Modular Phase 2 Study to Link Combination Immune-therapy to Patients With Advanced Solid and Hematologic Malignancies. Module 9: PDR001 Plus LAG525 for Patients With Advanced Solid and Hematologic Malignancies.
Phase: PHASE2
Conditions: Small Cell Lung Cancer, Gastric Adenocarcinoma, Esophageal Adenocarcinoma, Castration Resistant Prostate Adenocarcinoma, Soft Tissue Sarcoma, Ovarian Adenocarcinoma, Advanced Well-differentiated Neuroendocrine Tumors, Diffuse Large B Cell Lymphoma
Sponsor: Novartis Pharmaceuticals



Novartis
Confidential
Page 2
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................10
Protocol summary:.............................................................................................................15
1
Background........................................................................................................................20
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............20
1.1.1
Immune checkpoint blockade in cancer................................................20
1.1.2
Disease Background and overview .......................................................21
1.2
Introduction to investigational treatment(s) and other study treatment(s).............27
1.2.1
Overview of PDR001............................................................................27
1.2.2
Overview of LAG525 ...........................................................................29
1.2.3
Overview of the combination of LAG525 and PDR001.......................31
2
Rationale............................................................................................................................33
2.1
Study rationale and purpose...................................................................................33
2.2
Rationale for the study design ...............................................................................33
2.3
Rationale for dose and regimen selection..............................................................34
2.4
Rationale for choice of combination drugs............................................................34
2.5
Rationale for choice of comparators drugs............................................................35
2.6
Risks and benefits..................................................................................................35
3
Objectives and endpoints...................................................................................................36
4
Study design ......................................................................................................................37
4.1
Description of study design ...................................................................................37
4.2
Enrollment model ..................................................................................................37
4.3
Tumor cohort enrollment schema..........................................................................38
4.4
Timing of interim analyses ....................................................................................39
4.5
Early study termination..........................................................................................40
5
Population..........................................................................................................................40
5.1
Definition of End of Study ....................................................................................40
5.2
Patient population..................................................................................................40
5.3
Inclusion criteria ....................................................................................................40
5.4
Exclusion criteria...................................................................................................41
6
Treatment...........................................................................................................................44
6.1
Study treatment......................................................................................................44

Novartis
Confidential
Page 3
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
6.1.1
Dosing regimen.....................................................................................44
6.1.2
Ancillary treatments..............................................................................45
6.1.3
Rescue medication ................................................................................45
6.1.4
Guidelines for continuation of treatment ..............................................46
6.1.5
Treatment duration................................................................................46
6.2
Dose escalation guidelines.....................................................................................46
6.3
Dose modifications................................................................................................46
6.3.1
Dose modification and dose delay ........................................................46
6.3.2
Follow-up for toxicities.........................................................................47
6.3.3
Anticipated risks and safety concerns of the study drug.......................55
6.4
Concomitant medications ......................................................................................55
6.4.1
Permitted concomitant therapy .............................................................55
6.4.2
Permitted concomitant therapy requiring caution and/or action...........55
6.4.3
Prohibited concomitant therapy ............................................................55
6.4.4
Use of Bisphosphonates and radiotherapy............................................56
6.5
Patient numbering, treatment assignment or randomization .................................56
6.5.1
Patient numbering .................................................................................56
6.5.2
Treatment assignment or randomization...............................................57
6.5.3
Treatment blinding................................................................................57
6.6
Study drug preparation and dispensation...............................................................57
6.6.1
Study treatment packaging and labeling ...............................................57
6.6.2
Drug supply and storage........................................................................57
6.6.3
Study drug compliance and accountability ...........................................58
6.6.4
Disposal and destruction .......................................................................58
7
Visit schedule and assessments .........................................................................................58
7.1
Study flow and visit schedule................................................................................58
7.1.1
Molecular pre-screening........................................................................62
7.1.2
Screening...............................................................................................62
7.1.3
Run-in period ........................................................................................63
7.1.4
Treatment period...................................................................................63
7.1.5
Discontinuation of study treatment .......................................................64
7.1.6
Withdrawal of consent ..........................................................................65
7.1.7
Follow up for safety evaluations...........................................................65
7.1.8
Lost to follow-up...................................................................................66
7.2
Assessment types...................................................................................................66
7.2.1
Efficacy assessments.............................................................................66

Novartis
Confidential
Page 4
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
7.2.2
Safety and tolerability assessments.......................................................68
7.2.3
Pharmacokinetics ..................................................................................72
7.2.5
Resource utilization...............................................................................72
7.2.6
Patient reported outcomes.....................................................................72
8
Safety monitoring and reporting........................................................................................72
8.1
Adverse events.......................................................................................................72
8.1.1
Definitions and reporting ......................................................................72
8.1.2
Laboratory test abnormalities................................................................74
8.2
Serious adverse events...........................................................................................74
8.2.1
Definitions.............................................................................................74
8.2.2
SAE Reporting ......................................................................................75
8.3
Emergency unblinding of treatment assignment ...................................................76
8.4
Pregnancies............................................................................................................76
8.5
Warnings and precautions......................................................................................76
8.6
Data Monitoring Committee..................................................................................76
8.7
Steering Committee ...............................................................................................77
9
Data collection and management.......................................................................................77
9.1
Data confidentiality ...............................................................................................77
9.2
Site monitoring ......................................................................................................77
9.3
Data collection.......................................................................................................78
9.4
Database management and quality control............................................................78
10 Statistical methods and data analysis ................................................................................79
10.1
Analysis sets ..........................................................................................................79
10.1.1
Full Analysis Set ...................................................................................79
10.1.2
Safety set ...............................................................................................79
10.2
Patient demographics/other baseline characteristics .............................................79
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................79
10.3.1
Study medication...................................................................................79
10.3.1
Concomitant therapies...........................................................................80
10.4
Primary objective...................................................................................................80
10.4.1
Variable.................................................................................................80
10.4.2
Statistical hypothesis, model, and method of analysis..........................80
10.4.3
Evaluation of trial success and futility..................................................82
10.4.4
Handling of missing values/censoring/discontinuations.......................83
10.4.5
Supportive and Sensitivity analyses......................................................84

Novartis
Confidential
Page 5
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
10.5
Secondary objectives .............................................................................................84
10.5.1
Secondary efficacy objectives...............................................................84
10.5.2
Safety objectives ...................................................................................85
10.6
Exploratory objectives...........................................................................................86
10.7
Interim analysis......................................................................................................86
10.8
Sample size calculation..........................................................................................87
11 Ethical considerations and administrative procedures ......................................................87
11.1
Regulatory and ethical compliance........................................................................87
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................87
11.3
Informed consent procedures.................................................................................87
11.4
Discontinuation of the study..................................................................................88
11.5
Publication of study protocol and results...............................................................88
11.6
Study documentation, record keeping and retention of documents.......................88
11.7
Confidentiality of study documents and patient records .......................................89
11.8
Audits and inspections...........................................................................................89
11.9
Financial disclosures..............................................................................................89
12 Protocol adherence ............................................................................................................89
12.1
Amendments to the protocol..................................................................................90
13 References (available upon request)..................................................................................91
14 Appendices ........................................................................................................................92
14.1
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival and Overall Survival (based on RECIST 1.1) ...92
14.1.1
Introduction...........................................................................................94
14.1.2
Efficacy assessments.............................................................................94
14.1.3
Definitions.............................................................................................94
14.1.4
Disease measurability............................................................................94
14.1.5
Eligibility based on measurable disease................................................95
14.1.6
Methods of tumor measurement - general guidelines...........................95
14.1.7
Baseline documentation of target and non-target lesions .....................97
14.1.8
Follow-up evaluation of target and non-target lesions..........................98
14.1.9
Follow-up and recording of lesions.......................................................98
14.1.10
Non-nodal lesions..................................................................................98
14.1.11
Nodal lesions.........................................................................................99
14.1.12
Determination of target lesion response................................................99
14.1.13
Determination of non-target lesion response ......................................101
14.1.14
New lesions .........................................................................................102

Novartis
Confidential
Page 6
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.1.15
Evaluation of overall lesion response .................................................102
14.1.16
Efficacy definitions .............................................................................103
14.1.17
Best overall response...........................................................................103
14.1.18
Time to event variables .......................................................................105
14.1.19
Progression-free survival ....................................................................105
14.1.20
Overall survival...................................................................................106
14.1.21
Time to progression.............................................................................106
14.1.22
Time to treatment failure.....................................................................106
14.1.23
Duration of response ...........................................................................106
14.1.24
Time to response .................................................................................107
14.1.25
Definition of start and end dates for time to event variables ..............108
14.1.26
Handling of patients with non-measurable disease only at baseline...109
14.1.27
Sensitivity analyses .............................................................................110
14.1.28
Data handling and programming rules................................................112
14.1.29
Study/project specific decisions..........................................................112
14.1.30
End of treatment phase completion.....................................................112
14.1.31
End of post-treatment follow-up (study phase completion)................113
14.1.32
Medical validation of programmed overall lesion response ...............113
14.1.33
Programming rules..............................................................................114
14.1.34
Calculation of ‘time to event’ variables..............................................114
14.1.35
Incomplete assessment dates...............................................................114
14.1.36
Incomplete dates for last known date patient alive or death ...............114
14.1.37
Non-target lesion response..................................................................114
14.1.38
Study/project specific programming...................................................114
14.1.39
Censoring reason.................................................................................115
14.1.40
References (available upon request) ...................................................115
14.2
Appendix 2: Revised Response Criteria for Malignant Lymphoma, 
therapeutic response/outcome assessment in lymphoma studies (based on 
Cheson response criteria 2007)............................................................................117
14.3
Appendix 3: Eastern Cooperative Oncology Group (ECOG) performance 
status ....................................................................................................................128
14.4
Appendix 4: Adaptive Basket Trial for Combination Immune-therapy in 
Patients with Advanced Solid and Lymphoma....................................................129
14.5
Appendix 5: Recommended management algorithms for suspected toxicities...156
14.5.1
GI adverse event management algorithm............................................156
14.5.2
Renal adverse event management algorithm.......................................157
14.5.3
Pulmonary adverse event management algorithm ..............................158

Novartis
Confidential
Page 7
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.5.4
Hepatic adverse event management algorithm ...................................159
14.5.5
Endocrinopathy management algorithm .............................................160
14.5.6
Skin adverse event management algorithm.........................................161
14.5.7
References (available upon request) ...................................................162
List of figures
Figure 4-1
Study Start-up Design ...........................................................................38
Figure 4-2 
Study Design .........................................................................................38
List of tables
Table 3-1
Objectives and related endpoints ..........................................................36
Table 4-1
Tumor Cohorts ......................................................................................37
Table 6-1
Dose and treatment schedule.................................................................44
Table 6-2
Maximum permitted missed doses prior to permanent 
discontinuation of study treatment........................................................46
Table 6-3
Recommended Dose Delays ................................................................48
Table 6-4
Supply and storage of study treatments ................................................57
Table 7-1
Visit evaluation schedule (Cycle Length is 21 days/ 3 weeks).............60
Table 7-2
ECOG performance status.....................................................................69
Table 7-3
Local clinical laboratory parameters collection plan ............................70
Table 7-4
12 Lead ECG collection plan................................................................71
Table 10-1
Historical CBR for each group..............................................................82
Table 14-1
Response criteria for target lesions .......................................................99
Table 14-2
Response criteria for non-target lesions..............................................101
Table 14-3
Overall lesion response at each assessment ........................................102
Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................109
Table 14-5
Options for event dates used in PFS, TTP, duration of response........110

Novartis
Confidential
Page 8
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
List of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
CBR
Clinical Benefit Rate
CMO&PS
Chief Medical Office and Patient Safety
CPB
Checkpoint blockade
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CRS
Cytokine Release Syndrome
CSR
Clinical study report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional information 
that is not included in the CSR
DLT
Dose Limiting Toxicity
DOR
Duration of Response
ECG
Electrocardiogram
eSAE
Electronic Serious Adverse Event
FAS
Full Analysis Set
FIH
First In Human
FU
Follow Up
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
IO
Immuno-oncology
i.v.
intravenous(ly)
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN-γ
interferon gamma
IG
Immunogenicity
IRB
Institutional Review Board
LAG-3
Lymphocyte activation gene-3
mAb(s)
monoclonal Antibody(ies)
MAP
Master Analysis Plan documents project standards in the statistical methods which will 
be used within the individual clinical trial RAP documentation
MTD
Maximum Tolerated Dose
ORR
Overall Response Rate
OS
Overall survival
PD
Pharmacodynamics
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PFS
Progression free survival
PHI
Protected Health Information
Q3W
Every 3 weeks dosing schedule
RAP
Report and Analysis Plan
RECIST
Response Evaluation Criteria In Solid Tumors
REB
Research Ethics Board

Novartis
Confidential
Page 9
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
RP2D
Recommended phase two dose
SAE
Serious Adverse Event
SCLC
Small Cell Lung Cancer
SOP
Standard Operating Procedure
TCR
T Cell Receptor
TIL(s)
Tumor Infiltrating Lymphocyte(s)
TTP
Time To Progression
TTR
Time To Response

Novartis
Confidential
Page 10
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue,
urine, stool, etc. taken from a study subject or study patient
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g.: q21 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug.”
Investigational 
treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are tested 
in a fixed combination. Investigational treatment generally does not include other 
study treatments administered as concomitant background therapy required or 
allowed by the protocol when used in within approved indication/dosage
Subject Number 
(Subject No.)
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Screen failures
Patients who sign an informed consent but fail to be started on treatment for any 
reason will be considered a screen failures
Stage related to 
study timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body
Stop study 
participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. The cohorts are not expanded, new cohorts will be 
enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time-points
Withdrawal of 
consent
Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not 
want any further study related contact

Novartis
Confidential
Page 12
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Study Status
At the time of this amendment, the trial has enrolled 70 patients at 24 centers across the United 
States. Initial enrollment into 6 of the 7 tumor cohorts is completed, pending futility analysis to 
determine if the cohorts will re-open to enrollment. 
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the
protocol using strike through red font for deletions and red underline for insertions.
The Protocol Summary has been updated to incorporate the changes implemented throughout 
the document. 
Section 1.2.1.2. updated to include most recent data per PDR001 Investigator Brochure Editions 
7 and 7.1.
Section 1.2.2.2. updated to include the most recent single agent safety data from LAG525 
Investigator Brochure Edition 4. 
Section 1.2.3.2 updated to include safety data for the combination of PDR001 and LAG525 per 
the LAG525 Investigator Brochure Edition 4. 
Section 4 updated to change the name of table 4-1 from Tumor Groups to Tumor Cohorts. 
Similar language change implemented throughout this section, and to sections 4.3, 4.4, and 5.1.
Section 4.3 updated to include a simple schematic of the study design.
Section 5.3 updated to:
-
Include a criteria that patients have locally advanced or metastatic disease
-
Clarified the language in inclusion criteria #4
Section 5.4 updated as follows:
-
Criteria #6: Correct and inconsistency by indicating it is applicable to the IO exposed 
sub-group.
-
Criteria #13: Expand the list of prior IO therapies that patients may receive

Criteria #13(b): Revised the exclusion criteria for the expansion phase IO sub-
group to restrict:

Patients with a history of any grade immune-related ocular adverse event.

Patients with a history of Grade ≥ 3 immune-related adverse event.

Patients with evidence of active noninfectious pneumonitis or history of 
interstitial lung disease.

Patients with risk of reactivation of hepatitis B or C.

Patients who are on endocrine replacement therapy should be stable on the 
dose.

Novartis
Confidential
Page 14
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs) and 
Health Authorities. The changes described in this amended protocol require IRB/IEC approval 
prior to implementation. The changes herein affect the Informed Consent. Sites are required to 
update and submit for approval a revised informed consent that takes into account the changes 
described in this protocol amendment.

Novartis
Confidential
Page 15
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Protocol summary: 
Title
Modular phase 2 study to link combination immune-therapy to patients with 
advanced solid and hematologic malignancies
Brief title
Module 9: PDR001 plus LAG525 for patients with advanced solid and 
hematologic malignancies
Sponsor and Clinical 
Phase
Novartis
2
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this signal seeking study is to determine whether treatment with 
PDR001 and LAG525 demonstrates sufficient efficacy in advanced malignancies 
to warrant further study.
Primary Objective(s) 
Assess CBR at 24 weeks of PDR001+LAG525 in multiple solid malignancies and 
lymphoma. 
Secondary Objectives
Assess ORR, TTR, DoR, TTP, PFS rate at 1 and 2 years 
Safety incidence and severity of adverse events (AEs) and serious adverse 
events (SAEs) including changes in laboratory parameters, vital signs and ECGs
Tolerability: Dose interruptions, reductions and dose intensity.
Study design
This is a phase II, open-label, parallel-cohort study to determine the efficacy and 
safety of treatment with the combination of PDR001+LAG525 across multiple 
tumor types that are relapsed and/or refractory to available standard of care 
therapies. Patients will receive study treatment for a maximum of 2 years, or until 
disease progression, unacceptable toxicity, death or discontinuation from study 
treatment for any other reason (e.g., withdrawal of consent, start of a new anti-
neoplastic therapy or at the discretion of the investigator or patient). All patients 
who discontinue from study treatment due to disease progression must have 
their progression clearly documented. All disease assessments will be performed 
locally by the investigator.
Population
This study will be conducted in patients with select solid tumors or lymphoma as 
outlined in Table 4-1. Tumor types may be excluded or added during the course 
of the study in the case of early futility or success based upon an interim analysis 
or at the discretion of Novartis.
Selected Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following 
criteria:
1. Written informed consent must be obtained prior to any screening 
procedures.
2. Patient is ≥ 18 years of age on the day of consenting to the study
3. Patient must have had at least one prior line of therapy for their disease and 
must not be beyond 4th progression/relapse of disease (5 maximum prior lines).
4. Patient has a pathology confirmed diagnosis of a solid tumor or lymphoma
listed in Table 4-1 and measurable disease as per appropriate guidelines:

All Solid Tumors: by RECIST 1.1 (Appendix 1)
o
For advanced well-differentiated neuroendocrine tumors, the 
following also apply:

Pathologically confirmed, well-differentiated (Grade 1 or 
Grade 2), advanced (unresectable or metastatic), 
neuroendocrine tumor 

No history of and no active symptoms related to carcinoid 
syndrome

Patient has not had hepatic intra-arterial embolization 
within the last 6 months or cryoablation or radiofrequency 
ablation of hepatic metastases within 2 months of first 
dose

Novartis
Confidential
Page 16
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01

Diffuse Large B-cell Lymphoma: by the Revised Response Criteria for 
Malignant Lymphoma (Cheson et al 2007) (Appendix 2)
o
Relapsed/refractory disease as defined by relevant standardized 
response criteria (see Section 4)
o
Patients with prior autologous transplant are eligible
o
Patient has at least one measurable nodal lesion (≥2 cm). In case 
where the patient has no measurable nodal lesions ≥2 cm in the 
long axis at screening, then the patient must have at least one 
measurable extra-nodal lesion 
5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance 
status ≤ 1
6.  Patients must have locally advanced or metastatic disease
Selected Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1.
Presence of symptomatic CNS metastases, or CNS metastases that 
require local CNS-directed therapy (such as radiotherapy or surgery), or 
increasing doses of corticosteroids within the prior 2 weeks. Patients with 
treated brain metastases should be neurologically stable (for 4 weeks 
post-treatment and prior to study enrollment) and off steroids for at least 
2 weeks before administration of any study drug.
2.
History of severe hypersensitivity reactions to other mAbs. 
3.
Patient with out of range laboratory values:
a)
Creatinine clearance (calculated using Cockcroft-Gault formula, or 
measured) < 40 mL/min
b)
Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s 
syndrome who are excluded if total bilirubin > 3.0 x ULN or direct 
bilirubin > 1.5 x ULN
c)
Alanine aminotransferase (ALT) > 3 x ULN, except for patients that 
have tumor involvement of the liver, who are excluded if ALT > 5 x 
ULN
d)
Aspartate aminotransferase (AST) > 3 x ULN, except for patients 
that have tumor involvement of the liver, who are excluded if AST >
5 x ULN
e)
Absolute neutrophil count (ANC) < 1.0 x 10^9/L
f)
Platelet count < 75 x 10^9/L 
g)
Hemoglobin < 9 g/dL
4.
Impaired cardiac function or clinically significant cardiac disease, 
including any of the following:
a)
Clinically significant and/or uncontrolled heart disease such as 
congestive heart failure requiring treatment (NYHA Grade ≥ 2), 
uncontrolled hypertension or clinically significant arrhythmia
b)
QTcF > 470 msec on screening/baseline ECG or congenital long 
QT syndrome
c)
Acute myocardial infarction or unstable angina pectoris < 3 months 
prior to study entry
5.
Active, known or suspected autoimmune disease or a documented 
history of autoimmune disease within three years prior to screening with 
exception of:
a.
Patients with vitiligo, type I diabetes mellitus, residual 
hypothyroidism due to an autoimmune condition 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.
6.
If otherwise eligible for the expansion phase IO sub-group, Patients 
previously exposed to anti-PD-1/PD-L1 treatment who are adequately 
treated for skin rash or with replacement therapy for endocrinopathies 
should not be excluded

Novartis
Confidential
Page 17
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
7.
Active infection requiring systemic antibiotic therapy. Patients requiring 
systemic antibiotics for infection must have completed therapy before 
screening is initiated.
8.
Known history of HIV infection. Testing for HIV status is not necessary 
unless clinically indicated
9.
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. 
Testing for HBV or HCV status is not necessary unless clinically 
indicated or the patient has a history of HBV or HCV infection.
10. Patient with second primary malignancy within < 3 years of first dose of 
study treatment. Exceptions to this exclusion include the following: 
malignancies that were treated curatively and have not recurred within 2 
years prior to study treatment; completely resected basal cell and 
squamous cell skin cancers; any malignancy considered to be indolent 
and that has never required therapy; and completely resected carcinoma 
in situ of any type.
11. Any medical condition that would, in the investigator’s judgment, prevent 
the patient’s participation in the clinical study due to safety concerns, 
compliance with clinical study procedures or interpretation of study 
results.
12. Systemic anti-cancer therapy within 2 weeks of the first dose of study 
treatment. For cytotoxic agents that have major delayed toxicity, e.g. 
mitomycin C and nitrosoureas, 4 weeks is indicated as washout period.
13. Prior immunotherapy treatment with PD-1, PD-L1, CTLA-4, or LAG-3
antibodies, CAR-T therapy, gene therapies, and/or Provenge therapy
a.
This exclusion does not apply to patients enrolled in the 
immunotherapy pre-exposed subgroup (n=6 per tumor type) in 
those cohorts that undergo expansion to 30 patients.
b.
For patients in the immunotherapy pre-exposed subgroups:
i.
Prior IO therapy with PD-1, PD-L1, or LAG-3
antibodies, within 4 weeks of first dose of study 
treatment
ii.
CTLA-4 antagonist or vaccine as anticancer therapy 
within 6 weeks of first dose of study treatment 
iii.
Patients who discontinued prior anti-PD-1, PD-L1 or 
anti LAG-3 therapy due to therapy related toxicity
iv.
Patients with a history of any grade immune-related 
ocular adverse event.
v.
Patients with a history of Grade ≥ 3 immune-related 
adverse event.
vi.
Patients with evidence of active noninfectious 
pneumonitis or history of interstitial lung disease.
vii.
Patients with risk of reactivation of hepatitis B or C.
viii.
Patients who are on endocrine replacement therapy 
should be stable on the dose.
14. Systemic chronic steroid therapy or any immunosuppressive therapy 
(>10mg/day prednisone or equivalent). Topical, inhaled, nasal and 
ophthalmic steroids are allowed.
15. Use of any live vaccines against infectious diseases within 4 weeks of 
initiation of study treatment.
16. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, 
GM-CSF, M-CSF) or erythroid stimulating agents ≤ 2 weeks prior to start 
of study drug. 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.

