Note: When imputing a start date ensure that the new imputed date is logical, i.e. is 
prior to the end date of the AE or treatment. 
For missing end AE dates, the following will be applied: 
 
Missing day – impute the last day of the month unless month is the same as 
month of the last dose of study drug then impute last dose date. 
 
Missing day and month – impute 31st December unless year is the same as last 
dose date then impute last dose date. 
7. Statistical Methods 
7.1 General Principles 
All data processing, summarization and analyses will be performed using Covance’s 
SAS Environment / Version 9.4 (or later) of the SAS statistical software package. 
Descriptive statistics will be used for all variables, as appropriate. Summary 
statistics will be presented for continuous variables, by way of number (n), mean, 
standard deviation (SD), median, minimum and maximum and by way of group 






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The number of patients that were screen failuresas well as the number of patients 
screened but not assigned to treatment will be produced. No other information for 
screen failures will be presented. 
7.3 Protocol Deviations 
All protocol deviations will be listed and summarized by dose level for the FAS. 
All important protocol deviations see section 5.6 will be listed and summarized by 
dose level for the FAS population. 
7.4 Demographics and Other Baseline Characteristics 
 
Demographic and baseline characteristics will be listed and summarized by dose level 
and overall for the FAS. Standard descriptive statistics will be presented for the 
continuous variables of: 
 
age (years); 
 
baseline weight (kg); 
 
baseline height (cm); 
 
baseline body mass index (kg/m2) (BMI) [calculated as (weight/height2) 
where weight is in kg and height is in m];  
 
baseline body surface area (m2) (BSA) (calculated as ([body weight0.425 (kg) 
× height0.725 (cm) × 0.007184] or as ([sqrt(height (cm) × body weight 
(kg)/3600]), depending on the formula each site has used) 
 
The total counts and percentages of patients will be presented for the categorical 
variables of: 
 
 
age group (years) (grouped as <65 and 65); 
 
sex (Male, Female); 
 
race (White, Black or African American, Asian, Native Hawaiian or Other 
Pacific Islander, American Indian or Alaska Native, Multiple, Other); 
 
ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown); 
 
childbearing potential for females (Yes, No); 
 
tumor treatment history (medications, surgery, radiation); 
 
baseline Eastern Cooperative Oncology Group (ECOG) performance status 
(Grade 0,1, 2, 3, 4, 5); 
 
baseline Ca 19-9 tumor marker 


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 
number of target lesions (1, 2, 3) and locations of lesions (liver, lung, 
pancreas, lymph nodes, other) 
 
baseline tuberculosis/ hepatitis status (Present, Absent); 
 
disease history or diagnosis; 
o Pancreatic tumor location (Head, Body, Tail, Neck); 
o Disease type (Locally advanced, Metastatic); 
o Cancer type from biopsy pathology report (Ductal adenocarcinoma, 
Adenosquamous carcinoma, Mucinous adenocarcinoma, Hepatoid 
carcinoma, Medullary carcinoma, Signet ring cell carcinoma, 
Undefferentiated carcinoma, Undefferentiated carcinoma with 
osteoclast-like cells, Primary histology, Secondary histology, 
Other); 
o TNM Classification at Initial Diagnosis (TX, T0, Tis. T1a, etc.); 
o Prior anti-cancer therapies (Yes, No); 
 
 
prior systemic therapy; 
o Prior systemic therapy (Yes, No); 
o Treatment setting (Adjuvant, Neoadjuvant, Not Applicable); 
o Best Response ( CR, PR, SD, PD, NE, NA, NR NA); 
o Treatment regimen ending reason (Progressive Disease, Toxicity, 
Completion of planned regimen, Other);  
 
 
prior anti-pancreatic cancer surgeries 
o Prior pancreatic cancer related surgery (Yes, No); 
o Surgery (Pancreaticoduodenectomy, Distal pancreatectomy, Total 
pancreatectomy, Other); 
o Location; 
o Outcome (No residual tumor after resection, Tumor/metastases not 
resected completely with microscopic residual lesions, not resected 
completely with macroscopic residual lesions; Metastases, Other)  
 
 
prior anti-cancer radiotherapy; 
o Prior cancer related radiotherapy (Yes, No); 
o Radiotherapy site; 
No formal tests of statistical significance will be performed on the demographic and 
baseline data. 


