Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: NSCLC
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 8
Healthy volunteers: no

Brief summary:
The purpose of the study was to determine the safety and test the efficacy of the combination of radium-223 dichloride and pembrolizumab in patients with stage IV non-small cell lung cancer (NSCLC) with bone metastases who either had not received any systemic therapy for their advanced disease or had progressed on prior immunologic checkpoint blockade with antibodies against the programmed cell death protein-(ligand) 1 (PD-1/PD-L1). In this study researchers wanted to measure tumor shrinkage in response to treatment and how long that shrinkage lasted and gathered information on safety. Pembrolizumab is an immunologic checkpoint blocker that promotes an immune response against the tumor. Radium-223 dichloride is an alpha particle-emitting radioactive agent which kills cancer cells.

Detailed description:

Arms:
arm 1: Participants received radium-223 dichloride at 55 kBq/kg every 6 weeks in combination with pembrolizumab every 3 weeks. arm 2: Participants was planned to receive radium-223 dichloride at the maximum tolerated dose (MTD) to be determined in the Phase 1 part every 6 weeks in combination with 200 mg pembrolizumab every 3 weeks. arm 3: Participants was planned to receive 200 mg pembrolizumab every 3 weeks. arm 4: Participants was planned to receive radium-223 dichloride at the MTD to be determined in the Phase 1 part every 6 weeks in combination with 200 mg pembrolizumab every 3 weeks.

Interventions: intervention 1: Radium-223 dichloride (Xofigo, BAY 88-8223) intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: 55 kBq/kg, intravenous (IV) injection, every 6 weeks for up to 6 administrations intervention 2: 200 mg, IV infusion, every 3 weeks for a maximum of up to 35 administrations

Protocol document:
Prot_000.pdf: 
 
Document Type: Study Protocol 
Official Title: 
An open-label, multicenter, Phase 1/2 study of radium-223 
dichloride in combination with pembrolizumab in participants 
with stage IV non-small cell lung cancer 
NCT Number: 
NCT03996473 
Document Date: 
18 SEP 2020 
 
 


CONFIDENTIAL
Clinical Study Protocol BAY 88-8223 / 19781
Global AMD 2, 18 Sep 2020
Title Page
Protocol Title:
An open-label, multicenter, Phase 1/2 study of radium-223 dichloride in combination with 
pembrolizumab in participants with stage IV non-small cell lung cancer
Protocol Number: 19781
Global Amendment 2
Compound Number: BAY 88-8223 / radium-223 dichloride / Xofigo®
Study Phase: Phase 1/ 2
Short Title:
Phase 1/2 study of radium-223 dichloride in combination with pembrolizumab in non-small 
cell lung cancer
Sponsor Name: Bayer Consumer Care AG
Legal Registered Address:
Non-US: Bayer Consumer Care AG, Peter-Merian-Strasse 84, CH-4052 Basel, Switzerland
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany, NJ 07981-0915, USA
Regulatory Agency Identifier Number(s)
EudraCT: 2018-003 704-39
Medical Monitor Name and Contact Information will be provided separately.
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the Sponsor’s medically responsible person is filed in the TMF and available on 
request.
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.


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Clinical Study Protocol BAY 88-8223 / 19781
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Protocol amendment summary of changes table
DOCUMENT HISTORY
Document
Date
Amendment 2
18 SEP 2020
Amendment 1
29 OCT 2019
Original Protocol
28 FEB 2019
Amendment 2 (18 Sep 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall rationale for the amendment
This protocol amendment was mainly prepared to address the following points: clarification 
on eligibility criteria, adoption only of RECIST 1.1 criteria as primary/secondary endpoints, 
clarification on statistical assumptions and planned analyses, provision of additional guidance 
to the participating sites as well as additional background information on study rationale.
Section # and name
Description of change
Brief rationale
Title Page
Sponsor Signatory
The signature of the Sponsor’s 
medically responsible person 
was removed from the clinical 
study protocol.
Administrative change of 
Bayer process.
1.1 Synopsis
3. Objectives and Endpoints
9.4.1 Efficacy analyses
9.4.1.2. Phase 2 Efficacy
Variables
Tumor assessment per 
iRECIST moved from 
secondary to exploratory 
endpoints.
Listed efficacy endpoints for 
Phase 1.
Correction of typos in the 
subsection title.
To use iRECIST criteria as 
exploratory efficacy endpoints 
only.
Additions for completeness.
1.1 Synopsis
3. Objectives and Endpoints
PFS and OS added as 
exploratory endpoints to Phase 
1.
To explore additional 
indicators of efficacy of the 
combination of radium-223 
dichloride and pembrolizumab 
in Phase 1.
1.1 Synopsis
4.1.2.1 Phase 1 Part
Specified the number of 
evaluable participants at the 
RP2D in Phase 1 to be at least 
10 instead of approximately 10.
To ensure enough data are 
available before moving into 
Phase 2.


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Section # and name
Description of change
Brief rationale
1.1 Synopsis
4.1.3.1 Active follow-up
Clarification on withdrawal 
criteria for study intervention 
discontinuation and follow-up.
To align the study drug 
discontinuation and follow-up 
withdrawal criteria across the 
protocol.
1.3. Schedule of Activities
Addition of the option of 
additional contacts to collect 
survival data.
To allow survival sweeps for 
collection of up to date data for 
overall survival analysis.
1.3. Schedule of Activities
4.1.2.3 End of Treatment
8.2.4 Clinical Safety 
Laboratory Assessments
8.3.1 Time Period and 
Frequency for Collecting AE 
and SAE Information
Addition of description for EoT 
visit to be performed 14 days 
after decision of permanent 
discontinuation of treatment in 
case of dose delay/interruption.
To provide instructions on the 
EoT visit completion when the 
definitive decision of study 
drug discontinuation is made
following a study intervention 
delay/interruption.
1.3. Schedule of Activities
7.2. Participant 
Discontinuation/Withdrawal 
from the Study
8.2.7 Pregnancy Test
10.2 Appendix 2: Clinical 
Laboratory Tests
Added serum from C1 onwards 
as an acceptable sample for 
pregnancy testing.
Clarification to allow sites to 
indifferently use blood (serum) 
or urine testing according to 
local clinical practice.
1.3. Schedule of Activities
5.1 Inclusion Criteria
Addition of requirement for 
availability of BRAF testing 
results at baseline.
Clarification on tumor tissue 
requirements for driver mutation 
testing.
To align with international 
guidelines on driver mutation 
testing in NSCLC patients.
To ensure comparable testing 
results.
2.1 Study Rationale
2.2 Background
2.3. Benefit/Risk Assessment
Addition of more detailed 
preclinical and clinical 
information on synergy of 
radiotherapy and 
immunotherapy.
Addition of more details on 
available safety data of radium-
223 in combination therapy and 
expected toxicity in combination 
with pembrolizumab.
To ensure more 
comprehensive background 
information is available to the 
reader.
1.1 Synopsis
3. Objectives and Endpoints
8.2.6 Patient Reported 
Outcome
9.4.1.2 Phase 2 Efficacy
Variables
9.4.1.4 Statistical Methods for 
Phase 2 Efficacy Analyses
Specification of the endpoints 
and analyses for assessment of 
PRO.
To add clarity on the planned 
PRO endpoints and analyses.