Novartis
Confidential
Page 18
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
17. Presence of CTCAE ≥ grade 2 toxicity (except peripheral neuropathy and 
ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior cancer 
therapy.
18. Allogeneic stem cell transplant recipients 
19. Major surgery within 2 weeks of the first dose of study treatment 
(mediastinoscopy, insertion of a central venous access device, and 
insertion of a feeding tube are not considered major surgery).
20. Participation in an interventional, investigational study within 2 weeks 
prior to the first dose of study treatment.
21. Pregnant or lactating women, where pregnancy is defined as the state of 
a female after conception and until the termination of gestation, 
confirmed by a positive hCG laboratory test.
22. 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 the last 
dose of PDR001 and LAG525. 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 follow 
up hormone level assessment is she considered not of child-bearing 
potential. 
Highly effective contraception methods include:
a)
Total abstinence (when this is in line with the preferred and usual 
lifestyle of the subject). Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.
b)
Female sterilization (have had surgical bilateral oophorectomy with 
or without hysterectomy), total hysterectomy, or tubal ligation at 
least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level 
assessment.
c)
Male sterilization (at least 6 months prior to screening). The 
vasectomized male partner should be the sole partner for that 
subject.
d)
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.
e)
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.
23. Sexually active males unless they use a condom during intercourse 
while taking the drug and for 150 days after stopping study treatment 
and should not father a child in this period. A condom is required to be 
used also by vasectomized men as well as during intercourse with a 
male partner in order to prevent delivery of the drug via seminal fluid.
Investigational and 
reference therapy
LAG525 and PDR001
Efficacy assessments
The primary efficacy endpoint is clinical benefit rate as defined in Section 10.4. 
The secondary efficacy endpoint is overall response rate of PR or greater as 
defined in Section 10.5. Other secondary endpoints are time from the date of first 
dose to the date of first documented disease progression or relapse or death due 

Novartis
Confidential
Page 19
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
to any cause, time from the date of first dose to the date of death due to any 
cause, time from the first documented response to the date first documented 
disease progression or relapse or death due to any cause, and other safety 
measurements as defined in Section 10. The local investigator’s assessment will 
be used for the analysis and for treatment decision making.
Safety assessments
Adverse events.
Physical examination 
Performance status evaluation
Cardiac monitoring (ECGs, and assessment of LVEF)
Laboratory evaluations (hematology, biochemistries, pregnancy tests)
Data analysis
The Full Analysis Set (FAS) will include all patients who have received at least 
one dose of study drug.
Key words
PDR001 
LAG525 
Immune checkpoint blockade
Solid tumor malignancy 
lymphoma
Small cell lung cancer (SCLC)
Gastric/esophageal adenocarcinoma
Castration resistant prostate adenocarcinoma (CRPC)
Soft tissue sarcoma 
Ovarian adenocarcinoma
Advanced well-differentiated neuroendocrine tumors (NETs)
Diffuse large B cell lymphoma (DLBCL)

Novartis
Confidential
Page 20
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Immune checkpoint blockade in cancer 
Expression patterns of co-inhibitory and co-stimulatory receptors on tumor-specific T cells vary 
by both the maturation stage of the T cell as well as the location of the T cell (peripheral 
circulation v. intra-tumoral) (Baitsch 2012, Woo 2012). These patterns of expression together
with early studies of the effects of signaling suggest that the network of co-receptors may
deliver differential signals (Baitsch 2012). Tumor antigen-specific T cells isolated from the
tumor-draining lymph nodes of melanoma patients have an activation profile, whereas T cells
derived from the tumor bed display an exhausted phenotype with strong expression of multiple 
checkpoints, impaired cytokine secretion and activity (Matsuzaki 2010).
PD-1 (Programmed Death-1, CD-279) is a critical co-inhibitory receptor that is upregulated on 
T cells upon activation (Freeman 2008). It is also expressed by B cells, NK cells, dendritic cells, 
and activated monocytes. The ligands for PD-1, Programmed Death-Ligand 1 (PD-L1) and 
Programmed Death-Ligand 2 (PD-L2), are expressed by macrophages and monocytes, and can 
be induced on numerous cell types (T cells, endothelial cells, and tumor cells) during 
inflammation (Keir 2008). Engagement of PD-1 by its ligands transduces a signal that inhibits 
T-cell proliferation, cytokine production, and cytolytic function (Riley 2009). During 
tumorigenesis, cancer cells from a wide range of tumor types exploit immune checkpoint 
pathways, such as PD-1, to avoid detection by the adaptive immune system (Murphy 2011). 
Blockade of the PD-1 pathway has been shown to lead to both accumulation and increased 
activity of antitumor effector T cells and a reduced numbers of regulatory T cells (Tregs) at the 
tumor site (Wang 2009, Mangsbo 2010, Mkrtichyan 2011, Rosenblatt 2011).
LAG-3 (Lymphocyte Activation Gene-3, CD223) is a cell-surface molecule expressed on
activated CD4+ and CD8+ T effector cells, multiple populations of regulatory T cells, NK cells, 
B cells and plasmacytoid dendritic cells (Huard 1994, Triebel 1990, Kisielow 2005). LAG-3 
binds its ligand MHC Class II, and this interaction negatively regulates T cell signaling 
(Workman 2011). Blockade of LAG-3 has been shown to increase T cell proliferation and 
cytokine secretion, most notably IFN-γ (Huard 1997, Workman 2003). LAG-3 expression is 
also correlated with increased suppressive function in both FoxP3-positive natural regulatory T 
cells and induced FoxP3-negative regulatory cells (Huang 2004, Camisaschi 2010, Scurr 2014).
Checkpoint inhibitors have been successfully introduced to clinical practice with the approval 
of the antagonists to the CTLA-4 checkpoint (ipilimumab, BMS) and PD-1 (e.g nivolumab
[BMS] and pembrolizumab [Merck]). Although the checkpoint inhibitors generally result in 
similar enhanced anti-tumor T cell activation, their effects are mediated by distinct pathways 
and they demonstrate enhanced activity in combination. The combination of ipilimumab and 
nivolumab is more active than either single agent in advanced melanoma (Wolchok 2013). 
LAG-3 is a distinct co-inhibitory receptor that may cooperate with PD-1 to dampen immune 
responses. In preclinical studies, the combined inhibition of PD-1 and LAG-3 checkpoints 
synergistically enhances antitumor responses over inhibition of either checkpoint alone (Drake 

Novartis
Confidential
Page 21
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
2014, Woo 2012). Taken together, these data suggest that combined inhibition of LAG-3 and 
PD-1 in the clinic may have significant anti-tumor activity in several tumors.
1.1.2
Disease Background and overview
Although there is clinical evidence for activity of checkpoint blockade (CPB) monotherapy in 
several tumor types including melanoma, NSCLC, and Hodgkins lymphoma, multiple tumor 
types have significantly less response to CPB monotherapy. Despite the finding of somewhat 
predictive biomarkers of response to CPB, including mutational burden, PD-L1 expression, and 
presence of tumor infiltrating lymphocytes (TILs), there is to date, no biomarker or set of 
biomarkers that universally predicts response to CPB therapy. However, it is generally accepted 
that in order for CPB therapy to be effective in a tumor, the tumor must first have established 
immunogenicity and second, be actively engaged in immunosuppressive mechanisms, either 
through direct expression of immunosuppressive ligands on the tumor or indirectly through 
manipulation of cellular and molecular components of the tumor microenvironment (Pardoll 
2012). 
Therefore, we hypothesize that those tumors in which CPB monotherapy has shown low to 
moderate clinical activity (<30% overall response rate) must be immunogenic, but are so to a 
lesser degree or exhibit more effective immune blockade mechanisms than those tumors in 
which CPB monotherapy has high activity. Furthermore, the lower immunogenic response of 
such tumors may necessitate combination CPB or CPB -immune accelerator combinations to 
overcome immunosuppressive mechanisms and achieve responses similar to those seen with 
CPB monotherapy in highly immunogenic tumors. 
The tumor types being evaluated in this study include advanced solid tumors and lymphoma
that are relapsed and/or refractory to available standard of care therapies. The study will 
evaluate the efficacy and safety of combination CPB therapy with PDR001+LAG525 in patients 
with select advanced solid tumors and lymphoma that have suboptimal response rates 
(ORR<30%) to CPB monotherapy. Other tumors in which clinical data are not presently 
available with CPB therapy, but have pre-clinical evidence supporting use of CPB therapy or 
clinical data showing efficacy of other immune modulating therapies (e.g. cytokine therapy, 
IMIDs, adoptive cellular therapy) will also be studied in this trial. For the list of tumors included 
in the study, refer to Table 4-1. Tumor types may be excluded during the course of the study in 
the case of early futility or success, based upon an interim analysis or at the discretion of 
Novartis. Tumor types may be added at the discretion of Novartis based on emerging pre-
clinical or clinical data.
1.1.2.1
Small Cell Lung Cancer
Small cell lung cancer (SCLC) accounts for 15% of all lung cancers. The standard of therapy 
for patients with extensive stage SCLC consists of combination chemotherapy with a platinum 
doublet, typically cis/carboplatin plus etoposide. Despite response rates of 60-70% with 
combination chemotherapy, median overall survival is only 9-11 months. Recurrent SCLC with 
extensive stage disease has an even poorer prognosis with standard chemotherapy regimens, 
with a median PFS of only 1.5 months, underlining the high-unmet need for new therapies in 
this disease.

Novartis
Confidential
Page 22
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Clinical studies of CPB therapy in SCLC show moderate activity of both monotherapy and 
combination approaches. In a recently reported study (Antonia 2015) of the PD-1 inhibitor 
nivolumab in 128 patients with recurrent SCLC, ORR was 18% with nivolumab monotherapy 
and 17% with nivolumab/ipilimumab combination therapy. The disease control rate was 38% 
with monotherapy and 54% with combination therapy. The median OS was 4.4 months with 
monotherapy (95% CI [2.9, 9.4]) and 8.2 months with combination therapy (95% CI [3.7, not 
reached]). Another study of the PD-1 inhibitor, pembrolizumab (Ott 2015), in a similar 
population pre-selected for PD-L1 expression, the overall response rate (ORR) to 
pembrolizumab was 35% (95% CI [15%, 59%]), and the responses appeared durable with a 
median duration of response of 29.1 weeks (range: 0.1-29.1 weeks). Expression of both PD-L1
and LAG-3 has been observed in SCLC cell lines and/or primary tumor samples, although its 
predictive utility as a marker of response to CPB therapy is still unclear. In light of the moderate, 
but encouraging, response rates seen in studies with anti-PD-1 monotherapy, this study will 
explore combination CPB therapy with dual blockade of PD-1 and LAG-3 in patients with 
recurrent SCLC who have exhausted available SOC chemotherapies.
1.1.2.2
Gastro-esophageal adenocarcinoma
Gastric cancer is the second leading cause of cancer related death globally and is the fifth most 
common malignancy overall (Ferlay 2013). Esophageal carcinoma is the sixth most common 
malignancy and accounts for an additional 400,000 deaths annually (Ferlay 2013). The majority 
of gastric and esophageal cancer patients present with advanced disease, and have limited 
therapeutic options in the setting of relapsed disease. First-line treatment for advanced stage 
gastro-esophageal cancer (GEC) is platinum/5-FU-based chemotherapy with or without an 
anthracycline, in patients with good performance status. Such combination chemotherapy 
approaches result in median PFS and OS of 6 months and 9 months, respectively (Ruafi 2015). 
Although targeted therapies directed at HER2 or VEGF2 have shown responses in 
chemotherapy-refractory patients, overall survival for patients with metastatic disease still only 
approaches 1 year, highlighting the need for novel therapies.
Translational and molecular profiling studies of gastric and esophageal cancers strongly suggest 
these tumors to be good candidates for immune therapies including checkpoint blockade
therapy. Expression of the immune checkpoint PD-L1 has been observed in a substantial 
proportion of gastric adenocarcinoma resection specimens, ranging from 40% to 63% across 
various studies (Wu et al 2006, Hou et al 2014, Muro et al 2015). Increased PD-L1 expression 
in gastric and esophageal tumors correlates with poorer disease features, including nodal 
metastases, advanced stage, and worse PFS and OS. Further molecular characterization of 
gastric adenocarcinoma by the Cancer Genome Atlas Research Network has revealed four 
tumor subtypes that could categorize these tumors by levels of immunogenicity: Epstein Barr
virus positive tumors, microsatellite unstable tumors, genomically stable tumors, and tumors 
with chromosomal instability (TCGA 2014). EBV positive and MSI high tumors had higher 
rates of inhibitory checkpoint expression and tumor infiltrating lymphocytes, suggesting high 
likelihood of response to checkpoint blockade therapy.
Checkpoint blockade therapy has been evaluated in patients with advanced GEC, although 
patient numbers have been small. The largest trial in gastric cancer to date was the KEYNOTE-
12 study, a phase 1 study of the PD-1 inhibitor pembrolizumab. A total of 39 PD-L1 positive 

Novartis
Confidential
Page 23
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
(>1% by IHC) gastric cancer patients were enrolled in this trial and received pembrolizumab 
10mg/kg every 2 weeks until disease progression. An updated analysis of this trial showed an 
ORR of 22% with a median response duration of 24 weeks in a heavily pretreated population. 
The moderate ORR seen with single agent PD-1 blockade, combined with evidence of several 
other checkpoints being expressed within the tumor microenvironment, provide strong rationale 
to evaluate combination checkpoint blockade therapy in patients with advanced GEC.
1.1.2.3
Castrate resistant prostate adenocarcinoma
Prostate cancer accounts for 14% of all male cancers, making it the second most common cancer 
diagnosed in men (Gerristen 2012). Since it is a cancer strongly associated with aging, routine 
clinical screening with physical exams and PSA captures a large proportion of patients at early 
stages of the disease. In such patients, surgical resection or radiation therapy results in up to 80% 
of patients being free of metastatic disease for up to 15 years. With careful surveillance, 
recurrent or newly diagnosed late stage disease can be initially managed effectively with 
surgery/radiation combined with androgen deprivation. Eventually, most patients become 
refractory to androgen deprivation, and develop castrate resistant prostate cancer (CRPC). 
Patients with metastatic CRPC have a grim prognosis and limited treatment options. Current 
standards of therapy for such patients include docetaxel based systemic chemotherapy (for 
symptomatic patients), newer generation hormonal therapy, bisphosphonates, and radioisotope 
therapy (Gerristen 2012). Once patients have failed chemotherapy regimens and novel 
hormonal therapies, therapeutic options are very limited with median overall survival being less 
than a year.
Various principles of immune therapy have been successfully tested clinically in prostate cancer, 
including the FDA-approved tumor vaccination therapy, Sipuleucel-T. Studies of prostate 
cancer samples have shown tumor infiltration by several immune cell subtypes, including 
natural killer cells and T cells, suggesting roles for both the innate and adaptive branches of the 
immune system in anti- tumor response. Sipuleucel-T, an autologous dendritic cell vaccine 
generated by ex vivo culture of patient leukocytes with a GM-CSF-linked vaccine target 
(prostatic acid phosphatase), improved median overall survival by 4 months (HR 0.78, p=003) 
in a placebo controlled phase 3 study in patients with metastatic CRPC (Kantoff et al 2010). As 
with other immunotherapies, responses were often delayed and there was minimal difference in 
progression free survival between the two arms. Other vaccine approaches, including a poxvirus 
based vaccine (PROSTVAC-VF), are currently being explored in CRPC. CPB therapy has also 
been investigated in CRPC with encouraging early results. In a 14 patient pilot study of the 
CTLA-4 inhibitor ipilimumab, 8 patients had PSA declines <50%, and 2 patients >50% PSA 
decline lasting 135 and 60 days, respectively (Fong L et al 2008). In a phase 2 study of the same 
drug given as monotherapy, 14% of chemotherapy naïve patients had >50% decline in PSA 
(Small et al 2006). Therefore, combination strategies with CPB in CRPC are highly desirable 
to improve upon these single agent response rates.
1.1.2.4
Soft tissue Sarcoma
Soft tissue sarcomas comprise a heterogeneous group of rare mesenchymal tumors that can arise 
from multiple different tissues, including soft tissue and bone (Wilky et al 2014). 
Approximately 13,000 new cases of sarcoma are diagnosed annually in the US (Brennan et al 

Novartis
Confidential
Page 24
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
2012). Standard of care for newly diagnosed patients entails multimodality therapy involving 
surgery, radiation, and perioperative chemotherapy for several subtypes, including 
rhabdomyosarcoma, osteosarcoma, and Ewing’s sarcoma (D’Angelo et al 2014). Despite such 
aggressive therapy, 25-50% of patients develop recurrent or metastatic disease (Weitz et al 
2003). There are no curative therapies for metastatic, refractory disease in adults, unlike 
pediatric sarcomas, where multimodality therapies have dramatically improved outcomes 
(Wilky et al 2014). Overall survival for metastatic, refractory sarcomas in adults remains less 
than a year, highlighting a dire need for novel therapies.
Multiple historical observations support an important role for immune mediated anti-tumor 
effects in sarcomas, including patients whose tumors respond after infections (Curiel 2012), to 
the finding that sarcomas more commonly develop in immunosuppressed patients (Gatti et al 
1971). In a study of over 8000 allograft transplant recipients, 7.4% of 8724 malignancies that 
occurred were sarcomas, an incidence three times that seen in the general population (Penn et 
al 1995). Tumor mediated immune editing has been observed in murine models of sarcoma 
(Swann et al 2008). Several case reports of spontaneous tumor regression in sarcoma patients 
with various histologies, including Ewing’s sarcoma and GIST, have demonstrated lymphocytic 
infiltration of the tumor (Berghuis et al 2011, Brinkrolf et al 2009, Rusakiewicz et al 2013). 
Additionally, many sarcomas express several highly immunogenic epitopes including cancer 
testis antigens (NY-ESO1, LAGE-1, MAGE) and gangliosides, proteins that are typically 
expressed at much higher levels in tumor compared to normal tissue (D’angelo et al 2014). With 
respect to CPB therapy, a small phase 2 study of the anti-CTLA-4 antibody, ipilimumab did not 
demonstrate clinically meaningful activity in synovial sarcoma (Maki RG et al 2013). Although 
single agent CPB has failed to demonstrate clinical activity in selected sarcoma subtypes, other 
immune therapies including dendritic cell based vaccines (Mackall et al 2008), and cancer testis 
antigen directed adoptive T cell therapy (Rosenberg et al 2011) have demonstrated clinical 
activity in phase 2 studies. Therefore, exploring combination CPB therapy across a wide variety 
of sarcoma histologies may successfully identify responsive subtypes. 
1.1.2.5
Ovarian cancer
Ovarian cancer accounts for the fifth leading cause of cancer death in women, and the leading 
cause of death among gynecologic cancers (Liu et al 2010). Approximately 22,000 new cases 
of ovarian cancer are diagnosed annually in the US and accounts for up to 15,000 deaths a year 
(Liu et al 2010). Two thirds of patients with ovarian cancer are diagnosed at stages 3 and 4, 
accounting for the relatively low 5-year survival rate of 39% and 17% for stage 3 and 4 tumors, 
respectively (NCCN Guidelines 2015.2). Standard therapy for newly diagnosed patients 
involves maximal cytoreductive surgery, combined with intraperitoneal chemotherapy, 
followed by platinum-based adjuvant systemic chemotherapy (NCCN Guidelines Version 
2.2015). Patients with recurrent disease are divided into those with platinum resistant and 
sensitive disease, and are often treated with multiple courses of systemic chemotherapy. 
Platinum sensitive patients may have responses to retreatment with cisplatin/carboplatin as 
single agents or in combination with taxanes. For those who are platinum resistant, current 
options include single agent therapy with other drugs such as liposomal doxorubicin, etoposide, 
and gemcitabine. Prognosis for patients with recurrent disease, particularly those with platinum 
resistant disease, is poor with a median PFS of 3 months.

Novartis
Confidential
Page 25
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Similar to other immunogenic tumors, the presence of tumor infiltrating lymphocytes (TILs) 
has been shown to impact prognosis in ovarian cancer. In an immunohistochemical study of 
186 specimens from stage 3 and 4 ovarian cancer patients, CD3+ TILs were present in 55% of 
tumors and absent in 38% of tumors (Zhang et al 2003). The numbers of CD4+ and CD8+ 
tumors closely correlated in those tumors with TILs. Patients whose tumors contained TILs had 
a 5-year overall survival of 38% compared to 4.5% in those without TILs (Chang et al 2003). 
Other studies have corroborated the finding that presence of intraepithelial TILs in ovarian 
cancer correlated strongly with improved PFS and OS (Tomsova et al 2008). In ovarian tumors 
with high TILs, a higher CD8:CD4 and CD8:Treg ratio correlated with better disease outcomes, 
indicating the important suppressive role of regulatory T cells in the tumor microenvironment 
(Sato et al 2005). 
There is evidence that immune checkpoints specifically downregulate the anti-tumor activity of 
TILs in ovarian cancer. In a recent small study of the PD-1 inhibitor nivolumab, patients with 
refractory ovarian cancer had an ORR of 15%. In a study of tumor and peripheral blood samples 
of patients with NY-ESO-1 expressing ovarian cancer, tumor derived NY-ESO-1 specific 
CD8+ T cells demonstrated impaired effector function and enriched co-expression of LAG-3 
and PD-1 (Matsuzaki et al 2010). PD-1 and LAG-3 expression was upregulated by cytokines 
found in tumor-derived ascites, including IL10 and IL6 (Matsuzaki et al 2010). Consequently, 
dual blockade of PD-1 and LAG-3 during T cell priming augmented proliferation and IFN-
gamma production by these CD8+ TILs, providing strong rationale for dual CPB therapy in 
ovarian cancer (Matsuzaki et al 2010).
1.1.2.6
Advanced Neuroendocrine tumors
Neuroendocrine tumors (NET) are neoplasms with characteristic neuroendocrine differentiation 
markers that can arise in multiple anatomic locations, and are uniquely characterized by 
functionally active tumor cells that secrete various bioactive peptides (Kunz 2015). Although 
NETs have a low annual incidence of 2-5 per 100,000 patients, given the overall indolent nature 
of these tumors, their prevalence exceeds that of pancreatic and gastric cancers combined (Kunz 
2015). Median overall survival for metastatic NETs originating in the pancreas and small bowel 
with currently available therapies are 24 and 56 months, respectively (Yao et al 2008). Thus, 
there remains a high-unmet need for new therapies.
NETs are highly heterogeneous tumors with highly variable location, function and grade. 
Therefore, in addition to TNM staging, tumor location and grade are important factors in 
therapeutic decision-making (Dong et al 2012). Low-grade NETs (<2 mitoses/10 hpf) are 
typically well differentiated, have an indolent course, and produce secretory granules that often 
express chromogranin A and synaptophysin. In general, low grade NETs are functionally active 
and secrete bioactive peptides such as serotonin, histamine, prostaglandins, substance P, and 
others (Dong et al 2012). 
High grade NETs (>10 mitoses/hpf) are usually non-functional and poorly differentiated, often 
behaving like small cell lung cancer, and treated similarly with combination chemotherapy with 
platinum/etoposide doublet therapy (Dong et al 2012). Advanced, well differentiated (Grade 1 
or Grade 2) NETs will be considered for enrollment. Small Cell Lung Cancer NETs will be 
included in the SCLC group.

Novartis
Confidential
Page 26
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
The treatment of advanced well-differentiated NETs generally involves a multidisciplinary 
approach which includes systemic therapy with somatostatin analogues (SSA) such as 
octreotide to alleviate symptoms from peptide release, and may entail surgical resection and 
liver directed therapies to additionally control symptoms and tumor growth (Kunz 2015). Other 
systemic therapies that have been evaluated in differentiated NETs include biologic therapies 
including interferon alfa and drugs targeting VEGF and mTOR (Kunz P 2015). Two separate 
phase 3 studies of everolimus (mTOR inhibitor) and sunitinib (multikinase inhibitor) in 
combination with octreotide demonstrated improved PFS in both, but failed to show significant 
differences in ORR and OS, likely owing to crossover designs in both studies (Yao et al 2011, 
Raymond et al 2011). Although both drugs are approved for the treatment of advanced 
pancreatic NETs, median PFS remains less than a year for advanced NETs.
The role of immune modulation in the progression of NETs is suggested by the efficacy of 
immune activating therapies such as interferon-alfa in these tumors. Interferons are thought to 
exert antitumor effects through several mechanisms, including stimulation of T cells, induction 
of cell cycle arrest, and inhibition of angiogenesis (Detjen et al 2000). A recent study by 
Pyonteck et al revealed an important immunosuppressive role for tumor associated 
macrophages (TAM) in pancreatic NETs. When tumor specimens from patients with pancreatic 
NETs were immunohistochemically stained for the macrophage marker, CD68, a significant 
correlation was seen between increased macrophage levels and tumor stage, grade, and 
metastases to the liver (Pyonteck et al 2012). In subsequent mouse models of pancreatic NETs 
in animals deficient in the TAM promoting protein CSF1, tumor burden was significantly 
reduced compared to wild type mouse (Pyonteck et al 2012). Similar emerging evidence for the 
role of immune suppression within the tumor microenvironment in NETs argues for further 
exploration of combination immunotherapeutic approaches in these tumors.
1.1.2.7
Diffuse Large B-cell lymphoma
Diffuse large B cell lymphomas (DLBCL) are the most common lymphoid malignancies in 
adults accounting for 30% of NHLs diagnosed annually (NCCN Guidelines v2.2015). DLBCL 
comprises a large and heterogenous group of lymphomas comprising several subtypes including 
primary mediastinal large B cell lymphoma (PMBL), transformed indolent lymphomas 
including CLL and follicular lymphomas, gastric MALT, intravascular large B cell lymphoma, 
EBV-positive DLBCL, and chronic inflammation associated DLBCL, all of which are managed 
similarly (NCCN Guidelines v2.2015). Immunohistochemical and genomic profiling of 
DLBCL has revealed additional heterogeneity in the genetic and molecular profiles of DLBCL. 
Expression of surface markers such as CD10, BCL6, and IRF4/MUM1 correlates with gene 
expression profiling that categorizes DLBCL into 2 subtypes: germinal center B-cell (GCB) 
and non-GCB subtype, with the GCB subtype carrying better prognosis. While more refined 
molecular and genomic subtypes have revealed additional prognostic factors, such as Myc and 
Bcl2 rearrangements (“double hit” lymphomas), treatment paradigms have not yet evolved to a 
genomic/molecular profile based selection of therapy.
Therapy for newly diagnosed DLBCL is based on stage and risk prognostication using the 
International Prognostic Index (IPI) which takes into account several disease factors including 
age, performance status, stage, LDH, and extranodal involvement (NHL LPF Project 1993). 
Patients with Stage 1-2 disease typically get multimodality therapy involving radiation and 

Novartis
Confidential
Page 27
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
combination chemo-immunotherapy with anti-CD20 directed therapy. Those patients with 
advanced stage (stage 3-4) get induction chemo-immunotherapy (R-CHOP 21), or alternate 
regimens tailored to patient age, performance status, and sites of extranodal disease (NCCN 
Guidelines v2.2015). For the 30-40% of patients who have disease relapse, re-induction 
combination chemotherapy followed by autologous transplantation demonstrated a 5 year EFS 
rate of 46% compared to patients who did not undergo transplant (5 year EFS=12%) in an 
international randomized phase 3 study (Philip et al 1995), and is generally the standard 
approach for fit patients with relapsed disease. For patients unable to undergo autologous SCT, 
less intensive chemotherapy regimens such as bendamustine combined with rituximab (BR) has 
demonstated clinical benefit in small studies, with ORR of 45% and median PFS of 3.6 months 
(Vacrica et al 2014). Patients with relapsed/refractory disease after second line therapy 
including autologous transplant, have very poor outcomes with median survival ranging from 
3-6 months (Raut et al 2014).
There is accumulating evidence of active immune regulation in the tumor microenvironment of 
NHL, including cellular elements such as Tregs, myeloid derived suppressor cells, as well as 
proteins including IL10 and TGF-beta. Upregulation of inhibitory immune checkpoints such as 
CTLA-4 and PD-1 have been observed in various subsets of NHL in clinical trials of drugs 
blocking these pathways (Zhou et al 2010, Ansell et al 2009). To date small clinical trials of 
anti-CTLA-4 and anti-PD-1 blockade has shown preliminary signals of efficacy to single agent 
CPB therapy with response rates of less than 20% in heavily pre-treated patients, suggesting the 
potential efficacy of combination approaches. A recent trial in which the anti-PD-1 agent 
pidilizumab was given to patients immediately post-autologous transplant met its primary 
endpoint of exceeding the 16 month PFS threshold, with a continued response rate of 
approximately 50% in those patients with residual measurable disease after transplant (Armand 
et al 2013). While it is difficult to estimate the individual attributions of ASCT and pidilizumab 
to efficacy in this single arm phase 2 study, the observed efficacy signal with single agent CPB 
therapy argues strongly for the therapeutic potential of such therapy in relapsed/refractory 
DLBCL.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of PDR001
PDR001 is a high-affinity, ligand-blocking, humanized anti-programmed death-1 (PD-1) IgG4 
antibody, (stabilized hinge, S228P), that blocks the binding of Programmed death-ligand 1 (PD-
L1) and programmed death-ligand 2 (PD-L2) to PD-1. PDR001 recognizes PD-1 in cynomolgus 
monkeys and shows functional activity in vitro/ex vivo. For further details, please refer to 
[PDR001 Investigator’s Brochure].
1.2.1.1
Non-clinical experience
PDR001 binds specifically and with high affinity to human PD-1. In Biacore assays, the KD of 
PDR001 on human PD-1 is 0.083 nM. In ex vivo lymphocyte stimulation assays using human 
blood, PDR001 enhances IL-2 production by approximately 2-fold in response to super antigen 
stimulation with Staphylococcal enterotoxin B (SEB). PDR001 does not cross-react with rodent 

