Clinical trial NCT02545075
Conditions: Melanoma
Sponsor: Bristol-Myers Squibb
Start date: 2015-10-31; Completion date: 2019-04-19
Enrollment: 182 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether Ipilimumab will extend the life of chinese patients with Chemotherapy Naive Stage IV Melanoma more than Dacarbazine as well as to examine safety in this patient population.

Detailed description:

Arms: arm 1: Intravenously (IV) 3 mg/kg every 3 weeks (at week 1,4,7,10) and thereafter (q3w/4 doses) at the time of progression arm 2: IV solution 250 mg/m2 (Day 1-5, every 3weeks/at week 1, 4, 7, 10,13,16,19,22)
Interventions: intervention 1: Ipilimumab intervention 2: Dacarbazine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_001.pdf: 





































































































































































SAP_000.pdf: 
Official Title of Study: 
           A Randomized, Open-Label, Two-arm, Comparative Study in Chinese Subjects with 
Chemotherapy Naïve Stage IV Melanoma Receiving Ipilimumab (3 mg/kg) vs. Dacarbazine. 
 
NCT Number:  NCT02545075 
 
Document Date (Date in which document was last revised): 17 January 2019 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A RANDOMIZED, OPEN-LABEL, TWO-ARM, COMPARATIVE STUDY IN CHINESE 
SUBJECTS WITH CHEMOTHERAPY NAÏVE STAGE IV MELANOMA RECEIVING 
IPILIMUMAB (3 MG/KG) VS. DACARBAZINE.
PROTOCOL(S) CA184248
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................5
2
STUDY DESCRIPTION ..........................................................................................7
2.1
Study Design ............................................................................................................7
2.2
Treatment Assignment..............................................................................................7
2.3
Blinding and Unblinding...........................................................................................8
2.4
Protocol Amendments...............................................................................................8
3
OBJECTIVES ..........................................................................................................8
3.1
Primary.....................................................................................................................8
3.2
Secondary.................................................................................................................8
4
ENDPOINTS............................................................................................................9
4.1
Primary Endpoint......................................................................................................9
4.1.1
Two-Year Survival Rate............................................................................................9
4.2
Secondary Endpoints ................................................................................................9
4.2.1
One-Year Survival Rate ............................................................................................9
4.2.2
Overall Survival .......................................................................................................9
4.2.3
Progression Free Survival ........................................................................................9
4.2.4
Disease Control Rate..............................................................................................10
4.2.5
Best Overall Response Rate ....................................................................................10
4.2.6
Duration of Response .............................................................................................10
4.2.7
Duration of Stable Disease .....................................................................................10
4.3.1
Safety......................................................................................................................11
4.3.1.1
Adverse Events, Serious Adverse Events, Immune-Related Adverse Events 
and Immune-Mediated Adverse Reactions...............................................................11
4.3.1.2
Laboratory Tests.....................................................................................................12
4.3.2
Pharmacokinetics of Ipilimumab.............................................................................13
4.3.3
Anti-Drug Antibody ................................................................................................13
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4.3.4
Health Related Quality of Life ................................................................................13
4.3.4.1
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire (EORTC QLQ-C30)..................................................................13
4.3.4.2
European Quality of Life-5 Dimensions (EQ-5D) Questionnaire.............................14
4.3.5
Health Related Resource Utilization .......................................................................15
5
SAMPLE SIZE AND POWER...............................................................................15
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................15
6.1
Study Periods..........................................................................................................15
6.2
Treatment Regimens...............................................................................................16
6.3
Populations for Analyses ........................................................................................16
7
STATISTICAL ANALYSES..................................................................................18
7.1
General Methods ....................................................................................................18
7.2
Study Conduct........................................................................................................18
7.2.1
Accrual...................................................................................................................18
7.2.2
Protocol Deviations................................................................................................18
7.3
Study Population ....................................................................................................20
7.3.1
Subject Disposition.................................................................................................20
7.3.2
Demography and Subject Characteristics ...............................................................20
7.3.3
Medical History......................................................................................................20
7.3.4
Disease Characteristics ..........................................................................................20
7.3.5
Prior Therapy.........................................................................................................21
7.3.6
Clinical Complaints and Findings...........................................................................21
7.3.7
Baseline Laboratory Examinations .........................................................................21
7.4
Extent of Exposure .................................................................................................21
7.4.1
Administration of Study Therapy.............................................................................21
7.4.2
Discontinuation from Induction Phase....................................................................21
7.4.3
Interruption of Infusion or Delay of Study Therapy.................................................22
7.4.5
Other On-Study Therapy.........................................................................................22
7.4.6
Subsequent Therapy................................................................................................23
7.5
Efficacy..................................................................................................................23
7.5.1
Survival Rates at Specified Time Points ..................................................................23
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7.5.1.1
Subgroup Analyses .................................................................................................23
7.5.1.2
Sensitivity Analyses.................................................................................................24
7.5.2
Overall Survival .....................................................................................................24
7.5.2.1
Comparison between Treatment Groups .................................................................24
7.5.2.2
Subgroup Analyses .................................................................................................24
7.5.2.3
Sensitivity Analyses.................................................................................................25
7.5.3
Progression-Free Survival......................................................................................25
7.5.3.1
Sensitivity Analyses.................................................................................................26
7.5.4
Disease Control Rate..............................................................................................26
7.5.5
Best Overall Response ............................................................................................26
7.5.6
Best Overall Response Rate ....................................................................................26
7.5.7
Duration of Response .............................................................................................27
7.5.8
Duration of Stable Disease .....................................................................................27
7.6
Safety.....................................................................................................................27
7.6.1
Adverse Events .......................................................................................................27
7.6.2
Clinical Laboratory Evaluations.............................................................................32
7.6.3
Deaths ....................................................................................................................32
7.6.4
Resource Utilization ...............................................................................................32
7.6.5
Immunogenicity ......................................................................................................33
7.7
Pharmacokinetic Analyses ......................................................................................33
7.8
Health-Related Quality of Life................................................................................33
7.8.1
EORTC QLQ-C30 ..................................................................................................33
7.8.2
EuroQolEQ-5D-3L.................................................................................................33
8
CONVENTIONS....................................................................................................34
9
CONTENT OF REPORTS .....................................................................................35
10
DOCUMENT HISTORY........................................................................................36
APPENDIX 1
IMMUNE-RELATED ADVERSE EVENT SEARCH CRITERIA 
VERSION 20.0 (APRIL 2017) ...............................................................37
11
REFERENCES.......................................................................................................41
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LIST OF TABLES
Table 2.4-1:
Protocol Amendments ..............................................................................8
Table 7.2.2-1:
Relevant Protocol Deviation Criteria ......................................................19
Table 10-1:
Document History ..................................................................................36
LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic...........................................................................7
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2
STUDY DESCRIPTION
2.1
Study Design
This SAP addresses the randomized, open-label study, CA184248, for which the planned sample 
size is approximately 180 randomized subjects with 2:1 allocation to ipilimumab 3mg/kg or DTIC.
An overview of the administration of study drug and assessment schedule is presented in
Figure 2.1-1. Further details of the design are given in the Protocol.
Figure 2.1-1:
Study Design Schematic
  
2.2
Treatment Assignment
After informed consent has been obtained, the site will enroll a subject into the study at the time 
of eligibility screening by accessing a call-in Interactive Voice Response System (IVRS). A 
subject number will be assigned by the IVRS at this time. 
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Following completion of all Screening evaluations, all eligible subjects will be randomized to one 
of two arms in a 2:1 ratio (Ipilimumab:DTIC) using a stratified permuted block randomization 
method with the following stratification actors:

M-substage (M1a+M1b vs. M1c);