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Section # and name
Description of change
Brief rationale
5.1 Inclusion Criteria
Clarification on prior 
chemotherapy and immune 
checkpoint inhibitor treatment in 
IO refractory participants
To ensure participants are not 
deprived of any platinum-
based chemotherapy as of
local standard of care and 
have progressed within 12 
weeks from the last dose of a 
prior immunotherapy
5.1 Inclusion Criteria
Addition of requirement for male 
participants with a pregnant 
partner to use condom during 
sexual intercourse.
Addition that male participants 
should be advised on the 
conservation of sperm.
Additional precautionary 
measure for contraception.
Instruction because of 
potential effects on 
spermatogenesis associated 
with radiation.
6.1 Study Interventions 
Administered
Clarification on administration of 
radium-223 and 
pembrolizumab.
To provide guidance in case of 
dose delays for any study 
intervention administration.
6.5.1 Prohibited Concomitant 
Therapy
Addition of guidance on 
administration of live vaccines 
after the last dose of study 
intervention.
To better define the duration of 
avoidance.
6.6.1 Toxicity Management 
and Dose Modifications 
Recommendations for 
Radium-223
Changing of the requirement of 
participants non-hematological 
toxicities to be resolved to 
Grade ≤2 instead of Grade ≤1.
To align with dose modification 
guidelines across radium-223 
trials and consistency with the 
requirements at inclusion.
7.2. Participant 
Discontinuation/Withdrawal 
from the Study
8.1 Efficacy Assessments
Changing the participant’s 
withdrawal from intervention 
period and requirements for 
signing an additional informed 
consent from RECIST to 
iRECIST.
To align with the iRECIST 
criteria which allow treatment 
beyond progression (in case of 
iUPD).
8.4 Treatment of Overdose
8.5 Pharmacokinetics
8.8.2 Immunogenicity 
Assessments
Correction of the sample for 
analysis to be serum instead of 
plasma.
To align with laboratory 
requirements.
9.1 Statistical Hypotheses
9.1.2 Phase 2 Efficacy
Revision of the language to 
support the statistical 
hypotheses and correction of 
typos.
Clarification and correction.
9.3 Populations for Analyses
9.3.1 Phase 1
9.3.2 Phase 2
9.4.1.3 Statistical Methods for 
Phase 1 Efficacy Analyses
9.4.1.4. Statistical Methods for 
Phase 2 Efficacy Analyses
Clarification on analyses sets.
To properly define each 
analysis set across study 
phases and cohorts.
To clarify the handling where 
the assigned treatment is not 
followed.


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Section # and name
Description of change
Brief rationale
9.4.2 Safety analyses
Addition of reference to time to 
bone fracture analysis.
To align with past Radium-223 
AESI analyses.
9.5 Interim Analyses
9.5.1 Data Monitoring 
Committee
Delayed interim analysis for 
unconfirmed response.
To clarify interim for 
completeness.
10.1.3 Informed Consent 
Process
For Germany, participants who 
are not capable of providing 
informed consent will not be 
included in this study.
To meet Health Authority 
requirements.
In addition to the modifications described above, protocol text was revised to address changes 
of editorial nature including clarification to ensure consistency throughout the protocol.


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Table of Contents
Title Page................................................................................................................................... 1
Protocol amendment summary of changes table................................................................... 2
Table of Contents...................................................................................................................... 6
Table of Tables.......................................................................................................................... 8
Table of Figures........................................................................................................................ 8
1.
Protocol Summary............................................................................................................. 9
1.1
Synopsis ........................................................................................................................... 9
1.2
Schema........................................................................................................................... 12
1.3
Schedule of Activities.................................................................................................... 13
2.
Introduction ..................................................................................................................... 18
2.1
Study Rationale.............................................................................................................. 18
2.2
Background.................................................................................................................... 19
2.3
Benefit/Risk Assessment ............................................................................................... 21
3.
Objectives and Endpoints............................................................................................... 22
4.
Study Design .................................................................................................................... 23
4.1
Overall Design ............................................................................................................... 23
4.1.1
Screening Phase.......................................................................................................... 24
4.1.2
Treatment Phase.......................................................................................................... 24
4.1.3
Follow-up.................................................................................................................... 26
4.2
Scientific Rationale for Study Design............................................................................ 27
4.3
Justification for Dose ..................................................................................................... 28
4.4
End of Study Definition................................................................................................. 29
5.
Study Population ............................................................................................................. 30
5.1
Inclusion Criteria ........................................................................................................... 30
5.2
Exclusion Criteria .......................................................................................................... 32
5.3
Lifestyle Considerations ................................................................................................ 34
5.4
Screen Failures............................................................................................................... 34
6.
Study Intervention........................................................................................................... 35
6.1
Study Interventions Administered ................................................................................. 35
6.1.1
Radium-223 Dichloride .............................................................................................. 37
6.1.2
Dose Limiting Toxicities............................................................................................ 40
6.2
Preparation/Handling/Storage/Accountability............................................................... 41
6.3
Measures to Minimize Bias: Randomization and Blinding ........................................... 42
6.4
Study Intervention Compliance ..................................................................................... 42
6.5
Concomitant Therapy..................................................................................................... 42
6.5.1
Prohibited Concomitant Therapy................................................................................ 43
6.5.2
Permitted Concomitant Therapy................................................................................. 43
6.5.3
Drug-Drug Interactions Relevant for Pembrolizumab ............................................... 44
6.6
Dose Modification ......................................................................................................... 44
6.6.1
Toxicity Management and Dose Modifications Recommendations for Radium-223 44
6.6.2
Dose Modification and Toxicity Management for Immune-related AEs Associated 
with Pembrolizumab................................................................................................... 45
6.6.3
Dose Modification and Toxicity Management of Infusion-Reactions Related to 
Pembrolizumab........................................................................................................... 49