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Other baseline measurements, such as vital signs, ECG, will be summarized by dose 
level with the post-baseline measurements. 
ECOG will be also summarized by dose level. 
7.4.1 Medical History 
 
Medical history will be coded using the MedDRA Version 23.1 (or a later version if 
updated during the study)].  Relevant medical history and current medical conditions 
at baseline will be listed, and the number and percentage of patients with any medical 
history will be summarized separately for the FAS by system organ class (SOC) and 
preferred term (PT) for each dose level and overall.   
7.4.2 Previous and Concomitant Medications 
 
Prior medications and concomitant medications will be listed together for the SAF. 
The number and percentage of patients using each medication will be displayed 
together with the number and percentage of patients using at least one medication 
within each therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4), and 
generic term by dose level separately for prior and concomitant medications. 
 
7.5 Efficacy 
7.5.1 Primary Efficacy Analysis 
 
7.5.1.1 
Statistical Model, Hypothesis and Method of Analysis 
 


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For the dose confirmation of canakinumab and spartalizumab in combination with 
nab-paclitaxel and gemcitabine, a BLRM will be applied to estimate the relationship 
between dose and the probability of a patient experiencing a DLT. Some DLT data 
are available from previous studies on single agent and combination of canakinumab 
and spartalizumab (PDR001X2101, ACZ885I2202, PRD001X2103) and a phase I/II 
study of nab-paclitaxel + gemcitabine (Von Hoff D, et.al., 2011). These data will be 
incorporated 
into 
BLRM 
using 
a 
meta-analytic-predictive 
(MAC) 
approach 
(Neuenschwander et al 2016). The details are provided in Appendix B of the CSP. 
The decision on dose tolerability will be based on the totality of all relevant data from 
the ongoing study and a review of safety data from the first 8 weeks. A BLRM for 
combinations using the escalation with overdose control (EWOC) criterion to evaluate 
the risk of DLT will guide the decision. Additional information on the BLRM statistical 
model is provided in Appendix B of the CSP. 
 
7.5.1.2 
Assessment of Patient Risk 
 
Dose recommendations will be based on summaries of the posterior distribution of 
DLT rates for each dose level of the respective combination therapy. After each cohort 
of patients, the posterior distribution for the risk of DLT for new patients at 
combination doses of interest will be evaluated. The posterior distributions will be 
summarized to provide the posterior probability that the risk of DLT for each dose 
regimen lies within intervals (33%, 100%). 
Dosing regimen decisions are guided by the EWOC principle (Rogatko et al 2007). 
The possibility of excessive toxicity is of interest in this study as the objective is to 
confirm the safety of the proposed dose regimen. A dosing regimen may only be used 
for newly enrolled patients if the risk of excessive toxicity at that dosing regimen is 
less than 25%. 
Listing/Summary of DLTs 


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All DLTs will be listed and their incidences summarized by primary SOC, worst grade 
based on the CTCAE Version 5.0, type of adverse event, and by treatment group in 
the dose escalation. The DDS will be used for these summaries. 
Patients who are ineligible for the DDS will be excluded from the primary analysis 
(assessment of recommended dose using incidence of DLT during first 56 days of 
treatment with canakinumab in combination with spartalizumab, nab-paclitaxel and 
gemcitabine), although their data will be used for all remaining analyses.  
Reports on DLT Analysis 
Following reports will be produced for DLTs based on the DDS: 
 
The table of summary posterior interval probabilities will be presented in the 
body of the clinical study report (CSR) 
 
For each DEM, summary of recommendations will be included in Appendix 
16.1.9 of the (CSR) 
 
7.5.2 Secondary Efficacy Analysis 
Analyses of secondary efficacy endpoints as defined in section 3.2 will be performed 
in the FAS. 
ORR and DCR will be summarized by dose level. Summaries will present the number 
and percentage of patients achieving disease control (BOR of CR, PR and SD). 
The point estimate of the ORR along with the exact Clopper-Pearson (exact CI for a 
binomial proportion) 95% CI will be reported by dose level in the FAS  
Accompanying KM estimates of the median PFS and OS alongside associated 95% 
CIs will be presented by dose level in the FAS (by investigator assessment). The CIs 
will be derived based on Brookmeyer-Crowley method. 
KM estimates of PFS and OS at 3-monthly intervals will also be presented along with 
associated 95% confidence bands (derived based on Hall-Wallner method).  
The TTR  and DOR . based on the investigator assessment of RECIST 1.1. will be 
listed 