BRAF mutation status (yes vs. no).
2.3
Blinding and Unblinding
Not applicable (open-label study).
2.4
Protocol Amendments
This SAP reflects the protocol amendments described in Table 2.4-1:
Table 2.4-1:
Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
Revised Protocol 1
08-JUL-2015
- Update the dose of DTIC per China label requirement.
- Other changes per program level standards and model document.
Revised Protocol 2
23-DEC-2015
- Remove the use of a Data Monitoring Committee (DMC since:
1) This is an open-label study;
2) This is a single country study (China) and not a MRCT (Multi 
Regional Clinical Trial) and therefore an independent DMC is not 
required as per the Chinese regulation.
- Further clarification with regards to:
1) The infusion pump used for the administration of ipilimumab;
2) The T&E schedule (Endocrine assessments and collection of 
PK/ADA)
Revised Protocol 3
20-DEC-2018
-Change in primary objective and primary endpoint to 2-year OS rate 
from OS
-Change in allowable minimum scan time from baseline for 
determination of stable disease from 12 weeks to 8 weeks per RECIST 
v1.1 guidelines
3
OBJECTIVES
3.1
Primary

To compare the survival rate at 2 years in chemotherapy naive Chinese subjects with Stage IV 
melanoma who have been randomized to ipilimumab (3mg/kg) vs. DTIC (250mg/m² - Day 1 
- 5).
3.2
Secondary

To estimate survival rates at 1 year for each treatment arm;

To compare overall survival between the two arms

To compare PFS between the two arms by RECIST v1.1;

To compare disease control rate between the two arms by RECIST v1.1;
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
To estimate best overall response rate, duration of response, and duration of stable disease for 
each treatment arm by RECIST v1.1.
 
.
4
ENDPOINTS
4.1
Primary Endpoint
4.1.1
Two-Year Survival Rate
Two-year survival rate is defined as the probability that a subject is alive at 2 years following the 
randomization date and will be estimated via the Kaplan-Meier (KM) method.
4.2
Secondary Endpoints
Secondary response-based endpoints of PFS, DCR, DoR, DoSD, and BORR will be captured using 
the RECIST v1.1 criteria.
4.2.1
One-Year Survival Rate 
Survival rate at 1 year is defined as the probability that a subject is alive at 1 year following the
randomization date and will be estimated via the Kaplan-Meier (KM) method.
4.2.2
Overall Survival
OS is defined for each subject as the time between randomization date and the date of death (of 
any cause). If a subject has not died, the subject will be censored at the time of last contact (last 
known alive date).
A modified variable will be examined for the purposes of sensitivity analysis:
•
OS accounting for subsequent PD-1/PD-L1 therapy will be defined through addition of the 
following restriction to the primary definition: subjects who receive subsequent PD-1/PD-L1 
cancer therapy will be censored at the start date of subsequent PD-1/PD-L1 therapy.
4.2.3
Progression Free Survival
PFS is defined for each subject as the time between randomization date and the date of progression 
or death, whichever occurs first. The date of progression will be taken from the investigator 
assessment of progression on the CRF. A subject who dies without reported prior progression will 
be considered to have progressed on the date of death if no subsequent therapy prior to death date. 
For those who remain alive and have not progressed, PFS will be censored on the date of last 
evaluable tumor assessment (TA) prior to subsequent therapy. For those who remain alive and 
have no recorded evaluable TAs post baseline, PFS will be censored on the date of randomization.
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For subjects without baseline tumor assessment, PFS will also be censored on the date of 
randomizaion.
Modified variables will be examined for the purposes of sensitivity analysis:

PFS accounting for early TAs in DTIC group is defined in the same manner as PFS, except 
that for subjects randomized to DTIC with radiographic, photographic or clinical evidence of 
progression before Week 12, subjects will be considered to have PD at Week 12.
4.2.4
Disease Control Rate
Primary disease control rate (DCR) definition is defined as the number of subjects in the arm with 
Best Overall Response (BOR) of complete response (CR), partial response (PR), or stable disease 
(SD), divided by the total number of randomized subjects in the arm.
Per protocol DCR definition is defined as the number of response evaluable subjects in the arm
with BOR of complete response (CR), partial response (PR), or stable disease (SD), divided by the 
total number of response evalubale subjects in the arm.
4.2.5
Best Overall Response Rate
Primary BORR definition is defined as the number of subjects in the arm with a BOR of CR or 
PR, divided by the total number of randomized subjects in the arm.
Per protocol BORR definition is defined as the number of response evaluable subjects in the arm 
with a BOR of CR or PR, divided by the total number of response evaluable subjects in the arm.
4.2.6
Duration of Response
Primary duration of response (DoR) definition for the randomized subjects whose BOR is CR or 
PR is defined as the time between the date of response of CR or PR (whichever occurs first) and 
the first date of progressive disease (PD) or the date of death (whichever occurs first). 
Per protocol DoR definition for the response evaluable subjects whose BOR is CR or PR is defined
as the time between the date of response of CR or PR (whichever occurs first) and the first date of 
progressive disease (PD) or the date of death (whichever occurs first). 
For both definitions, for subjects who underwent tumor resection following response but prior to 
disease progression, DoR will be censored on the date of the last evaluable TA prior to resection. 
For subjects who remain alive and have not progressed following response, DoR will be censored 
on the date of last evaluable TA prior to subsequent therapy.
4.2.7
Duration of Stable Disease
Primary duration of stable disease (DoSD) definition for the randomized subjects whose BOR is 
SD is defined as the time between the randomization date and the first date of PD or the date of 
death (whichever occurs first). 
Per protocol DoSD definition for the response evaluable subjects whose BOR is SD is defined as 
the time between the randomization date and the first date of PD or the date of death (whichever 
occurs first). 
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For both definitions, for subjects who underwent tumor resection following SD but prior to disease 
progression, DoSD will be censored on the date of the last evaluable TA prior to resection. For 
subjects who remain alive and have not progressed following SD, DoSD will be censored on the 
date of last evaluable TA prior to subsequent therapy.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5
SAMPLE SIZE AND POWER
Approximately 180 Chinese subjects will be randomized to ipilimumab and DTIC at a 2:1 ratio
and followed  at least 2 years after randomization to ensure 80% power through simulation using 
a  chi-squared test with a Type I error rate of 0.20 to reject the null hypothesis of no difference in 
2-year survival rate between treatment groups, assuming a HR [ipilimumab vs DTIC] of 0.67. 
Under an exponential distribution, this hazard ratio (HR) would correspond to an 12 month median 
OS for the ipilimumab arm with an 8 month median OS in the DTIC arm8(or equivalently 25% 
and 12.5% in the ipilimumab and DTIC arm). The accrual duration is approximately 18 months, 
assuming a monthly rate of 10 subjects per month. The  primary analysis will be performed about 
42 months after the first subject is randomized.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods

Baseline period:

Baseline evaluations or events will be defined as evaluations or events that occur before
the date and time of the first dose of study treatment. Evaluations on the same date and
time of the first dose of study treatment will be considered as baseline evaluations.

In cases where the time (onset time of event or evaluation time and dosing time) is missing 
or not collected, the following definitions will apply:
Pre-treatment AEs will be defined as AEs with an onset date prior to but not including 
the day of the first dose of study treatment.
Baseline evaluations (laboratory tests, etc.) will be defined as evaluations with a date 
on or prior to the day of first dose of study treatment.
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If there are multiple valid assessments, the assessment that is closest to day (and time if collected) 
of the first dose of study treatment will be used as the baseline in the analyses. If multiple 
assessments are collected on the same date (and time, if collected), the assessment with the latest 
database entry date (and time, if collected) will be considered as baseline, unless mentioned 
otherwise.

Post baseline period:

On-treatment AEs will be defined as AEs with an onset date and time on or after the date
and time of the first dose of study treatment (or with an onset date on or after the day of
first dose of study treatment if time is not collected or is missing). For subjects who are off 
study treatment, AEs will be included if event occurred within a safety window of 90 days
after the last dose of study treatment. No ‘subtracting rule’ will be applied when an AE 
occurs both pre-treatment and posttreatment with the same preferred term and grade.