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6.7
Intervention after the End of the Study.......................................................................... 50
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 50
7.1
Discontinuation of Study Intervention........................................................................... 50
7.1.1
Temporary Discontinuation........................................................................................ 50
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 50
7.3
Lost to Follow-up........................................................................................................... 52
8.
Study Assessments and Procedures............................................................................... 52
8.1
Efficacy Assessments..................................................................................................... 53
8.2
Safety Assessments........................................................................................................ 54
8.2.1
Physical Examinations................................................................................................ 54
8.2.2
Vital Signs .................................................................................................................. 54
8.2.3
Electrocardiograms (ECGs)........................................................................................ 54
8.2.4
Clinical Safety Laboratory Assessments .................................................................... 54
8.2.5
ECOG Performance Status ......................................................................................... 55
8.2.6
Patient Reported Outcome.......................................................................................... 55
8.2.7
Pregnancy Test............................................................................................................ 55
8.2.8
Baseline Characteristics.............................................................................................. 56
8.3
Adverse Events and Serious Adverse Events ................................................................ 57
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 57
8.3.2
Method of Detecting AEs and SAEs .......................................................................... 58
8.3.3
Follow-up of AEs and SAEs....................................................................................... 58
8.3.4
Regulatory Reporting Requirements for SAEs........................................................... 58
8.3.5
Pregnancy ................................................................................................................... 59
8.3.6
Adverse Events of Special Interest............................................................................. 59
8.4
Treatment of Overdose................................................................................................... 60
8.5
Pharmacokinetics ........................................................................................................... 61
8.6
Pharmacodynamics ........................................................................................................ 61
8.7
Genetics.......................................................................................................................... 61
8.8
Biomarkers..................................................................................................................... 61
8.8.1
Biomarker Overview .................................................................................................. 61
8.8.2
Immunogenicity Assessments .................................................................................... 62
8.9
Medical Resource Utilization and Health Economics ................................................... 62
9.
Statistical Considerations ............................................................................................... 63
9.1
Statistical Hypotheses .................................................................................................... 63
9.1.1
Phase 1........................................................................................................................ 63
9.1.2
Phase 2 Efficacy ......................................................................................................... 63
9.1.3
Phase 2 Safety............................................................................................................. 63
9.2
Sample Size Determination............................................................................................ 63
9.2.1
Phase 1........................................................................................................................ 63
9.2.2
Phase 2........................................................................................................................ 64
9.3
Populations for Analyses ............................................................................................... 64
9.3.1
Phase 1........................................................................................................................ 64
9.3.2
Phase 2........................................................................................................................ 64
9.4
Statistical Analyses ........................................................................................................ 65
9.4.1
Efficacy Analyses ....................................................................................................... 65
9.4.2
Safety Analyses .......................................................................................................... 68
9.4.3
Other Analyses............................................................................................................ 68
9.5
Interim Analyses ............................................................................................................ 69


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9.5.1
Data Monitoring Committee....................................................................................... 69
10. Supporting Documentation and Operational Considerations .................................... 70
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 70
10.1.1
Regulatory and Ethical Considerations ...................................................................... 70
10.1.2
Financial Disclosure ................................................................................................... 70
10.1.3
Informed Consent Process.......................................................................................... 70
10.1.4
Data Protection ........................................................................................................... 71
10.1.5
Dissemination of Clinical Study Data ........................................................................ 71
10.1.6
Data Quality Assurance.............................................................................................. 71
10.1.7
Source Documents...................................................................................................... 72
10.1.8
Study and Site Closure ............................................................................................... 72
10.1.9
Publication Policy....................................................................................................... 73
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 73
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .............................................................................................. 74
10.3.1
Definition of AE ......................................................................................................... 74
10.3.2
Definition of SAE....................................................................................................... 75
10.3.3
Recording and FU of AE and/or SAE ........................................................................ 76
10.3.4
Reporting of SAEs...................................................................................................... 78
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 79
10.5
Appendix 5: Patient Reported Outcome: EORTC QLQ-C30 and EORTC QLQ-C13.. 81
10.6
Appendix 6: Participant Identification Number............................................................. 83
10.7
Appendix 7: Response Evaluation Criteria in Solid Tumors (RECIST) and iRECIST. 84
10.7.1
RECIST ...................................................................................................................... 84
10.7.2
iRECIST ..................................................................................................................... 87
10.8
Appendix 8: New York Heart Association Functional Classification........................... 92
10.9
Appendix 9: Line of Treatment...................................................................................... 92
10.10 Appendix 10: Definition of PD/L1 refractory................................................................ 92
10.11 Appendix 11: Abbreviations.......................................................................................... 93
10.12 Protocol Amendment History ........................................................................................ 96
11. References ........................................................................................................................ 97
Table of Tables
Table 1-1: Study Periods .......................................................................................................... 12
Table 1-2: Schedule of Assessments........................................................................................ 13
Table 6-1: Study Intervention Administered............................................................................ 36
Table 6-2: Dose Modification and Toxicity Management Guidelines for Immune-Related AEs 
Associated with Pembrolizumab ........................................................................... 46
Table 6-3: Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines 49
Table 8-1: Definitions for ECOG PS Grading ......................................................................... 55
Table 10-1: Protocol-Required Safety Laboratory Assessments ............................................. 73
Table 10-2: RECIST v1.1: Response for participants with target and non-target lesions ....... 86
Table 10-3: Imaging and Treatment after First Radiologic Evidence of PD ........................... 91
Table of Figures
Figure 4-1: Overall Study Design: Phase 1/ 2.......................................................................... 24


