Clinical trial NCT03647488
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Non-small-cell lung carcinoma Non-small-cell lung cancer NSCLC epidermal growth factor receptor wild type EGFRwt Anaplastic lymphoma kinase negative ALK- INC280 capmatinib and spartalizumab combination therapy docetaxel
Sponsor: Novartis Pharmaceuticals
Start date: 2018-12-26; Completion date: 2020-09-07
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this trial was to evaluate the safety and efficacy of capmatinib in combination with spartalizumab in adult participants with epidermal growth factor receptor (EGFR) wild type (for exon 19 deletions and exon 21 L858R substitution mutations), anaplastic lymphoma kinase (ALK) rearrangement negative in locally advanced (stage IIIB, not eligible for definitive chemo-radiation) or metastatic (stage IV) Non-small cell lung cancer (NSCLC) after failure of platinum doublet and checkpoint inhibitor treatment.

Detailed description:
This was a two-part prospectively designed, multicenter, open-label, randomized phase II study.

Part 1: Run-in. Prior to the randomized part of the study, a run-in to assess the safety and tolerability as well as preliminary efficacy of the capmatinib and spartalizumab combination was conducted. Participants were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days. A review was planned to take place after all participants had at least 24 weeks of follow-up. The decision to expand the study to the randomized part was to be based on the safety, tolerability, and preliminary efficacy of the capmatinib and spartalizumab combination.

Part 2: Randomized. Subjects were planned to be randomized to one of the following arms in a 2:1 ratio: 1) combination of capmatinib 400 mg BID and spartalizumab 400 mg i.v. once every 28 days; 2) docetaxel 75 mg/m2 i.v. following local guidelines as per standard of care and product labels. Based on the results obtained in the run-in part of the study, the randomized part was not opened.

For the run-in part of the study, the treatment period began on Cycle 1 Day 1 and continued in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of informed consent, pregnancy, lost to follow-up, or death irrespective of start of new anti-neoplastic therapy. After treatment discontinuation, all subjects were followed for safety evaluations during the safety follow-up period, and the subject's status was collected every 8 weeks as part of the survival follow-up

Arms: arm 1: Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days arm 2: Participants (enrolled in the randomized part) treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days arm 3: Participants (enrolled in the randomized part) treated with docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days
Interventions: intervention 1: Capmatinib intervention 2: Spartalizumab intervention 3: Docetaxel
Intervention descriptions: intervention 1: Capmatinib 400 mg (tablets) orally taken twice daily intervention 2: Spartalizumab 400 mg via intravenous infusion once every 28 days intervention 3: Docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days

Protocol documents:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................8
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................14
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.1.1
MET and capmatinib (INC280) ............................................................19
1.1.2
Spartalizumab (PDR001) ......................................................................21
1.1.3
Combination of capmatinib with a checkpoint inhibitor.......................22
1.2
Purpose ..................................................................................................................24
2
Objectives and endpoints...................................................................................................25
3
Study design ......................................................................................................................26
4
Rationale............................................................................................................................29
4.1
Rationale for study design .....................................................................................29
4.2
Rationale for dose/regimen and duration of treatment ..........................................29
4.2.1
Capmatinib in combination with spartalizumab ...................................29
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................31
4.4
Purpose and timing of interim analyses/design adaptations..................................31
4.5
Risks and benefits..................................................................................................31
4.5.1
Capmatinib............................................................................................32
4.5.2
Spartalizumab........................................................................................32
4.5.3
Capmatinib combined with spartalizumab............................................33
4.5.4
Docetaxel...............................................................................................33
4.5.5
Risks of Imaging Procedures ................................................................34
5
Population..........................................................................................................................34
5.1
Inclusion criteria ....................................................................................................34
5.2
Exclusion criteria...................................................................................................36
6
Treatment...........................................................................................................................39
6.1
Study treatment......................................................................................................39
6.1.1
Investigational and control drugs..........................................................40
6.1.2
Additional study treatments ..................................................................40
6.1.3
Treatment arms/group ...........................................................................41
6.1.4
Guidelines for continuation of treatment ..............................................41




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9
Study discontinuation and completion ............................................................................114
9.1
Discontinuation....................................................................................................114
9.1.1
Discontinuation of study treatment .....................................................114
9.1.2
Withdrawal of informed consent.........................................................115
9.1.3
Lost to follow-up.................................................................................116
9.1.4
Early study termination by the sponsor...............................................116
9.2
Study completion and post-study treatment ........................................................116
9.2.1
Follow up for safety evaluations.........................................................117
9.2.2
Follow up for efficacy evaluations......................................................117
9.2.3
Survival follow up...............................................................................118
10 Safety monitoring and reporting......................................................................................118
10.1
Definition of adverse events and reporting requirements....................................118
10.1.1
Adverse events ....................................................................................118
10.1.2
Serious adverse events ........................................................................121
10.1.3
SAE reporting......................................................................................122
10.1.4
Pregnancy reporting ............................................................................122
10.1.5
Reporting of study treatment errors including misuse/abuse..............123
10.2
Additional Safety Monitoring..............................................................................123
11 Data Collection and Database management....................................................................123
11.1
Data collection.....................................................................................................123
11.2
Database management and quality control..........................................................124
11.3
Site monitoring ....................................................................................................124
12 Data analysis and statistical methods ..............................................................................125
12.1
Analysis sets ........................................................................................................125
12.2
Subject demographics and other baseline characteristics....................................126
12.3
Treatments ...........................................................................................................126
12.4
Analysis of the primary endpoint(s) ....................................................................127
12.4.1
Definition of primary endpoint(s).......................................................127
12.4.2
Statistical model, hypothesis, and method of analysis........................127
12.4.3
Handling of missing values/censoring/discontinuations.....................128
12.4.4
Sensitivity and supportive analyses ....................................................129
12.5
Analysis of secondary endpoints .........................................................................129
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)..................................129
12.5.2
Safety endpoints..................................................................................129
12.5.3
Pharmacokinetics ................................................................................131
133
12.7
Interim analyses...................................................................................................135




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Table 6-5
Number of prior lines of systemic therapy............................................49
Table 6-6
Criteria for defining dose limiting toxicities (DLTs)............................51
Table 6-7
Dose reduction steps for capmatinib.....................................................53
Table 6-8
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Haematological Adverse 
Events....................................................................................................55
Table 6-9
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Creatinine Increases............57
Table 6-10
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for liver laboratory 
alterations..............................................................................................57
Table 6-11
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Amylase and/or Lipase 
Elevation Related Adverse Events........................................................61
Table 6-12
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Cardiac Related Adverse 
Events....................................................................................................61
Table 6-13
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Gastrointestinal Adverse 
Events....................................................................................................63
Table 6-14
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Skin and Subcutaneous 
Tissue Adverse Events..........................................................................66
Table 6-15
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Respiratory, Thoracic and 
Mediastinal Adverse Events..................................................................67
Table 6-16
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Endocrine Adverse 
Events....................................................................................................69
Table 6-17
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for General and 
Administration Site Adverse Events .....................................................71
Table 6-18
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Other Potential Immune-
Related Adverse Events of Special Interest including Cytokine 
Release Syndrome.................................................................................71
Table 6-19
Criteria for interruption and re-initiation of docetaxel treatment..........74
Table 6-20
Dose and treatment schedule.................................................................79
Table 8-1
Allowable window for subject assessments..........................................82
Table 8-2
Assessment Schedule, Run-in and Arm 1 (capmatinib and 
spartalizumab combination) - length of a cycle is 28 days ...................83




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Table 16-11
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single-agent spartalizumab model 
parameters ...........................................................................................186
Table 16-12
Historical dose-DLT data from spartalizumab single agent clinical 
studies..................................................................................................186
Table 16-13
Historical dose-DLT data from capmatinib in combination with 
spartalizumab 300 mg Q3W................................................................187
Table 16-14
Prior distribution for the model parameters ........................................187
Table 16-15
Summary of prior distribution of DLT rates.......................................188
Table 16-16
Hypothetical DLT scenarios ...............................................................188
List of figures
Figure 3-1
Study Design Part 1: Run-in .................................................................27
Figure 3-2
Study Design Part 2: Randomized ........................................................28
Figure 6-1
Optional Treatment Beyond Disease Progression.................................43
Figure 16-1
Safety follow-up diagram for run-in and arm 1 ..................................182


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List of abbreviations
Ab
Antibody
ACTH
Adrenocorticotropic hormone
ADA
Anti-drug Antibodies
ADL
Activity daily living
ADR
Adverse drug reaction
AE
adverse event
AESI
adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALP
alkaline phosphatase
alpha-FP
alpha-fetoprotein
ALT
alanine aminotransferase
ANC
Absolute neutrophil count
ANP
Atrial natriuretic peptide
aPTT
Activated Partial Thromboplastin Time
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
ATP
Adenosine triphosphate
AUC
Area under curve
BAL
Bronchoalveolar lavage
BID
Twice a day
BIRC
blinded independent review committee
BLQ 
Below the limit of quantification
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
BSA
Body Surface Area
BSC
best supportive care
BUN
blood urea nitrogen
BVN
bivariate normal
C
Cycle
CFR
Code of Federal Regulation
CI
Confidence Interval
CK
Creatine kinase
Cmax
The maximum (peak) concentration of drug in plasma
CMO&PS
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CNS
Central Nervous System
COA
Clinical Outcome Assessments
COPD
Chronic obstructive pulmonary disease
CPK
creatine phosphokinase
CR
Complete Response
CRA
Clinical research associate
CRF
Case Report/Record Form (paper or electronic)
CRS
case retrieval strategy
CSF
Colony-stimulating factor
CSR
Clinical study report


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CT
Computerized Tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CV
coefficient of variation
D
Day
D5W
dextrose 5% in water
DBP
Diastolic Blood Pressure
DCR
Disease control rate
DDE
direct data entry
DDI
Drug-drug interaction
DDS 
Dose-determining set
DILI 
Drug-Induced Liver Injury
DLCO
Diffusing capacity of the lungs for carbon monoxide
DLT
Dose Limiting Toxicity
DNA
deoxyribonucleic acid
DOR
Duration of response
DRID
Dose reference ID
EBV
Epstein–Barr virus
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EGFR
epidermal growth factor receptor
ELISA
Enzyme-linked immunosorbent assay
EM
electromagnetic
EMA
European Medicines Agency
EOT
End of treatment
EPR
early progression rate
ESA
Erythropoiesis agent
EU
European Union
EWOC
Escalation with overdose control
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose positron emission tomography
FISH
Fluorescent in situ hybridization
FPFV
First patient first visit
FPG
Fasting plasma glucose
FSH
Follicle-stimulating hormone
GABA
Gamma-Aminobutyric acid
GCN
Gene copy number
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GI
Gastrointestinal
h
hour
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody


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HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HBV DNA
Hepatitis B virus DNA
HCC
Hepatocellular carcinoma
hCG
human chorionic gonadotrophin
HCV
Hepatitis C virus
HCV RNA 
Hepatitis C virus RNA
Hgb
Hemoglobin
HGF
Hepatocyte growth factor
HIV
human immunodeficiency virus
HR
Hazard ratio
HSV
Herpes simplex virus
i.v.
intravenous
IB
Investigator's brochure
ICF
Informed consent form
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
IEC
Independent Ethics Committee
IFN
Interferon
IG
Immunogenicity
IgG4 
Immunoglobulin G4
IHC
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IL-2
Interleukin
ILD
Interstitial lung disease
INR
International normalized ratio
IO
Immuno-oncology
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to treat




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PLT
Platelet
PPI
Proton-pump inhibitor
PR
Partial response
PS
Performance status
QD
Daily
QMS
Quality management system
QTcF 
Fridericia QT correction formula
QxW
Every x week(s)
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RoW
Rest of the World
RP2D
Recommended Phase 2 dose regimen
RT-PCR
Reverse transcription polymerase chain reaction
SAE
serious adverse event
SAP
The Statistical Analysis Plan (SAP) is a regulatory document which provides evidence of 
preplanned analyses
SBP
Systolic blood pressure
SD
standard deviation
SD 
Stable Disease
SOD
Sum of Diameter
SOP
Standard operating procedure
SUSARs
Suspected unexpected serious adverse reactions
TBIL
Total bilirubin
TdP
Torsades de Pointes
TFQ
Trial feedback questionnaire
TKI
Tyrosine kinase inhibitor
TL
Target lesion
TNBC
Triple negative breast cancer
TP
Time point
TSH
Thyroid-stimulating hormone
TTF
Time to treatment failure
TTP
Time to progression
TTR
Time to response
UC
Unchanged
ULN
upper limit of normal
UNK
Unknown
US
United States, ultrasound
VAS
Visual analogue scale
VATS
Video-assisted thoracic surgery
WHO
World Health Organization
wt
wild type


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which is used as a 
comparator to the investigational drug being tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg once a day, 
75 mg twice a day)
Investigational 
drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is synonymous 
with “investigational new drug” or “test substance”
Medication number
A unique identifier on the label of each study drug package in studies that dispense 
study drug using an IRT system.
Part
A single component of a study which contains different objectives or populations within 
that single study. Common parts within a study are: a single dose part and a multiple 
dose part, or a part in patients with established disease and in those with newly-
diagnosed disease.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Personal Data
Subject information collected by the Investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes subject identifier information, study 
information and biological samples.
Withdrawal of study consent: Withdrawal of consent from the study occurs only when a 
subject does not want to participate in the study any longer, and does not allow any 
further collection of personal data
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a specific 
treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or when study drug was 
discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; may or may 
not also be the point/time of premature subject withdrawal.
Study treatment
Any drug administered to the study participants as part of the required study procedures; 
includes investigational drug (s), control(s) or non-investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the defined study 
treatment completion date
Study treatment 
interruption 
Includes any delay or withholding of study treatment for any reason as well as an 
interruption during an infusion of study treatment for any reason
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to identify 
the subject throughout the study for all data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm 
Variable 
Information used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject does not want to 
participate in the study any longer, and does not want any further visits or assessments, 
and does not want any further study related contact, and does not allow analysis of 
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Protocol summary
Protocol number
CINC280D2201
Full Title
A phase II, multicenter, randomized, two-arm study of capmatinib (INC280, an oral 
MET inhibitor) and spartalizumab (PDR001, a PD-1 inhibitor) combination therapy 
versus docetaxel in pretreated adult patients with EGFR wild-type, ALK 
rearrangement negative locally advanced/metastatic non-small cell lung cancer.
Brief title
Study of efficacy and safety capmatinib (INC280, an oral MET inhibitor) and 
spartalizumab (PDR001, a PD-1 inhibitor) combination therapy versus docetaxel in 
pretreated adult patients with locally advanced/metastatic non-small cell lung 
cancer
Sponsor and Clinical 
Phase
Novartis, Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this prospective, multicenter, randomized phase II study is to 
evaluate the safety and efficacy of the combination of capmatinib and 
spartalizumab in subjects with EGFR wt (for exon 19 deletions and exon 21 L858R 
substitution mutations), ALK-negative rearrangement, advanced/metastatic (stage 
IIIB (not amenable for definitive chemo-radiotherapy) or IV) NSCLC, regardless of 
MET and PD-L1 status
The study will enroll subjects with advanced/metastatic NSCLC which are EGFR wt, 
ALK negative, after failure of prior platinum doublet and checkpoint inhibitor 
administered for the treatment of the advanced stage disease. Subjects must be 
docetaxel naive. A Run-in part will be conducted to determine safety, tolerability 
and preliminary efficacy of the capmatinib and spartalizumab combination.A 
Randomized part will be conducted to assess the overall survival (OS) of the 
combination of capmatinib and spartalizumab in comparison to docetaxel.
Primary Objective(s)
Part 1: Run-in 
● To assess the safety and tolerability of the capmatinib and spartalizumab 
combination.
Part 2: Randomized
● To assess the overall survival of the combination of capmatinib and 
spartalizumab in comparison to docetaxel.
Secondary Objectives
Part 2 Randomized part: To assess objective response rate (ORR), disease control 
rate (DCR), progression-free survival (PFS), duration of response (DOR) and time 
to response (TTR) based on RECIST 1.1 (Response Evaluation Criteria in Solid 
Tumors). To assess the incidence and severity of adverse events (AEs) and 
serious adverse events (SAEs).
Study design
This is a two-part prospectively designed, multicenter, open-label, randomized 
phase II study to evaluate the safety and the efficacy of capmatinib in combination 
with spartalizumab in adult subjects with EGFR wild type and ALK rearrangement 
negative advanced stage IIIB or IV NSCLC after failure of platinum doublet 
chemotherapy and checkpoint inhibitor treatment.
Part 1: run-in phase: will confirm the safety and tolerability and assess the efficacy 
of the combination of capmatinib and spartalizumab.
Part 2: randomized phase: will evaluate the efficacy and safety of the combination 
of capmatinib and spartalizumab compared to docetaxel
Population
The study population (15 subjects in run-in phase and 90 subjects in randomized 
phase, total of 105 subjects) will include adult subjects with locally advanced stage 
IIIB/IV non-small cell lung cancer. Subjects will be docetaxel naive, and subjects 
with EGFR mutations and ALK rearrangements will be excluded.




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1
Introduction
1.1
Background
Lung cancer has been the most common cancer in the world for several decades. In 2012, there 
were an estimated 1.8 million new cases, representing 12.9% of all new cancers worldwide. It 
was also the most common cause of death from cancer, with 1.6 million deaths representing 
19.4% of the total deaths from cancer (Ferlay et al 2015). For 2017, approximately 155,870 
deaths due to lung cancer are expected in the United States (US) (Siegel et al 2017) and 275,700 
deaths are predicted in the European Union (Malvezzi et al 2017).
The World Health Organization (WHO) divides lung cancer into 2 major classes based on its 
biology, therapy, and prognosis: non-small cell lung cancer (NSCLC) and small cell lung cancer. 
NSCLC accounts for more than 85% of all lung cancer cases, and it includes 2 major types: (1) 
non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma, other cell types); 
and (2) squamous cell (epidermoid) carcinoma. Adenocarcinoma (40% of lung cancers; 47% in 
NSCLC) is the most common type of lung cancer seen in the United States and is also the most 
frequently occurring cell type in nonsmokers (Novello et al 2016). One reason for the high 
mortality rate of lung cancer is the advanced stage at diagnosis; only 25 to 30% of new NSCLC 
cases are diagnosed with localized disease that is potentially curable with surgery 
(Nguyen et al 2012). The majority of subjects are diagnosed with locally advanced or metastatic 
disease and they are not candidates for surgery.
Platinum combination therapy is superior to best supportive care in subjects with advanced, 
incurable disease, and platinum doublet chemotherapy (i.e., cisplatin or carboplatin in 
combination with other chemotherapy agents, with or without bevacizumab) has been the 
standard initial (i.e., first-line) treatment for subjects with locally advanced or metastatic (i.e, 
stage IIIB or IV) NSCLC in absence of a druggable molecular driver or PD-L1 (Programmed 
Death-Ligand 1) expression >1% (Novello et al 2016, NCCN 2018). Pemetrexed-based 
platinum doublet therapy has become a standard first-line treatment option for NSCLC subjects 
with non-squamous histology. In a Phase 3, non-inferiority trial of chemotherapy-naive subjects 
with stage IIIB or IV NSCLC, pemetrexed plus cisplatin (pemetrexed/cisplatin) was shown to 
be non-inferior to (median OS 10.3 versus 10.3 months, respectively) and better tolerated than 
gemcitabine/cisplatin (Scagliotti et al 2008). With respect to OS, pemetrexed/cisplatin was 
superior to gemcitabine/cisplatin in the subset of subjects with adenocarcinoma (OS 12.6 versus 
10.9 months, respectively) and large-cell carcinoma (10.4 versus 6.7 months, respectively).
Single agent chemotherapy like pemetrexed (in non-squamous) or docetaxel (in any histology) 
are established treatment options for pretreated NSCLC subjects and have served as the control 
arms of several prospective, randomized trials in second or third setting. In a randomized trial 
comparing both agents in the second-line setting, efficacy was similar with both treatments (the 
response rate of approximately 9-10%, median PFS of 2-3 months, and median OS of 
approximately 7-8 months), although pemetrexed was associated with less toxicity 
(Hanna et al 2004). Overall, the reported response rates to second-line chemotherapy also with 
other single agent chemotherapeutics have generally been < 11% with median PFS and OS 
generally 
below 
4 
and 
11 
months 
respectively (de Marinis and Grossi 2008, 
Weiss and Stinchcombe 2013, Novello et al 2016, NCCN 2018). Upon progression after 
second-line chemotherapy, subjects may be candidates for further treatment, although 


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randomized evidence is scarce and most data come from phase II trials or retrospective analyses. 
Subjects have often limited response to third line therapy, although it may have a useful 
palliative 
effect 
(Shepherd et al 2005, 
de Marinis and Grossi 2008, 
Eccles et al 2011, 
Reck et al 2014, Besse et al 2014, NCCN 2018).
Activating mutations in EGFR and ALK translocations have been the first molecular drivers to 
show strong predictive value of improved efficacy and better tolerance of EGFR and ALK 
Tyrosine Kinase Inhibitors (TKIs) when compared with standard chemotherapy in subjects 
harboring EGFR activating mutations and ALK translocations, becoming the new standard of 
care in both the pretreated setting and in treatment naive setting (Ettinger et al 2010, 
Sequist et al 2013, 
Zhou et al 2011, 
Fukuoka et al 2011, 
Shaw and Engelman 2013, 
Shaw et al 2013, Rosell et al 2012, Solomon et al 2014, NCCN 2018). Importantly, due to the 
high oncogenic addiction to the molecular abnormality during the course of the disease, the 
efficacy of these targeted therapies seem to be independent of line of treatment, and high 
response rates are still observed in subjects who received several treatments (generally 
excluding therapies targeting the same pathway) before receiving the given targeted therapy 
(Camidge et al 2012 ). The success of EGFR and ALK TKIs highlights the importance of 
identifying specific molecular drivers of NSCLC to appropriately direct targeted agents in 
specific subject populations. Similarly, other TKIs targeting rarer targets like ROS1 
translocation
and BRAF mutation are now available in these subject subsets 
(Solomon et al 2014, Hamanishi et al 2016). The potential for prolonged response by targeting 
these oncogenic drivers delays the need for chemotherapy or other treatments. The landscape 
of NSCLC treatment is changing and the treatment paradigm of “one size fits all” has 
progressively switched to a personalized therapy.
Monoclonal antibody (mAb) inhibitors of immunological checkpoints, including PD-1 and PD-
L1, have demonstrated significant antitumor activity in subjects with various solid tumors with 
less toxicity than chemotherapy or broad immune activators, such as IL-2 (interleukin-2) and 
IFN-α (interferon-α). PD-1 is a particularly important immunological target, with inhibitors 
active across a variety of solid tumors. Two mAbs targeting PD-1, pembrolizumab and 
nivolumab, have demonstrated significant single agent activity in melanoma, NSCLC and other 
solid tumors (Hamanishi et al 2016).
Inhibitors of programmed death 1 (PD-1) and its ligand PD-L1 are effective therapies for 
metastatic NSCLC lacking sensitizing EGFR or ALK mutations. PD-(L)1 inhibitors (nivolumab, 
pembrolizumab, atezolizumab) are now standard of care in second/third-line NSCLC; 
pembrolizumab is also approved in first-line (PD-L1 ≥◦50%) and in combination with platinum 
chemotherapy 
(irrespective 
of 
PD-L1 
status). 
Results 
of 
several 
studies 
with 
immunotherapy/platinum 
chemotherapy 
and 
immunotherapy 
plus 
immunotherapy 
(ipilimumab/nivolumab, tremelimumab/durvalumab) are becoming available in 2018/19 which 
might further reshape the treatment landscape in first-line, shifting treatment paradigms in later 
lines of treatment (Gandhi et al 2018).
Checkpoint inhibitors are currently being evaluated in additional phase III studies with 
immunotherapy-based treatment in both pretreated and first-line setting, with several regulatory 
approvals expected in 2018 and 2019.
Overall, currently approved PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab) 
inhibitors have shown ORR 17-19%, median PFS 2-4 months, and overall survival of 9-14 


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months, in subjects who progressed after first line platinum doublet in randomized phase 3 
studies versus docetaxel (Herbst et al 2016, Rittmeyer et al 2017, Borghaei et al 2015).
With the advancement of immunotherapy in the treatment of NSCLC, more and more subjects 
are exposed to checkpoint inhibitors in the course of their disease, either as single agents or in 
combination with other anticancer therapies. As disease progression is inevitable in these 
subjects, the need to develop innovative therapies which are effective in this post-
immunotherapy, second, and third-line setting is currently critically important. The efficacy of 
standard therapies, including docetaxel or rechallenging with immunotherapy-based therapies 
after progression on checkpoint inhibitors, is currently unknown (UNK) with only anecdotal 
reports (Park and Cheung 2017, Schvartsman et al 2017).
1.1.1
MET and capmatinib (INC280)
In human malignant disease, the MET pathway is frequently dysregulated, triggering a diverse 
set of signaling cascades (including the RAS-MAPK as well as the PI3K-AKT pathway), which 
are promoting proliferation, survival, motility and angiogenesis (Christensen et al 2005). In 
addition, various roles of MET/HGF signaling in immune cells, primarily of the myeloid lineage, 
have 
been 
proposed 
that 
could 
lead 
to 
MET-dependent 
immune 
suppression 
(Molnarfi et al 2015). Several mechanisms have been identified by which the MET pathway 
becomes aberrantly activated in cancer such as gene amplification, receptor overexpression, 
mutations, autocrine or paracrine secretion of its ligand HGF. MET amplification and MET 
mutations are currently the most studied MET dysregulations in NSCLC, being evaluated as 
predictors of response to MET inhibitors. Overall MET dysregulation is rare.
MET amplification (with gene copy number [GCN] > 6) is reported in ~3-4% of NSCLC 
(Comprehensive molecular profiling of lung adenocarcinoma, 2014) with up to 1% of these 
tumors demonstrating even higher levels of amplification (GCN ≥ 10). Responses to MET 
inhibitors in NSCLC harboring high levels of MET amplification have been reported in clinical 
trials (Schuler et al 2016, Wolf 2017, Camidge et al 2018).
MET mutations causing skipping of exon 14, thereby removing the juxtamembrane domain of 
MET, leads to protein stabilization and oncogenic activation (Kong-Beltran et al 2006). Next 
generation sequencing of tumor specimens identified many different variants that can result in 
exon 14 skipping. These variants are primarily found in lung cancer at a frequency of about 3% 
(Frampton et al 2015, Schrock et al 2016). Recent clinical observations indicate that such 
mutations are predictors of response to capmatinib and other MET targeting agents 
(Frampton et al 2015, Paik et al 2015, Jenkins et al 2015, Mendenhall and Goldman 2015, 
Waqar et al 2015, Liu et al 2015, Schuler et al 2016, Drilon 2016, Cedrés et al 2018).
Numerous effects of MET signaling on immune cells have been reported in the preclinical 
literature (Molnarfi et al 2015). For example, activation of MET through HGF was found to 
impact the differentiation of dendritic cells towards a “tolerogenic” (i.e. immunosuppressive) 
phenotype (Rutella et al 2006), suggesting that MET inhibition could have a positive 
immunomodulatory effect on the activation of T cells by dendritic cells.
Recent studies in multiple mouse models have demonstrated that MET-positive neutrophils 
suppress immune therapy-induced T cell expansion and effector functions, and that concomitant 
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MET driven tumor models (Glodde et al 2017). It has also been reported that MET is expressed 
on a subset of cytotoxic T lymphocytes suppressing their function when activated by HGF. 
These observations demonstrate an immunomodulatory potential of MET and HGF by directly 
acting on immune cells, irrespective of the MET dysregulation. MET inhibitors also may restore 
immune cell function by preventing/reducing hepatocyte growth factor (HGF) signaling. 
Additional information supporting the role of MET inhibitors like capmatinib as 
immunomodulators can be found in Section 4.2.1.
MET dysregulation is a negative prognostic factor in patients with NSCLC (Guo et al 2014, 
Landi et al 2017, Awad et al 2017), particularly when both MET amplification and mutation 
occur in the same tumor (Awad et al 2017 ).
While no selective MET inhibitors or antagonists have been approved for use in cancer patients 
to date, several investigational agents are being currently evaluated in clinical trials.
Capmatinib (INC280) is a small adenosine triphosphate (ATP) competitive, orally bioavailable, 
highly potent, and selective reversible inhibitor of the MET receptor tyrosine kinase 
(Liu et al 2011) capable of blocking MET activation developed primarily in MET dysregulated 
solid tumors. Capmatinib also exhibits preclinical immunomodulatory activity in tumor models 
irrespective of MET dysregulation.
Overall, preclinical and early clinical data indicate that capmatinib has a manageable safety 
profile. As of the cut-off date of 28-Sep-2017, a total of 1109 cancer subjects and 158 non-
cancer subjects have received capmatinib. A total of 622 subjects with solid tumors have been 
treated with capmatinib as a single agent, and 487 subjects have been treated with capmatinib 
in combination therapies. Treatment was with either the capsule formulation or tablets or both. 
Twenty-one clinical studies are currently ongoing with capmatinib. A total of 19 subjects have 
experienced 25 Dose Limiting Toxicities (DLTs): 6 subjects in single agent studies and 13 in 
combination studies. For more information, please refer to the current [capmatinib 
Investigator’s Brochure (IB)].
Overall, the majority of the reported adverse events (AEs) are mild or moderate in severity. The 
most frequent AEs suspected to be related to capmatinib of any grade reported in the largest 
single agent trial [CINC280A2201] (220 subjects) were edema peripheral (77 subjects, 
[35.0%]), nausea (69 subjects, [31.4%]), vomiting (40 subjects, [18.2%]), blood creatinine 
increased (39 subjects, [17.7%]), and fatigue (34 subjects, [15.5%]), majority Grade 1/2. The 
most frequently occurring Grade 3/4 AEs suspected to be related to capmatinib as a single agent 
included edema peripheral and lipase increased (each in 9 subjects, [4.1%]), fatigue (8 subjects, 
[3.6%]), alanine aminotransferase increased (ALT) (7 subjects, [3.2%]), aspartate 
aminotransferase increased (AST), hypophosphataemia, nausea and vomiting (each in 3 
subjects, [1.4%]).
Caution is recommended when capmatinib is administered in combination with other anticancer 
drugs with a known risk of hepatotoxicity. One case of liver function test (LFT) abnormal 
meeting Hy’s Law criteria for hepatotoxicity (PHHO2015CN003025) has been reported for a 
subject enrolled in the NSCLC combination study with gefitinib [CINC280X2202]. The event 
could not be attributed solely to either drug alone or to the combination. The subject 
permanently discontinued both study drugs. Liver function tests improved after treatment 
discontinuation.


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As of the IB cut-off of 28-Sep-2017, pneumonitis and ILD (interstitial lung disease) have been 
reported from both capmatinib single agent and combination studies with the EGFR TKIs, 
including events with fatal outcomes. Investigators are advised to carefully monitor subjects for 
signs and symptoms of pneumonitis and implement dose modification and follow-up 
evaluations described in the protocol in all capmatinib studies, both single agent and in 
combination studies.
The maximum tolerated dose (MTD) for capmatinib capsules or tablets as single agent was not 
reached. The RP2D (Recommended Phase 2 dose regimen) for capmatinib as a single agent has 
been determined to be 600 mg BID (twice a day) in capsule formulation and 400 mg BID in 
tablet formulation. For more information, please refer to the current [capmatinib Investigator’s 
Brochure].
1.1.2
Spartalizumab (PDR001)
Spartalizumab (PDR001) is a monoclonal antibody (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 (Freeman and Sehn 2018). Engagement of PD-1 by its ligands, 
PD-L1 and PD-L2 (Programmed Death-Ligand 2), transduces a signal that inhibits T-cell 
proliferation, cytokine production, and cytolytic function (Riley et al 2009). During 
tumorigenesis, cancer cells from a wide range of tumor types exploit immune checkpoint 
pathways, such as PD-(L)1, to avoid detection by the adaptive immune system 
(Murphy et al 2011). Monoclonal antibody (mAb) inhibitors of immunological checkpoints, 
including PD-1 and PD-L1 mAb’s, have demonstrated significant antitumor activity in patients 
with various solid tumors.
Spartalizumab is a high-affinity, ligand-blocking, humanized immunoglobulin G4 (IgG4) 
antibody directed against PD-1 that blocks the binding of PD-L1 and PD-L2 and enhances 
interleukin-2 production in ex-vivo lymphocyte stimulation assays. It does not cross react with 
rodent PD-1; therefore, toxicology studies were performed only in cynomolgus monkeys where 
there was acceptable cross reactivity with monkey PD-1. Anti-drug antibodies (ADA) to 
spartalizumab were observed in some spartalizumab treated cynomolgus monkeys. A trend of 
reduced drug exposure was observed in these ADA-positive animals. For further details, please 
refer to the latest [spartalizumab Investigator’s Brochure].
As of 19-Jan-2018 (latest IB cut-off date), approximately 1239 subjects across 23 Novartis-
sponsored clinical studies have been treated with spartalizumab. Of these, a total of 517 subjects 
were exposed to spartalizumab single agent, and 722 subjects were exposed to spartalizumab 
in combination with other agents (LBH589, LCL161, CJM112, EGF816, ACZ885 and TMT212, 
LAG525, MBG453; other combination studies with spartalizumab have not yet gathered 
sufficient PK data to warrant inclusion in the IB).
The available safety data from these clinical studies indicate that spartalizumab is generally 
well tolerated. In the dose escalation phase of the first-in-man study CPDR001X2101 in patients 
with advanced solid tumors, no DLTs were reported. The preliminarily identified safety risks 
associated with spartalizumab are consistent with and characteristic of agents that inhibit the 
PD-1 receptor, and an advanced cancer population investigated in the respective trials. Severe 
immune-related adverse events (irAEs) were infrequent and typically manageable with dose 


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interruption and use of immunosuppressive treatment or other supportive therapy as clinically 
indicated; discontinuations due to irAEs were rare.
Based on pooled safety data from four studies comprising 513 patients treated with single agent 
spartalizumab across different regimen (400 mg Q4W [n=382], 300 mg Q3W [n=59] and 1-10 
mg/kg Q2W or Q4W [n=76]) and various advanced solid tumors types (i.e. mainly NSCLC, 
melanoma, triple negative breast cancer (TNBC), anaplastic thyroid carcinoma, neuroendocrine 
tumors and nasopharyngeal carcinoma), the most common AEs (>10%), all grades, regardless 
of relationship with study treatment included: fatigue (23.6%), decreased appetite (19.7%), 
anemia (19.1%), nausea (19.1%), dyspnea (18.9%), cough (17.2%), pyrexia (16.0%), 
constipation (15.4%), diarrhea (13.8%), vomiting (12.9%), asthenia (11.5%) and abdominal 
pain (11.3%). Most common AEs (>3%), all grades, suspected to be study drug related included 
fatigue (13.1%), hypothyroidism (6.4%), nausea (6.2%), decreased appetitive (5.8%), diarrhea 
(5.7%), rash (5.5%), pruritus (4.9%), pyrexia (4.7%), asthenia (4.3%), anemia (3.7%), AST 
increase (3.5%) and ALT increase (3.1%).
Most common SAEs (>1%), all grades, regardless of relationship with study treatment were 
dyspnea (3.5%), pleural effusion (2.5%), abdominal pain (2.3%), pneumonia (2.3%), pyrexia 
(1.8%), hypercalcemia (1.6%), anemia (1.4%), sepsis (1.4%) and vomiting (1.2%). There were 
no SAEs suspected to be study drug related that occurred in more than 1% of patients.
Adverse events of special interest (AESI) for spartalizumab include endocrinopathies, colitis, 
skin reactions, hepatitis, nephritis, pneumonitis and other irAEs, and infusion reactions.
Based on the available pharmacokinetics (PK) and safety data, two RP2Ds for spartalizumab 
have been declared: 400 mg Q4W or 300 mg Q3W, with the choice between these two regimens 
determined by scheduling convenience, for example in combination settings. The safety profile 
was similar across the different dose and disease groups and is consistent with the safety profile 
of other similar PD-1 inhibitors.
For further details, please refer to the latest version of the [spartalizumab Investigator’s 
Brochure], as well as Section 4.5 (Risks and Benefits) and Section 6.5.3.1 (Dose Modifications) 
of the protocol.
1.1.3
Combination of capmatinib with a checkpoint inhibitor
1.1.3.1
Combination of capmatinib and nivolumab
The combination of capmatinib and nivolumab has been explored in the study 
[CEGF816X2201C]. This is an ongoing phase II, open-label, study of capmatinib in 
combination with nivolumab in adult subjects with advanced immunotherapy immuno-
oncology (IO)-naive NSCLC (either with high or low MET expression). As of the data cutoff 
of 10-Aug-2017, 18 subjects have been enrolled and treated with capmatinib 400 mg BID + 
nivolumab 3 mg/kg Q2W.
All 18 subjects (100%) experienced AEs of any grade, regardless of causality. The most 
common AEs (occurring in more than 20% of subjects) of any grade were nausea (77.8%), 
vomiting (61.1%), diarrhea (44.4%), rash (group term that includes rash, macular rash, 
maculopapular rash, and eczema, 44.4%), constipation (33.3%), peripheral edema (33.3%), 
decreased appetite (27.8%), fatigue (27.8%), pyrexia (27.8%), increased amylase (22.2%), 


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arthralgia (22.2%), asthenia (22.2%), back pain (22.2%), and dyspnoea (22.2%); the majority 
of AEs were Grade 1/2.
With regard to AEs suspected to be related to study treatment, all 18 subjects (100%) 
experienced AEs of any grade. The most frequent AEs (occurring in more than 10% of subjects) 
of any grade suspected to be related to study treatment were nausea (77.8%), diarrhea (44.4%), 
rash (group term, 44.4%), vomiting (44.4%), peripheral edema (33.3%); decreased appetite 
(27.8%), increased amylase (22.2%), asthenia (22.2%), fatigue (22.2%), arthralgia (22.2%), 
increased blood creatinine (16.7%), hypoalbuminemia (16.7%), lethargy (16.7%), neutropenia 
(16.7%), pyrexia (16.7%), constipation (11.1%), dry skin (11.1%), increased lipase (11.1%), 
pruritus (11.1%), and thrombocytopenia (11.1%); the majority of AEs were Grade 1/2.
Ten subjects (55.6%) experienced at least one SAE regardless of causality. Five subjects 
(27.8%) experienced at least one SAE suspected to be related to study treatment. These included 
SAEs of lethargy, gastroesophageal reflux disease, somnolence, and temporal arteritis in one 
subject; pyrexia in one subject; pyrexia, maculopapular rash, neutropenia, thrombocytopenia, 
and disseminated intravascular coagulation in one subject; anaphylactic reaction in one subject; 
macular rash and vomiting in one subject; and colitis, vomiting, and diarrhea in one subject. 
Each of these suspected related SAEs were reported as recovered, except for temporal arteritis 
(recovering) and colitis (not recovered).
Overall, the safety profile of this combination was manageable; however, the data generated in 
this study are still preliminary, and caution is warranted due to the partial overlapping toxicity 
from both single agents.
This study has provided initial information regarding the safety of the combination of a PD-1 
inhibitor and capmatinib; efficacy data generated in this setting of pretreated advanced NSCLC 
subjects will further support the rationale for combining capmatinib with spartalizumab in 
advanced NSCLC in this CINC280D2201 study.
1.1.3.2
Combination of capmatinib and spartalizumab
Capmatinib in combination with spartalizumab is currently being evaluated in the dose 
escalation and expansion study [CINC280X2108] in subjects with hepatocellular carcinoma 
(HCC).
This is an ongoing phase Ib/II, open-label, multi-center study of capmatinib in combination 
with spartalizumab or spartalizumab single agent conducted in advanced IO-naive 
hepatocellular carcinoma after sorafenib failure.
As of the data cut-off of 25-Sep-2017 [capmatinib Investigator’s Brochure], 20 subjects were 
enrolled and treated in the dose escalation (phase Ib) part of the study, at three dose levels: 200 
mg BID capmatinib (N=6), 300 mg BID capmatinib (N=8) and 400 mg BID capmatinib (N=6), 
all in combination with 300 mg Q3W spartalizumab.
One DLT was reported for a subject treated with capmatinib 400 mg (BID) in combination with 
spartalizumab 300 mg (Q3W): Grade 3 diarrhea, suspected to be related to study treatment. 
Seven subjects (35%) have permanently discontinued study treatment, 1 subject (5%) due to an 
AE, 4 subjects (20%) due to progression of disease, 1 subject (5%) due to subject/guardian 
decision and 1 subject (5%) due to death (caused by progression of disease).