On-treatment evaluations (laboratory tests, etc.) will be defined as evaluations taken after 
the day (and time, if collected and not missing) of first dose of study treatment. For subjects 
who are off study treatment, evaluations should be within a safety window of 90 days after 
the last dose of study treatment.
6.2
Treatment Regimens
The treatment group “as randomized” will be retrieved from the IVRS system

Arm A: ipilimumab

Arm B: DTIC
The treatment group “as treated” will be the same as the arm randomized by IVRS. However, if 
a subject received the incorrect drug for the entire period of treatment, the subject’s treatment 
group will be defined as the incorrect drug the subject actually received.
6.3
Populations for Analyses
The statistical analyses in this study will be defined with respect to the following data sets.
All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IVRS. Subject disposition will be based on all enrolled subjects.
All Randomized Subjects: All enrolled subjects who were randomized to a treatment arm 
(ipilimumab or DTIC). Unless otherwise indicated, analyses of most of study population and 
efficacy endpoints will be based on all randomized subjects and will be performed using the 
treatment group as randomized (i.e. on an intent-to-treat basis). Analyses of QoL will also be based 
on the all randomized subjects population: subjects with both baseline and on-study measurements 
will contribute to the analyses of change at on-study time-points.
Response Evaluable Subjects: All randomized subjects who have measurable disease (i.e., at 
least one measurable lesion) at baseline.
All Treated Subjects: All subjects who received at least one dose of treatment with ipilimumab
or DTIC. Unless otherwise specified, analyses of safety and extent of exposure will be based on 
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all treated subjects. Analyses of all treated subjects will be performed using the treatment group as 
treated. 
Pharmacokinetic Subjects: All available pharmacokinetic data from subjects who received 
ipilimumab will be included.
ADA Evaluable Subjects: All treated subjects with baseline and at least one post-baseline 
ipilimumab immunogenicity assessment
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7
STATISTICAL ANALYSES
7.1
General Methods
No interim analyses are planned for this study. The final analysis will be performed when a 
minimum of 2 year follow-up is reached by all randomized subjects.
Unless otherwise noted, the bulleted titles in the following subsections describe tabulations of
discrete variables, by the frequency and proportion of subjects falling into each category, grouped 
by treatment (with total). Percentages given in these tables will be rounded to the first decimal and, 
therefore, may not always sum to 100%. Percentages less than 0.1 will be indicated as ‘< 0.1’.
Continuous variables will be summarized by treatment group (with total) using the mean, standard 
deviation, median, minimum and maximum values. Subject listings will be produced to 
accompany the tabulations. Time-to-event variables (e.g. time-to resolution) will be analyzed 
using the Kaplan-Meier technique. When specified, the median will be reported along with 80% 
CI using Brookmeyer and Crowley method9 (using log-log transformation for constructing the 
confidence intervals). The conventions to be used for imputing partial dates for analyses requiring 
dates are described in Section 8.
Frequency tables of subject characteristics and subset analyses of efficacy endpoints (including
those by M-substage and BRAF mutation status) will be based on the assessment recorded on the
baseline CRF. However, stratified analyses will be based on the variables used by the IVRS to
randomize the subject.
Assessments taken during re-induction and subsequent progression follow-up phase will not 
contribute to derived endpoints, such as BOR or PFS, since these assessments are necessarily 
following an initial progression. However exploratory version of these endpoints corresponding to 
the administration of re-induction therapy may be performed (if there are sufficient data) - details
will be provided in the DPP.
All statistical analyses will be carried out using SAS software (SAS Institute, Cary, North Carolina, 
USA), unless otherwise noted.
7.2
Study Conduct
Summaries of study conduct will be based on all randomized subjects.
7.2.1
Accrual

Accrual by country and site

Accrual by region

Accrual by month randomized
7.2.2
Protocol Deviations
Each subject’s data will be examined for deviation from protocol criteria (including violation of
eligibility criteria and on-study deviations). ‘Significant’ deviations include those that could have
an impact on the primary results of the study, those of ethical concern and those which pose a 
safety risk to the subject. The ‘Relevant’ deviations are those ‘Significant” deviations that 
significantly affect interpretability of the study results. (Subjects who never received their 
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randomized treatment [at least one dose] will also be considered relevant deviations.) Subjects 
with relevant deviations will be determined programmatically (based on eCRF or central lab data). 
Only programmable relevant deviations will be summarized and listed by the statistical team. 
Programmable relevant deviation criteria are given in Table 7.2.2-1.
Table 7.2.2-1:
Relevant Protocol Deviation Criteria
Timeframe
Deviation 
Type
Protocol Deviation
Specification
E1
Pretreatment
Eligibility
Subjects with wrong diagnosis: Disease Stage at study entry is 
not Stage IV malignant melanoma
E2
Pretreatment
Eligibility
Subjects with ECOG PS not equal to 0 or 1 during screening 
period. 
E3
Pretreatment
Eligibility
Subject has no lesion (measurable or non-measurable) at 
screening
P1
On treatment
Not 
Discontinued
On-treatment laboratory test results that do not meet protocol-
specified re-treatment criteria: ALT, AST, TBILI
P2
On treatment
Not 
Discontinued
Treated subjects whose study drug dosing continued after 
experiencing drug-related AEs requiring permanent 
discontinuation per protocol.
P3
On treatment
Incorrect 
Dosing
Dosing not delayed for Gr 3 or higher skin AE regardless of 
causality 
P4
On treatment
Incorrect 
Dosing
Dosing not started within 3 days of randomization
P5
On treatment
Incorrect 
Dosing 
Treatment assignment as randomized different from actual 
treatment given (as per Section 6.2)
P6
 
 
 
 
 
 
 
Relevant deviations will be summarized and will be listed by subject.
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7.3
Study Population
Summaries of study population will be based on all randomized subjects except: subject 
disposition (based on all enrolled subjects), time from advanced disease diagnosis to first dose of 
study therapy (based on all treated subjects).
7.3.1
Subject Disposition

Disposition of enrolled subjects (number of subjects randomized, treated, not treated [with 
reason])
7.3.2
Demography and Subject Characteristics

Age (< 65, 65; summary statistics)

The age of a subject is the truncated difference in years between the date of the informed 
consent and the date of birth, plus 1 day.

Height (summary statistics)

Weight (summary statistics)

Gender (male, female)

ECOG performance status (0, 1)

M-substage at study entry (M1a, M1b, M1c)

Baseline LDH (ULN, > ULN)

Baseline LDH (2 ULN, > 2 ULN)

BRAF mutation status (positive, negative, unknown)
The following summaries of factors used in IVRS to stratify subjects will be produced.

M-substage stratification factor (M1a/M1b, M1c) x BRAF mutation status (yes, no)

M-substage: stratification factor compared to CRF (M1a/M1b, M1c)

BRAF mutation status: stratification factor compared to CRF (yes, no)
7.3.3
Medical History

General medical history (head, eyes, ears, nose, throat; cardiovascular; peripheral vascular; 
respiratory; gastrointestinal; hepatobiliary; renal; genitourinary; endocrine-metabolic; 
hematologic-lymphatic; 
musculoskeletal; 
dermatologic; 
neurologic; 
psychiatric; 
immunology/allergies; neoplasia; alcohol use; tobacco use; drug abuse)
7.3.4
Disease Characteristics

Time from advanced disease diagnosis to first dose of study therapy (summary statistics)

Baseline TA (site of disease, number of disease sites)

Baseline  target lesions (number and site of target lesions, procedures for evaluating target 
lesions; summary statistics and quartiles of sum of reference diameters of target lesions)

TAs on or prior to first dose date will be considered as baseline. The latest assessment for 
each lesion will be considered.

Melanoma subtype (mucosal, cutaneous, acral, ocular/uveal, and other)
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7.3.5
Prior Therapy

Prior therapy (systemic cancer, radiotherapy, surgery related to cancer)

Duration of prior systemic therapy (summary statistics)
7.3.6
Clinical Complaints and Findings
Events with onset prior to the date of first dose will be examined (whether recorded on the pre-
treatment events CRF or on the on-treatment adverse events CRF).