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7.5.3 Secondary Pharmacokinetic Analysis 
 
A listing of PK blood sample collection times as well as derived sampling time 
deviations and all reportable concentrations will be presented for each analyte 
(canakinumab, spartalizumab, nab-paclitaxel and gemcitabine) separately for all 
patients for the PAS. Plasma concentrations will be summarised for the PK analysis 
set for each time point by dose level using protocol scheduled times and 
appropriate descriptive statistics (i.e., n, n below LLOQ, geometric mean [gmean], 
gmean+geometric standard deviation [gSD], gmean-gSD, geometric coefficient of 
variance expressed as a percentage [gCV%], arithmetic mean [mean], arithmetic 
SD [SD], coefficient of variance expressed as a percentage [CV%], median, 
minimum and maximum. 
The gmean is calculated as exponential (μ), where μ is the arithmetic mean 
calculated using log transformed data. 
The gCV% is calculated as 100 x sqrt[exp(s2)-1], where s is the SD of the log-
transformed data. 
The gmean±gSD (gmean-gSD and gmean+gSD) are calculated as exp[μ±s]. 
Individual concentrations below the LLOQ of the bioanalytical assay will be reported 
as Not Quantifiable (NQ) in the listings with the LLOQ defined in the footnotes of 
the relevant tables, figures and listings. 
Individual plasma concentrations that are Not Reportable will be reported as NR and 
those that are missing will be reported as NS (No Sample) in the listings.  
Plasma concentrations that are NQ, NR or NS will be handled as follows for the 
provision of descriptive statistics: 
Any values reported as NR or NS or flaggged for exclusion by pharmacokineticist 
(eg. due to concomitant medication, dose modification, etc) will be excluded from 
the summary tables and corresponding figures. 
All concentration values below the lower limit of quantitation (LLOQ) are set to zero 
by the Bioanalyst, and will be displayed in the listings as zero and flagged.  
LLOQ values will be treated as zero in any calculations of summary statistics, and 
treated as missing for the calculation of the geometric means and their CV%. The 
number of non-zero concentrations will also be reported in the summary statistics. 
Missing values for any PK data will not be imputed and will be treated as missing 


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If all values are NQ at a time point, no descriptive statistics will be calculated for 
that time point. The gmean, mean, minimum, median and maximum will be 
reported as NQ and gmean±gSD, gCV%, SD and CV% as NC. 
The number of values below LLOQ (n <LLOQ) will be reported for each timepoint 
together with the total number of collected values (n). 
Three observations >LLOQ are required as a minimum for a plasma concentration 
to be summarised. Two values >LLOQ are presented as a minimum and maximum 
with the other summary statistics as NC. 
Plasma concentrations that are NQ will be handled as follows for display in figures: 
 
For gmean concentration-time plots: NQ concentrations will be handled as 
described for the descriptive statistics. If this handling results in a geometric 
mean of “NQ”, then the value plotted at that time-point will be zero for linear 
plots and set to missing for semi-logarithmic plots. Any gmean±gSD error 
bar values that are negative will be truncated at zero on linear concentration-
time plots and omitted from semi-logarithmic plots. 
 
For individual plots and combined individual plots: NQ values prior to the first 
quantifiable concentration in that profile will be set to zero (linear plots only); 
after the first quantifiable concentration of the profile any NQ values will be 
set to missing. 
 
Plasma PK parameters such as mentioned below (if reportable) for each analyte 
separately will be summarised for the PAS by dose level using the following 
descriptive statistics: 
 
Cmax, Clast and AUClast, will present n, gmean, gmean+gSD, gmean-gSD, 
gCV(%), mean, SD, CV%, median, min and max. 
 
tmax and tlast will present only n, median, min and max. 
 
t1/2 (if reported) will present n, mean, SD, CV%, median, min and max. 
It should be noted that not all PK parameters are applicable to all study drugs. For 
the calculation of summary statistics of PK parameters, all not reportable (NR) and 
not calculated (NC) values or parameters flagged for exclusion by the 
pharmacokineticist (eg. due to concomitant medication, dose modification, etc) will 
be set to missing. Three reportable values are required as a minimum for a PK 
parameter to be summarised. Two values are presented as a minimum and 
maximum with the other summary statistics as NC. If one or more values for a 
given parameter is zero (or imputed with zero), then no geometric statistics will be 