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AEs, all grades, regardless of relationship to study drug, were reported in 19 subjects (95%) 
overall, with the most frequent AEs being peripheral edema (10 subjects, 50%), nausea (7 
subjects, 35%), blood creatinine increased, fatigue (each in 6 subjects, 30%), and rash (5 
subjects, 25%).
Of the 20 subjects treated, 9 (45%) experienced Grade 3 or Grade 4 AEs regardless of 
relationship to study drug. The most frequent Grade 3/4 AEs included nausea, dyspnoea, ALT 
increased, bilirubin increased (each in 2 subjects, 10%). Seven subjects (35%) had Grade 3/4 
AEs suspected to be related to study treatment: nausea (2 subjects, 10%), peripheral edema, 
ALT increased, diarrhea, stomatitis, hypotension, platelet count decreased, acute myocardial 
infarction, unstable angina, blood bilirubin increased, dehydration and neutropenia (each in 1 
subject, 5%).
Of the 20 subjects treated, 17 (85%) experienced AEs (all grades) suspected to be related to 
study treatment. The most frequent suspected AEs included peripheral edema (9 subjects, 45%), 
fatigue, rash (each in 5 subjects, 25%), blood creatinine increased, nausea, vomiting (each in 4 
subjects, 20%).
SAEs, all grades, regardless of relationship to study drug, were reported in 4 subjects (20%). 
50% of the SAEs were Grade 3 or 4 (3 out of 6). SAEs suspected to be related to study treatment 
included unstable angina pectoris, dehydration and diarrhea.
Similar to the combination with nivolumab described in Section 1.1.3.1, the safety profile of 
the combination of capmatinib and spartalizumab was manageable. The RP2D of the 
combination of capmatinib and spartalizumab has been established at a dose of capmatinib 400 
mg BID and spartalizumab 300 mg Q3W. At this dose level the combination was well tolerated 
and there was one DLT, Grade 3 diarrhea, as outlined above. While the safety findings 
generated in this study might be extrapolated to other disease settings, it should be noted that 
HCC subjects tend to represent a unique subject population, prone to exacerbated toxicity due 
to their underlying disease and related comorbidities. Further monitoring and confirmation of 
the safety of this drug combination in this NSCLC indication will be conducted in this 
CINC280D2201 study, which will use a different schedule for spartalizumab (400 mg Q4W).
1.2
Purpose
The purpose of this prospective, multicenter, randomized phase II study is to evaluate the safety 
and efficacy of the combination of capmatinib and spartalizumab in subjects with EGFR wt (for 
exon 19 deletions and exon 21 L858R substitution mutations), ALK-negative rearrangement, 
advanced/metastatic (stage IIIB [not amenable for definitive chemo-radiotherapy] or IV) 
NSCLC, regardless of MET and PD-L1 status. Subjects must have progressed on prior 
treatment with a platinum doublet and a checkpoint inhibitor (either approved or 
investigational), either as single treatments or in combination. A run-in phase will be conducted 
before starting the randomized phase to evaluate safety, tolerability and preliminary efficacy of 
the combination of capmatinib 400 mg BID and spartalizumab 400 mg i.v. Q4W in the selected 
NSCLC setting.
This study will generate clinical data with the proposed combination doses/schedule for 
capmatinib and spartalizumab in advanced NSCLC. Additionally, this study will be the first to 
evaluate the activity of capmatinib in combination with a checkpoint inhibitor in NSCLC in a 


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post-checkpoint and post-platinum setting and will also confirm the efficacy of docetaxel in this 
setting.
2
Objectives and endpoints
Objectives and related endpoints are described in Table 2-1 below.
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
● Run-in part: To assess safety and tolerability of 
capmatinib and spartalizumab combination
● Run-in part: Incidence and severity of AEs and SAEs, 
including changes in laboratory values, vital signs and 
ECGs, dose interruptions, reductions, and dose 
intensity.
● Randomized part: To assess the overall survival 
of combination of capmatinib and spartalizumab in 
comparison to docetaxel
● Randomized part: Overall Survival
Secondary objective(s)
Endpoint(s) for secondary objective(s)
● To assess the objective response rate (ORR), 
disease control rate (DCR), progression-free 
survival (PFS), duration of response (DOR), and 
time to response (TTR) of the capmatinib and 
spartalizumab combination and that of docetaxel
● Objective response rate (ORR), disease control rate 
(DCR), progression-free survival (PFS), duration of 
response (DOR), and time to response (TTR) based on 
RECIST 1.1 
● To assess the safety profile of capmatinib and 
spartalizumab combination therapy
● Incidence and severity of AEs and SAEs
● To characterize the pharmacokinetics of 
capmatinib and spartalizumab as a combination 
therapy in this patient population
● Pharmacokinetic parameters (e.g. Ctrough, Cmax, 
AUC)
● To evaluate the prevalence and incidence of 
immunogenicity
● Antidrug antibodies (ADA) prevalence at baseline and 
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3
Study design
This is a two-part prospectively designed, multicenter, open-label, randomized phase II study 
to evaluate the safety and efficacy of capmatinib in combination with spartalizumab in adult 
subjects with EGFR wt (for exon 19 deletions and exon 21 L858R substitution mutations), ALK 
rearrangement negative in locally advanced (stage IIIB, not eligible for definitive chemo-
radiation) or metastatic (stage IV) NSCLC after failure of platinum doublet and checkpoint 
inhibitor treatment. The study will enroll approximately 105 subjects (approximately 15 
subjects in the run-in [part 1] and 90 subjects in the randomized phase [part 2]). Crossover is 
not allowed.
Part 1: Run-in
Prior to the randomized part of the study, a run-in to assess the safety and tolerability as well as 
preliminary efficacy of the capmatinib and spartalizumab combination will be conducted. 
Approximately 15 subjects will be enrolled and treated with capmatinib and spartalizumab
combination. A review meeting will take place after all subjects have at least 24 weeks of 
follow-up. The decision to expand the study to the randomized part will be based on the safety, 
tolerability, and preliminary efficacy of the capmatinib and spartalizumab combination.
Refer to Figure 3-1 for an overview of the Part I study design.


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Figure 3-1
Study Design Part 1: Run-in
pts: patients FUP: follow-up
Part 2: Randomized
In the randomized part, approximately 90 subjects will be randomized in a 2:1 ratio to either 
capmatinib plus spartalizumab (n=60) or docetaxel (n=30). Subjects will be stratified based on 
the number of prior lines of therapy (1 vs. >1). The primary objective of part 2 is to assess the 
overall survival of the combination of capmatinib with spartalizumab in comparison to 
docetaxel.
Subjects will continue treatment with capmatinib and spartalizumab combination or docetaxel 
until they experience any of the following: documented disease progression by RECIST 1.1 (as 
assessed by the investigator), withdrawal of consent, pregnancy, lost to follow-up, or death 
irrespective of start of new anti-neoplastic therapy (please refer to Section 9).


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For all subjects (either in the run-in part or randomized to capmatinib and spartalizumab or 
randomized to docetaxel), the respective treatment (either with capmatinib and spartalizumab 
combination or docetaxel) may be continued beyond initial disease progression as per RECIST 
1.1 (as assessed by the investigator) if, in the judgment of the investigator, there is evidence of 
clinical benefit, and the subject wishes to continue on the study treatment (for additional details 
please refer to Section 6.1.5.1).
After treatment discontinuation, all subjects will be followed for safety evaluations during the 
safety follow-up period, and the subject’s status will be collected every 8 weeks as part of the 
survival follow-up (for additional details please refer to Section 9).
Refer to Figure 3-2 for an overview of the Part 2 study design.
Figure 3-2
Study Design Part 2: Randomized


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pts: patients FUP: follow-up
4
Rationale
4.1
Rationale for study design
The rationale for the study design is described in the table below.
Table 4-1
Rationale for study design
Study Design Aspect
Rationale
Subject population
The study will enroll subjects with advanced/metastatic NSCLC which are EGFR wt, 
ALK negative, after failure of prior platinum doublet and checkpoint inhibitor 
administered for the treatment of the advanced stage. Subjects must be docetaxel 
naive.
Subjects with targetable oncogenic drivers (such as EGFR-sensitizing mutations, or 
ALK translocation) will be excluded given the preferred approach for these subjects 
is targeted therapy with small-molecules. For more details on subject population, 
please refer to Section 5.
Two-part study (Part 1: 
run-in and Part 2: 
randomized) 
The randomized part will be preceded by a run-in in order to assess the safety, 
tolerability and preliminary efficacy of the combination of capmatinib and 
spartalizumab.
Comparator treatment
Docetaxel was selected as the comparator treatment as it is a globally established 
treatment in this pretreated setting, irrespective of the histology and has been used 
as a comparator in many phase III studies in the post-platinum setting.
Open-label
The trial is open-label for the following reasons: 1) double blinding would require 
two sets of i.v. administration for subjects due the difference in dosing schedules 
between the two arms, which would pose an unnecessary burden for the subject; 
and 2) effective blinding would be difficult, given the varying toxicities between the 
study treatments.
Stratification factors
Number of prior lines of therapy was chosen as a stratification factor due the 
expected difference in clinical outcome between subjects based on the number of 
prior lines of therapy received.
Randomization and 2:1 
ratio
Subjects will be randomized as the efficacy of standard therapies, including 
docetaxel in this post-platinum doublet/post-checkpoint inhibitors setting is currently 
unknown with only anecdotal reports (Park and Cheung 2017, 
Schvartsman et al 2017). The randomization 2:1 increases the chances for subjects 
to receive the innovative combination of immunotherapy and a MET inhibitor, which 
exhibits preclinical immunomodulatory properties and synergistic effect with 
immunotherapy. Furthermore, a 2:1 randomization ratio will allow for increased 
chance to detect adverse events with the capmatinib and spartalizumab 
combination.
Treatment beyond 
disease progression
This is to ensure those subjects (in either arm) who are clinically stable, tolerate the 
treatment, and are deriving clinical benefit can continue to receive treatment. 
Timely follow-up after the initial PD will ensure that subjects with confirmed/rapid 
progression will be discontinued and can initiate adequate subsequent therapies.
4.2
Rationale for dose/regimen and duration of treatment
4.2.1
Capmatinib in combination with spartalizumab
Inhibition of MET by pharmacological or genetic means can enhance T cell mediated anti-
tumor immunity in a variety of treatment regimens and mouse tumor models (including 
melanoma lung, breast, and colon cancer models) (Glodde et al 2017).


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Glodde et al. proposed a model in which capmatinib counteracts an HGF-driven negative 
feedback loop in a T cell inflamed tumor microenvironment, activated immune cells and/or 
tumor-associated stroma secrete HGF, which is mirrored by an increased serum HGF level. As 
a consequence, MET-positive neutrophils are mobilized and invade tumor and adjacent lymph 
nodes, where they acquire immunosuppressive properties, dampening the T cell response 
(Glodde et al 2017).
In order to independently reproduce these results, the combination of anti-PD1 and capmatinib 
was tested in two syngeneic mouse models at Novartis [RD-2017-00370]. Combination 
treatment led to increased T cell infiltration in the short term, and an improved anti-tumor 
immune response with a higher cure rate than either single agent in the long term. The in vivo
studies were extended in a second model (cervical carcinoma) that was generated at Novartis 
in a genetically engineered mouse strain with error-prone DNA (deoxyribonucleic acid) 
replication, which also leads to a high mutation burden. Again, addition of capmatinib to anti-
PD1 therapy led to an increased cure rate, while the MET inhibitor was largely inactive on its 
own.
Besides these direct functional data in mouse models, the reported immunosuppressive effects 
of HGF/MET on dendritic cells and T cells (Section 1.1.1) further support the rationale for 
combining anti-PD1 and capmatinib, because both agents have the potential to enhance T cell 
mediated anti-tumor immunity through complementary mechanisms. While inhibition of 
HGF/MET signaling is expected to enhance antigen presentation and T cell stimulation by 
dendritic cells and potentially even increase cytotoxicity of a subset of T cells, anti-PD1 
antibodies will prevent suppression of T cell function through PD-L1 expressed on tumor cells 
or other immune cells.
The feasibility of the combination of capmatinib with a checkpoint inhibitor has already been 
confirmed in two studies ([CINC280X2108] and [CEGF816X2201C]). (For details, please refer 
to Section 1.1.3.1 and Section 1.1.3.2).
The combination of capmatinib with spartalizumab has been evaluated in the study 
[CINC280X2108] (which used a fixed dose of spartalizumab 300 mg with a Q3W schedule) 
conducted in HCC where, based on the BLRM-EWOC (Bayesian Logistic Regression Model -
Escalation With Overdose Control) model, the RP2D was declared at 400 mg BID for 
capmatinib in combination with 300 mg spartalizumab Q3W.
In the current study [CINC280D2201], the alternate dosing regimen of spartalizumab 400 mg 
Q4W will be used. Pharmacokinetic and safety data across dose levels in study 
[CPDR001X2101] supported the declaration of two RP2Ds, 300 mg Q3W and 400 mg Q4W 
for spartalizumab as a single agent. Based on the population PK model simulations, both 
regimens are expected to achieve similar exposure range at steady-state and achieve a mean 
steady-state Ctrough value higher than the ex vivo EC50 for antigen-stimulated IL-2 production, 
a translational biomarker for PD-1 blockade (for additional information, please refer to 
Section 1.1.2). Two RP2Ds were chosen to allow more convenient scheduling of treatments for 
subjects receiving combination therapy with spartalizumab. In this study, a Q4W schedule has 
been chosen based on scheduling convenience in this setting of advanced NSCLC. The activity 
of docetaxel in the context of post-platinum and post-checkpoint inhibitor is unknown with 
anecdotal reports (Park and Cheung 2017Schvartsman et al 2017).


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4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Docetaxel is an established treatment option for pretreated NSCLC subjects and has served as 
a control arm for several prospective, randomized trials in the second- or third-line setting 
including the most recent phase 3 studies with PD-(L)1 inhibitors (Herbst et al 2016, 
Rittmeyer et al 2017, Borghaei et al 2015, Brahmer et al 2015, Hanna et al 2004), and it is 
approved for the use in NSCLC irrespective of tumor histology. In the context of the post-
platinum setting, a response rate of approximately 9-13%, median PFS of 3-4 months, and 
median OS of approximately 8-10 months is expected with docetaxel (Hanna et al 2004, 
Herbst et al 2016, Rittmeyer et al 2017, Borghaei et al 2015, Brahmer et al 2015). Overall, the 
reported response rates to second-line chemotherapy (including other single agent 
chemotherapeutics) have generally been < 11%, with median PFS and OS generally below 4 
and 11 months, respectively (de Marinis and Grossi 2008, Weiss and Stinchcombe 2013, 
NCCN 2018, Novello et al 2016). Upon progression after second-line chemotherapy, subjects 
may be candidates for further treatment, although randomized evidence is scarce and most data 
come from phase II trials or retrospective analyses. Subjects often have limited response to 
third-line therapy, although it may have some palliative effect (Shepherd et al 2005, 
de Marinis and Grossi 2008, Eccles et al 2011, Reck et al 2014, Besse et al 2014, NCCN 2018). 
The activity of docetaxel in the context of post-platinum and post-checkpoint inhibitor is 
unknown with anecdotal reports (Park and Cheung 2017, Schvartsman et al 2017).
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable.
4.5
Risks and benefits
Subjects in this study have advanced non-small cell lung cancer and have progressed after one 
or two lines of prior approved chemotherapy, radiotherapy and/or immunotherapy. Given the 
clinical and molecular characteristics of their disease they have limited therapeutic options and 
the established standard, single agent chemotherapy regimens approved for this setting are of 
limited benefit.
Synergistic antitumor effect has been shown preclinically with capmatinib in combination with 
checkpoint inhibitors in non-MET driven tumor models. The safety profile of capmatinib and 
spartalizumab as monotherapies is well characterized (see Section 1.1.1 and Section 1.1.2). This 
new combination has been proven to be safe at the dose of 400 mg BID capmatinib and 
spartalizumab 300 mg Q3W in HCC subjects treated in study [CINC280X2108] (see 
Section 1.1.3.2). The 24 weeks follow-up of this run-in phase is intended not only to allow a 
thorough assessment of the safety profile of this new schedule but also to assess the preliminary 
efficacy of this combination before enrolling more subjects into the randomized part.
Appropriate eligibility criteria and stopping rules are included in this protocol. Recommended 
guidelines for prophylactic or supportive treatment for expected toxicities, including the 
management of study-drug induced AEs, (e.g. infusion reaction, pneumonitis) are provided in 
Section 6.5. The risk to subjects in this trial may be minimized by compliance with the 
eligibility criteria and study procedures, as well as by close clinical monitoring.


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As with any clinical study, there may be unforeseen risks with the combination studied, which 
could be serious. The specific risks for each compound are discussed below. For more details, 
refer to the toxicity data provided in the [capmatinib Investigator's Brochure] and in the 
[spartalizumab Investigator's Brochure]
4.5.1
Capmatinib
Based upon the clinical experience with capmatinib to date, the overall risk-benefit assessment 
of capmatinib is considered favorable with a manageable safety profile. Most of the AEs that 
have been reported, irrespective of relationship to study drug, have been manageable and 
generally mild or moderate in severity.
Caution is recommended when capmatinib is administered in combination with other anticancer 
drugs with a known risk of hepatotoxicity. One case of liver function test abnormal meeting 
Hy’s Law criteria for hepatotoxicity (PHHO2015CN003025) has been reported for a subject 
enrolled in the NSCLC combination study with gefitinib [CINC280X2202]. The event could 
not be attributed solely to either drug alone or to the combination.
As of the IB cut-off of 28-Sep-2017, pneumonitis and ILD have been reported from both 
capmatinib single agent and combination studies with the EGFR TKIs, including events with 
fatal outcomes. Investigators are advised to carefully monitor subjects for signs and symptoms 
of pneumonitis and implement dose modification and follow-up evaluations described in the 
protocol in all capmatinib studies, both single agent and in combination studies.
For further information on potential toxicities, please refer to Section 1.1.1 and the current 
[capmatinib Investigator's Brochure].
4.5.2
Spartalizumab
Spartalizumab is a humanized mAb which belongs to a class of agents known as immune-
checkpoint inhibitors, specifically anti-PD-1. This class of compounds has demonstrated 
significant improvement in efficacy combined with a tolerable and manageable safety profile, 
supporting regulatory approvals in various indications.
Overall, clinical experience with spartalizumab to date suggests that it can cause 
irAEs. Immune-checkpoint inhibitors of this class may be associated with the occurrence of 
immune-mediated adverse events (irAE). In general, irAE can potentially involve every organ 
system but gastrointestinal (GI) (e.g. diarrhea, colitis), dermatologic (e.g. rash, pruritus), hepatic 
(e.g. hepatitis), pulmonary (e.g. pneumonitis), renal (e.g. nephritis) and endocrine toxicities (e.g. 
hypothyroidism, hyperthyroidism, type I diabetes, hypophysitis including hypopituitarism and 
adrenal insufficiency) being typically the most frequent. Other immune-mediated AEs may 
rarely include the nervous system (e.g. encephalitis, Guillain-Barre syndrome, myasthenia 
gravis), eye (e.g. uveitis, 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 epidermonecrolysis or 
Steven Johnson syndrome. Furthermore, complications in patients with bone marrow or solid 
organ transplant have been reported (e.g. organ rejection, severe graft-versus-host disease).
These side effects are generally manageable and reversible with dose interruption and 
administration of corticosteroids and/or other immunosuppressants. However, fatal events have 


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been reported in some cases with checkpoint inhibitors; furthermore, some events like 
endocrinopathies may require life-long hormonal replacement. While most irAEs are expected 
to occur during the treatment with spartalizumab, onset may be delayed and irAEs may also 
occur after discontinuation of study treatment (Spain et al 2016, Hofmann et al 2016, 
Champiat et al 2016, Brahmer et al 2018, Haanen et al 2017). In addition, mAb’s can be 
associated with infusion-related reactions some of which can be severe; these are often 
immediate and usually occur within minutes of the exposure to the study drug. Therefore, 
infusions should take place in a facility with appropriate resuscitation equipment available at 
the bedside and a physician readily available, and patients monitored for respective signs and 
symptoms. Patients who experience severe or life-threatening irAEs or infusion reactions may 
need to permanently discontinue spartalizumab (see Section 6.5.3.1 for further guidance).
It is therefore important to be vigilant and carefully identify events that may be suggestive of 
potential irAEs, as their appearance may be sub-clinical (for example an asymptomatic 
laboratory abnormality), and early diagnosis is critical for appropriate management and 
possibly prevent complications. Serological, immunological and histological assessments (such 
as biopsy of the affected tissue) should be performed as deemed appropriate by the investigator 
to verify the potential immune-mediated nature of the AE and to exclude alternative diagnoses 
or disease progression. Following appropriate and complete evaluation, an empiric trial of 
corticosteroids may contribute to the identification of irAEs.
It is expected that spartalizumab would have a similar safety profile as other immune checkpoint 
inhibitors with the above-mentioned side effects possibly occurring in subjects treated with 
spartalizumab. For further detail on potential adverse events with spartalizumab treatment 
please refer to Section 1.1.2 of this protocol.
4.5.3
Capmatinib combined with spartalizumab
Pharmacokinetic drug-drug interaction (DDI) is anticipated to be low for the combination of 
capmatinib and spartalizumab.
Both capmatinib and spartalizumab are well tolerated as single agents. There is no 
pharmacological or clinical evidence that would anticipate any cumulative, interactive or 
unexpected toxicity between the compounds if given in combination. The combination is 
currently being evaluated in the dose escalation and expansion study [CINC280X2108] in 
subjects with hepatocellular carcinoma (HCC). To date, the safety profile of the combination in 
this disease setting has been manageable.
For further detail on potential adverse events with the combination of capmatinib and 
spartalizumab please refer toSection 1.1.3.2 of this protocol.
4.5.4
Docetaxel
In this patient population, safety and efficacy of docetaxel has been well-established since its 
approval in 1996. Docetaxel is licensed as single agent and indicated for the treatment of 
patients with locally advanced or metastatic non-small cell lung cancer after failure of prior 
platinum chemotherapy. The median survival was 9.0 months with docetaxel versus 4.6 months 
for best supportive care (BSC) (P = 0.016 ). Quality-of-life analysis showed significant 
improvement in several disease-related symptoms in patients who received docetaxel.


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The common adverse reactions to docetaxel are infections, neutropenia, anemia, febrile 
neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, 
anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, 
alopecia, skin reactions and myalgia.
Please refer to the current prescribing guidelines for docetaxel in this disease setting.
4.5.5
Risks of Imaging Procedures 
Tumor assessments required by the trial include Computerized Tomography (CT) and Magnetic 
Resonance Imaging (MRI) scanning. There are both benefits and risks associated with the use 
of CT and MRI for imaging.
Contrast enhancement is a standard tool to evaluate potential metastatic lesions; subjects with 
contrast allergy are exempted from its use. The ordering physician should ensure that subjects 
are well hydrated and precautions taken to avoid renal injury due to contrast agents.
MRI is considered a very safe imaging modality; however, there is an underlying risk of 
potential injury to subjects due to the strong electromagnetic (EM) fields used in MRI scanning. 
Subjects with known metallic foreign bodies or implanted devices should not have MRI scans.
5
Population
The study population will include adult subjects with locally advanced (stage IIIB, not eligible 
for definitive chemo-radiation) or metastatic (stage IV) non-small cell lung cancer. Subjects 
must be docetaxel naive, and subjects with EGFR mutations and ALK rearrangement will be 
excluded.
To be eligible, patients must have progressed on prior treatment with a platinum doublet and a 
PD-L1 checkpoint inhibitor (either approved or investigational), either as single treatments 
(with the checkpoint inhibitor as last treatment) or in combination:

Patients who have progressed after receiving a checkpoint inhibitor in combination with a 
platinum doublet, as first-line therapy.

Patients who have progressed on anti-PD-(L)1 checkpoint inhibitor as second-line therapy, 
after receiving a platinum doublet as first-line therapy.

Finally, patients who have received a checkpoint inhibitor as maintenance after platinum 
chemo-radiotherapy for stage III NSCLC and progressed to advanced stage within 12 
months since the end of this therapy are also eligible.
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational clinical studies. The investigator or designee must ensure that only patients who 
meet all the following inclusion and none of the exclusion criteria are offered treatment in the 
study.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures
2. Adult ≥ 18 years old at the time of informed consent 


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3. Histologically confirmed locally advanced/metastatic (stage IIIB or IV per AJCC/IASLC 
v. 8) NSCLC
4. Histologically or cytologically confirmed diagnosis of NSCLC that is both EGFR wt 
status and ALK- negative rearrangement status:

Patients with NSCLC of pure squamous cell histology can enter screening without 
EGFR mutation or ALK rearrangement testing or result; however, patients with pure 
squamous cell histology who are known to have EGFR mutations in exons 19 or 21 or 
ALK rearrangements will be excluded
5. Patients must have demonstrated progression of locally advanced/ metastatic NSCLC 
(stage IIIB, not amenable for definitive chemo-irradiation, or stage IV) following one 
prior platinum doublet and one prior PD-(L)1 checkpoint inhibitor (either alone or in 
combination)

Maintenance therapy given after first-line chemotherapy will be considered as part of 
the first-line therapy if given to patients with documented response or stable disease 
before starting the maintenance therapy.

Neo-adjuvant and adjuvant systematic therapies will count as one prior line of 
systemic treatment for the advanced stage if relapse occurred within 12 months from 
the end of the neoadjuvant or adjuvant systemic therapy.

The most recent line of therapy should include a PD-(L)1 checkpoint inhibitor (either 
alone or in combination)
6. Patients must be candidates for single agent chemotherapy with docetaxel
7. Patients must have recovered from all toxicities related to prior anticancer therapies to 
grade ≤ 1 (CTCAE v5.0). Patients with any grade of alopecia are allowed to enter the 
study
8. At least one measurable lesion as defined by RECIST 1.1. A previously irradiated site 
lesion may only be counted as a target lesion if there is clear sign of progression since the 
irradiation
9. Patients must have adequate organ function including the following laboratory values at 
the screening visit:

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support

Platelets ≥ 75 x 109/L

Hemoglobin (Hgb) ≥ 9 g/dL

Calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 45 mL/min

Total bilirubin (TBIL) ≤ 1.5 x ULN (upper limit of normal)

Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver metastasis, 
who may only be included if AST ≤ 5 x ULN

Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis, 
who may only be included if ALT ≤ 5 x ULN

Alkaline phosphatase (ALP) ≤ 5.0 x UL

Asymptomatic serum amylase ≤ Grade 2. Patients with Grade 1 or Grade 2 serum 
amylase at the beginning of the study must be confirmed to have no signs and/or 


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symptoms suggesting pancreatitis or pancreatic injury (e.g. elevated P-amylase, 
abnormal imaging findings of pancreas, etc.)

Serum lipase ≤ ULN

Fasting plasma glucose ≤ 160 mg/dL (≤ 8.9 mmol/L)
10. ECOG performance status (PS) of 0 or 1
11. Willing and able to comply with scheduled visits, treatment plan and laboratory tests
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Prior treatment with a MET inhibitor or HGF-targeting therapy
2. Any untreated central nervous system (CNS) lesion. However, patients are eligible if all 
known CNS lesions have been treated with radiotherapy or surgery and remained stable 
for ≥ 4 weeks after treatment. Patients must be off corticosteroid therapy for ≥ 2 weeks
3. Carcinomatous meningitis
4. Patients with known hypersensitivity to any of the excipients of capmatinib 
(crospovidone, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, 
magnesium stearate, colloidal silicon dioxide, and various coating premixes) or 
intolerance to docetaxel excipients (as per local product label)
5. History of severe hypersensitivity reactions to other monoclonal antibodies, which in the 
opinion of the investigator may pose an increased risk of serious infusion reaction
6. Presence or history of a malignant disease other than NSCLC that has been diagnosed 
and/or required therapy within the past 2 years. Exceptions to this exclusion include: 
completely resected basal cell and squamous cell skin cancers, and completely resected 
carcinoma in situ of any type
7. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, M-CSF), 
thrombopoietin mimetics or erythroid stimulating agents ≤ 2 weeks prior start of study 
treatment. 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
8. Patients receiving treatment with medications that meet one of the following criteria and 
that cannot be discontinued at least 1 week prior to Cycle 1 Day 1 and for the duration of 
the study:

Strong inhibitors of CYP3A4 (patients randomized to the docetaxel arm only will 
need to comply with this criterion for the whole duration of the study treatment)

Strong inducers of CYP3A4 (patients randomized to both capmatinib containing arm 
and docetaxel arm will need to comply with this criterion for the whole duration of 
the study treatment)
9. Use of any live vaccines against infectious diseases within 3 months of initiation of study 
treatment. Patients randomized to the spartalizumab containing arm will need to comply 
with this criterion for the whole duration of the study treatment
10. Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be 
discontinued at least 1 week before first dose of study treatment, and for the duration of 
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11. Systemic chronic steroid therapy (≥ 10 mg/day prednisone or equivalent) or any 
immunosuppressive therapy 7 days prior to planned date of first dose of study treatment. 
Topical, inhaled, nasal and ophthalmic steroids are allowed. Steroid premedication for 
docetaxel infusion does not apply
12. Concomitant medication(s) with a “Known Risk of Torsades de Pointes” per 
www.qtdrugs.org that cannot be discontinued or replaced by safe alternative medication.
13. Clinically significant, uncontrolled heart diseases:

Unstable angina within 6 months prior to screening

Myocardial infarction within 6 months prior to screening

History of documented congestive heart failure (New York Heart Association
functional classification III-IV)

Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without 
antihypertensive medication. Initiation or adjustment of antihypertensive
medication(s) is allowed prior to screening

Ventricular arrhythmias

Supraventricular and nodal arrhythmias not controlled with medication

Other cardiac arrhythmia not controlled with medication

Fridericia QT correction formula (QTcF) ≥ 470 ms on the screening 
Electrocardiogram (ECG) (as mean of triplicate ECG)

Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome
14. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting Cycle 1 Day 1 or patients 
who have not recovered from radiotherapy-related toxicities. For all other anatomic sites 
(including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to 
Cycle 1 Day 1, or patients who have not recovered from radiotherapy-related toxicities. 
Palliative radiotherapy for bone lesions or radio-surgery for isolated brain lesions ≤ 2 
weeks prior to Cycle 1 Day 1 is allowed
15. Major surgery within 4 weeks prior to starting study treatment (2 weeks for resection of 
brain metastases), or patients who have not recovered from the side effects of such a 
procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be 
counted as major surgery and patients can be enrolled in the study ≥1 week after the 
procedure
16. Impairment of GI function or GI disease that may significantly alter the absorption of 
capmatinib 
17. Active, known or suspected autoimmune disease or a documented history of autoimmune 
disease. Note: patients with vitiligo, controlled type I diabetes mellitus on stable insulin 
dose, residual autoimmune-related hypothyroidism only requiring hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger are permitted to enroll.
18. Previous anti-cancer and investigational agents within 4 weeks or ≤ 5 x half-life of the 
agent (whichever is longer) before first dose of study treatment. If previous treatment is a 
monoclonal antibody or an anti PD-(L)1 checkpoint inhibitor, then the treatment must be 


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discontinued at least 4 weeks before first dose of study treatment. If previous treatment is 
an oral targeted agent, then the treatment must be discontinued at least 5 x half-life of the 
agent
19. History of allogenic bone marrow or solid organ transplant
20. Presence or history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or 
requiring therapeutic intervention)
21. Other severe, acute, or chronic medical or psychotic conditions or laboratory 
abnormalities that in the opinion of the investigator may increase the risk associated with 
study participation, or that may interfere with the interpretation of study results
22. Known history of testing positive for Human Immunodeficiency Virus (HIV) infection. 
Positive HIV test at screening where locally required
23. Patients with active hepatitis B infection (HBsAg positive) will be excluded. Note: 
patients with antecedent events of hepatitis B (anti-HBc positive, HBsAg and HBV DNA 
negative) are eligible. Patients with active hepatitis B (HBsAg positive) must receive 
antiviral treatment with lamivudine, tenofovir, entecavir, or other antiviral agents before 
the initiations of study treatment and show a suppressed viral replication (e.g. HBV DNA 
< 100 UI/ml) may be included. Indications for the screening/follow-up of hepatitis B and 
duration of prophylactic antiviral therapy should be dictated by institutional guidelines or 
specified in the protocol
24. Patients with positive test for hepatitis C ribonucleic acid (HCV RNA). Patients in whom 
Hepatitis C virus (HCV) infection resolved spontaneously (positive HCV antibodies 
without detectable HCV RNA) or those that achieved a sustained virological response 
after antiviral treatment and show absence of detectable HCV RNA ≥ 6 months (with the 
use of IFN-free regimes) or ≥ 12 months (with the use of IFN-based regimes) after 
cessation of antiviral treatment are eligible
25. Pregnant or nursing (lactating) women confirmed by a positive human chorionic 
gonadotrophin (hCG) laboratory test within 72 hours prior to initiating study treatment. 
Note: low levels of hCG may also be considered a tumor marker, therefore if low hCG 
levels are detected, another blood sample at least 4 days later must be taken to assess the 
kinetics of the increase and transvaginal ultrasound must be performed to rule out 
pregnancy
26. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 150 days after stopping treatment with the spartalizumab in 
combination with capmatinib. For female patients treated with docetaxel, highly effective 
contraception must be used during the study and for at least 6 months after stopping 
docetaxel as per the locally approved package label. Highly effective contraception 
methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 


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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.Women are considered post-menopausal and not of child bearing potential 
if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by laboratory assessment is she 
considered not of child bearing potential
27. Sexually active males unless they use a condom during intercourse while on treatment and 
during the follow-up periods mentioned below. Sexually active men should not father a 
child in these periods.

Male subjects who receive treatment with spartalizumab in combination with 
capmatinib must use a condom during intercourse for 7 days after stopping treatment.

Male subjects who receive treatment with docetaxel must use a condom during 
intercourse for at least 6 months after the last dose of docetaxel or as per the locally 
approved package label.
A condom is required to be used by vasectomized men as well during intercourse in order 
to prevent delivery of the drug via semen
28. Unable or unwilling to swallow tablets as per dosing schedule
29. Any other condition that would, in the investigator’s judgment, contraindicate patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures, e.g., infection, inflammation, intestinal obstruction, social/ psychological 
issues, etc.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects.
6
Treatment
6.1
Study treatment
For this study, the investigational drugs are capmatinib and spartalizumab. The study treatment 
is defined as capmatinib in combination with spartalizumab, or docetaxel. Both investigational 
drugs will be labeled and provided to sites by Novartis in compliance with legal requirements 
for each country. Docetaxel will be procured locally as it is commercially available in each 
participating country.


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6.1.1
Investigational and control drugs
The treatment period begins on Cycle 1 Day 1. In other words, the first dose of study drug 
(capmatinib plus spartalizumab or docetaxel) is given on Day 1 of Cycle 1. Cycle 1 Day 1 
should occur no later than 3 days after registration into the IRT (Interactive Response 
Technology) system.
All dosages prescribed and administered to subjects and all dose interruptions and changes 
during the study must be recorded on the study treatment eCRF (electronic Case Report/Record 
Form). Refer to Section 6.7.2 for study drug prescribing and administration information.
Table 6-1
Investigational and control drugs
Investigational/Control 
Drugs 
(Name and Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Drug package
Supplier 
(global or 
local)
Capmatinib (INC280) 150 
mg or 200 mg
Film-coated tablet
Oral use
Open-label subject 
specific; bottles
Global
Spartalizumab (PDR001) 
100 mg
Concentrate for 
solution for infusion
Intravenous use
Open-label subject 
specific; 4 x 100 mg 
vials
Global
Docetaxel (as per local 
product available)
Concentrate for 
solution for infusion
Intravenous use
Open-label bulk supply; 
vials
Local
6.1.2
Additional study treatments
Spartalizumab (Infusion Reactions)
If a subject experiences an infusion reaction, he/she may receive pre-medication on subsequent 
dosing days. The pre-medication should be chosen per institutional standard of care, at the 
discretion of the treating physician.
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status.
If a subject experiences a Grade 3 infusion or anaphylactic/anaphylactoid reaction, the subject 
will discontinue spartalizumab treatment. Further guidelines on management of spartalizumab 
infusion reactions are provided in Section 6.5.3.
The CTCAE category of “Infusion related reaction” should be used to describe study treatment 
related infusion reactions, unless the investigator considers another category, such as “Allergic 
reaction”, “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a specific 
situation.
Docetaxel
Pre-medication schemes should follow local guidelines as per standard of care and product 
labels.


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6.1.3
Treatment arms/group
Part 1: Run-in
In the run-in part of the study, subjects will be treated with capmatinib and spartalizumab as 
described below.

Combination of capmatinib and spartalizumab

Capmatinib 400 mg (tablets) orally twice daily (BID) with or without food followed 
by spartalizumab 400 mg intravenously (i.v.) every 28 days

Capmatinib will be given as continuous daily dosing, and the first dose is 
administered at the study center.

Spartalizumab will be administered on Day 1 of each 28 day cycle.

A complete cycle of treatment is defined as 28 days of continuous capmatinib 
treatment and an infusion of spartalizumab every 28 days.
Part 2: Randomized
In the randomized part of the study, subjects will be assigned at Cycle 1 Day 1 to one of the 
following two treatment arms/groups in a ratio of 2:1 according to stratification.

Arm 1: Combination of capmatinib and spartalizumab

Capmatinib 400 mg (tablets) orally twice daily (BID) with or without food followed 
by spartalizumab 400 mg intravenously (i.v.) every 28 days

Capmatinib will be given as continuous daily dosing, and the first dose is 
administered at the study center

Spartalizumab will be administered on Day 1 of each 28 day cycle

A complete cycle of treatment is defined as 28 days of continuous capmatinib 
treatment and an infusion of spartalizumab every 28 days.

Arm 2: Reference chemotherapy

Docetaxel 75 mg/m2 intravenously (i.v.) following local guidelines as per standard of 
care and product labels (including steroid premedication)

First infusion day defines Cycle 1 Day 1

Administered every 21 days

A complete cycle of treatment is defined as an infusion of docetaxel every 21 days.
6.1.4
Guidelines for continuation of treatment
Guidelines on the management of common capmatinib-, spartalizumab- and docetaxel-
associated toxicities and dose modification instructions are provided in Section 6.5.3.
6.1.5
Treatment duration
Subjects will continue capmatinib and spartalizumab combination (for both Part 1: run-in and 
Part 2: randomized) or docetaxel until they experience any of the following: documented 
disease progression by RECIST 1.1 as assessed by the investigator, withdrawal of consent, 






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6.2
Other treatment(s)
6.2.1
Concomitant therapy
In general, the use of any concomitant medication/therapy deemed necessary for the care of the 
subject (e.g. such as anti-emetics, anti-diarrhea) is permitted except when specifically 
prohibited (see Section 6.2.2).
The subject must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (excluding study treatment and prior 
antineoplastic treatments), blood transfusions, surgeries and procedures (including physical 
therapy) administered within 28 days prior to the first dose administration of capmatinib and 
spartalizumab combination or docetaxel through 30 days after the last dose of capmatinib and 
spartalizumab combination or docetaxel will be recorded in the concomitant medications or 
surgical and medical procedures eCRF, respectively. Medications include not only physician 
prescribed medications, but also all over-the counter medications, herbal medications, food 
supplements and vitamins.
The following restrictions apply during the entire duration of the study:

No other investigational therapy should be given to subjects

No anticancer agents other than the study medication (capmatinib and spartalizumab 
combination or docetaxel) should be given to subjects.
Subjects are permitted to use the following medications while taking capmatinib and 
spartalizumab combination:

Oral or topical antibiotics

Medications to prevent or treat nausea, vomiting or diarrhea

Hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), 
thrombopoietin mimetics or erythroid stimulating agents are allowed as per local or 
published guidelines; in case of anemia, thrombocytopenia or neutropenia, potential 
immune-mediated etiology should be ruled out.

Treatment with bisphosphonates (please refer to Section 6.2.1.2)

Oxygen therapy and blood products or transfusions

Local radiotherapy (please refer to Section 6.2.1.2)

Anti-diarrheal medications (e.g., loperamide) for subjects who develop diarrhea

Pain medication to allow the subject to be as comfortable as possible

Immunosuppressive agents to treat suspected irAEs

Nutritional support or appetite stimulants (e.g. megestrol)

Inactivated vaccines

Topical, inhaled, nasal and ophthalmic steroids are allowed.
The subject 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 
eCRF.