Pre-treatment events (worst CTC grade of any event and of events by SOC)
7.3.7
Baseline Laboratory Examinations

Baseline hematology (CTC grade for hemoglobin, WBC, ANC, platelet count, ALC)

Baseline liver function (CTC grade for ALT, AST, total bilirubin, ALP)

Baseline renal function (CTC grade for creatinine)

Baseline pancreatic function: (CTC grade for amylase)
7.4
Extent of Exposure
Summaries of exposure will be based on all treated subjects, except for the summary for 
subsequent therapies (based on all randomized subjects).
7.4.1
Administration of Study Therapy

Time from randomization to first dose of ipilimumab (0 to 3 days, > 3 to 7, > 7 to 14, > 14 to 
21, > 21 to 28, > 28)

Number of doses of study therapy (summary statistics)

Cumulative dose of study therapy (summary statistics) 
Cumulative dose of ipilimumab/dacarbazine in mg is defined as the sum of all calculated doses 
(mg) at each dosing. Cumulative dose of ipilimumab in mg/kg and dacarbazine in mg/m2 is 
defined as the sum of all doses (in mg/kg and mg/m2 respectively) received by the subject. 
Ipilimumab dose in mg/kg is calculated as the dose in mg divided by the most recent weight in 
kg prior to infusion. If the subject’s weight is missing, the last observation carried forward 
approach will be used.
Dacarbazine dose in mg/m2 is calculated as the dose in mg divided by the most recent body 
surface area (BSA) prior to infusion. BSA is derived from most recent weight and baseline 
height. If the subject’s weight is missing, the last observation carried forward approach will be 
used.
Cumulative dose will be listed by subject.
7.4.2
Discontinuation from Induction Phase
Failure to complete the (re-)induction phase will be tabulated.

Number of subjects who completed or failed to complete (with reason) the 
(re-)induction phase.
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
Discontinuation from study therapy in induction phase (subjects with study therapy
discontinued, reason for discontinuation).

Discontinuation from ipilimumab in re-induction phase (subjects with study therapy
discontinued, reason for discontinuation).
7.4.3
Interruption of Infusion or Delay of Study Therapy
An infusion interruption refers to an interruption of the infusion of study therapy, whether or not 
the infusion is resumed. A dose delay refers to a delay in the administration of ipilimumab (but 
not a discontinuation thereof) relative to the protocol schedule. A dose omission refers to an
omission in the administration of DTIC (but not a discontinuation thereof) relative to the protocol 
schedule.

Infusion interruption in induction phase (subjects with at least one interrupted dose, reason for 
first dose interruption, number of interruptions).

Infusion rate reduction in induction phase (subjects with at least one infusion with IV rate 
reduced, reason for first infusion IV rate reduced, number of infusions with IV rate reduced).

Dose delay of ipilimumab in induction phase (subjects with at least one delayed dose, reason 
for first dose delay, number of delays).

Dose omission of DTIC in induction phase (subjects with at least one omitted dose, reason for 
first dose omitted, number of omissions).

Infusion interruption of ipilimumab in re-induction phase (subjects with at least one interrupted 
dose, reason for first dose interruption, number of interruptions).

Infusion rate reduction of ipilimumab in re-induction phase (subjects with at least one infusion 
with IV rate reduced, reason for first infusion IV rate reduced, number of infusions with IV 
rate reduced).

Dose delay of ipilimumab in re-induction phase (subjects with at least one delayed dose, reason 
for first dose delay, number of delays).
 
 
 
7.4.5
Other On-Study Therapy 
Non-protocol-specified medical treatment procedures which occur on-study (i.e. on or after the 
first day of study therapy and within 90 days following the last dose of study therapy) will be 
summarized and listed.

On-study surgery (with reason)

On-study radiotherapy (with reason)
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7.4.6
Subsequent Therapy
Therapies received subsequent to discontinuation of study therapy will be summarized and listed.

Frequency of subsequent systemic therapies by medication class and generic name

Frequency of subsequent systemic therapy type (any, and classes, e.g.: immunotherapy only, 
chemotherapy only, immunotherapy and chemotherapy, other)

Frequency of subsequent surgery

Frequency of subsequent radiotherapy

Time from randomization to first subsequent therapy (median, range)

Listing of subsequent therapies (including dates of therapy)
7.5
Efficacy
All hypothesis testing will be two-sided and will be based upon a significance level of 0.20.
No type I error rate multiplicity adjustment will be made for secondary endpoint testing. P-values
associated with the comparisons of OS, DCR and PFS will be purely descriptive in nature. All
efficacy analyses will be based on all randomized subjects, as randomized, unless indicated.
7.5.1
Survival Rates at Specified Time Points
Yearly survival rates will be calculated for each treatment group using the KM product-limit 
method, along with their corresponding log-log transformed 80% CIs10.
Two-year survival rate is the primary endpoint. The survival rate at 2 years will be compared 
between treatment group using a chi-square test stratified by M substage (M1a+M1b versus M1c) 
and BRAF mutation status (yes vs no), as recorded in the IVRS. The stratified chi-square test is 
defined by the following formula:
߯ଶ=
൫∑
ܵመଵ௦(ݐ) −ܵመଶ௦(ݐ)
௠
௦ୀଵ
൯
ଶ
∑
ܸ෠ቀܵመଵ௦(ݐ)ቁ+ ܸ෠ቀܵመଶ௦(ݐ)ቁ
௠
௦ୀଵ
,
where ܵመ௞௦(ݐ) and V෡ቀS෠୩ୱ(t)ቁbe the Kaplan-Meier estimate and variance based on the Greenwood 
formula for the sth stratum in the kth treatment group at time t.
7.5.1.1
Subgroup Analyses
Two-year survival rates along with two-sided 80% CI based on the log-log transformation will be 
presented within subsets defined by information recorded on the baseline CRF.
This summary and comparison based on the unstratified chi-square test will be provided for the 
following subgroups:
•
by age (< 65, 65)
•
by gender (male, female)
•
by M-Substage at study entry (M1a/M1b, M1c)
•
by ECOG performance status (0, 1)
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•
by baseline LDH (ULN, > ULN)
•
by baseline LDH (2 ULN, > 2 ULN)
•
by BRAF mutation status (positive, negative, unknown)
•
by subtype (acral, cutaneous, other)
In case a subgroup includes less than 10 subjects, the analysis for the given subgroup will not be 
carried out (or the possibility of combining subgroups will be considered).
7.5.1.2
Sensitivity Analyses
The following analyses will be conducted

An unstratified chi-square test will be performed to compare survival rate at 2 years after 
randomization between treatment groups

The stratified and unstratified chi-square tests based on the modified OS accounting for 
subsequent PD-1/PD-L1 therapy.
7.5.2
Overall Survival
OS within treatment group, estimated using the KM product-limit method, will be plotted. 
Summary tables will report the median OS together with a two-sided 80% confidence interval (CI)
for the median, calculated using the method of Brookmeyer and Crowley. All available events 
(deaths) in the database will contribute to the analysis of OS.
The extent of follow-up within treatment group, defined as the time between randomization and 
last known alive date whether status is alive or dead, will be summarized, as will be the currentness 
of follow-up, defined as the time between last known alive date and data cut-off date (defined by 
last patient last visit date). Subjects who died and subjects with last known date alive on or after 
data cut-off date will be considered as current.

Summary of OS

Extent of follow-up

Currentness of follow-up
7.5.2.1
Comparison between Treatment Groups
OS is the  key secondary efficacy endpoint. The distribution of OS will be compared between
treatment groups using a two-sided log-rank test stratified by M substage (M1a+M1b versus M1c) 
and BRAF mutation status (yes vs no), as recorded in the IVRS. The HR, and its associated two-
sided 80% CI, of ipilimumab to DTIC will be estimated using a Cox proportional hazards model, 
stratified by the factors described above, and with treatment as the single covariate.