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1.
Protocol Summary
1.1
Synopsis
Protocol Title: An open-label, multicenter, Phase 1/2 study of radium-223 dichloride in 
combination with pembrolizumab in participants with stage IV non-small cell lung cancer
Short Title: Phase 1/2 study of radium-223 dichloride in combination with pembrolizumab in 
non-small cell lung cancer
Rationale:
For the past two decades, platinum-based combination chemotherapy has been the standard 
of-care first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). 
Over the last years, new treatment options including immunotherapy have led to improvement 
in overall survival (OS) in first and later lines of treatment in these patients. 
Radiation has been shown to induce increased antigen expression, to release pro-inflammatory 
cytokines, to recruit immune cells, and ultimately to induce immunogenic cell death. While 
most data have been generated with gamma radiation, effects of radium-223 are expected to 
not be impacted by hypoxia (which is a known resistance mechanism against gamma 
radiation). In addition, radium-223 is targeting osteoclasts which exhibit immunosuppressive 
properties in bone metastases. In vitro, radium-223 increases antigen expression and stress 
response and induces immunogenic cell death markers in prostate, breast and lung cancer cell 
lines (Malamas et al. 2016). 
Based on complementary modes of action between radium-223 dichloride and immune 
checkpoint inhibitors, and their potentially synergistic effects on the cancer-immunity 
pathway, the addition of radium-223 dichloride to pembrolizumab therapy might provide a 
greater clinical benefit to NSCLC patients.
The safety profile of both, radium-223 dichloride and pembrolizumab, are well characterized. 
Overlapping side effects such as gastrointestinal (GI) toxicities are possible, but further 
overlapping toxicities are not expected to be observed. 
Altogether, available data support the evaluation of radium-223 dichloride in combination 
with pembrolizumab in NSCLC. 
The purpose of the study is to determine the safety and assess the efficacy of the combination 
of radium-223 dichloride and pembrolizumab in participants with stage IV NSCLC with bone 
metastases who are either treatment naïve or have progressed on prior anti programmed cell 
death protein (ligand) 1 (PD-L1/PD-1) therapy.
Objectives and Endpoints:
Phase 1
Objectives
Endpoints
Primary

To assess the safety of the combination of 
radium-223 dichloride and pembrolizumab 
and to determine the recommended Phase 2 
dose (RP2D) 

Adverse events (AE) assessments using 
National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events 
(CTCAE) (v.5.0) and Incidence of dose 
limiting toxicities (DLTs)


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Objectives
Endpoints
Secondary

To assess the efficacy of the combination of 
radium-223 dichloride and pembrolizumab

Objective response rate (ORR) per 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 

Duration of response (DoR) per RECIST 
v1.1 

Disease control rate (DCR) per RECIST 
v1.1 
Tertiary/Exploratory

To evaluate predictive, prognostic and 
pharmacodynamic biomarkers

PD-L1, tumor mutational burden (TMB), 
bone markers, immune cell analysis and 
circulating protein markers

To assess the pharmacokinetics (PK) and 
immunogenicity of pembrolizumab in 
combination with radium-223 dichloride (if 
applicable)

To explore additional indicators of efficacy 
of the combination of radium-223 dichloride 
and pembrolizumab

Trough PK Concentrations and Titers for 
anti-drug antibodies (ADAs) and 
neutralizing antibodies (nABs) for 
pembrolizumab (if applicable)

ORR per iRECIST

DoR per iRECIST

DCR per iRECIST

Progression free survival (PFS) per v1.1
RECIST and iRECIST

Overall survival (OS)
Phase 2 (Cohort 1 and 2)
Objectives
Endpoints
Primary

To assess the efficacy of the combination of 
radium-223 dichloride and pembrolizumab 
(for Cohort 1: compared to pembrolizumab 
alone)

ORR per RECIST v1.1
Secondary

To assess the efficacy of the combination of 
radium-223 dichloride and pembrolizumab 
(for Cohort 1: compared to pembrolizumab 
alone)

DoR per RECIST v1.1 

DCR per RECIST v1.1 

Progression free survival (PFS) per RECIST 
v1.1 

OS

To evaluate the safety of the combination of 
radium-223 dichloride and pembrolizumab 
(for Cohort 1: compared to pembrolizumab 
alone)

AE assessments using NCI CTCAE (v.5.0)
Tertiary/Exploratory

To assess the efficacy of the combination of 
radium-223 dichloride and pembrolizumab 
(for Cohort 1: compared to pembrolizumab 
alone)

Symptomatic skeletal event-free survival
(SSE-FS)

ORR per iRECIST

DoR per iRECIST

DCR per iRECIST

PFS per iRECIST

To evaluate predictive prognostic and 
pharmacodynamics biomarkers

PD-L1, TMB, bone markers, immune cell 
analysis and circulating protein markers

To assess patient reported outcome (PRO)
(only applicable to Cohort 1)

Time to deterioration in global health status

Time to deterioration in dyspnea

Change from baseline on European 


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Objectives
Endpoints
Organization for Research of Cancer 
(EORTC) Quality of Life Questionnaire 
(QLQ)-C30 quality of life scale score 
and item scores

Change from baseline in EORTC QLQ-
LC13 scale scores and item scores

To assess the PK and immunogenicity of 
pembrolizumab in combination with 
radium-223 dichloride (if applicable)