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6.2.1.1
Permitted concomitant therapy requiring caution and/or action
6.2.1.1.1 Capmatinib: permitted concomitant therapy requiring caution and/or action

Capmatinib is a moderate CYP1A2 inhibitor. Coadministration of capmatinib increased 
sensitive CYP1A2 probe substrate (caffeine) AUC by 135% (see Section 1.1.1). The dose 
of CYP1A2 substrates with a narrow therapeutic index may need to be reduced when used 
concurrently with capmatinib as capmatinib may increase their exposure. Consult the 
product information of the concomitant drug for dose adjustment.

Coadminstration of capmatinib increased Pgp substrate (digoxin) exposure (AUC and 
Cmax by 47% and 74%, respectively) and BCRP substrate (rosuvastatin) exposure (AUC 
and Cmax by 108% and 204%, respectively) (please refer to Section 1.1.1). Monitor 
subjects closely for symptoms of increased exposure to Pgp or BCRP substrates. Consult 
the concomitant Pgp or BCRP substrate product information when considering dose 
adjustment.

Coadministration of capmatinib with a strong CYP3A4 inhibitor (itraconazole) increased 
capmatinib AUC by 42%. There is no change in capmatinib Cmax. Execute caution when 
use strong CYP3A4 inhibitors concurrently with capmatinib.

While the data on the concurrent use of PPI and food have to be considered preliminary as 
they have been generated in a small cohort of subjects of the study [CINC280A2108], the 
decrease in exposure imposes caution on the use of PPI when capmatinib is taken.

Short acting gastric acid modulators containing aluminum hydroxide and magnesium 
hydroxide, or calcium carbonate can be taken; however, it is recommended to take these 
drugs at least 1 hour before or 2 hours after administration of capmatinib.

H2 receptor antagonists should be used with caution. If subjects are using H2 receptor 
antagonists during the course of this study, capmatinib should be administered at least 3 
hours before or 6 hours after taking H2 receptor antagonists.

Capmatinib is a weak- to-moderate inhibitor of CYP2C8, CYP2C9 and CYP2C19 in vitro. 
Substrates of CYP2C8, CYP2C9 and CYP2C19 with a narrow therapeutic window should 
be administered with caution.
Refer to Table 6-2 below for a list of the medications (presented by mechanism of interaction) 
that require caution when concomitantly used with capmatinib.
Table 6-2
Capmatinib: drugs to be used with caution during co-administration
Mechanism of Interaction
Drug Name
Strong CYP3A inhibitor
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak), indinavir/ritonavir, 
tipranavir/ritonavir, ritonavir, cobicistat, indinavir, ketoconazole, 
troleandomycin, telaprevir, danoprevir/ritonavir, eltegravir/ritonavir, 
saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, voriconazole, mibefradil, 
posaconazole, telithromycin, grapefruit juice, conivaptan, nefazodone, 
nelfinavir, idelalisib, boceprevir, atazanavir/ritonavir, darunavir/ritonavir
CYP1A2 substrate with NTI
theophylline, tizanidine
CYP2C9 substrate with NTI
(S)-warfarin
CYP2C19 substrate with NTI
(S)-mephenytoin


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Mechanism of Interaction
Drug Name
P-gp substrates
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, 
aprepitant, atorvastatin, , boceprevir, bosentan, carvedilol, caspofungin, 
ceritinib, colchicine, cyclosporine, dabigatran, digoxin, docetaxel, doxepin, 
doxorubicin, eribulin, everolimus, fentanyl, fexofenadine, fidaxomicin, 
fluvastatin, fosamprenavir, idelalisib, iloperidone, indacaterol, irbesartan, 
lacosamide, lapatinib, levetiracetam, linagliptin, linezolid, loperamide, losartan, 
maraviroc, mirabegron, nadolol, naloxegol, nateglinide, nevirapine, nintedanib, 
olodaterol, paclitaxel, pantoprazole, paroxetine, pazopanib, proguanil, 
posaconazole, pravastatin, ranolazine, ritonavir, riociguat, risperidone, 
rivaroxaban, saquinavir, silodosin, simeprevir, simvastatin, sirolimus, 
sitagliptin, sofosbuvir, sorafenib, tacrolimus, telaprevir, tenofovir, ticagrelor, 
tipranavir, tolvaptan, topotecan, umeclidinium, valsartan, vardenafil, 
vincristine, voriconazole
BCRP substrates
atorvastatin daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, paritaprevir, pitavastatin, rosuvastatin, irinotecan, 
ethinyl estradiol, simvastatin, sofosbuvir, sulfasalazine, tenofovir, topotecan, 
venetoclax
Proton pump inhibitor
esomeprazole, pantoprazole, omeprazole, lansoprazole, rabeprazole, 
dexlansoprazole
H2-receptor antagonists
ranitidine, nizatidine, famotidine, cimetidine
Antacids
aluminum hydroxide, aluminum carbonate, calcium hydroxide, calcium 
carbonate, bismuth subsalicylate
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s 
Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction 
Studies”.
NTI: narrow therapeutic index
6.2.1.1.2 Spartalizumab: permitted concomitant therapy requiring caution and/or 
action
If a subject 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 subjects 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 sampling according to the 
institutional guidelines.
Topical, inhaled, nasal and ophthalmic steroids are allowed.
6.2.1.1.3 Docetaxel: permitted concomitant therapy requiring caution and/or action
Please follow local guidelines as per standard of care and product labels.
6.2.1.2
Use of bisphosphonates and local radiotherapy
Treatment with bisphosphonates for pre-existing bone metastases is permitted, if clinically 
indicated, and following existing local guidelines and documented discussion with Novartis. 
Treatment with bisphosphonates should preferably begin before the study treatment is initiated, 
but can also be initiated during therapy only if absence of radiological bone disease progression 


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is well documented (in this case, the reason for its use must be clearly documented; i.e. “pre-
existing, non-progressing, bone metastases”).
Local bone radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be 
carried out if required after documented discussion with Novartis. If palliative radiotherapy 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 ruled out. The study treatment must be interrupted on 
the days of radiotherapy and can be resumed the day after its completion. Caution is advised 
for radiation to fields that include lung tissue. The radiotherapy must be documented in the 
eCRF.
6.2.2
Prohibited medication
During the course of the study, subjects must not receive other antineoplastic therapies (e.g. 
investigational drugs, devices, chemotherapy, immunotherapies) or any other therapies that may 
be active against cancer or modulate the immune responses; however, limited-field palliative 
radiotherapy may be allowed as a concomitant therapy (see Section 6.2.1.2).
Subjects enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies while on treatment.
6.2.2.1
Capmatinib: prohibited medication
Coadministration of capmatinib with a strong CYP3A4 inducer (rifampicin) has decreased 
capmatinib AUC by 67% and Cmax by 56%. Concurrent use of strong CYP3A4 inducers should 
be prohibited as decreased capmatinib exposure may lead to reduced efficacy [capmatinib 
Investigator’s Brochure].
The prohibited medications are listed in the Table 6-3 below.
Drugs with a known risk of Torsades de Pointes (TdP) are prohibited. For identification of drugs 
with known risk of TdP please refer to www.qtdrugs.org (refer to Table 6-4).
Table 6-3
Capmatinib: prohibited drugs
Mechanism of Interaction
Drug Name
Strong CYP3A4 inducer
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, rifabutin, 
rifampicin, mitotane, St. John's wort (Hypericum perforatum)
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s 
Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction 
Studies”
Table 6-4
Drugs with a known risk of Torsades de Pointes
TdP Risk
Generic Names
Known
amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, chloroquine, 
chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, clarithromycin, disopyramide, 
dofetilide, domperidone, donepezil, dronedarone, droperidol, erythromycin, escitalopram, 
flecainide, fluconazole, gatifloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, 
levomepromazine, levosulpiride, methadone, moxifloxacin, ondansetron, oxaliplatin, papaverine 
HCl (intra-coronary), pentamidine, pimozide, procainamide, propofol, quinidine, roxithromycin, 
sevoflurane, sotalol, sulpiride, sultopride, terlipressin, terodiline, thioridazine, vandetanib


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TdP Risk
Generic Names
Check crediblemeds.org/healthcare-providers/drug-list for the most updated list.
6.2.2.2
Spartalizumab: prohibited medication
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed except 
for the treatment of infusion reaction, irAEs, and for prophylaxis against imaging contrast dye 
allergy, standard pre-medication for chemotherapy or replacement-dose steroids in the setting 
of adrenal insufficiency (providing this is < 10 mg/day prednisone or equivalent), or transient 
exacerbations of other underlying diseases such as COPD requiring treatment. If systemic 
corticosteroids are required for the control of infusion reactions or irAEs, it must be tapered and 
be at non-immunosuppressive doses (< 10 mg/day of prednisone or equivalent) before the next 
administration of study treatment. If the dose of prednisone or equivalent cannot be reduced to 
< 10 mg/day before the administration of next dose of study treatment then spartalizumab and 
capmatinib must be discontinued (note: next dose of spartalizumab can be delayed up to 12 
weeks).
The use of live vaccines is not allowed through the whole duration of the study. Inactivated 
vaccines are allowed.
There are no prohibited therapies during the post-treatment follow-up period.
6.2.2.3
Docetaxel: prohibited medication
Please follow local guidelines as per standard of care and product labels.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis/sponsor to the investigative site) with a 
sequential subject number suffixed to it, so that each subject is numbered uniquely across the 
entire database. Upon signing the informed consent form (ICF), the subject is assigned to the 
next sequential Subject No. available.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the subject to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject. In case of re-screening a new Subject No. will be assigned 
to patient through the Clinical Data Management System interface and this new Subject No. 
will be provided to IRT for registration as re-screened patient. If the subject fails to be 
randomized or start treatment for any reason, the reason will be entered into the disposition 
page.
6.3.2
Treatment assignment, randomization
Prior to dosing, for all subjects who fulfill all inclusion/exclusion criteria, the investigator or 
his/her delegate will log on to the IRT system and confirm that the subject fulfills all the 


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inclusion/exclusion criteria by completing the key eligibility criteria checklist embedded in the 
system.
Part 1: Run-in
During the run-in part, approximately 15 subjects will be enrolled via IRT for treatment with 
capmatinib and spartalizumab combination.
Part 2: Randomized
During the randomized part, approximately 90 subjects will be randomized via IRT to one of 
two treatment arms (capmatinib plus spartalizumab [n=60] or docetaxel [n=30]) in a 2:1 ratio.
During the randomized part, the IRT will assign a randomization number to the subject, which 
will be used to link the subject to a treatment arm and will specify a unique medication number 
for the first package of study treatment to be dispensed to the subject. The randomization 
number will not be communicated to the investigator or his/her delegate. The randomization
numbers will be generated using the following procedure to ensure that treatment assignment 
is unbiased. A subject randomization list will be produced by the IRT provider using a validated 
system that automates the random assignment of subject numbers to randomization numbers. 
Random permuted blocks scheme will be used for this study. The randomization numbers are 
linked to the different treatment arms, which in turn are linked to medication numbers. A 
separate medication randomization list will be produced by or under the responsibility of 
Novartis Global Clinical Supplies using a validated system that automates the random 
assignment of medication numbers to medication packs containing each of the study treatments. 
Randomization will be stratified by the number of prior lines of therapy received. Please refer 
to Table 6-5 for the number of prior lines of therapy received.
During Part 1 and Part 2 of the study, the study treatment phase begins on Cycle 1, Day 1 with 
the first administration of capmatinib and spartalizumab combination or the first administration 
of docetaxel. Cycle 1 Day 1 should occur no later than 3 days after registration into IRT system.
Table 6-5
Number of prior lines of systemic therapy
Number of prior systemic therapies for 
eligibility and stratification factors
Definition
Treatment, which counts as chemotherapy for 
advanced/ metastatic disease
Platinum chemotherapy for stage IIIB/IV NSCLC
Adjuvant/ neoadjuvant platinum chemotherapy and 
progressed within 12 months of end of therapy.
Treatment, which doesn’t count as 
chemotherapy for advanced/ metastatic 
disease
Adjuvant/ neoadjuvant platinum chemotherapy and 
progressed > 12 months of end of therapy.
Eligible number of prior therapies
Eligible patients must have received one platinum 
chemotherapy AND one PD-(L)1 inhibitor
Enrolled as 2nd line population
Platinum based chemotherapy and PD-(L)1 inhibitor were 
received concurrently or there was no PD between 
chemotherapy and PD-(L)1 inhibitor (therefore counted as 
one line)
Enrolled as 3rd line population
Platinum based chemotherapy and PD-(L)1 inhibitor 
were received as sequencential therapies. There was a PD 
between chemotherapy and PD-(L)1 inhibitor


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6.4
Treatment blinding
Treatment assignment will be open to subjects, investigator staff, persons performing the 
assessments, and the Novartis representatives from the Clinical Trial Team.
6.5
Dose escalation and dose modification
No dose escalations are permitted.
6.5.1
The run-in review meeting
To assess the safety and tolerability of capmatinib and spartalizumab combination as well as 
preliminary efficacy prior to the randomized part of the study, the run-in part of the study will 
enroll approximately 15 subjects who will be treated with the capmatinib 400 mg (BID) and 
spartalizumab 400 mg intravenously (i.v.) once every 28 days.
Subjects will be considered evaluable for tolerability decision if the subject:

has received at least 1 infusion of spartalizumab and taken at least 50% of the planned 
dose of capmatinib in the first 56 days (8 weeks) of treatment and

has safety assessments for a minimum of 56 days (8 weeks) or has had a DLT during the 
first 8 weeks.
A review meeting will take place after all subjects have at least 24 weeks of follow-up. Decision 
on tolerability will be made by Investigators and Novartis study personnel. The decisions will 
be based on a synthesis of all relevant data available including safety information, DLTs, all 
CTCAE v5.0 ≥ Grade 2 toxicity data during the first 8 weeks (56 days) of the study treatment, 
pharmacokinetic data and preliminary efficacy data from evaluable subjects. The decision will 
be guided by the BLRM with EWOC principle evaluating the probability of DLT from all 
subjects enrolled in the run-in prior to opening the randomized phase. In particular, overall 
safety will be assessed in the context of the known safety data generated with the capmatinib 
and spartalizumab combination and will be used for decisions prior to opening the randomized 
phase.
6.5.1.1
Implementation of safety and tolerability decisions
To implement tolerability decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs) and the recommendations from the 
BLRM will be evaluated by the Investigators and Novartis study personnel (including the study 
physician and statistician) during a dose decision meeting by teleconference.
6.5.1.2
Implementation of dose escalation decisions
Not applicable.
6.5.1.3
Intra-Subject dose escalation
Intra-subject dose escalation is not permitted at any time.


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6.5.2
Definitions of dose limiting toxicities (DLTs)
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to 
disease, disease progression, inter-current illness, or concomitant medications that occurs 
during the first 56 days (8 weeks) of treatment with capmatinib and spartalizumab and meets 
any of the criteria included in Table 6-6. The National Cancer Institute Common Terminology 
Criteria for Adverse events (NCI-CTCAE) v5.0 will be used for all grading. For the purpose of 
tolerability decisions, DLTs will be considered and included in the BLRM.
The investigator must notify the sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities.
Criteria for defining dose limiting toxicities (DLTs)
Table 6-6
Criteria for defining dose limiting toxicities (DLTs)
TOXICITY
DLT CRITERIA
Blood and lymphatic 
system disorders
Anemia CTCAE Grade 4
Thrombocytopenia Grade 3 with clinically significant bleeding
Thrombocytopenia CTCAE grade 3 (for ≥7 consecutive days)
Thrombocytopenia Grade 4
Neutropenia Grade 3 (for ≥ 7 consecutive days)
Neutropenia Grade 4
Febrile neutropenia CTCAE Grade ≥ 3
Cardiac
Grade ≥ 3 or cardiac event that is symptomatic or requires medical intervention
Clinical signs of cardiac disease, such as unstable angina or myocardial 
infarction, or Grade ≥ 3 Troponin elevation
QTc interval prolonged Grade ≥ 3 (QTcF ≥ 501 ms) on at least two separate 
ECGs for > 7 consecutive days
Vascular 
disorders/Hypertension
Persistent hypertension CTCAE Grade 3 requiring more than one drug or more 
intensive therapy than previously administered.
Grade 4 Hypertension (any duration)
Gastrointestinal
Nausea and vomiting:
● CTCAE grade ≥3 > 48 hours despite standard anti-emetics
● CTCAE grade 4
Diarrhea:
● Recurrence of CTCAE grade 2 (despite anti-diarrheal treatment)
● CTCAE grade ≥ 3 >48 hours despite maximal anti-diarrheal treatment
● CTCAE grade 4
Skin and subcutaneous 
tissue
Rash / photosensitivity CTCAE Grade ≥ 3 for > 7 consecutive days despite skin 
toxicity treatment
Stevens-Johnson syndrome, toxic epidermal necrolysis and other serious or life-
threatening skin reactions.
Hyperglycemia
Hyperglycemia Grade 3 (FPG > 250 - 500mg/dL) for > 7 consecutive days despite 
anti-diabetic treatment Hyperglycemia Grade 4 (FPG > 500 mg/dL) 
Hyperglycemia leading to diabetic keto-acidosis, hospitalization for intravenous 
insulin infusion, or non-ketotic coma.
Infection
CTCAE grade 3 infection or fever in the absence of neutropenia if they persist > 5 
days.
CTCAE Grade 4 infection of any duration.
Pneumonitis (interstitial 
lung disease)
● CTCAE Grade 2 pneumonitis if it persists > 7 days despite treatment with 
corticosteroids.
● Grade 3-4 pneumonitis of any duration


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TOXICITY
DLT CRITERIA
Metabolism and nutrition 
disorders: Calcium-
phosphate heterostasis 
tCa x Pi increase
● tCa x Pi > 55 mg2/dL2 ≤ 70 mg2/dL2 for > 7 consecutive days
● tCa x Pi >70 mg2/dL2
Fatigue/Asthenia
● Fatigue/Asthenia CTCAE grade ≥ 3 and lasting > 7 consecutive days is a DLT
Immune-related toxicities 
(except pneumonitis)
● CTCAE Grade 3 immune-related toxicities that persist > 14 days with same 
severity despite treatment with corticosteroids.
● Immune-related toxicities CTCAE Grade 4 of any duration
Other Adverse Events
Other clinically significant toxicities, including a single event or multiple 
occurrences of the same event that lead to a dosing delay of > 7 days in cycles 1 
and 2, may be considered to be DLTs by the Investigators and Novartis, even if 
not CTCAE grade 3 or higher.
Investigations
Isolated total bilirubin* > 1.5 – 3.0 x ULN for > 7 days
Isolated total bilirubin* > 3.0 x ULN
Isolated AST or ALT* > 5.0 – 10.0 x ULN for subjects with baseline value ≤3 x 
ULN (>10.0-20.0 x ULN for subjects with liver metastases and baseline value 
>3.0-5.0 ULN) for >7 days
Isolated AST or ALT* > 10.0 ULN for subjects with baseline value ≤3 x ULN (> 
20.0 x ULN for subjects with liver metastases and baseline value >3.0-5.0 ULN)
For subjects with normal baseline AST and ALT and total bilirubin value:
AST or ALT >3.0xULN combined** with total bilirubin >2.0 x ULN without 
evidence of cholestasis***
OR
For subjects with abnormal baseline AST or ALT or total bilirubin value:
[AST or ALT>2x baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], 
whichever is lower, combined with [total bilirubin > 2 x baseline AND > 2.0 x ULN]
Serum lipase and/or serum amylase (asymptomatic) CTCAE Grade 3 > 7 
consecutive days
Serum lipase and/or serum amylase (asymptomatic) CTCAE Grade 4
Serum creatinine CTCAE Grade ≥ 3
Serum CK/CPK CTCAE Grade ≥ 3 for > 7 consecutive days
Serum CK/CPK CTCAE Grade 4
Symptomatic serum amylase or lipase elevation, requiring medical intervention.
*“Isolated total bilirubin” increase defined as: total bilirubin increase without ALT or AST increase; “isolated AST 
or ALT” increase defined as: AST or ALT increase without total bilirubin increase
**“Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold
***“Cholestasis” defined as: ALP elevation [>2.0 xULN and R value < 2] in subjects without bone metastasis, or 
elevation of ALP liver fraction in subjects 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)
6.5.3
Dose modifications
For subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow subjects to continue 
the study treatment.
There are no dose reductions allowed in this study for spartalizumab. Dose interruptions for 
spartalizumab are permitted per Section 6.5.3.1.
Dose reductions and interruptions are permitted for capmatinib per Section 6.5.3.1.


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Dose reductions and interruptions are permitted for docetaxel per the investigator's judgment 
and local guidelines. Please refer to Section 6.5.3.2.
Permanent treatment discontinuation is mandatory for specific events as indicated in 
Section 6.5.3.1 (capmatinib and spartalizumab subjects) and Section 6.5.3.2 (docetaxel 
subjects).
Overall, AEs are to be graded according to NCI-CTCAE v5.0 (http://ctep.cancer.gov). All dose 
reductions and interruptions and the reason for the dose reductions/interruptions must be 
documented in the eCRF.
6.5.3.1
Capmatinib/Spartalizumab dose modifications
Capmatinib dose reduction will follow the dose reduction steps described in Table 6-7. For each 
subject, a maximum of two dose level modifications is allowed after which the subject must be 
discontinued from treatment with capmatinib. The lowest dose allowed, 200 mg BID in tablets, 
is expected to be pharmacologically active, as the observed steady state plasma trough 
concentrations ([CINC280X1101], [CINC280X2202], n=6) were above the concentration 
associated with full MET inhibition in xenograft mice models (IC90, 120 nM total 
concentration).
Table 6-7
Dose reduction steps for capmatinib
Starting dose level - 0
Dose level - 1
Dose level - 2
capmatinib
400 mg BID
300 mg BID
200 mg BID
* Dose reduction should be based on the worst toxicity demonstrated at the last dose.
** Dose reduction below 200 mg is not allowed.
No changes in dose of spartalizumab are allowed.
Overall, subjects 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 this section. In general, study treatment must be permanently 
discontinued in case of:

Any life-threatening adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy)

Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to ≤ Grade 1

Inability to reduce the dose of steroids (for the management of irAE) to 10 mg/day or less 
of prednisone or equivalent (or as indicated in the tables below) within 12 weeks

Any severe or Grade 3 recurring treatment-related adverse reaction
The 12 weeks’ timeframe will begin from the time the irAE reaches a grade that leads to 
spartalizumab interruption. Investigators should refer to the latest [capmatinib Investigator’s 
Brochure] and [spartalizumab Investigator’s Brochure] for additional information regarding the 
background of capmatinib and spartalizumab and the management of other AEs or potential 
safety-related issues not specifically mentioned in the protocol.


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Identification and management requirement for AEs of potential immune-
mediated etiology (irAE)
Adverse events of special interest (AESI) include AEs of a potential immune-mediated etiology 
(irAE) that are associated with spartalizumab treatment. 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 (i.e. 
diarrhea/colitis), skin (i.e. rashes), liver (i.e. hepatitis), lung (i.e. pneumonitis), kidneys (i.e. 
nephritis) and endocrine systems (e.g. hypothyroidism, hyperthyroidism, type I diabetes, 
hypophysitis including hypopituitarism and adrenal insufficiency variety of endocrinopathies). 
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 epidermonecrolysis or Steven Johnson syndrome. Furthermore, complications in 
patients with bone marrow or solid organ transplant have been reported (e.g. organ rejection, 
severe graft-versus-host disease). 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 treatment discontinuation.
Serological, immunological and histological assessments should be performed as deemed 
appropriate by the investigator, to verify the potential immune-related nature of the AE, and 
exclude a neoplastic, infectious or metabolic origin of the AE.
Severe grade or persistent lower grade irAEs typically require interrupting or permanently 
discontinuing treatment and administration of systemic steroids, and sometimes other 
immunosuppressive medications (i.e. tumor necrosis factor alpha antagonists, mycophenolate 
or tacrolimus, etc.). Early recognition and work-up of irAEs and initiation of treatment are 
critical to reduce the risk of complications, since the majority of irAEs are reversible with the 
use of steroids and other immune suppressants. Some events like endocrinopathies may require 
life-long hormonal replacement. Tapering of steroids should not be too rapid to avoid recurrence 
or worsening of irAEs. The management of irAEs may further include initiation of antibiotics 
for prophylaxis against opportunistic infections.
Subjects should be instructed to return to the study site as soon as possible (instead of waiting 
for their next scheduled visit) if they experience symptoms consistent with an irAE. Patients 
who experience a new or worsening irAE should be contacted and/or evaluated by the study 
site more frequently.
Based on experience 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 regarding how to manage irAEs that may occur in subjects 
receiving spartalizumab. Dose modification requirements and AE management guidelines for 
the potential irAEs are provided in the following tables: haematological (Table 6-8), renal 


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(Table 6-9), hepatic (Table 6-10), metabolic (Table 6-11), cardiac (Table 6-12), gastrointestinal 
(Table 6-13), skin and subcutaneous tissue (Table 6-14), respiratory, thoracic and mediastinal 
(Table 6-15), endocrine (Table 6-16), general and administration site (Table 6-17), other 
potential immune-related adverse events (Table 6-18). Any Grade 4 irAE must result in 
permanent discontinuation of spartalizumab. In addition, guidance for management of 
spartalizumab-infusion reaction and cytokine release syndrome is provided in Table 6-18.
Investigators are encouraged to contact the Sponsor as needed to discuss cases that warrant 
separate discussion outside of the scope of the current instructions.
The dosing modification requirements are mandatory, however, the AE management guidelines 
are recommendations and can be modified according to the local practices.
Table 6-8
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Haematological Adverse 
Events
Hematological Adverse Events 
Grade (Worst Toxicity)
Dose Modification 
Recommended 
Clinical Management
Neutrophil Count Decreased (NCI-CTCAE v5.0)
Grade 1
(ANC < LLN - 1500/mm3; 
< LLN - 1.5 x 109/L)
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and schedule
● Treat per 
local/institutional 
guidelines
Grade 2
(ANC < 1500 - 1000/mm3; 
< 1.5 - 1.0 x 109/L)
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and schedule
● Treat per 
local/institutional 
guidelines
Grade 3
(ANC < 1000 - 500/mm3; 
< 1.0 - 0.5 x 109/L)
Mandatory: omit capmatinib and spartalizumab dose 
until resolved to ≤ Grade 2, then:
If resolved in ≤ 7 days, resume capmatinib and 
spartalizumab treatment at the same dose level and 
schedule
If resolved in > 7 days, then restart capmatinib at ↓ 1 
dose level and spartalizumab at the normal dose and 
schedule.
● Treat per 
local/institutional 
guidelines
Grade 4
(ANC < 500/mm3; < 0.5 x 
109/L)
Mandatory: omit capmatinib and spartalizumab dose 
until resolved to ≤ Grade 2, then:
If resolved in ≤ 7 days, resume capmatinib and 
spartalizumab treatment at the same dose level and 
schedule
If resolved in > 7 days, then restart capmatinib at ↓ 1 
dose level and spartalizumab at the normal dose level 
and schedule.
● Treat per 
local/institutional 
guidelines
Febrile Neutropenia
(ANC < 1000/mm3 (< 1.0 
x 109/L), fever > 38.3°C)
Mandatory: omit capmatinib and spartalizumab dose 
level until resolved to ≤ Grade 2, then:
If resolved in ≤ 7 days, then restart capmatinib at ↓ 1 
dose level and spartalizumab at the normal dose level 
and schedule.
If resolved in > 7 days, discontinue subject from all 
study drug treatments
● Treat per 
local/institutional 
guidelines
Platelet Count Decreased (Thrombocytopenia) (NCI-CTCAE v5.0)
Grade 1
(PLT < LLN - 75,000/mm3; 
< LLN - 75 x 109/L)
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and schedule
● Treat per 
local/institutional 
guidelines


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Hematological Adverse Events 
Grade (Worst Toxicity)
Dose Modification 
Recommended 
Clinical Management
Grade 2
(PLT < 75,000 -
50,000/mm3; < 75 - 50 x 
109/L)
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and schedule
● Treat per 
local/institutional 
guidelines
Grade 3
(PLT < 50,000 -
25,000/mm3; < 50 - 25 x 
109/L)
Mandatory: omit capmatinib and spartalizumab dose 
until resolved to ≤ Grade 2, then:
If resolved in ≤ 7 days, resume capmatinib and 
spartalizumab treatment at the same dose level and 
schedule
If resolved in > 7 days, then restart capmatinib at ↓ 1 
dose level and spartalizumab at the normal dose and 
schedule.
● Treat per 
local/institutional 
guidelines
Grade 4
(PLT < 25,000/mm3; < 25 
x 109/L)
Mandatory: omit capmatinib and spartalizumab dose 
until resolved to ≤ Grade 2, then:
If resolved in ≤ 7 days, restart capmatinib at ↓ 1 dose 
level and spartalizumab at the normal dose level and 
schedule.
If resolved in > 7 days, permanently discontinue 
subject from all study drug treatments
● Treat per 
local/institutional 
guidelines
Hemoglobin Decreased (Anemia) (NCI-CTCAE v5.0)
Grade 1
(Hgb < LLN - 10.0 g/dL; < 
LLN - 6.2 mmol/L; < LLN -
100 g/L)
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and schedule
● Treat per 
local/institutional 
guidelines
Grade 2
(Hgb < 10.0 - 8.0 g/dL; < 
6.2 – 4.9 mmol/L; < 100 -
80 g/L)
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and schedule
● Treat per 
local/institutional 
guidelines
Grade 3
(Hgb < 8.0 g/dL; < 4.9 
mmol/L; < 80 g/L)
Mandatory: omit capmatinib and spartalizumab dose 
until resolved to ≤ Grade 2, then:
If resolved in ≤ 7 days, resume capmatinib and 
spartalizumab treatment at the same dose level and 
schedule
If resolved in > 7 days, then restart capmatinib at ↓ 1 
dose level and spartalizumab at the normal dose level 
and schedule.
● Treat per 
local/institutional 
guidelines
Grade 4
(Life – threatening 
consequences, urgent 
intervention indicated)
Mandatory: omit capmatinib and spartalizumab dose 
until resolved to ≤ Grade 2, then:
If resolved in ≤ 7 days, resume capmatinib and 
spartalizumab treatment at the same dose level and 
schedule
If resolved in > 7 days, then restart capmatinib at ↓1 
dose level and spartalizumab at the normal dose level 
and schedule.
If toxicity recurs, permanently discontinue subject from 
all study drug treatments
● Treat per 
local/institutional 
guidelines
Autoimmune hemolytic 
anemia, hemolytic 
uremic syndrome, or
acquired hemophilia 
grade ≥ 3
Mandatory: permanently discontinue subject from all 
study drug treatments

● Consult with 
specialist

● Consider 
systemic 
corticosteroids and 
other therapies as 
appropriate (e.g. 
transfusion) per 


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Hematological Adverse Events 
Grade (Worst Toxicity)
Dose Modification 
Recommended 
Clinical Management
local institutional 
guidelines
All dose modifications should be based on the worst preceding toxicity.
Table 6-9
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Creatinine Increases
Renal Adverse Events 
Grade (Worst 
Toxicity)
Dose Modification 
Recommended Clinical Management
Creatinine Increased (NCI-CTCAE v5.0)
Grade 1
(> ULN - 1.5 x ULN)
Recommendation: maintain 
capmatinib and spartalizumab 
at normal dose level and 
schedule
1. Monitor creatinine weekly
2. If creatinine returns to baseline resume routine 
creatinine monitoring per protocol
3. Promote hydration
4. Consider cessation of nephrotoxic drugs
Grade 2
(> 1.5 - 3.0x 
baseline, >1.5-3.0 x 
ULN)
Mandatory: omit capmatinib 
and spartalizumab dose until 
resolved to ≤ Grade 1, then 
resume treatment at same dose 
level and schedule
1. Monitor creatinine every 2 to 3 days
2. Initiate 0.5 to 1 mg/kg/day prednisone or 
equivalents if other causes are ruled-out
3. If worsening or no improvement: 1 to 2 mg/kg/day 
prednisone or equivalents
4. Promote hydration and cessation of nephrotoxic 
drugs
5. Consult with specialist and consider renal biopsy
Rule-out other causes (e.g. fluids, medications, IV 
contrast)
If worsening or no improvement: 1 to 2 mg/kg/d 
prednisone or equivalents
Grade 3
(>3 x baseline, > 3.0 
- 6.0 x ULN)
AND
Grade 4(> 6.0 x 
ULN)
Mandatory:
Permanently discontinue 
subject from all study drug 
treatments
1. Monitor creatinine every 1 to 2 days
2. Start 1 to 2 mg/kg/day prednisone or equivalents.
Once event improves to Grade ≤1, slowly taper 
steroids over at least 4-6 weeks
3. Promote hydration and cessation of nephrotoxic 
drugs
4. Consult with specialist and consider renal biopsy
All dose modifications should be based on the worst preceding toxicity.
Table 6-10
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for liver laboratory alterations
Hepatic Adverse Events 
Grade (Worst 
Toxicity) 
Dose Modification 
Recommended Clinical Management
Blood Bilirubin Increased d (NCI-CTCAE v5.0)
Grade 1
(> 1.5 x ULN if 
baseline was 
normal; >1.0- 1.5 x 
ULN if baseline was 
abnormal)
Recommendation: maintain 
capmatinib and spartalizumab 
at normal dose level and 
schedule
● Monitor LFTs per protocol or more frequently if 
clinically indicated


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Hepatic Adverse Events 
Grade (Worst 
Toxicity) 
Dose Modification 
Recommended Clinical Management
Grade 2
(> 1.5 - 3.0 x ULN if 
baseline was 
normal; > 1.5 - 3.0 x 
ULN if baseline was 
abnormal)
Mandatory: omit capmatinib 
and spartalizumab dose until 
resolved to ≤ Grade 1, then 
restart capmatinib at ↓ 1 dose 
level and spartalizumab at the 
normal dose level and 
schedule.
● Frequent monitoring of LFTs, (every 2-3 days) 
until resolved to ≤ 1.5 x ULN
● Rule-out alternative causes (e.g. concomitant 
medications, infection, disease progression)
Grade 3
(> 3.0 - 10.0 x ULN if 
baseline was 
normal; > 3.0 - 10.0 
x ULN if baseline 
was abnormal)
Mandatory: permanently 
discontinue subject from all 
study drug treatments
● Frequent monitoring of LFTs, (every 2-3 days), 
until resolved to ≤ baseline. If resolved in > 7 days, 
after discontinuing the subject from capmatinib 
permanently, the subject should be monitored 
weekly (including LFTs), or more frequently if 
clinically indicated, until total bilirubin have resolved 
to baseline or stabilization over 4 weeks
Grade 4
(> 10.0 x ULN 
baseline was 
normal; > 10.0 x 
ULN baseline was 
abnormal)
Mandatory: permanently 
discontinue subject from all 
study drug treatments
● After permanently discontinuing the subject from 
study treatment, the subject should be monitored 
weekly (including LFTs), or more frequently if 
clinically indicated, until total bilirubin have resolved 
to baseline or stabilization over 4 weeks. See 
additional recommendation below for AST/ALT 
Grade 3/4.
Isolated AST or ALT Elevation (Alanine Aminotransferase Increased or Aspartate Aminotransferase 
Increased) (NCI-CTCAE v5.0)
Grade 1
(> 3.0 x ULN if 
baseline was 
normal; >1.5 – 3.0 x 
ULN if baseline was 
abnormal)
Recommendation: maintain 
capmatinib and spartalizumab 
at normal dose level and 
schedule
Treat per local/institutional guidelines
Grade 2
(> 3.0 -5.0 x ULN if 
baseline was 
normal;> 3.0- 5.0 x 
ULN if baseline was 
abnormal)
Mandatory: omit capmatinib 
and spartalizumab dose until 
resolved to ≤ Grade 1, then 
restart capmatinib at ↓ 1 dose 
level and spartalizumab at the 
normal dose level and 
schedule.
Patients with baseline grade 2 
AST/ALT value (>3.0-5.0 x 
ULN) may continue treatment
● For subjects with baseline value ≤ 3.0 x ULN: 
repeat LFTs as soon as possible, preferably within 
48-72 hours from awareness of the abnormal 
results; if abnormal lab values are confirmed upon 
the repeated test, then monitor LFTs weekly, or 
more frequently if clinically indicated, until resolved 
to ≤ 3.0 x ULN
● For subjects with baseline value > 3.0 - 5.0 x ULN: 
monitor LFTs per protocol or more frequently if 
clinically indicated


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Hepatic Adverse Events 
Grade (Worst 
Toxicity) 
Dose Modification 
Recommended Clinical Management
Grade 3
(> 5.0 - 20.0 x ULN if 
baseline was 
normal;> 5.0 - 20.0 x 
ULN if baseline was 
abnormal)
Mandatory: permanently 
discontinue subject from all 
study drug treatments
1. Monitor hepatic laboratory tests daily until 
returned to baseline values.
2.Consider viral serology i.e. hepatitis A/B/C, CMV.
3. Rule out other potential cause of liver injury such 
as conmeds or alcohol
4. Consult with hepatologist and perform liver biopsy 
to establish etiology of hepatic injury
5. If after 2-3 days liver assessment shows 
worsening of laboratory tests consider to initiate 
treatment with steroids prednisone 1-2 mg/kg/day or 
i.v. equivalents.
6. Add prophylactic antibiotics for opportunistic 
infections as appropriate
7. When symptoms/liver function tests improve to 
Grade ≤1, taper steroids over at least 4 weeks.
8. If serum transaminase levels or bilirubin do not 
decrease 48 hours after initiation of systemic 
steroids, oral mycophenolate mofetil 500 mg every 
12 hours may be given as per local treatment 
guidance.
Infliximab is not recommended due to its potential 
for hepatotoxicity
Grade 4
(> 20.0 x ULN if 
baseline was 
normal; > 20.0 x 
ULN if baseline was 
abnormal)
Mandatory: permanently 
discontinue subject from all 
study drug treatments
As for Grade 3 toxicity above.


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Hepatic Adverse Events 
Grade (Worst 
Toxicity) 
Dose Modification 
Recommended Clinical Management
Combined elevations of AST or ALT and Total Bilirubin a, c
Any Grade
For subjects with 
normal baseline ALT 
and AST and total 
bilirubin value:
AST or ALT > 3.0 x 
ULN combined with 
total bilirubin > 2.0 x 
ULN without 
evidence of 
cholestasis b
OR
For subjects with 
elevated baseline 
AST or ALT or total 
bilirubin value:
[AST or ALT > 2 x 
baseline AND > 3.0 
x ULN] OR [AST or 
ALT > 8.0 x ULN], 
whichever is lower, 
combined with total 
bilirubin > 2 x 
baseline AND > 2.0 
x ULN
Mandatory: permanently 
discontinue subject from all 
study drug treatmentsPatients 
with baseline grade 2 AST/ALT 
value (>3.0 5.0 ULN) may 
continue spartalizumab treatme
nts
After permanently discontinuing the subject from 
study treatment, repeat LFTs as soon as possible, 
preferably within 48 hours from awareness of the 
abnormal results, then with weekly monitoring of 
LFTs, or more frequently if clinically indicated, until 
AST, ALT, or bilirubin have resolved to baseline or 
stabilization over 4 weeks
All dose modifications should be based on the worst preceding toxicity. 
a “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST 
increase to the defined threshold
b “Cholestasis” defined as: ALP elevation (> 2.0 x ULN and R value (ALT/ALP in x ULN) < 2.0) in 
subjects without bone metastasis, or elevation of ALP liver fraction in subjects with bone metastasis
c If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please 
follow the instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and 
take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the 
situation when omit dose is needed for one parameter and discontinue treatment is required for 
another parameter). After all elevations resolve to the defined thresholds that allow treatment re-
initiation, re-start the treatment either at the same dose or at one dose lower if meeting a criterion for 
dose reduction
d If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as 
the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear 
and haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion of the 
investigator.