Comparison of OS
7.5.2.2
Subgroup Analyses
OS will be summarized within subsets defined by information recorded on the baseline CRF (with 
two-sided 80% CI for the median OS calculated via the method of Brookmeyer and Crowley). For 
informal comparisons of OS within these subsets, the HR, and its 80% two-sided CI, of ipilimumab 
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to DTIC will be computed using an unstratified Cox proportional hazards model with treatment as 
the single covariate.
This summary and comparison will be provided for the following subgroups:

by age (< 65, 65)

by gender (male, female)

by M-Substage at study entry (M1a/M1b, M1c)

by ECOG performance status (0, 1)

by baseline LDH (ULN, > ULN)

by baseline LDH (2 ULN, > 2 ULN)

by BRAF mutation status (positive, negative, unknown)

by subtype (acral, cutaneous, other)
In case a subgroup includes less than 10 subjects, the analysis for the given subgroup will not 
be carried out (or the possibility of combining subgroups will be considered).
7.5.2.3
Sensitivity Analyses
An unstratified log-rank test will be performed to compare OS between treatment groups. The HR 
of ipilimumab to DTIC and the corresponding two-sided 80% CI will also be estimated using an 
unstratified, multivariate Cox proportional hazards model, with covariates for stratification factors 
(from CRF), as well as for treatment group.

Comparison of OS using unstratified log-rank test

Comparison of OS using multivariate Cox model

Furthermore, the following analyses will be presented for the modified OS (defined in 
Section 4.2.2):

Summary of OS accounting for subsequent PD-1/PD-L1 therapy

Comparison of OS accounting for subsequent PD-1/PD-L1 therapy

KM plot of OS accounting for subsequent PD-1/PD-L1 therapy
7.5.3
Progression-Free Survival
PFS is one of the secondary endpoints. Similar methods as defined for OS will be used for PFS.
PFS within treatment group, estimated using the KM product-limit method, will be plotted. The 
plot will display the median PFS, together with a two-sided 80% CI for the median, calculated 
using the method of Brookmeyer and Crowley.
For the comparison of PFS between the treatment groups, a two-sided log-rank test, stratified by 
M substage (M1a+M1b versus M1c) and BRAF mutation status (yes vs no), as recorded in the 
IVRS, will be used. 
The HR, and its two-sided 80% CI, of ipilimumab to DTIC will be estimated using a Cox 
proportional hazards model, stratified by the factors described above, and with treatment as the 
single covariate.
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
Summary of PFS 

Comparison of PFS
7.5.3.1
Sensitivity Analyses
An unstratified log-rank test will be performed to compare PFS between treatment groups. The 
HR of ipilimumab to DTIC and the corresponding two-sided 80% CI will also be estimated using 
an unstratified, multivariate Cox proportional hazards model, with covariates for stratification 
factors (from CRF), as well as for treatment group.

Comparison of PFS using unstratified log-rank test

Comparison of PFS using multivariate Cox model

Furthermore, the following analyses will be presented for the modified PFS variables (defined 
in Section 4.2.3):

Summary of PFS accounting for early TAs in DTIC group

Comparison of PFS accounting for early TAs in DTIC group

KM plot of PFS accounting for early TAs in DTIC group
7.5.4
Disease Control Rate
Exact, two-sided 80% CI for DCR within treatment group will be calculated using the method of 
Clopper and Pearson11.
For the comparison of DCR between treatment groups, a Cochran-Mantel-Haenszel (CMH) test 
with an associated odds ratio estimate and exact two-sided 80% CI, stratified by M substage 
(M1a+M1b versus M1c) and BRAF mutation status (yes vs. no), as recorded in the IVRS, will be 
applied. 

Summary of DCR (primary definition)

Comparison of DCR (primary definition)

Summary of DCR (per protocol definition)

Comparison of DCR (per protocol definition)
7.5.5
Best Overall Response

Summary of BOR (primary definition)

Summary of BOR (per protocol definition)
7.5.6
Best Overall Response Rate
An exact, two-sided 80% CI for BORR within treatment group will be calculated using the method 
of Clopper and Pearson.

Summary of BORR (primary definition)

Summary of BORR (per protocol definition)
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7.5.7
Duration of Response
The DoR in subjects with a BOR of CR or PR, estimated using the KM product-limit method, will 
be plotted. The plot will display the median duration, together with a two-sided 80% CI for the 
median, calculated using the method of Brookmeyer and Crowley.

Summary of DoR (primary definition)

Summary of DoR (per protocol definition)
7.5.8
Duration of Stable Disease
The DoSD in subjects whose BOR is SD, estimated using the KM product-limit method, will be 
plotted. The plot will display the median duration, together with a two-sided 80% CI for the 
median, calculated using the method of Brookmeyer and Crowley.

Summary of DoSD (primary definition)

Summary of DoSD (per protocol definition)
7.6
Safety
Summaries of safety will be based on all treated subjects by treatment arm, except for the resource 
utilization (based on all randomized subjects).
7.6.1
Adverse Events
Adverse Events, Serious Adverse Events
The following summary tables of AEs and SAEs will be restricted to events occurring in the on-
study phase (see Section 4.3.1.1).

On-study phase AEs (worst CTC grade [Any grade, 3-4, 5] of any event and of events by SOC) 

On-study phase AEs (worst CTC grade [1, 2, 3, 4, 5, unknown, any grade] of any event and of 
events by SOC) 

On-study non-serious AEs occurring in at least 5% of subjects (worst CTC grade [Any grade, 
3-4, 5] of any event and of events by SOC) 

On-study phase SAEs (worst CTC grade [Any grade, 3-4, 5] of any event and of events by 
SOC)

On-study phase SAEs (worst CTC grade [1, 2, 3, 4, 5, unknown, any grade] of any event and 
of events by SOC)

On-study phase drug-related AEs (worst CTC grade [Any grade, 3-4, 5] of any event and of 
events by SOC) 

On-study phase drug-related AEs (worst CTC grade [1, 2, 3, 4, 5, unknown, any grade] of any 
event and of events by SOC)

On-study phase drug-related SAEs (worst CTC grade [Any grade, 3-4, 5] of any event and of 
events by SOC) 

On-study phase drug-related SAEs (worst CTC grade [1, 2, 3, 4, 5, unknown, any grade] of 
any event and of events by SOC) 
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
On-study phase AEs leading to discontinuation of ipilimumab (worst CTC grade [Any grade, 
3-4, 5] of any event and of events by SOC)

On-study phase AEs leading to discontinuation of ipilimumab (worst CTC grade [1, 2, 3, 4, 5, 
unknown, any grade] of any event and of events by SOC)
Listings by subject will be produced for all AEs (including drug-related AEs and those leading to 
discontinuation of ipilimumab), all AEs leading to discontinuation of ipilimumab (including drug-
related AEs), all SAEs (including drug-related SAEs).
Immune-Related Adverse Events
Summaries irAEs will be based on all treated subjects and will use the pre-defined list of MedDRA 
high-level group terms, high-level terms and preferred terms that is current at the time of analysis. 
(APPENDIX 1 contains the most recent version of the list, version 20.0)
The following summary tables of irAEs will be restricted to events occurring in the on-study phase
(see Section 4.3.1.1).

On-study phase irAEs (worst CTC grade [Any grade, 3-4, 5] of any event and of events by 
SOC) 

On-study phase irAEs (worst CTC grade [1, 2, 3, 4, 5, unknown, any grade] of any event and 
of events by SOC) 

On-study phase irAEs by subcategory (worst CTC grade [Any grade, 3-4, 5] by subcategories 
of GI, liver, skin, endocrine, neurological, other) 

On-study phase irAEs by subcategory (worst CTC grade [1, 2, 3, 4, 5, unknown, any grade] 
by subcategories of GI, liver, skin, endocrine, neurological, other) 

Time to onset of on-study phase grade 3-5 irAEs by subcategory (GI, liver, skin, endocrine, 
neurological).