Novartis
Confidential
Page 28
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
PD-1, and cannot be evaluated in murine tumor models. It does cross-react with cynomolgus 
monkey PD-1, and is functionally active, making cynomolgus monkey a relevant species for 
toxicology studies. A GLP tissue cross reactivity study using frozen human and cynomolgus 
monkey tissues was also done in support of the safety of PDR001. There was no unexpected 
binding observed.
The non-clinical toxicology of PDR001 was evaluated in a five week GLP toxicology study in 
cynomolgus monkeys with safety pharmacology endpoints and an eight week recovery. Repeat 
administration of PDR001 to monkeys was well tolerated at all doses tested in the GLP 
toxicology study. No test article-related in-life, mortality, organ weight changes, or 
macroscopic findings were noted. There were no PDR001-related effects seen in any of the 
safety pharmacology endpoints assessed (cardiovascular, neurobehavioral, and respiratory). 
Macrophage infiltrates into the splenic white pulp were observed in animals given 100 
mg/kg/week and mononuclear cell infiltrates, often associated with fibrosis, around the 
injection site blood vessel (saphenous vein) in a few animals given 25 mg/kg/week. These 
PDR001-related microscopic changes were fully reversible after an eight week recovery.
The following changes were noted in main phase and recovery treated animals as well as control 
recovery animals. Mostly low grade changes were noted in several tissues in the form of 
mononuclear infiltrates in the vascular and perivascular space. In general, in most organs, 
vascular/perivascular changes were limited to one or a few blood vessels in each organ and 
sometimes involved a segment of a blood vessel with occasional vessel wall degeneration. No 
evidence of parenchymal damage was associated with the vascular/perivascular changes in any 
of the organs examined and the changes were not associated with any frank tissue injury. While 
these effects were not exclusive to treated animals, because of their nature and close association 
with the expected pharmacology of PD1 blockade, a potential PDR001 related effect cannot be 
excluded and possibly explained by mild enhanced pharmacology of PDR001. There were no 
test article related effects seen in the cardiovascular (CV) assessments. All other microscopic 
findings were considered spontaneous or otherwise unrelated to PDR001 administration.
Dose-dependent exposure to PDR001 in each dose group was confirmed. A pharmacodynamic 
ex vivo superantigen stimulated whole blood assay measuring IL-2 release was performed. 
Blood from untreated control animals showed augmentation of IL-2 release when PDR001 was 
added ex vivo, whereas blood from treated animals at all doses did not show augmented IL-2 
release, indicating target engagement and inability to further dis-inhibit the SEB induced 
response with the further addition of PDR001. The HNSTD dose in this study was 100 mg/kg.
1.2.1.2
Clinical experience
The CPDR001X2101 study started enrollment on 27 April 2015 and is ongoing. As of 
November13, 2017, a total of 303 patients had been treated in the study. In the phase I part of 
the study, 58 patients had been treated at doses of 1 mg/kg Q2W (16 patients) for up to 78 
weeks, 3 mg/kg Q2W (15 patients) for up to 60 weeks, 10 mg/kg Q2W (11 patients) for up to 
34 weeks, 3 mg/kg Q4W (6 patients) for up to 33 weeks and 5 mg/kg Q4W (10 patients) for up 
to 57 weeks. In the phase II part of the study, 245 patients had been treated in five groups: 
NSCLC 400 mg Q4W (59 patients), NSCLC 300 mg Q3W (59 patients), melanoma 400 mg 
Q4W (61 patients), TNBC 400 mg Q4W (40 patients) and anaplastic thyroid cancer 400 mg 

Novartis
Confidential
Page 29
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Q4W (26 patients). In the Phase II part of the study, the median duration of exposure to study 
treatment was 8.0 weeks (range 1.0 - 35.1).
The PK analysis of the dose escalation data using a population approach and the expected wide 
therapeutic index of PD-1 inhibitors support the use of flat dosing for PDR001 of 400 mg Q4W 
or 300 mg Q3W. The expected PDR001 Ctrough concentrations using either dosing regimen 
exceed the EC50 for PD-1 blockade by approximately 75-fold in an ex vivo assay in PBMCs. 
Based on the available PK and safety data, the RP2D of PDR001 has been declared as 400 mg 
i.v. Q4W or 300 mg i.v. Q3W for combination treatment regimens for which this may be more 
convenient. For further details, please consult the most recent edition of the [PDR001 
Investigator’s Brochure].
PDR001 is currently being studied alone or in combination with other agents in ongoing phase 
I/Ib/II clinical trials. As of January 19, 2018, 1,239 patients across 23 Novartis-sponsored 
studies have been treated with PDR001. The preliminary toxicity profile appears to be similar 
to that of marketed inhibitors of PD-1 including the type, severity and frequency of occurrence 
of immune-mediated adverse events. As observed with other PD-1 inhibitors, immune-
mediated toxicities observed with PDR001 are reversible in many cases. In some cases, they 
may require treatment with corticosteroids. Certain toxicities are expected to be lifelong and 
may require replacement therapy with hormones, for example in the case of hypothyroidism. 
Based on the preliminary data, PDR001 is well tolerated with a safety profile similar to those 
of other marketed anti-PD-1 antibodies. For further details, please consult the most recent 
edition of the [PDR001 Investigator’s Brochure].
1.2.2
Overview of LAG525
LAG525 is a high-affinity, ligand-blocking, humanized anti-LAG-3 IgG4 antibody (stabilized 
hinge, S228P) which blocks the binding of the known LAG-3 ligand MHC class II to LAG-3. 
LAG525 is cross-reactive in cynomologus monkeys and shows functional activity.
1.2.2.1
Non-clinical experience of LAG525
LAG525 binds specifically and with high affinity to human LAG-3. In Biacore assays, the KD
of LAG525 on human LAG-3 is 0.109 nM and in cell binding assays, LAG525 binds CHO-
hLAG-3 expressing cells with an affinity of 1.9 nM. LAG525 does not cross-react with rat or 
mouse LAG-3, and therefore cannot be evaluated in murine tumor models. It does cross-react 
with cynomolgus monkey LAG-3 (affinity of 2.3 nM on cynomolgus LAG-3-expressing cells), 
making cynomolgus monkey a relevant species and the only species for toxicology studies. A 
GLP tissue cross reactivity study was conducted with both human and cynomolgus monkey 
tissue specifically to assess the potential for off target binding. There was no binding observed 
even for tissues known to express LAG-3. This was likely due to reagent sensitivity issues and 
possibly the lower expression of the target.
Safety was evaluated in a five week repeat dose GLP toxicology study as well as in a limited 
panel in a single dose PK study, both in cynomolgus monkeys. In the single dose study, clinical 
observations, clinical chemistry, and hematology endpoints were evaluated as part of an in-life 
assessment of safety. There were no findings related to LAG525 administration in this single 
dose study.

Novartis
Confidential
Page 30
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
In the five week GLP toxicology study, repeat administration of LAG525 to monkeys 
(3/sex/main and 2/sex/recovery groups) at doses of 6, 25, and 100 mg/kg was well tolerated at 
all doses tested. After the fifth dose, the eight week recovery period began for control and high 
dose animals assigned to recovery. Animals assigned to the main phase were sacrificed seven 
days after the last dose was administered. Minimal increases in fibrinogen at 100 mg/kg and 
globulin (relative change from pretest only) in males at 25 and 100 mg/kg were noted. 
Association with LAG525 administration is unclear but cannot be excluded. A female animal 
in the 6 mg/kg group displayed a hypersensitivity reaction soon after the third dose, consisting 
of vomiting and clinical signs of a swollen muzzle and flushed face. The animal was 
subsequently treated with diphenhydramine and the symptoms resolved shortly after treatment. 
This animal was then pre-treated with diphenhydramine prior to the last two doses and no 
further intervention was required. It was confirmed that this animal was positive for the 
presence of anti-drug antibodies. A statistically significant increase in proliferating CD4+ T 
cells was observed in animals given 100 mg/kg/week compared to control animals, a 
pharmacodynamic effect observed in vitro with LAG-3 blockade (Huard 1997; Workman 2003). 
There were no other test article related effects. The highest non-severely toxic dose (HNSTD) 
and the ‘no observed adverse effect level’ (NOAEL) was 100 mg/kg. LAG525 has a favorable 
safety profile in monkeys that supports the proposed human starting dose of 1 mg/kg.
1.2.2.2
Clinical experience
The first in human (FIH) study for LAG525 began in June 2015. The Phase I part of the study 
is ongoing for both single agent and combination.  The safety information is summarized below. 
As of the data cut-off date of October 18, 2017, a total of 320 patients were treated on the first-
in-human clinical study of LAG525, 134 as a single agent and 186 in combination with PDR001.  
In the single-agent part of the study 134 patients were treated with LAG525 at doses ranging 
from 1 to 15 mg/kg on Q2W and Q4W schedules. Preliminary PK parameters demonstrated 
approximately dose-proportional increases in exposure observed from 1 to 15 mg/kg with low 
to moderate interpatient variability. The observed median half-life for LAG525 ranged from 
7.4 to 15.4 days. 
Dose Limiting Toxicities (DLTs): Four DLTs have been reported and include: Gr 3 localized 
intra-abdominal fluid collection (1mg/kg Q2W); Gr 3 lipase increase (5mg/kg Q2W); Gr 3
vomiting (5mg/kg Q2W) and Gr 4 acute kidney injury (10mg/kg Q4W).
Adverse events (AEs): all grades, regardless of relationship to study drug, were reported in 
132 patients (98.5%) overall, with the most frequently reported (>20%) AEs being constipation 
(33 patients, 24.6 %), fatigue (35 patients, 26.1%), nausea (35 patients, 26.1%), abdominal pain 
(31 patients, 23.1%), decreased appetite (32 patients, 23.9%), and anemia (31 patients, 23.1%). 
The safety profile appeared similar across different dose groups. 
Grade 3/ Grade 4 AEs: Of the 134 patients treated, 75 (56%) experienced Grade 3 or Grade 4 
AEs regardless of relationship to study drug. The most frequently reported AEs occurring in 5% 
or more of patients included anemia (14 patients, 10.4%) and dyspnea (7 patients, 5.2%), 
AEs suspected to be related to study treatment: Of the 134 patients treated, 76 (56.7%) 
experienced AEs (all grades) suspected to be related to study treatment. The most frequently 
reported events, occurring in >3% of patients, included fatigue (12 patients,9.0%), nausea (11

Novartis
Confidential
Page 31
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
patients, 8.2%), pyrexia (6 patients, 4.5%), increased alanine aminotransferase, (4 patients, 
3.7%), decreased appetite (7 patients, 5.2%), arthralgia (5 patients, 3.7%), pruritus 7 patients, 
5.2%), hypothyroidism (5patients, 3.7%), vomiting (7 patients, 5.2%), myalgia (6patients, 
4.5%), diarrhea (5 patients 3.7%),  rash (4 patients, 3%), lipase increased (4 patients, 3%), 
lethargy (4 patients, 3%), dry mouth (4 patients, 3%).  Of the 76 patients who experienced AEs 
suspected related to study treatment the following Gr 3 or 4 AEs were reported in 10 patients, 
(7.5%): intra-abdominal fluid collection (1 patient), increased lipase (2 patients), anemia (1 
patient), abdominal pain (1 patient), melena (1 patient), increased AST (2 patients), and fatigue 
(1 patient). One patient experienced multiple Gr 3 or 4 AEs suspected related to study treatment 
which included increased lipase and increased amylase. Another patient experienced multiple 
AEs including wound infection, nausea, and vomiting. Another patient experienced multiple 
AEs including acute kidney injury, tumor lysis syndrome, vomiting, decreased urine output, 
increased blood creatinine, hyperuricemia, hypotension, multiple organ dysfunction syndrome 
and metabolic acidosis. 
Serious adverse events (SAEs): of all grades, and regardless of relationship to study drug, 
were reported in 53 patients (39.6%). The majority of SAEs (49 out of 53 patients who 
experienced SAEs) were Grade 3 or 4 in severity. Of the 53 patients who experienced SAEs, 
19 events among 7 patients were suspected related to study treatment and included localized 
intraabdominal fluid collection (DTL) (1 patient, 1 mg/kg Q2W),abdominal pain and melena (1 
patient, 3 mg/kg Q2W), infection and vomiting (DLT) (1 patient, 5 mg/kg Q2W), increased 
lipase, (DLT), diarrhea (1 patient, 5 mg/kg Q2W), diarrhea (1 patient, 5 mg/kg Q2W), and 
nausea, vomiting, anorexia, fatigue, and failure to thrive (1 patient, 240 mg Q2W). One patient 
experienced multiple SAEs suspected related to the study treatment which included acute 
kidney injury, tumor lysis syndrome, vomiting (worsening), multiple organ failure, and 
metabolic acidosis. This patient was treated with LAG525 at a dose of 10mg/kg Q4W and 
presented with acute kidney injury 26 days after the first and only dose of LAG525. The patient 
rapidly deteriorated in hospital and died 3 days after admission. An autopsy showed widespread 
metastatic disease consistent with the underlying diagnosis of cancer. The events, (acute kidney 
injury, vomiting, metabolic acidosis and tumor lysis syndrome) were considered possibly 
related to LAG525.
1.2.3
Overview of the combination of LAG525 and PDR001
1.2.3.1
Nonclinical experience with the combination of LAG525 and PDR001
Woo (Woo 2012) described a series of experiments with dual LAG-3/PD-1 knockout (KO) 
mice evaluating both tumor efficacy and the KO phenotype in these animals. Compared to wild-
type (WT), the dual KO mice developed an early onset (4 weeks of age) of a lethal autoimmune 
condition that resulted in approximately 80% of the mice moribund by approximately 10 weeks. 
The major histopathologic manifestations included diffuse fibrosing lymphohistiocytic 
endocarditis, myocarditis, and pancreatitis. In contrast, LAG-3 and PD-1 single KO mice lacked 
any disease manifestations or histopathology over this period of observation. These results show 
that the PD-1 and LAG-3 pathways synergistically regulate immune self-reactivity. These 
results demonstrate a theoretical risk of the simultaneous disinhibition of both the LAG-3 and 
PD-1 receptor pathways. However, intermittent blocking of both receptors in patients where the 
pathways have been biologically and physiologically intact since birth seems unlikely to 

Novartis
Confidential
Page 32
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
produce such a severe clinical picture. In addition, in the setting of a clinical trial with intense 
safety monitoring and clear guidance on drug interruption and withdrawal, the management of 
immune adverse events should be possible. Any theoretical risk is also balanced by the well-
documented efficacy of these agents, both alone and in combination, in a host of tumor models 
and for PD-1 inhibition in the clinical setting.
1.2.3.2
Clinical experience with the combination of LAG525 and PDR001
LAG525 combined with PDR001 is being tested in an ongoing, multicenter, open-label study 
CLAG525X2101C with a phase I dose escalation part followed by a phase II dose expansion 
part. Dosing began in June 2015. 
As of a data cut-off date of October 18, 2017, a total of 320 patients were treated on the first-
in-human clinical study of LAG525 as a single agent and in combination with PDR001. The 
Phase I part of the study is ongoing for both single agent and combination. In the single-agent 
part of the study 134 patients were treated with LAG525 at doses ranging from 1 to 15 mg/kg 
on Q2W and Q4W schedules. Preliminary PK parameters demonstrated approximately dose-
proportional increases in exposure observed from 1 to 15 mg/kg with low to moderate 
interpatient variability. The observed median half-life for LAG525 ranged from 7.4 to 15.4 days.  
In the combination part of the study, 186 patients were treated with LAG525 in combination 
with PDR001.  PDR001 or LAG525 in combination with showed comparable PK to the single-
agent data at the same dose levels from the ongoing PDR001 studies. The observed median 
half-life for PDR001 ranged from 7.2 to 23.8 days, which was similar to the results from the 
ongoing CPDR001X2101 study.
Adverse Events: Of the 186 patients treated, with the combination of PDR001-LAG525, AEs, 
all grades, regardless of relationship to study treatment, were reported in 171 patients, (91.9 %). 
The most frequently reported, occurring in more than 15 % of patients include; fatigue (51 
patients, 27.4 %), nausea, (51 patients, 27.4 %), diarrhea (39 patients, 21%), decreased appetite 
(37 patients, 19.9%), vomiting (36 patients, 19.4%), constipation (35 patients, 18.8%), and 
cough (30 patients, 16.1%).
Dose-Limiting Toxicities (DLTs): Four patients experienced DLTs which included: Gr3 
hyperglycemia (80 mg LAG525 Q2W and 400 mg PDR001 Q4W), Gr4 autoimmune hepatitis 
and Gr3 fatigue (1000 mg LAG525 Q4W and 400 mg PDR001 Q4W), Gr3 brain tumor edema 
(600 mg LAG525 Q3W and 300 mg PDR001 Q3W), Gr3 pneumonitis (400 mg LAG525 and 
400 mg PDR001 Q4W).
Grade 3/ Grade 4 AEs: 79 patients,  (42.5%), experienced Grade 3 or Grade 4 AEs regardless 
of relationship to study treatment. The most common Grade 3/grade 4 AEs, regardless of 
relationship to study treatment, occurring in more than 20% of patients, include: anaemia (11 
patients, 5.9%), asthenia (5 patients, 2.7%), fatigue (4 patients, 2.2%), and dyspnea (4 patients, 
2.2%).
AEs suspected to be related to study treatment: 110 patients,(59.1%), experienced AEs (all 
grades) suspected to be related to study treatment. The most common AEs, suspected to be 
related to study treatment, occurring in more than 5% of patients include: fatigue (26 patients, 
14 %), diarrhea (19 patients, 10.2%), nausea (17 patients, 9.1 %), rash (16 patients, 8.6%), and 

Novartis
Confidential
Page 33
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
rash maculo-papular (11 patients, 5.9%). The safety profile appeared similar across the different 
dose groups.
Serious adverse events (SAEs): SAEs, all grades, regardless of relationship to study treatment, 
were reported in n=65 (34.9%). The majority of these patients (53 out of 65) experienced SAEs 
that were Grade 3 or 4 in severity. Among the 65 patients who experienced SAEs, 17 events in 
12 patients were suspected related to study treatment. The most common SAEs, regardless of 
relationship to study treatment, experienced by more than 2% patients, include: pyrexia (6 
patients, 3.2%), dyspnea (4 patients, 2.2%), fatigue (4 patients, 2.2%), and nausea (4 patients, 
2.2%).
2
Rationale
2.1
Study rationale and purpose
Although there is clinical activity of checkpoint blockade (CPB) monotherapy in several tumor 
types including melanoma, NSCLC, and Hodgkin lymphoma, multiple tumor types have 
significantly less response to CPB monotherapy. Despite the finding of somewhat predictive 
biomarkers of response to CPB, including mutational burden, PD-L1 expression, and presence 
of tumor infiltrating lymphocytes (TILs), there is to date, no biomarker or set of biomarkers 
that universally predicts response to CPB therapy. However, it is generally accepted that in 
order for CPB therapy to be effective in a tumor, the tumor must first have established 
immunogenicity and second, be actively engaged in immunosuppressive mechanisms, either 
through direct expression of immunosuppressive ligands on the tumor or indirectly through 
manipulation of cellular and molecular components of the tumor microenvironment (Pardoll 
2012). 
Therefore, we hypothesize that those tumors in which CPB monotherapy has shown low to 
moderate clinical activity must be immunogenic, but to a lesser degree than those in which CPB 
monotherapy has high activity. Furthermore, the lower baseline immunogenicity of such tumors 
may necessitate combination CPB or CPB -immune accelerator combinations to overcome 
immunosuppressive mechanisms and achieve responses similar to those seen with CPB 
monotherapy in highly immunogenic tumors. Accordingly, we propose to conduct a phase II 
open-label study evaluating the efficacy and safety of combination CPB therapy with 
PDR001+LAG525 in patients with select advanced solid tumors and lymphoma that have 
suboptimal response rates (less than 30% ORR) to CPB monotherapy. Other tumors in which 
clinical data are not presently available with CPB therapy, but have pre-clinical evidence 
supporting use of CPB therapy or clinical data showing efficacy of other immune modulating 
therapies (e.g. cytokine therapy, IMIDs, adoptive cellular therapy) will also be studied in this 
trial. Tumor types may be excluded during the course of the study in the case of early futility 
or success based upon an interim analysis or at the discretion of Novartis. Tumor types may be 
added at the discretion of Novartis based on emerging pre-clinical or clinical data.
2.2
Rationale for the study design
There is currently a lack of validated patient preselection markers for combination 
immunotherapy. Given robust early clinical and/or preclinical evidence supporting the potential 

Novartis
Confidential
Page 34
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
efficacy of combination CPB in several tumor types, a clinical trial employing a broad signal
finding strategy across multiple tumor types is warranted. This is a phase II, open-label, study 
to determine the efficacy and safety of treatment with the combination of PDR001+LAG525 in 
patients with a diagnosis of select solid tumors or lymphoma, that are hypothesized to respond 
to combination CPB therapy based on existing clinical and/or preclinical data.  
There are patterns of disease response unique to CPB therapy including delayed responses and 
apparent disease progression prior to response (pseudoprogression). In melanoma patients 
treated with CTLA-4 blockade, the median time to response in patients who achieved an 
ultimate complete response was 30 months (Prieto PA et al 2012). In a study of the anti-PD-1 
mAb pembrolizumab, 10% of patients had apparent disease progression before achieving 
clinical benefit in the form of either stable disease or partial response (Hodi SF et al 2014).  
Consequently, there are limitations to using time-dependent overall response rate as the primary 
endpoint in a study evaluating combination CPB therapy, since immune-mediated anti-tumor 
effects may manifest clinically as long standing stable disease or delayed responses. Therefore, 
the primary endpoint for this study will be the clinical benefit rate (CBR) at 24 weeks of 
treatment, with a secondary endpoint of overall response.
2.3
Rationale for dose and regimen selection
PDR001+LAG525 combination is being tested in an ongoing, multicenter, open-label study 
CLAG525X2101C with a phase I dose escalation part followed by a phase II dose expansion
part. The recommended phase II dose is PDR001 300 mg Q3W with LAG525 400 mg Q3W   
2.4
Rationale for choice of combination drugs 
In vivo studies have demonstrated a synergistic effect in antitumor activity of the dual blockade 
of the LAG-3 and PD-1 co-inhibitory receptors when compared to the inhibition of either 
checkpoint alone. CD4+ and CD8+ TIL from Sa1N fibrosarcoma, MC38 colon carcinoma and 
B16 melanoma have previously been shown to co-express PD-1 and LAG-3; Woo and 
colleagues demonstrated some single agent activity of anti-LAG-3 treatment in both Sa1N 
fibrosarcoma and MC38 colon carcinoma. Importantly, combined LAG-3 and PD-1 blockade 
led to rapid and complete regression of established tumors in 70% of Sa1N fibrosarcoma and 
80% of MC38 colon carcinoma within 50 days of the initiation of therapy. Using the maximum 
likelihood model, this demonstrated synergy of co-blockade over single agent activity. Both 
TILs and lymphocytes from draining lymph nodes harvested from treated mice had increased 
numbers of CD8+IFN-gamma+ TIL, further supporting the anti-tumor role of co-blockade 
(Woo 2012).
The growth of syngeneic tumors was also studied in LAG-3 and PD-1 double deficient mice 
(Lag3-/-Pdcd1-/-). While combination blockade (using murine antibody reagents) did not show 
efficacy in B16 melanoma, both Pdcd1-/- and doubly deficient mice showed inhibited tumor 
growth. Depletion of CD4+ and CD8+ T cells led to restoration of normal tumor growth, 
demonstrating the dependency of the phenotype on T cell alteration. MC38 colon carcinoma 
implanted in doubly deficient mice showed 80% reduction (compared to 40% in Pdcd1-/- mice), 
confirming the synergistic action of PD-1 and LAG-3 seen in the co-blockade experiments 
(Woo 2012).

Novartis
Confidential
Page 35
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Taken together, these preclinical data demonstrate that co-blockade of the PD-1 and LAG-3 
pathways leads to anti-tumor activity superior to blockade of either inhibitory protein alone. 
(Woo 2012).
2.5
Rationale for choice of comparators drugs 
Not applicable
2.6
Risks and benefits 
Appropriate eligibility criteria, as well as specific dose delays and stopping rules are included 
in this protocol. Recommended guidelines for prophylactic or supportive management of study-
drug induced adverse events are provided in Section 6. The risk to subjects in this trial may be 
minimized by compliance with the eligibility criteria and study procedures, close clinical 
monitoring, and stopping rules. 
Infusion of drugs such as PDR001 and /or LAG525 can be associated with reactions especially 
during the first exposure. Infusion reactions usually consist of symptoms such as fever, chills, 
nausea, vomiting, headache, dizziness, dyspnea, hypotension, rash, and asthenia.
PDR001: The most frequent side effects caused by single-agent PDR001 include: diarrhea, 
nausea, vomiting, constipation, gastritis, hypothyroidism, hyperthyroidism, itchiness, skin 
reactions (such as rash, dryness, redness, hives), low red blood cell count, dry mouth, 
inflammation in the mouth, canker sores, loss of appetite, decreased blood sodium, increased 
blood sugar, pain in joints, muscles, nerves & skin, swelling in the face or limbs, pneumonia, 
abnormal liver function tests, increased lipase, decreased lymphocytes, weight loss, fever, chills, 
malaise, weakness, fatigue, abdominal discomfort and pain, shortness of breath during exercise 
or at rest, cough, vertigo/dizziness, and headache.
Less frequent side effects caused by single agent PDR001 include the following severe immune 
reactions:  colitis requiring hospitalization; pneumonitis & pneumonia, hepatitis with abnormal 
liver test results; and polymyositis with muscle weakness, 
LAG525: The most frequent side effects caused by single-agent LAG525 include: fatigue, 
nausea, vomiting, fever, abnormal liver function tests, loss of appetite, joint and muscle pain,  
itchiness, skin reactions such as rash, dryness, redness & hives, hypothyroidism, increased 
amylase, increased lipase, hyperkalemia, hyperuricemia, constipation, dry mouth, lack of 
energy, abdominal pain, diarrhea, and weight loss.
One case of acute kidney injury possibly related to LAG525 occurred in the setting of 
widespread metastatic disease, tumor lysis syndrome, and multiple organ failure leading to 
death.  Kidney function is evaluated in all patients regularly throughout this study.
Combination of PDR001 and LAG525:  While the incidence of immune related adverse 
events with single agents has been well characterized, there may be a higher incidence of 
immune related adverse events with combination immune therapies including the combination 
of PDR001 and LAG525. These adverse events may be serious and include, but are not limited 
to, allergic reactions, inflammation of the heart, pneumonitis, colitis, diabetes, hepatitis, and 
other autoimmune disorders, increased phosphate, distortion of taste, flatulence, flushing, and 
headache.

Novartis
Confidential
Page 36
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
The combination of PDR001 and LAG525 is hypothesized to improve upon responses to single-
agent anti-PD-1/PD-L1 therapies. The ongoing study, LAG525X2102C, A Phase I/II, open-
label, multicenter study of the safety and efficacy of LAG525 single agent and in combination 
with PDR001 administered to patients with advanced malignancies, provides encouraging data 
on the tolerability and response rate of this combination treatment, lending support to this 
hypothesis. 
Therefore, the potential benefit of combination therapy with PDR001 and LAG525 is thought 
to outweigh the risk in those patients with advanced malignancies and minimal therapeutic 
options who are still eligible by standard criteria for participation in clinical trials.
For additional information on risk-benefit assessment, please refer to [PDR001 Investigators 
Brochure] and [LAG525 Investigators Brochure].
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Assess CBR at 24 weeks of 
PDR001+LAG525 by tumor 
type in multiple solid and 
lymphoma
Refer to Section 10.4
The primary objective is to assess clinical benefit rate after 24 
weeks of treatment with PDR001+LAG525 based on local 
investigator assessment.
For patients with solid tumors the assessment criteria will be 
RECIST 1.1 and will include responses of CR or PR or SD. For 
lymphoma, assessment criteria will be the Revised Response 
Criteria for Malignant Lymphoma, (Cheson et al 2007).
Secondary
Assess ORR by RECIST 1.1 
in solid tumors and by the
Revised Response Criteria 
for Malignant Lymphoma 
(Cheson et al 2007) in 
lymphoma
TTR, DoR, TTP, PFS/ rate at 
1 and 2 years 
Safety incidence and 
severity of adverse events 
(AEs) and serious adverse 
events (SAEs) including 
changes in laboratory 
parameters, vital signs and 
ECGs
Tolerability: Dose 
interruptions, reductions and 
dose intensity.
Refer to Section 10.5.
To assess Overall Response (OR) of Partial Response (PR) or 
Complete Response (CR) based on local investigator 
assessment.
Time to response (TTR) is defined as the time from the date of 
first dose to the date of first documented response of CR or 
PR. 
The duration of response (DOR) applies only to patients whose 
best response was PR or CR. The duration of response is 
defined as the time from the first documented response to the 
date first documented disease progression or relapse or death 
due to any cause. The duration of response will be 
summarized descriptively for each tumor cohort.
Time to progression (TTP) is defined as the time from the date 
of first dose to the date of first documented disease 
progression or relapse.
Progression free survival (PFS) is defined as the time from the 
date of first dose to the date of first documented disease 
progression or relapse or death due to any cause.