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Table 6-11
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Amylase and/or Lipase 
Elevation Related Adverse Events
Metabolic Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Symptomatic 
Amylase and/or 
Lipase elevation of 
any grade
Mandatory: permanently discontinue 
subject from all study drug treatments
● Test weekly (or more frequently) until 
≤ CTCAE Grade 2.
● A CT scan or equivalent imaging 
procedure to assess the pancreas, liver, 
and gallbladder is recommended within 
7 days of the first occurrence of any ≥ 
CTCAE Grade 3 result, to exclude 
disease progression or potential other 
liver or pancreatic disease.
Asymptomatic Amylase and/or Lipase elevation
Grade 1
(> ULN - 1.5 x ULN)
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and 
schedule
Treat per local/institutional guidelines
Grade 2
(> 1.5 - 2.0 x ULN)
Recommendation: interrupt study 
treatments until recovery to ≤ Grade 1 or 
baseline
Treat per local/institutional guidelines
Grade 3
(> 2.0 - 5.0 x ULN)
Mandatory: omit capmatinib and 
spartalizumab dose until resolved to ≤ 
Grade 1, then:
If resolved in ≤14 days, resume capmatinib 
and spartalizumab treatment at the same 
dose level and schedule
If resolved in >14 days, then restart 
capmatinib at ↓ 1 dose level and 
spartalizumab at the normal dose level and 
schedule.
If toxicity recurs permanently discontinue 
subject from all study drug treatments
Treat per local/institutional guidelines
Grade 4
(> 5.0 x ULN)
Mandatory: permanently discontinue 
subject from all study drug treatments
Treat per local/institutional guidelines
All dose modifications should be based on the worst preceding toxicity.
Table 6-12
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Cardiac Related Adverse 
Events
Cardiac Related Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Fridericia QT correction formula (QTcF) interval prolonged (NCI-CTCAE v5.0)
Grade 1
(QTcF 450-480 ms)
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and 
schedule
Treat per local/institutional guidelines
Grade 2
(QTcF 481-500 ms)
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and 
schedule
Treat per local/institutional guidelines


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Cardiac Related Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Grade 3
(QTcF ≥ 501 ms on 
at least two separate 
ECGs)
Mandatory: omit capmatinib and 
spartalizumab dose until resolved to ≤ 
Grade 2, then:
If resolved in ≤7 days, resume capmatinib 
and spartalizumab treatment at the same 
dose level and schedule
If resolved in >7 days, then restart 
capmatinib at ↓ 1 dose level and 
spartalizumab at the normal dose level and 
schedule.
If toxicity recurs permanently discontinue 
subject from all study drug treatments
● When QTcF ≥ 501 ms (Grade 3), 
perform the following: 
● Request an immediate manual 
read of the ECG.
● Perform an analysis of serum 
potassium, calcium, phosphorus, and 
magnesium, and if below lower limit of 
normal, correct with supplements to 
within normal limits.
● Review concomitant medication 
usage for the potential to inhibit 
CYP3A4/5 (Table 6-2) and/or to prolong 
the QT-interval (Table 6-4).
● Check compliance with correct 
dose and administration of capmatinib.
● Perform a repeat ECG within one 
hour of the first QTcF of ≥501 ms.
● If QTcF remains ≥ 501 ms, repeat 
ECG as clinically indicated, but at least 
once daily until the QTcF returns to < 
501 ms.
● Repeat ECGs 7 days and 14 days 
(and then every 21 days) after dose 
resumption for all subjects who had 
therapy interrupted due to QTcF ≥ 501 
ms.
● If QTcF of ≥ 501 ms recurs, repeat 
ECGs as described above.
Notes:
The investigator should contact the 
Novartis Medical Lead or designee 
regarding any questions that arise if a 
subject with QTcF prolongation should 
be maintained on study.
If the ECG report shows a QTcF ≥ 501 
msec (not previously documented on 
the site machine), contact the subject 
and instruct him/her to suspend 
capmatinib and return to repeat the 
ECG as soon as possible. The ECG 
reader should be called for a manual 
read of the repeat ECG immediately, 
and the above guidance followed.
Grade 4
(QTcF ≥ 501 or > 60 
ms change from 
baseline and 
Torsades de pointes 
or polymorphic 
ventricular 
tachycardia or 
signs/symptoms of 
serious arrhythmia)
Mandatory: permanently discontinue 
subject from all study drug treatments
As for Grade 3 toxicity above


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Oncology Clinical Trial Protocol (Version No. 00)
Protocol No. CINC280D2201
Cardiac Related Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Myocarditis grade 
≥2 or other cardiac 
event grade ≥3
Mandatory: permanently discontinue 
subject from all study drug treatments
1. Initiate systemic corticosteroids 
(prednisone or equivalent) at a dose of 
1-2 mg/kg QD
2. Consult with cardiologist 
hospitalization as indicated
All dose modifications should be based on the worst preceding toxicity.
Table 6-13
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Gastrointestinal Adverse 
Events
Gastrointestinal Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Pancreatitis
Grade 2
Recommendation:
see Table 6-11
● Evaluate for pancreatitis (clinical 
assessment, abdominal imaging and/or 
MRCP as appropriate) PDR001 may be 
continued in case of asymptomatic, isolated 
enzyme elevations without evidence for 
pancreatitis
Treat per local/institutional guidelines
Grade ≥3
Mandatory: permanently discontinue 
subject from all study drug treatments
Treat per local/institutional guidelines
Diarrhea and/or Colitis a
Grade 1
(despite appropriate 
anti-diarrheal 
medication)
Recommendation: maintain 
capmatinib and spartalizumab at 
normal dose level and schedule
Symptomatic treatment (loperamide, 
hydration, diet)
● Investigate potential concomitant 
medication, food or comorbidity driven 
causes of diarrhea (including infectious 
causes) and remedy for these causes if 
possible (e.g. discontinuation of concomitant 
medication, dietary modification, treatment of 
comorbidity).
● The subject should be monitored for signs 
of dehydration and instructed to take 
preventive measures against dehydration as 
soon as diarrhea occurs. Antidiarrheal 
medication must be initiated at the first sign 
of abdominal cramping, loose stools or overt 
diarrhea. Concomitant medication for the 
treatment of diarrhea should follow local 
practice and the investigator’s best judgment 
and may follow the "recommended guidelines 
for the treatment of cancer treatment-induced 
diarrhea” (Benson et al 2004).


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Oncology Clinical Trial Protocol (Version No. 00)
Protocol No. CINC280D2201
Gastrointestinal Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Pancreatitis
Grade 2
(despite maximal 
anti-diarrheal 
medication)
Mandatory:
1st occurrence:
Omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 1, then 
resume treatment at same dose level 
and schedule
2nd occurrence:
If toxicity recurs, omit capmatinib and 
spartalizumab dose until resolved to ≤ 
Grade 1, then resume capmatinib at ↓ 
1 dose level and spartalizumab at the 
normal dose level and schedule.
1. Consult with GI specialist
2. Stool evaluation, imaging and endoscopy 
as clinically indicated
3. Symptomatic treatment (loperamid, 
hydration, diet)
4. 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.
5. Slowly taper steroids once symptoms 
improve to Grade 1 (i.e. over 4-6 weeks) as 
per Section 6.5.3.1.1
Grade 3
(despite appropriate 
anti-diarrheal 
medication)
Mandatory:
1st occurrence: Omit capmatinib and 
spartalizumab dose until resolved to ≤ 
Grade 1, then resume capmatinib at ↓ 
1 dose level and spartalizumab at the 
normal dose level and schedule.
2nd occurrence: permanently 
discontinue subject from all study drug 
treatments
● 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 initial 
treatment with IV steroids (1 to 2 mg/kg/d 
of methylprednisolone or equivalent)
● Consider antibiotics as appropriate
● 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: Life-
threatening 
consequences; 
urgent intervention 
indicated
Mandatory: permanently discontinue 
subject from all study drug treatments
Urgent hospitalization, supportive care and 
specialist consultation as outlined above in 
Grade 3
Vomiting
Grade 1 (despite 
appropriate anti-
emetics)
Recommendation: maintain 
capmatinib and spartalizumab at 
normal dose level and schedule
Individualized supportive and anti-emetic 
treatment should be initiated, as appropriate, 
at the first signs and/or symptoms of these 
AEs. In subjects with vomiting, the subject 
should be monitored for signs of dehydration 
and instructed to take preventive measures 
against dehydration.
Concomitant medication for the treatment of 
nausea and/or vomiting should follow local 
practice and the investigator`s best 
judgement.


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Oncology Clinical Trial Protocol (Version No. 00)
Protocol No. CINC280D2201
Gastrointestinal Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Pancreatitis
Grade 2 (despite 
appropriate anti-
emetics)
Mandatory:
1st occurrence:
Omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 1, then 
resume treatment at same dose level 
and schedule
2nd occurrence:
If toxicity recurs > Grade 2 omit 
capmatinib and spartalizumab dose 
until resolved to ≤ Grade 1, then 
resume capmatinib at ↓ 1 dose level 
and spartalizumab at the normal dose 
level and schedule.
As for Grade 1 toxicity above
Grade 3 (despite 
appropriate anti-
emetics)
Mandatory:
1st occurrence:
Omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 1, then 
resume treatment at same dose level 
and schedule
2nd occurrence:
If toxicity recurs > Grade 2 omit 
capmatinib and spartalizumab dose 
until resolved to ≤ Grade 1, then 
resume capmatinib at ↓ 1 dose level 
and spartalizumab at the normal dose 
level and schedule.
Treat per local/institutional guidelines
Grade 4 (despite 
appropriate anti-
emetics)
Mandatory:
1st occurrence:
Omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 1, then 
resume treatment at same dose level 
and schedule.
2nd occurrence:
If toxicity recurs > Grade 2 omit 
capmatinib and spartalizumab dose 
until resolved to ≤ Grade 1, then 
resume capmatinib at ↓ 1 dose level 
and spartalizumab at the normal dose 
level and schedule.
Treat per local/institutional guidelines
Nausea
Grade 1 or 2 
(despite appropriate 
anti-emetics)
Recommendation: maintain 
capmatinib and spartalizumab at 
normal dose level and schedule
Treat per local/institutional guidelines


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Oncology Clinical Trial Protocol (Version No. 00)
Protocol No. CINC280D2201
Gastrointestinal Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Pancreatitis
Grade 3 (despite 
appropriate anti-
emetics)
Mandatory:
1st occurrence
Omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 1, then 
resume treatment at same dose level 
and schedule
2nd occurrence:
If toxicity recurs > Grade 2 omit 
capmatinib and spartalizumab dose 
until resolved to ≤ grade 1, then 
resume capmatinib at ↓ 1 dose level 
and spartalizumab at the normal dose 
level and schedule.
Treat per local/institutional guidelines
All dose modifications should be based on the worst preceding toxicity. 
a Antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or 
overt diarrhea
● Loperamide: initially 4 mg, followed by 2 mg every four hours or after every unformed stool; 
maximum 16 mg/day. Continue until diarrhea free for 12 hours;
● Diarrhea > 24 hours: loperamide 2 mg every two hours; maximum 16 mg/day. Consider adding oral 
antibiotics.
● Diarrhea > 48 hours: loperamide 2 mg every two hours; maximum 16 mg/day. Consider other 
second-line therapies for diarrhea (e.g: octreotide, oral diphenoxylate) and oral antibiotics
Table 6-14
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Skin and Subcutaneous 
Tissue Adverse Events
Skin and Subcutaneous Tissue Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Rash/Photosensitivity
During the whole duration of treatment with capmatinib, the subject is recommended to use precautionary 
measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing and avoid sunbathing or 
using a solarium intensively).
Grade 1
Rash covering < 
10% Body Surface 
Area (BSA)
Recommendation: maintain 
capmatinib and spartalizumab at 
normal dose level and schedule
1. Monitor weekly
2. Initiate prophylactic and symptomatic 
treatment measures.
3. Consider use of antihistamines and /or 
topical corticosteroids or urea containing 
creams in combination with oral antipruritics 
or moderate strength topical steroid 
(hydrocortisone 2.5% cream or fluticasone 
propionate 0.5% cream)
4. Reassess after 2 weeks.


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Protocol No. CINC280D2201
Skin and Subcutaneous Tissue Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Grade 2
Rash covering 10-
30% of BSA
Recommendation: consider dose 
interruption until tolerable or recovery 
to Grade ≤1 or baseline; once 
recovered resume treatment at the 
same dose and schedule
Mandatory: in case of bullous 
dermatitis, acute generalized 
exanthematous pustulosis or Drug 
Rash with Eosinophilia and Systemic 
Symptoms, interrupt capmatinib and 
spartalizumab until recovery to Grade 
≤1 or baseline.
1. Monitor weekly
2. Consider to initiate 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
3. If symptoms persist or recur consider skin 
biopsy.
Grade 3
Rash covering more 
than 30% of BSA, 
despite skin toxicity 
therapy
Other severe 
cutaneous adverse 
reactions
Bullous dermatitis
Mandatory:
Omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 1, then, 
if resolved in ≤7 days resume 
treatment at same dose level and 
schedule.
If resolved in > 7 days (despite 
appropriate skin toxicity therapy), then 
discontinue subject from all study drug 
treatments
For patients with severe cutaneous 
adverse reaction or bullous dermatitis, 
risk/benefit before resuming treatment 
should be carefully considered
1. Monitor daily
2. Consult with dermatologist and consider 
skin biopsy.
3. Initiate systemic steroids (1 mg/kg/d 
prednisone or IV equivalent); consider 
increasing if no improvement
4. High-potency topical steroids
5. Topical emollients, oral antihistamines as 
indicated
6. Consider GABA agonists or aprepitant in 
case of severe pruritus
Grade 4
Life-threatening
Mandatory: permanently discontinue 
subject from all study drug treatments
Urgent dermatologic consultation and 
additional measures as per local guidelines
Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis
Mandatory: permanently discontinue 
subject from all study drug treatments
Hospitalization and urgent dermatology 
consultation
Institute supportive care immediately as per 
local/institutional guidelines
All dose modifications should be based on the worst preceding toxicity.
Table 6-15
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Respiratory, Thoracic and 
Mediastinal Adverse Events
Respiratory, Thoracic and Mediastinal Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
ILD and 
pneumonitis a
Mandatory: interrupt capmatinib and 
spartalizumab during diagnostic work 
up for ILD/ pneumonitis.
Subjects on combination therapy with 
capmatinib and spartalizumab should be 
monitored for pulmonary symptoms indicative 
of ILD/pneumonitis.
In addition, withhold capmatinib and 
spartalizumab for acute onset of new or 
progressive unexplained pulmonary symptoms, 
such as dyspnea, cough and fever and during 
diagnostic workup for ILD/pneumonitis to 
exclude alternative causes such as, but not 
limited to infections, lymphangitic 
carcinomatosis, cardiogenic edema, or 
pulmonary hemorrhage.


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Oncology Clinical Trial Protocol (Version No. 00)
Protocol No. CINC280D2201
Respiratory, Thoracic and Mediastinal Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Grade 1
Radiographic 
changes only-
asymptomatic
Mandatory: interrupt capmatinib and 
spartalizumab during diagnostic work 
up for ILD/ pneumonitis.
In presence of a diagnosis of 
ILD/pneumonitis after diagnostic 
workup, it is mandatory to 
permanently discontinue capmatinib 
and spartalizumab.
Only in the absence of a diagnosis of 
ILD/pneumonitis, capmatinib and 
spartalizumab may be restarted at 
the same dose level and schedule.
2nd occurrence
If it recurs after resumption of study 
drug it is mandatory to permanently 
discontinue both study drugs.
1. Exclude infections or other etiologies
2. CT scan (high-resolution with lung windows) 
recommended, with serial imaging to monitor 
for resolution or progression- re-image at least 
every 3 weeks
3. Monitor for symptoms every 2-3 days
4. Clinical evaluation and laboratory work-up 
for infection
5. Monitoring of oxygenation via pulse oximetry 
recommended
6. Consultation with pulmonologist 
recommended
Grade 2
Symptomatic; 
medical intervention 
indicated; limiting 
instrumental Activity 
daily living (ADL)
Mandatory: interrupt capmatinib and 
spartalizumab during diagnostic work 
up for ILD/pneumonitis.
In presence of a diagnosis of 
ILD/pneumonitis after diagnostic 
workup, it is mandatory to 
permanently discontinue capmatinib 
and spartalizumab.
Only in the absence of a diagnosis of 
ILD/pneumonitis, capmatinib and 
spartalizumab may be restarted at 
the same dose level and schedule
2nd occurrence
If it recurs after resumption of study 
drug it is mandatory to permanently 
discontinue both study drugs.
1. Exclude infections or other etiologies
2. CT scan (high-resolution with lung windows)
3. Monitor symptoms daily, consider 
hospitalization
4. Clinical evaluation and laboratory work up 
for infection
5. Consult pulmonologist
6. Pulmonary function tests b - if normal at 
baseline, repeat every 8 weeks
7. Bronchoscopy d with biopsy and/or BAL 
recommended
8. Symptomatic therapy including 
corticosteroids c if clinically indicated (1 to 2 
mg/kg/day prednisone or equivalent as 
clinically indicated).
Grade 3 or 4
Severe symptoms; 
limiting self care 
ADL; oxygen 
indicated or life-
threatening 
respiratory 
compromise; urgent 
intervention 
indicated (e.g., 
tracheotomy or 
intubation)
Mandatory: permanently discontinue 
subject from all study drug 
treatments
1. CT scan (high-resolution with lung windows)
2. Clinical evaluation and laboratory work-up 
for infection
3. Commence oxygen therapy
4. Consult pulmonologist
5. Pulmonary function tests b -if < normal, 
repeat every 8 weeks until ≥ normal
6. Bronchoscopy d with biopsy and/or BAL if 
possible
7. Treat with i.v. steroids c (methylprednisolone 
125 mg) as indicated. When symptoms 
improve to ≤ Grade 1, a high dose oral steroid 
(prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours).
8. If i.v. steroids followed by high dose oral 
steroids do not reduce initial symptoms within 
48 to 72 hours, consider non-corticosteroid 
immunosuppressive medication


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All dose modifications should be based on the worst preceding toxicity. 
a Note: except if the subject is grade 2 at baseline in which case: it is ≥ CTCAE grade 3. 
b Pulmonary function tests to include: diffusing capacity corrected for hemoglobin (DLCO); spirometry; 
resting oxygen saturation. Guideline for significant deterioration in lung function: Decrease in 
spirometry and/or DLCO of 30% and/or O2 saturation ≤ 88% at rest on room air. 
c Duration and dose of course of corticosteroids will vary according to circumstances but should be as 
limited as possible. Consider tapering dosage at end. 
d If bronchoscopy is performed, bronchoalveolar lavage (BAL) should be done where possible to 
exclude alveolar hemorrhage, opportunistic infections, cell count + determination lymphocyte CD4/8 
count where possible.
Table 6-16
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Endocrine Adverse Events
Endocrine Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Grade 1
Asymptomatic , 
intervention not 
indicated (e.g. 
hyperthyroidism or 
hypothyroidism)
Recommendation: maintain 
capmatinib and spartalizumab at 
normal dose level and schedule
1. If TSH <0.5x LLN, or TSH >2x ULN, or 
consistently out of range in two subsequent 
measurements, check free T4 at subsequent 
cycles as clinically indicated
2. Consider endocrinologist consultation.
3. If hypophysitis is suspected, consider 
pituitary gland imaging (MRIs with gadolinium 
and sellar cuts); evaluate hormone levels as 
clinically indicated
4. Repeat labs in 1 to 3 weeks/MRI in 1 
month if laboratory abnormalities persist but 
normal lab/pituitary scan


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Oncology Clinical Trial Protocol (Version No. 00)
Protocol No. CINC280D2201
Endocrine Adverse Events
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management
Grade 2 or 3
Symptomatic 
endocrinopathy 
(e.g., hypophysitis, 
adrenal insufficiency, 
hypothyroidism, 
hyperthyroidism)
Mandatory: interrupt capmatinib and 
spartalizumab until diagnosis 
established and/or recovery to mild or 
no symptoms and controlled with 
hormone replacement therapy, then 
restart capmatinib and spartalizumab 
at the normal dose level and schedule.
Recommended: hypothyroidism may 
be managed with replacement therapy 
without treatment interruption (unless 
life-threatening)
Mandatory: permanently discontinue 
subject from all study treatments for 
life-threatening endocrinotherapies 
(i.e. hyperthyroidism, adrenal 
insufficiency, hypophysitis) or recurring 
severe/life-threatening events not 
controlled by hormone replacement 
therapy.
1. Endocrine laboratory panel (TSH, T4, 
ACTH, FSH, LH, Prolactin, serum cortisol, 
aldosterone) and imaging (e.g. brain MRI) as 
clinically indicated
2. Consider endocrinologist consultation
3. If hypophysitis is considered, pituitary 
gland imaging should be considered (MRIs 
with gadolinium and selective cuts of the 
pituitary can show enlargement or 
heterogeneity and confirm the diagnosis)
4. Repeat labs in 1 to 3 weeks, MRI in 1 
month if laboratory abnormalities persist but 
normal lab/pituitary scan
5. Rule out infection/sepsis and other 
alternative causes with appropriate cultures 
and imaging
6. Treat with an initial dose of 
methylprednisolone 1 to 2 mg/kg 
intravenously followed by oral prednisone 1 
to 2 mg/kg per day in case of severe 
hypophysitis or thyrotoxicosis.
7. Consider beta-blocker in case of severe 
hyper-thyroidism
8. Replacement of appropriate hormones 
may be required as the steroid dose is 
tapered
9. Hypophysitis with clinically significant 
adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities 
(such as hyponatremia and hyperkalemia) 
constitutes adrenal crisis
10. Consider hospitalization (e.g. in case of 
severe adrenal insufficiency/crisis), fluid 
replacement, and other supportive measures 
as clinically indicated
Autoimmune 
diabetes
(Grade 3 or 
symptomatic 
hyperglycemia)
Autoimmune 
diabetes
(Grade 4 
hyperglycemia or 
life-threatening 
complications)
Mandatory:
Omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 1 or 
baseline, then resume treatment at 
same dose level and schedule.
2nd occurrence: in case of recurring 
severe/life-threatening events not 
controlled by anti-glycemic therapy, 
permanently discontinue subject from 
all study drug treatment
1. Initiate anti-glycemic therapy (i.e. insulin) 
as medically indicated
2. Monitor glucose levels regularly until 
metabolic control is achieved
3. Consider endocrinology consultation
4. Evaluate for ketoacidosis as medically 
indicated
5. Consider hospitalization (e.g. in case of 
ketoacidosis)
All dose modifications should be based on the worst preceding toxicity.


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Table 6-17
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for General and Administration 
Site Adverse Events
General and Administration Site Adverse Events
Grade
Dose Modification
Recommended Clinical 
Management
Fatigue/ Asthenia
Grade 1 or 2
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and schedule
Treat per local/institutional 
guidelines
Grade 3
Mandatory: omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 1, then:
If resolved in ≤7 days, resume capmatinib and 
spartalizumab treatment at the same dose level 
and schedule
If resolved in >7 days, then restart capmatinib at 
↓ 1 dose level and spartalizumab at the normal 
dose level and schedule.
Treat per local/institutional 
guidelines
Peripheral edema
Grade 1 or 2
Recommendation: maintain capmatinib and 
spartalizumab at normal dose level and schedule
Consider conservative measures 
such as leg elevation, compression 
stockings and dietary salt 
modification as clinically indicated
Grade 3
Mandatory: omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 1 or baseline, 
then resume treatment at same dose level and 
schedule.
Intensify as above and treat per 
local/institutional guidelines
Grade 4
Mandatory: permanently discontinue subject 
from all study drug treatments
Intensify as above and treat per 
local/institutional guidelines
Other adverse events
Grade 1 or 2
Recommendation:
Continue capmatinib and spartalizumab at 
normal dose level and schedule
For any intolerable Grade 2 (e.g.: limiting 
instrumental ADL), consider omitting the dose 
until resolved to ≤ grade 1, then↓ capmatinib 1 
dose level and continue spartalizumab at normal 
dose level and schedule
Treat per local/institutional 
guidelines
Grade 3
Mandatory: omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 2, then resume 
treatment at same dose level and schedule.
Treat per local/institutional 
guidelines
Grade 4
Mandatory: permanently discontinue subject 
from all study drug treatments
Treat per local/institutional 
guidelines
All dose modifications should be based on the worst preceding toxicity.
Table 6-18
Dose Modifications of Capmatinib and Spartalizumab and 
Recommended Clinical Management for Other Potential Immune-
Related Adverse Events of Special Interest including Cytokine 
Release Syndrome
Other Potential Immune-Related Adverse Events (e.g. Autoimmune neuropathy, demyelinating 
polyneuropathy, Guillain Barre, Myasthenia Gravis-like syndrome, encephalitis, non-infectious 
myocarditis, pericarditis, pancreatitis, grade 3 fatigue with rapid onset in absence of disease 
progression, etc.)
Grade (Worst 
Toxicity)
Dose Modification
Recommended Clinical Management


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Grade 1 (Mild, 
asymptomatic)
Recommendation: maintain 
capmatinib and spartalizumab at 
normal dose levels and schedules
Treat per local/institutional guidelines
Grade 2
Mandatory: omit capmatinib and 
spartalizumab dose until resolved to ≤ 
Grade 1 or baseline, then resume 
treatment at same dose level and 
schedule.
1. Ensure adequate evaluation to confirm 
etiology or exclude other causes
2. Provide symptomatic treatment
3. Systemic corticosteroids may be indicated
4. Consider biopsy for confirmation of 
diagnosis
5. A specialist should be consulted
Grade 3
Mandatory:
Omit capmatinib and spartalizumab 
dose until resolved to ≤ Grade 1 or 
baseline May restart treatment at the 
same dose and schedule taking into 
account the risks and benefits;
2nd occurrence:
If toxicity recurs > Grade 2 
permanently discontinue subject from 
all study drug treatments
1. Ensure adequate evaluation to confirm 
etiology or exclude other causes
2. Provide symptomatic treatment
3. Initiate systemic corticosteroids 
(prednisone at a dose of 1-2 mg/kg/d or 
equivalent) and other therapies as 
appropriate
4. Consider biopsy for confirmation of 
diagnosis
5. A specialist should be consulted
Grade 4
Mandatory: permanently discontinue 
subject from all study drug treatments
1. Hospitalization and consult with specialist
2. Initiate systemic corticosteroids 
(prednisone a dose of 1-2 mg/kg/d or 
equivalent) and other therapies as 
appropriate
Encephalitis or aseptic meningitis 
Any Grade
Mandatory: permanently discontinue 
subject from all study drug treatments
1. Rule out infectious or other causes of 
moderate to severe neurologic deterioration
2. Consult with specialist.
3. If other etiologies are ruled out, administer 
corticosteroids at a dose of 1 to 2 mg/kg/day 
prednisone equivalents.
Guillain-Barre 
Severe peripheral or autonomic neuropathy, or transverse myelitis
Any Grade
Mandatory: permanently discontinue 
subject from all study drug treatments
1. Rule out infectious or other causes of 
moderate to severe neurologic deterioration, 
and consult with specialist.
2. If other etiologies are ruled out, administer 
corticosteroids at a dose of 1 to 2 mg/kg/day 
prednisone equivalents
Myasthenia gravis
Grade 2
Mandatory: omit capmatinib and 
spartalizumab dose until resolved to 
≤Grade 1 or baseline, then resume 
treatment at same dose level and 
schedule.
1. Consult with specialist
2. Consider pyridostigmine and systemic 
corticosteroids (prednisone or equivalent) at 
a dose of 1-2 mg/kg/d; other therapies as 
appropriate (e.g. i.v. immunoglobulin)
3. Hospitalization in case of severe cases
Grade 3 and 4
Mandatory: permanently discontinue 
subject from all study drug treatments
As Grade 2 toxicity above
Ocular events
Grade 2
Mandatory: omit capmatinib and 
spartalizumab dose until resolved to 
≤Grade 1 or baseline, then resume 
treatment at same dose level and 
schedule.
Consult with ophthalmologist
Grade 3 and 4
Mandatory: permanently discontinue 
subject from all study drug treatments
As Grade 2 toxicity above


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Infusion Related Reactions
Grade 1
Recommendation: maintain 
spartalizumab at normal dose level 
and schedule.
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
Consider slowing infusion rate until recovery 
of symptoms
Grade 2
Mandatory: Permanently discontinue 
of spartalizumab in case of recurring 
infusion related reaction despite 
adequate premedication and 
prolonged/slow infusion
1. Stop Infusion
2. Additional appropriate medical therapy as 
per local institutional guidelines may include 
but is not limited to:
● i.v. fluids
● Antihistamines
● NSAIDS
● Acetaminophen
● Narcotics
● Oxygen and corticosteroids as 
indicated
3. 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.
4. Premedicate patient ~ 1.5h prior to next 
infusion of spartalizumab with:
● Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
● Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic).
● Or as per local institutional guidelines
Grade 3 or 4
Mandatory: permanently discontinue 
subject from all study drug treatments
1. Stop Infusion
2. Additional medical therapy as per local 
institutional guidelines that may include:
● IV fluids
● Antihistamines
● NSAIDS, acetaminophen
● Narcotics
● Oxygen
● Corticosteroids
● Epinephrine
3. Close monitoring of vital signs, pulse 
oximetry and ECG as medically indicated 
until the patient is deemed medically stable
4. Hospitalization may be indicated.
All dose modifications should be based on the worst preceding toxicity.
6.5.3.1.1 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.


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6.5.3.2
Docetaxel dose modifications
Every attempt should be made to maintain the treatment dosing cycle schedule of every 21 days. 
For subjects who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted per the local approved label in order to keep the subject on treatment. For 
toxicities outlined below, docetaxel dose reduction will follow the local guidelines and 
approved product label. For each subject, a maximum of two dose modifications is allowed, 
after which the subject should be discontinued from treatment with docetaxel. If a subject 
misses more than two cycles of treatment, the subject should be discontinued from the study. 
However, if the Investigator and the Sponsor conclude that a subject, who has experienced a 
treatment interruption more than two cycles, could benefit from additional treatment, 
continuation may be allowed. 
According to the manufacturer’s label:
A new cycle of docetaxel will NOT be initiated if:

Bilirubin > ULN, or

AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN or

Neutrophils < 1.5 x 109/L or

Platelets < 100 x 109/L.
Subjects who are dosed initially at 75 mg/m2 and who experience any of the following should 
have treatment withheld until resolution of the toxicity and then resume at the reduced dose as 
per Table 6-18:

Febrile neutropenia,

Neutrophils < 500 cells/mm3 for more than one week,

Severe or cumulative cutaneous reactions,

Other Grade 3 or 4 non-hematological toxicities.
Subjects who develop ≥ Grade 3 peripheral neuropathy should have docetaxel treatment 
discontinued entirely.
Dose changes must be recorded on the study treatment eCRF.
Table 6-19
Criteria for interruption and re-initiation of docetaxel treatment
Worst toxicity (CTCAE v5.0 Grade)
Dose Modifications for Docetaxel
HEMATOLOGICAL – Neutropenia (ANC)
Nadir ANC <500/mm3 and nadir platelets ≥ 
50,000/mm3.
Withhold until ANC is ≥ 1500 cells/mm3 and platelet count is ≥ 
100,000 cells/mm3, then resume at 75% of previous dose
Nadir platelets <50,000/mm3 without bleeding 
regardless of nadir ANC
Withhold until ANC is ≥ 1500 cells/mm3 and platelet count is ≥ 
100,000 cells/mm3, then resume at 75% of previous dose
Nadir platelets <50,000/mm3 with bleeding, 
regardless of nadir ANC
Withhold until ANC is ≥ 1500 cells/mm3 and platelet count is ≥ 
100,000 cells/mm3, then resume at 50% of previous dose
NONHEMATOLOGICAL (excluding neurotoxicity)
Any Grade 3 or 4 toxicities except mucositis
Withhold until resolution to ≤ the pre-therapy value, then 
resume at 75% of previous dose
Any diarrhea requiring hospitalization 
(irrespective of Grade) or Grade 3 or 4 
diarrhea
Withhold until resolution to ≤ to the pre-therapy value, then 
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Grade 3 or 4 mucositis
Withhold until resolution to ≤ to the pre-therapy value, then 
resume at 50% of previous dose
NEUROTOXICITY
Grade 3, 4
Discontinue
6.5.4
Follow-up for toxicities
Capmatinib and spartalizumab
Subjects whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for four weeks, and 
subsequently at approximately four week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologists, endocrinologists, 
dermatologists, psychiatrists etc. should be consulted as deemed necessary. Further guidelines 
and recommendations for the management of specific study drug combination induced 
toxicities (hyperglycemia, diarrhea and skin toxicity) are provided in Section 6.5.3. All subjects 
must be followed for adverse events and serious adverse events after discontinuation of 
spartalizumab and capmatinib. Please refer to Section 9.2.1 for additional details. 
The emergence of 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 (Section 6.5.3) have been developed to 
assist investigators in assessing and managing the most frequently occurring irAEs.
Subjects whose treatment is interrupted or permanently discontinued due to an irAE, AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 30 days, and 
subsequently at approximately 30 day intervals (or more frequently if required by institutional 
practices, or if clinically indicated), until resolution or stabilization of the event, whichever 
comes first. Appropriate clinical experts should be consulted as deemed necessary.
If an AE is suspected to be immune-related the relevant immunological assessments (e.g. 
rheumatoid factor, anti-DNA Ab, etc.) should be performed. If cytokine release syndrome is 
suspected, the assessments outlined in Table 6-17 must be performed.
Table 6-8, Table 6-9, Table 6-10, Table 6-11, Table 6-12, Table 6-13, Table 6-14, Table 6-15, 
Table 6-16, Table 6-17, Table 6-18 outline the follow-up evaluations recommended for selected 
toxicities.
Docetaxel
Safety follow-up for toxicities related to docetaxel should follow the local guidelines and 
approved product label. All subjects must be followed for adverse events and serious adverse 
events after discontinuation of docetaxel. Please refer to Section 9.2.1 for additional details.


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6.5.4.1
Follow up on potential drug-induced liver injury (DILI) cases
Subjects with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important event.
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBIL 
value; subjects meeting any of the following criteria will require further follow-up as outlined 
below:

For subjects 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 subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in subjects without bone metastasis, or elevation 
of ALP liver fraction in subjects 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.
In the absence of cholestasis, these subjects should be immediately discontinued from study 
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.
4. PK samples should be obtained, as close as possible to last dose of, if PK analysis is 
performed in the study.
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE and reported as SAE using the term “potential 
drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.


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6.6
Additional treatment guidance
6.6.1
Treatment compliance
Every time the study treatment is to be administered, IRT needs to be accessed (please refer to 
the IRT manual). The date and time of study treatment administration during the study and any 
deviations from the protocol treatment schedule will be captured on the appropriate study 
treatment dispensing form. The investigator must promote compliance by instructing the subject 
to take the study treatment exactly as prescribed and by stating that compliance is necessary for 
the subject’s safety and the validity of the study. The subject must also be instructed to contact 
the investigator if he/she is unable for any reason to take the study treatment as prescribed.
For treatment with spartalizumab or with docetaxel: exposure to the study treatment will be 
based on the number of injections administered. Compliance with the study treatment will be 
assessed by the Clinical Research Associate (CRA) at each visit using vial counts and 
information provided by the pharmacist or by the investigator. All study treatment dispensed 
and returned must be recorded in a drug accountability log.
For treatment with capmatinib: compliance will be assessed by the investigator and/or study 
personnel at each visit using pill counts and information provided by the subject. This 
information should be captured in the source document at each visit. All study treatment 
dispensed and returned must be recorded in a drug accountability log.
Pharmacokinetic parameters will be determined in all subjects treated with capmatinib and 
spartalizumab combination, as detailed in pharmacokinetics section. Please refer to 
Section 8.5.2.
6.6.2
Emergency breaking of assigned treatment code
Not applicable.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs Section 6.1.1.
Capmatinib
The investigator or responsible site personnel must instruct the subject or caregiver to take the 
study treatment as per protocol. Study treatment will be dispensed to the subject by authorized 
site personnel only. All dosages prescribed to the subject and all dose changes during the study 
must be recorded on the study treatment eCRF.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT system and obtaining the medication number(s). The study medication has a two-part 
label (base plus tear-off label). Immediately before dispensing the medication kit to the subject, 
site personnel will detach the outer part of the label from the packaging and affix it to the source 
document.


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Spartalizumab
Study treatment will be dispensed and administered to the subject by authorized site personnel 
only. All dosages prescribed to the subject and all dose changes during the study must be 
recorded on the study treatment eCRF. A unique medication number is printed on the study 
medication label.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT system and obtaining the medication number(s). The study medication has a two-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the subject, 
site personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
Spartalizumab will be administered intravenously as a 30 minute infusion (up to 2 hours, if 
clinically indicated). Infusion must take place in a facility with appropriate resuscitation 
equipment available at the bedside and a physician readily available during the period of drug 
administration. Clinical monitoring during and post infusion should be performed according to 
local practice and institutional guidelines, and as outlined in Section 6.7.2.2. Further 
instructions for the preparation and dispensation of spartalizumab are described in the [Study 
Pharmacy Manual].
Docetaxel
Preparation and dispensation of docetaxel should follow local guidelines as per standard of care 
and product labels.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the [capmatinib Investigator’s Brochure] and
[spartalizumab Investigator’s Brochure]. Clinical supplies are to be dispensed only in 
accordance with the protocol. Technical complaints are to be reported to the respective 
Novartis Country Organisation Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 


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accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable.
6.7.2
Instruction for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
Table 6-20
Dose and treatment schedule
Investigational / Control 
Drug
Dose
Frequency and/or 
Regimen
Capmatinib (INC280)
150 mg or 200 mg
400 mg orally
(2 x 200 mg or 2 x 150 mg [if dose is reduced 
to 300 mg BID] or 1 x 200 mg [if dose is 
reduced to 200 mg BID], if applicable)
Twice daily 
(28 day cycles)
Spartalizumab (PDR001)
100 mg
400 mg i.v.
(4 x 100 mg vials)
Once every 28 days
Docetaxel (as per local product 
available)
75 mg/m2 i.v. infusion per product label and 
local guidelines (as per standard of care)
Once every 21 days
6.7.2.1
Capmatinib
Capmatinib tablets will be administered orally on a continuous twice daily (BID) dosing 
schedule, from Day 1 till Day 28 of each 28 day cycle. The starting dose of capmatinib will be 
400 mg BID (total daily dose: 800 mg) on a flat scale of mg/day and not individually adjusted 
by weight or body surface area. A complete cycle of treatment is defined as 28 days of twice 
daily treatment with capmatinib. The investigator must instruct the subject to take the study 
drug exactly as prescribed.

Including days of PK sampling, subjects should take 400 mg of capmatinib tablets twice 
daily (BID) at approximately the same time each day starting at Cycle 1 Day 1.

Each dose of capmatinib is to be taken with a glass of water (at least 8 ounces –
approximately 250 mL) and consumed over as short a time as possible (i.e., not slower 
than 1 tablet every 2 minutes).

Subjects should be instructed to swallow the tablets whole and not to chew them.

Capmatinib can be administered with or without food. The morning and the evening doses 
should be taken 12 (± 4) hours apart, although a 12-hour interval is highly recommended. 
The morning dose should be taken at the same time each morning. If a dose is not taken 
within 4 hours of the planned dosing time, the missed dose should not be replaced.

On days of co-administration of capmatinib with spartalizumab, subjects should be 
instructed to take the morning dose of capmatinib during the clinic visit, when instructed 
by site personnel. Capmatinib will be administered prior to spartalizumab infusion along 
with its pre-medication (if pre-medication is necessary). The sequence will allow 
consistent time of daily dosing for capmatinib. A minimum of 1 hour must pass from the 
time of capmatinib (morning dose) administration to the administration of spartalizumab.


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
On days when PK blood samples are to be collected, subjects will be instructed to hold 
their dose until arrival at the study center. Capmatinib will be administered at the site in 
the morning prior to the post-dose PK sample blood draws supervised by a member of the 
research team. The pre-dose PK samples will be taken right before capmatinib 
administration. The exact time of drug administration should be recorded in the 
appropriate eCRF. If a subject vomits within 4 hours of capmatinib dosing, the time of 
vomiting should be recorded on the eCRF.

Subjects should be instructed not to make up for missed doses or partial doses (i.e., when 
the entire dose is not taken as instructed). A missed or partial dose will be defined when 
the full dose is not taken within 4 hours of the scheduled twice daily dosing. If that occurs, 
then the dose (or part of the remaining dose) should not be taken and dosing should restart 
with the next scheduled dose. If vomiting occurs, no attempt should be made to replace the 
vomited dose before the next scheduled dose.