Time to resolution of on-study phase grade 3-4 irAEs by subcategory (GI, liver, skin, 
endocrine, neurological)

Number of episodes of on-study phase grade 3-4 irAEs by subcategory (GI, liver, skin, 
endocrine, neurological)
Listings by subject will be produced for all on-study and post-study irAEs (including steroid 
therapy received and details of resolution).
Immune-Mediated Adverse Reactions
Summaries of imARs will be based on all treated subjects.
The following summaries for on-study phase imARs will be provided (for subcategories as 
specified in the core imAR SAP):

Summary of subjects with worst grade of grade 2 on-study phase imAR

Summary of subjects with worst grade of grade 3-4 on-study phase imAR
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
Summary of subjects with worst grade of grade 5 on-study phase imAR

Summary of subjects with worst grade of grade 2-5 on-study phase imAR and outcome of 
hospitalization by subcategory (worst CTC grade [2+, 3-4, 5] by subcategories)

Summary of subjects with worst grade of grade 2-5 on-study phase imAR who received blood 
transfusion by subcategory (worst CTC grade [2+, 3-4, 5] by subcategories)

Time to first onset (any grade) of imARs for subjects with worst grade of grade 2-5 on-study
phase imAR by subcategory 

Time to resolution of imARs for subjects with worst grade of grade 2-5 on-study phase imARs 
by outcome of resolution by subcategory 

Time to resolution of imARs for subjects with worst grade of grade 2-5 on-study phase imARs 
by use of systemic corticosteroids and outcome of resolution by subcategory 

Time to resolution of imARs for subjects with worst grade of grade 2-5 on-study phase imARs 
by use of high dose systemic corticosteroids and outcome of resolution by subcategory 

Time to resolution of imARs for subjects with worst grade of grade 2-5 on-study phase
dermatitis imARs by use of topical corticosteroids and outcome of resolution

imARs leading to study drug discontinuation by use of high dose systemic corticosteroids for 
subjects with worst grade of grade 2-5 imARs, by subcategory

Distribution of outcome (last reported grade) of imARs for subjects with worst grade of grade 
2-5 on-study phase imARs by subcategory 

Distribution of outcome (last reported grade) of imARs for subjects with worst grade of grade 
2-5 on-study phase imARs by use of systemic corticosteroids by subcategory 

Distribution of outcome (last reported grade) of imARs for subjects with worst grade of grade 
2-5 on-study phase imARs by use of high dose systemic corticosteroids by subcategory 

Distribution of outcome (last reported grade) of imARs for subjects with worst grade of grade 
2-5 on-study phase dermatitis imARs by use of topical corticosteroids

Distribution of outcome (last reported grade) of imARs for subjects with worst grade of grade 
3-5 on-study phase imARs by subcategory 

Duration of administration of systemic corticosteroids for imARs for subjects with worst grade 
of grade 2-5 on-study phase imARs by subcategory 

Duration of administration of systemic corticosteroids for imARs for subjects with worst grade 
of grade 2-5 on-study phase imARs by high dose systemic corticosteroids, by subcategory 

Duration of administration of topical corticosteroids for imARs for subjects with worst grade 
of grade 2-5 on-study phase dermatitis imARs

Distribution of immunosuppression administration for imARs for subjects with worst grade of
grade 2-5 imARs by subcategory 

Distribution of administration of hormonal therapy for immune-mediated endocrinopathies for 
subjects with worst grade of grade 2-5 on-study phase immune-mediated endocrinopathies by 
use of high dose of systemic corticosteroids by subcategory 

Summary of Dosage of Systemic Corticosteroids for Subjects with Worst Grade of Grade 2-5 
imARs, by subcategory 
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
Number of Subjects Receiving High Dose Systemic Corticosteroids for any imAR for Subjects 
with Worst Grade of Grade 2-5 imARs 

Cross-tabulation of imAR Grade at First Onset Versus Worst imAR Grade, by Class 

Time From First Non-Severe (Grade 1 or 2) to First Severe (Grade 3-5) Onset for imARs, by 
Class 
For endocrinopathies only: 

Time on Hormonal Replacement Therapy for Endocrinopathy imARs, by type of therapy 
(adrenal replacement therapy [identified as systemic corticosteroids (identified by the BMS 
physicians) used for adrenal replacement (as indicated by the investigator on the concomitant 
medication CRF, use=adrenal insufficiency)], thyroid medication, testosterone medication) 
and by medication status (therapy discontinued, therapy ongoing) 

Distribution of Outcome (Last Reported Grade) of Endocrinopathy imARs for Subjects with 
Worst Grade of Grade 2-5 imARs, by Hormonal Replacement Therapy Status (adrenal 
replacement therapy discontinued, adrenal replacement therapy ongoing, hormonal 
replacement therapy other than adrenal replacement therapy, no hormonal replacement 
therapy) 

Serious Endocrinopathy imARs for Subjects with Worst Grade of Grade 2-5 Endocrinopathy 
imARs, by Hormonal Replacement Therapy Status (adrenal replacement therapy discontinued, 
adrenal replacement therapy ongoing, hormonal replacement therapy other than adrenal 
replacement therapy, no hormonal replacement therapy) 

Listing of Endocrinopathy imARs and Hormonal Replacement Therapy status for subjects with 
on-study endocrinopathy imARs 

Time on Systemic Corticosteroid for Endocrinopathy imARs, by medication status (therapy 
discontinued, therapy ongoing) 
Present the table for 3 categories:

ANY SYSTEMIC CORTICOSTEROID

SYSTEMIC CORTICOSTEROIDS USED FOR ADRENAL REPLACEMENT 

SYSTEMIC 
CORTICOSTEROIDS 
FOR 
USE 
OTHER 
THAN 
ADRENAL 
REPLACEMENT

Listing of Time on Systemic Corticosteroids for Endocrinopathy imARs, for subjects with on-
study endocrinopathy imARs, by medication status (therapy discontinued, therapy ongoing)
Present the listing for 2 categories:

SYSTEMIC CORTICOSTEROIDS USED FOR ADRENAL REPLACEMENT 

SYSTEMIC 
CORTICOSTEROIDS 
FOR 
USE 
OTHER 
THAN 
ADRENAL 
REPLACEMENT

Distribution of Outcome (Last Reported Grade) of Endocrinopathy imARs by Use of Systemic 
Corticosteroids for Subjects with Worst Grade of Grade 2-5 Endocrinopathy imARs
Present the table for 3 categories:

SYSTEMIC CORTICOSTEROIDS USED FOR ADRENAL REPLACEMENT 
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
SYSTEMIC 
CORTICOSTEROIDS 
FOR 
USE 
OTHER 
THAN 
ADRENAL 
REPLACEMENT

NO SYSTEMIC CORTICOSTEROIDS

Time to Resolution for Endocrinopathy imARs by use of Systemic Corticosteroids and by 
Outcome of Resolution for Subjects with Worst Grade of Grade 2-5 Endocrinopathy imARs
Present the table for 3 categories:

SYSTEMIC CORTICOSTEROIDS USED FOR ADRENAL REPLACEMENT 

SYSTEMIC 
CORTICOSTEROIDS 
FOR 
USE 
OTHER 
THAN 
ADRENAL 
REPLACEMENT

NO SYSTEMIC CORTICOSTEROIDS
The following listings will be produced for all class imARs: 

Listing of On-Study and Post-Study imARs

For events with imAR=Yes or Unknown or No, and including reasons for imAR=Yes/No 

Post induction events at class level (i.e., events that occur for the first time after the 
induction period and prior to the start of the re-induction period without any events in the 
same class that occurred during the induction period) will be flagged. 

Novel re-induction events will be flagged. 

This listing will include all classes: enterocolitis, dermatitis, hepatitis, endocrinopathies, 
neuropathies, other. 

Present all treatment regimens. 

Listing of Time to Onset and Resolution of on-study imAR

This listing will include classes: enterocolitis, dermatitis, hepatitis, endocrinopathies, and 
neuropathies. 

Present only ipilimumab containing regimens. 

Listing of imARs Initiated After 90 Days of Last Dose Corresponding to on-study imARs Class

This listing will include classes: enterocolitis, dermatitis, hepatitis, endocrinopathies, and 
neuropathies. 

Present only ipilimumab containing regimens. 

Listing of New imARs Initiated During High Dose Systemic Corticosteroid Treatment of Early 
Onset imARs for subjects with on-study imAR

This listing will include all classes: enterocolitis, dermatitis, hepatitis, endocrinopathies, 
neuropathies, and other. 