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calculated for that parameter and the results for geometric statistics will be set to 
“NA”, not applicable.PK concentration and parameter data from patients excluded 
from the PK analysis set will be included in the data listings, but not in the 
descriptive statistics or in mean figures or combined individual figures. Extra 
measurements (such as unscheduled or repeat assessments) will also not be 
included in summary tables, but will be included in patient listings. 
Individual plasma concentrations versus actual elapsed time after dose will be 
plotted on both the linear and semi-logarithmic scales for each analyte (each 
analyte will have a different timeframe). 
Combined individual plasma concentration versus actual elapsed times after dose 
will be plotted on both the linear and semi-logarithmic scale for each analyte 
separately. Plots will be grouped by dose level. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.7 Safety 
 
The overall observation period will be divided into three mutually exclusive segments: 
 
Pre-treatment period: from day of subject’s informed consent to the day before 
first dose of study treatment 
 
On-treatment period: from day of first dose of study medication to 30 days after 
last dose of study treatment 
 
Post-treatment period: starting at day 30+1 after last dose of study treatment 
Safety summaries (tables, figures) will include only data from the on-treatment 
period with the exception of baseline data which will also be summarized where 
appropriate (e.g. change from baseline summaries) and deaths, which will be 
presented for the on-treatment  and post-treatment period. AE data will be 
summarised separately for the on-treatment and post-treatment period. 
 
7.7.1 Secondary Safety Analysis 
7.7.1.1 
Adverse Events 
 
All adverse events (AEs) recorded on the eCRF will be coded using the MedDRA 
dictionary Version 23.1 (or a later version if updated during the study). 
Assessment of AE severity will be based on the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). 
The number of patients experiencing TEAEs (as defined in section 3.3.1.1) by 
MedDRA system SOC (sorted alphabetically) and or MedDRA PT (sorted by 
descending overall total) will be presented for each dose level and overall, with 
further splits by CTCAE 5.0 severity grade, causal relationship to study medication 
and type of adverse event. TEAE data will be summarised separately for the on-
treatment and post-treatment period  


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The relationship between an AE and each of study drugs is assessed as suspected 
or not suspected. A study drug-related AE is an AE considered by the investigator 
as related to study drug or with unknown/missing relationship to study drug.(AEs 
with unknown/missing relationship to study drug will be summarized along with 
study drug related AEs and separately).An overview table will summarize the 
number and percentage of patients with at least one of the following TEAEs by dose 
level, where patients with more than one TEAE in a particular category are counted 
only once in that category: 
 
Any TEAEs; 
 
Any TEAEs causally related to treatment; 
 
Any TEAEs by maximum CTCAE severity (Grade 1, Grade 2 , Grade 3 , Grade 
4 [life-threatening], Grade 5 [death]); 
 
Any TEAEs of CTCAE grade 3 or higher causally related to any study 
treatment; 
 
Any TEAEs with outcome of death; 
 
Any TEAEs with outcome of death causally related to treatment; 
 
Any TESAEs; 
 
Any TESAEs causing discontinuation of each of the study medications; 
 
Any TESAEs causing discontinuation of each of the study medications; 
causally related to treatment; 
 
Any TEAEs leading to dose interruption (or to dose interval modified for 
canakinumab)of each of the study medications; 
 
Any TEAEs causing discontinuation of each of the study medications; 
 
Any TEAEs causing discontinuation of each of the study medications; causally 
related to treatment; 
 
Any AESIs 
 
The number and percentage of patients reporting each AE will be summarized by 
System Organ Class (SOC), Preferred Term (PT) and dose level  for the SAF.  Tables 
will be sorted alphabetically by SOC.  PTs will be sorted by descending overall total.  
The following summaries will be produced: 
 
TEAEs, by SOC and PT; 
 
TEAEs by PT; 
 
TEAEs causally related to treatment, by SOC and PT; 
 
TEAEs causally related to treatment, by PT; 


Statistical Analysis Plan  
Sponsor Name: Pancreatic Cancer Action Network  
Sponsor Protocol ID: PanCAN-SRI 
 