During the whole duration of treatment with capmatinib, the subject is recommended to 
use precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective 
clothing, avoid sunbathing or using a solarium).
The investigator should instruct the subject to take capmatinib exactly as prescribed. All 
dosages prescribed and dispensed to the subject and all dose changes during the study must be 
recorded on the study treatment eCRF.
The orally administered film-coated tablet formulation will be provided in up to two strengths 
of 150 mg and 200 mg free base equivalent. For the list of excipients, please refer to the current 
[capmatinib Investigator’s Brochure].
6.7.2.2
Spartalizumab
Spartalizumab will be supplied in a vial as liquid solution for infusion. Spartalizumab (liquid) 
will be diluted in dextrose 5% in water (D5W). Due to incompatibility, 0.9% sodium chloride 
must not be used.
The dose of spartalizumab is 400 mg every 4 weeks given as a 30 minute infusion (up to 2 hours, 
if clinically indicated). A dose may be delayed by up to seven days. If a dose cannot be 
administered within the planned window then the dose on that cycle should be skipped. The 
dose may be interrupted for up to 12 weeks. The safety assessments (as per Table 8-2) should 
be performed according to the actual day of infusion.
Infusion must take place in a facility with appropriate resuscitation equipment available at the 
bedside, and a physician readily available during the period of drug administration.
Subjects 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. The same may apply for the subsequent spartalizumab infusions 
if medically indicated. Subjects should be further provided instructions to notify study 
personnel if symptoms of infusion reaction occur after any spartalizumab infusion.
On days when PK blood samples are to be collected, study visits should be scheduled in the 
morning so that a predose PK blood sample can be collected. The exact time of drug 
administration should be recorded in the appropriate eCRF.




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A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
Subjects will be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. (Please refer to Section 8.5.1).
8
Visit schedule and assessments
Assessment schedules Table 8-2 (capmatinib and spartalizumab treated subjects [including run-
in]) and Table 8-3 (docetaxel treated subjects) list all of the assessments and indicate with an 
“X” or “S” the visits when they are performed. All data obtained from these assessments must 
be supported in the subject’s source documentation.
Written informed consent must be obtained before any study specific assessments are 
performed. Main screening evaluations and baseline radiological tumor assessments should be 
performed within 28 days of treatment start. All visits are to be scheduled according to the 
appropriate number of calendar days from Cycle 1 Day 1 of study drug administration. Visit 
windows per Table 8-1 are allowed.
Table 8-1
Allowable window for subject assessments
Visit name
Window allowed
Screening
-28 days from 1st dose of study drug
C1D1
Within 3 days after enrollment (part 1) or randomization (part 
2)
C1D15
± 1 day
C2D1
± 3 days
C3D1
± 3 days
C3D4
± 1 day (applicable only to intensive PK group)
C3D8
± 1 day (applicable only to intensive PK group)
C3D15
± 1 day
C4D1
± 3 days
Day 1 visit of all subsequent cycles
± 3 days
Imaging evaluations
± 7 days
EOT
≤ 7 days after stopping study treatment
30 day safety follow-up visit
+ 7 days
60, 90, 120 day follow-up phone call/onsite 
visit
± 14 days
150 day follow-up phone call/onsite visit
+ 14 days
Survival follow-up
± 14 days
Every effort must be made to follow the schedule of assessments within the windows outlined 
in the protocol. If a given visit is out of window, the next visit should be performed with 
reference to the day of first dose in order to get the subject back on schedule. If an off-schedule 
imaging assessment is performed, subsequent imaging assessments should be performed in 
accordance with the original imaging schedule. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, during which all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the eCRF.


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Table 8-2
Assessment Schedule, Run-in and Arm 1 (capmatinib and spartalizumab combination) - length of a cycle is 28 
days
Period
Screenin
g
Treatment
Safety Follow-Up (FUP)
Efficacy FUP 
(until PD)
Survival 
FUP
Visit Name
Screenin
g
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 
day
-
-
Days
-28 to -1
D1 D15 D1
D1
D
4
D8
D15 D1
D1
D1
D1
-
-
-
-
-
-
every 8 weeks 
until PD
every 8 
weeks
Informed consent
X
ICF for treatment 
beyond 
progression
X (subjects who meet the criteria outlined in Section 6.1.5.1)
Inclusion / 
Exclusion criteria
X
IRT Eligibility 
check
S
HIV history
S
Demography
X
Medical 
history/current 
medical 
conditions
X
Diagnosis and 
extent of cancer
X
Smoking history
X
Prior 
antineoplastic 
therapy
X
Prior medications
X


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Period
Screenin
g
Treatment
Safety Follow-Up (FUP)
Efficacy FUP 
(until PD)
Survival 
FUP
Visit Name
Screenin
g
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 
day
-
-
Days
-28 to -1
D1 D15 D1
D1
D
4
D8
D15 D1
D1
D1
D1
-
-
-
-
-
-
every 8 weeks 
until PD
every 8 
weeks
Concomitant 
medications
X (from 28 days prior to starting treatment until 150 day safety follow-up or start of new antineoplastic medication 
(ANP), whichever is sooner. If new ANP is started, only medications relative to suspected AEs/SAEs that are reported 
should be collected)
IRT registration
X1
S2
S2
S2
S2
S2
S2
S3
Physical 
Examination4
S
S (if clinically indicated)
Targeted Physical 
Examination
S
S
S
S
S
S
S
S
Body Height
X
Body Weight
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Performance 
status
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel X
X (if clinically indicated)
Serum Pregnancy 
test
S (within 
72h prior 
to first 
dose)
S
S
S
Urine Pregnancy 
test
S
S
S
S
S
S
S
S
S
Urinalysis
S
S (if clinically indicated)
Thyroid 
stimulating 
hormone
X
X
X
X
X
X
X
X
X


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Period
Screenin
g
Treatment
Safety Follow-Up (FUP)
Efficacy FUP 
(until PD)
Survival 
FUP
Visit Name
Screenin
g
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 
day
-
-
Days
-28 to -1
D1 D15 D1
D1
D
4
D8
D15 D1
D1
D1
D1
-
-
-
-
-
-
every 8 weeks 
until PD
every 8 
weeks
Thyroid Panel –
Free T3 and Free 
T4
X
X (only if TSH is abnormal)
Hepatitis screen
X
X (if clinically indicated)
HIV testing if 
locally required
S
Cytokines
X
X (anytime when a suspected cytokine release syndrome occurs, immediately after the AE, and one week 
after occurrence of the AE)
CT/MRI of chest 
and abdomen 
(with intravenous 
contrast 
enhancement)
X
X
X
X5
X6
X5
CT/MRI of pelvis 
and brain
X
X7
X7
X7
X7
X7
Whole body bone 
scan
X
X (if clinically indicated)
Localized bone 
scan (CT, MRI or 
X-ray)
X8
X7
X7
X7
X7
X7
CT/MRI of other 
metastatic sites
X (if 
clinically 
indicated)
X7
X7
X7
X7
X7
Photography for 
any skin lesion 
X
X7
X7
X7
X7
X7


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Period
Screenin
g
Treatment
Safety Follow-Up (FUP)
Efficacy FUP 
(until PD)
Survival 
FUP
Visit Name
Screenin
g
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 
day
-
-
Days
-28 to -1
D1 D15 D1
D1
D
4
D8
D15 D1
D1
D1
D1
-
-
-
-
-
-
every 8 weeks 
until PD
every 8 
weeks
Electrocardiogram 
(ECG)
X
X
X 
(onl
y 
Run
-in)
X 
(onl
y 
Run
-in)
X 
(onl
y 
Run
-in)
X
X (every 
subsequent 
third cycle)
X
Adverse Events
X (suspected AEs up to Day 150; non-suspected AEs up to Day 150 or start of new post treatment anti-neoplastic 
medication, whichever is sooner)
Serious Adverse 
Events
X (suspected SAEs up to Day 150 and beyond; non-suspected SAEs up to Day 150 or start of new post treatment anti-
neoplastic medication, whichever is sooner)
X (SAEs related to study 
treatment)
Newly obtained 
tumor biopsy 
(preferred) or 
archival tumor 
sample
X
Optional and if not 
already provided: 
additional tissue 
material or block 
collected after 
disease 
progression on 
PD-(L)1 
checkpoint 
inhibitor treatment
X


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Period
Screenin
g
Treatment
Safety Follow-Up (FUP)
Efficacy FUP 
(until PD)
Survival 
FUP
Visit Name
Screenin
g
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 
day
-
-
Days
-28 to -1
D1 D15 D1
D1
D
4
D8
D15 D1
D1
D1
D1
-
-
-
-
-
-
every 8 weeks 
until PD
every 8 
weeks
Blood for 
circulating tumor 
DNA
X
X
X
X
X (every
subsequent 
third cycle)
X (at the time of first disease progression prior to the 
initiation of new anti-cancer therapies)
Blood for cytokine 
analysis
X
X
X
X
X
X (at the time of first disease progression prior to the 
initiation of new anti-cancer therapies)
Blood for gene 
expression
X
X
X
X (at the time of first disease progression prior to the 
initiation of new anti-cancer therapies)
Trial Feedback 
Questionnaire
S
S
S
PK blood 
collection - sparse
X
X
X
X
X
X
X
X (at C8, 
C10, C12 
and every 6 
cycles 
thereafter) 
X
X
X9


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Period
Screenin
g
Treatment
Safety Follow-Up (FUP)
Efficacy FUP 
(until PD)
Survival 
FUP
Visit Name
Screenin
g
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 
day
-
-
Days
-28 to -1
D1 D15 D1
D1
D
4
D8
D15 D1
D1
D1
D1
-
-
-
-
-
-
every 8 weeks 
until PD
every 8 
weeks
PK blood 
collection -
intensive
X
X
X
X
X
X
X
X
X
X (at C8, 
C10, C12 
and every 6 
cycles 
thereafter) 
X
X
X9
Immunogenicity
X
X
X
X
X
X (at C8, 
C10, C12 
and every 6 
cycles 
thereafter) 
X
X
X9
Study drug 
administration: 
capmatinib
X (continuous twice daily (BID) dosing)
Study drug 
administration: 
spartalizumab
X
X
X
X
X
X
X
Disposition
X
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
X
Safety follow-up
X 
(visit)
X 
(call)
X 
(call)
X 
(call)
X 
(visit 
or 
call)9
Survival status
X


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Period
Screenin
g
Treatment
Safety Follow-Up (FUP)
Efficacy FUP 
(until PD)
Survival 
FUP
Visit Name
Screenin
g
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 
day
-
-
Days
-28 to -1
D1 D15 D1
D1
D
4
D8
D15 D1
D1
D1
D1
-
-
-
-
-
-
every 8 weeks 
until PD
every 8 
weeks
X Assessment to be recorded in the clinical database
S Assessment to be recorded in the source documentation only
1 For Arm1 only: randomization at Cycle 1 Day 1, see Section 6.1.1
2 For dispensing visit 
3 For permanent drug discontinuation
4 Including neurological exams
5 Every 8 weeks for the first 12 months and every 12 weeks thereafter until confirmed progressive disease per RECIST 1.1
6 If not done within 28 days
7 If lesions were documented at screening, follow the same schedule as CT/MRI of the chest and abdomen, or if clinically indicated
8 Mandated at Screening for lesions identified on whole body bone scan that are not visible on CT/MRI of chest, abdomen, and pelvis
9 Visit for child-bearing women with serum pregnancy test, if possible


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Table 8-3
Assessment Schedule, Arm 2 (Docetaxel) - length of a cycle is 21 days
Period
Screening Treatment
Safety 
FUP
Efficacy FUP
Survival 
FUP
Visit Name
Screening C1
C2
C3
C4
Subsequent cycles
EOT
30 day
-
-
Days
-28 to -1
D1
D15 D1
D1
D15 D1
D1
-
-
every 8 weeks 
until PD
every 8 
weeks
Informed consent
X
ICF for treatment beyond progression
X (subjects who meet the criteria outlined in Section 
6.1.5.1)
Inclusion / Exclusion criteria
X
IRT Eligibility check
S
HIV history
S
Demography
X
Medical history/current medical conditions
X
Diagnosis and extent of cancer
X
Smoking history
X
Prior antineoplastic therapy
X
Prior medications
X
Concomitant medications
X (from 28 days prior to starting treatment until 30 day safety follow-up or start of new 
antineoplastic medication (ANP), whichever is sooner. If new ANP is started, only 
medications relative to suspected AEs/SAEs that are reported should be collected)
IRT registration
X1
S2
S2
S2
S2
S3
Physical Examination4
S
S (if clinically indicated)
Targeted Physical Examination
S
S
S
S
S
S
Body Height
X
Body Weight
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X


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Period
Screening Treatment
Safety 
FUP
Efficacy FUP
Survival 
FUP
Visit Name
Screening C1
C2
C3
C4
Subsequent cycles
EOT
30 day
-
-
Days
-28 to -1
D1
D15 D1
D1
D15 D1
D1
-
-
every 8 weeks 
until PD
every 8 
weeks
Coagulation Panel
X
X (if clinically indicated)
Serum pregnancy test
S (within 
72h prior 
to first 
dose)
S
S
Urine Pregnancy test
S
S
S
S
Urinalysis
S
S (if clinically indicated)
Hepatitis screen
X
X (if clinically indicated)
HIV testing if locally required
S
CT/MRI of chest and abdomen (with intravenous 
contrast enhancement)
X
X
X5
X6
X5
CT/MRI of pelvis and brain
X
X7
X7
X7
X7
Whole body bone scan
X
X (if clinically indicated)
Localized bone scan (CT, MRI or X-ray)
X8
X7
X7
X7
X7
CT/MRI of other metastatic sites
X (if 
clinically 
indicated)
X7
X7
X7
X7
Photography for any skin lesion 
X
X7
X7
X7
X7
Electrocardiogram (ECG)
X
X
X
X (every subsequent 
third cycle)
X
Adverse Events
X (suspected AEs up to Day 30; non-suspected AEs up to Day 30 or start of new 
post treatment anti-neoplastic medication, whichever is sooner)
Serious Adverse Events
X (suspected SAEs up to Day 30 and beyond; non-suspected SAEs up to Day 30 or 
start of new post treatment anti-neoplastic medication, whichever is sooner)
X (SAEs related to study 
treatment)
Newly obtained tumor biopsy (preferred) or archival 
tumor sample
X


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Period
Screening Treatment
Safety 
FUP
Efficacy FUP
Survival 
FUP
Visit Name
Screening C1
C2
C3
C4
Subsequent cycles
EOT
30 day
-
-
Days
-28 to -1
D1
D15 D1
D1
D15 D1
D1
-
-
every 8 weeks 
until PD
every 8 
weeks
Optional and if not already provided: additional 
tissue material or block collected after disease 
progression on PD-(L)1 checkpoint inhibitor 
treatment
X
Blood for circulating tumor DNA
X
X
X
X (every subsequent 
third cycle)
X (at the time of first disease 
progression prior to the initiation of 
new anti-cancer therapies)
Blood for cytokine analysis
X
X
X
X
X
X (at the time of first disease 
progression prior to the initiation of 
new anti-cancer therapies)
Trial Feedback Questionnaire 
S
S
S
Study drug administration: docetaxel
X
X
X
X
X
Disposition
X
X
Antineoplastic therapies since discontinuation of 
study treatment
X
Safety follow-up
X (visit)
Survival status
X


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Period
Screening Treatment
Safety 
FUP
Efficacy FUP
Survival 
FUP
Visit Name
Screening C1
C2
C3
C4
Subsequent cycles
EOT
30 day
-
-
Days
-28 to -1
D1
D15 D1
D1
D15 D1
D1
-
-
every 8 weeks 
until PD
every 8 
weeks
X Assessment to be recorded in the clinical database
S Assessment to be recorded in the source documentation only
1 Randomization at cycle 1 day 1, see section 6.1.1
2 For dispensing visit 
3 For permanent drug discontinuation
4 Including neurological exams
5 Every 8 weeks for the first 12 months and every 12 weeks thereafter until confirmed progressive disease per RECIST 1.1
6 If not done within 28 days
7 If lesions were documented at screening, follow the same schedule as CT/MRI of the chest and abdomen, or if clinically indicated
8 Mandated at Screening for lesions identified on whole body bone scan that are not visible on CT/MRI of chest, abdomen, and pelvis


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8.1
Screening
All subjects must provide a signed main ICF prior to performing any screening procedures to 
determine subject eligibility. Subjects will be evaluated against all study inclusion and 
exclusion criteria. Baseline evaluations must be performed within 4 weeks (≤ 28 days) prior to 
the first dose of study drug.
After signing the study ICF, the screening assessments will be done within 1 to 28 days prior 
to the first dose of study drug. Laboratory parameters may be retested within the 28 day 
screening window (Day -28 to Day -1) period for an individual subject if such parameters meet 
an exclusion criterion when initially tested. Laboratory assessments performed as part of the 
screening evaluations will not be required to be repeated prior to dosing (except serum 
pregnancy test if not done within 72 hours prior to treatment start, and hematology/chemistry if 
not done within 7 days prior to treatment start) unless deemed clinically necessary by the 
investigator and/or required as per local institutional policies. The cardiac eligibility criteria 
should be assessed with the ECG report. Imaging assessments will be performed at screening 
between Day -28 and Day -1. Imaging assessments already completed during the regular work-
up of the subject within 28 days prior to start of treatment, including before signing the main 
study ICF can be considered as the baseline images for this study. Any imaging assessments 
obtained after first dose of study treatment cannot be considered baseline images. For details 
on screening assessments, refer to Table 8-2 and Table 8-3.
A new ICF will need to be signed if the investigator chooses to re-screen the subject after a 
subject has screen failed. A new subject number will be assigned to the patient. The rescreen 
form will have to be completed in the eCRF and in IRT to provide the original subject number. 
All required screening activities must be performed when the subject is re-screened for 
participation in the study. An individual subject may only be re-screened once for the study. 
Once the number of subjects screened and enrolled is likely to ensure target enrollment, the 
Sponsor may close the study to further screening. In this case, the subjects who screen failed 
will not be permitted to re-screen.
Subjects who are randomized and fail to start treatment, e.g. subjects randomized in error, will 
be considered as early terminations. The reason for early termination should be recorded on the 
appropriate eCRF.
8.1.1
Eligibility screening
When all screening procedures are completed and once the subject’s eligibility has been 
checked and confirmed (i.e., all inclusion/exclusion criteria have been verified), the key 
eligibility criteria checklist will be completed prior to the first dose of study drug in the IRT 
system by the investigator or designee. The eligibility check will be embedded in the IRT 
system. For the randomized part of the study, allocation to one of the two study arms will also 
be registered via IRT.
Please refer to Section 6.3.2 and as well as comply with detailed guidelines in the IRT manual.






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
CT/MRI of the brain

Whole body bone scan

Localized bone CT, MRI or x-ray, for any lesions identified on the whole body bone scan 
that are not visible on the chest, abdomen and pelvis CT or MRI

CT or MRI of other metastatic sites (e.g., neck), if clinically indicated

Color photography with a scale/ruler for any skin lesions present
If a subject is known to have a contraindication to CT intravenous (i.v.) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest plus a contrast-
enhanced MRI (if possible) of the abdomen and pelvis should be performed (MRI is not 
recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead).
Brain MRI or CT must be completed. Contrast enhanced brain MRI is preferred; however, if 
MRI contrast is contraindicated, then MRI without contrast or CT with/without contrast is 
acceptable.
A whole body bone scan must be performed per institutional standard of care (e.g., Tc-99 bone 
scan, whole body bone MRI, Fluorodeoxyglucose positron emission tomography [FDG-PET] 
or sodium fluoride [NaF] PET). Localized CT, MRI or X-rays should be acquired for all skeletal 
lesions identified on the screening whole body bone scan, which are not visible on the chest, 
abdomen, pelvis or brain CT/MRI.
If clinically indicated, CT or MRI of other areas of disease (e.g., neck), as appropriate, must be 
performed.
If skin lesions are present at screening, color photography must be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can be 
determined from the photograph.
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of i.v. contrast media. At the discretion of the 
investigators, FDG-PET scans may be performed to document progressive disease per RECIST 
1.1 (Section 16.1).
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion.
Chest x-rays and ultrasound should not be used to measure tumor lesions.
Post-baseline imaging assessments
Imaging assessments as described in Table 8-4 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing (see 
Table 8-1) and will be performed every 8 weeks (+/- 7 days) for the first 12 months and then 
every 12 weeks until study discontinuation criteria are met per Section 9.1. Each lesion that is 
measured at baseline must be measured by the same method and, when possible, the same local 
radiologist/physician throughout the study so that the comparison is consistent. The same is true 


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for any new lesions that occur after start of treatment. They should be imaged using the same 
modality at each subsequent time point. Imaging assessments should be scheduled using the 
date of first dose of study treatment as the reference date (not the date of the previous tumor 
assessment), and should be respected regardless of whether study treatment is temporarily 
withheld or unscheduled assessments performed. If an unscheduled imaging assessment is 
performed because progression is suspected, subsequent imaging assessments should be 
performed in accordance with the original imaging schedule.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary.
Treatment beyond disease progression
Following determination of disease progression, if the investigator believes the subject may 
derive benefit from continuing study treatment, the subject will be permitted to continue 
treatment beyond initial disease progression as per RECIST 1.1. Please see Section 6.1.5.1 for 
additional information.
Efficacy follow-up
For subjects who discontinue treatment for reasons other than initial disease progression as per 
RECIST 1.1, tumor assessments must continue to be performed as outlined in Table 8-2 and 
Table 8-3. Please refer to Section 9.2.2 for additional information.
Overall survival
All Subjects will enter the survival follow-up period once they complete the safety follow-up 
and efficacy follow-up after treatment discontinuation (whichever is longer).Survival status will 
be collected every 8 weeks regardless of treatment discontinuation reason (except if consent is 
withdrawn or subject is lost to follow-up) until death, lost to follow-up, or withdrawal of consent 
for survival follow-up. Additional survival assessments may be performed outside the 8 weeks 
follow-up schedules if a survival update is required for an interim assessment to meet safety or 
regulatory needs. Survival information can be obtained via phone, and information will be 
documented in the source documents and relevant eCRFs.Information on the therapies received 
for NSCLC, if any, after study treatment has been completed will be collected.
8.3.2
Appropriateness of efficacy assessments
Tumor response as specified in Section 8.3.1 will be assessed locally according to the Novartis 
guideline version 3.2 based on RECIST 1.1 (Section 16.1) (Eisenhauer et al 2009) 
 
 Tumor assessments every 8-12 weeks are 
consistent with the standard clinical practice. National Comprehensive Cancer Network 
(NCCN) guidelines for NSCLC recommend response assessment every 6-12 weeks. In patients 
with NSCLC previously treated with platinum chemotherapy, the median PFS is approximately 
4 months or 16 weeks. 


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8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to Section 10.1.1.
Table 8-5
Physical Assessments
Assessments
Specification
Physical 
examination
Significant findings that were present prior to the signing of informed consent must be 
included as medical history on the subject’s eCRF. Significant new findings that begin or 
worsen after informed consent must be recorded as an adverse event on the appropriate 
eCRF.
Physical examination
At screening, a complete physical examination will be performed including the examination 
of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular, and neurological systems. More 
frequent examinations may be performed at the discretion of the investigator and if medically 
indicated. Information about the physical examination must be present in the source 
documentation.
Targeted physical examination
A targeted physical exam will be performed at all visits as indicated in Table 8-2 and 
Table 8-3  during treatment except where a complete physical examination is required (see 
above). It will include at least the examination of general appearance and vital signs (blood 
pressure [SBP and DBP] and pulse). If indicated based on symptoms, additional exams will 
be performed.
Information for all physical examinations must be included in the source documentation at 
the study site and additionally reported in appropriate eCRF pages for blood pressure (SBP 
and DBP), vital signs, height and weight.
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature. They will be measured at screening and at 
subsequent time points as specified in Table 8-2 and Table 8-3.
Height and 
weight
Height will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 8-2 and Table 8-3.
Performance 
status
The performance status will be assessed according to the Eastern Cooperative Oncology 
Group (ECOG) Performance Status Scale as specified in Table 8-6 following the schedule 
given in Table 8-2 and Table 8-3. 
Table 8-6
ECOG Performance Status
Grade
ECOG status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
8.4.1
Laboratory evaluations
Central laboratories will be used for the analysis of scheduled hematology, biochemistry and 
other blood specimens collected as part of safety monitoring (as detailed in Table 8-2 and 


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Table 8-3). Additional time points should be added as deemed necessary per the investigator's 
best judgment to make sure the toxicity profile is sufficiently characterized and dose 
adjustments are performed to safeguard the safety of the subject.
Dipstick urinalysis (macroscopic panel) will be performed at the site. In the event of any out of 
range parameters, a local laboratory microscopic panel will be performed.
Laboratory values obtained during the screening phase from the central laboratory will be used 
to assess the subject’s eligibility and will not be required to be repeated prior to dosing (except 
seum 
pregnancy 
test 
if 
not 
done 
within 
72 
hours 
prior 
to 
treatment 
start, and hematology/chemistry if not done within 7 days prior to treatment start) unless 
deemed clinically necessary by the investigator and/or required as per local institutional 
policies. The time windows granted for laboratory evaluations are identical to the corresponding 
visit time windows for each visit (refer to Table 8-1) except as stated above.
The site does not need to wait for the results of centrally-analyzed laboratory assessments when 
an immediate clinical decision needs to be made (e.g. confirmation of eligibility, study drug 
interruption, re-initiation, and/or termination) and in those cases locally unscheduled testing 
may be performed and used for eligibility assessments. Details on the collection, shipment of 
samples and reporting of results by the central laboratory are provided to investigators 
separately in the central laboratory manual. Visit windows are allowed for all visits. Please refer 
to Table 8-1.
If at any time a subject has laboratory parameters obtained from a different (outside) laboratory, 
Novartis must be provided with a copy of the normal ranges and units for this laboratory and 
the laboratory certification, when possible. The investigator is responsible for reviewing all 
laboratory reports for subjects in the study and evaluating any abnormalities for clinical 
significance.
The results of the local laboratory will be recorded in the eCRF if any the following criteria are 
met:

A treatment decision was made based on the local results, or

There are no concomitant central results available, or

Local lab results document an AE not reported by the central lab, or

Local lab results document an AE where the severity is worse than the one reported by the 
central lab.
At any time during the study up to safety follow-up, abnormal laboratory parameters which are 
clinically relevant and require an action to be taken with study treatment (e.g., require dose 
modification and/or interruption of study treatment, lead to clinical symptoms or signs, or 
require therapeutic intervention), whether specifically requested in the protocol or not, will be 
recorded on the adverse event eCRF page. The severity of laboratory data will be graded using 
the Common Terminology Criteria for Adverse events (CTCAE) v5.0. (See Section 10.1 for 
additional information.) Additional analyses are left to the discretion of the investigator.


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Table 8-7
Laboratory Assessments
Test Category
Test Name
Hematology
Hemoglobin, Platelets, Hematocrit, White blood cells, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other (absolute value 
preferred, %s are acceptable))
Chemistry
Albumin, Alkaline Phosphatase, ALT, Amylase, AST, Calcium, Creatinine, Creatinine 
Clearance, Total Bilirubin, Direct Bilirubin (only if total bilirubin is ≥ grade 2), Indirect 
Bilirubin, Prothrombin Time, GGT, Lipase, Magnesium, Sodium, Potassium, fasting 
Glucose (non- fasting glucose allowed post-baseline), Blood Urea Nitrogen (BUN) or 
Urea, Bicarbonate, Chloride and Uric Acid: at screening and thereafter as clinically 
indicated, Lactate dehydrogenase (LDH), Phosphorus, Creatine kinase, Total 
Cholesterol
Urinalysis
Local Laboratory: Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, 
Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
If dipstick is abnormal then perform local laboratory Microscopic Panel (Red Blood 
Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells)
Coagulation
Activated Partial Thromboplastin Time (aPTT), International Normalised Ratio (INR)
Thyroid
TSH (Thyroid Stimulation Hormone), Free T3 and Free T4. At the subsequent visits as 
indicated in Table 8-2: TSH only. If TSH is abnormal, central lab will test Free T3 and 
Free T4
Hepatitis marker
HBV DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR
Safety cytokines (for 
cytokine release 
syndrome)
IFN-γ, IL-6, IL-1,TNF-α
Pregnancy Test
A serum pregnancy test must be performed at screening (at the local laboratory) within 
≤ 72 hours before first dose of study treatment, then the schedule of serum and urine 
pregnancy tests should be performed as indicated in Section 8.4.3. If local 
requirements dictate otherwise, local regulations should be followed.
8.4.1.1
Hematology
Hematology tests are to be performed according to the Visit Schedules outlined in Table 8-2
and Table 8-3. For details of the hematology panel refer to Table 8-7. Hematology should be 
assessed on the actual scheduled day, even if study drug is being withheld.
Laboratory assessment done ≤ 7 days of first dose of study treatment are permitted to be used 
as Cycle 1 Day 1 labs and do not need to be repeated.
More frequent hematology testing may also be performed as medically necessary. Additional 
results from unscheduled hematology lab evaluations should be recorded on the appropriate 
unscheduled visit eCRF.
8.4.1.2
Clinical chemistry
Clinical chemistry tests are to be performed according to the visit schedule outlined in Table 8-2
and Table 8-3. For details of the biochemistry panel see Table 8-7. Biochemistry should be 
assessed on the actual scheduled day, even if study drug is being withheld.
Laboratory assessment done ≤ 7 days of first dose of study treatment are permitted to be used 
as Cycle 1 Day 1 labs and do not need to be repeated.
More frequent chemistry testing may also be performed as medically necessary. Additional 
results from unscheduled chemistry lab evaluations should be recorded on the appropriate 
unscheduled visit eCRF.


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8.4.1.3
Urinalysis
Urinalysis is to be performed according to the visit schedules outlined in Table 8-2 and 
Table 8-3. For details of the urinalysis panel see Table 8-7.
8.4.1.4
Coagulation
INR and aPTT are to be performed according to the visit schedule outlined in Table 8-2 and 
Table 8-3.
8.4.1.5
Thyroid function
Thyroid function will be performed at:

Screening/baseline: TSH, Free T3, Free T4

Day 1 of subsequent cycles, EOT, 30 day safety follow-up: TSH

If TSH is abnormal, central lab will test Free T3 and Free T4.
8.4.1.6
Hepatitis marker
Hepatitis panels outlined in Table 8-7 will be performed at screening and as clinically indicated 
while on study treatment as per the assessment schedule in Table 8-2 and Table 8-3. HBV DNA 
serology (including HBV DNA, HBsAg, HBsAb, HBcAb) and HCV RNA-PCR test will be 
performed at baseline screening (≤ 28 days prior to start of study treatment) and as clinically 
indicated (hepatitis markers should be evaluated for precautionary safety monitoring of viral re-
activation while on study treatment.)
During the screening period, subjects must be screened for HBV and HCV (current or past 
history of infection). Careful medical history must be taken for all subjects to look for risk 
factors (family history of HBV and HCV, intravenous drug abuse, unprotected sex, dialysis, 
blood transfusions, etc.) and any past or present HBV symptoms (e.g., jaundice, dark urine, 
light colored stools, right upper quadrant pain).
Hepatitis B: 
At screening, all subjects will be tested for:

HBV DNA level

Hepatitis B surface antigen (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis B surface antibody (HBsAb)
Hepatitis C: 
At screening, all subjects will be tested for quantitative HCV RNA-PCR. After start of the study 
treatment and until 30 day safety follow-up, testing for HBV and HCV should be performed if 
clinically indicated. (e.g., criteria of hepatitis reactivation, rule out viral causality in case of 
DILI).


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8.4.1.7
Cytokine analysis
Samples for safety cytokine panel at screening will be stored below -70°C and analyzed only if 
post-screening samples are received. Cytokine panel is to be performed according to the visit 
schedules outlined in Table 8-2.
8.4.2
Electrocardiogram (ECG)
ECGs should be recorded after the subject has been resting for 10 minutes in the supine position 
to ensure a stable baseline, followed by the first ECG recording over the next 5 minutes. 
Triplicate ECGs should be performed approximately 2 minutes apart prior to the time point 
indicated in Table 8-8, Table 8-9 , and Table 8-10 below. ECGs should be performed within 
20 minutes prior to the collection of PK sample where applicable. The preferred sequence of 
cardiovascular data collection during study visits is ECG collection first, followed by vital signs, 
and blood sampling.
The Fridericia QT correction formula (QTcF) should be used for clinical decisions. The QTcF 
values from the triplicate ECGs will be averaged for each time point.
Triplicate ECGs for assessment will be collected at certain visits and whenever abnormality 
occurs at any time. Clinically significant ECG findings must be recorded as adverse events.
Table 8-8
ECG collection plan Part 1: Run-in
Cycle
Day
Time
ECG Type
Screening
Anytime
12 Lead, triplicate
1
1
Pre-dose
12 Lead, triplicate
1
15
Pre-dose
12 Lead, triplicate
2
1
1h post spartalizumab end of infusion
12 Lead, triplicate
3
1
Pre-dose and 1h post spartalizumab end of infusion
12 Lead, triplicate
4
1
Anytime
12 Lead, triplicate
Every subsequent third 
cycle
Anytime
12 Lead, triplicate
End of treatment
Anytime
12 Lead, triplicate
Unscheduled ECG
Anytime if clinically indicated
12 Lead, triplicate
Table 8-9
ECG collection plan Part 2: Randomized to Arm 1: capmatinib and 
spartalizumab combination
Cycle
Day
Time
ECG Type
Screening
Anytime
12 Lead, triplicate
1
1
Anytime
12 Lead, triplicate
4
1
Anytime
12 Lead, triplicate
Every subsequent third 
cycle
Anytime
12 Lead, triplicate
End of treatment
Anytime
12 Lead, triplicate
Unscheduled ECG
Anytime if clinically indicated
12 Lead, triplicate
Table 8-10
ECG collection plan Part 2: Randomized to Arm 2: docetaxel
Cycle
Day
Time
ECG Type
Screening
Anytime
12 Lead, triplicate


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Cycle
Day
Time
ECG Type
1
1
Anytime
12 Lead, triplicate
4
1
Anytime
12 Lead, triplicate
Every subsequent third 
cycle
Anytime
12 Lead, triplicate
End of treatment
Anytime
12 Lead, triplicate
Unscheduled ECG
Anytime if clinically indicated
12 Lead, triplicate
Note: An unscheduled ECG may be repeated at the discretion of the investigator at any time 
during the study and as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Interpretation of the tracing must be made by a 
qualified physician and documented on the ECG eCRF page.
Each ECG tracing should be labeled with the study number, subject initials (where regulations 
permit), subject number and date and kept in the source documents at the study site. Clinically 
significant ECG abnormalities present at screening should be reported on the medical history 
eCRF page. New or worsened clinically significant findings occurring after informed consent 
must be recorded on the adverse events eCRF page.
8.4.3
Pregnancy and assessments of fertility
All sexually active males and sexually active females of child-bearing potential are required to 
use highly effective methods of contraception during the study and for the follow-up time period 
as specified in Section 5.2. For a definition of highly effective contraception, assessment of 
fertility (males and females), and the definition of post-menopausal, please refer to Section 5.2.
All women of child-bearing potential will have a serum pregnancy test within 72 hours prior to 
the first dose of study treatment. hCG may also be considered a tumor marker, therefore if hCG 
levels are detected, another blood sample at least 4 days later must be taken to assess the kinetics 
of the increase, and a transvaginal ultrasound must be performed to rule out pregnancy.
Women treated with capmatinib and spartalizumab combination
Monthly urine pregnancy tests will then be required to be performed on Day 1 of every cycle 
beginning with Cycle 2, followed by serum pregnancy test at the end of treatment visit, 30 day 
and 150 day safety follow-up visit. During the follow-up period after the 30 day safety follow-
up visit through the 120 day safety follow-up telephone call, women of child-bearing potential 
will perform at-home urine pregnancy testing every 30 days using kits provided. Every effort 
must be made for the women of child-bearing potential to return to the site for the final 
pregnancy test. However, if the subject is unable to return then the subject will administer the 
urine pregnancy test at home using the kit provided. For all pregnancy tests performed at home, 
the site personnel will follow-up with the subject via telephone call to collect the date and the 
test results and document the information in the subject’s source documents. If the subject 
returns to the site for the serum pregnancy test at the 150 day safety follow-up, the results must 
be documented in the subject’s source documents.
Women of child-bearing potential will be instructed to contact the site immediately at any time 
during the study (on-treatment or during follow-up) should they have a positive pregnancy test. 
In case of positive urine pregnancy testing, additional testing must be performed to confirm the 
pregnancy, and, if confirmed, follow the reporting requirements as described in Section 10.1.4. 


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A positive pregnancy test requires immediate discontinuation of study treatment. If a positive 
pregnancy test is performed in between study visits, the subject must immediately notify the 
investigator. Male subjects must notify the investigator in case their partner is confirmed with 
positive pregnancy test results during the treatment period. See Section 10.1.4 for pregnancy 
reporting.
Local pregnancy test and associated results will not be collected on the eCRF.
Women treated with docetaxel
Monthly urine pregnancy tests will then be required to be performed on Day 1 of every cycle 
beginning with Cycle 2, followed by a serum pregnancy test at the end of treatment visit and at 
the 30 day safety follow-up visit. Every effort must be made for the women of child-bearing 
potential to return to the site for the final pregnancy test.
Women of child-bearing potential will be instructed to contact the site immediately at any time 
during the study (on-treatment or during follow-up) should they have a positive pregnancy test. 
In case of positive urine pregnancy testing, additional testing must be performed to confirm the 
pregnancy, and, if confirmed, follow reporting requirements as described in Section 10.1.4. A 
positive pregnancy test requires immediate discontinuation of study treatment. If a positive 
pregnancy test is performed in between study visits, the subject must immediately notify the 
investigator. Male subjects must notify the investigator in case their partner is confirmed with 
positive pregnancy test results during the treatment period. See Section 10.1.4 for pregnancy 
reporting.
Local pregnancy test and associated results will not be collected on the eCRF.
Assessments of fertility
For both treatment arms, when non-child-bearing potential status is determined during the study,
further pregnancy testing will not be continued. For further details on the assessment of fertility, 
please refer to the study exclusion criteria in Section 5.2.
If local requirements dictate otherwise, local regulations should be followed.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
Trial Feedback Questionnaire (TFQ)
This trial will include an anonymized questionnaire, the "Trial Feedback Questionnaire," for 
subjects to provide feedback on their clinical trial experience. Individual subject level responses 
will not be reviewed by investigators. Responses may be used by the sponsor (Novartis) to 
understand where improvements can be made in the clinical trial process. This questionnaire 
does not collect data about the subject's disease, symptoms, treatment effect or adverse events, 
and, therefore, will not be trial data.