Novartis
Confidential
Page 37
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
4
Study design
4.1
Description of study design
This is a phase II, open-label study to determine the efficacy and safety of treatment with the 
combination of PDR001+LAG525 across multiple tumor types that are relapsed and/or 
refractory to available standard of care therapies (Table 4-1).  
Table 4-1
Tumor Cohorts
Group
Malignancy
1
Small cell lung cancer
2
Gastric/esophageal adenocarcinoma
3
Castration resistant prostate adenocarcinoma (CRPC)
4
Soft tissue sarcoma
5
Ovarian adenocarcinoma
6
Advanced well-differentiated neuroendocrine tumors*
7
Diffuse large B cell lymphoma (DLBCL)*
*Please refer to Section 5 for disease specific inclusion/exclusion
Tumor cohorts may be excluded during the course of the study in the case of early futility or 
success based upon interim analyses or at the discretion of Novartis. Additional tumor cohorts
may be added at the discretion of Novartis based on emerging pre-clinical or clinical data.
Patients will receive study treatment for a maximum of 2 years, or until disease progression 
(assessed by investigator per RECIST 1.1 or the Revised Response Criteria for Malignant 
Lymphoma criteria (Cheson et al 2007)), unacceptable toxicity, death or discontinuation from 
study treatment for any other reason (e.g., withdrawal of consent, start of a new anti-neoplastic 
therapy or at the discretion of the investigator or patient). All patients who discontinue from 
study treatment due to disease progression must have their progression clearly documented. All 
disease assessments will be performed locally by the investigator.
Radiological disease assessments will be performed every 6 weeks (±7days), starting 12 weeks
after first dose of study drug and continuing through week 24. The frequency of radiological 
disease assessments will be reduced to every 12 weeks after patients have completed 24 weeks 
on treatment and will continue until confirmed disease progression. Additional response 
assessments may be performed at the discretion of the investigator. 
4.2
Enrollment model
This study is intended for patients who have a pathologically confirmed diagnosis of any tumor 
listed in Table 4-1, and have relapsed and/or refractory disease. Once the patient has been 
identified, treating physicians who are qualified investigators may contact Novartis or designee 
to consider enrollment in the appropriate tumor cohort. Informed consent must be signed before 
any screening activities take place. If all eligibility criteria are met (see Section 5), the patient 
will initiate therapy with the combination of PDR001 and LAG525. The patient may not receive 
any additional anti-cancer therapy during treatment with PDR001 and LAG525.
A schematic representation of the study start-up design is shown in Figure 4-1.

Novartis
Confidential
Page 38
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Figure 4-1
Study Start-up Design
4.3
Tumor cohort enrollment schema
Accrual to each tumor cohort will consist of a futility and expansion stage based on the observed 
24 week CBR rates. The 24 week CBR rate will be continually assessed for futility and early 
success by comparing posterior quantities for the rate to pre-specified futility and expansion 
criteria for each cohort (see Section 10). Analysis for both futility and expansion will borrow 
information across cohorts with a hierarchical model (see Section 10). The hierarchical model 
allows dynamic borrowing of information between cohorts such that more borrowing occurs 
when the cohorts are consistent and less borrowing occurs when the cohorts differ. In this way, 
the model is a compromise between the two alternate extremes of either a completely pooled 
analysis or a separate analysis in each cohort. We additionally incorporate a clustering 
mechanism that allows borrowing within clusters but treats clusters separately. This minimizes 
borrowing across cohorts that are quite different in terms of CBR.
Figure 4-2 
Study Design 

Novartis
Confidential
Page 39
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Depending on whether or not pre-specified criteria for stopping (for futility) or continuing
enrollment (for early success) is met, each tumor cohort can enroll a minimum of 5 patients and 
a maximum of 30 patients during the course of the study. When at least 5 patients within a 
group have completed 24 weeks of treatment and have CBR data available, analysis for futility 
and early success (expansion) will commence to inform a “go/no-go" decision for that cohort. 
For tumor cohorts in which treatment is not declared futile and pre-specified CBR rate for early 
success is met, a “go” decision will be made to continue enrolling to a maximum of 30 patients
for that cohort. Expanded tumor cohorts will continue to have ongoing analysis for futility to 
allow for early stopping in the event that observed 24 weeks CBR rates do not meet pre-
specified final success criteria (see Section 10). For tumor cohorts in which treatment has not 
been declared futile, but criteria for expansion has not been met, enrollment will be paused at 
10 patients until a “go/no-go” decision can be made based on information gleaned from the 
dynamic borrowing of CBR data across tumor cohorts (see Section 10). A “no-go” decision can 
be made for a tumor cohort if: 1) 24 week CBR rates of the first 5-10 patients show treatment 
to be futile and cohort will not expand; 2) subsequent analysis in a cohort that expanded fails to 
demonstrate continued evidence of activity such that 24 weeks CBR is not predicted to meet 
pre-specified criteria for final success (See Section 10).
Primary analysis for all stages will be intent-to-treat. Those patients who discontinue study 
treatment for any reason other than disease progression or treatment related toxicity may be 
replaced (at the discretion of Novartis), until at least 5 patients with 24 weeks of CBR data are 
accrued within a cohort. All patients enrolled into a tumor cohort prior to expansion must not 
have been exposed to prior immuno-oncology (IO) therapy as specified in exclusion criteria 
(Section 5.3). 
Once a tumor cohort is selected for expansion, the cohort shall continue to enroll patients until 
the cohort enrolls a total of 30 patients. 
In each expansion cohort, it is permissible to enroll patients that have received previous CPB 
therapy as follows: 

A maximum of 6 of the 30 patients enrolled into an expansion cohort may have received 
previous CPB therapy. 

All patients enrolled prior to expansion must be IO naive

24 of the 30 patients enrolled into each tumor cohort must be IO naive. 

In the event an expanded cohort does not enroll 30 patients, the previously treated patients 
must not comprise more than 20% of total number of patients enrolled in the cohort.

The patients previously exposed to CPB therapy must satisfy all inclusion-exclusion 
criteria as set forth in sections 5.3 and 5.4 
4.4
Timing of interim analyses
Given the adaptive enrollment model and signal finding nature of this study, frequent interim 
analyses may be required to inform futility, early success (go/no-go decisions), and final success 
declarations within the tumor cohorts. The first interim analysis for the primary endpoint will 
occur when one or more tumor cohorts have accrued 5 patients with 24 week CBR data.
Subsequent interim analyses will occur when at least 10 additional patients enrolled to the study 

Novartis
Confidential
Page 40
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
have 24 week CBR data available AND at least 3 months have elapsed since the previous 
interim analysis cut off. Interim analyses for primary endpoint will continue at minimum 3 
month intervals until end of study (provided at least 10 additional patients have 24 week CBR 
data at each interim analysis).
There is no plan for a formal interim analysis of safety or other secondary endpoints for this 
study. However, for publication or other purposes, interim data review of clean data will be
performed as necessary. At these interim reviews, patient demographics/baseline characteristics, 
the primary and secondary endpoints as applicable, and all important safety endpoints will be 
summarized. No formal report will be issued for these data reviews.
4.5
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible for End of Treatment (EOT) visit and the same 
assessments for EOT should be performed as described in Section 7 for a discontinued or 
withdrawn patient. 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 patient’s interests. 
The investigator will be responsible for informing IRBs and/or ECs of the early termination of 
the trial.
5
Population
5.1
Definition of End of Study
Patient accrual to the study will end when all tumor cohorts have completed initial futility and 
expansion analysis AND all expanded cohorts have accrued 30 patients. The study will end 
when all enrolled patients have either discontinued or completed 2 years of study therapy AND 
150 days of safety follow up. 
5.2
Patient population
This study will be conducted in 35-210 patients with select solid tumors or hematological 
malignancies as outlined in Table 4-1. Tumor types may be excluded or added during the course 
of the study in the case of early futility or success based upon an interim analysis or at the 
discretion of Novartis.
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device 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.
5.3
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures.
2. Patient is ≥ 18 years of age on the day of consenting to the study

Novartis
Confidential
Page 41
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
3. Patient must have had at least one prior line of therapy for their disease and must not be 
beyond 4th progression/relapse of disease (5 maximum prior lines).
4. Patient has a pathology confirmed diagnosis of a solid tumor or lymphoma listed in Table 
4-1 and measurable disease as per appropriate guidelines:

All Solid Tumors: by RECIST 1.1 (Appendix 1)

For advanced well differentiated neuroendocrine tumors, the following also 
apply:

Pathologically confirmed, well-differentiated (Grade 1 or Grade 2), 
advanced (unresectable or metastatic), neuroendocrine tumor 

No history of and no active symptoms related to carcinoid syndrome

Patient has not had hepatic intra-arterial embolization within the last 6 
months or cryoablation or radiofrequency ablation of hepatic metastases 
within 2 months of first dose

Diffuse Large B-cell Lymphoma: by the Revised Response Criteria for 
Malignant Lymphoma (Cheson et al 2007) (Appendix 2)

Relapsed/refractory disease as defined by relevant standardized response criteria 
(see Section 4)

Patients with prior autologous transplant are eligible

Patient has at least one measurable nodal lesion (≥2 cm). In case where the 
patient has no measurable nodal lesions ≥2 cm in the long axis at screening, then 
the patient must have at least one measurable extra-nodal lesion 
5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
6. Patient must have locally advanced or metastatic disease. 
5.4
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Presence of symptomatic CNS metastases, or CNS metastases that require local CNS-
directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids 
within the prior 2 weeks. Patients with treated brain metastases should be neurologically 
stable (for 4 weeks post-treatment and prior to study enrollment) and off steroids for at 
least 2 weeks before administration of any study drug.
2. History of severe hypersensitivity reactions to other mAbs
3. Patient with out of range laboratory values:
a. Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 40 
mL/min
b. Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s syndrome who are 
excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
c. Alanine aminotransferase (ALT) > 3 x ULN, except for patients that have tumor 
involvement of the liver, who are excluded if ALT > 5 x ULN
d. Aspartate aminotransferase (AST) > 3 x ULN, except for patients that have tumor 
involvement of the liver, who are excluded if AST > 5 x ULN

Novartis
Confidential
Page 42
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
e. Absolute neutrophil count (ANC) < 1.0 x 10^9/L
f.
Platelet count < 75 x 10^9/L
g. Hemoglobin < 9 g/dL
4. Impaired cardiac function or clinically significant cardiac disease, including any of the 
following:
a. Clinically significant and/or uncontrolled heart disease such as congestive heart 
failure requiring treatment (NYHA Grade ≥ 2), uncontrolled hypertension or 
clinically significant arrhythmia
b. QTcF > 470 msec on screening/baseline ECG or congenital long QT syndrome
c. Acute myocardial infarction or unstable angina pectoris < 3 months prior to study 
entry
5. Active, known or suspected autoimmune disease or a documented history of autoimmune 
disease within three years prior to screening with exception of:
a. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to an 
autoimmune condition 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.
6. If otherwise eligible for the IO sub-group, patients previously exposed to anti-PD-1/PD-
L1 treatment who are adequately treated for skin rash or with replacement therapy for 
endocrinopathies should not be excluded
7. Active infection requiring systemic antibiotic therapy. Patients requiring systemic 
antibiotics for infection must have completed therapy before screening is initiated.
8. Known history of HIV infection. Testing for HIV status is not necessary unless clinically 
indicated
9. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Testing for HBV or 
HCV status is not necessary unless clinically indicated or the patient has a history of HBV 
or HCV infection.
10. Patient with second primary malignancy within < 3 years of first dose of study treatment. 
Exceptions to this exclusion include the following: malignancies that were treated 
curatively and have not recurred within 2 years prior to study treatment; completely 
resected basal cell and squamous cell skin cancers; any malignancy considered to be 
indolent and that has never required therapy; and completely resected carcinoma in situ of 
any type.
11. Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns, compliance with clinical study 
procedures or interpretation of study results.
12. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For 
cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, 4 
weeks is indicated as washout period.
13. Prior immunotherapy treatment with PD-1, PD-L1, CTLA-4, or LAG-3 antibodies, CAR-
T therapy, gene therapies, and/or Provenge therapy.
a. This exclusion does not apply to patients enrolled in the immunotherapy pre-exposed 
subgroup (n=6 per tumor type) in those cohorts that undergo expansion to 30 patients.

Novartis
Confidential
Page 43
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
b. For patients in the immunotherapy pre-exposed subgroups:

Prior IO therapy with PD-1, PD-L1, or LAG-3 antibodies, within 4 weeks of first 
dose of study treatment

CTLA-4 antagonist or vaccine as anticancer therapy within 6 weeks of first dose of 
study treatment 

Patients who discontinued prior anti-PD-1, PD-L1 or anti LAG-3 therapy due to 
therapy related toxicity

Patients with a history of any grade immune-related ocular adverse event.

Patients with a history of Grade ≥ 3 immune-related adverse event.

Patients with evidence of active noninfectious pneumonitis or history of interstitial 
lung disease.

Patients with risk of reactivation of hepatitis B or C.

Patients who are on endocrine replacement therapy should be stable on the dose.
14. Systemic chronic steroid therapy or any immunosuppressive therapy (>10mg/day 
prednisone or equivalent). Topical, inhaled, nasal and ophthalmic steroids are allowed.
15. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study 
treatment.
16. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF) 
or erythroid stimulating agents ≤ 2 weeks prior to start of study drug. 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.
17. Presence of CTCAE ≥ grade 2 toxicity (except peripheral neuropathy and ototoxicity, 
which are excluded if ≥ CTCAE grade 3) due to prior cancer therapy.
18. Allogeneic stem cell transplant recipients 
19. Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy, 
insertion of a central venous access device, and insertion of a feeding tube are not 
considered major surgery).
20. Participation in an interventional, investigational study within 2 weeks prior to the first 
dose of study treatment.
21. Pregnant or lactating women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test.
22. 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 the last dose of PDR001 and LAG525.  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 follow up hormone level assessment is she considered not of child 
bearing potential. 

Novartis
Confidential
Page 47
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
PDR001
3
LAG525
3
Patients who discontinue the study for a study related AE or a study-related abnormal laboratory 
value must be followed as described in Section 6.3.2. All interruptions or change to study drug 
administration must be recorded on the Dose Administration Record eCRF.
Dose delays for adverse events related to the study medication are summarized in Appendix 5. 
Generally, following resolution of the adverse event to Grade 1 or to the patient’s baseline value, 
the patient may resume study treatment on the same dosing schedule, if there is no evidence of 
disease progression.
6.3.2
Follow-up for toxicities
The emergence of irAEs 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. Management algorithms (Appendix 5) have been developed 
to assist investigators in assessing and managing the following groups of AEs: Gastrointestinal; 
Renal; Pulmonary; Hepatic; Endocrinopathy and Skin. 
For subjects who do not tolerate the protocol-specified dosing schedule, dose or schedule 
adjustments are permitted in order to allow the subject to continue the study treatment. The 
following guidelines need to be applied:

If a subject experiences an AE meeting the criteria for DLT, treatment must be withheld. 

For clinical management of suspected immune-related events, reference to consensus 
management guidelines is recommended such as those provided in the National 
Comprehensive Cancer Network (NCCN) Guidelines for the Management of 
Immunotherapy-Related Toxicities (available at : 
https://www.nccn.org/professionals/physician_gls/default.aspx#immunotherapy), the 
American Society for Clinical Oncology clinical practice guideline for Management of 
Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor 
Therapy (Brahmer 2018) or the European Society for Medical Oncology (ESMO) Clinical 
Practice Guidelines for Management of Toxicities from Immunotherapy (Haanen 2017).  
Note that in general, study treatment should be interrupted for grade 3 and 4 toxicities and 
for a subset of lower grade toxicities.

Consider early referral to specialists with expertise in the diagnosis and management of 
immune-related AEs to thoroughly investigate events of uncertain etiology.

Events not included in the study protocol or the reference guidance documents should be 
managed per institutional preference.

A decision to resume treatment following the occurrence of a DLT, grade 3 or 4 or serious 
adverse suspected immune-related events, may be taken only after documented discussion 
with the Novartis medical monitor.
Patients whose treatment is interrupted or permanently discontinued due to an irAE, AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 

Novartis
Confidential
Page 48
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. All patients must be followed up for irAEs, AEs and SAEs for 150 
days following the last dose of study treatment. 
Table 6-3 outlines the recommended dose delays and follow-up evaluations for selected 
toxicities. 
Table 6-3
Recommended Dose Delays and re-initiation of treatment for 
adverse drug reactions
Worst Toxicity CTCAE 
v4.03 Grade
Recommended Dose Delays
Cardiac disorders
ECG QTc-Interval 
prolonged
Grade 2 (except myocarditis)
Grade 2 myocarditis, 
Grade 3
Grade 4
Hold study treatment. Upon resolution to Grade ≤ 1 or baseline, may resume 
study treatment without dose modification after discussion with the Novartis 
Medical Monitor.
Discontinue study treatment
Omit dose of LAG525 and PDR001until returned to CTCAE Grade ≤ 1 or < 30 
msec difference from baseline. Baseline ECG refers to the ECG(s) collected at 
screening.
May resume study treatment without modifications after discussion with 
Novartis Medical Monitor.
Discontinue study treatment.
Cardiac disorders – others
Grade 1 and 2
Grade ≥ 3
Maintain dose level of LAG525 and PDR001.
Discontinue study treatment.
Skin toxicity
Rash/photosensitivity
Grade 1
Grade 2
Grade 3 or Grade 4
Bullous dermatitis 
Maintain dose level of LAG525 and PDR001and manage per institutional 
standard guidelines. (Topical steroids, antihistamines, topical emollients)
Consider holding study treatment.
Topical or oral steroids, antihistamines.
If study treatment is held and resolution to ≤ Grade 1, resume study treatment 
without dose modification.
hold dose of LAG525 and PDR001 until returned to CTCAE Grade ≤ 1. Treat 
according to institutional practice which generally includes anti-histamine 
regimen, corticosteroid treatment (oral or topical) can be considered for 
symptomatic rash (e.g. pruritus).
consider resuming therapy after expert consultation and documented 
discussion with Novartis Medical Monitor.

Novartis
Confidential
Page 49
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Worst Toxicity CTCAE 
v4.03 Grade
Recommended Dose Delays
Stevens-Johnson Syndrome 
(SJS), or Lyell 
syndrome/toxic epidermal 
necrolysis (TEN)
Hold study treatment.
Grade 1-2 bullous dermatitis: discussion with the Novartis Medical Monitor is 
required before considering resuming study treatment.  
Grade 3 bullous dermatitis: consider resuming therapy after expert 
consultation and documented discussion with the Novartis medical monitor
Permanently discontinue study treatment.
GI disorders
Diarrhea/Colitis
Grade 1
Grade 2 & Grade 3
Grade 4
AST and/or ALT elevation
Grade 2 AST and/or ALT
Grade 2 transaminitis with 
bilirubin >1.5 x ULN (unless 
Gilbert’s syndrome)
Grade 3 AST and/or ALT
Grade 4 AST and/or ALT
Isolated total bilirubin 
elevation
Grade 2
Note: anti-diarrheal medication is recommended at the first sign of abdominal 
cramping, loose stools or overt diarrhea.
Maintain dose level of LAG525 and PDR001and manage per institutional 
standard guidelines which should include corticosteroid therapy and anti-
diarrheal treatment as needed consideration of corticosteroid therapy, and 
hydration. 
Hold study treatment.
GI consultation.
Upon resolution to ≤ Grade 1 and tapering of steroid requirement to ≤ 10 mg 
prednisone per day, resume study treatment without dose delay after 
discussion with the Novartis Medical Monitor.
Discontinue study treatment  
Hold study treatment.
Manage per institutional practice.
Upon resolution to ≤ Grade 1 or baseline, consider resuming study treatment 
without dose modification.
Discontinue study treatment.
Hold study treatment.
Manage per institutional practices.
Upon resolution to ≤ Grade 1 or baseline within 7 days, consider resuming 
study treatment without dose modification after discussion with the Novartis 
Medical Monitor. Otherwise, discontinue study treatment.
Discontinue Study Treatment

Novartis
Confidential
Page 50
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Worst Toxicity CTCAE 
v4.03 Grade
Recommended Dose Delays
Grade 3
Grade 4
Asymptomatic amylase 
and/or lipase elevation
Grade 3 or Grade 4, not 
associated with symptoms or 
clinical manifestations of 
pancreatitis
Hold study treatment. Upon resolution to ≤ Grade 1 or baseline, may continue 
study treatment without dose modification.
Hold study treatment. Upon resolution to ≤ Grade 1 or baseline, may consider 
resuming study treatment after discussion with the Novartis Medical Monitor.  
Discontinue study treatment. Exception: If Grade 3 or 4 hyper-bilirubinemia 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 delay study 
treatment until resolved ≤ Grade 1, and resume study treatment at the 
discretion of the investigator.
Continue study treatment. 
If levels do not resolve to ≤ Grade 2 within ≤ 14 days after the initial report, 
hold study treatment.
Upon resolution to ≤ Grade 2, may resume study treatment without dose 
modification, after discussion with the Novartis Medical Monitor.
A CT scan or other imaging study to assess the pancreas, liver, and 
gallbladder must be performed within one week of the first occurrence of any ≥ 
Grade 3 of amylase and/or lipase.
Pancreatitis*
Grade 1
Grade 2/radiologic evidence
Grade 3 or Grade 4
Maintain dose level of LAG525 and PDR001and manage per institutional 
standard guidelines.
Omit dose of LAG525 and PDR001 until returned to CTCAE Grade ≤ 1. Treat 
according to institutional practice. Upon resolution to ≤ Grade 1, may resume 
study treatment without dose modification, if no clinical evidence of 
pancreatitis and after discussion with the Novartis Medical Monitor.
Discontinue study treatment
Discontinue study treatment
Pulmonary disorders
Pneumonitis
Any Grade
Grade 1 
Omit LAG525 and PDR001 for any case of suspected pneumonitis.
Initiate institutional protocol for pneumonitis management which generally includes 
obtaining appropriate imaging (high resolution CT scan) and consider bronchoalveolar 
lavage if clinically indicated for biopsy. Treatment with high dose corticosteroid 
therapy is recommended. Concurrent corticosteroid and antibiotic therapy is 
recommended if infectious causes have not been ruled out.
Consider study treatment hold.
Manage per institutional practice.
Consider resuming study treatment upon radiographic evidence of 
improvement.

Novartis
Confidential
Page 51
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Worst Toxicity CTCAE 
v4.03 Grade
Recommended Dose Delays
Grade 2
Grade 3 or 4
Hold study treatment.
Pulmonary and infection workup.
Upon resolution to ≤ Grade 1, may resume study treatment without dose 
modification.
Discontinue study treatment
Infusion reactions
Grade 1
Grade 2
Grade 3 or 4
Decrease infusion rate until recovery of the symptoms. 
Stop infusion immediately, and keep line open. Provide supplemental oxygen 
and fluids, as needed.
Monitor vital signs (e.g., blood pressure, pulse, and temperature) every 15 ± 5 
minutes until resolution. 
Administer medications for symptomatic relief as needed: Urticaria: 
Diphenhydramine (25 to 100 mg i.v.) as needed every 4 to 6 hours, or 
alternative as appropriate. 
Fever: Acetaminophen/paracetamol (650-1000 mg by mouth) as needed every 
4 to 6 hours, or alternative as appropriate. 
Rigors: Meperidine 25 mg i.v. as needed every 6 hours or alternative as 
appropriate. Corticosteroids may be administered, as needed.
Resume infusion once infusion reaction resolves (within 8 hours of initial 
start of infusion):
Maintain dose level. Administer oral pre-medication (e.g.1000 mg of 
acetaminophen/paracetamol, 50-100 mg diphenhydramine hydrochloride or 
alternative antihistamine), within 60 minutes of restarting the infusion.
Restart infusion at 50% of previous rate under continuous observation. Ensure 
that there is a minimum observation period of 1 hour prior to restarting the 
infusion.
- If the AE recurs at the reinitiated slow rate of infusion, and despite oral pre-
medication, then discontinue patient from study treatment.
Discontinue infusion immediately, and permanently discontinue patient from 
study treatment.
Provide supplemental oxygen, fluids, and other resuscitative measures as 
needed. Guidance provided above. Monitor vital signs (e.g., blood pressure, 
pulse, respiration, and temperature) every 15 ± 5 minutes until resolution.
Type 1 Diabetes mellitus
Monitor patients for hyperglycemia or other signs and symptoms of diabetes 
and diabetic ketoacidosis. Administer insulin for type 1 diabetes.
In patients with severe hyperglycemia omit dose of LAG525 and PDR001 and 
manage as per Institutional guidelines until resolved to ≤ Gr 1
Cytokine Release Syndrome (CRS)
Grade 2
Grade 3 or Grade 4
See Instructions for Grade 2 Infusion Reactions. 
Discontinue study treatment
Follow-up CRS as per institutional guidelines. 