PK trough concentrations and titers for 
ADAs and nABs for pembrolizumab (if 
applicable)
Overall Design:
This is an open-label, multicenter, Phase 1/2 study which includes a safety run-in as well as 
two distinct cohorts to assess the efficacy of the combination of radium-223 dichloride and 
pembrolizumab in participants with NSCLC. 
Phase 1
The Phase 1 part of the study will include participants with stage IV NSCLC either treatment 
naïve (PD-L1 tumor protein score [TPS] ≥ 50%) or after progression on prior therapy with 
immune checkpoint inhibitors (irrespective of PD-L1 TPS). It is designed to determine the 
tolerable dose of radium-223 dichloride in combination with standard dose of pembrolizumab 
(200 mg pembrolizumab every 3 weeks for a maximum of 35 cycles). Participants enrolled in 
the Phase 1 part of the study will receive the starting dose of 55 kilo Becquerel (kBq)/kg body 
weight of radium-223 dichloride which is the approved monotherapy dose for metastatic 
Castration Resistant Prostate Cancer (mCRPC). Radium-223 dichloride will be administered 
every 6 weeks for up to 6 administrations. All participants will be evaluated for occurrence of 
DLTs during the DLT observation window (6 weeks after first dose of pembrolizumab). In 
case of DLTs, the radium-223 dichloride dose may be reduced by one dose level to 33 kBq/kg 
body weight (see Section 4.1.2.1).
Phase 2
The main purpose of the Phase 2 part of the study is to evaluate the efficacy of the 
combination of radium-223 dichloride and pembrolizumab. The Phase 2 includes 2 distinct 
cohorts. In Cohort 1 participants with treatment naïve stage IV NSCLC (PD-L1 TPS ≥ 50%) 
will be randomized 1:1 to receive either radium-223 dichloride plus pembrolizumab or 
pembrolizumab monotherapy. In Cohort 2 (single arm) participants with stage IV NSCLC 
who have progressed on prior therapy with immune checkpoint inhibitors (irrespective of PD-
L1 TPS) will receive radium-223 dichloride plus pembrolizumab. Radium-223 dichloride will 
be administered every 6 weeks at the RP2D as determined in the Phase 1 part (for a total of up 
to 6 administrations). Pembrolizumab 200 mg will be administered every 3 weeks for a 
maximum of 35 cycles.
Disclosure Statement:
This is an open-label study consisting of a Phase 1 part to determine the RP2D of radium-223 
dichloride in combination with pembrolizumab and a Phase 2 part to evaluate the efficacy and 
safety of radium-223 dichloride in combination with pembrolizumab.


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Number of Participants:
In Phase 1, approximately 10 – 20 participants will be treated for a total of at least 10 
evaluable participants at the RP2D
In Phase 2, Cohort 1, approximately 104 participants will be randomized to study 
intervention. All randomized participants will be considered part of the Full Analysis Set 
(FAS).
In Phase 2, Cohort 2, approximately 40 participants will be treated. A participant that has
started treatment is considered evaluable.
Intervention Groups and Duration:
Pembrolizumab will be administered every 3 weeks for up to 35 cycles or until progressive 
disease (PD), death, unacceptable toxicity, withdrawal of consent or other withdrawal criteria 
are met (whichever occurs first). Radium-223 dichloride will be administered every other 
cycle of pembrolizumab (every 6 weeks) for a total of up to 6 administrations or until PD, 
death, unacceptable toxicity, withdrawal of consent or other withdrawal criteria are met
(whichever occurs first). 
Regular safety calls with participation of the sponsor and the investigators:  
Yes (Phase 1)
Data Monitoring Committee:
Yes (Phase 2)
1.2
Schema
Table 1-1: Study Periods
On study
Off study
Screening
Treatment
Active
FUa
Long Term 
FU 
Day -21
Cycle1 Day1
6 weeks after 1st
pembrolizumab 
dose
informed
consent
Phase 1: radium-223 
dichloride + 
pembrolizumab
Phase 2 Cohort 1: 
radium-223 dichloride + 
pembrolizumab or 
pembrolizumab 
monotherapy
Phase 2 Cohort 2: 
radium-223 dichloride + 
pembrolizumab
end of DLT observation 
periodb
last dosing 
of study 
drugs
EoT visit
last 
protocol-
stipulated 
procedure
DLT = dose-limiting toxicity; EoT = end of treatment ; FU = follow-up
a: Active FU visits, if applicable
b: DLT observation period applicable to phase 1 only


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1.3
Schedule of Activities
Table 1-2: Schedule of Assessments
Procedure
Screening
Intervention Perioda
EoT 
Visith
Active FUb
Long-Term 
FUb
Notes and Indices
C1
C2
≥ C3 - C35
Within 21 
days
D1
D15*
D1
D15*
D1
30 days 
after last 
dose of 
study 
inter-
vention
Every 3 
months until 
PD, death or, 
withdrawal of 
consent
Every 6 months 
until death, 
withdrawal of 
consent 
*D15 applies to phase 1 only
Time window
±3 
daysc
±3 
daysc
±3 
daysc
±3 daysc
+7 days
±14 days
±28 days
Signing of informed consent
X
General
Check of inclusion / 
exclusion criteria
X
Demographic data
X
Documentation of primary 
diagnosis 
X
including classification of cancer under study, previous 
systemic anti-cancer treatment and radiotherapy
Smoking history
X
Medical history
X
including prior fractures, bone-associated events (e.g.,
osteoporosis)
Height
X
Prior and concomitant 
medication 
X
X
X
X
X
X
X
X
X
in active FU and long-term FU only BHAs need to be 
reported
First new anticancer therapy
X
X
X
Safety
ECOG PS assessment
X
X
X
X
X
X
X
Physical examination 
X
X
X
X
X
X
X
including neurological examination
AE/SAE assessment
X
X
X
X
X
X
X
X
X
including fractures, and any bone-associated events 
(e.g., osteoporosis) regardless of the investigator’s 
causality assessment. Please refer to 4.1.3 for 
collection of AEs/SAEs in active and long-term FU
12-lead ECG
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
not required on Day 1 of Cycle 1, if done ≤ 5 days prior 
to start of treatment.
Blood chemistry
X
X
X
X
X
X
X
ALT, AST, ALP, creatinine, urea/BUN, total bilirubin, 
total protein, albumin, sodium, potassium, chloride, 
calcium, magnesium, phosphorus, glucose (non-
fasting); not required on Day 1 of Cycle 1, if done ≤5 
days prior to start of treatment