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8.5.2.1
Pharmacokinetic blood collection and handling
The exact date and clock times of drug administration and PK blood draw will be recorded on 
the appropriate eCRF page. If vomiting occurs within 4 hours following capmatinib 
administration on the day of post dose PK blood sampling, the clock time of vomiting should 
be recorded in the dosage administration PK eCRF page.
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. A total of 3 mL of blood will be collected at specified time points for capmatinib 
and CMN288 analysis in plasma. Another 2 mL of blood will be collected for spartalizumab 
analysis in serum and 3.5 mL will be collected for IG analysis in serum. For time points when 
spartalizumab PK and IG are to be measured, a single blood sample will be collected for both 
IG and spartalizumab PK. Blood samples should be collected from the arm opposite from 
the investigational drug infusion, or from another site. Refer to the study's laboratory manual 
for detailed instructions for the collection, handling, and shipment of PK and IG samples.
If subjects experience a SAE or an AE leading to the discontinuation of the study treatment, an 
unscheduled PK blood sample should be obtained whenever possible. The date and time of the 
last dose and the time of PK blood draw should be recorded.
8.5.2.2
Pharmacokinetic sampling for capmatinib
PK blood samples for capmatinib and CMN288 are outlined in Table 8-11 and Table 8-12. The 
first 10 subjects who receive treatment dose for both capmatinib (BID) and spartalizumab for 
at least 12 weeks will be involved in the intensive PK cohort. If the 10 subjects are not recruited 
to the intensive PK cohort from the run-in part, the recruitment for the intensive PK cohort can 
extend into the randomized part of the study.
Table 8-11
Intensive PK cohort: Schedule of blood collection (plasma) for 
capmatinib (BID) PK
Cycle
Day
Scheduled Time (hours)
Dose Reference ID
Sample Number
3
1
Predosea
1/101b
111
3
1
0.5 h (±5 minutes)
1
112
3
1
1 h (±10 minutes)
1
113
3
1
2 h (±15 minutes)
1
114
3
1
4 h (±30 minutes)
1
115
3
1
8 h (±2 hr)
1
116
4
1
Predosea
2/201b
117
4
1
1 h (±10 minutes)
2
118
6
1
Predosea
3/301b
119
6
1
1 h (±10 minutes)
3
120
8
1
Predosea
4
121
8
1
1 h (±10 minutes)
4/401b
122
Unscheduled
Anytime
1001+
a Take samples immediately prior to administration of capmatinib
b The first Dose Reference ID (DRID) is for last dose the subject received prior to the collection of the PK 
sample, while the second DRID is for the current dose


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Table 8-12
Sparse PK cohort: Schedule of blood collection (plasma) for 
capmatinib (BID) PK
Cycle
Day
Scheduled Time (hours)
Dose Reference ID
Sample Number
3
1
Predosea
1/101b
211
3
1
1 h (±10 minutes)
1
212
4
1
Predosea
2/201b
213
4
1
1 h (±10 minutes)
2
214
6
1
Predosea
3/301b
215
6
1
1 h (±10 minutes)
3
216
8
1
Predosea
4
217
8
1
1 h (±10 minutes)
4/401b
218
Unscheduled
Anytime
2001+
a Take samples immediately prior to administration of capmatinib
b The first Dose Reference ID (DRID) is for last dose the subject received prior to the collection of the PK 
sample, while the second DRID is for the current dose
8.5.2.3
Pharmacokinetic and immunogenicity (IG) sampling for Spartalizumab
Blood samples for spartalizumab and IG analysis will be collected as outlined in Table 8-13
and  Table 8-14. The first 10 subjects who receive treatment dose for both capmatinib (BID) 
and spartalizumab for at least 12 weeks will be involved in intensive PK cohort. If the 10 
subjects are not recruited to the intensive PK cohort from the run-in part, the recruitment for the 
intensive PK cohort can extend into the randomized part of the study.
If the dosing of Cycle 3 Day 1 is delayed, the PK sampling for the full PK profile should be 
delayed accordingly to match the scheduled time points for Cycle 3 as outlined in Table 8-13. 
PK and IG samples will be collected also at the end of treatment visit and in the event of a 
clinically significant AE (such as infusion reaction/anaphylaxis) or if IG is suspected. After the 
cut-off for the primary analysis is reached, no additional PK and IG samples will be collected 
for the subjects still ongoing in the study.
Table 8-13
Intensive PK cohort: schedule of blood collection (serum) for 
spartalizumab PK and IG
Cycle
Day
Scheduled 
Time 
(hours)**
Analytes
Dose 
Reference ID
PK 
Sample 
Number
IG 
Sample 
Number
1
1
Predosea
PK/IG*
11
41
51
1
15
336 h (± 24h)
PK
11
42
2
1
Predosea
PK/IG*
11/12c
43
52
3
1
Predosea
PK/IG*
12/13c
44
53
3
1
1 h (± 5 min)b
PK
13
45
3
4
72 h (± 8h)
PK
13
46
3
8
168 h (± 8h)
PK
13
47
3
15
336 h (± 24h)
PK
13
48
4
1
Predosea
PK/IG*
13/14c
49
54
6
1
Predosea
PK/IG*
15/16c
50
55
8
1
Predosea
PK/IG*
17/18c
51
56
10
1
Predosea
PK/IG*
19/20c
52
57


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Cycle
Day
Scheduled 
Time 
(hours)**
Analytes
Dose 
Reference ID
PK 
Sample 
Number
IG 
Sample 
Number
12
1
Predosea
PK/IG*
21/22c
53
58
Every 6 cycles after C12D1 
until discontinuation of study 
treatment
1
Predosea
PK/IG*
23/24c,d
411+e
511+f
EOT
Anytime
PK/IG*
401
501
30-day safety follow-up
Predosea
PK/IG*
402
502
150-day safety follow-upg
Predosea
PK/IG*
403
404
Unscheduled
Anytime
PK/IG*
4001+
5001+
*IG samples are collected together with PK samples.
**PK samples are collected from the arm opposite from infusion site, or alternatively, the infusion site will need 
to be flushed with 10 mL of saline.
a Take samples immediately prior to the administration of spartalizumab.
b After completion of the infusion.
c The first Dose Reference ID (DRID) is for last dose the subject received prior to the collection of the PK 
sample, while the second DRID is for the current dose.
d Dose reference ID will be labeled sequentially from 25, 26…. ….before EOT
e PK sample number will be labeled sequentially from 412, 413, 414, …. ….before EOT
f IG sample number will be labeled sequentially from 512, 513, 514, …. ….before EOT
g For patients who return to the site for 150-day onsite serum pregnancy test
Table 8-14
Sparse PK cohort: schedule of blood collection (serum) for 
spartalizumab PK and IG
Cycle
Day
Scheduled 
Time 
(hours)**
Analytes
Dose 
Reference ID
PK 
Sample 
Number
IG 
Sample 
Number
1
1
Predosea
PK/IG*
11
61
71
1
15
336 h (± 24h)
PK
11
62
2
1
Predosea
PK/IG*
11/12b
63
72
3
1
Predosea
PK/IG*
12/13b
64
73
3
15
336 h (± 24h)
PK
13
65
4
1
Predosea
PK/IG*
13/14b
66
74
6
1
Predosea
PK/IG*
15/16b
67
75
8
1
Predosea
PK/IG*
17/18b
68
76
10
1
Predosea
PK/IG*
19/20b
69
77
12
1
Predosea
PK/IG*
21/22b
70
78
Every 6 cycles after C12D1 
until discontinuation of study 
treatment
1
Predosea
PK/IG*
23/24b,c
611+d
711+e
EOT
Anytime
PK/IG*
601
701
30-day safety follow-up
Predosea
PK/IG*
602
702
150-day safety follow-upf
Predosea
PK/IG*
603
703
Unscheduled
Anytime
PK/IG*
6001+
7001+
*IG samples are collected together with PK samples.
**PK samples are collected from the arm opposite from infusion site, or alternatively, the infusion site will need 
to be flushed with 10 mL of saline.


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Cycle
Day
Scheduled 
Time 
(hours)**
Analytes
Dose 
Reference ID
PK 
Sample 
Number
IG 
Sample 
Number
a Take samples immediately prior to the administration of spartalizumab.
b The first Dose Reference ID (DRID) is for last dose the subject received prior to the collection of the PK 
sample, while the second DRID is for the current dose.
c Dose reference ID will be labeled sequentially from 25, 26…. ….before EOT
d PK sample number will be labeled sequentially from 612, 613, 614, …. ….before EOT
e IG sample number will be labeled sequentially from 712, 713, 714, …. ….before EOT
f For patients who return to the site for 150-day onsite serum pregnancy test
8.5.2.4
Analytical methods
Pharmacokinetic samples for spartalizumab, capmatinib and its metabolite CMN288 will be 
quantified using validated LC/MS/MS assays. The assay to quantify and assess the IG will be 
a validated homogeneous ELISA.


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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Subjects may voluntarily discontinue from the study treatment for any reason at any time.
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. An end of treatment visit will 
be performed when subjects permanently discontinue the study treatment to which they were 
assigned at study entry.
Study treatment must be discontinued under the following circumstances

Subject/guardian decision

Investigator decision

Any situation in which study participation might result in a safety risk to the subject

Adverse event requiring permanent discontinuation of study treatment as per 
Section 6.5.3.1 and Section 6.5.3.2

Progressive disease per RECIST 1.1 
 (with the exception of 
continuation of treatment beyond disease progression.). Please see Section 8.3 and 
Section 6.1.5.1 for additional information.

Protocol deviation that results in significant risk to subject’s safety

Use of prohibited treatment as per Section 6.2.2

Pregnancy (Pregnancy may be followed for outcome as per Section 10.1.4)

Withdraw of consent (Please see Section 9.1.2)

Study is terminated by the sponsor (Please see Section 9.1.4)
If premature discontinuation of study treatment occurs, the investigator should make a 
reasonable effort to understand the primary reason for the subject’s discontinuation of study 


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treatment and record this information. The investigator must also contact IRT to register the 
subject’s discontinuation from study treatment.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent Section 9.1.2). Where possible, they should 
return for the assessments indicated in the assessment schedule (refer to Table 8-2 and 
Table 8-3). If they fail to return for these assessments for unknown reasons, every effort (e.g. 
telephone, e-mail, letter) should be made to contact the subject/pre-designated contact as 
specified in the lost to follow-up section. This contact should preferably be done according to 
the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule (refer to 
Table 8-2 and Table 8-3).
All subjects who discontinue study treatment should return for the safety assessments indicated 
in Section 9.2.1, and if applicable, for the efficacy assessments indicated in  Section 9.2.2.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.


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9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final 
visit) and treated as a prematurely withdrawn subject. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the subject’s interests. The investigator or sponsor, depending on the local 
regulations, will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
The primary analysis will be conducted when approximately 60 overall survival events are 
observed in the randomized phase of the study. The primary analysis data will be summarized 
in the primary clinical study report (CSR). Following the cut-off date for the analysis reported 
in the primary CSR, the study will remain open. As long as subjects derive benefit from study 
treatment, ongoing subjects will continue to receive study treatment and be followed as per the 
schedule of assessments, except for 
, PK assessments, and the Trial Feedback 
Questionnaire which will no longer be required.
The end of study is defined as the earliest occurrence of one of the following:

All subjects have died or discontinued from the study.

Another clinical study becomes available that can continue to provide capmatinib and 
spartalizumab combination in this subject population, and all subjects ongoing are eligible 
to be transferred to that clinical study.
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting (e.g. Novartis managed access program) to 
subjects who, in the opinion of the investigator, are still deriving clinical benefit. The final 
analysis will occur at the end of the study. All available data from all subjects up to this cut-off 
date will be analyzed and summarized in a final CSR.
At the time of the end of this study, subjects continuing to derive benefit from docetaxel in the 
opinion of the investigator may continue such treatment at the Investigator’s discretion 
according to local clinical practice, and every effort will be made to continue provision of study 
treatment outside this study through an alternative setting (e.g. Novartis managed access 
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All treated subjects should have a safety follow-up visit conducted 30 days after last 
administration of study treatment. Due to the half-life of spartalizumab and the possible delayed 
onset of ADRs, subjects will be followed for safety up to 150 days after the last dose of 
spartalizumab. Please refer to Section 9.2.1.
9.2.1
Follow up for safety evaluations
After treatment discontinuation, all subjects will be followed for safety evaluations and should 
have a safety follow-up after the last administration of the study treatment as per below:
Subjects treated with the capmatinib and spartalizumab combination
Due to the half-life of spartalizumab and the possible delayed onset of ADRs, subjects will be 
followed for safety up to 150 days after the last dose of spartalizumab or up to 30 days after the 
last dose of capmatinib, whichever was stopped last. All subjects will have a 30 day (+ 7 days) 
onsite safety follow-up visit, following which, subjects will be followed (via telephone call or 
onsite visit if subject happens to be visiting the site) at 60 (± 14 days), 90 (± 14 days), 120 (± 
14 days) and 150 (+ 14) days after the last dose of spartalizumab. All safety assessments should 
be completed as per Table 8-2. For female subjects of child-bearing potential, a pregnancy test 
will be performed at the time points listed in Table 8-2. Please refer to the safety follow-up flow 
diagram in Section 16.3.
If the subject begins any post-treatment antineoplastic medication before the 150 day safety 
follow-up period is complete, the collection of new SAEs and AEs unrelated to the capmatinib 
and spartalizumab combination will stop, and, thereafter, only suspected AEs and suspected 
SAEs will continue to be collected up to day 150. Suspected SAEs will continue to be collected 
beyond the 150 day safety visit.
Data collected should be added to the appropriate eCRF pages. 
Subjects treated with docetaxel
Subjects randomized to the docetaxel arm will be contacted for an onsite safety follow-up 30 
days after the last dose of docetaxel. For female subjects of child-bearing potential, a pregnancy 
test will be performed as listed in Table 8-3. If the subject begins any post treatment 
antineoplastic medication before the 30 day safety follow-up period is complete, the collection 
of new SAEs and AEs unrelated to docetaxel will stop, and, thereafter, only suspected AEs and 
suspected SAEs will continue to be collected up to day 30. Suspected SAEs will continue to be 
collected beyond the 30 day safety visit.
Data collected should be added to the appropriate eCRF pages.
9.2.2
Follow up for efficacy evaluations
All subjects who discontinue study treatment for reasons other than initial disease progression 
as per RECIST 1.1, should continue tumor assessments at the same intervals as per Table 8-2
and Table 8-3 until treatment discontinuation criteria are met per Section 9.1.
All subjects may be permitted to continue study treatment beyond initial disease progression as 
per RECIST 1.1. Please refer to Section 6.1.5.1 for details.


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9.2.3
Survival follow up
Subjects will enter the survival follow-up period once they complete the safety follow-up and 
efficacy follow-up after treatment discontinuation (whichever is longer). Subjects will then be 
contacted by telephone every 8 weeks to follow-up on their survival status. Any new 
antineoplastic therapies that have been started since the last contact date will also be collected 
during these phone calls.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. The investigator has the responsibility for managing the 
safety of the individual subject and identifying adverse events. Novartis qualified medical 
personnel will be readily available to advise on trial-related medical questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events (including lab abnormalities that constitute AEs) must be recorded in the 
adverse events eCRF under the signs, symptoms or diagnosis associated with them, rather than 
individual underlying signs and symptoms and must be accompanied by the following 
information (as far as possible) (if the event is serious refer to Section 10.1.2):

Adverse events will be assessed and graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0 

Grade 1 to 4 will be used to characterize the severity of the Adverse Event. If CTCAE 
grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening (corresponding respectively to Grades 1 - 4) will be used.

Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be "not suspected". The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject.

Its duration (start and end dates) or if the event is ongoing. An outcome of not 
recovered/not resolved must be reported.

Whether it constitutes a SAE (see Section 10.1.2 for the definition of a SAE) and which 
seriousness criteria have been met.


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
Action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose reduced/increased

Drug interrupted/withdrawn

Its outcome 

Not recovered/not resolved;

Recovered/resolved;

Recovered/resolved with sequelae;

Fatal; or unknown.
If the event worsens, the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For Grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined, a new entry for this event should be reported in the eCRF noting 
the start date when the event improved from having been Grade 3 or Grade 4. Conditions that 
were already present at the time of informed consent should be recorded in medical history 
eCRF of the subject.
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of the appropriate 
method (e.g., as per RECIST criteria for solid tumors), should not be reported as an adverse 
event, except if the investigator considers that progression of malignancy is related to study 
treatment. Adverse events separate from the progression of malignancy (for example, deep vein 
thrombosis at the time of progression or hemoptysis concurrent with finding of disease 
progression) will be reported as per usual guidelines used for such events with proper attribution 
regarding relatedness to the drug.
Abnormal laboratory values or test results constitute AEs 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
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease.
Following the last dose of study treatment, AE monitoring should be continued as described 
in Section 9.2.1.


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Any AEs experienced after the follow-up safety evaluations timeframe as specified in 
Section 9.2.1 should only be reported to Novartis Safety if the investigator suspects a causal
relationship to study treatment.
Information about adverse drug reactions for the investigational drugs can be found in the 
[capmatinib Investigator's Brochure] and [spartalizumab Investigator's Brochure].
10.1.1.1 Adverse events of special interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
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. and include:

For capmatinib: 

Hepatotoxicity,

Pneumonitis/ILD,

Central nervous system toxicity,

Renal dysfunction,

Pancreatitis,

QTc interval prolongation,

Teratogenicity,

Phototoxicity,

Drug-drug interactions with strong CYP3A4 inducers

For spartalizumab: 

Endocrinopathies (i.e. hypothyroidism, hyperthyroidism, diabetes, hypophysitis and 
hypopituitarism, adrenal insufficiency),

Pneumonitis,

Colitis,

Hepatitis,

Nephritis,

Encephalitis,

Rash,

Other immune-mediated events,

Infusion reactions
Details regarding these adverse events are provided in the [capmatinib Investigator’s Brochure] 
and the [spartalizumab Investigator’s Brochure]. Potential emergent new AEs will be monitored 
during the course of the study.


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10.1.2
Serious adverse events
A SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria:

Fatal

Life-threatening 

Life-threatening in the context of a SAE refers to a reaction in which the subject was 
at risk of death at the time of the reaction; it does not refer to a reaction that 
hypothetically might have caused death if it were more severe (please refer to the 
ICH-E2D Guidelines)

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Requires subject hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (e.g. loss of response, treatment failure) 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

Treatment on an emergency out-subject basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

Is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met, and the malignant neoplasm is not a disease progression of the 
study indication (progression of malignancy [including fatal outcomes], if documented by use 
of the appropriate method [e.g. for example, as per RECIST criteria for solid tumors], should 
not be reported as a serious adverse event.)
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.


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10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent must be reported to Novartis safety within 24 hours of learning of 
its occurrence. Detailed instructions regarding the submission process and requirements are to 
be found in the investigator folder provided to each site.
The following SAE reporting time frames apply:
1. Screen Failures (e.g. a subject who is screened but is not treated or randomized): SAEs 
occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis
2. Randomized OR Treated Subjects: SAEs collected between the time the subject signs ICF 
until the timeframes specified in Section 9.2.1 after the subject has discontinued or 
stopped study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. A SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new
occurrence) and is thought to be related to the study treatment, a CMO&PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the follow-up safety evaluations timeframe as specified in 
Section 9.2.1 should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.
10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.


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Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration eCRF irrespective of whether or not associated with an AE/SAE and 
reported to Safety only if associated with an SAE. Misuse or abuse will be collected and 
reported in the safety database irrespective of it being associated with an AE/SAE within 24 
hours of the investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose Administration 
(DAR) eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated 
with an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a 
SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 10.1.1 and Section 10.1.2.
10.2
Additional Safety Monitoring
Not applicable.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs and allow modification and/or verification of the 
entered data by the investigator staff.




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subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject), in case of wet signature.
The investigator must give the CRA access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
The primary efficacy and safety analysis will be performed when approximately 60 overall 
survival events are observed in the randomized part. In the primary analysis, analysis of all 
primary, secondary, 
 objectives will be carried out.
12.1
Analysis sets
The Full Analysis Set (FAS) comprises all subjects in the run-in who received at least one dose 
of any component of study treatment and all subjects in the randomized part to whom study 
treatment has been assigned by randomization. In the randomized part according to the intent 
to treat principle, subjects will be analyzed according to the treatment they have been assigned 
to during the randomization procedure.
The Safety Set includes all subjects who received at least one dose of study treatment (i.e. at 
least one dose of spartalizumab [including incomplete infusion or of capmatinib], or at least one 
dose of docetaxel [including incomplete infusion]). Subjects will be analyzed according to the 
study treatment received, where treatment received is defined as the randomized treatment if 
the subject took at least one dose of that treatment or the first treatment received if the 
randomized treatment was never received.
The Dose-Determining Set (DDS) includes all patients from the Safety Set in the run-in part 
who met the minimum exposure criterion and had sufficient safety evaluations, or experienced 
a dose limiting toxicity (DLT) during the first 56 days (8 weeks) of dosing.
A subject has met the minimum exposure criterion if the subject receives at least 1 infusion of 
spartalizumab and takes at least 50% of the planned dose of capmatinib within the first 8 weeks 
of treatment.
Subjects who do not experience a DLT during the first 56 days of dosing are considered to have 
sufficient safety evaluations if they have been observed for ≥ 56 days following the first dose, 
and are considered by both the sponsor and investigators to have enough safety data to conclude 
that a DLT did not occur.
The capmatinib pharmacokinetic analysis set (PAS-INC280) includes all subjects who provide 
at least one evaluable capmatinib PK concentration. For a concentration to be evaluable, 
subjects are required to:

Take a planned dose of capmatinib prior to sampling.


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
For pre-dose samples, do not vomit within 4 hours after the dosing of capmatinib prior to 
sampling; for post-dose samples, do not vomit within 4 hours after the dosing of 
capmatinib.

For pre-dose sample, have the sample collected before the next dose administration and 9-
15 hours after the last dose administration.
The spartalizumab pharmacokinetic analysis set (PAS-PDR001) includes all subjects who 
provide at least one evaluable spartalizumab PK concentration. For a concentration to be 
evaluable, subjects are required to:

Receive one of the planned treatments of spartalizumab prior to sampling.

For pre-dose samples, have the sample collected before the next dose administration.

For end-of-infusion samples, have the sample collected within 2 hours post end of 
infusion.
The immunogenicity (IG) set includes two parts: IG prevalence set and IG incidence set:

The IG prevalence set includes all subjects in the Full analysis set with a determinant 
baseline IG sample or at least one determinant post-baseline IG sample.

The IG incidence set includes all subjects in the IG prevalence set with a determinant 
baseline IG sample and at least one determinant post-baseline IG sample.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS and safety set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment group.
12.3
Treatments
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure in weeks to spartalizumab and capmatinib as well as the dose intensity 
(computed as the ratio of actual cumulative dose received and actual duration of exposure) and 
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 duration of exposure will also be presented for the study treatment by arm.
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group, and all dosing data 
will be listed.


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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 treatment group.
12.4
Analysis of the primary endpoint(s)
Primary Objectives
Part 1: Run-in
To assess safety and tolerability of capmatinib and spartalizumab combination in subjects with 
NSCLC, who have received one or more prior lines of systemic therapy for the locally 
advanced/metastatic stage of disease and are potential candidates for docetaxel single agent 
chemotherapy.
Part 2: Randomized
To assess the overall survival of combination of capmatinib and spartalizumab in comparison 
to docetaxel.
12.4.1
Definition of primary endpoint(s)
Part 1: Run-in
Incidence of DLTs during the first 8 weeks (56 days) of treatment for patients in the DDS.
Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital 
signs, and ECGs.
Tolerability: Dose interruptions, reductions, and dose intensity.
Part 2: Randomized
Overall Survival (OS) is defined as the time from date of randomization to date of death due to 
any cause. 
12.4.2
Statistical model, hypothesis, and method of analysis
Part 1: Run-in
Assessing the safety and tolerability of capmatinib and spartalizumab combination will be based 
on the safety data including dose administration, adverse event, lab, vital signs and ECG data 
when all patients in this phase have at least 24 weeks of follow-up, pharmacokinetic data and 
preliminary efficacy data from all enrolled subjects in run-in phase. All dose administration 
data, safety, pharmacokinetic, and preliminary efficacy data will be listed for all subjects 
enrolled in the run-in.
The safety and tolerability assessment in run-in will be guided by a Bayesian analysis of DLT 
data for capmatinib and spartalizumab combination in the first 8 weeks (56 days) of treatment 
for subjects in the DDS. The relationship between dose and the probability of DLT is modeled 
using Bayesian logistic regression model (BLRM).


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The dose-limiting toxicity (DLT) relationship is modeled by a 5-parameter BLRM that 
comprises single-agent toxicity parts and interaction part to describe the two-way drug safety 
interactions. Single agent toxicity is modeled using logistic regression for the probability of a 
subject experiencing a DLT against log-dose. The odds of a DLT for each dose regimen are 
then calculated under no interaction for the two single agent toxicities, and interaction is 
accounted for by adjusting these odds with additional model parameter (odds multiplier). 
Details of the model are provided in Section 16.4.
After the run-in, posterior distributions for the risk of DLT will be summarized to provide the 
posterior probability that the risk of DLT lies within the following intervals:

Under-dosing: [0, 16%)

Targeted toxicity: [16%, 33%)

Excessive toxicity: [33%, 100%]
Assessing the safety and tolerability of the combination is guided by the EWOC principle
(Rogatko et al 2007). A dose may be considered tolerable if the risk of excessive toxicity at that 
dose is < 25%.
Listing of DLTs
DLTs will be listed, and their incidence summarized by system organ class and preferred term, 
and worst grade (CTCAE v5.0 grades). Listings and summaries will be based on the DDS.
Part 2: Randomized
The primary analysis will be carried out when approximately 60 overall survival events are 
observed in the randomized phase of the study. The analysis of OS will be based on full analysis 
set which includes all randomized subjects. For the primary endpoint of OS, all the data 
collected up to the cut-off date for the analysis will be included. If a patient is not known to 
have died at the time of analysis cut-off, OS will be censored at the date of last contact. The 
estimated hazard ratio (HR) between capmatinib and spartalizumab combination and docetaxel 
and exact 80% confidence interval will be provided.
Capmatinib and spartalizumab combination is considered to have clinically relevant activity if 
the following two criterion are satisfied:
1. The observed HR of OS for capmatinib and spartalizumab combination vs docetaxel is ≤ 
0.667.
2. The upper limit of two sided 80% CI of HR of OS for capmatinib and spartalizumab 
combination vs docetaxel is < 1.0.
Other efficacy data such as ORR, PFS, DCR, TTR, and DOR may be taken into consideration 
to assess clinically relevant activity.
12.4.3
Handling of missing values/censoring/discontinuations
Part 1: Run-in
Subjects who are excluded from the DDS will be excluded from the BLRM analysis of run-in 
part, although their data will be used for all the remaining analyses.
Part 2: Randomized


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OS will be censored if no OS event is observed prior to the analysis cut-off date.
If a patient is not known to have died at the time of analysis cut-off, or lost to follow-up, OS 
will be censored at the date of last contact.
12.4.4
Sensitivity and supportive analyses
Sensitivity and supportive analyses may be conducted for the primary objective in the 
randomized part, if appropriate, and the details of these analyses will be defined in the SAP.
12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
The secondary efficacy endpoints, objective response rate (ORR), disease control rate (DCR), 
progression free survival (PFS), time to response (TTR), duration of response (DOR) and 
disease control rate (DCR) based on the investigator assessed as per RECIST 1.1 as described 
in Section 16.1 will be analyzed. Analysis of all secondary efficacy endpoints will be performed 
using the FAS.

ORR is defined as the proportion of subjects with best overall response (BOR) of 
complete response (CR) or partial response (PR).

Disease control rate (DCR) is defined as the proportion of subjects with best overall 
response of CR or PR or SD.

Progression free survival (PFS) is defined as the time from the date of randomization 
(randomized part) or start of treatment (run-in part) to the date of the first documented 
radiological progression or death due to any cause.

Time to response (TTR) is defined as the time from the date of randomization 
(randomized part) or start of treatment (run-in part) to the first documented response of 
either CR or PR, which must be subsequently confirmed (although date of initial response 
is used, not date of confirmation).

Duration of response (DOR) only applies to subjects for whom best overall response is 
complete response (CR) or partial response (PR). DOR is defined as the time between the 
date of first documented response (CR or PR) and the date of first documented 
progression or death due to underlying cancer. If progression or death due to underlying 
cancer has not occurred, then the subject is censored at the date of last adequate tumor 
assessment.
ORR and DCR will be summarized with accompanying 95% confidence interval (CI). PFS, 
TTR, DOR and the Kaplan-Meier curves, medians and 95% confidence intervals of the medians 
will be presented.
Individual lesion measurements and overall response assessments per RECIST 1.1 will be listed 
by assessment date. Best overall response per RECIST 1.1 will also be listed.
12.5.2
Safety endpoints
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
treatment group.


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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. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from the day of the subject’s informed consent to the day before the 
first dose of study treatment.
2. On-treatment period: from the day of the first dose of study medication to 150 days after 
the last dose of spartalizumab, or 30 days after the last dose of capmatinib, whichever is 
later for the spartalizumab and capmatinib arm, or from the day of the first dose of study 
medication to 30 days after the last dose of docetaxel (including start and stop dates).
3. Post-treatment period: starting at 151 days after last dose of spartalizumab, or 31 days after 
last dose of capmatinib, whichever is later and 31 days after the last dose of docetaxel.
Adverse events
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period (the treatment-emergent AEs).
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE grades), 
type of adverse event, and relation to study treatment.
Serious adverse events, non-serious adverse events and adverse events of 
special interest
(AESI) during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
Spartalizumab specific AESIs are defined in the case retrieval strategy (CRS) with regular 
updates whenever necessary, see also Section 10.1.1.1. For each specified AESI, number and 
percentage of subjects with at least one adverse event (Preferred term) corresponding to the 
AESI will be reported.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time, and, if ranges are 
available, abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time.
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
12-lead ECGs including PR, QRS, QT, QTcF intervals and heart rate (HR) will be 
obtained for each subject during the study. ECG data will be read and interpreted locally.

Categorical Analysis of QT/QTc interval data based on the number of subjects meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from 
baseline will be presented. In addition, a listing of these subjects will be produced (by 
treatment group).
Clinical laboratory evaluations
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. CTCAE Grade 0 will be assigned for all non-missing values not graded as 
1 or higher. Grade 5 will not be applicable. For laboratory tests where grades are not defined 
by CTCAE v5.0, results will be categorized as low/normal/high based on laboratory normal 
ranges. The following listings/summaries will be generated separately for hematology, and 
biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE v5.0 
grades if applicable and the classifications relative to the laboratory normal ranges.
For laboratory tests where grades are defined by CTCAE v5.0:

Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment 
value.
For laboratory tests where grades are not defined by CTCAE v5.0:

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
Listing of all laboratory data with values flagged to show the corresponding CTCAE v5.0 
grades, if applicable, and the classifications relative to the laboratory normal ranges will be 
presented.
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 statistical analysis plan (SAP).
Immunogenicity
Immunogenicity will be characterized descriptively by tabulating anti-drug antibodies (ADA) 
prevalence at baseline and ADA incidence on-treatment.
The impact of immunogenicity on PK, safety, and efficacy may be explored, and further details 
will be specified in the SAP.
12.5.3
Pharmacokinetics
The respective PAS for each study drug will be used in the pharmacokinetic data analysis.


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Descriptive statistics (n, m number of non-zero concentrations, mean, CV%, SD, median, 
geometric mean, geometric CV%, minimum and maximum) for spartalizumab and capmatinib 
concentrations will be presented at each scheduled time point. All concentration data for 
spartalizumab and capmatinib will be displayed graphically.
Concentrations below LLOQ will be displayed in listings as zero with a flag and handled as 
zero in any calculations of summary statistics, but handled as missing for the calculation of the 
geometric means and their CV. Individual concentration-time profiles as well as mean 
concentration-time profile will be plotted when applicable.
PK parameters will be determined for intensive PK cohort in randomized part by applying non-
compartmental method(s) using Phoenix WinNonlin version 6.4 or above (Pharsight, Mountain 
View, CA). The descriptive statistics (n, mean, CV%, standard deviation [SD], median, 
geometric mean, geometric CV%, minimum and maximum) will be presented for all PK 
parameters, including but not limited to those listed in Table 12-1 except Tmax, where only n, 
median, minimum and maximum will be presented. Any missing PK parameter data will not to 
be imputed.
Table 12-1
Non-compartmental pharmacokinetic parameters  
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x 
volume-1) 
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)
Cmax
The maximum (peak) observed plasma serum concentration after single dose administration (mass 
x volume-1)
Ctrough
The minimum (peak) observed plasma serum concentration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (lz) of a semi logarithmic concentration-
time curve (time). Use qualifier for other half-lives
12.5.3.1 Handling of missing values/censoring/discontinuations
Missing values for any PK parameters or concentrations will not be imputed and will be treated 
as missing. Below the limit of quantitation (BLQ) values will be set to zero by the bioanalyst 
and will be displayed in the listings as zero and flagged. BLQ values will be treated as missing 
for the calculation of the geometric means and geometric CV%.
12.5.3.2 Population pharmacokinetic analysis
If data permit, a mixed-effects model may be applied to the spartalizumab and/or capmatinib 
concentration-time data to generate post hoc estimates of pharmacokinetic parameters using 
NONMEM to characterize spartalizumab and/or capmatinib exposure. If there are sufficient 
data for analysis, the details of the population pharmacokinetic analyses will be provided in a 
separate reporting and analysis plan, and the results may be reported in a separate population 
pharmacokinetic report. Data from this and other studies may be pooled for analysis.


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12.7
Interim analyses
Not Applicable.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
No formal statistical power calculations to determine sample size were performed for this study.
In the randomized part approximately 90 subjects will be randomized in a 2:1 ratio in this study; 
60 subjects in capmatinib and spartalizumab combination arm and 30 subjects in docetaxel arm. 
The primary endpoint of the study will be overall survival. The sample size is based on 
observing a clinically relevant OS in capmatinib and spartalizumab combination arm compared 
to docetaxel arm.
The expected median OS for docetaxel as second-line chemotherapy is ~8 months 
(Herbst et al 2016, Rittmeyer et al 2017). It is therefore reasonable to assume the median OS of 
~8 months for docetaxel in this study and 33.3% reduction in hazard rate for overall survival in 
capmatinib plus spartalizumab arm compared to docetaxel arm, which corresponds to an 
increase in median OS by 4 months under the exponential assumption.
Therefore

The HR of OS for capmatinib and spartalizumab combination vs docetaxel is ≤ 0.667

The upper limit of two sided 80% CI of HR of OS for capmatinib and spartalizumab 
combination vs docetaxel is < 1.0
are considered clinically relevant activity in subjects in the capmatinib and spartalizumab 
combination arm.
Considering a 2:1 randomization, with approximately 60 OS events, the probability of 
observing clinically relevant activity is 66% when the true HR is 0.60 and the probability of 
observing clinically relevant activity is 24% when the true HR is 0.80. The operating 
characteristics are presented in Table 12-2.
With 60 subjects in capmatinib and spartalizumab combination arm and 30 subjects in docetaxel 
arm, and assuming a median OS of 8 months in docetaxel arm and a HR of 0.66, 60 OS events 
will be observed in ~18 months with a recruitment rate of 15 subjects per month.


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Table 12-2
Operating characteristics
True Median OS of docetaxel vs 
Median OS of capmatinib and 
spartalizumab
True HR
Probability of success (%)
6 vs 8
0.75
32.5
6 vs 10
0.60
65.9
6 vs 12
0.50
86.8
8 vs 8
1.0
5.8
8 vs 10
0.80
24.1
8 vs 12
0.66
50.0
8 vs 13
0.62
62.3
8 vs 14
0.57
72.5
12.8.2
Secondary endpoint(s)
Not applicable.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit, 
LPLV) and finalization of the study report, the results of this trial will be submitted for 
publication and posted in a publicly accessible database of clinical trial results, such as the 
Novartis clinical trial results website and all required Health Authority websites (e.g. 
Clinicaltrials.gov, EudraCT etc.).


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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances, including 
incidental collection, is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action, and the IRB/IEC at the study site should be informed according to 
local regulations.




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16
Appendices
16.1
Appendix 1: Guidelines for Response, Duration of Overall 
Response,  TTF, TTP, Progression-Free Survival, and Overall 
Survival  (based on RECIST 1.1)
Document type:
TA Specific Guideline
Document status:
Version 3.2: February 11, 2016
Version 3.1: November 29, 2011
Version 3: October 19, 2009 Version 2: January 18, 2007 Version 
1: December 13, 2002
Release date:
11-Feb-2016
Authors (Version 3.2):
Kalyanee Appanna, Bharani Dharan, Steven Green, Randi 
Isaacs, Susan Schnakenberg, Jessica Wang, Cristian Massacesi
Authors (Version 3.1):
Kalyanee Appanna, Bee Chen, Bharani Dharan, Steven Green, 
Diana Porshneva, Kannan Subramanian, Michel Gauthier, Nilima 
Patel, Sandra Chica, Aruna Vattikola, Emmanuel Zuber
Authors (Version 3):
Kalyanee Appanna, Steven Green, Samit Hirawat, David 
Lebwohl, Cristian Massacesi, Liza Morgan, Haren Rupani, Jeffrey 
Stuart, Aruna Vattikola, Gabriele von Ingersleben
Authors (Version 2):
Renaud Capdeville, Bee Chen, Insa Gathmann, Steven Green, 
David Lebwohl, Michael Murawsky, Lixia Wang, Emmanuel Zuber
Authors (Version 1):
Insa Gathmann, William Mietlowski, Beate Kiese, Kathy Mellars, 
Renaud Capdeville, Margaret Dugan
16.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 16.1.2 and the definition of best response in 
Section 16.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.1.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming.
16.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), and revised 
RECIST guidelines (version 1.1) (Eisenhauer et al 2009).


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16.1.2.1 Definitions
16.1.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.
Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed 
by cytology/histology.
For patients without measurable disease see Section 16.1.3.2.9.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥ 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥ 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.

Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no septations, 
and low CT density [water-like] content) should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as target 
lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with ≥ 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
16.1.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations. Guidance on how patients with just non-measurable disease at baseline will 


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be evaluated for response and also handled in the statistical analyses is given in 
Section 16.1.3.2.8.
16.1.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v.) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm). All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow-up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response assessment 
can be justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up 
assessments by CT will be needed to determine if there is truly progression occurring at 
that site. In all cases PD will be the date of confirmation of new disease by CT (or some 
other conventional technique such as MRI) rather than the date of the positive PET scan. 
If there is a positive PET scan without any confirmed progression at that site by CT, then a 
PD cannot be assigned.


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
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Physical exams: Evaluation of lesions by physical examination is accepted when lesions 
are superficial, with at least 10mm size, and can be assessed using calipers.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by the 
protocol. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful 
to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination.

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, some 
disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, PSA 
for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be integrated 
as non-target disease. If markers are initially above the upper normal limit they must 
normalize for a patient to be considered in complete clinical response when all lesions 
have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
If the protocol is considering specific symptoms as objective signs of clinical progression, e.g. 
bone pain or GI bleeding, then the criteria for clear worsening of these non-measurable ‘lesions’ 
indicative of PD should be clearly specified in the protocol. In that case, the protocol should 
clearly specify that additional criteria are used to complement RECIST criteria.


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16.1.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 16.1.2.1.1.

Nodal target: See Section 16.1.2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
16.1.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-1) and non-target lesions (Table 16-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-3) as well as the presence or absence of new lesions.
If tumor markers are used as non-target lesions to evaluate response, please specify criteria for 
CR, SD and PD in the protocol, e.g. CR='Normalization of tumor marker level', PD='Elevation 
of tumor markers to certain level', SD='Not qualifying for CR or PD'. These criteria are 
indication and study specific. In that case, the protocol should clearly specify that additional 
criteria are used to complement RECIST criteria.
16.1.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 


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lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.

Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.

Nodal lesions
A nodal lesion < 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to < 10 mm in its short axis, it will be considered 
normal for response purpose determination. The lymph node measurements will continue to be 
recorded to allow the values to be included in the sum of diameters for target lesions, which 
may be required subsequently for response determination.
16.1.2.4.2
Determination of target lesion response
Table 16-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response 
(CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.


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Response Criteria
Evaluation of target lesions
Progressive Disease 
(PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm 2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3
1. SOD for CR may not be zero when nodal lesions are part of target lesions
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR
3. In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgment based on the available information (see Notes on target 
lesion response and methodology change in Section 16.1.2.2).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities:

The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease

The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 16-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at 
or after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.

For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.

Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.

Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.


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
Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation.

Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0 mm” 
should be entered for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if < 10 mm in size, will contribute to the 
calculation of target lesion response in the usual way with slight modifications.

Since lesions < 10 mm are considered normal, a CR for target lesion response should be 
assigned when all nodal target lesions shrink to < 10 mm and all non-nodal target lesions 
have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters.

A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression 
in which case the investigator might assign an SD target lesion response; however, this 
should be done with caution and conservatively as the response categories have well 
defined criteria.
16.1.2.4.3
Determination of non-target lesion response
Table 16-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response 
(CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease 
(PD):
Unequivocal progression of existing non-target lesions.1


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Response Criteria
Evaluation of non-target lesions
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK):
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than 
baseline2.
1. The assignment of PD solely based on change in non-target lesions in light of target lesion response of CR, 
PR or SD should be exceptional. In such circumstances, the opinion of the investigator or central reviewer does 
prevail.
2. It is recommended that the investigator and/or central reviewer should use expert judgment to assign a Non-
UNK response wherever possible (see notes section for more details)
Notes on non-target lesion response

The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned.

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. ≥ 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 16.1.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
16.1.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 


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there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion.