Novartis
Confidential
Page 52
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Worst Toxicity CTCAE 
v4.03 Grade
Recommended Dose Delays
Ocular (uveitis, eye pain, blurred vision)
Grade 1
Continue study treatment without dose modification.
Ophthalmology consultation.
Grade 2 
Hold study treatment.
Urgent ophthalmology consultation.
Upon resolution to ≤ Grade 1 may consider resuming study treatment without 
dose reduction after discussion with the Novartis Medical Monitor and in 
consultation with ophthalmology.
Grade 3 or Grade 4
Discontinue study treatment.
Urgent ophthalmology consultation.
Renal
Serum Creatinine
Grade 2 
Hold study treatment.
Manage per institutional practice.
Upon resolution to ≤ Grade 1, may resume study treatment without dose 
modification after discussion with the Novartis Medical Monitor.
Grade 3 or 4
Discontinue Study Treatment
Musculoskeletal
Grade 2 or Grade 3
Hold study treatment.
Consider resuming study treatment without dose modification upon resolution 
to ≤ Grade 1 with appropriate management.
Grade 4
Discontinue study treatment 
In some cases, resuming study treatment may be considered after discussion 
with the Novartis Medical Monitor and consultation with a rheumatologist.
Endocrine
Hypothyroidism or hyperthyroidism
Grade 2
May continue study treatment without dose modification.
Management according to institutional practice.
Grade 3
Hold Study Treatment
Upon resolution to Grade ≤ 1 with appropriate management, may resume 
study treatment without dose modification.
Grade 4 
Hold Study Treatment. May resume study treatment following resolution or 
control with physiologic hormone replacement
Other Endocrine Disorders
Grade 2 and Grade 3
Hold study treatment. 
Upon resolution to Grade ≤ 1 with appropriate management, may resume 
study treatment without dose modification.
Grade 4
Hold study treatment.
Grade 4 treatment-related endocrinopathies, such as 
adrenal insufficiency, adrenocorticotropic hormone 
(ACTH) deficiency, hyper- or hypothyroidism, or glucose intolerance, which 
resolve or are adequately controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, 
may not require discontinuation after discussion with and approval from the 
Novartis Medical Monitor.
Neurology
Grade 1
Consider study treatment hold, particularly for clinical 

Novartis
Confidential
Page 53
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Worst Toxicity CTCAE 
v4.03 Grade
Recommended Dose Delays
suspicion of Guillain-Barre syndrome, encephalitis, aseptic meningitis, 
transverse myelitis, or peripheral neuropathy.
Grade 2
Hold study treatment.  
In some cases, resuming study treatment may be considered after discussion 
with the Novartis Medical Monitor.
Grade 3 or Grade 4 
Discontinue study treatment.
Hematology
Neutropenia (ANC)
Grade 3 or Grade 4
Hold study treatment. 
Upon resolution to ≤ Grade 2 or baseline within ≤ 7 days, resume study 
treatment without dose modification, after discussion with the Novartis Medical 
Monitor.
Febrile Neutropenia
Grade 3 or Grade 4
Hold study treatment.
Upon resolution of fever and improvement of neutropenia to ≤ Grade 2 or 
baseline, resume study treatment without dose modification, after discussion 
with the Novartis Medical Monitor.
Thrombocytopenia
Grade 3 
Grade 4
Hold study treatment.
Upon resolution to ≤ Grade 2 or baseline, resume study treatment without 
dose modification.
For Grade 3 associated with major bleeding, discontinue study treatment.
Discontinue study treatment.
Anemia
Grade 3 or Grade 4
Hold study treatment. 
Upon resolution to ≤ Grade 2 or baseline within ≤ 7 days, resume study 
treatment without dose modification.
Lymphoma
Any Grade
Treatment-related lymphopenia does not require study treatment hold or 
discontinuation.
Other laboratory adverse events, not specified elsewhere in table and not included in the consensus 
guidelines
Grade 3
Hold study treatment. 
Upon resolution to ≤ Grade 1, resume study treatment without dose 
modification.
Grade 4
Isolated Grade 4 electrolyte abnormalities not associated with clinical
sequelae and corrected after appropriate management within 72 hours of their 
onset do not require discontinuation.
In the case of Grade 4 electrolyte imbalances associated with clinical 
sequelae, or not resolved to ≤ Grade 1 within 72 hours despite appropriate 
management, discontinue study treatment.
Other non-laboratory adverse events, not specified elsewhere in table and not included in the 
consensus guidelines
Grade 2
Consider study treatment hold, at Investigator discretion.
Upon resolution to ≤ Grade 1, resume study treatment without dose 
modification.
Grade 3
Hold Study Treatment
Upon resolution to ≤ Grade 1, resuming study treatment must be discussed 
with the Novartis Medical Monitor.
Grade 4
Discontinue Study Treatment

Novartis
Confidential
Page 54
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Worst Toxicity CTCAE 
v4.03 Grade
Recommended Dose Delays
In patients experiencing AE not meeting the criteria above of Grade ≥ 3, study drugs should be omitted until 
resolved to Grade ≤ 1 or baseline. If AE resolves to Grade ≤1 or baseline in 21 days or less, then treatment 
may restart with a less frequent dosing schedule after consultation with Novartis.
All dose modifications should be based on the worst preceding toxicity. Once a dose has been administered 
less frequently it will not be administered more frequently at a later time even if there is no toxicity.
6.3.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastases, or elevation 
of ALP liver fraction in patients with bone metastases.
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 patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2 . A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 

Novartis
Confidential
Page 55
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.3.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-drug induced adverse events are provided 
in Section 6. Refer to preclinical toxicity and or clinical data found in the [Investigator’s 
Brochure].
6.4
Concomitant medications 
6.4.1
Permitted concomitant therapy
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the patient are allowed.
The patient must be told to notify the investigational site about any new medications, herbal 
remedies and dietary supplements he/she takes after the start of the study treatment. All 
medications (other than study treatment) and significant non-drug therapies (including physical 
therapy, herbal/natural medications and blood transfusions) administered during the study must 
be listed on the Prior/Concomitant Medications or the Surgical and Medical Procedures eCRFs.
6.4.2
Permitted concomitant therapy requiring caution and/or action 
If a patient is using erythropoiesis stimulating agents (ESAs) prior to enrollment (at least 2 
weeks before start of study treatment), he/she may continue at the same dose.
Anticoagulation therapy is permitted if the patients are already at stable doses of warfarin or 
stable doses of low molecular weight heparin (LMWH) for > 2 weeks at time of first dose and 
International Normalized Ratio (INR) should be monitored as clinically indicated per 
investigator’s discretion. However, ongoing anticoagulant therapy should be temporarily 
discontinued to allow tumor sample collection according to the institutional guidelines if 
applicable.
Anti-hypertensive therapy is allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration should be 
given to withholding anti-hypertensive medications for 12 hours prior to the infusion of study 
drugs.
A brief (< 24 hours) course of steroids for prophylaxis against imaging contrast dye allergy is 
permitted for patients undergoing tumor assessments.
6.4.3
Prohibited concomitant therapy
As far as possible, avoid co-administering QT prolonging drugs. If during the course of the 
study, concomitant administration of drugs with a known potential to cause Torsades de Pointe 
is required and cannot be avoided, study drug must be interrupted until an assessment of the 
potential safety risk has been performed. A definitive list of drugs associated with QT 

Novartis
Confidential
Page 56
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
prolongation and/or TdP is available online at www.qtdrugs.org. If, based on the investigator 
assessment and clinical need study treatment is resumed, close ECG monitoring is advised.
Treatment with hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-
CSF) may not be taken during the study. 
During the course of the study, patients must not receive other additional investigational drugs, 
devices, chemotherapy, or any other therapies that may be active against cancer or modulate 
the immune responses.
Limited-field palliative radiotherapy to non-target lesion(s) may be allowed as concomitant 
therapy after documented discussion with Novartis. Such local therapies administered during 
the study treatment must be listed on the Concomitant Antineoplastic Therapy – Radiotherapy 
CRF. Additionally, no other therapeutic monoclonal antibodies and no immunosuppressive
medication may be administered while on this study unless given for the management of 
immune toxicity. 
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed except 
for the treatment of infusion reaction, irAEs, for prophylaxis against imaging contrast dye 
allergy or replacement-dose steroids in the setting of adrenal insufficiency (providing this is < 
10 mg/day prednisone or equivalent), or transient exacerbations of other underlying diseases 
such as chronic obstructive pulmonary disease (COPD) requiring treatment for < 3 weeks. 
Systemic corticosteroids required for the control of infusion reactions or irAEs must be tapered 
and be at non-immunosuppressive doses (< 10 mg/day of prednisone or equivalent) before the 
next study drug administration. If more than 10 mg/day prednisone is used, study treatment 
should be suspended. Topical, inhaled, nasal and ophthalmic steroids are allowed.
The use of live vaccines is not allowed through the duration of the study. Inactivated vaccines 
are allowed.
6.4.4
Use of Bisphosphonates and radiotherapy
6.4.4.1
Bisphosphonates
The use of bisphosphonates is allowed regardless of indication provided patients have been on 
stable doses optimally for at least 4 weeks prior to the start of treatment. Patients requiring 
initiation of bisphosphonate treatment during the course of the study should be assessed by 
appropriate image modalities to exclude disease progression; if disease progression is 
documented, the patient should discontinue study treatment. 
6.4.4.2
Palliative radiotherapy
Palliative radiation is permitted if done solely for bone relief. It should not be delivered to a 
target lesion and it should not encompass more than 25% of irradiated bone marrow.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 

Novartis
Confidential
Page 58
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Study treatment will be administered to the patient by the study site staff at the study sites. 
Compliance will be assured by administration of the study treatment under the supervision of 
investigator or his/her designee. Information will be captured in the Drug Accountability Form. 
This information must be captured in the source document at each patient visit.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis or designee monitor or to the Novartis address provided in 
the investigator folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. 
No CRF will be used as a source document. 
Screening/baseline evaluations must be performed ≤ 21 days before Cycle 1 Day 1.
Assessments required on Cycle 1 Day 1 that are performed as part of the screening evaluations 
and within 4 days prior to the first dose of study treatment, do not need to be repeated on Cycle 
1 Day 1 (except Pregnancy test which needs to be completed within 72 hours prior to the first 
dose). Laboratory and radiological assessments performed as part of standard of care prior to
signing informed consent may be used if performed within the screening time window.
During the course of the study visits, test and/or procedures should occur on schedule
whenever possible. A visit window of +/- 4 days is allowed for visits and a window of +/- 7 
days is allowed for radiological assessments.

Novartis
Confidential
Page 59
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
For the 30-day and 150-day safety follow-up visits, a window of +7 days is allowed. For the 
60-day, 90-day, and 120-day safety follow-up, a window of ± 14 days is allowed.
If the infusion of either study drug is delayed (see Section 6), the visit will be shifted 
accordingly.  

Novartis
Confidential
Page 60
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Table 7-1
Visit evaluation schedule (Cycle Length is 21 days/ 3 weeks)
Protocol 
Section 
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
End of 
study 
treatment 
(EoT)
Safety Follow up 
Visit Name
1
2
3
4
5
6
7,8,9…
Day of cycle
1
8
1
8
1
1
30, 90, & 150
60 & 120
All Patients
Obtain Informed Consent
x
Demography
x
Inclusion/exclusion criteria
x
Medical History
x
Diagnosis and extent of cancer
x
Antineoplastic therapy
x
x
x
x
Physical examination
7.2.2.1
x
x
x
x
x
x
x
x
ECOG Performance status
7.2.2.4
x
x
x
x
x
x
Height 
7.2.2.3
x
Weight
7.2.2.3
x
x
x
x
x
x
Vital signs
7.2.2.2
x
x
x
x
x
x
Hematology
7.2.2.5.1
x
x
x
x
x
x
x
x
Chemistry (including liver function tests)  
7.2.2.5.2
x
x
x
x
x
x
x
x
Thyroid function (Free T4 and TSH)
7.2.2.5.5
x
x
x
x
x
x
Coagulation
7.2.2.5.3
x
Urinalysis
7.2.2.5.4
x
HIV, HBV, HCV
x
Pregnancy test 
7.2.2.5.6
x
x
x
x
x
x
x *
x *
ECG
(See Table 7-4 for time points)
7.2.2.6.1
x
x
x
x
X(C4-C6 
only)
x
Cardiac imaging (MUGA/ECHO)
7.2.2.6.2
x

Novartis
Confidential
Page 61
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Protocol 
Section 
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
End of 
study 
treatment 
(EoT)
Safety Follow up 
Visit Name
1
2
3
4
5
6
7,8,9…
Day of cycle
1
8
1
8
1
1
30, 90, & 150
60 & 120
Adverse events
8.1
Continuous
Prior/concomitant medications
6.4
Continuous
Surgical and medical procedures
Continuous
Study Drug administration LAG525(Q3W)
6.1
x
x
x
x
Study Drug Administration PDR001(Q3W)
6.1
x
x
x
x
Imaging and radiological tumor 
assessment
7.2.1
x
Every 6 weeks starting at week 12 through week 24 
and every 12 weeks thereafter 
Serum prostate-specific antigen (PSA) 
(Prostate cancer only)
7.2.1.1.1
x
Every 6 weeks starting at week 12 through week 24 
and every 12 weeks thereafter 
Cancer Antigen-125
(ovarian cancer only) 
7.2.1.1.2
x
Every 6 weeks starting at week 12 through week 24 
and every 12 weeks thereafter
Measurement of superficial disease (if 
present)
7.2.1.1.3
x
Every 6 weeks starting at week 12 through week 24 
and every 12 weeks thereafter
Lymphoma Patients Only
Exam for enlarged spleen or liver
7.2.1.1.4
x
To confirm response of CR 
Measurement of superficial B symptoms
7.2.1.1.5
x
x
x
x
x
PET scan 
7.2.1.1.7
x
To confirm response of CR 
Bone Marrow Biopsy or aspirate
7.2.1.1.6
To confirm response of CR 
* Can be performed at home or at a local doctor’s office if the patient is not coming to the clinic. 

Novartis
Confidential
Page 62
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
7.1.1
Molecular pre-screening 
Not Applicable
7.1.2
Screening
All screening evaluations must be performed as closely as possible to the beginning of treatment 
and never more than 21 days prior to starting study drug.
The study IRB/IEC informed consent form must be signed and dated before any screening
procedures are performed, except for evaluations (for example imaging assessments) performed 
as part of standard of care within the screening window. Patients will be evaluated against study 
inclusion and exclusion criteria and safety assessments. For details of assessments, refer to 
Table 7-1.
Screening assessments must be repeated if performed outside of the specified screening window 
Section 7.1. For laboratory evaluations used to determine eligibility, a repeated evaluation 
within the screening window is permitted for screening results out of the defined range. If the 
repeated laboratory result meets the criteria, that result may be used to determine eligibility. If
the repeated laboratory result does not meet the criteria, the patient will be considered ineligible 
and a screening failure.
A patient who has a laboratory test result(s) that does not satisfy the entrance criteria may have 
the test(s) repeated. These test(s) may be repeated to satisfy the entrance criteria, but should be 
completed within 21 days of the original screening visit date. In this case, the subject will not 
be required to sign another ICF, and the original patient ID number assigned by the investigator 
will be used. In the event that the laboratory test(s) cannot be performed within 21 days of the 
original screening visit, or the re-test(s) do not meet the entrance criteria, or other eligibility 
criteria have changed and are not met anymore, the patient is considered a screen failure, and 
must be discontinued from the study.
Disease assessments must be performed within 21 days of enrollment and will be assessed 
locally by the investigator. Patients who fail to start on treatment within 21 days of screening 
may be re-screened. A new ICF will need to be signed if the investigator chooses to re-screen 
the patient after a patient has screen failed, however, if the patient is rescreened a new patient 
ID will be assigned. All required screening activities must be performed when the patient is re-
screened for participation in the study. An individual patient may only be re-screened once for 
the study. The Sponsor may close the study to further screening. In this case, the patients who 
screen failed will not be permitted to re-screen.
For details of assessments, refer to Table 7-1.
Upon signing the Informed Consent Form (ICF), a patient will be assigned a unique subject 
identifier for the study. 

Novartis
Confidential
Page 63
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
7.1.2.1
Eligibility screening 
Once all screening procedures are completed, eligibility should be confirmed prior to the subject 
receiving the first dose of study drug.
7.1.2.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). 
7.1.2.3
Patient demographics and other baseline characteristics
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, diagnosis and extent of tumor, details of prior anti-neoplastic 
treatments (including medications, radiations and surgeries), prior medication, procedures, 
significant non-drug therapies and any other assessments that are done for the purpose of 
determining eligibility for inclusion in the study.
7.1.3
Run-in period 
Not applicable
7.1.4
Treatment period
A treatment cycle is defined as 21 days for the purposes of scheduling procedures and 
evaluations. Please refer to Table 7-1 for details of the timing of required assessments and 
Section 7.1 for visit windows. 
Patients will receive study treatment for a maximum of 2 years, or until disease progression 
(assessed by investigator per RECIST 1.1 and the Revised Response Criteria for Malignant 
Lymphoma criteria (Cheson et al 2007) for lymphoma), unacceptable toxicity, death or 
discontinuation from study treatment for any other reason (e.g., withdrawal of consent, start of 
a new anti-neoplastic therapy or at the discretion of the investigator or patient), otherwise 
known as End of Treatment.
Clinical experience indicates that objective responses to immunotherapy follows delayed 
kinetics of weeks or months, and can be preceded by initial apparent radiological progression 
or appearance of new lesions or some enlarging lesions while other target lesions are regressing 
(“mixed response”) (Wolchock 2009). Therefore, patients with disease progression, may remain 
on treatment, if the Investigator considers it to be in in the patient’s best interest, and after 
documented discussion with the Novartis Medical Monitor.
These considerations should be balanced by clinical judgment as to whether the patient is 
clinically deteriorating and unlikely to receive any benefit from continued treatment.

Novartis
Confidential
Page 64
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Patients with an unconfirmed progressive disease who show signs of clinical deterioration or 
toxicity will enter the 150-day safety follow-up period. Such deterioration will be assessed to 
have occurred after a clinical event that, in the investigator’s opinion, is attributable to disease 
progression, is unlikely to reverse with continued study treatment and therefore indicates that 
the patient is not benefiting from study treatment and cannot be managed by the addition of 
supportive care. 
7.1.5
Discontinuation of study treatment
Patients may voluntarily discontinue from the investigational treatment for any reason at any
time. If a patient decides to discontinue, the investigator should make a  reasonable effort 
(e.g. telephone, e-mail, letter) to understand the primary reason for this decision and record this
information in the patient’s chart and on the appropriate CRF pages. They may be considered
withdrawn if they state an intention to withdraw, fail to return for visits, or become lost to
follow-up for any other reason.
The investigator should discontinue investigational treatment for a given patient if he/she
believes that continuation would be detrimental to the patient’s well-being.
Study treatment may be discontinued if any of the following occur:

Adverse event

Lost to follow-up

Physician’s decision

Progressive disease per defined response criteria

Study terminated by the sponsor

Subject/guardian decision

Protocol deviations that result in significant risk to the patients’ safety

Technical problems
Patients will be withdrawn if any of the following occur:

Pregnancy

Death
At the time patients discontinue study treatment, a visit should be scheduled as soon as possible, 
and within 14 days of the last dose of study drug or within 14 days of the decision to 
permanently discontinue study treatment, at which time all of the assessments listed for the 
EOT visit will be performed (Table 7-1). If the decision to withdraw the patient occurs at a 
regularly scheduled visit, that visit may become the EOT visit rather than having the patient 
return for an additional visit. An End of Treatment Phase Disposition CRF page should be 
completed, giving the date and reason for stopping the study treatment. End of 
treatment/Premature withdrawal visit is not considered as the end of the study. 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 150 days following 
the last dose of study treatment.

Novartis
Confidential
Page 65
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
7.1.5.1
Replacement policy 
Those patients who discontinue study treatment for any reason other than disease progression 
or treatment related toxicity may be replaced at the discretion of Novartis, until a minimum of 
5 patients with 24 weeks of CBR data are accrued within a cohort.
7.1.6
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone,
e-mail, letter) to understand the primary reason for this decision and record this information.
Study treatment must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
7.1.7
Follow up for safety evaluations
150-day safety follow up period
All patients must have safety evaluations for 30, 90 and 150 days after the last dose of study 
treatment. Antineoplastic therapies since discontinuation of study drug will be collected during 
this follow-up period. Concomitant medications will be collected until the 30-day safety follow-
up has been completed or the start of a new antineoplastic therapy, whichever occurs first. 
Information related to AEs (including concomitant medication taken for ongoing AEs) will be 
collected for 150 days after the last dose of study drug. All AEs suspected to be related to study 
treatment should be followed up weekly or as clinically indicated until resolution or 
stabilization. Data collected should be added to the Adverse Events CRF, the antineoplastic 
therapies since discontinuation of study treatment CRF and the Concomitant Medications CRF. 
For a female participant of childbearing potential, a urine pregnancy test will be performed on 
Day 30, 60, 90, 120 and 150 after stopping the study treatment. Please see Section 7.2.2 for 
details
If patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact them or a knowledgeable informant by telephone to determine if the patient had disease 
progression.

Novartis
Confidential
Page 66
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
7.1.8
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
The primary efficacy endpoint is clinical benefit rate as defined in Section 10.4. The secondary 
efficacy endpoint is overall response rate of PR or greater as defined in Section 10.5. Other 
secondary endpoints are time from the date of first dose to the date of first documented disease 
progression or relapse or death due to any cause, time from the date of first dose to the date of 
death due to any cause, time from the first documented response to the date first documented 
disease progression or relapse or death due to any cause, and other safety measurements as 
defined in Section 10. The local investigator’s assessment will be used for the analysis and for 
treatment decision making.
Clinical suspicion of disease progression at any time will require assessment and confirmation 
to be performed promptly, rather than waiting for the next scheduled tumor assessment. In case 
of an unscheduled or delayed tumor assessment for any reason, subsequent disease assessments 
must be performed according to the originally planned schedule from baseline.
7.2.1.1
Radiological Tumor Assessment
At screening, all patients will undergo CT with i.v. contrast of the chest, abdomen and pelvis. 
Additionally, patients with lymphoma will also undergo CT with i.v. contrast of the neck and a 
PET scan. MRI should only be used to evaluate sites of disease that are not adequately imaged 
by CT. If a patient is intolerant of iodine-based contrast agents, CTs may be performed without 
contrast. MRI may be used to evaluate sites of disease where a CT without i.v. contrast is not 
adequate. Visible skin lesions and easily palpable subcutaneous tumors may be measured by 
physical examination using a ruler or calipers. Ultrasound should not be used to measure sites 
of disease.
No modality change would be allowed during the study when assessing overall tumor status. 
For subsequent scans in the same patient, the radiologist must account for all lesions that were 
present at screening and must use the same technique as used at screening. If possible, a single 
radiologist should perform all tumor response evaluations for an individual patient. Only in 
exceptional cases when during the study a patient develops intolerance to the CT scan contrast 
medium, a CT scan without contrast will be acceptable to avoid modality change. 
Tumor assessments will be performed at the time points specified in Table 7-1. 

Novartis
Confidential
Page 67
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Radiological disease assessments will be performed every 6 weeks (±7 days), starting 12 weeks 
after first dose of study drug and continuing through week 24. The frequency of radiological 
disease assessments will be reduced to every 12 weeks after patients have completed 24 weeks 
on treatment and will continue until confirmed disease progression. Solid tumor response will 
be determined locally according to RECIST 1.1 (Appendix 1).  Lymphoma response will be 
determined locally according to Revised Response Criteria for Malignant Lymphoma, (Cheson 
et al 2007) (Appendix 2).
The local investigator’s assessment will be used for the analysis of response and for treatment-
making decisions. Clinical experience indicates that objective responses to immunotherapy 
follows delayed kinetics of weeks or months, and can be preceded by initial apparent 
radiological progression or appearance of new lesions or some enlarging lesions while other 
target lesions are regressing (“mixed response”) (Wolchock 2009). Therefore, patients with 
confirmed disease progression, may continue to receive treatment, beyond initial disease 
progression, if the Investigator considers it to be in in the patient’s best interest to remain on 
the study, and after documented discussion with the Novartis Medical Monitor.
7.2.1.1.1 Prostate Specific Antigen (PSA)  (prostate cancer only)
Prostate Specific Antigen (PSA) will be used in the assessment of prostate cancer at screening. 
Subsequent tumor assessments must be performed on the same schedule as radiological tumor 
assessments (see Table 7-1).
7.2.1.1.2 Cancer Antigen-125 (ovarian cancer only) 
Cancer Antigen-125 (CA-125) will be used in the assessment of ovarian cancer at screening by 
revised GCIC criteria. Subsequent tumor assessments must be performed on the same schedule 
as radiological tumor assessments (see Table 7-1).
7.2.1.1.3 Physical examination for superficial disease (if applicable)
Clinical assessment of any existing superficial lesions (skin nodules and palpable lymph nodes) 
at screening and at each subsequent tumor assessment must be performed on the same schedule 
as radiological tumor assessments (see Table 7-1).
Skin lesions should be documented using a digital camera (color photography) in clear focus 
showing the ruler or calipers and the corresponding measurement in such a way that the size of 
the lesion(s) can be determined from the photograph. Skin photographs should be continued at 
subsequent tumor assessments for any lesions that were photographed at screening.
7.2.1.1.4 Enlarged spleen and liver  (Lymphoma only)
The presence of enlarged spleen or liver before start of treatment on the basis of CT scan (or 
MRI scan) should be recorded on the corresponding eCRF at baseline, and reassessed if the 
patient has a radiological CR.
A maximum of four of the largest dominant measurable nodules representing all involved 
anatomic locations should be selected as splenic and hepatic index lesions to be measured.

Novartis
Confidential
Page 68
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
All other splenic or hepatic nodules (both measurable and non-measurable) are considered as 
non-index lesions.
7.2.1.1.5 Physical examination for superficial disease and B symptoms (Lymphoma 
only)
Tumor assessment by physical examination and evaluation of disease related B symptoms 
(unexplained fever of ≥ 38°C; unexplained, recurrent drenching night sweats; or unexplained 
loss of >10% body weight within the previous 6 months) will be performed at screening and 
day 1 of every cycle (±4 days) until progression of disease or patient withdrawal. Refer to 
Appendix 2 for specifications and measurement.
Skin lesions should be documented using a digital camera (color photography) in clear focus 
showing the ruler or calipers and the corresponding measurement in such a way that the size of 
the lesion(s) can be determined from the photograph. Skin photographs should be continued at 
subsequent tumor assessments for any lesions that were photographed at screening.
7.2.1.1.6 Bone marrow assessment  (Lymphoma only)
Information on the patient’s bone marrow involvement based on documented history prior to 
study entry must be present in his/her source documents. Prior tumor bone marrow involvement 
should be entered on the corresponding eCRF.
Core bone marrow biopsy will not be performed at screening but is required to confirm 
complete responses (at the first occurrence of radiological and clinical evidence of CR) in 
patients with bone marrow tumor involvement prior to study treatment who achieve Complete 
Response based on clinical and radiological evidence. The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core). Bone marrow 
biopsy should be obtained no later than at the next visit immediately following clinical and 
radiological evidence of CR (i.e. < 28 days ± 7 days from the date of the radiological assessment, 
on which the CR is based on).
7.2.1.1.7 Positron emission tomography (PET)
All Lymphoma Patients will have a PET scan completed at screening and then a follow up scan 
to confirm a complete response to study treatment (see Table 7-1).
7.2.2
Safety and tolerability assessments
Safety will be monitored by physical examination, vital signs, body height and weight, 
performance status, hematology, chemistry, coagulation, urinalysis, thyroid function, 
pregnancy, ECG, cytokine testing, as well as collecting of the AEs at every visit. For details on 
AE collection and reporting, refer to Section 8.
7.2.2.1
Physical examination
Physical examination will be performed at the time points indicated in Table 7-1. 

Novartis
Confidential
Page 69
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
At Screening and Cycle 1 Day 1, prior to study drug infusion, a complete physical examination 
will be performed and will include the examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and 
neurological. If indicated based on medical history and/or symptoms, rectal, external genitalia, 
breast, and pelvic exams will be performed.
From Cycle 2 onwards, a short physical examination will be performed. A short physical exam 
will include the examination of general appearance, vital signs (blood pressure [BP] and pulse) 
and body sites as directed by symptoms.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF. 
7.2.2.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure) must be assessed prior to dosing and 
as indicated in Table 7-1.
7.2.2.3
Height and weight
Height in centimeters (cm) or inches and body weight (to the nearest 0.1 kilogram [kg], or to 
the nearest 0.1 pound, in indoor clothing, but without shoes) will be measured as indicated in 
Table 7-1.
7.2.2.4
Performance status
ECOG performance status will be assessed according to the time points in Table 7-1, using the 
criteria in Table 7-2.
Table 7-2
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
7.2.2.5
Laboratory evaluations
All laboratory parameters assessed for safety purposes will be evaluated locally. Refer to Table 
7-3 for a summary of the parameters to be evaluated according to Table 7-1. On days of dosing, 
samples for these parameters will be collected prior to the infusion of study drug.
More frequent evaluations may be performed at the investigator’s discretion if medically 
indicated; results should be recorded as unscheduled laboratory assessments.