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Table 1-2: Schedule of Assessments
Procedure
Screening
Intervention Perioda
EoT 
Visith
Active FUb
Long-Term 
FUb
Notes and Indices
C1
C2
≥ C3 - C35
Within 21 
days
D1
D15*
D1
D15*
D1
30 days 
after last 
dose of 
study 
inter-
vention
Every 3 
months until 
PD, death or, 
withdrawal of 
consent
Every 6 months 
until death, 
withdrawal of 
consent 
*D15 applies to phase 1 only
Time window
±3 
daysc
±3 
daysc
±3 
daysc
±3 daysc
+7 days
±14 days
±28 days
Coagulation 
X
X
X
X
X
X
X
aPTT, PT/INR; not required on Day 1 of Cycle 1, if done 
≤5 days prior to start of treatment
Vital signs: blood pressure, 
heart rate, body temperature
X
X
X
X
X
X
X
Calculation of eGFR 
X
X
X
X
by Cockcroft Gault, only if Creatinine > 1.5 X ULN; not 
required on Day 1 of Cycle 1, if done ≤5 days prior to 
start of treatment
Weight
X
X
X
X
Thyroid function 
X
X
X
X
TSH, T3 free and T4 free every 2nd cycle; not required 
on Day 1 of Cycle 1, if done ≤5 days prior to start of 
treatment
Pregnancy test 
X
X
X
X
X
serum at screening and urine or serum after C1; Female 
participants of child-bearing potential only
DLT assessment (Phase1 
only)
X
X
X
X
X
DLT window: 6 weeks after 1st dose of pembrolizumab
Efficacy
Imaging/tumor assessment 
(Chest, abdominal and 
pelvic MRI or CT scan)
X
X 
Following Cycle1 Day 1 every 6 weeks (±7 days) up to week 36, 
thereafter every 9 weeks (±7 days) up to 2 years, after 2 years every 3 
months (±14 days).
Assessments acc. to RECIST 1.1 and iRECIST by local 
investigator/radiologist. Bone metastases detected by 
bone scan should be confirmed by MRI (preferable) or 
CT. At screening tumor scans are acceptable if taken 
within 4 weeks of randomization/confirmation of 
eligibility
Technetium-99m bone scan
X
Bone metastases detected by bone scan should be 
confirmed by MRI (preferable) or CT. At screening bone 
scan is acceptable if taken within 4 weeks of 
randomization/confirmation of eligibility. If in the opinion 
of the investigator, the bone scan is not considered 
appropriate, whole-body FDG-PET or FDG-PET/CT 
scan is acceptable.
Symptomatic Skeletal 
Events (SSEs) (Phase 2 
only)g
X
X
X
X
X
X
SSEs need to be reported as either AEs or SAEs 
regardless of the investigator’s causality assessment


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Table 1-2: Schedule of Assessments
Procedure
Screening
Intervention Perioda
EoT 
Visith
Active FUb
Long-Term 
FUb
Notes and Indices
C1
C2
≥ C3 - C35
Within 21 
days
D1
D15*
D1
D15*
D1
30 days 
after last 
dose of 
study 
inter-
vention
Every 3 
months until 
PD, death or, 
withdrawal of 
consent
Every 6 months 
until death, 
withdrawal of 
consent 
*D15 applies to phase 1 only
Time window
±3 
daysc
±3 
daysc
±3 
daysc
±3 daysc
+7 days
±14 days
±28 days
PRO (Phase 2 cohort 1)e
X
X
X
D1, every 2nd cycle
PRO (Phase 2 cohort 2)
X
Study intervention 
administration
Randomization (Phase 2 
cohort 1 only)
X
Radium-223 dichloride 
administrationd
X
X
every 2nd cycle of pembrolizumab for a total of 6 
administrations or until progression, death or withdrawal 
of consent (whatever comes first) 
First administration should occur not later than 14 days 
after C1D1 of pembrolizumab. Thereafter the radium-
223 administration should occur not later than 7 days 
after pembrolizumab infusion in the respective cycle
Pembrolizumab 
administration 
X
X
X
for up to 35 cycles or until progression, death or 
withdrawal of consent (whatever comes first)
Survival status
X
Participants may be contacted at additional times 
throughout the course of the study in order to collect 
survival data
Research sample 
collection/analysesf
PK samplingf
X
X
C4, C6, C8,
C12 + every 
4th cycle 
thereafter 
X
pembrolizumab PK blood samples in all participants. 
The PK blood samples will be stored, and analysis will 
be performed only if required. If ongoing PK sampling is 
deemed to be unnecessary by the sponsor, it may be 
reduced or discontinued.
Immunogenicity 
(ADA/NABs) samplingf
X
X
C4, C6, C8,
C12 + every 
4th cycle 
thereafter 
X
immunogenicity samples in all participants. The 
samples will be stored, and analysis will be performed 
only if required. If ongoing immunogenicity sampling is 
deemed to be unnecessary by the sponsor, it may be 
reduced or discontinued.
Biomarker fresh or archival 
X
PD-L1, TMB, exploratory biomarkers