Labcorp Study ID: 000000203412 
 
 
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 
 TEAEs by maximum severity (mild, moderate, severe, life-threatening, 
death); 
 
TEAEs of CTCAE grade 3 or higher, by SOC and PT; 
 
 TEAEs of CTCAE grade 3 or higher causally related to treatment, by SOC 
and PT; 
 
 TEAEs with outcome of death, by SOC and PT; 
 
 TEAEs with outcome of death causally related to treatment, by SOC and PT; 
 
TESAEs leading discontinuation of each of the study medications, by SOC 
and PT; 
 
 TESAEs leading to discontinuation of each of the study medications causally 
related to treatment, by SOC and PT; 
 
 TEAEs leading to discontinuation of each of the study medications, by SOC 
and PT; 
 
TEAEs leading to discontinuation of each of the study medications causally 
related to treatment, by SOC and PT; 
 
 TEAEs leading to dose modification/reduction of nab-paclitaxek and 
gemcitabine, by SOC and PT; 
 
 TEAEs leading to dose interruption (or to dose interval modified for 
canakinumab) of each of the study medications, by SOC and PT; 
 
AESIs by SOC and PT 
A summary of deaths with associated primary reason for death by dose level will be 
provided during the on-treatment and post-treatment period separately. 
A separate summary will be produced that presents any adverse events that occur 
prior to dosing (Pre-treatment period) or starting more than 30 days after 
discontinuing therapy (Post-treatment period); 
The number and percentage of patients who reported treatment-emergent adverse 
events of special interest will be summarized by SOC, preferred term and dose 
level. 
SOC names will be sorted alphabetically and, within each risk name, the preferred 
terms will be sorted in descending order of frequency in the overall dose level. If a 
patient reported more than one adverse event with the same preferred term, the 
adverse event will be counted only once. If a patient reported more than one 
adverse event within the same system organ class, the patient will be counted only 
once at that SOC. 
 
All AE data will be listed by dose level. In addition, corresponding listings of serious 
AEs , deaths, SAEs, AESIs, AEs leading to discontinuation of study drug, AEs resulting 


Statistical Analysis Plan  
Sponsor Name: Pancreatic Cancer Action Network  
Sponsor Protocol ID: PanCAN-SRI 
 
Labcorp Study ID: 000000203412 
 
 
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in death, AEs that led to dose reduction, discontinuation of treatment or death, and 
treatment-related AEs will be produced and those starting during the pre-treatment 
and post-treatment period will be flagged. Dose Limiting Toxicity AEs will be flagged 
as well.Deaths will also be listed and post-treatment deaths will be flagged.  
No statistical comparisons of AEs between dose levels will be performed. 
7.7.1.2 
Clinical Laboratory Evaluations 
 
Laboratory data (biochemistry, hematology, and urinalysis) will be summarized by 
dose level and listed as described below: 
Shift tables will be provided for select tests, where shift from baseline to the worst 
on-treatment value will be summarized using CTCAE grades(for tests where grades 
are not defined by CTCAE , laboratory normal ranges will be used).Laboratory data 
outside the reference ranges will be indicated in the listings. 
Laboratory data absolute and change from baseline values for biochemistry, 
hematology and urinalysis will be summarized at each scheduled assessment time 
by dose level.  
Continuous laboratory parameters will be summarized with descriptive statistics. If 
a patient has multiple results for a particular test at a particular time window, the 
first non-missing scheduled value will be used for the summary 
Listings of all laboratory values for each patient will be presented with abnormal 
values flagged. Abnormal lab values which qualify as DLT will be flagged as well. 
Shift tables for laboratory values by worst common toxicity criteria (CTC) grade will 
be produced. For parameters with no CTCAE grading, shift tables from baseline to 
worst value on-treatment will be provided. 
For all laboratory variables included in the current version of CTCAE, the CTCAE grade 
will be summarized.    
Raw values and changes from baseline for laboratory data at each timepoint will 
presented using box and whiskers plots and any data not included between the 
whiskers should be plotted as outliers. 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST, and alkaline 
phosphatase (ALP). The number (%) of participants with worst post-baseline values 
as per Novartis Liver Toxicity guidelines will be summarized: 
 