Novartis
Confidential
Page 70
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Novartis will be provided with a copy of the laboratory certification and tabulation of the normal 
ranges for each parameter required. In addition, if at any time a patient has laboratory 
parameters obtained from a different outside laboratory, Novartis must be provided with a copy 
of the certification and a tabulation of the normal ranges for that laboratory.
Table 7-3
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands (absolute value 
preferred))
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, Lactate dehydrogenase (LDH), Bicarbonate, 
Calcium, Magnesium, Phosphorus, Chloride, Sodium, Potassium, Creatinine, Total 
Bilirubin (also measure direct and indirect if total bilirubin is > grade 1), Blood Urea 
Nitrogen (BUN) or Urea, Amylase, Lipase, Glucose
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, pH, Protein, Specific 
Gravity, White Blood Cells) 
Coagulation
Prothrombin time (PT) or, International normalized ratio [INR], Activated partial 
thromboplastin time (APTT)
Thyroid
Total or Free T4, TSH
Pregnancy Test
At screening, a serum test within 72 hours before the first dose. 
Day 1 of each cycle starting with Cycle 2, EOT, during the follow-up period on Day 30, 
60, 90, 120 and 150 after stopping the study treatment serum or urine pregnancy test
7.2.2.5.1 Hematology
Hematology panel outlined in Table 7-3 will be performed as per the assessment schedule in 
Table 7-1.
7.2.2.5.2 Clinical chemistry
Clinical chemistry panel outlined in Table 7-3 will be performed as per the assessment schedule 
in Table 7-1. Patients without pre-existing diabetes or previously determined to be 
normoglycemic shown to have an abnormal random blood glucose at screening must have a 
fasting blood glucose test performed and any subsequently diagnosed hyperglycemia should be 
managed appropriately as per Institutional guidelines.
7.2.2.5.3 Coagulation
Coagulation panel outlined in Table 7-3 will be performed as per the assessment schedule in 
Table 7-1.
7.2.2.5.4 Urinalysis
Urinalysis panel outlined in Table 7-3 will be performed as per the assessment schedule in Table 
7-1.

Novartis
Confidential
Page 71
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
7.2.2.5.5 Thyroid function
Thyroid function panel outlined in Table 7-3 will be performed as per the assessment schedule 
in Table 7-1.
7.2.2.5.6 Pregnancy and assessments of fertility
Pregnancy tests will be performed for women of child bearing potential. At screening, a serum 
pregnancy test must be performed within 72 hours before the first dose. During the study (Day 
1 of each cycle starting with Cycle 2) a serum or urine pregnancy test must be performed. At 
End of Treatment, a serum or urine pregnancy test must also be performed. Pregnancy test will 
also be performed during the follow-up period on Day 30, 60, 90, 120 and 150 after stopping 
the study treatment.
If the patient is not coming to the clinic during the safety follow-up, it can be performed at home 
or at a local doctor’s office, and the results will be communicated to the site staff. These follow-
up pregnancy tests will be recorded only in the source documentation, not in the CRF.
7.2.2.6
Cardiac assessments 
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as per the assessment schedule in Table 7-1 and 
Table 7-4. Blood samples scheduled at the same time point should be taken after the ECGs are 
completed. The ECGs on C1D1, C2D1, C3D1, C4D1, C5D1 and C6D1 must be performed in 
triplicate. The post-dose ECGs will be collected after the completion of the last dose of infusion.
Table 7-4
12 Lead ECG collection plan
Cycle
Day
Time
Screening
-21 to -1
Anytime
1
1
*Pre-dose
1
1
*1h (±5 min) hour post dose
2
1
*Pre-dose
2
1
*1h (±5 min) hour post dose
3
1
*Pre-dose
3
1
*1h (±5 min) hour post dose
4
1
*Pre-dose
4
1
*1h (±5 min) hour post dose
5
1
*Pre-dose
5
1
*1h (±5 min) hour post dose
6
1
*Pre-dose
6
1
*1h (±5 min) hour post dose
EoT
-
Anytime
Unscheduled
-
Anytime
*ECGs Performed in triplicate.

Novartis
Confidential
Page 72
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History CRF page. Clinically significant findings must be discussed 
with Novartis prior to enrolling the patient in the study. New or worsened clinically significant 
findings occurring after informed consent must be recorded on the Adverse Events CRF page.
7.2.2.6.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
MUGA scan or echocardiogram (ECHO) will be used to assess LVEF at screening and during 
the treatment phase as clinically indicated to assess signs or symptoms of cardiotoxicity. In case 
of clinically significant abnormalities, they should be reported on the Adverse Events eCRF.
7.2.3
Pharmacokinetics
Not Applicable.
7.2.4
Biomarkers
Not Applicable.
7.2.4.1
Tumor Collection (Expansion Cohorts Only)
Not Applicable.
7.2.5
Resource utilization
Not applicable.
7.2.6
Patient reported outcomes
Not applicable.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 

Novartis
Confidential
Page 73
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page. Adverse event monitoring should be continued for at 
least 150 days following the last dose of study treatment. After initiation of new post-treatment 
antineoplastic therapy, only AEs suspected to be related to study treatment will be collected in 
the Adverse Events CRF. Adverse events (including lab abnormalities that constitute AEs) 
should be described using a diagnosis whenever possible, rather than individual underlying 
signs and symptoms. When a clear diagnosis cannot be identified, each sign or symptom should 
be reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected through a Death 
form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:

The severity grade (CTCAE Grade 1-4)

Its duration (Start and end dates) 

Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)

Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)

Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)

Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
and which seriousness criteria have been met 

Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.

Novartis
Confidential
Page 74
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (RECIST or as per guidelines for hematological malignancies), should not be reported 
as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Novartis
Confidential
Page 75
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, 
Note that hospitalizations for the following reasons should not be reported as serious adverse 
events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition
Note that treatment on an emergency outpatient basis that does not result in hospital admission 
and involves an event not fulfilling any of the definitions of a SAE given above is not a serious 
adverse event
8.2.2
SAE Reporting
For patients who sign the study ICF, SAE collection will start upon signing whether the patient 
is a screen failure or not.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 150 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. If a 
patient starts a post treatment antineoplastic therapy, then only SAEs suspected to be related to 
study treatment will be reported.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any SAEs experienced after the 150 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.  
Information about all SAEs is collected and recorded on the Serious Adverse Event Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough 
report. The investigator must assess and record the relationship of each SAE to each specific 
study treatment (if there is more than one study treatment), complete the SAE Form in English, 
and submit the completed form within 24 hours to Novartis. Detailed instructions regarding the 
SAE submission process and requirements for signatures are to be found in the investigator 
folder provided to each site
Follow-up information is submitted in the same way as the original SAE . Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that event 

Novartis
Confidential
Page 76
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, and whether the patient continued or withdrew 
from study participation.
If the SAE is not previously documented in the Investigator’s Brochure and is thought to be 
related to the Novartis study treatment, an oncology Chief Medical Office and Patient Safety 
(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 drug 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 Directive 2001/20/EC or as per national regulatory requirements in 
participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Chief Medical Office and Patient Safety (CMO&PS). Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the investigational treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes must 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.  
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee 
Not applicable.

Novartis
Confidential
Page 77
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
8.7
Steering Committee 
Not applicable.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit, Novartis personnel (or designated CRO) will 
review the protocol and CRFs with the investigators and their staff. During the study, the field 
monitor will visit the site regularly to check the completeness of patient records, the accuracy 
of entries on the CRFs, the adherence to the protocol, to Good Clinical Practice, the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits.

Novartis
Confidential
Page 80
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
10.3.1
Concomitant therapies
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drugs will be listed and summarized for the FAS by Anatomical Therapeutic Chemical 
Classification System (ATC) term, preferred term and treatment arm by means of frequency 
counts and percentages. These summaries will include medications starting on or after the start 
of study treatment (defined as cycle 1 day 1) or medications starting prior to the start of study 
treatment and continuing after the start of study treatment.
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed. The safety set will be used for all above mentioned 
concomitant medication tables and listings.
10.4
Primary objective
The primary objective is to assess the clinical benefit of treatment with PDR001 + LAG525 at 
24 weeks of treatment based on local investigator assessment.
For patients with solid tumors, the assessment criteria will be RECIST 1.1 and will include 
responses of CR or PR or SD. For lymphoma the Revised Response Criteria for Malignant 
Lymphoma (Cheson et al 2007) criteria will apply. Response criteria are included in the 
appendices.
For solid tumors, an assessment of CR or PR using RECIST 1.1 must be confirmed at least 4 
weeks after initial observation. If the two assessments differ, the best overall response will be 
determined by Table 14-3 of Appendix 1.
For efficacy parameters, data will be listed, summarized, or analyzed by tumor cohort.
10.4.1
Variable 
The primary efficacy variable is the clinical benefit rate (CBR) (e.g. defined as CR, PR or SD) 
at week 24 by RECIST 1.1 for solid tumors and the Revised Response Criteria for Malignant 
Lymphoma, (Cheson et al 2007), for Lymphoma.
10.4.2
Statistical hypothesis, model, and method of analysis
The study will enroll patients from 7 tumor cohorts.
These seven pre-specified tumor cohorts (also referred to as “groups”) are:
Group
Malignancy
1
Small cell lung cancer
2
Gastric/esophageal adenocarcinoma
3
Castration resistant prostate adenocarcinoma (CRPC)
4
Soft tissue sarcoma 
5
Ovarian adenocarcinoma
6
Advanced well-differentiated neuroendocrine tumors*
7
Diffuse large B cell lymphoma (DLBCL)*

Novartis
Confidential
Page 81
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
We let Yi be the response indicator for the ith subject, and let Rg be the assumed probability of 
response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability 
of response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.:
 = log 

1 −
 −log 

1 −

Thus, θg is the group specific logistic regression coefficient for group g. The primary analysis 
is a set of group specific tests that θg>0, meaning that the treatment is better than the assumed 
control rate for that group. Thus, we wish to test the set of hypotheses
H0g : θg≤0
H1g : θg>0
We proceed in a Bayesian fashion, assigning a prior distribution (discussed below) and 
computing the posterior probability of H1g within each group g. If, at the final analysis,
Pr(θg>0 | data) > 0.80
then group g will be declared a success. Hence, the final analysis produces a separate decision 
for each group. The trial allows for early stopping of groups for futility, described below. No 
early stopping for success is allowed.
The statistical design borrows information across subgroups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 
differ. In this way, the model is a compromise between the extremes of a completely pooled 
analysis as opposed to a separate analysis in each group. We additionally incorporate a 
clustering mechanism that allows borrowing within clusters but treats clusters separately. This 
minimizes borrowing across groups that are quite different in terms of CBR effects.
The hierarchical model approach involves two stages. The goal of both stages is to allow the 
data to drive the amount of borrowing across groups. If the data indicate a large amount of 
borrowing is appropriate (due to similar results), the model will borrow more and thus increase 
the overall power of the trial within each group. In contrast, if the data indicate a small amount 
of borrowing is appropriate (due to dissimilar results) the model will adjust and each group will 
stand more on its own. This “dynamic” borrowing property is distinct from other approaches 
which use a fixed informative prior or apriori assume an amount of borrowing across groups. 
Here the approach includes two stages to identify the appropriate amount of borrowing based 
on the data.
The first stage of model places the groups into distinct clusters. The purpose of this stage is to 
minimize borrowing of information across groups that appear to be quite different. Thus, for 
example, should 2 of the groups appear similar while the others differ significantly, the model 
may place a large probability on two clusters, one containing the two similar groups with the 

Novartis
Confidential
Page 82
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
other containing the remaining groups. The model does not pick one particular clustering, but 
instead incorporates the uncertainty of the data in this determination, producing a probability 
distribution over the possible clustering. Thus, in our example, the model may consider it highly 
likely that the 2 similar groups are in one cluster with the remaining groups in another, but it 
would also retain lower probabilities on the possibility all groups are in one cluster (e.g. we are 
simply seeing differences in the two groups by chance) as well as other possibilities. The 
complete analysis averages over this uncertainty.
At the second stage, we place hierarchical models over the groups within each cluster (thus, 
conditional on the clustering, there is no borrowing of information across clusters, only within 
clusters). The hierarchical model assumes that the  have an across groups distribution
θg ~ N(μ, τ2)
The across group mean µ and variance τ2 are unknown, and hence have a prior distribution 
which is combined with the data to produce estimates of µ and τ2.
The variance component τ controls the degree of borrowing among groups. Small values of τ
result in a greater degree of borrowing while large values of τ correspond to less borrowing. 
The parameter τ is estimated using the data, so the observed between group variation is a key 
component of the model behavior. 
Combined, the two stages allow groups with similar results to borrow information between 
them (they will have a high probability of being in the same cluster) while groups with different 
results with borrow far less information between them (they will have a low probability of being 
in the same cluster).
Details of the hierarchical model is provided in Appendix 4.
10.4.3
Evaluation of trial success and futility
Interim monitoring will occur once 5 subjects have CBR data available within a cohort. Interim 
analyses will continue every 3 months thereafter provided at least 10 subjects contribute new
CBR data to the subsequent interim. Simulation studies in this document approximate this 
interim plan, as they are timed 12 weeks apart without any restrictions on the number of new 
observations within the analysis.
At each interim analysis, the groups will be evaluated for early futility and sample size 
expansion by comparing posterior quantities for the CBR to pre-specified early stopping criteria.
Table 10-1
Historical CBR for each group
Group 
Index
Tumor Type
Median PFS 
(mo.)
Hist. CBR (%)
Hypothetical Yearly Average 
Accrual (Subjects)
1
SCLC
1.5
6.25
20
2
Gastroesophageal
5
43.50
16
3
STS
6.2
51.10
13
4
Prostate
4
35.40
11
5
Ovarian
3
25.00
10

Novartis
Confidential
Page 83
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
6
Advanced NET
5
43.50
7
7
DLBCL
3
25.00
6
Early Futility
If there is less than 20% probability that the response rate in a subgroup exceeds the historical 
rate Rg, then the group will stop enrollment early for futility. Formally, enrollment will stop 
early for futility if:
Pr(πg > Rg) < 0.20.
A group is only eligible for early stopping once a minimum of 5 patients have been evaluated 
for response in that group.
Early Success
If there is at least 70% probability that the response rate in a subgroup exceeds the historical 
rate, then the subgroup will stop enrollment early for success. Formally, enrollment will stop 
early for success if:
Pr(πg > Rg) > 0.70.
A minimum of 5 subjects will need to be evaluated prior to declaring a group to be efficacious. 
This eligibility remains effective until the next interim analysis is conducted, at which point 
eligibility is re-evaluated based on the currently available data and corresponding model 
outcomes.  
Post-Expansion Futility
If there is less than a 60% probability that the clinical benefit rate in a group exceeds the 
historical rate, then the group will stop enrollment early for futility. Formally, enrollment will 
stop early for futility if:
Pr(πg > Rg) < 0.60.
A group is only eligible for this post-expansion stopping criterion once the group has expanded 
to a sample size beyond 10 subjects enrolled. Note this post-expansion futility is a stricter 
futility rule than that used prior to sample size expansion.
Final Analysis
The final analysis will occur when both accrual and follow-up are complete for all groups. If, 
at the completion of the trial, there is at least 80% probability that the response rate in a group 
exceeds the historical rate, then the group will be considered a success. Formally:
Pr(πg > Rg) > 0.80. 
10.4.4
Handling of missing values/censoring/discontinuations
A patient who has not progressed or died at the date of the analysis cut-off would have his/her 
PFS and OS censored at the time of the last adequate assessment before the cut-off date. Any 

Novartis
Confidential
Page 84
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
disease assessment indicating response status other than “unknown” or “not done” is considered 
an adequate response assessment.
10.4.5
Supportive and Sensitivity analyses
Not Applicable.
10.5
Secondary objectives
10.5.1
Secondary efficacy objectives
Tumor response will be determined per local investigators’ assessment, according both RECIST 
1.1 and the Revised Response Criteria for Malignant Lymphoma, (Cheson et al 2007). Response 
related efficacy assessments will be defined and analyzed based on both RECIST 1.1 and the 
Revised Response Criteria for Malignant Lymphoma, (Cheson et al 2007).
For all efficacy parameters, data will be listed, summarized, or analyzed by tumor group.
The secondary objectives of the study:

To assess Overall Response (OR) of Partial Response (PR) or Complete Response (CR) 
based on local investigator assessment. For patients with solid tumors the assessment 
criteria will be RECIST 1.1 and will include responses of CR and/or PR. For lymphoma
the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007) criteria will 
apply. Response criteria are included in the appendices. The overall response rate (ORR, 
PR plus CR) and its 95% exact confidence interval will be provided for each patient 
group. In the event where sample size in each patient group is small (<10), only ORR 
summary for entire study cohort will be presented

To assess the following, based on local investigator assessment per RECIST 1.1 for solid 
tumors, or the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007)
for lymphoma: 

Time to Progression (TTP)

Time to Response (TTR)

Progression Free Survival (PFS)

Duration of Response (DOR)

To assess safety and tolerability.
Time to progression (TTP) is defined as the time from the date of first dose to the date of first 
documented disease progression or relapse. Time to response (TTR) is defined as the time from 
the date of first dose to the date of first documented response of CR or PR. The secondary 
efficacy variable progression free survival (PFS) is defined as the time from the date of first 
dose to the date of first documented disease progression or relapse or death due to any cause
during study medication or within 150 days from last dosing date.
PFS, TTP and TTR will be summarized and graphed using the Kaplan-Meier product-limit 
method for each patient group. Patients who drop-out without progression will be censored at 

Novartis
Confidential
Page 85
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
the time of last adequate assessment. The estimates of the 25th, median, 75th percentiles of the 
PFS and their 95% confidence intervals will be provided, if applicable.
The duration of response (DOR) applies only to patients whose best response was PR or CR. 
For patients with solid tumors the assessment criteria will be RECIST 1.1 and will include 
responses of CR and/or PR. For lymphoma the Revised Response Criteria for Malignant 
Lymphoma (Cheson et al 2007) will apply.  The duration of response is defined as the time 
from the first documented response to the date first documented disease progression or relapse 
or death due to any cause. The duration of response will be summarized descriptively for each 
patient group.
10.5.2
Safety objectives
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
patient groups.
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g., 
electrocardiogram, vital signs) will be considered as appropriate. All safety data will be listed.
The safety summary tables will include only assessments collected no later than 150 days after 
study treatment discontinuation. Those collected later than 150 days after study treatment 
discontinuation will be flagged in listings.
10.5.2.1 Analysis set and grouping for the analyses
10.5.2.1.1
Adverse events (AEs)
All adverse events recorded during the study will be summarized. The incidence of treatment-
emergent adverse events (new or worsening from baseline) will be summarized by system organ 
class and/or preferred term, maximum severity (based on CTCAE v4.03), type of adverse event, 
relationship to the study treatment by tumor cohort. Deaths reportable as SAEs and non-fatal 
serious adverse events will be listed by patient and tabulated by type of adverse event and 
patient group.
Adverse events will be summarized by presenting the number and percentage of patients by 
system organ class and/or preferred term, the maximum severity (based on CTCAE v4.03) and 
treatment arm. Adverse events related to study treatment will also be summarized. In addition, 
adverse events of related nature may be analyzed by categories regrouping the relevant 
preferred terms, as appropriate.
10.5.2.1.2
Laboratory abnormalities
All laboratory values will be converted into SI units and the severity grade will be calculated 
using appropriate common terminology criteria (CTCAE v4.03).
A severity grade of 0 will be assigned when the value is within normal limits. For lab parameters 
for which severity grades are determined both through normal limits and absolute cut-offs, in 
the unlikely case when a local laboratory normal range overlaps into the higher (i.e. non-zero) 

Novartis
Confidential
Page 86
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
CTCAE grade, the laboratory value will still be taken as within normal limits and assigned a 
CTCAE grade of zero.
A listing of laboratory values will be provided by laboratory parameter, patient, and treatment 
arm. A separate listing will display notable laboratory abnormalities (i.e., newly occurring 
CTCAE grade 3 or 4 laboratory toxicities). Lab values collected later than 150 days after study 
treatment discontinuation will be flagged in the listings
The following by-group summaries will be generated separately for hematology, and 
biochemistry parameters:

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, 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 
grades and the classifications relative to the laboratory normal ranges.
10.5.2.1.3
Other safety data
Summary statistics for data from other tests will be provided, notable values will be flagged, 
and any other information collected will be listed as appropriate.
Descriptive summary statistics will be provided for :

Electrocardiograms: changes from baseline to last available ECG results

Cardiac imaging: number and percentage of patients with notable LVEF values

Vital signs: number and percentage of patients with at least one post-baseline vital sign 
abnormality

ECOG performance status: shift table comparing baseline to worst post baseline ECOG 
performance status.

All other safety related procedures as required

Listings with flagged notable values and any other information collected will be provided 
as appropriate.
10.6
Exploratory objectives 
Not applicable.
10.7
Interim analysis
Scheduled interim data reviews will occur for the primary endpoint of clinical benefit rate only 
as required by the Bayesian Hierarchical design. The first interim data review will be performed 
after the 5 subjects have CBR data available within a cohort. Interim analyses will continue 
every 3 months thereafter provided at least 10 subjects contribute new CBR data to the 
subsequent interim. At each interim analysis, the tumor cohorts will be evaluated for early 

Novartis
Confidential
Page 87
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
futility and early success by comparing posterior quantities for the response rate to pre-specified 
early stopping criteria.
There is no plan for a formal interim analysis of safety or other secondary endpoints for this 
study. However, for publication or other purposes, interim data review of clean data will be 
performed as necessary. At these interim reviews, patient demographics/baseline characteristics, 
the primary and secondary endpoints as applicable, and all important safety endpoints will be 
summarized. No formal report will be issued for these data reviews.
10.8
Sample size calculation
The sample size was chosen by the usual criteria of obtaining adequate power for the alternative 
hypothesis of interest as given in Sections 6.2.3 and 6.2.2 of Appendix 4. This hypothesis 
corresponds to a generally effective treatment across cohorts and incorporates variation in 
treatment effects to reflect the realistic expectation that treatment effects may differ by cohort. 
In this setting, analytical power calculations are not possible, but the design was simulated to 
obtain the power of the study as shown in the appendix. The sample sizes shown (minimum of 
5 for futility stopping, minimum of 10 for early success and maximum of 24 as a cohort cap) 
achieve adequate power for the alternative hypothesis. The simulations included the expected 
variable accrual by simulating a Poisson process with expected accrual also shown in the 
appendix.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. 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 Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 

Novartis
Confidential
Page 88
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 

Novartis
Confidential
Page 89
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
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 

Novartis
Confidential
Page 90
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
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/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
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 but not later than 10 working days.

Novartis
Confidential
Page 91
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
13
References (available upon request)
Antonia SJ et al., Phase I/II study of nivolumab with or without ipilimumab for treatment of 
recurrent small cell lung cancer (SCLC): CA209-032. J Clin Oncol 33, 2015 (suppl; abstr 
7503)
Ott PA et al., Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung
cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028. J Clin Oncol 
33, 2015 (suppl; abstr 7502)
Curiel TJ. Historical perspectives and current trends in cancer immunotherapy. In: Curiel TJ, 
editor. Cancer Immunotherapy: Paradigms, Practice and Promise. New York, NY, USA: 
Springer; 2012.

Novartis
Confidential
Page 93
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiform
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown

Novartis
Confidential
Page 94
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.1.1
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 14.1.2 and the definition of best response in 
Section 14.1.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.18 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 14.1.28 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
14.1.3
Definitions
14.1.4
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 14.1.26.
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.

Novartis
Confidential
Page 95
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01

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 non-cystic 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/pulmonic, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
14.1.5
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 (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in Section 
14.1.26.
14.1.6
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), using a ruler or 
calipers. 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.

Novartis
Confidential
Page 96
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01

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 change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. 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 the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

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.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. 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.

Novartis
Confidential
Page 97
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01

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). Cytological
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 cytological 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.
14.1.7
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 14.1.4.

Nodal target: See Section 14.1.4.

Novartis
Confidential
Page 98
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
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.
14.1.8
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 14-1) and non-target lesions (Table 14-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-3) as well as the presence or absence of new lesions.
14.1.9
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 
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.
14.1.10
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.

Novartis
Confidential
Page 99
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
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.
14.1.11
Nodal lesions
A nodal lesion less than 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 less than 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.
14.1.12
Determination of target lesion response
Table 14-1
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.
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 mm2.
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. Methodology change See Section 14.1.6.
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 

Novartis
Confidential
Page 100
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
change the 0 value, then the investigator/radiologist has to decide between the following three 
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 14-1 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.
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.

Novartis
Confidential
Page 101
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 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.
14.1.13
Determination of non-target lesion response
Table 14-2
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
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 baseline.
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response

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 any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

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 

Novartis
Confidential
Page 102
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
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 14.1.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.1.14
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 
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 14.1.15).

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 14.1.6.
14.1.15
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 14-3.
Table 14-3
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

Novartis
Confidential
Page 103
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
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 14.1.8.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
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.
14.1.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.1.17
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 
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 less than 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

Novartis
Confidential
Page 104
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01

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) > 6 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)
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.

Novartis
Confidential
Page 105
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
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

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) 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.
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 and Zee (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).
14.1.18
Time to event variables
14.1.19
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 

Novartis
Confidential
Page 106
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
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.
14.1.20
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.
14.1.21
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.
14.1.22
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.
14.1.23
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 
a treatment with a significantly higher response rate had a significantly shorter duration of 

Novartis
Confidential
Page 107
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
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.
14.1.24
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 14.1.23. It is recommended 

Novartis
Confidential
Page 108
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
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 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 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.
14.1.25
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.
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.

Novartis
Confidential
Page 109
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01

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 
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 14.1.26).
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.
14.1.26
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 measurable 
disease is derived slightly differently according to Table 14-4.
Table 14-4
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

Novartis
Confidential
Page 110
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Non-target lesions
New Lesions
Overall lesion response
Any
Yes
PD
1 As defined in Section 14.1.8.
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 
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.
14.1.27
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 14.1.25, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) 
as a reference, the following analyses can be considered:
Table 14-5
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
C1
Progression or death after exactly one
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed

Novartis
Confidential
Page 111
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Situation
Options for end-date (progression or
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
C2
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) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
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 14.1.25
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.1.25.
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), i.e. censoring at last adequate assessment may be 
used as a default in this case.

Novartis
Confidential
Page 112
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
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 14-5 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.
14.1.28
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).
14.1.29
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).
14.1.30
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-
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

Novartis
Confidential
Page 113
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol 
14.1.31
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

New therapy for study indication

Progressive disease

Study terminated by the sponsor
14.1.32
Medical validation of programmed overall lesion response
As RECIST 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 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), these UNK 
assessments may be re-evaluated by clinicians 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 

Novartis
Confidential
Page 114
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
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.
14.1.33
Programming rules
The following should be used for programming of efficacy results:
14.1.34
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.
14.1.35
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 14.1.25). 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.
14.1.36
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.
14.1.37
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)’.
14.1.38
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.

Novartis
Confidential
Page 115
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.1.39
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 14-5)

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 14.1.25. 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-
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.
14.1.40
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465

Novartis
Confidential
Page 116
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont. Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16

Novartis
Confidential
Page 117
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.2
Appendix 2: Revised Response Criteria for Malignant 
Lymphoma, therapeutic response/outcome assessment in 
lymphoma studies (based on Cheson response criteria 2007)

Novartis
Confidential
Page 118
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
List of Abbreviations
CMR
Complete metabolic response
CR
Complete response
CT
Computed tomography
DLBCL
Diffuse large B cell lymphoma
FDG
Fluorodeoxyglucose
FL
Follicular lymphoma
LDi
Longest transverse diameter of a lesion
MRI
Magnetic resonance imaging
NMR
No metabolic response
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression free survival
PMD
Progressive metabolic disease
PMR
Partial metabolic response
PR
Partial response
PPD
Product of the Perpendicular Diameters
SD
Stable disease
SDi
Shortest axis perpendicular to LDi
SPD
Sum of the product of the perpendicular diameters for multiple lesions
SUV
Standard Uptake Value
5PS
PET Five Point Scale
Disease assessments will be based on the International Working Group response criteria 
(Cheson 1999), and the International Harmonization Project revised response criteria (Cheson 
et al 2007b). Further clarification on these criteria has been published by (Cheson 2007a).
1
Definitions and criteria for normalization
a. Definitions
i. Nodal vs extranodal lesion
A lesion is categorized based on the location as:

Nodal lesion,

Extranodal lesion, if it is located in organs other than lymph node or nodal mass, but 
including spleen and liver.
2
Measurability of Tumor Lesions at Baseline
All tumor lesions/lymph nodes will be categorized as measurable or non-measurable as follows:
a. Measurable Nodal and extranodal lesions
A lesion will be called measurable if it can be measured accurately in 2 perpendicular 
dimensions and:

Novartis
Confidential
Page 119
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01

For nodal lesion, if the long axis is > 15 mm, regardless of the length of the short axis,

For extranodal lesion, if the long and short axes are ≥ 10 mm.
Patients should have at least one measurable nodal lesion greater than 20 mm in the long 
axis.
In cases where the patient has no measurable nodal lesions greater than 20 mm in the long axis 
at Screening, then the patient must have at least one measurable extranodal lesion
b. Classification of lymph nodes
Lymph nodes are classified according to their size and/or relationship to the disease:

A lymph node meeting the measurability requirement above will constitute a measurable 
nodal lesion.