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 16.1.2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to ≥10 mm for the first time in the study plus 5 
mm absolute increase. FDG-PET: can complement CT scans in assessing progression 
(particularly possible for ‘new’ disease). See Section 16.1.2.2.
16.1.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in Table 16-3.
Table 16-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 16.1.2.4
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
16.1.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
16.1.3.1 Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 


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since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not < 4 weeks after the 
criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 7 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression ≤ 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6 
week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment.


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Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (≥ 30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not ≥ 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided
from different sources:

Investigator overall lesion response

Novartis calculated overall lesion response (based on measurements from Investigator )
The primary analysis of the best overall response will be based on the sequence of 
investigator//calculated (investigator) overall lesion responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
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Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The time point for 
EPR is study specific. EPR is used for the multinomial designs of Dent et al 2001 and counts 
all patients who at the specified assessment (in this example the assessment would be at 8 weeks 
± window) do not have an overall lesion response of SD, PR or CR. Patients with an unknown 
(UNK) assessment at that time point and no PD before, will not be counted as early progressors 
in the analysis but may be included in the denominator of the EPR rate, depending on the 
analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach).
16.1.3.2 Time to event variables
16.1.3.2.1
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan-Meier estimate is used to assess this endpoint.
16.1.3.2.2
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.


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16.1.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
16.1.3.2.4
PFS2
A recent EMA guidance (EMA Guidance 2012) recommends a substitute end point 
intermediate to PFS and OS called PFS2, a surrogate for OS when OS cannot be measured 
reliably, which assesses the impact of the experimental therapy on next-line treatment. The main 
purpose of this endpoint is to assess long term maintenance strategies, particularly of 
resensitizing agents and where it is necessary to examine the overall “field of influence”.
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol.
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments.
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues with respect to censoring foreseen.
16.1.3.2.5
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
16.1.3.2.6
Duration of response
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 


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a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by 
Morgan 1988.
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates... If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al 2008. It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed) the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
16.1.3.2.7
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 16.1.3.2.6. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 


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is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options:

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
16.1.3.2.8
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 


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occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 16.1.3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
16.1.3.2.9
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with non-
measurable disease is derived slightly differently according to Table 16-4.
Table 16-4
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 16.1.2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 


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only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main ITT analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
16.1.3.2.10
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 16.1.3.2.7, and using the draft FDA guideline on 
endpoints 
(FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and Biolog
ics) as a reference, the following analyses can be considered:
Table 16-5
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or censoring)1
(1) = default unless specified differently in the 
protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before 
next scheduled assessment
(1) Date of progression 
(2) Date of next scheduled assessment2
Progressed
Progressed
C
1
Progression or death after 
exactly one missing 
assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C
2
Progression or death after 
two or more missing 
assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation 
due to ‘Disease progression’ 
without documented 
progression, i.e. clinical 
progression based on 
investigator claim
(1) Ignore clinical progression and follow situations 
above
(2) Date of discontinuation (visit date at which clinical 
progression was determined)
As per above 
situations
Progressed


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Situation
Options for end-date (progression or censoring)1
(1) = default unless specified differently in the 
protocol or RAP
Outcome
F
New anticancer therapy 
given
(1) Ignore the new anticancer therapy and follow 
situations above (ITT approach)
(2) Date of last adequate assessment prior to new 
anticancer therapy
(3) Date of secondary anti-cancer therapy
(4) Date of secondary anti-cancer therapy
As per above 
situations
Censored
Censored
Event
G
Deaths due to reason other 
than deterioration of ‘Study 
indication’
(1) Date of last adequate assessment
Censored (only 
TTP and duration 
of response)
1. Definitions can be found in Section 16.1.3.2.7.
2. After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 16.1.3.2.7.
3. The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy.
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 


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8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan.
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 16-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
16.1.4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
16.1.4.1 Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
16.1.4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-


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up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
Death is a reason which “must” lead to discontinuation of patient from trial.
16.1.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor
16.1.4.4 Medical validation of programmed overall lesion response
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 


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evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
16.1.4.5 Programming rules
The following should be used for programming of efficacy results:
16.1.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
16.1.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 16.1.3.2.8). If all measurement dates have 
no day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
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16.1.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
16.1.4.5.4
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
16.1.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
16.1.4.5.6
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 16-5)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
* Adequate assessment is defined in Section 16.1.3.2.7. This reason is applicable when 
adequate evaluations are missing for a specified period prior to data cut-off (or prior to any 
other censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off.

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-


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cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.


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16.3
Appendix 3: Safety follow-up diagram
Figure 16-1
Safety follow-up diagram for run-in and arm 1
conMeds: concomitant medications


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16.4
Appendix 4: Bayesian logistic regression model (BLRM)
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical data, and the results of the Bayesian analyses and respective dosing decisions for 
some hypothetical data scenarios.
16.4.1
Statistical model
The statistical model comprises single-agent toxicity parts, which allow the incorporation of 
single-agent toxicity data, and an interaction part.
16.4.1.1 Single agent parts
Let πINC (dINC) be the risk of DLT for capmatinib given as a single agent at dose dINC; πPDR (dPDR) 
be the risk of DLT for spartalizumab given as a single agent at dose dPDR. Single agent toxicity 
is modelled using logistic regression for the risk of DLT against log-dose:
Capmatinib: logit(πINC (dINC)) = log(αINC) + βINC log(dINC/ 400)
Spartalizumab: logit(πPDR (dPDR)) = log(αPDR) + βPDR log(dPDR/ 400)
where 400mg is used to scale the doses of both capmatinib and spartalizumab. Hence, αINC and
αPDR (>0) are the single-agent odds of a DLT at 400mg (BID, total daily dose 800mg) and 
400mg (q4w), respectively; and βINC and βPDR (>0) are the increase in the log-odds of a DLT by 
a unit increase in log-dose for capmatinib and spartalizumab respectively.
The statistical model comprises single-agent toxicity parts, which allow the incorporation of 
single-agent toxicity data, and an interaction part.
16.4.1.2 Interaction
Under no interaction, the risk of a DLT at dose dINC of capmatinib and dose dPDR of 
spartalizumab is:
π0comb(dINC, dPDR) = 1 - (1 - πINC (dINC)) (1 - πPDR (dPDR))
To allow for interaction between capmatinib and spartalizumab, an odds multiplier is introduced. 
The risk of DLT for combination dose (dINC, dPDR) is then given by:
odds (πcomb (dINC, dPDR)) = exp (η x dINC / 400 x dPDR / 400) x odds (π0comb (dINC, dPDR)),
where odds(π) = π / (1 - π); and η is the log-odds ratio between the interaction and no interaction 
model at the reference doses. Here η = 0 corresponds to no interaction, with η > 0 and η < 0
representing synergistic and antagonistic toxicity respectively.
16.4.2
Prior specifications
The Bayesian approach requires the specification of prior distributions for all model parameters, 
which include the single agent parameters log(αINC), log(βINC) for capmatinib, log(αPDR), 
log(βPDR) for spartalizumab, and the interaction parameter η. A meta-analytic-predictive (MAP) 
approach was used to derive the prior distribution for the single-agent model parameters based 
upon available DLT data.


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16.4.2.1 Prior distribution for the logistic parameters
Description of the meta-analytic-predictive (MAP) approach
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
(log(α*),log(β*)) of the new trial using DLT data from historical studies.
Let rds and nds be the number of patients with a DLT, and the total number of patients at dose d
in historical trial s (s = 1, ... , S). The corresponding probability of a DLT is πds. The model 
specifications for the derivation of the MAP prior are as follows:
rds | πds  Bin (πds, nds)
logit(πds) = log(αs) + βs log(d / dref)
(log(αs), log(βs)) | μ, Ψ ~ BVN (μ, Ψ), s = 1, ... , S
(log(α*), log(β*)) | μ, Ψ ~ BVN (μ, Ψ)
where dref is the reference dose. The parameters μ = (μ1, μ2) and Ψ are the mean and between-
trial covariance matrix for the logistic parameters, the latter with standard deviations τ1, τ2, and 
correlation ρ. The parameters τ1 and τ2 quantify the degree of between trial heterogeneity. The 
following priors will be used for these parameters:
!
normal priors for μ1 and μ2,
!
log-normal priors for τ1 and τ2, and
!
a uniform prior for ρ.
The MAP prior for single-agent model parameters in the new trial, (log(α*), log(β*)), is the 
predictive distribution
(log(α*), log(β*)) | (rds, nds : s = 1, ... , S)
Since the predictive distribution is not available analytically, MCMC is used to simulate values 
from this distribution. This is implemented using JAGS version 3.4.0. The sample from this 
distribution is then approximated by a mixture of bivariate normal (BVN) distributions. BVN 
mixtures with increasing numbers of mixture components are fitted to the sample using the 
expectation-maximization (EM) algorithm (Dempster et al 1977, Wu CFJ 1983). The optimal 
number of components of the mixture is then identified using the Akaike information criterion 
(Akaike 1974).
Single agent capmatinib
For the MAP model for capmatinib, reference dose dref = 400 mg (BID) is used, and data from 
S = 2 historical studies are available.
Weakly informative normal priors are assumed for μ1 and μ2, with means corresponding to an 
assumed 10% risk of DLT at the reference dose of 400 mg, and a doubling in dose leading to a 
doubling in the odds of the risk of a DLT, respectively. Priors for τ1 and τ2 are assigned such 
that (1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander et al 2010).
The prior distributions for the model used for deriving the MAP priors are specified in 
Table 16-9.


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Table 16-9
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single-agent capmatinib model parameters
Parameter
Prior distribution
μ1
N(mean = logit(0.1), sd = 2)
μ2
N(mean = 0, sd=0.001)
τ1
log-normal(mean = 0.25, sd = log(2)/1.96)
τ2
log-normal(mean = 0.125, sd = log(2)/1.96)
ρ
uniform(-1,1)
Historical data
The dose-DLT data of capmatinib single agent in tablet formulation and BID dosing schedule 
from the following clinical studies are considered as the relevant information (Table 16-10) and 
used to derive the prior distribution for the BLRM parameters (log(αINC), log (βINC)).

CINC280X2102: a Phase I study on adult patients with MET dependent advanced solid 
tumors.

CINC280X1101: a Phase I study of capmatinib in Japanese adult patients with advanced 
solid tumors.
The DLT observation window was 4 weeks in both trials. The AE records of the patients did 
not show any events that had occurred during the 5th and 6th weeks post-baseline and met the 
specified DLT criteria.
Table 16-10
Historical dose-DLT data from capmatinib single agent clinical studies
Dose in BID (mg) 
Number of evaluable patients
Number of DLTs
CINC280X2102
400
4
0
CINC280X1101
200
3
0
400
10
1
Single agent spartalizumab
The prior distribution of spartalizumab single agent BLRM model parameters (log(αPDR), log 
(βPDR)) is a mixture of two components: a MAP prior, and a robustification component, used to 
allow for a dose/toxicity relationship for spartalizumab in combination that differs substantially 
from that in single agent. The components form a mixture prior with respective weights (0.95, 
0.05).
Component 1:
For the MAP model for spartalizumab, reference dose dref = mg (q4w) is used, and data from S 
= 1 historical studies is available.
Weakly informative normal priors are assumed for μ1 and μ2, with means corresponding to an 
assumed 10% risk of DLT at the reference dose of 400 mg, and a doubling in dose leading to a 
doubling in the odds of the risk of a DLT, respectively. Priors for τ1 and τ2 are assigned such 
that (1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander et al 2010).


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The prior distributions for the model used for deriving the MAP priors are specified in 
Table 16-11.
Table 16-11
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single-agent spartalizumab model parameters
Parameter
Prior distribution
μ1
N(mean = logit(0.1), sd = 2)
μ2
N(mean = 0, sd=0.001)
τ1
log-normal(mean = 0.25, sd = log(2)/1.96)
τ2
log-normal(mean = 0.125, sd = log(2)/1.96)
ρ
uniform(-1,1)
Historical data
The dose-DLT data of spartalizumab single agent from the following clinical study are 
considered as the relevant information (Table 16-12) and used to derive the prior distribution 
for the BLRM parameters (log(αPDR), log (βPDR)).

CPDR001X2101: open label multicenter Phase I/II study of the safety and efficacy of 
spartalizumab administered to patients with advanced malignancies.
The DLT observation window in the Phase I dose escalation part of this trial was 4 weeks. The 
6-week AE records of the patients did not show difference from the 4-week data in DLT 
observation. It is assumed that DLT rate is associated with total exposure of PDR00l within the 
observation window, and the average weight of a patient is 80 kg. Then each dose level in the 
historical data dqKw[mg/kg] (K = 2 or 4) can be converted to a flat dose level in a q4w dosing 
schedule, dq4w [mg], using the following:
dq4w [mg] = dqKw[mg/kg] * 80[kg] / K[week] *4[week].
Table 16-12
Historical dose-DLT data from spartalizumab single agent clinical 
studies
Dosing schedule 
Dose level (mg/kg)
Converted to dose 
level in q4w (mg) 
Number of 
evaluable patients
Number of DLTs
q2w
1
160
16
0
q2w
3
480
15
0
q2w
10
1600
8
0
q4w
3
240
6
0
q4w
5
400
10
0
Component 2:
To take into account the potential situation that spartalizumab in combination is substantially 
more toxic than when administered as single agent, and that the longer DLT period of 56 days 
may increase the chance of experiencing toxicity, a second high-toxicity prior component with 
vague bivariate normal distribution is added to improve the robustness of the final prior. The 
parameters of this weekly informative prior distribution are described below:

The mean (log (α(c2)PDR), log (β(c2)PDR)) = (logit(0.33), 0), i.e. the median DLT rate at the 
reference dose (400 mg) was assumed to be 0.33 and doubling in dose was assumed to 
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
The standard deviations of log (α(c2)PDR) and log (β(c2)PDR) are set to 2 and 1, respectively.

The correlation between log (α(c2)PDR) and log (β(c2)PDR) is set to 0, assuming 
independence.
16.4.2.2 Prior distribution for the interaction parameter
Although no interaction is expected for the two agents, uncertainty remains. Therefore, a normal 
prior for the log-odds multiplier η centered at 0 is used that allows for both synergistic and 
antagonistic toxicity. The following assumptions will be used for interaction parameter.

η is normally distributed, with mean 0, and standard deviation

At the run-in dose of 400mg (BID) capmatinib in combination with 400mg spartalizumab 
q4w, η distribution corresponds to a best guess of no interaction and a 97.5% probability 
of having more than 2-fold increase in odds of DLT due to interaction compared to no 
interaction for capmatinib in combination with spartalizumab
Additional historical data for capmatinib and spartalizumab combination
The dose-DLT data for the combination from CINC280X2108 are considered as relevant 
information (Table 16-13) and will be incorporated into the prior model using discounted 
weighting.
CINC280X2108: A phase Ib/II, open-label, multi-center study of capmatinib in combination 
with spartalizumab or spartalizumab single agent in advanced hepatocellular carcinoma
The DLT observation window was 6 weeks.
Data from CINC280X2108 will be incorporated into the prior model using discounted 
weighting, where weight is determined as:
weight = 1 / (1+2nτ2 / sd2), where n refers to study sample size and τ and sd correspond to the 
assumed mean and standard deviation for between-trial heterogeneity. In this case, a moderate 
between-trial heterogeneity is assumed (τ = 0.250, sd = 2).
Table 16-13
Historical dose-DLT data from capmatinib in combination with 
spartalizumab 300 mg Q3W
Capmatinib dose in BID 
(mg) 
Number of evaluable 
patients
Number of DLTs
Weight to be used in 
prior model
CINC280X2108
0.62
200
5
0
300
6
0
400
9
1
16.4.2.3 Summary of prior distributions
The prior distributions of the model parameters are summarized in Table 16-14. The prior 
distribution of DLT rates are summarized in Table 16-15.
Table 16-14
Prior distribution for the model parameters
Parameter
mean
Standard deviations
correlation
weight
Capmatinib single agent model


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Parameter
mean
Standard deviations
correlation
weight
(log(α NC), log(βINC)) ~ BVN
(MAP)
(-2.848, 0)
(1.012, 0)
0
1
Spartalizumab single agent model
(log(αPDR), log(βPDR)) ~ BVN mixture
Component 1 
(MAP)
(-5.034,0)
(1.199, 0.141)
0.003
0.95
Component 2 
(robustification)
(-0.708, 0)
(2, 1)
0
0.05
Interaction parameter
Normal
η
0
0.354
N/A
N/A
Table 16-15
Summary of prior distribution of DLT rates
Capmatinib
BID dose 
(mg)
Prior probabilities that P(DLT) is in the 
interval :
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33,1]
2.5%
50%
97.5%
In combination with spartalizumab 400 mg Q4W
capmatinib 
=400
0.915
0.081
0.004
0.078
0.057
0.013
0.064
0.227
16.4.2.4 Hypothetical data scenarios
To illustrate the performance of the Bayesian model used to guide the run-in part, hypothetical 
DLT scenarios are displayed. In each case, the possibility of going to the randomized phase is 
shown. The safety and tolerability of the dose is determined using the model based assessment 
of the risk of DLT in future patients and the rules as described in Section 6.5.1.
The dose may be recommended to continue if probability of excessive toxicity (i.e. DLT rate ≥ 
33%) < 0.25, satisfying the EWOC criteria.
Table 16-16
Hypothetical DLT scenarios
Scenario
Number of
Patients
Number of DLTs
Posterior probabilities
Median
P(DLT)
P(excessive
toxicity)
1
10
5
0.224
0.159
2
10
6
0.227
0.318
3
12
6
0.251
0.222
4
12
7
0.298
0.388
5
15
7
0.259
0.233
6
15
8
0.304
0.395
If ≤ 5 DLT’s are observed in 10 evaluable patients in run-in, the probability of excessive toxicity 
satisfies the EWOC criteria.
If ≥ 6 DLT’s are observed in 10 evaluable patients in run-in, the probability of excessive toxicity 
do not satisfy the EWOC criteria. In this case, it would be recommended to stop the study.
If ≤ 6 DLT’s are observed in 12 evaluable patients in run-in, the probability of excessive toxicity 
satisfies the EWOC criteria.


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If ≥ 7 DLT’s are observed in 12 evaluable patients in run-in, the probability of excessive toxicity 
do not satisfy the EWOC criteria. In this case, it would be recommended to stop the study.
If ≤ 7 DLT’s are observed in 15 evaluable patients in run-in, the probability of excessive toxicity 
satisfies the EWOC criteria.
If ≥ 8 DLT’s are observed in 15 evaluable patients in run-in, the probability of excessive toxicity 
do not satisfy the EWOC criteria. In this case, it would be recommended to stop the study.

SAP_001.pdf: 


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Document History – Changes compared to previous final version of SAP
Date
Version
Reason for update
Outcome for update
04-Oct-2018
1.0
N/A
N/A - First version
05-Oct-2020
2.0 (Amemdment 
1)
Decision not to 
start 
randomization 
part
Only a final CSR will be 
prepared as
an abbreviated report based 
on the
data from run-in part and 
with reduced analyses.


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
Definition of primary endpoint(s)............................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................13
2.2.1
Subgroup of interest ..............................................................................15
2.3
Patient disposition, demographics and other baseline characteristics ...................15
2.3.1
Patient disposition.................................................................................16
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................18
2.4.1
Study treatment / compliance................................................................18
2.4.2
Prior, concomitant and post therapies...................................................24
2.5
Analysis of the primary objective..........................................................................25
2.5.1
Primary endpoint...................................................................................25
2.5.2
Statistical hypothesis, model, and method of analysis..........................25
2.5.3
Handling of missing values/censoring/discontinuations.......................27
2.5.4
Supportive analyses...............................................................................27
2.6
Analysis of the key secondary objective ...............................................................27
2.7
Analysis of secondary efficacy objective(s)..........................................................27
2.7.1
Secondary efficacy endpoints ...............................................................27
2.7.2
Statistical hypothesis, model, and method of analysis..........................29
2.7.3
Handling of missing values/censoring/discontinuations.......................30
2.8
Safety analyses.......................................................................................................31
2.8.1
Adverse events (AEs)............................................................................31
2.8.2
Deaths....................................................................................................33
2.8.3
Laboratory data .....................................................................................33
2.8.4
Other safety data ...................................................................................34
2.9
Pharmacokinetic endpoints....................................................................................37
2.10
Immunogenicity and PK/PD analyses ...................................................................38
2.10.1
Immunogenicity ....................................................................................38
2.11
Other Exploratory analyses....................................................................................40


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2.12
Interim analysis......................................................................................................40
3
Sample size calculation .....................................................................................................40
3.1
Primary analysis.....................................................................................................40
3.2
Power for analysis of key secondary variables......................................................40
4
Change to protocol specified analyses ..............................................................................41
5
Appendix ...........................................................................................................................41
5.1
Imputation rules.....................................................................................................41
5.1.1
Study drug.............................................................................................41
5.1.2
AE, ConMeds and safety assessment date imputation..........................42
5.2
AEs coding/grading ...............................................................................................44
5.3
Laboratory parameters derivations ........................................................................44
5.4
Statistical models...................................................................................................45
6
Reference...........................................................................................................................45


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
Bid
CD8
bis in diem/twice a day
Cluster of differentiation 8
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DDS
Dose Determining Set
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee 
ECG
Electrocardiogram
FAS
Full Analysis Set
eCRF
IHC
Electronic Case Report Form
Immunohistochemistry
irRECIST
Immune-related RECIST
IVR
Interactive Voice Response
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NSCLC
Non-small Cell Lung Cancer
o.d.
Once Daily
OS
Overall Survival
PD-1
Programmed Death 1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
qd
Qua’que di’e / once a day
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This abbreviated statistical analysis plan (SAP) describes all planned analyses for the Clinical 
Study Reports (CSRs) of study CINC280D2201, a phase II, multicenter, randomized, two-arm 
study of capmatinib (INC280, an oral MET inhibitor) and spartalizumab (PDR001, a PD-1 
inhibitor) combination therapy versus docetaxel in pretreated adult patients with EGFR wild-
type, ALK rearrangement negative locally advanced/metastatic non-small cell lung cancer.
The content of this SAP is based on protocol [CINC280D2201-v00--protocol]. All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock of the study data.
During the run-in part of the study (18 subjects enrolled), we explored the safety and 
preliminary efficacy of this combination testing the hypothesis of immunomodulatory and 
synergistic activity of capmatinib with spartalizumab in subjects previously treated with 
platinum and checkpoint inhibitor (anti-PD(L)-1).
The primary objective for the run-in part (safety) was met with no new safety signal observed. 
Nevertheless the preliminary efficacy data, suggests early on that the probability to observe the 
strong efficacy signal in proof of concept randomized part, which will lead to change of standard 
of care, is low. Based on these preliminary results, the randomized part of the study will not be 
opened.
In consideration of the early permanent recruitment halt and given that the randomized part of 
the study will not be opened, the final analysis will not be performed as originally planned for 
all endpoints. This abbreviated SAP describes the analyses to be performed.
1.1
Study design
This is a two-part prospectively designed, multicenter, open-label, randomized phase II study 
to evaluate the safety and efficacy of capmatinib in combination with spartalizumab in adult 
subjects with EGFR wt (for exon 19 deletions and exon 21 L858R substitution mutations), ALK 
rearrangement negative in locally advanced (stage IIIB, not eligible for definitive chemo-
radiation) or metastatic (stage IV) NSCLC after failure of platinum doublet and checkpoint 
inhibitor treatment. The study was planned to enroll approximately 105 subjects (approximately 
15 subjects in the run-in [part 1] and 90 subjects in the randomized phase [part 2]). 
The final analysis results will be summarized in the final abbreviated clinical study report (CSR).
Part 1: Run-in
The primary objective of this part was to assess the safety and tolerability as well as preliminary 
efficacy of the capmatinib and spartalizumab combination. Eighteen subjects were enrolled and 
treated with capmatinib and spartalizumab combination. A review meeting took place after all 
subjects have at least 24 weeks of follow-up. 
Refer to Figure 1-1 for an overview of the Part I study design.


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Figure 1-1
Study Design Part 1: Run-in
pts: patients FUP: follow-up
Part 2: Randomized
Based on the preliminary results of the run-in part, the randomized part of the study will not be opened.
Definition of primary endpoint(s)
Part 1: Run-in
Incidence of DLTs during the first 8 weeks (56 days) of treatment for patients in the DDS.
Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital 
signs, and ECGs.
Tolerability: Dose interruptions, reductions, and dose intensity.


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Part 2: Randomized
Based on the preliminary results of the run-in part, the randomized part of the study will not be 
opened.
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below. In consideration of the 
early permanent recruitment halt and given that the randomized part of the study will not be 
opened, the final analysis will not be performed as originally planned for all endpoints. This
abbreviated SAP describes the analyses to be performed for the run-in part of the study.
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

Run-in part: To assess safety and 
tolerability of capmatinib and spartalizumab 
combination

Run-in part: Incidence and severity of AEs 
and SAEs, including changes in laboratory 
values, vital signs and ECGs, dose 
interruptions, reductions, and dose intensity.

Randomized part: To assess the overall 
survival of combination of capmatinib and 
spartalizumab in comparison to docetaxel

Randomized part: Overall Survival
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the objective response rate 
(ORR), disease control rate (DCR), 
progression-free survival (PFS), duration of 
response (DOR), and time to response 
(TTR) of the capmatinib and spartalizumab 
combination and that of docetaxel

Objective response rate (ORR), disease 
control rate (DCR), progression-free survival 
(PFS), duration of response (DOR), and time 
to response (TTR) based on RECIST 1.1 

To assess the safety profile of capmatinib 
and spartalizumab combination therapy

Incidence and severity of AEs and SAEs

To characterize the pharmacokinetics of 
capmatinib and spartalizumab as a 
combination therapy in this patient 
population

Pharmacokinetic parameters (e.g. Ctrough, 
Cmax, AUC)

To evaluate the prevalence and incidence 
of immunogenicity

Antidrug antibodies (ADA) prevalence at 
baseline and ADA incidence on treatment


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Objective(s)
Endpoint(s)
2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis and/or a designated CRO. SAS version 9.4 or 
later and R version 3.2.3 or later software will be used to perform all data analyses and to 
generate tables, figures and listings.
Data included in the analysis
The analysis cutoff date for the final analysis of study data will be established at the end of the 
study. All statistical analyses will be performed using all data collected in the database up to
the data cut-off date. All data with an assessment date or event start date (e.g. vital sign
assessment date or start date of an adverse event) prior to or on the cut-off date will be
included in the analysis. Any data collected beyond the cut-off date will not be included in the
analysis and will not be used for any derivations.
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these cases, the end date will not be imputed and 
therefore will not appear in the listings.
The end of study is defined as the earliest occurrence of one of the following:

All subjects have died or discontinued from the study.

Another clinical study becomes available that can continue to provide capmatinib 
and spartalizumab combination in this subject population, and all subjects ongoing 
are eligible to be transferred to that clinical study.


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General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
; a missing category will be included as applicable. Percentages will be
calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by
treatment group.
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, will refer to capmatinib or spartalizumab. The term investigational drug 
and study drug are used interchangeably. Whereas, study treatment will refer to capmatinib in 
combination with spartalizumab. 
Date of first administration of investigational drug
The date of first administration of investigational drug (capmatinib or spartalizumab) is 
defined as the first date when a non-zero dose of investigational drug (capmatinib or 
spartalizumab) is administered and recorded on ‘Study Treatment: Capmatinib (INC280)’
and ‘Study Treatment_Infusion_Spartalizumab (PDR001)’ (e)CRF pages. 
Example: if 1st dose of capmatinib is administered on 05-Jan-2019, and 1st dose of 
spartalizumab is administered on 03-Jan-2019, then the date of first administration of study 
drug is on 03-Jan-2019. The date of first administration of study drug will also be referred as 
start of investigational drug.
Date of last administration of investigational drug
The date of last administration of investigational drug (capmatinib or spartalizumab) is 
defined as the last date when a nonzero dose of investigational drug (capmatinib or 
spartalizumab) is administered and recorded on 
‘Study Treatment: Capmatinib (INC280)’ and ‘Study Treatment_Infusion_Spartalizumab 
(PDR001)’ (e)CRF pages. 
Example: if last dose of capmatinib is administered on 15-Jan-2020, and last dose of 
spartalizumab is administered on 17-Jan-2020, then the date of last administration of study drug 
is on 17-Jan-2020. The date of last administration of investigational drug will also be referred 
as end of investigational drug.


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Date of first administration of study treatment 
The date of first administration of study treatment is defined as the first date when a non-zero 
dose of any component of study treatment is administered and recorded on the respective 
component-specific Study Treatment eCRF. 
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a non-zero 
dose of any component of study treatment was administered and recorded on the respective 
component-specific Study Treatment eCRF.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date.
The reference start date for all assessments (e.g. safety, efficacy, PK, 
, etc.) is the start of 
study treatment. 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.
Note: Some measurements may belong to safety measurement and to efficacy measurement
(death’ is an efficacy endpoint, but it can also be included in the safety analysis). For safety,the 
‘study day’ will be calculated relative to start of study treatment.
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is reported in 
years, duration in days will be divided by 365.25.
Baseline
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of start of study treatment (for the run-in part) is taken as “baseline” value 
or “baseline” assessment.  
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as “baseline” assessment.
In case time of assessment and time of treatment start is captured (e.g. pre-dose ECG), the last 
available assessment before the treatment start date/time is used for baseline.


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For safety parameters (e.g ECGs or vital signs), where study requires multiple replicates per 
time point, the average of theses measurements would be calculated for baseline (if not already 
available in the database).
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: 

If values are from central and local laboratories, the value from central assessment 
should be considered as baseline. 

If multiple values are from the same laboratory (local or central) or collected for ECGs 
or vital signs, then the last value should be considered as baseline.
If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments: 
1. Pre-treatment period: from the day of the subject’s informed consent to the day before the 
first dose of study treatment.
2. On-treatment period: from the day of the first dose of study treatment to 150 days after the 
last dose of spartalizumab, or 30 days after the last dose of capmatinib, whichever is later 
(including start and stop dates).
3. Post-treatment period: starting at 151 days after last dose of spartalizumab, or 31 days after 
last dose of capmatinib, whichever is later.
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. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). However, all safety data (including those from the post-treatment 
period) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
Additional summaries will be displayed to report deaths, all AEs, AEs related to study 
treatment, all SAEs and SAEs related to study treatment collected up to 150 days after last 
administration of spartalizumab or up to 30 days after the last dose of capmatinib whichever 
comes last.
Note: If a patient starts a post-treatment antineoplastic therapy after the last administration of 
study treatment, only adverse events suspected to be related to study treatment will be collected 
up to 150 days after discontinuation of spartalizumab or up to 30 days after discontinuation of 
capmatinib whichever comes last. All AEs/ all SAEs are planning to be reported up to 150 days 
after discontinuation of spartalizumab or up to 30 days after discontinuation of capmatinib 
acknowledging that complete collection of data may not be feasible for each patient.


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Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-2
Last contact date data sources
Source data
Conditions
Last contact date/last date subject was known to 
be alive from Survival Follow-up page
Subject status is reported to be alive, lost to 
follow-up or unknown
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.
Start/End dates from study treatment pages
Non-missing dose. Doses of 0 are allowed.
End of treatment date from disposition page at 
end of treatment
No condition.
Tumor (RECIST / 
) assessment date
Evaluation is marked as ‘done’.
Verification for treatment beyond RECIST1.1 PD
At least one non missing parameter value
Laboratory/PK/IG collection dates
Was sample taken? = ‘Yes’. 
Vital signs date
At least one non-missing parameter value
Performance Status date
Non-missing performance status
Start/End dates of AE 
Non-missing verbatim term
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the subject was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring if coming from ‘Survival information’ eCRF. 
2.2
Analysis sets
Full Analysis Set
The Full Analysis Set (FAS) comprises all subjects in the run-in who received at least one dose 
of any component of study treatment..
Safety
The Safety Set includes all subjects who received at least one dose of study treatment (i.e. at 
least one dose of spartalizumab [including incomplete infusion] or of capmatinib). FAS and 
safety set are the same in the run-in part of this study.
Dose-Determining Set 
The Dose-Determining Set (DDS) includes all patients from the Safety Set in the run-in part 
who met the minimum exposure criterion and had sufficient safety evaluations, or experienced 
a dose limiting toxicity (DLT) during the first 56 days (8 weeks) of dosing.


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A subject has met the minimum exposure criterion if the subject receives at least 1 infusion of 
spartalizumab and takes at least 50% of the planned dose of capmatinib within the first 8 weeks 
of treatment.
Subjects who do not experience a DLT during the first 56 days of dosing are considered to have 
sufficient safety evaluations if they have been observed for ≥ 56 days following the first dose, 
and are considered by both the sponsor and investigators to have enough safety data to conclude 
that a DLT did not occur.
Pharmacokinetic analysis set (PAS)
The capmatinib pharmacokinetic analysis set (PAS-INC280) includes all subjects who provide 
at least one evaluable capmatinib PK concentration. For a concentration to be evaluable, 
subjects are required to:

take a planned dose of capmatinib prior to sampling.

for pre-dose samples, do not vomit within 4 hours after the dosing of capmatinib prior to 
sampling; for post-dose samples, do not vomit within 4 hours after the dosing of capmatinib.

for pre-dose sample, have the sample collected before the next dose administration and 9-
15 hours after the last dose administration.
The spartalizumab pharmacokinetic analysis set (PAS-PDR001) includes all subjects who 
provide at least one evaluable spartalizumab PK concentration. For a concentration to be 
evaluable, subjects are required to:

receive one of the planned treatments of spartalizumab prior to sampling.

for pre-dose samples, have the sample collected before the next dose administration.

for end-of-infusion samples, have the sample collected within 2 hours post end of infusion.
Immunogenicity (IG) analysis sets
The immunogenicity (IG) set includes two parts: IG prevalence set and IG incidence set:

The IG prevalence set includes all subjects in the Full analysis set with a determinant 
baseline IG sample or at least one determinant post-baseline IG sample.

The IG incidence set includes all subjects in the IG prevalence set with a determinant 
baseline IG sample and at least one determinant post-baseline IG sample.
Patient Classification: 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 
2-3. 


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Table 2-3
Subject classification based on protocol deviations and non-PD 
criteria
Analysis set
Protocol 
deviations 
leading to exclusion
Non protocol deviation leading to exclusion
FAS 
No written informed
consent
Not applicable
Safety set
No written informed
consent
Not applicable
PAS-INC280
No written informed
consent
No evaluable capmatinib PK concentration
PAS-PDR001
No written informed
consent
No evaluable spartalizumab PK 
concentration
IG prevalence set
No written informed
consent
Subject not in the FAS
No determinant baseline IG sample and no 
determinant post-baseline IG sample
IG incidence set
No written informed
consent
Subject not in the FAS
No determinant baseline IG sample or no 
determinant post-baseline IG sample
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF. 
Death events may be used in the analysis if captured from public records (registers), local law 
and subject informed consent permiting.
Additional data for which there is a separate informed consent, e.g. PK, biomarker etc., 
collected in the clinical database without having obtained that consent will not be included in 
the analysis. These data will be excluded by the presence of the appropriate protocol deviation 
criterion.
2.2.1
Subgroup of interest
Not applicable for the run-in part.
2.3
Patient disposition, demographics and other baseline
characteristics
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries and listings will be reported to assess baseline 


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comparability.  Of note, all patients from the run-in part may be presented in the summaries, if 
relevant. No inferential statistics will be provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data (e.g. gender, age groups: <65 and ≥ 65 years, race, ethnicity, ECOG 
performance status, smoking history) will be summarized by frequency counts and percentages;
the number and percentage of patients with missing data will be provided. Continuous data (e.g. 
age, weight, height, body mass index) will be summarized by descriptive statistics (N, mean, 
median, standard deviation, minimum and maximum). 
Body mass index (BMI) (kg/m2) will be calculated as:
BMI [kg/m2] = weight[kg] / (height[m]2) using weight at Baseline. 
Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include
the
following:
primary site
of
cancer,
details of tumor histology/cytology,
histological grade, stage at initial diagnosis, time since initial diagnosis, time from initial 
diagnosis to first recurrence/progression (in months), time since most recent relapse/progression 
to start of treatment (in months), stage at time of study entry, presence/absence of target and 
non-target lesions, number and type of metastatic sites involved. Note: Presence/absence of 
target and non-target lesions will be based on the data collected on RECIST target/non-target 
lesion assessment eCRF pages. Metastatic sites will be based on diagnosis page.
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on (e) CRF will be summarized and listed. Separate summaries will be presented for 
ongoing and historical medical conditions.  The summaries will be presented by primary system 
organ class (SOC), preferred term (PT). Medical history and current medical conditions will be
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 
MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable tables/listings.
Other
All data collected at baseline including source of patient referral and exploratory biomarker 
informed consent, and treatment beyond progression informed consent will be listed.
2.3.1
Patient disposition
The number (%) of treated patients included in the FAS will be presented overall. The number 
(%) of patients in the FAS who are still on treatment, who discontinued the study phases and 
the reason for discontinuation will be presented.
The following summaries will be provided (with % based on the total number of FAS patients):


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
Number (%) of patients who were treated (based on the study treatment eCRF pages 
of each study treatment component completed with non-zero dose administered)

Number (%) of patients who are still on-treatment (based on the ‘End of 
Treatment’ page not completed); 

Number (%) of patients who discontinued the study treatment phase (based on the 
‘End of Treatment’ page) 

Primary reason for study treatment phase discontinuation (based on the ‘End of 
Treatment’ page)

Number (%) of patients who have entered the post-treatment follow-up (based on 
the ‘End of Treatment’ page);

Number (%) of patients who have discontinued from the post-treatment follow-up
(based on the ‘Disposition’ page);

Reasons for discontinuation from the post-treatment follow-up (based on 
Study’Disposition’);

Number (%) of patients who have entered the survival follow-up (based on the 
‘End of Treatment’ or ’Disposition’page).
Protocol deviations
The number (%) of subjects in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the edit checks specification) overall for the FAS. All 
protocol deviations will be listed.
The outbreak of the Covid-19 pandemic necessitated some changes to the study conduct such 
that the protocol could not be followed strictly. To understand the effect of the pandemic on the 
execution and outcome of the study, deviations will be identified and recorded as protocol 
deviations. 
In addition to the pre-defined standard PD terms, Novartis has defined 6 new protocol 
deviations and the corresponding relationship (health status related vs. site lockdown, patient 
concerns, etc.) to the COVID-19 pandemic in line with “FDA Guidance on Conduct of Clinical 
Trials of Medical Products during COVID-19 Public Health Emergency” (March 2020) and 
“Guidance on the management of clinical trials during the COVID-19 (coronavirus) pandemic” 
(April 2020) from EMA as listed below. 

Missing visits

Changes in procedures and assessments

Planned visits not done at sites

Changes in drug supply method

Treatment not given

Patient discontinuation due to COVID-19 situation
The COVID-19 related protocol deviations will be summarized if applicable.


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Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity
(RDI) will be summarized separately for each component of study treatment. Duration of 
exposure will also be calculated for the study treatment.
Duration of exposure and relative dose intensity will be categorized into time intervals; 
frequency counts and percentages will be presented for the number(%) of subjects in each 
interval. 
The number (%) of subjects who have dose reductions or interruptions, and the reasons, will be 
summarized for all subjects. Subject level listings of all doses administered on treatment along 
with dose change reasons will be produced.  
The safety set will be used for all summaries and listings of study treatment. 
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to capmatinib and spartalizumab.
Duration of exposure to study treatment (INC280+PDR001) = (last date of exposure to study 
treatment) – (date of first administration of study treatment) + 1.
The last date of exposure to study treatment (INC280+PDR001) is the latest of the last dates of 
exposure to capmatinib and spartalizumab (see Table 2-4).
Duration of exposure to study drug (capmatinib/spartalizumab)
Duration of exposure to capmatinib (days) = (last date of exposure to capmatinib) – (date of 
first administration of capmatinib) + 1.
The last date of exposure to capmatinib is the end date from the last dose administration record 
non-zero capmatinib dose is recorded in the study treatment eCRF.
Duration of exposure to spartalizumab (days) = (last date of exposure to spartalizumab) – (date 
of first administration of spartalizumab) + 1.
With:

The last date of exposure to spartalizumab is the end date from the last dose 
administration record non-zero spartalizumab dose is recorded in the study treatment 
eCRF + 27 days (if no death or no lost to follow-up is observed).


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
The last date of exposure to spartalizumab is the earliest date among last dose 
administration record non-zero spartalizumab dose + 27 days and date of death if the 
subject died.