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Table 1-2: Schedule of Assessments
Procedure
Screening
Intervention Perioda
EoT 
Visith
Active FUb
Long-Term 
FUb
Notes and Indices
C1
C2
≥ C3 - C35
Within 21 
days
D1
D15*
D1
D15*
D1
30 days 
after last 
dose of 
study 
inter-
vention
Every 3 
months until 
PD, death or, 
withdrawal of 
consent
Every 6 months 
until death, 
withdrawal of 
consent 
*D15 applies to phase 1 only
Time window
±3 
daysc
±3 
daysc
±3 
daysc
±3 daysc
+7 days
±14 days
±28 days
tumor tissue  
Biomarker bloodf
X
X
X
X
X
FACS
Biomarker serumf
X
X
X
X
X
bone markers (PINP, bCTX, ICTP, bone specific 
alkaline phosphatase, osteocalcin)
Biomarker urinef
X
X
X
X
X
bone markers (N-telopeptide, creatinine, calculation 
urine n-telopeptide/creatinine)
Biomarker plasmaf
X
X
X
X
X
ctDNA/proteins
PD-L1 testing/results 
(mandatory for participants 
eligible for first line treatment 
only)
X
EGFR/ALK/ROS/BRAF
testing results 
X
Testing must be performed on tumor tissue
Abbreviations: acc. = accordingly; ADA = anti-drug antibodies; AE = adverse event; ALK = anaplastic lymphoma kinase; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; bCTX = B-carboxyl-terminal cross-linking telopeptide of type I collagen;
BHA = bone health agent; BRAF = v-Raf murine sarcoma viral oncogene homolog B; BUN = blood urea nitrogen; C = cycle; CT = computed tomography; ctDNA = 
circulating tumor DNA; D = day; DLT = dose limiting toxicity; EBRT = external beam radiation therapy; ECG = electrocardiogram; ECOG PS = Eastern Cooperative 
Oncology Group performance status; eGFR = estimated glomerular filtration rate; EGFR = epidermal growth factor receptor; EoT = end of treatment; FACS = fluorescence 
activated cell sorting; FDG = 2-deoxy-[18F]fluoro-D-glucose; FU = follow-up; ICTP = C-terminal cross-linking telopeptide of type I collagen; INR = international normalized 
ratio; MRI = magnetic resonance imaging; NAB =neutralizing antibodies; PD = progressive disease; PD-L1 = programmed cell death protein ligand 1; PET = positron 
emission tomography; PINP = procollagen-type-Ι-N-terminal propeptide; PK = pharmacokinetics; PRO = patient reported outcome; PT = prothrombin time; RECIST = 
response evaluation criteria in solid tumors; ROS =reactive oxygen species; SAE = serious adverse event; SSE = symptomatic skeletal event; TMB = tumor mutational 
burden; TSH = thyroid stimulating hormone; T3= triiodothyronine; T4 =  thyroxine; ULN = upper limit of normal


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a:
a cycle is defined as 3-week interval 
b:
via phone call or on site visit
c:
indicated time-windows refer to cycles/pembrolizumab infusion only
d:
not applicable to participants randomized to pembrolizumab monotherapy in Phase 2 Cohort 1
e: 
completion of PRO questionnaires as the first activity before any other assessment, procedure, measurement or treatment 
f: 
Biomarker, PK, and immunogenicity (ADA/NABs) samples should be taken on the day of pembrolizumab administration
g:
Symptomatic Skeletal Events:
o
use of EBRT to relieve skeletal symptoms
o
new symptomatic pathological bone fractures (vertebral and nonvertebral)
o
tumor-related orthopedic surgical intervention
o
spinal cord compression
h:
If the treatment was permanently discontinued after dose interruption/delay per protocol and the decision to withdraw the participant occurred more than 30 days after 
last dose of study treatment, the EoT visit should be performed within 14 days of the permanent discontinuation


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2.
Introduction
2.1
Study Rationale
For the past 2 decades, platinum-based combination chemotherapy has been the standard-of-
care first-line treatment for patients with advanced NSCLC. Over the last years, new treatment 
options including immunotherapy have led to improvement of OS in first and later lines of 
treatment in these patients.
However, although additional treatments have become available for NSCLC over the last years, 
not all patients will respond and will eventually progress. New treatment options are needed to 
induce longer lasting responses in more patients and improve their outcome.
Radiation has been shown to induce increased antigen expression, to release pro-inflammatory 
cytokines, to recruit immune cells, and ultimately to induce immunogenic cell death (Soukup 
and Wang 2015). While most data have been generated with gamma radiation, effects of 
radium-223 are expected to not be impacted by hypoxia (which is a known resistance 
mechanism against gamma radiation) (Kassis and Adelstein 2005). In addition, radium-223 is 
targeting osteoclasts which exhibit immunosuppressive properties in bone metastases. In vitro, 
radium-223 increases antigen expression and stress response and induces immunogenic cell 
death markers in prostate, breast and lung cancer cell lines (Malamas et al. 2016). There is a 
robust, growing body of preclinical data describing mechanistic synergy between external beam 
radiation and immunotherapy (Rodriguez-Ruiz et al. 2019).
Clinical studies (Antonia et al. 2017, Antonia et al. 2018, Shaverdian et al. 2017, Theelen et al. 
2019) that combined radiotherapy with immune checkpoint inhibitors have demonstrated 
synergistic antitumor responses in NSCLC. The data have been generated in both early lines as 
well as later lines of therapy.
In the randomized, Phase 3 PACIFIC trial, patients with NSCLC who received at least 2 cycles 
of platinum-based chemotherapy with radiation and did not develop disease progression were 
randomly assigned in a 2:1 manner to receive durvalumab, anti–programmed death ligand 1 
(PD-L1) antibody, at 10 mg/kg every 2 weeks up to 12 months or placebo (Antonia et al. 2017, 
Antonia et al. 2018). With a median follow-up of 25.2 months, the overall survival in the 
intent-to-treat analysis was significantly increased among patients who received durvalumab 
compared with placebo, with a hazard ratio of 0.68 (p=0.0025). The median overall survival 
was not reached in the durvalumab arm and was 28.7 months in the placebo arm. Progression-
free survival was significantly improved with durvalumab (17.2 months vs 5.6 months). The 
secondary endpoints also favored durvalumab, and safety was similar in both the durvalumab 
and placebo groups.
The safety and efficacy of combined pembrolizumab and stereotactic body radiotherapy (SBRT) 
in NSCLC patients (regardless of PD-L1 status) has been studied in a Phase 2 study 
(PEMBRO-RT) (Theelen et al. 2019). Of the 92 patients enrolled, 76 were randomized to 
receive pembrolizumab (200 mg every 3 weeks) either alone (control arm) or after radiotherapy 
(3 doses of 8 Gy) (experimental arm) to a single tumor site. Doubling of ORR in the 
experimental arm was observed (36% vs. 18%), although the results did not meet the study’s 
pre-specified endpoint criteria for meaningful clinical benefit. Progression-free survival (PFS) 
(6.6 vs 1.9 months, HR 0.74 (95% CI 0.42 - 1.18); p = 0.19) and OS (15.9 vs 7.6 months, HR 
0.66 (95% CI 0.37 - 1.18); p = 0.16) were improved in the experimental arm. Subgroup 
analyses showed the largest benefit from the addition of radiotherapy in patients with PD-L1–
negative tumors. No increase in treatment-related toxic effects was observed in the 
experimental arm.