A lymph node not meeting the measurability requirement but with long axis ≥15 mm (e.g. 
short axis cannot be measured accurately) will constitute a non-measurable nodal lesion.

A lymph node not meeting the measurability criteria but with a size of 11 mm to 15 mm in 
the long axis and ≥ 10 mm in the short axis will be checked for relationship to disease:

If it is thought to be disease related, it will constitute a non-measurable nodal lesion

If it is not thought to be disease related, it will constitute an abnormal lymph node
but not a lesion.

All other lymph nodes will be considered normal and will not constitute nodal lesions.
c. Criteria for normalization of lesions
The normalization of lesions is defined as follow:

A measurable nodal lesion must become ≤ 15 mm in long axis to be considered 
normalized.

A non-measurable nodal lesion must decrease to ≤ 10 mm in the short axis and be ≤ 15 
mm in long axis to be considered normalized.

An extranodal lesion must disappear completely (assigned a size of 0 mm x 0 mm) to be
considered normalized.
3
Specification by methods of measurement
a. Measurement of lesions
All radiological measurements should be taken in two perpendicular dimensions and recorded 
in metric notation, using a ruler or calipers.
i. PET
Visual assessment currently is considered adequate for determining whether a PET scan is 
positive, and use of the standardized uptake value is not necessary.1 In brief, a positive scan is 
defined as focal or diffuse FDG uptake above background in a location incompatible with 

Novartis
Confidential
Page 120
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
normal anatomy or physiology, without a specific standardized uptake value cutoff.1 Other 
causes of false-positive scans should be ruled out. Exceptions include mild and diffusely 
increased FDG uptake at the site of moderate- or large-sized masses with an intensity that is 
lower than or equal to the mediastinal blood pool, hepatic or splenic nodules 1.5 cm with FDG 
uptake lower than the surrounding liver/spleen
ii. CT scan (or MRI)
For optimal evaluation of patients, the same methods of assessment and technique should be 
used to characterize each identified and reported lesion at Screening and during follow-up. 
Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed using a 
5mm 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 Screening a 
patient is known to be allergic to CT contrast or develops allergy 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 change in technique (e.g. from CT to MRI, or 
vice-versa), or a change in any other imaging modality. A change in methodology will result 
by default in an “Unknown” overall radiological response assessment. However, another overall 
radiological response than the Novartis calculated “Unknown” response may be accepted from 
the investigator if a definitive overall radiological response can be justified to be based on the 
available information.
In order to calculate the sum of the product of the diameters (SPD) of all index lesions (or 
extranodal lesions), their size must be entered throughout the study.
Actual lesion measurements should be entered on the corresponding eCRFs. If, during the 
course of the study, either of the perpendicular diameters of a lesion cannot be reliably measured 
because of its small size, it is recommended to enter the minimum limit of detection as the 
diameter size (e.g. 5 mm for spiral CT). In other cases when, during the course of the study, the 
diameter cannot be reliably measured for reasons other than its size (i.e. borders of the lesion 
are confounded by neighboring anatomical structures), no measurement should be entered and 
the lesion cannot be evaluated.
If lesions become confluent over time, it is recommended to measure them as one lesion, report 
the overall diameters to one of the lesions and assign 0 mm x 0 mm to each of the other 
previously measured lesions. If a lesion splits during the study, each sub-lesion should be 
measured separately for all subsequent assessments and all sub-lesions contribute to the SPD.
iii. Bone marrow assessment
Documentation of status of bone marrow involvement by lymphoma based on prior bone 
marrow biopsy or aspirate findings is required at Screening for all patients.

Novartis
Confidential
Page 121
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
If no such documentation is available then a bone marrow biopsy or aspirate should be 
performed at Screening.
If bone marrow involvement is assessed by biopsy, the biopsy sample should have a goal of > 
20 mm unilateral core. If the biopsy sample is indeterminate by morphology 
(immunohistochemistry), then flow cytometry may be performed on bone marrow aspirate to 
confirm the findings.
iv. Physical examination and assessment of B-symptoms
Skin lesions, if the size is ≥ 20 mm in at least one diameter, must be histologically confirmed 
for lymphoma involvement (the investigational site must document the histological 
confirmation (yes or no) on the corresponding eCRF) and photographed including a ruler (color 
photography using digital camera). Tumor assessment will be performed and results will be 
recorded on the corresponding eCRF at Screening and at Day 1 of every cycle (±4 days) after 
first dose of study drug.
B-symptoms are of importance in determining prognosis and should resolve completely in 
patients who have achieved complete response. B-symptoms in lymphoma patients are disease 
related clinical symptoms and are not caused by anticancer therapy (or drug toxicity).
B-symptoms are defined as follows:

Significant unexplained fever (≥ 38°C),

Unexplained, recurrent drenching night sweats

Unexplained loss of > 10% body weight within the previous 6 months, as assessed and 
reported (present vs. absent) by the Investigator.
4. Evaluation of Radiological Response
For the sake of simplicity, complete remission and complete response will both be referred to 
as complete response.
Definitions of Response for Lymphoma patients are listed in Table 4-1. To evaluate disease 
response to treatment, all index and non-index lesions will be followed and assessed throughout 
the study. At each assessment, response is evaluated separately for the index lesions (Table 4-
1) and non-index lesions (Table 4-2) identified at Screening, then a combined overall 
radiological response is determined (Table 4-3).
Table 4-1
Response Definition for Lymphoma
Response
Definition
Nodal Masses
Spleen. Liver
Bone Marrow
CR
Disappeara
nce of all 
evidence of 
disease
a FDG-avid or PET positive prior to 
therapy; mass of any size permitted if 
PET negative
b Variably FDG-avid or PET negative; 
regression to normal size on CT
Not palpable, 
nodules 
disappeared
Infiltrate cleared 
on repeat biopsy; 
if indeterminate 
by morphology, 
immunohistoche
mistry should be 
negative

Novartis
Confidential
Page 122
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Response
Definition
Nodal Masses
Spleen. Liver
Bone Marrow
PR
Regression 
of 
measurable 
disease and 
no new sites
≥ 50% decrease in SPD of up to 6 
largest dominant masses; no increase 
in size of other nodes
a FDG-avid or PET positive prior to 
therapy; one or more PET positive at 
previously involved site
b Variably FDG-avid or PET negative; 
regression on CT
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or spleen
Irrelevant if 
positive prior to 
therapy; cell type 
should be 
specified
SD
Failure to 
attain 
CR/PR or 
PD
a FDG-avid or PET positive prior to 
therapy; PET positive at prior sites of 
disease and no new sites on CT or 
PET
b Variably FDG-avid or PET negative; 
no change in size of previous lesions 
on CT
Relapsed 
disease or 
PD
Any new 
lesion or 
increase by 
≥ 50% of 
previously 
involved 
sites from 
nadir
Appearance of a new lesion(s) > 1.5 
cm in any axis, ≥50% increase in SPD 
of more than one node, or ≥ 50% 
increase in longest diameter of a 
previously identified node > 1 cm in 
short axis
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior to 
therapy
> 50% increase 
from nadir in the 
SPD of any 
previous lesions
New or recurrent 
involvement
a.
Evaluation of Index Lesions (nodal and extranodal)
i. When index nodal lesions are not in complete response
The response for index lesions is evaluated by calculating the Sum of the Products of Diameters 
(SPD) of all index lesions (see Table 4-2), except when there is a Complete Response for index 
nodal lesions (i.e. complete normalization of all index nodal lesions) (see Section ii.).
Table 4-2
Radiological status based on SPD calculation for all index lesions
Response Criteria1
Evaluation of index lesions
Complete Response (CR)
See Table 4-4 below (not based on SPD calculation for all index lesions)
Partial Response (PR)
At least 50% decrease from Screening in the SPD of all index lesions
Stable Disease (SD)
Failure to attain the criteria needed for CR or PR and failure to fulfill the 
criteria for PD
Progressive Disease (PD)
At least a 50% increase from nadir2 in the SPD of all index lesions
1 At each assessment (if the index nodal lesions are not in CR status), the response status based on SPD 
calculation will be first assessed for meeting PD status criteria, then PR status and SD status.
2 Nadir is defined as the smallest sum of the product of the diameters of all index lesions recorded so far, at or 
after Screening.

Novartis
Confidential
Page 123
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
ii. When index nodal lesions are in complete response
When there is a Complete Response for index nodal lesions (i.e. complete normalization of all 
index nodal lesions as defined in Section v.: all index lesion ≤ 15 mm in long axis), the SPD for 
these index nodal lesions may not be equal to zero and therefore a calculation of a SPD for all 
index lesions may be misleading. Therefore, by default, a specific response for extranodal index 
lesions needs to be evaluated, based on the SPD calculation restricted to all index extranodal 
lesions only (see Table 4-3).
Table 4-3
Radiological response criteria for index extranodal lesions in case 
of CR in index nodal lesions
Response Criteria1
Evaluation of index extranodal lesions
Complete Response (CR)
Complete disappearance of all index extranodal lesions
Partial Response (PR)
At least 50% decrease from Screening in the SPD restricted to all index 
extranodal lesions
Stable Disease (SD)
Failure to attain the criteria needed for CR or PR and failure to fulfill the 
criteria for PD
Progressive Disease (PD)
At least a 50% increase from nadir2 in the SPD restricted to all index 
extranodal lesions
1 At each assessment, response will be first assessed for meeting CR status. If CR status is not met, response 
will be assessed for PD status, then PR status and SD status.
2 Nadir is defined as the smallest sum of the product of the diameters restricted to all index extranodal lesions 
recorded so far, at or after Screening.
The algorithm for evaluating the response integrating index extranodal lesions and the SPD 
calculated on all index lesions (where appropriate) provides an overall response for index 
lesions.
iii. Evaluation of response for all index lesions
The evaluation of response for all index lesions is based on the combination of the response for 
index nodal lesions (CR or non-CR), the response for index extranodal and the status based on 
the SPD calculated on all index lesions (nodal and extranodal), as described in Table 4-4.
Table 4-4
Radiological response for index lesions
Response for index 
nodal lesions1
Response for index 
extranodal lesions1
Status based on SPD 
calculation for all index lesions
Response for index 
lesions
CR
CR
Not calculated
CR
CR
SD/ PR
Not calculated
PR
CR
PD
PD
PD
CR
PD
PR
PR
CR
PD
SD
SD
Non-CR
Not evaluated
PD
PD
Non-CR
Not evaluated
PR
PR
Non-CR
Not evaluated
SD
SD

Novartis
Confidential
Page 124
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Response for index 
nodal lesions1
Response for index 
extranodal lesions1
Status based on SPD 
calculation for all index lesions
Response for index 
lesions
1 If no index nodal lesions are present at Screening, then index lesions response is equal to the index 
extranodal lesions response. A similar rule applied if no index extranodal lesions are present at Screening, then 
index lesions response is equal to the index nodal lesions response.
In case of missing measurements of any of the index lesions, the radiological response for index 
lesions at that assessment will be “Unknown (UNK)”, unless progression was seen.
All lesions must have been measured with the same method as the one used at Screening, 
otherwise the radiological response for index lesions at that assessment will be “Unknown 
(UNK)”.
iv. Evaluation of non-index lesions (including nodal, splenic 
and/or hepatic nodules and other extranodal lesions)
At each reassessment, a non-index lesion (or a group of non-index lesions) will be given one of 
the following designations:

Normalization (non-index nodal lesion has regressed to normal size; non-index extranodal 
lesion is no longer present). Normalization of non-index nodal lesions should be 
determined based on their size at Screening.

Improved, stable or worsened, but without unequivocal evidence of disease progression 
(non-index lesion is present but there is not sufficient worsening to declare PD based on 
the existing non-index lesions).

Unequivocal evidence of disease progression (worsening of existing non-index lesions is 
sufficient to declare PD)

Not assessed
Then, this status for each non-index lesion (or group of non-index lesions) will lead to a global 
response for non-index lesions (Table 4-5):
Table 4-5
Response criteria for non-index lesions (nodal, splenic and/or 
hepatic nodules and other extranodal lesions)
Response Criteria
Evaluation of non-index lesions
Complete Response (CR)
Complete normalization of all non-index nodal and extranodal lesions: 
Radiological regression to normal size of all lymph nodes and complete 
disappearance of all extranodal (including splenic and/or hepatic nodules) lesions
Stable Disease (SD)
Failure to attain the criteria needed for CR and failure to fulfill the criteria for PD
Progressive Disease (PD)
Unequivocal disease progression of any existing non-index lesions (nodal or 
extranodal)
In case of a missing status of any of the non-index lesions, the radiological response for non-
index lesions at that assessment will be “Unknown (UNK)”, unless progression was seen.
All lesions must have been measured with the same method as the one used at Screening, 
otherwise the radiological response for non-index lesions at that assessment will be “Unknown 
(UNK)”.

Novartis
Confidential
Page 125
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
v.
New lesions
The appearance of

any new nodal lesion ≥15 mm in any axis. New nodal lesion is defined by:

either a previously normal lymph node becoming > 15 mm in any axis,

or a previously identified abnormal lymph node showing an increase of at least 50% 
in the long axis,

as assessed by investigator
OR

any discrete extranodal (including splenic and/or hepatic nodules) lesions reliably 
appearing on CT scan or MRI after Screening
is always considered as Progressive Disease (PD) and has to be recorded as a new lesion in the 
appropriate module of the eCRF. Determination of new lymphoma involvement in organs other 
than lymph nodes or liver or spleen should be confirmed histologically and the site must 
document that in a comment to the corresponding eCRF.
vi. Overall radiological response
Overall radiological response is calculated as shown in Table 4-6.
Table 4-6
Overall radiological response at each assessment
Index lesions
Non-index lesions1
New lesions
Overall radiological response
CR
CR
No
CR
CR
SD
No
PR
PR
CR or SD
No
PR
SD
CR or SD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1If no non-index lesions are present at Screening, then this column is not used in evaluating overall radiological 
response.
If the evaluation of any of the index or non-index lesions identified at Screening could not be 
made during follow-up or if the index or non-index response is “Unknown (UNK)”, the overall 
response status at that assessment must be “Unknown (UNK)” unless progression or a new 
lesion was seen.
vii. Evaluation of overall disease response
The evaluation of overall disease response at each assessment is a composite of the individual 
radiological responses (index and non-index lesions, new lesions), laboratory test (bone marrow) 
and clinical responses (lymphoma related clinical symptoms).

Novartis
Confidential
Page 126
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
viii. Bone marrow re-assessment at time of radiological CR
In order to confirm a Complete disease response (CR), bone marrow biopsy or aspirate may be 
required when a radiological CR has been achieved. Details are provided in the Study Protocol. 
The infiltrate of lymphoma in bone marrow must have cleared on repeat bone marrow biopsy 
or aspirate. Patients who achieve a CR by other criteria but who have persistent morphologic 
positive or inconclusive bone marrow involvement will be considered partial responders. New 
or recurrent bone marrow involvement anytime during the follow up will be considered PD. 
Bone marrow biopsy or aspirate will be performed after the first assessment of CR or when 
clinically indicated.
The biopsy sample of bone marrow must be adequate (with a goal of > 20 mm unilateral core). 
If the sample is indeterminate by morphology, it should be negative by immunohistochemistry.
ix. Overall disease response
If a patient has an overall radiological response of CR then this response must be confirmed by 
bone marrow biopsy or aspirate (if required as per the Study Protocol), presence of normal liver 
and spleen size, and evaluation of lymphoma related B-symptoms. The patient’s overall 
response will be calculated as follows:
A patient will be deemed to have overall disease response of CR if bone marrow biopsy or 
aspirate becomes negative for tumor involvement (if the bone marrow was involved by 
lymphoma at Screening) and the liver and spleen are normal in size and there are no lymphoma 
related B-symptoms in addition to radiological CR.
If assessments of any of the following: lymphomatous infiltration of bone marrow (If required 
as per the Study Protocol), or evaluation of B-symptoms is not done, unknown or indeterminate 
or B-symptoms are still present when the overall radiological response is assessed as CR or the 
liver or spleen are enlarged, then the overall disease response will be assessed as PR until 
evaluation of these factors have shown normalized results and recorded on the corresponding 
eCRF.
For patients whose radiological response is anything other than CR, assessment of bone marrow, 
liver, spleen and B-symptoms will not be required in evaluating overall response and overall 
disease response is the same as radiological response. However any new or recurrent bone 
marrow involvement at any time during follow-up will be considered PD.
Of note, appearance of B-symptoms or enlarged spleen or liver will not in themselves constitute 
documentation of progression. They are however expected to be associated with progressive 
disease. Every effort should be made to document that evidence radiologically and report the 
corresponding tumor assessments. Such tumor assessments are expected to be performed within 
2 months of appearance of B-symptoms or enlarged spleen or liver.
5.
References (available upon request)
Cheson BD (2007a) The international harmonization project for response criteria in 
lymphoma clinical trials. Hematol Oncol Clin N Am 21:841-854.

Novartis
Confidential
Page 127
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Cheson BD (2009) The case against heavy PETing. J Clin Oncol 27:1742-1743.
Cheson BD, Horning SJ, Coiffier B, et al (1999) Report of an International Workshop to 
standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244-1253.
Cheson BD, Pfistner B, Juweid ME, et al (2007b) Revised response criteria for malignant 
lymphoma. J Clin Oncol 25:579-586.
FDA Guideline (2005) Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.

Novartis
Confidential
Page 128
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.3
Appendix 3: Eastern Cooperative Oncology Group (ECOG) 
performance status
Score
Performance 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 housework, 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

Novartis
Confidential
Page 129
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.4
Appendix 4: Adaptive Basket Trial for Combination Immune-
therapy in Patients with Advanced Solid and Lymphoma
1
Introduction
This document outlines the adaptive design framework to be used for a single-arm Phase II 
study for the investigation combination immune-therapy across multiple cancer subtypes.
Seven pre-specified tumor cohorts, (also referred to as “groups”) are planned for the analysis:
Small-cell lung cancer (SCLC)
Gastroesophageal
Soft tissue sarcoma (STS)
Prostate
Ovarian
Advanced NET
Diffuse large B-cell lymphoma (DLBCL)
The primary endpoint in each group is clinical benefit rate (CBR) assessed at 24 weeks.  All 
patients will receive the experimental treatment.
The trial incorporates analyses based on a hierarchical model that allows for the possibility that 
the effect profile for the population of tumor types may be homogeneous or heterogeneous. 
There may be ‘clusters’ or subsets of tumor types – some in which the treatment is effective, 
and others not. The analysis borrows information, in a limited sense, from the tumor types that 
demonstrate similar CBR effects based on the trial data. The clustering used to characterize the 
distribution of tumor via a Dirichlet process prior (Escobar & West, 1995; Neal, 2000) is solely 
based on the observed CBRs. As described in Berry et al. [Berry, 2013], borrowing via a 
hierarchical model is a type of shrinkage estimation; it provides a formal mechanism by which 
extreme observations are shrunk toward the mean.
Prospectively, the model is developed by evaluating its performance from simulated trials. 
Hence, the false-positive rate can be controlled and power assessed. The advantages to 
borrowing are 1) increased precision of CBR estimates and 2) better decisions regarding CBRs.
2
Primary Analysis
We let Yi be the response indicator for the ith subject.  We define πg = Pr(Yi = 1 | gi = g) as the 
underlying probability of clinical benefit for group g for the experimental treatment and Rg as 
the assumed probability of clinical benefit for group g within the control population.  We 
transform to the logit scale for modeling purposes.  Let θg be the mean log odds treatment effect, 
i.e.:
 = log 

1 −
 −log 

1 −
.
Thus, θg is the logistic regression coefficient for the treatment within group g. The primary 
analysis is a set of group specific tests of θg>0, meaning that the treatment is better than the 
assumed control rate within that group. Thus, we wish to test the set of hypotheses
H0g : θg≤0,
H1g : θg>0.

Novartis
Confidential
Page 130
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
We proceed in a Bayesian fashion, assigning a prior distribution (discussed below) and 
computing the posterior probability of H1g within each group g. If, at the final analysis,
Pr(θg>0 | data) > 0.80,
then group g will be declared a success.  Hence, the final analysis produces a separate decision 
for each group. The trial allows for early stopping of groups for futility, described below.  No 
early stopping for success is allowed.
3
Trial Logistics
For the primary population for which primary analyses, including the hierarchical modeling, 
will be conducted, the maximal sample size is 24 subjects per group.  An additional 6 subjects 
per group may be enrolled in an exploratory population but will not be included in the primary 
analysis. 
In simulations, interim analyses are conducted every 13 weeks, with the first interim analysis 
occurring once any group has 5 subjects with CBR data or 10 subjects are enrolled. In practice, 
interims will be spaced such that 3 months have elapsed since the previous interim AND at least 
10 additional subjects contribute new CBR data to the next interim.
Interim decisions are driven by Pr(θg>0 | data), the probability that the treatment is better than 
control (this is the same probability that drives the final analysis).
At each interim, Pr(θg>0 | data) is computed for each group.  If at any interim Pr(θg>0 | data) is 
too small (<0.20) the group is stopped for futility. To expand enrollment beyond 10 subjects, 
Pr(θg>0 | data) must be sufficiently large (>0.70) at the most recent interim.  Note interims are 
not conducted at the time of enrolling the 11th subject in a group, but rather the most recent 
interim results are used for expansion. If Pr(θg>0 | data) is not sufficiently large and 10 subjects 
are already enrolled in a group, the group will pause enrollment (it is not futile, simply not 
promising enough for more investigation). Should this probability reach the required level at a 
later interim analysis, enrollment may start again and the group sample size would then expand 
from 10 to 24 subjects.  Once a group expands beyond 10 subjects, if at any future time Pr(θg>0 
| data) shrinks sufficiently low (<0.60) the group is stopped for futility. Thus, should an 
expansion be started but the expansion data not be trending in the right direction (toward the 
needed 0.80 at the final analysis), the expansion will be halted. A minimum of 5 subjects with 
CBR data will be required in a group before it may discontinue enrollment for futility or expand 
from 10 to 24 subjects.
Enrollment will continue until no more subjects can be enrolled and all current subjects have 
completed 24 weeks of follow-up. This occurs when all groups have either stopped for futility, 
enrolled to 24 subjects, or enrolled to 10 subjects and are not expanding. The final analysis will 
occur once enrollment is complete and all subjects have been followed to their endpoint.
4
Statistical Modeling
We let Yi be the response indicator for the ith subject.  We define πg = Pr(Yi = 1 | gi = g) as the 
underlying probability of clinical benefit for group g for the experimental treatment and Rg as 

Novartis
Confidential
Page 131
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
the assumed probability of clinical benefit for group g within the control population.  We 
transform to the logit scale for modeling purposes.  Let θg be the mean log odds treatment effect, 
i.e.:
 = log 

1 −
 −log 

1 −
.
The statistical design borrows information across subgroups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 
differ.  In this way, the model is a compromise between the extremes of a completely pooled 
analysis as opposed to a separate analysis in each group. We additionally incorporate a 
clustering mechanism that allows borrowing within clusters but treats clusters separately. This 
minimizes borrowing across groups that are quite different in terms of CBR effects.
The purpose of such an analysis (discussed in more detail in the appendix) is to produce higher 
power or lower type I error in situations where we see some commonality (identical effects are 
not required) among the groups. The model will borrow more in situations where the groups 
appear similar than in situations where the groups appear different.
4.1
Hierarchical Model with Clustering
Our hierarchical approach involves two stages. The goal of both stages is to allow the data to 
drive the amount of borrowing across groups. If the data indicate a large amount of borrowing 
is appropriate (due to similar results), the model will borrow more and thus increase the overall 
power of the trial within each group. In contrast, if the data indicate a small amount of borrowing 
is appropriate (due to dissimilar results) the model will adjust and each group will stand more 
on its own. This “dynamic” borrowing property is distinct from other approaches which use a 
fixed informative prior or apriori assume an amount of borrowing across groups. Here the 
approach includes two stages to identify the appropriate amount of borrowing based on the data.
The first stage of model places the groups into distinct clusters. The purpose of this stage is to 
minimize borrowing of information across groups that appear to be quite different. Thus, for 
example, should 2 of the groups appear similar while the others differ significantly, the model 
may place a large probability on two clusters, one containing the two similar groups with the 
other containing the remaining groups. The model does not pick one particular clustering, but 
instead incorporates the uncertainty of the data in this determination, producing a probability 
distribution over the possible clusterings. Thus, in our example, the model may consider it 
highly likely that the 2 similar groups are in one cluster with the remaining groups in another, 
but it would also retain lower probabilities on the possibility all groups are in one cluster (e.g. 
we are simply seeing differences in the two groups by chance) as well as other possibilities. The 
complete analysis averages over this uncertainty. This clustering approach is implemented 
through a Dirichlet Process Mixture (DPM) model, described in the appendix.
At the second stage, we place hierarchical models over the groups within each cluster (thus, 
conditional on the clustering, there is no borrowing of information across clusters, only within 
clusters). The hierarchical model assumes that the  have an across groups distribution

Novartis
Confidential
Page 132
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
θg ~ N(μ, τ2)
The across groups mean µ and variance τ2 are unknown, and hence have a prior distribution 
which is combined with the data to produce estimates of µ and τ2.
The variance component τ controls the degree of borrowing among groups.  Small values of τ
result in a greater degree of borrowing while large values of τ correspond to less borrowing. 
The parameter τ is estimated using the data, so the observed between group variation is a key 
component of the model behavior. 
Combined, the two stages allow groups with similar results to borrow information between 
them (they will have a high probability of being in the same cluster) while groups with different 
results with borrow far less information between them (they will have a low probability of being 
in the same cluster).
Details of the two stages may be found in the Appendix.
5
Evaluation of Trial Futility, Sample Size Expansion, and Success
Interim monitoring will occur once 5 subjects have CBR data available within a group or 10 
subjects have been enrolled within a group. Interim analyses will continue every 3 months 
thereafter provided at least 10 subjects contribute new CBR data to the subsequent interim. 
Simulation studies in this document approximate this interim plan, as they are timed 13 weeks 
apart without any restrictions on the number of new observations within the analysis.
At each interim analysis, the groups will be evaluated for early futility and sample size 
expansion by comparing posterior quantities for the CBR to pre-specified early stopping criteria.
5.1
Early Futility
If there is less than 20% probability that the clinical benefit rate in a group exceeds the historical 
rate Rg, then the group will stop enrollment early for futility.  Formally, enrollment will stop 
early for futility if:
Pr(πg > Rg) < 0.20.
A group is only eligible for early stopping once a minimum of 5 subjects has been evaluated 
for response in that group.
5.2
Sample Size Expansion
If there is at least 70% probability that the clinical benefit rate in a group exceeds the historical 
rate, then the group is eligible to expand its overall sample size from 10 to 24 subjects. Formally, 
a group is eligible to expand if, at the last conducted interim:
Pr(πg > Rg) > 0.70.
A group is only eligible for sample size expansion once a minimum of 5 subjects has been 
evaluated for CBR in that group. This eligibility remains effective until the next interim analysis 
is conducted, at which point eligibility is re-evaluated based on the currently available data and 
corresponding model outcomes.  