The last date of exposure to spartalizumab is the earliest date among last dose 
administration record non-zero spartalizumab dose + 27 days and date of last contact 
date if the subject was lost to follow-up.
Note :  If the derived last date of exposure goes beyond the data cutoff date, it should be 
truncated to the date of data cutoff.
Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components, 
respectively. 
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of study treatment component administration. The planned 
cumulative dose is not summarized/listed. It is used for relative dose intensity calculations.
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the in the Study treatment –
Capmatinib/ Study  Treatment_Infusion_Spartalizumab eCRF pages.
For patients who did not take any drug the cumulative dose is by definition equal to zero.
For capmatinib (continuous dosing), the actual cumulative dose is the sum of the non-zero doses 
recorded over the dosing period. The planned cumulative dose is the planned starting dose 
summed over the same dosing period.
For spartalizumab (intermittent dosing), the actual cumulative dose should be defined based on 
the days when the subject is assumed to have taken a non-zero dose during dosing periods 
(number of infusions taken over the treatment period). The planned cumulative dose is the 
planned starting dose summed over the number of expected infusions during treatment period 
(e.g, a subject treated for 60 days is expected to have three infusions).
Planned cumulative dose is calculated as follows:
Spartalizumab in mg
400(mg) * W, 
where W is the integer part of [duration of exposure (days)/28]
Capmatinib in mg
800 mg/day*d where d is the duration of exposure in days
Dose intensity and relative dose intensity
For dose intensity calculations, the unit of time for capmatinib will be days and for 
spartalizumab will be cycles.
For capmatinib, the dose intensity (DI) is defined as follows: 
DI (mg / days) = Actual Cumulative dose (mg) / Duration of exposure to capmatinib (days).


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For example: 
The duration of exposure is 56 days and the subject received 50 days of full dosing
DI (mg/day) = 40 000 (mg) / 56 (Day) = 714 (mg/day)
For spartalizumab, the dose intensity (DI) is defined as follows: 
DI (mg / cycles) = length of cycle * (Actual Cumulative dose (mg) / duration of exposure to 
spartalizumab (days)).
For example: 
The duration of exposure is 56 days and the subject received two complete infusions
DI (mg/cycle) = 28 (days) * (800 (mg) / 56 (days)) = 400 (mg/cycle)
For patients who did not take any drug the DI is by definition equal to zero. 
For capmatinib, the Planned dose intensity (PDI) is defined as follows:
PDI (mg / days) = Planned Cumulative dose (mg) / Duration of exposure to capmatinib (days)
For example: 
The duration of exposure is 56 days and the subject is planned to receive 56 days of dosing
PDI (mg/day) = 44 800 (mg) / 56 (Day) = 800 (mg/day)
For capmatinib, the Planned dose intensity (PDI) will always be 800 mg/day.
For spartalizumab, the Planned dose intensity (PDI) is defined as follows: 
PDI (mg / cycles) = length of cycle * (Planned Cumulative dose (mg) / duration of exposure to 
spartalizumab (days)).
For example: 
The duration of exposure is 56 days and the subject is planned to receive two infusions
PDI (mg / cycles) = 28 (days) * (800 (mg) / 56 (days)) = 400 (mg/cycle)
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg / unit of time) / PDI (mg / unit of time)
DI and RDI will be summarized separately for each of the study treatment components, using 
the duration of exposure of each of the components. RDI will be summarized in percentages. 
Summary of RDI includes categorical summaries. The RDI categories are < 50%, ≥ 50% - < 
75%, ≥ 75% - < 90%, ≥ 90% - < 110% and ≥ 110%.
Dose reductions, interruptions or permanent discontinuations
The number of patients who have dose reductions, interruptions, permanent discontinuations, 
and the reasons will be summarized separately for each of the study treatment components in 
the run-in part. 


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‘Dose changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
Dosage Administration Record (DAR) CRF pages will be used to determine the dose reductions, 
dose interruptions, and permanent discontinuations, respectively.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons.
Interruption: An interruption is defined as a dose of zero given on one or more days between 
two non-zero dosing records. 
For the purpose of summarizing interruptions and reasons, any two or more consecutive zero 
doses of capmatinib or spartalizumab will be counted as one interruption if the reasons for these 
two consecutive dose interruptions are the same. It will be counted as two different interruptions 
only if the reasons are different. If an interruption occurs for more than one day due to the same 
reason, but the days are not consecutive, i.e., there is at least one dosing day in between, then 
each dose interruption will be counted as a different occurrence. For patients who have dose 
interruption checked but never resume non-zero dose, the dose interruption will not be counted.
Reduction (For Capmatinib only): A dose reduction is defined as a decrease of the total 
capmatinib daily dose from the protocol planned starting dose (400mg BID) to another non-
zero dose or a decrease from the previous non-zero dose that is less than protocol planned 
starting dose to another non-zero dose, even if the decrease has been directly preceded by an 
interruption. The number of reductions will be derived programmatically  based on the change 
and the direction of the change.
For example, in the sequence 800 mg total daily to 0 mg to 600 mg to 400 mg, 600 mg and 400 
mg total daily will be counted as reductions. On the other hand, if the dose decrease is followed 
by an interruption, with the dose resuming at the same level prior to the interruption (e.g. in the 
sequence 800 mg total daily to 600 mg to 0 mg to 600 mg), the second 600 mg will not be 
counted as dose reduction.
If, due to a dosing error, a patient receives a higher than planned starting dose and moves down 
to the planned starting dose then this is not considered a dose reduction. However if the dose 
change is from a higher than planned starting dose down to a lower than protocol planned 
starting dose, then this is considered a dose reduction. (e.g. in the sequence: 1000 mg total daily 
to 800 mg total daily to 600 mg total daily, 600 mg is considered as a dose reduction assuming 
that 800 mg total daily is the protocol planned starting dose).
If a patient receives a lower than previous non-zero dose and resumes later at the protocol 
specified dose reduction, then the lower dose received due to dosing error and protocol specified 
dose reduction are dose reductions (e.g. in the sequence: 800 mg daily to 400 mg daily to 600 
mg daily, then 400 mg and 600 mg are considered as dose reductions assuming that 800 mg 
daily is the protocol planned starting dose).
If due to interruption, a patient receives half of the dose during 1 day and followed by an 
interruption (due to the same reason) then this is not a dose reduction. Dose interruption starts 
on the day that half of the dose is administered. For example, in the sequence: 800 mg total 
daily to 400 mg once a day to 0 mg to 600 mg BID, 400 mg is not a dose reduction, 600 mg is 
a dose reduction.


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If due to permanent discontinuation, a patient receives half of the dose the last day of treatment 
then this is not a dose reduction.
The following are different examples of dose reduction.
Case 1: If a patient did not receive the protocol planned dose for any reason (for e.g. see table 
below), then this is a dose reduction (e.g. 200/400 mg, 800 mg).
Patient ID
Start date
End date
Dose
Regimen
Reason
Reduction
(derived)
Comments
400
ONCE PER DAY
DOSING ERROR
Y
1st administration 
different from protocol 
planned dose (800 mg)
800
2 TIMES PER
DAY
Case 2: If, due to a dosing error, a patient receives higher than protocol planned dose and moves 
down to the planned dose then this is not a dose reduction (800 mg, 1000 mg, 800 mg); However 
if the change is directly from a higher than planned dose down to a lower than protocol planned 
dose, then this is a dose reduction (e.g. In the sequence, 800 mg, 1000 mg, 400 mg, is a dose 
reduction).
Patient ID
Start date
End date
Dose
Regimen
Reason
Reduction
(derived)
Comments
800
2 TIMES PER 
DAY
0
ADVERSE EVENT
600
2 TIMES PER 
DAY
ADVERSE EVENT
Y
700
2 TIMES PER 
DAY
DOSING ERROR
Y
800
2 TIMES PER 
DAY
1000
2 TIMES PER 
DAY
DOSING ERROR
800
2 TIMES PER 
DAY
N
moves down to the 
dose administered just 
before dosing error
800
2 TIMES PER 
DAY
0
ADVERSE EVENT
600
2 TIMES PER 
DAY
ADVERSE EVENT
Y
700
2 TIMES PER 
DAY
DOSING ERROR
Y
800
2 TIMES PER 
DAY
1000
2 TIMES PER 
DAY
DOSING ERROR
600
2 TIMES PER 
DAY
Y
moves down to a lower 
dose administered just 
before dosing error




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levels (for ex: 600 mg 2 times per day from 
, and 300 mg once 
per day on 
).
Patient
ID
Start date
End date
Dose
Regimen
Reason
Permanently 
discontinuation
Reduction
(derived)
800
2 TIMES PER 
DAY
400
ONCE PER DAY
ADVERSE EVENT
Y
N
2.4.2
Prior, concomitant and post therapies
Prior anti-neoplastic therapy
The number and percentage of patients who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized based on 
FAS. Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery.
Prior anti-neoplastic medications will be summarized by number of prior regimens of anticancer 
medications, therapy type, therapy type at last treatment, setting at last treatment, best response 
to last treatment. Prior antineoplastic medications will also be summarized by ATC class, and 
preferred term. The medication therapy type of any combination therapy will be classified based 
on the following order: immunotherapy, chemotherapy, biologic therapy (other than 
immunotherapy), targeted therapy, hormonal therapy. For example, a combination therapy of 
chemotherapy and immunotherapy will be classified as ‘immunotherapy’.The summary of prior 
anti-neoplastic radiotherapy will include the radiotherapy locations, (including all locations 
recorded for each subject), setting at last radiotherapy, and the time (in months) between the 
last radiotherapy to start of study treatment.
The summary of prior anti-neoplastic surgery will include the time (in months) between the last 
surgery (non-biopsy procedure) to start of study treatment, procedure at last surgery and residual 
disease at last surgery.
Anti-neoplastic medications will be coded using the NovDTD/WHO Drug Dictionary (WHO-
DD); anti-neoplastic surgery will be coded using MedDRA. Details regarding MedDRA and 
WHO-DD/ NovDTD version will be included in the footnote in the tables/listings. 
Post treatment anti-neoplastic therapy
Anti-neoplastic therapies since discontinuation of study treatment-medications will be
summarized by ATC class, preferred term, by means of frequency counts and percentages. 
Antineoplastic radiotherapy  (concomitant and since discontinuation of study treatment) will 
will also be summarized, by means of frequency counts and percentages. Antineoplastic surgery 
will also be summarized by system organ class and preferred term.
The above analyses will be performed using the FAS.


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Concomitant therapy
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference  Listing  (DRL)  dictionary  that  employs  the  WHO  Anatomical  Therapeutic 
Chemical (ATC) classification system and summarized by lowest ATC class and preferred term
using frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. Concomitant medications will be 
summarized by lowest ATC class and preferred term using frequency counts and percentages.
These summaries will include:
1. Medications starting on or after the start of study treatment but no later than 30 days 
after last dose of capmatinib or 150 days after the last dose of spartalizumab, 
whichever comes last
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment.
All reported concomitant therapies will be listed.
Any concomitant therapies starting and ending prior to the start of study treatment or starting
more than 150 days after the last dose of spartalizumab or 30 days after last dose of capmatinib, 
whichever comes last, will be flagged in the listing. 
The safety set will be used for all concomitant medication tables and listings.
2.5
Analysis of the primary objective
The primary objective is to assess the safety and tolerability of capmatinib and spartalizumab 
combination
2.5.1
Primary endpoint
Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs 
and ECGs, dose interruptions, reductions, and dose intensity.
DLT is defined in the study protocol (See Section 6.5.4, Table 6-6).
2.5.2
Statistical hypothesis, model, and method of analysis
The adaptive BLRM guided by EWOC principle will be used to assess the safety and tolerability 
of capmatinib (INC280) in combination with spartalizumab (PDR001). The BLRMs will be 
fitted on the dose-limiting toxicity data (i.e. absence or presence of DLT) during the 56 day 
DLT window accumulated to model the dose-toxicity relationship.
The dose-toxicity (DLT) relationship is modeled by a 5-parameter BLRM as follows. Let π1(d1) 
be the probability of DLT if PDR001 is given as a single-agent at Q4W dose d1, and π2(d2) the 


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probability of DLT if capmatinib is given as a single-agent at total daily dose of d2. It is assumed 
that the toxicity of capmatinib is driven primarily by AUC and therefore it is critical to use a 
total daily dose irrespective of regimen, e.g. 400 mg bid will correspond to 800 mg total daily 
dose. π12(d1,d2) denotes the probability of DLT if PDR001 is given in combination with 
capmatinib at Q4W dose d1 of PDR001 and total daily dose d2 of capmatinib. The possibility 
of synergism or antagonism between the safety profiles of the two drugs is captured in the model 
of odds of DLT rate with combination doses.
PDR001: logit(π1(d1)) = log(α1) + β1log(d1/d1*)
capmatinib: logit(π2(d2)) = log(α2) + β2log(d2/d2*)
Odds(π12(d1,d2))) = π12(d1,d2)/(1- π12(d1,d2))
= exp(η(d1/d1*)(d2/d2*))(π1(d1)+ π2(d2) – π1(d1) π2(d2))/((1- π1(d1))(1- π2(d2))),
where logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], d1* = 400 mg and d2*= 400 mg are the reference 
doses of PDR001 and capmatinib respectively, α1, α2, β1, β2 >0 and -∞ <η <∞ is the interaction 
coefficient.
The Bayesian approach requires the specification of prior distributions for the model parameters. 
The prior distributions for the BLRM are derived based on available clinical data on PDR001 
(CPDR001X2101) and capmatinib (CINC280X2102 and CINC280C1101). For further details 
on the BLRM including the prior specification for the model parameters, refer to Appendix 4
of the protocol.
After the run-in part, the posterior distribution for the risk of DLT for new subjects at doses of 
interest will be evaluated. The posterior distributions will be summarized to provide the 
posterior probability that the risk of DLT lies within the following intervals:

Under-dosing: [0, 16%)

Targeted toxicity: [16%, 33%)

Excessive toxicity: [33%, 100%]
Dosing decisions are guided by the EWOC principle (Rogatko et al, 2007). A dose may only 
be used for newly enrolled subjects if the risk of excessive toxicity at that dose is less than 25%. 
The final estimate of the MTD will also satisfy this criterion.
Listing and summary of DLTs
A summary of the posterior distribution of the model parameters and the posterior distribution 
of DLT rates based on the DLT data from all subjects included in the DDS will be provided. 
The corresponding results of the BLRM will also be presented graphically.
DLTs will be listed and their incidence summarized by primary system organ class, worst grade 
based on the CTCAE version 5.0. The DDS will be used for these summaries.
Safety and Tolerability
See Section 2.8 for details of analysis.


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2.5.3
Handling of missing values/censoring/discontinuations
Subjects who are excluded from the DDS will be excluded from the BLRM analysis of the run-
in part, although their data will be used for all the remaining analyses.
2.5.4
Supportive analyses
Not applicable.
2.6
Analysis of the key secondary objective
Not applicable.
2.7
Analysis of secondary efficacy objective(s)
The secondary efficacy objectives are to assess the objective response rate (ORR), disease 
control rate (DCR), progression-free survival (PFS), duration of response (DOR), and time to 
response (TTR) of the capmatinib and spartalizumab combination.
2.7.1
Secondary efficacy endpoints
The secondary efficacy endpoints are: objective response rate (ORR), disease control rate 
(DCR), progression-free survival (PFS), duration of response (DOR), and time to response 
(TTR) based on RECIST 1.1 as per local investigator’s assessment.
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 (see Appendix 1 of the study 
protocol). The best overall response is the best response recorded using local investigator’s 
review based on RECIST 1.1 from start of treatment until disease progression/recurrence, death, 
start of new anti-neoplastic therapy, withdrawal of consent or cut-off date, whichever occurs 
first.
ORR will be calculated based on the FAS using local investigators review of tumor assessment 
data. Tumor assessments performed before the start of any further anti-neoplastic therapy (i.e. 
any additional secondary antineoplastic therapy or surgery) will be considered in the assessment 
of BOR. Localized radiotherapy or limited-field palliative radiotherapy are permitted as per 
protocol, in which case these should not be considered in determining anti-neoplastic therapy 
usage. 
Disease control rate (DCR)
DCR is defined as the proportion of patients with a best overall response (BOR) of CR or PR, 
or stable disease (SD) according to RECIST 1.1 criteria. DCR will be calculated using the FAS 
based on the investigators’ tumor assessments. 


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Progression free survival (PFS)
PFS is defined as the start of treatment to the date of the first documented progression or death 
due to any cause. PFS will be based on local investigators review of tumor assessments and 
using RECIST 1.1 criteria.
The analysis will be based on FAS and will include all data observed up-to the cut-off date. If 
a patient has not progressed or died  at the analysis cut-off date, PFS will be censored at the 
date of the last adequate tumor evaluation date before the cut-off date. PFS events documented 
after the initiation of new anti-neoplastic therapy (i.e. RECIST 1.1. documented disease 
progression or death) will be considered provided tumor assessments continue after initiation 
of new anti-neoplastic therapy. (See Section 2.7.3 for additional details regarding censoring 
rules and determination of date of last adequate tumor assessment). Discontinuation due to
disease progression (collected on the ‘disposition’ page) without supporting objective evidence
satisfying progression criteria per RECIST 1.1 will not be considered disease progression for 
PFS derivation. Clinical deterioration will not be considered as a qualifying event for 
progression.
Censoring pattern of PFS
Number of patients with a PFS event and number of patients censored for the PFS analysis will 
be summarized.
In addition, a summary of reasons for PFS censoring will be provided by dose level based on 
the following reasons:
1: Ongoing without event
2: Lost to follow-up
3: Withdrew consent
4: Adequate assessment no longer available
5: Event after ≥ 2 missing tumor assessments
The PFS censoring reasons are defined in the following way. 
If the time interval between the last adequate TA date and the earliest of the following dates is 
smaller or equal to interval of 2 missing tumor assessments:
1. Analysis cut-off date, 
2. Date of consent withdrawal,
3. Visit date of study treatment discontinuation or end of post-treatment follow-up 
discontinuation due to lost to follow-up.
Then the PFS censoring reason will be:
1. ‘Ongoing’, 
2. ‘Withdrew consent’,
3. ‘Lost to follow-up’,  
If the time interval is larger than the interval of 2 missing tumor assessments with no event 
observed, then the PFS censoring reason will always default to ‘Adequate assessment no longer 
available’. If the time interval between the last adequate tumor assessment date and the PFS 


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event date is larger than the interval of 2 missing tumor assessments then the patient will be 
censored and the censoring reason will be 'Event documented after two or more missing tumor 
assessments'.
These summaries on censoring reasons will be produced for PFS by investigator. 
Duration of response (DOR)
DOR is defined as the time from the date of first documented CR or PR (date of initial response 
is used, not date of confirmation) to the first documented progression according to RECIST 1.1
based on local investigators review of tumor assessment data or death due to any cause. Patients 
continuing without progression or death will be censored at the date of their last adequate tumor 
assessment using the censoring rule described for PFS analysis. 
Time to response (TTR)
Time to response (TTR) is defined as the time from the start of treatment (run-in part) to the 
first documented response of either CR or PR, which must be subsequently confirmed (date of 
initial response is used, not date of confirmation) using local investigators review of tumor 
assessment data and according to RECIST 1.1. 
All patients in the FAS will be included in the time to response calculation. Patients who did 
not achieve a confirmed PR or CR will be censored at:

the maximum follow-up time (i.e. FPFV - LPLV used for the analysis) for patients 
who had a PFS event (i.e. either progressed or died due to any cause);

the last adequate tumor assessment date for all other patients.
2.7.2
Statistical hypothesis, model, and method of analysis
Response rates
ORR and DCR will be summarized using descriptive statistics (N, %) along with two-sided 
exact binomial 95% CIs [Clopper and Pearson 1934]. 
PFS 
PFS will be analyzed in the FAS as defined in Section 2.2 and including all data observed up to 
the cut-off date. The survival distribution of PFS will be estimated using the Kaplan-Meier 
method. The medians of PFS and 95% confidence intervals of the medians [Brookmeyer and 
Crowley 1982], along with the proportion of subjects alive at 3, 6 and 9 months and the 
associated 95% confidence intervals, will be presented. Date of PD, last date free of PD, date 
of death, principle cause of death and last date know alive for all subjects will be listed.
TTR
TTR will be summarized using the KM method based on FAS only if there are at least 10 
subjects with a confirmed BOR of CR and PR. Since there are not enough responses, no 
summary statistics is applicable. By patient listing will be provided.


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DOR
DOR is analyzed based on FAS for patients with confirmed BOR of CR or PR if there are at 
least 10 subjects with a confirmed BOR of CR and PR . Since there are not enough responses, 
no summary statistics is applicable. By patient listing will be provided.
2.7.3
Handling of missing values/censoring/discontinuations
PFS
PFS will be censored at the last adequate tumor assessment (TA) if one of the following occurs: 
absence of event; the event occurred after two or more missing tumor assessments. The term 
“missing adequate tumor assessment” is defined as a TA not performed or tumor assessment 
with overall lesion response of “UNK”. The rule to determine number of missing TAs is based 
on the time interval between the date of last adequate tumor assessment and the date of an event. 
If the interval is greater than  twice the protocol-specified interval between the TAs and 2 times 
the protocol-allowed time window around assessments, then the number of missing assessments 
will be 2 or more. The date of last adequate tumor assessment is the date of the last tumor
assessment with overall lesion response of CR, PR or SD or non-CR/non-PD before an event 
or a censoring reason occurred. If no post-baseline assessments are available (before an event 
or a censoring reason occurred) then the date of start date of study treatment will be used.
Refer to Table 2-5 for censoring and event date options and outcomes for PFS.
Table 2-5
Outcome and event/censor dates for PFS analysis
Situation
Date
Outcome
No baseline assessment
Date of start of treatment
Censored
Progression or death at or 
before next scheduled 
assessment
Date of progression (or death)
Progressed
Progression or death after 
exactly one missing assessment
Date of progression (or death)
Progressed
Progression or death after two or 
more missing assessments
Date of last adequate 
assessment prior to missed 
assessment 
Censored
No progression (or death)
Date of last adequate 
assessment 
Censored
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. 
clinical progression based on 
investigator claim
Date of last adequate 
assessment 
Censored
New anticancer therapy given 
prior to protocol defined 
progression
Ignore the new anticancer 
therapy and follow situations 
above 
As per above 
situations
Death before first PD 
assessment
Date of death
Progressed


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ORR
Patients with unknown or missing best overall response (BOR) will be counted as failures. If 
there is no baseline tumor assessment, all post-baseline overall lesion responses are expected to 
be ‘Unknown’. If no valid post-baseline tumor assessments are available, the best overall 
response must be “Unknown” unless progression is reported. For the computation of ORR, 
these patients will be included in the FAS and will be counted as ‘failures’.
Of note, patients with only non-measurable disease at baseline are not allowed in the study. 
However, in case there are such patients, they will be part of the analysis and will be included 
in the numerator only if a CR was observed (as “responders”).
Only tumor assessments performed on or before the start of a new antineoplastic treatment other 
than study drug(s) (not considering palliative radiotherapy) will be considered in the assessment 
of BOR.
2.8
Safety analyses
For all safety analyses, the Safety Set will be used.
2.8.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on treatment period. Additional summaries 
will be displayed to report all AEs, AEs related to study treatment, all SAEs and SAEs related 
to study treatment collected up to 150 days after the last dose of spartalizumab, or 30 days after 
the last dose of capmatinib, whichever is later (including start and stop dates). All AEs collected 
in the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency.
The following adverse event summaries will be produced: overview of adverse events and 
deaths (number and % of subjects who died, with any AE, any SAE, any dose 
reductions/interruptions etc use OSO shell), AEs by SOC and PT, summarized by relationship 
(all AEs and AEs related to study treatment), seriousness (SAEs and non-SAEs), leading to 
treatment discontinuation, leading to dose interruption/adjustment, requiring additional therapy. 
In addition, a summary of serious adverse events with number of occurrences will be produced 


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(an occurrence is defined as >1 day between start and prior end date of record of same preferred
term). 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment adverse events which are not serious adverse events with an incidence greater than 
5% and on on-treatment serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block; if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
For DLTs, summary will be produced (See Section 2.5).
2.8.1.1
Adverse events of special interest / grouping of AEs
Adverse Events of Special Interest (AESI) consist of one or more well-defined safety events 
which are similar in nature and for which there is a specific clinical or safety interest in 
connection with the study compound. All definitions of AESI for capmatinib and 
spartalizumab will be stored in their respective Case Retrieval Strategy (CRS) sheet with clear 
versioning and reference to the MedDRA version used. If a CRS update is necessary, the final 
version needs to be available in a reasonable time ahead of the DBL. The CRS version will be 
included as a footnote of the AESI tables. 
Data analysis of AESIs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound capmatinib or spartalizumab. These groupings are 
defined using MedDRA terms, SMQs (standardized MedDRA queries), HLGTs (high level 
group terms), HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis 
MedDRA queries, NMQ) may also be used. A 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. 
All AESI definitions or AE grouping are specified in the electronic Case Retrieval Strategy 
(eCRS), in which they are identified by the flag “SP”. This file may be updated based on review 
of accumulating trial data, and therefore the groupings are also subject to potential change. The 
most up-to-date version of the eCRS will be used at the time of the analysis.


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For each specified AESI, number and percentage of patients with at least one event of the AESI 
occurring during on treatment period will be summarized.
Summaries of these AESIs will be provided  (specifying grade, SAE, relationship, leading to 
treatment discontinuation, leading to dose adjustment/interruption, hospitalization, death, etc.).
If sufficient number of events occurred, analysis of time to first occurrence will be applied. The 
analysis will be performed for AESI regardless of study drug relationship and for AESI 
suspected to be study drug related. 
Time to first occurrence of an AESI is defined as time from start of study treatment to the date 
of first occurrence of first event within an AESI, i.e. time in days is calculated as (start date of 
first occurrence of event ) – (start of study treatment) +1. 
In the absence of an event during the on-treatment period, the censoring date applied will be 
the earliest of the following dates: 

death date

new anticancer antineoplastic therapy start date (not considering palliative radiotherapy), 

end date of on-treatment period

data cut-off date

withdrawal of informed consent date.
The corresponding censoring reason will be used: death, new anti cancer therapy, treatment 
discontinuation, ongoing at cut-off date or consent withdrawal.
Median together with 95% confidence interval as well as 25th percentile and 75th percentile 
will be presented. 
In addition, the median time to occurrence for the subset of subjects who experienced the event
of interest will be calculated. Simple descriptive statistics, median, min and max as well as 25th 
percentile and 75th percentile, will be presented.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced for all subjects by system organ class and preferred term. Additional summary will 
be displayed to report all deaths up to 150 days after the last dose of spartalizumab or up to 30 
days after the last dose of capmatinib whichever comes last.
All deaths  will be listed, post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened subjects.
2.8.3
Laboratory data
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include only on-treatment assessments (see Section 2.1.1).
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment):


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
Worst post-baseline CTC grade (CTC v5.0) regardless of the baseline status. Each subject
will be counted only for the worst grade observed post-baseline.

Shift tables using CTC grades to compare baseline to the worst on-treatment value

For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  

Listing of all CTC grade 3 or 4 laboratory toxicities.
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values as per 
Novartis Liver Toxicity guidelines will be summarized:
The following summaries will be produced:

ALT >3×ULN, >5×ULN, >8xULN, >10×ULN, >20×ULN

AST >3×ULN, >5×ULN, >8×ULN, >10xULN, >20×ULN

ALT or AST >3×ULN, >5xULN, >8×ULN, >10xULN, >20×ULN

TBL > 2xULN, >3×ULN

ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3×ULN & TBL > 2×ULN & ALP ≥ 2×ULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN 
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
At scheduled visits, triplicate 12-lead ECG’s will be performed. ECG machines will 
automatically calculate heart rate and measures of HR, PR, QRS, QT, QTcB and QTcF intervals. 
ECG data will be read and interpreted locally. 
An unscheduled ECG may be repeated at the discretion of the investigator at any time during 
the study and as clinically indicated. Unscheduled ECGs with clinically significant findings 
should be collected in triplicate. Interpretation of the tracing must be made by a qualified 
physician and documented on the ECG eCRF page.


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Data handling
In case the study requires ECG replicates at any assessment, the average of the ECG parameters 
at that assessment should be used in the analyses.
Data analysis
The number and percentage of patients with notable ECG values will be presented overall and 
by dose level (if applicable). 

QT, QTcF, QTcB
-
New value of > 450 and ≤ 480 ms
-
New value of > 480 and ≤ 500 ms
-
New value of > 500 ms
-
Increase from Baseline of > 30 ms to ≤  60ms
-
Increase from Baseline of > 60 ms

HR
-
Increase from baseline >25% and to a value > 100 bpm
-
Decrease from baseline >25% and to a value < 50 bpm

PR
-
Increase from baseline >25% and  to a value > 200 ms
-
New value of > 200 ms

QRS
-
Increase from baseline >25% and  to a value > 120 ms 
-
New values of QRS > 120 ms 
A listing of all ECG assessments will be produced  and notable values will be flagged. In the 
listing, the assessments collected during the post-treatment period will be flagged.
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: weight (kg), body temperature (°C), pulse rate (beats per 
minute), systolic and diastolic blood pressure (mmHg).
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings.
Data analysis
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-6
below.


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Table 2-6
Clinically notable changes in vital signs
Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase > 10% from Baseline
decrease  > 10% from Baseline
Systolic blood 
pressure 
(mmHg)
≥ 180 with increase from baseline of ≥ 
20
≤ 90 with decrease from baseline of ≥ 20
Diastolic blood 
pressure 
(mmHg)
≥ 105 with increase from baseline of ≥ 
15
≤ 50 with decrease from baseline of ≥ 15
Pulse rate 
(bpm)
≥ 100 with increase from baseline 
of >25%
≤ 50 with decrease from baseline of > 
25%
Body 
temperature
≥39.1
-
The number and percentage of subjects with notable vital sign values (high/low) will be
presented.  Trends of systolic and diastolic blood pressures over time will be displayed via 
boxplots for scheduled assessment timepoints along with corresponding tables displaying the 
statistics used for the box plots.      
A listing of all vital sign assessments will be produced and notable values will be flagged. In 
the listing, the assessments collected outside of on-treatment period will be flagged. 
2.8.4.3
ECOG performance status
The ECOG PS scale (Table 2-7 will be used to assess physical health of patients, ranging from 
0 (most active) to 5 (least active):
Table 2-7
ECOG Performance Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than  50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
Shift tables of ECOG performance status at baseline to worst post-baseline ECOG performance 
status by score will be provided using the safety set; shift tables of ECOG performance status 
at baseline to best post-baseline ECOG performance status by score will also be provided. 
ECOG performance status at each time point will be listed.


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2.9
Pharmacokinetic endpoints
The secondary objective for PK is to characterize the pharmacokinetics of capmatinib and 
spartalizumab as a combination therapy in this patient population
The respective PAS for each study drug will be used in the pharmacokinetic data analysis.
PK parameters
The descriptive statistics (n, mean, CV%, standard deviation (SD), median, geometric mean, 
geometric CV%, minimum and maximum) will be presented for all PK parameters, including 
but not limited to those listed in Table 2-8 except Tmax, where only n, median, minimum and 
maximum will be presented. Any missing PK parameter data will not to be imputed. All 
individual PK parameters will be listed using the Pharmacokinetic analysis set.
Table 2-8
Non-compartmental pharmacokinetic parameters  
AUClast
The AUC from time zero to the last 
measurable concentration sampling time 
(tlast) (mass x time x volume-1) 
AUCtau
The AUC calculated to the end of a dosing 
interval (tau) at steady-state (amount x time 
x volume-1)
Cmax
The maximum (peak) observed plasma 
serum concentration after single dose 
administration (mass x volume-1)
Ctrough
The minimum (peak) observed plasma 
serum concentration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, 
blood, serum, or other body fluid drug 
concentration after single dose 
administration (time)
T1/2
The elimination half-life associated with the 
terminal slope (lambda_z) of a semi 
logarithmic concentration-time curve (time). 
Use qualifier for other half-lives
PK concentrations 
Descriptive statistics (n, m (number of non-zero concentrations), mean, CV%, SD, median, 
geometric mean, geometric CV%, minimum and maximum) for spartalizumab and capmatinib 
concentrations will be presented at each scheduled time point. All concentration data for 
spartalizumab and capmatinib will be displayed graphically.


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The arithmetic mean (SD) and geometric mean and individual concentration versus time 
profiles for spartalizumab and capmatinib will be displayed graphically for patients in 
Pharmacokinetic analysis set on the linear and semi-log view.
All individual plasma for spartalizumab and capmatinib concentration data will be listed for the 
Full analysis set.
Handling of PK data below LLOQ or missing
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.
2.10
Immunogenicity and PK/PD analyses
Another secondary  objective is to evaluate the prevalence and incidence of immunogenicity.
2.10.1
Immunogenicity
Immunogenicity will be characterized descriptively by tabulating anti-drug antibodies (ADA) 
prevalence at baseline and ADA incidence on-treatment. Sample ADA status will be listed.
2.10.1.1 Sample ADA Status
Each IG sample is assessed in a three tiered anti-drug anti-body (ADA) testing approach. All 
IG samples are analyzed in the initial screening assay (first tier). Samples testing negative in 
the screening assay are not subject to a confirmatory assay.  Samples testing positive in the 
screening assay are then subjected to the confirmatory assay to demonstrate that ADA are 
specific for the therapeutic protein product (second tier). The titer of confirmatory positive 
samples will be subsequently determined in the titration assay (third tier). Samples identified as 
positive in the confirmatory assay are considered ADA positive. Samples can test negative in 
either the screening or confirmatory assay but for analysis purposes they are not differentiated.
The following properties of each sample will be provided in the source data: 

Result of assay according to pre-specified confirmatory cut point: ADA positive (yes) or 
ADA negative (no)

Titer (for positive samples): numerical representation of the magnitude of the ADA response

Drug tolerance level: highest drug concentration that does not interfere in the ADA 
detection method

Fold titer change (i.e. x-fold): threshold for determining treatment boosted
Sample ADA status will be defined for spartalizumab, based on their respective PK 
concentrations. Sample ADA status is determined based on the following definitions:


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
ADA-inconclusive sample: Sample where assay is ADA negative and spartalizumab PK 
concentration at the time of IG sample collection is greater than or equal to the drug 
tolerance level or missing.  

Unevaluable sample: Sample where assay is not available.

Determinant sample: Sample that is neither ADA-inconclusive nor unevaluable.
The following definitions apply only to determinant samples:

ADA-negative sample: Determinant sample where assay is ADA negative and 
spartalizumab PK concentration at the time of IG sample collection is less than the drug 
tolerance level. 

ADA-positive sample: Determinant sample where assay is ADA positive.
The following definitions apply only to post-baseline ADA-positive samples with a 
corresponding determinant baseline sample.  To be classified as treatment-boosted or 
treatment-unaffected, both the post-baseline and baseline titer must be non-missing:

treatment-induced ADA-positive sample: ADA-positive sample post-baseline with ADA-
negative sample at baseline. 

treatment-boosted ADA-positive sample: ADA-positive sample post-baseline with titer that 
is at least the fold titer change greater than the ADA-positive baseline titer.

treatment-unaffected ADA-positive sample: ADA-positive sample post-baseline with titer 
that is less than the fold titer change greater than the ADA-positive baseline titer.
NOTE: PK concentrations which are flagged for exclusion will still be used to determine 
ADA-inconclusive and ADA-negative samples.
The following summaries of ADA sample status (n and %) will be provided using 
Immunogenicity prevalence set: 
•
ADA-positive samples (i.e. ADA prevalence)  both overall and by time point (including 
baseline). For summaries by time point, the denominator is the number of subjects at that 
time point with a determinant sample.
Listings will be provided of sample ADA status (including titer for positive samples).
2.10.1.2   Subject ADA status
Any IG sample collected after 150 days of the last dose of spartalizumab will not be used for 
summaries or derivations and will only be included in the listing.
Subject ADA status is defined as follows:

Treatment-induced ADA-positive subject: subject with ADA-negative sample at 
baseline and at least one treatment-induced ADA-positive sample. 

Treatment-boosted ADA-positive subject: subject with ADA-positive sample at baseline 
and at least one treatment-boosted ADA-positive sample.

Treatment-unaffected ADA-positive subject: subject with ADA-positive sample at 
baseline, no treatment-boosted ADA-positive samples, and at least one treatment-
unaffected ADA-positive sample. 


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
Treatment-reduced ADA-positive subject: subject with ADA-positive sample at baseline
and at least one post baseline determinant sample, all of which are ADA-negative 
samples. 

ADA-negative subject: subject with ADA-negative sample at baseline and at least one 
post baseline determinant sample, all of which are ADA-negative samples.  

Inconclusive subject: subject who does not qualify as treatment-induced ADA-positive, 
treatment-boosted
ADA-positive, treatment-unaffected ADA-positive, treatment-
reduced ADA-positive, or ADA-negative.  
The following summaries of ADA subject status (n and %) will be provided using 
Immunogenicity incidence set: 

Treatment-boosted ADA-positive subjects; denominator is the number of subjects with 
ADA-positive sample at baseline. 

Treatment-induced ADA-positive subjects; denominator is the number of subjects with 
ADA-negative sample at baseline. 

ADA-negative subjects: denominator is the number of subjects in Immunogenicity 
incidence set.

ADA-positive subjects (i.e. ADA incidence): calculated as the number of treatment-
boosted ADA-positive and treatment-induced ADA-positive subjects; denominator is 
the number of subjects in Immunogenicity incidence set. 
Listings will be provided of subject ADA status.
2.11
Other Exploratory analyses
Not applicable.
2.12
Interim analysis
Not applicable.
3
Sample size calculation
3.1
Primary analysis
No formal statistical power calculations to determine sample size were performed for this study.
3.2
Power for analysis of key secondary variables
Not applicable.


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4
Change to protocol specified analyses
Not applicable.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going:
The patient should be treated as on-going and the cut-off date should be used as the dose end
date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available:
Case 1: T-he dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.


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5.1.2
AE, ConMeds and safety assessment date imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  


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Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule
(*=last treatment date plus 30 days (150 days for PDR001) not > (death 
date, cut-off date, withdrawl of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
5.1.2.1
Other imputations
Incomplete date of initial diagnosis of cancer and  date of most recent 
recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
Incomplete assessment dates for tumor assessment
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the latest of all investigation dates (e.g. MRI scan, CT scan) if 
the overall response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is 
progression – the assessment date is calculated as the earliest date of all investigation dates at 
that evaluation number.  If all measurement dates have no day recorded, the 1st of the month is 
used. If the month is not completed, for any of the investigations, the respective assessment will 
be considered to be at the date which is exactly between previous and following assessment. If 
a previous and following assessment is not available, this assessment will not be used for any 
calculation.
Applying the cut-off to tumor assessment
For tumor related assessments, if an evaluation has some assessments done prior to cut-off date 
and others after the cut-off date , then the evaluation is considered post-cut-off date and will 
be excluded from analysis.


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5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. The latest available MedDRA version at the time of the analyses should be used. 
The MedDRA version used should be specified in the footnote of relevant tables.  
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). 
5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version v5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version 5.0 at the time of analysis will be used. 
For laboratory tests where grades are not defined by CTCAE v5.0, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
Imputation Rules  
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]


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In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading
5.4
Statistical models
Kaplan-Meier estimates
An estimate of the survival function will be constructed using Kaplan-Meier (product-limit) 
method as implemented in PROC LIFETEST with METHOD=KM option. The PROC
LIFETEST statement will use the option CONFTYPE=LOGLOG.
Median survival will be obtained along with 95% confidence intervals calculated from PROC
LIFETEST output using the method of [Brookmeyer and Crowley 1982]. Kaplan-Meier
estimates of the survival function with 95% confidence intervals at specific time points
will be summarized. The standard error of the Kaplan-Meier estimate will be calculated
using Greenwood’s formula [Collett 1994].
Treatment of ties
The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties. The PHREG procedure in SAS with option TIES=EXACT will be used to fit the Cox 
proportional hazards model.
6
Reference
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time. 
Biometrics, 38, 29 - 41. 
Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the 
case of the binomial.  Biometrical, 26, 404-413.
Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall.
Herbst RS, Baas P, Kim DW, et al (2016) Pembrolizumab versus docetaxel for previously 
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a 
randomised controlled trial. Lancet p. 1540-50.
Rittmeyer A, Barlesi F, Waterkamp D, et al (2017) Atezolizumab versus docetaxel in patients 
with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre 
randomised controlled trial. Lancet p. 255-265.