ALT or AST > 3xULN  
 
ALT or AST > 5xULN  
 
ALT or AST > 8xULN  
 
ALT or AST > 10xULN  
 
ALT or AST > 20xULN  


Statistical Analysis Plan  
Sponsor Name: Pancreatic Cancer Action Network  
Sponsor Protocol ID: PanCAN-SRI 
 
Labcorp Study ID: 000000203412 
 
 
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 
TBL > 2xULN  
 
TBL > 3xULN  
 
AST and ALT =< ULN at baseline 
 
ALT or AST >3x ULN & BILI >2x ULN 
 
ALT or AST >3x ULN & BILI >2x ULN & ALP >=2x ULN 
 
ALT or AST >3x ULN & BILI >2x ULN & ALP <2x ULN 
 
AST and ALT > ULN at baseline 
 
Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) 
 
Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) & ALP >=2x ULN 
 
Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) & ALP <2x ULN 
* Elevated AST or ALT defined as: >3x ULN if =< ULN at baseline, or (>3x Bsl or 
8x ULN) if > ULN at baseline 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-
baseline TBILI > 2xULN, ALT> 3xULN or AST > 3xULN will be provided.   
A plot of maximum (worst) post-baseline total bilirubin vs maximum (worst) post-
baseline ALT, both relative to the ULN will be provided with different symbols for 
different dose level  groups. This eDISH plot (evaluation of drug-induced 
hepatoxicity) will have reference lines at 3xULN for ALT and at 2xULN for total 
bilirubin.An additional eDISH plot might be considered of peak total bilirubin versus 
peak AST” if there are potential cases based on AST rather than ALT. 
Data for the following hematology, biochemistry, and urinalysis analytes as presented 
in the below table will be provided: 
 




Statistical Analysis Plan  
Sponsor Name: Pancreatic Cancer Action Network  
Sponsor Protocol ID: PanCAN-SRI 
 
Labcorp Study ID: 000000203412 
 
 
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The duration of (total or intended) exposure (in days) as well as dose intensity 
(percentage dose intensity and relative dose intensity) , as defined in sections 
3.3.2.1 and 3.3.2.2 will be listed and summarized separate for each study drug 
using descriptive statistics for each dose level group and by cycle for the SAF. 
The number and percentage of patients with duration of exposure in the following 
categories will also be summarized for the SAF:  
 
≤2 months 
 
>2 and ≤6 months 
 
>6 and ≤10 months 
 
>10 months 
Total exposure will be summarized by the following: mean, standard deviation, 
minimum, maximum, median and number of observations.   
Dose intensity data will be summarised using means, standard deviation, medians, 
and quartiles as well as the minimum and maximum values and number of 
observations. 
In addition, the number and percentage of patients with neither dose interruption nor 
dose reduction , at one dose interruption or dose reduction, at least one dose 
interruption, at least one dose reduction along with their associated reasons where 
applicable will be presented by dose level and study drug. 
All dosing data will be listed.  
 
7.7.2.2 
Vital Signs 
Vital signs as described in 3.3.2.3 will be listed by dose level, patient and visit/time 
and summarized by dose level and visit and normal range groups  Vital sign values 
measured outside of on-treatment period will flagged. 
Vital signs data and changes from baseline in vital signs will be summarized by visit 
and dose level using standard descriptive statistics for the SAF.   
 
7.7.2.3 
Physical Examination 
Physical examination will be summarised by dose level and listed by dose level, 
patient and visit/time. 
7.8 Interim Analysis 
No interim analysis will be performed for this study.  




Statistical Analysis Plan  
Sponsor Name: Pancreatic Cancer Action Network  
Sponsor Protocol ID: PanCAN-SRI 
 
Labcorp Study ID: 000000203412 
 
 
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11. Appendices 
Appendix 1: 
Document History 
Document Version, Status, Date 
Summary/Reason for Changes 
Version 1.0, Final, ”16Sep 2022 
Include revisions of Version 1.0 of 02Oct 
2020 and 18 Feb2022 (inclusive of updated 
definition for exposure) , 21Jul2022 & 
29Aug  
Version 1.0, Final, 02Oct 2020 
Include revisions of Version 0.2 
Version 0.2, Draft, 04 Sep 2020 
Include revisions of Version 0.1 
Version 0.1, Draft, 31 Jul 2020 
Not applicable; the first version