Novartis
Confidential
Page 133
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
5.3
Post-Expansion Futility
If there is less than a 60% probability that the clinical benefit rate in a group exceeds the 
historical rate, then the group will stop enrollment early for futility.  Formally, enrollment will 
stop early for futility if:
Pr(πg > Rg) < 0.60.
A group is only eligible for this post-expansion stopping criterion once the group has expanded 
to a sample size beyond 10 subjects enrolled. Note this post-expansion futility is a stricter 
futility rule than that used prior to sample size expansion.
5.4
Final Analysis
The final analysis will occur when both accrual and follow-up are complete in all groups. If, at 
the completion of the trial, there is at least 80% probability that the clinical benefit rate in a 
group exceeds the historical rate, then the group will be considered a success. Formally:
Pr(πg > Rg) > 0.80.
6
Simulation
Extensive simulations have been conducted to develop and understand the performance of the 
adaptive design, the hierarchical model including clustering mechanism, interim monitoring, 
and decision criteria. We evaluated the design under a variety of possible “truths” for the 
underlying CBR within each group.
6.1
Simulation Assumptions
6.1.1 Trial Enrollment
The assumed average accrual is 124 subjects in 18 months across the 7 groups.  The average 
group rate of accrual varies by group, with some groups enrolling at a faster rate than others.  
Hypothetical yearly accrual rates are provided in Table 1.  It is anticipated that the yearly accrual 
rates will vary by group, but based on a different pattern across groups than that assumed for 
simulations.  A Poisson distribution with these assumed mean rates dictate trial entry for 
simulated subjects.  Hence, actual accrual rates within each simulated trial will vary from the 
mean based on this distributional assumption.
No dropouts are assumed for this simulation; hence, the final endpoint will be observed for 
every subject.
6.1.2 Historical Control Rates
The assumed control CBRs (Rg) vary by group and are provided in the below table. Many of 
these rates are not directly available in the literature. Rather, we have estimated the CBR based 
on estimates of the median PFS time (and assuming exponential PFS). The median PFS times 
and estimated historical CBR rates are shown in Table 1. Because these rates vary, a numbering 
scheme (1 through 7) is used in simulations and corresponding results to index the 7 groups.

Novartis
Confidential
Page 134
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Group
Index
Tumor Type
Median PFS 
(mo)
Hist. CBR (%)
Hypothetical Yearly Average 
Accrual (Subjects)
1
SCLC
1.5
6.25
20
2
Gastroesophageal
5
43.50
16
3
STS
6.2
51.10
13
4
Prostate
4
35.40
11
5
Ovarian
3
25.00
10
6
Advanced NET
5
43.50
7
7
DLBCL
3
25.00
6
Table 1 – Historical CBR for each group
6.2.3 Treatment Clinical Benefit Rate Scenarios
Due to the borrowing nature of the model, the design is evaluated across six scenarios, which 
represent a variety of potential outcomes for the distribution of true CBRs across the groups.  
These include:
a. ‘All Great’ scenario: treatment is effective in all groups
b. ‘All Null’ scenario: the treatment has no effect for any group
c. ‘Half’ scenario: all odd-indexed groups are effective at the same level as ‘All Great’ while 
all even-indexed groups are ineffective at the historical CBRs
d. ‘2 Great’ scenario: groups 2 and 5 are effective at the same level as ‘All Great’ while all 
other groups are ineffective at the historical CBRs
e. ‘2 Null’ scenario: the same two groups (2 and 5) are ineffective at the historical CBRs 
while all other groups are effective at the same levels as those in the ‘All Great’ scenario
f.
‘Mixed’ scenario: varying levels of effectiveness across the groups, such that groups 2 and 
5 are effective at the same level as ‘All Great’, groups 1, 4, and 7 have a moderate effect 
that is smaller, and groups 3 and 6 are ineffective
Since the control CBR differs across groups, we define the treatment effects for each scenario 
on the log-odds scale. A “great” effect is an increase of 0.7 on the log-odds scale. A “moderate” 
effect assumes an increase of 0.35 on the log-odds scale.
The assumed treatment rates for each scenario are shown in the table below and plotted in 
Figures 1-6.  Values identical to the control are show in red, values associated with a great effect 
are shown in green, and values with a moderate level of effect more difficult to detect are shown 
in blue.
Group
Hist. CBR (%)
All Great
All Null
Half
2 Great
2 Null
Mixed
1
6.25
11.84
6.25
11.84
6.25
11.84
8.64
2
43.50
60.79
43.50
43.50
60.79
43.5
60.79
3
51.10
67.79
51.10
67.79
51.1
67.79
51.1
4
35.40
52.46
35.40
35.40
35.4
52.46
43.75
5
25.00
40.16
25.00
40.16
40.16
25
40.16
6
43.50
60.79
43.50
43.50
43.5
60.79
43.5
7
25.00
40.16
25.00
40.16
25
40.16
32.11

Novartis
Confidential
Page 135
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Table 2 – Treatment CBR profiles for each scenario by group
Figure 1 – Assumed CBRs for ‘All Great’. All groups have an increase of 0.7 on the log-odds scale, 
indicated by green x’s.
Figure 2 – Assumed CBRs for ‘All Null’. No groups are effective, indicated by red x’s.
Figure 3 – Assumed CBRs for ‘Half’. Odd numbered groups are effective, indicated by green x’s, with 
log-odds increase of 0.7. Even numbered groups are ineffective, indicated by red x’s.
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1
2
3
4
5
6
7
Group
CBR
Ineffective Treatment CBR
Moderate Treatment CBR
Great Treatment CBR
Historical CBR
All Great
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1
2
3
4
5
6
7
Group
CBR
Ineffective Treatment CBR
Moderate Treatment CBR
Great Treatment CBR
Historical CBR
All Null
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1
2
3
4
5
6
7
Group
CBR
Ineffective Treatment CBR
Moderate Treatment CBR
Great Treatment CBR
Historical CBR
Half

Novartis
Confidential
Page 136
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Figure 4 – Assumed CBRs for ‘2 Great’. Groups 2 and 5 are effective, indicated by green x’s, with log-
odds increase of 0.7. All other groups are ineffective, indicated by red x’s.
Figure 5 – Assumed CBRs for ‘2 Null’. Groups 2 and 5 are ineffective, indicated by red x’s. All other 
groups are effective, indicated by green x’s, with log-odds increase of 0.7.
Figure 6 – Assumed CBRs for ‘Mixed’. Groups 3 and 6 are ineffective, indicated by red x’s, groups 2 
and 5 are effective with log-odds increase of 0.7, indicated by green x’s, and groups 1, 4, and 7 have 
moderate effect, log-odds increase of 0.35, indicated by blue x’s.
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1
2
3
4
5
6
7
Group
CBR
Ineffective Treatment CBR
Moderate Treatment CBR
Great Treatment CBR
Historical CBR
Two Great
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1
2
3
4
5
6
7
Group
CBR
Ineffective Treatment CBR
Moderate Treatment CBR
Great Treatment CBR
Historical CBR
Two Null
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1
2
3
4
5
6
7
Group
CBR
Ineffective Treatment CBR
Moderate Treatment CBR
Great Treatment CBR
Historical CBR
Mixed

Novartis
Confidential
Page 137
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
6.2.4 Simulation Details
For each assumed scenario, 1,000 trials were simulated.  For each analysis (i.e. each interim 
within each trial), posterior distributions were estimated via Markov chain Monte Carlo 
(MCMC) methods using 50,000 iterations, discarding the first 5,000 iterations as burn-in.  The 
simulations were performed using custom software coded in C ++.
6.2.5 Simulation Output
For each scenario, overall descriptive measures are reported and include:

Proportion of trials that declare each group successful at the final analysis 

Average number of correct and incorrect decisions

Proportion of studies that expand each group to an overall sample size of 24 

Proportion of trials that expand 0, 1, 2, …, 7 groups 

The proportion of group expansions that declare success (averaging over groups)

Average group sample size

Average trial sample size

Probability of stopping enrollment early for futility

Average trial duration
In-depth information is also provided for one simulated example trial.  This illustrates the flow 
and outcome of possible trials based on the pre-specified statistical decision rules.
These results are compared to an alternative design approach in which each group is 
independently analyzed, without the borrowing of the hierarchical model. This comparison 
helps illustrate the effect of the borrowing on the operating characteristics.  
These results are also compared to an alternative design approach in which no early futility 
stopping prior to sample size expansion is conducted.  This comparison elucidates the patient 
savings achieved with early futility testing.
6.3
Results
6.3.1 Probability of Group Success
We evaluated the probability of group success for each group in each of the six scenarios for 
the distribution of assumed true CBRs for each group.  If the group is truly effective (great or 
moderate), this represents the power for detecting this effect in the group. For groups where the 
treatment is truly ineffective (null), declaring trial success represents a mistake. Our goal is to 
correctly classify the 7 groups into effective and ineffective groups.
Table 3 shows the probability of success by group. Entries in red represent groups where the 
treatment effect is 0 (e.g. the treatment is ineffective). Entries in green appear where the 
treatment is great, and thus indicate the power of the design. Entries appear in blue for a 
moderate effect, also indicating the power of the design. Results are provided in tabular and 
graphical format.

Novartis
Confidential
Page 138
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Group
Hist. CBR (%)
All Great
All Null
Half
2 Great
2 Null
Mixed
1
6.25
0.565
0.049
0.399
0.095
0.445
0.232
2
43.50
0.809
0.126
0.231
0.638
0.266
0.694
3
51.10
0.824
0.108
0.715
0.161
0.750
0.199
4
35.40
0.802
0.118
0.199
0.156
0.718
0.430
5
25.00
0.769
0.082
0.663
0.584
0.220
0.635
6
43.50
0.810
0.099
0.186
0.140
0.738
0.187
7
25.00
0.762
0.088
0.636
0.138
0.667
0.395
Table 3 – Probability of group success
The probability of trial success is dependent upon the historical control rates and distribution of 
true CBRs across the groups.  When the treatment effects are the same across all groups (All 
Great, All Null), estimation efficiencies, due to borrowing, result in strong trial performance.  
In the All Null scenario the individual groups have less than a 13% chance of mistakenly 
declaring group success.   In the All Great scenario, power generally ranges from 76.2%-82.4%. 
The groups that have a small historical control rate tend to have lower power.  This is due to 
the selection of scenarios whereby power is assessed for detecting a 0.7 log-odds improvement, 
which is more difficult for lower historical control rates.  In addition, the global type I error 
(proportion of trials that declare at least one group successful in the All Null scenario) is 
controlled at 0.431.
When the treatment effects vary across the groups, the amount of appropriate borrowing also 
varies, impacting the operating characteristics.  Power is reduced and the probability of 
mistakenly classifying an ineffective group as effective is larger in these situations.  For the 
scenarios simulated, the power varies considerably; from roughly 40%-75% while the largest 
probability of incorrectly declaring an ineffective group effective is 0.266.
In the ‘Mixed’ scenario, the moderate effects are difficult to detect. These groups typically have 
around 40% power.

Novartis
Confidential
Page 139
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Figure 7 – Probability of success in each group for each scenario.
For each trial, there are 7 decisions to be made regarding the success in a group. For a group 
that is truly effective (great or moderate), declaring success is a correct decision. For a group 
that is truly ineffective, declaring success is an incorrect decision. Table 4 shows the average 
number of correct and incorrect decisions per scenario, averaged across all groups. Table 5 
provides additional detail about the tradeoff between detecting truly ineffective groups versus 
not detecting truly effective groups.
All Great
All Null
Half
2 Great
2 Null
Mixed
Correct
5.3
6.3
4.8
5.5
4.8
4
Incorrect
1.7
0.7
2.2
1.5
2.2
3
Table 4 – Average number of correct and incorrect decisions
Subset
Decision
All 
Great
All Null
Half
2 Great
2 Null
Mixed
Effective
Final Success Met
5.3
NA
2.4
1.2
3.3
2.4
Effective
Final Success Not Met
1.7
NA
1.6
0.8
1.7
2.6
Ineffective
Final Success Met
NA
0.7
0.6
0.7
0.5
0.4
Ineffective
Final Success Not Met
NA
6.3
2.4
4.3
1.5
1.6
Two Great
Two Null
Mixed
All Great
All Null
Half
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Group
Probability of Success
Truth
Great
Moderate
Ineffective
Probability of Success

Novartis
Confidential
Page 140
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Table 5 – Average number of true effective and ineffective groups meeting success and not meeting 
success
6.3.2 Sample Size Expansion
The probability of expanding from an overall sample size of 10 to 24 is examined for each group 
within each scenario (Table 6, Figure 8).  Groups that are in truth effective tend to have large 
probabilities of expanding to n=24 subjects (68%-90%). For scenarios in which there are only 
a few effective groups (‘2 Great’), the probability of expanding those groups drops to 72%-74%.  
Likewise, the probability of expanding ineffective groups is largely dependent upon the 
distribution of effects across the groups. When no groups are effective, the model tends to 
correctly detect moderate effects as spurious ‘highs’ and down-weights those estimates leading 
to less chance of expanding to n=24.
Group
Hist. CBR 
(%)
All Great
All Null
Half
2 Great
2 Null
Mixed
1
6.25
0.688
0.196
0.574
0.302
0.636
0.475
2
43.50
0.863
0.385
0.511
0.744
0.530
0.782
3
51.10
0.901
0.357
0.820
0.439
0.854
0.488
4
35.40
0.875
0.332
0.488
0.409
0.831
0.628
5
25.00
0.857
0.303
0.777
0.721
0.501
0.764
6
43.50
0.891
0.324
0.481
0.415
0.843
0.470
7
25.00
0.859
0.290
0.766
0.391
0.788
0.608
Table 6 – Probability of expanding from 10 to 24 subjects.

Novartis
Confidential
Page 141
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Figure 8 – Probability of expanding from 10 to 24 subjects.
The proportion of trials that expand 0, 1, 2, …, 7 groups are reported (Table 7, Figure 9).  When 
all groups are effective (All Great), typically 5-7 groups expand (on average, 5.934 groups 
expand).  When no groups are effective (All Null), the likelihood of expanding multiple groups 
decreases greatly, with an average of 2.187 groups expanding.
Groups
All Great
All Null
Half
2 Great
2 Null
Mixed
Average
5.934
2.187
4.417
3.421
4.983
4.215
0
0
0.161
0.013
0.043
0.003
0.019
1
0.002
0.238
0.045
0.105
0.022
0.069
2
0.011
0.235
0.093
0.190
0.048
0.110
3
0.031
0.156
0.140
0.177
0.087
0.124
4
0.057
0.097
0.161
0.182
0.149
0.170
5
0.181
0.065
0.256
0.174
0.274
0.256
6
0.342
0.038
0.202
0.096
0.281
0.170
7
0.376
0.010
0.090
0.033
0.136
0.082
Table 7 – Number of Group Expansions (0, 1, 2,…,7)
Two Great
Two Null
Mixed
All Great
All Null
Half
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Group
Probability
Truth
Great
Moderate
Ineffective
Probability of Expansion

Novartis
Confidential
Page 142
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Figure 9 – Number of Group Expansions (0, 1, 2,…,7)
The proportion of group expansions that declare success, averaged over groups within each trial, 
is provided in Table 8.
Scenario
Proportion
All Great
0.899
All Null
0.306
Half
0.685
2 Great
0.559
2 Null
0.763
Mixed
0.657
Table 8 – Proportion of group expansions that declare success
6.3.3 Average Sample Size 
The average sample size for each group and for each trial (summing over groups) within each 
scenario are provided in Tables 9 and 10, and graphically in Figure 10. In the ‘All Great’ 
scenario, each group is likely to expand and thus the average sample size is close to the 
maximum per group. In the ‘All Null’ scenario, the average sample size is smaller per group 
due to early futility stopping and the expansion criteria identifying when enrollment may 
expand from 10 to 24 subjects.   
Two Great
Two Null
Mixed
All Great
All Null
Half
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
Number of Expansions
Proportion
Number of Group Expansions

Novartis
Confidential
Page 143
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
The average trial size varies from 94.3 subjects to 150.6 subjects.  The average trial size reduces 
as the number of groups that stop enrollment for futility increase.   The maximum trial sample 
size is 168 subjects (full enrollment of 24 subjects within each of 7 groups).
Group
Hist. CBR (%)
All Great
All Null
Half
2 Great
2 Null
Mixed
1
6.25
19.6
12.6
17.8
14.1
18.7
16.5
2
43.50
21.8
14.7
16.5
20.0
16.8
20.6
3
51.10
22.3
14.0
21.1
15.1
21.5
15.8
4
35.40
21.9
13.7
15.8
14.8
21.2
18.1
5
25.00
21.6
13.3
20.4
19.5
15.8
20.2
6
43.50
22.0
13.3
15.2
14.4
21.3
15.1
7
25.00
21.4
12.8
20.0
14.0
20.4
17.3
Table 9 – Average group sample size
Trial Sample 
Size
All Great
All Null
Half 
2 Great
2 Null
Mixed
150.6
94.3
126.9
111.9
135.6
123.6
Table 10 – Average trial sample size
Figure 10 – Average group sample size
Two Great
Two Null
Mixed
All Great
All Null
Half
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
0
5
10
15
20
25
0
5
10
15
20
25
0
5
10
15
20
25
0
5
10
15
20
25
0
5
10
15
20
25
0
5
10
15
20
25
Group
Number of Subjects
Truth
Great
Moderate
Ineffective
Average Sample Size

Novartis
Confidential
Page 144
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
6.3.4 Early Futility
Table 11 and Figure 11 summarize the proportion of trials that stop early (either by futility 
before enrolling 10 subjects, by not meeting the expansion criteria, or by futility after 
expansion).
Group
Hist. CBR (%)
All Great
All Null
Half
2 Great
2 Null
Mixed
1
6.25
0.318
0.832
0.449
0.731
0.390
0.559
2
43.50
0.166
0.721
0.585
0.300
0.546
0.259
3
51.10
0.136
0.781
0.218
0.692
0.196
0.654
4
35.40
0.156
0.786
0.651
0.708
0.219
0.459
5
25.00
0.176
0.819
0.280
0.336
0.649
0.295
6
43.50
0.153
0.809
0.699
0.749
0.219
0.701
7
25.00
0.194
0.836
0.300
0.763
0.272
0.523
Table 11 – Probability of stopping early for futility
Figure 11 – Probability of stopping early for futility
6.3.5 Trial Duration
Based on the currently assumed hypothetical accrual rates, the average trial duration across 
scenarios ranges from 3.4 years to 4.6 years as shown in Table 12. The ‘All Null’ scenario tends 
Two Great
Two Null
Mixed
All Great
All Null
Half
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Group
Probability
Truth
Great
Moderate
Ineffective
Probability of Early Futility

Novartis
Confidential
Page 145
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
to have shorter trials due to many groups stopping early for futility. Duration is largely 
dependent upon accrual.  The majority of the groups stop enrollment much earlier than the 
average values as described in Table 13.  Due to the assumed non-constant accrual rate, slow-
enrolling groups take extra time to enroll, thereby increasing the duration of the overall trial.  In 
practice, faster or slower accrual rates (than those simulated) for all groups will largely impact 
these numbers.
All Great
All Null
Half
2 Great
2 Null
Mixed
4.6
3.4
4.4
3.7
4.6
4.1
Table 12 – Average trial duration in years
Number of Years from First 
Subject First Visit
Scenario
All Great
All Null
Half 
2 Great
2 Null
Mixed
1
6.8
5.7
6.4
6.2
6.5
6.5
2
5.9
4.2
5.3
5
5.6
5.3
3
3.3
2.2
3.3
2.8
3.6
3.1
4
1.7
1
1.9
1.3
2.1
1.6
5
0.5
0.3
0.7
0.4
0.7
0.5
6
0.1
0
0.2
0.1
0.1
0.1
Table 13 – Average number of groups continuing to enroll subjects after 1, 2, 3, 4, 5, and 6 years
6.4
Example Trials
6.4.1 Overview
In this section, we present an example of the trial to illustrate the adaptive process.
The trial is described graphically in a series of plots.  Each plot describes the current data at the 
time of the interim. The plots include the following features:

Light gray bars represent the number of subjects enrolled.

Dark gray bars represent the number of subjects with CBR data

Bars may be outlined blue, yellow, red, or green.  Blue indicates a group may continue to 
enroll; yellow indicates that enrollment has been paused for the group; red indicates a 
group has permanently stopped for futility; and green indicates a group has declared 
success.

Vertical dashed lines are provided at 10 and 24 subjects.

Text columns to the right of the plot display the following summary statistics for each 
group:

Pr(>Ctrl): The probability that the CBR exceeds that group’s corresponding historical 
control based on the hierarchical model

Data: The observed number of events/the number of subjects with CBR data available

Obs. CBR: The observed CBR

Novartis
Confidential
Page 151
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
approach pooling. In contrast, when τ is large we expect large amount of across group variation, 
and thus even though the groups are in the same cluster the θg values may be quite different. 
Apriori we have no way of knowing τ, so we estimate it using the data combined with the prior 
distributions
μ ~ N(0, 1.82)
and
τ2 ~ IG(3,0.5),
where IG(α, β) is the inverse gamma distribution defined by:
(| , ) = "#$ %
⁄
"'(( ).
When the entire model is implemented (via Markov Chain Monte Carlo) we consider the full 
joint distribution of the clustering combined with the hierarchical model parameters. We 
average over the entire range of the uncertainty in the parameters to produce the posterior 
distribution for each group parameter θg, which is then used to drive the decisions in the design. 
8
Comparison of Analysis Approaches: Hierarchical Borrowing versus 
Independent Analyses
The Bayesian hierarchical model-based analysis approach for the 7 groups is compared to 
instead conducting independent analyses for each of the groups.  These analysis approaches are 
compared within the context of this exact trial design with identical futility and sample size 
expansion criteria.  For independent analyses, the final success criteria are instead based on 
exact binomial tests at the 0.20 level.  Note that this comparison does not compare the adaptive 
design to a standard fixed design. The adaptive features are included in both, the only change 
is the final analysis. Operating characteristics to compare these analysis approaches are 
provided.
8.1
Probability of Success
For effective groups, the probability of success is consistently higher across most scenarios 
relative to independent analyses.
Group
All Great
All Null
Half
3 Great
3 Null
Mixed
1
0.565/0.470
0.049/0.091
0.399/0.404
0.095/0.112
0.445/0.434
0.232/0.243
2
0.809/0.733
0.126/0.157
0.231/0.180
0.638/0.645
0.266/0.186
0.694/0.680
3
0.824/0.732
0.108/0.113
0.715/0.680
0.161/0.126
0.750/0.699
0.199/0.135
4
0.802/0.727
0.118/0.132
0.199/0.163
0.156/0.152
0.718/0.689
0.430/0.406
5
0.769/0.629
0.082/0.072
0.663/0.590
0.584/0.560
0.220/0.083
0.635/0.572
6
0.810/0.743
0.099/0.116
0.186/0.147
0.140/0.134
0.738/0.702
0.187/0.146
7
0.762/0.616
0.088/0.082
0.636/0.578
0.138/0.099
0.667/0.586
0.395/0.281
Table 17 – Probability of success (borrowing/independent analyses)

Novartis
Confidential
Page 152
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Figure 19 – Probability of success (borrowing versus independent analyses)
8.2
Mean Squared Error
The mean squared error (MSE) is a measure of the average vale of (estimate − truth)2. It 
incorporates both the bias and variance associated with the estimate. The MSE values for the 
borrowing analysis are consistently lower than that of independent analyses.
Group
All Great
All Null
Half
3 Great
3 Null
Mixed
1
0.002/0.007
0.001/0.004
0.002/0.007
0.001/0.003
0.002/0.007
0.001/0.005
2
0.009/0.018
0.008/0.016
0.009/0.017
0.015/0.019
0.009/0.017
0.013/0.019
3
0.008/0.016
0.010/0.019
0.011/0.017
0.010/0.019
0.010/0.017
0.010/0.020
4
0.009/0.017
0.007/0.016
0.008/0.016
0.008/0.016
0.011/0.018
0.009/0.017
5
0.008/0.017
0.005/0.012
0.011/0.017
0.013/0.017
0.006/0.012
0.011/0.017
6
0.009/0.017
0.009/0.019
0.009/0.019
0.009/0.019
0.011/0.019
0.009/0.019
7
0.009/0.018
0.005/0.014
0.012/0.020
0.005/0.014
0.011/0.019
0.008/0.017
Table 18 – MSE (borrowing/independent analyses)
Two Great
Two Null
Mixed
All Great
All Null
Half
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Group
Probability of Success
Analysis 
Method
Borrowing
Independent Analyses
Probability of Success

Novartis
Confidential
Page 153
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
Figure 20 – MSE (borrowing versus independent analyses)
9
Comparison of Design Approaches: Planned Design with or without 
Early Futility prior to Sample Size Expansion
Simulated trial data has been applied to two designs:
1. The planned design as described in this report but with early futility prior to sample size 
expansion removed
2. The planned design as described in this report
The former approach describes the design (including sample size expansion and post-expansion 
futility stopping) but without early futility stopping prior to sample size expansion.  If early 
futility stopping were permitted, a fraction of the trials (this varies based on the scenario and 
group) will halt enrollment earlier than it otherwise would have and prohibit those groups from 
ultimately meeting success.  For groups that would otherwise have met success, the early futility 
leads to a missed success and reduction in power.  While for groups that did not ultimately meet 
success, the early futility stopping provides a savings in patients and resources. Inherent in the 
futility stopping is a trade-off between power reduction and subject savings.  The goal is to 
minimize any potential reduction in power while allowing the design to reduce its required 
sample size required to determine success in each group.
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Two Great
Two Null
Mixed
All Great
All Null
Half
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
0.000
0.005
0.010
0.015
0.020
0.000
0.005
0.010
0.015
0.020
0.000
0.005
0.010
0.015
0.020
0.000
0.005
0.010
0.015
0.020
0.000
0.005
0.010
0.015
0.020
0.000
0.005
0.010
0.015
0.020
Group
MSE
Analysis 
Method
●
●
Borrowing
Independent Analyses
MSE

Novartis
Confidential
Page 156
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.5
Appendix 5: Recommended management algorithms for 
suspected toxicities
These general guidelines for management of toxicities (Postow 2015) constitute guidance to the 
Investigator and are not intended to substitute institutional standard of care practice.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
14.5.1
GI adverse event management algorithm

Novartis
Confidential
Page 157
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.5.2
Renal adverse event management algorithm

Novartis
Confidential
Page 158
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.5.3
Pulmonary adverse event management algorithm

Novartis
Confidential
Page 159
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.5.4
Hepatic adverse event management algorithm

Novartis
Confidential
Page 160
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.5.5
Endocrinopathy management algorithm

Novartis
Confidential
Page 161
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.5.6
Skin adverse event management algorithm

Novartis
Confidential
Page 162
Oncology Clinical Protocol v01.00 (Clean)
Protocol No. CPDR001XUS01
14.5.7
References (available upon request)
Postow MA, Chesney J, Pavlick AC, et al (2015). nivolumab and ipilimumab versus 
ipilimumab in untreated melanoma. N Engl J Med.;372(21):2006-17 (supplementary 
appendix).