Present only ipilimumab containing regimens. 
The following summaries for novel re-induction imARs will be provided:

Summary of subjects with worst grade of grade 2 imAR

Summary of subjects with worst grade of grade 3-4 imAR

Summary of subjects with worst grade of grade 5 imAR
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Multiple Events Analyses
For the multiple event analyses, the following summary tables will be provided:

A table showing the total number and rate (exposure-adjusted) of occurrences for all on-study 
AEs occurring in at least 5% of the subjects treated 

A table showing the total number and rate (exposure-adjusted) of occurrences for all on-study 
irAEs 

A table showing the number of subjects experiencing an on-study AE once or multiple times 
No formal comparisons/statistical testing will be performed. A listing will be produced that 
displays the unique instances of all AEs, i.e. after duplicates have been eliminated and overlapping 
and contiguous occurrences of the same event have been collapsed.
7.6.2
Clinical Laboratory Evaluations
Laboratory parameters will be analyzed based on all treated subjects with an on-study test 
conducted. For the list of laboratory parameters, see Section 7.3.7.

On-study hematology (worst CTC grade)

Baseline vs. on-study hematology (worst CTC grade) 

On-study liver function (worst CTC grade) 

Baseline vs. on-study liver function (worst CTC grade) 

On-study renal function (worst CTC grade) 

Baseline vs. on-study renal function (worst CTC grade)

On-study pancreatic function (worst CTC grade) 

Baseline vs. on-study pancreatic function (worst CTC grade)
7.6.3
Deaths
Deaths will be analyzed based on all treated subjects.

All deaths (with reason) 

Deaths within 30 days of last dose received

Deaths within 90 days of last dose received 
All deaths, together with the reason, will be listed by subject; deaths occurring within 
30 days following the last day of study treatment, and within 90 days following the last day of 
study treatment will be indicated.
7.6.4
Resource Utilization
The number of subjects hospitalized, with primary reason for hospitalization, will be tabulated, as 
will be type of non-protocol-specified visit. Summary statistics (N, mean with SD, median, 
minimum, maximum) will be provided by treatment group for number of hospitalizations per 
subject, length of stay, number of non-protocol-specified visits per subject. 

Summary of hospitalization
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Summary of non-protocol-specified visits
7.6.5
Immunogenicity
A listing will be provided of all available ADA assessments. The frequency of ADA positive 
subjects and of neutralizing ADA positive subjects will be tabulated.
7.7
Pharmacokinetic Analyses
PK parameters will be summarized and listed. PK data obtained from this study may be pooled
with data from other studies to perform an integrated population PK analysis (including assessment 
of covariate effects on PK), as well as exposure-response analysis for selected safety and efficacy 
endpoints. These analyses will be described in (a) separate report(s).
7.8
Health-Related Quality of Life
At each time point for analysis, the number of subjects who completed the questionnaires will be 
reported as a percentage of eligible subjects. Change from baseline analyses will be based on all 
randomized subjects who have a baseline measurement and an on-study assessment for the time-
point of interest.
7.8.1
EORTC QLQ-C30
The following descriptive analyses will be conducted: 

EORTC QLQ-C30 questionnaire completion rate, defined as the proportion of questionnaires 
actually received out of the expected number (i.e., number of subjects on treatment or in follow 
up), will be calculated and summarized for each assessment time point by treatment group.

Mean scores and post-baseline score changes will be summarized using descriptive statistics 
(N, mean with SD and 80% CI, median, first and third quartiles, minimum, maximum) for all 
scales at each assessment time point. 

A line graph summarizing the mean post-baseline score changes will be produced for all scales.
7.8.2
EuroQolEQ-5D-3L
The following descriptive analyses will be conducted: 

EQ-5D-3L questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number (i.e. number of subjects on treatment or in follow up), will 
be calculated and summarized for each assessment time point by treatment group. 

A by-subject listing of the level of problems in each dimension, corresponding EQ-5D-3L
health state (i.e., 5-digit vector), EQ-5D-3L utility index score, and EQ-5D-3L VAS score will 
be provided.

Proportion of subjects reporting problems for the 5 EQ-5D-3L dimensions at each assessment 
timepoint will be summarized by level of problem and by treatment group. Percentages will be 
based on number subjects assessed at assessment time point.

For the EQ-5D-3L utility index and VAS scores, separately:
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
Mean score and mean change from baseline at each assessment time point will be 
summarized by treatment group using descriptive statistics (N, mean with SD and 80% CI, 
median, first and third quartiles, minimum, maximum).

A line graph summarizing the mean post-baseline score changes will be produced 
8
CONVENTIONS
Unless otherwise noted, the following conventions should be understood to apply. Further 
conventions may be detailed in the Data Presentation Plan.
The duration between two dates will be calculated as [later date] – [earlier date] + 1 day. Study 
day will be calculated as















.
,
1
,
,
medication
first
after
or
on
assessment
if
day
date
medication
first
date
assessment
medication
first
before
assessment
if
date
medication
first
date
assessment
Day
Assessment times will be calculated relative to the first date of study medication, i.e. Day 1.
Events will be considered as occurring within X days (e.g. deaths within 30 days, deaths and AEs 
within 90 days) of last dose of study medication if [event date] – [last dosing date] X. 
The following factors will convert days to months or years: 1 month = 30.4375 days, 
1 year = 365.25 days.
Conventions for Partial/Missing Dates
Unless specified otherwise the following conventions will be used for imputing partial dates:

If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day.

If both the day and the month are missing, "July 1" will be used to replace the missing 
information.

If a date is completely missing, it will be considered as missing.
For date of death:

If only the day of the month is missing, in principle the 1st of the month will be used to replace 
the missing day - but the imputed day of death will still be compared to the last known alive 
date (date of censoring for survival), and may be adjusted to ensure consistency.

If both the day and the month are missing, in principle "Jan 1" will be used to replace the 
missing information - but the imputed day of death will still be compared to the last known 
alive date (date of censoring for survival), and may be adjusted to ensure consistency.

If date is missing, death date will be imputed as the last known alive date + 1 day.
For date of progression:

If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day(*).
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
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
(*) In case the date of death is present (complete date), the imputed progression date will be 
compared with the date of death. The minimum of the (imputed progression date, date of death) 
will be considered as the date of progression.
For date of last tumor assessment:

If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day(*).

If the day and month are missing or a date is completely missing, it will be considered as 
missing.
(*) In case the date of death is present (complete date), the imputed date will be compared with 
the date of death. The minimum of the (imputed date, date of death) will be considered as the 
date of last tumor assessment.
Otherwise, missing values will not in general be imputed. Regardless of missing data, all subjects 
will contribute to the calculation of the following tumor response endpoints (as detailed in 
Sections 4.2.3-4.2.6): BORR and disease control rate (by inclusion in the denominators); and in 
the Kaplan-Meier analyses (by censoring, as appropriate) of DoR (for subjects with confirmed CR 
or PR), DoSD (for subjects whose BOR is SD) and PFS.
Conventions for EQ-5D:
The EQ-5D descriptive system will be converted into a single summary index score which 
provides a simple measure of health on a scale of 0 to 1 (0 = death and 1 = perfect health) as 
follows12:
X = 1 - 0.146016*MO2 - 0.557685*MO3 - 0.1753425*SC2 - 0.4711896*SC3 -
0.1397295*UA2 - 0.3742594*UA3 - 0.1728907*PD2 - 0.5371011*PD3 - 0.156223*AD2 
- 0.4501876*AD3 + 0.1395949*D1 - 0.0106868*I2^2 + 0.1215579*I3 + 0.0147963*I3^2,
where 

MO2, SC2, UA2, PD2, and AD2 are dummy variables for level 2 in dimensions mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression, respectively;

MO3, SC3, UA3, PD3, and AD3 are dummy variables for level 3 in dimensions mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression, respectively;

D1 is an ordinal variable: the number of movements away from Full health (1) beyond the first 
(i.e. it took on values ranging from 0 to 4);

I2 is an ordinal variable: the number of dimensions at level 2 beyond the first;

I3 is an ordinal variable: the number of dimensions at level 3 beyond the first.
9
CONTENT OF REPORTS
Study reports will be written corresponding to the final analysis of the study. The table, figure and 
listing outputs that will be produced are described in the Data Presentation Plan for the study.
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10
DOCUMENT HISTORY
Table 10-1:
Document History
Version
Author
Summary of Changes
1.0
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update 2-year OS rate as primary endpoint and OS as 
secondary endpoint
-Add clarifications in health related quality of life
-General updates for typos, inconsistencies, etc
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APPENDIX 1
IMMUNE-RELATED ADVERSE EVENT SEARCH CRITERIA 
VERSION 20.0 (APRIL 2017)
The following MedDRA terms (MedDRA version 20.0) will be used for generating irAE
AEs/SAEs among all adverse events reported by investigators as possibly, probably or certainly
related or with unknown causality (PTs from primary SOC will be used for multi-category PTs
with exception as noted). 
GI IRAEs
HLGT-Gastrointestinal haemorrhages NEC - except PT-mesenteric hematoma, PT mesenteric haemorrhage
HLGT-Gastrointestinal inflammatory conditions (1 new PT: Lymphocytic oesophagitis)
HLGT-Gastrointestinal ulceration and perforation  (2 new PTs: :Lower GI perforation, Upper GI 
perforation)
HLT-Diarrhoea (excl infective)
HLT-Stomatitis and ulceration
PT - Peritonitis
PT - Gastrointestinal wall thickening
Skin IRAEs
PT-Rash papular
PT- Rash pustular
PT - Macule
PT - Papule
PT - Folliculitis
PT - Pruritus genital
PT - Vulvovaginal pruritus
PT - Dermatitis acneiform
PT- Anal pruritus
PT- Ear pruritus
PT- Lip pruritus
PT- Alopecia
PT- Alopecia areata
HLT- Rashes, eruptions and exanthems NEC
HLT- Skin vasculitides
HLT-Pruritus NEC
HLT-Bullous conditions
HLT-Dermatitis and eczema
HLT-Dermatitis ascribed to specific agent (except Periarticular thenar erythema with onycholysis, 
Symmetrical drug-related intertriginous and flexural exanthema)
HLT-Erythemas
HLT-Exfoliative conditions
HLT-Granulomatous and deep cutaneous inflammatory conditions (except Annular elastolytic giant cell 
granuloma)
HLT-Hypopigmentation disorders
HLT-Pigmentation changes NEC (except Haemosiderin stain)
HLGT- Angioedema and urticaria
PT-Drug reaction with eosinophilia and systemic symptoms
PT Paraneoplastic dermatosis
Hepatic IRAEs
HLT-Cholestasis and jaundice
HLT-Hepatic enzymes and function abnormalities
HLT-Hepatic failure and associated disorders
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HLT-Hepatocellular damage and hepatitis NEC
HLT-Liver function analyses
PT- Liver sarcoidosis 
PT-Liver function test increased
Endocrine IRAEs
HLT-Adrenal cortical hypofunctions (1 new PT: Cortisol deficiency)
HLT-Adrenal cortical hyperfunctions (except PTs-Nelson’s syndrome, pseudoaldosteronism, alcoholic 
pseudocushing’s syndrome)
HLT-Anterior pituitary hypofunction (except PT-postpartum hypopituitarism) (1 new PT: Thyroid 
stimulating hormone deficiency)
HLT-Acute and chronic thyroiditis
HLT-Thyroid hyperfunction disorders
HLT-Thyroid hypofunction disorders
PT-Hypoparathyroidism
PT-endocrine disorder 
PT-Hypophysitis
PT-Lymphocytic hypophysitis
HLGT-Endocrine investigations (incl sex hormones)
HLGT-Endocrine disorders of gonadal function
HLGT-Gonadotrophin and sex hormone changes
PT - DIABETES MELLITUS
PT - DIABETES MELLITUS INADEQUATE CONTROL
PT - DIABETES WITH HYPEROSMOLARITY
PT - INCREASED INSULIN REQUIREMENT
PT - PANCREATOGENOUS DIABETES
PT - INSULIN-REQUIRING TYPE 2 DIABETES MELLITUS
PT - LATENT AUTOIMMUNE DIABETES IN ADULTS
PT - TYPE 1 DIABETES MELLITUS
PT - TYPE 2 DIABETES MELLITUS
PT - FULMINANT TYPE 1 DIABETES MELLITUS
PT - ACQUIRED LIPOATROPHIC DIABETES
PT - GLUCOSE TOLERANCE IMPAIRED
PT - HYPERGLYCAEMIA
PT - IMPAIRED INSULIN SECRETION
PT - IMPAIRED FASTING GLUCOSE
PT - HYPOINSULINAEMIA
PT - BLOOD GLUCOSE ABNORMAL
PT - BLOOD GLUCOSE INCREASED
PT - GLUCOSE TOLERANCE DECREASED
PT-Inappropriate thyroid stimulating hormone secretion 
PT-Malignant exophthalmos
PT-Premature menarche
Neurological IRAEs
PT- Cerebral sarcoidosis 
PT-Meningitis
PT-Meningitis aseptic
PT-Meningism
PT-Meningitis noninfective
PT-Peripheral motor neuropathy
PT-Peripheral sensory neuropathy
PT -Autoimmune neuropathy
PT- Cranial nerve disorder
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PT - Neuropathy peripheral
PT - Neuralgia
PT - Hyperaesthesia
PT - Hypoaesthesia
PT - Paraesthesia
PT - Facial paresis
PT - Facial spasm
PT - Motor dysfunction
PT - Radiculopathy
PT - Ocular myasthenia
PT- Encephalitis
PT- Noninfective encephalitis
PT- Noninfective encephalomyelitis
PT- NEUROSENSORY HYPOACUSIS
PT - ENCEPHALITIS AUTOIMMUNE 
HLT-Acute polyneuropathies
HLT-Neuromuscular junction dysfunction
PT - Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids
PT - Morvan syndrome
PT - Autoimmune demyelinating disease
PT - Autoimmune encephalopathy
PT - Toxic leukoencephalopathy
PT-Neuromyelitis optica spectrum disorder
PT-Neurosarcoidosis
PT-Intensive care unit acquired weakness
Other IRAEs 
PT-Systemic inflammatory response syndrome
PT - Myositis
PT- Necrotising myositis
PT - Polymyositis
PT-Arthritis
PT-Arthritis allergic
PT-Polyarthritis
PT- Autoimmune arthritis
PT-Hyperamylasaemia
PT-Hyperlipasaemia 
PT-Optic Neuritis
PT-Episcleritis
PT-Scleritis
PT-Iritis
PT-Uveitis
PT- Intermediate uveitis
PT - Autoimmune uveitis
PT- Retinal depigmentation
PT- Iris hypopigmentation
PT- Noninfective chorioretinitis
PT- Noninfective conjunctivitis
PT- Noninfective retinitis
PT- Lung infiltration
PT-Interstitial lung disease
PT-Acute interstitial pneumonitis
PT- Haemolytic anaemia
PT- Aplastic anaemia
PT- Aplasia pure red cell
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PT- Agranulocytosis
PT- Immune thrombocytopenic purpura
PT-eosinophil count increased
PT-Allergic eosinophilia
PT-Cytokine Abnormal
PT-Cytokine test
PT-Immune recovery uveitis
PT-Multiple organ dysfunction syndrome
HLGT-Allergic conditions
HLGT-Autoimmune disorders
HLGT- Immune disorders NEC (except Eosinophilic granulomatosis with polyangiitis)
HLT-Acute and chronic pancreatitis
HLT-Digestive enzymes 
HLT-Nephritis NEC
HLT-Glomerulonephritis and nephrotic syndrome
HLT-Lower respiratory tract inflammatory and immunologic conditions (except PT-aspiration pneumonia)
HLT-Eosinophilic disorders, 
HLT-Anaemias haemolytic immune
HLT- Noninfectious myocarditis
HLT-Arterial inflammations
PT - Idiopathic orbital inflammation
PT - Pancreatic toxicity
PT - Pancreatic enzyme abnormality
PT - Pancreatic insufficiency
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