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The primary objective of the Phase 1 KEYNOTE-001 study was to determine the tolerability 
and safety profile as well as the anti-tumor activity of pembrolizumab in patients with advanced 
NSCLC (Shaverdian et al. 2017). Patients received pembrolizumab at a dose of either 2 mg/kg 
or 10 mg/kg of bodyweight every 3 weeks, or 10 mg/kg every 2 weeks. Forty-two (43%) of 97 
patients had previously received any radiotherapy for the treatment of NSCLC before the first 
cycle of pembrolizumab. For secondary analysis, patients were divided into subgroups to 
compare patients who previously received radiotherapy with patients who had not. Study 
results showed that previous treatment with radiotherapy in patients with advanced NSCLC 
resulted in longer PFS (4.4 vs 2.1 months, HR 0.56 (95% CI 0.34 – 0.91); p = 0.019) and OS 
(10.7 vs 5.3 months, HR 0.58 (95% CI 0.36 – 0.94);p = 0.026) with pembrolizumab treatment 
than that seen in patients who did not have previous radiotherapy, with an acceptable safety 
profile. 
Based on available preclinical as well as clinical data as outlined above and based on 
complementary modes of action between radium-223 dichloride and immune checkpoint 
inhibitors, and their potentially synergistic effects on the cancer-immunity pathway, the 
addition of radium-223 dichloride to pembrolizumab therapy might provide a greater clinical 
benefit to NSCLC patients.
The purpose of the study is to determine the safety and assess the efficacy of the combination 
of radium-223 dichloride and pembrolizumab in participants with stage IV NSCLC with bone 
metastases who are either treatment naïve or have progressed on prior anti programmed cell 
death protein (ligand) 1 (PD-1/PD-L1) therapy.
2.2
Background
NSCLC remains the most common cancer worldwide in terms of new cases (1.8 million in 
2012) (Ferlay et al. 2015) as well as death cases. Common sites of metastases are bone, lung, 
brain, liver, and adrenal glands. Bone metastases are detected with an incidence of 20% to 40% 
during the clinical course of the disease (Kuchuk et al. 2013). The presence of bone metastases 
is not only known to represent a negative prognostic factor for patients with NSCLC 
(O'Connell et al. 1986), but it also significantly affects the quality of life of patients.
Radium-223 dichloride solution for injection is a targeted alpha particle-emitting 
radiopharmaceutical that exhibits a dual targeting mechanism of action: it destroys tumor cells 
and inhibits tumor-induced pathological bone reaction. The bone-targeting property of 
radium-223 is similar to that of other alkaline earth elements, like calcium or strontium-89. 
However, the radiation characteristics of an alpha particle-emitting radionuclide appear to be 
more advantageous than that of a beta-emitting radionuclide. Radium-223, with a physical 
half-life (t½) of 11.4 days, emits high linear energy transfer (LET) alpha radiation, with a range 
limited to less than 100 micrometers. The high LET of alpha emitters (80 keV/micrometer) 
leads to a high frequency of double-strand DNA breaks in adjacent cells, resulting in an 
antitumor effect on bone metastases.
Radium-223 is an isotope which decays and is not metabolized by any enzyme. No impact on 
radium-223 is, therefore, expected by polymorphic enzymes. Radium-223 dichloride is 
administered intravenously (IV); therefore, absorption related differences are not applicable for 
this compound. Given these properties of radium-223 dichloride, it is unlikely that PK 
interaction may occur.
Radium-223 dichloride was first approved in the EU in 2013 to treat men with mCRPC and 
symptomatic bone metastases based on data from the ALSYMPCA study. In this study radium-
223 dichloride increased OS (hazard ratio [HR] 0·70, p<0·001), reduced the risk of 


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Page 20 of 98
symptomatic skeletal events (SSEs) (HR 0·66, p<0·001), and improved quality of life (odds 
ratio 1·82, p=0·004) compared with placebo when added to best standard of care in patients
with mCRPC and bone metastases who previously had either received docetaxel or were not 
candidates for docetaxel treatment (Nilsson et al. 2016, Parker et al. 2013, Parker et al. 2017).
There were fewer treatment-emergent AEs with radium-223 dichloride than with placebo 
(Parker et al. 2013) in ALSYMPCA, confirmed with data from long-term FU (Parker et al. 
2017). 
In ERA-223 – a Phase 3, double-blind, randomized controlled trial, concurrent treatment of 
abiraterone acetate plus prednisone/prednisolone (AAP) plus radium-223 dichloride resulted in 
an increased fracture risk compared to AAP alone in patients with mCRPC. At the primary 
analysis, treatment-emergent fractures occurred in 103 (26%) of 392 patients in AAP plus 
radium-223 dichloride group and 38 (10%) of 394 patients in the AAP plus placebo group. 
Most fractures were outside of sites of bone metastases in both treatment groups. Osteoporotic 
fractures accounted for most of the observed differences in fracture incidence between the 
study groups. Bone health agent (BHA) use at baseline was lower in patients who experienced 
a fracture than in those who had not. Concurrent treatment with AAP plus radium-223 
dichloride did not improve symptomatic skeletal event-free survival (SSE-FS) compared to 
treatment with AAP plus placebo. There was no statistically significant difference in OS 
between the groups.
While ERA-223 demonstrates that radium-223 dichloride should not be administered in 
combination with AAP, radium-223 dichloride remains a life-prolonging treatment option for 
patients with bone-dominant mCRPC and disease progression, based on robust clinical and 
post-marketing data.
As summarized in the Investigator’s Brochure (IB), radium-223 dichloride has also been 
studied in combination with other anticancer treatments (beyond antiandrogens), namely 
paclitaxel (tumors with bone metastases, study #17110), docetaxel (prostate cancer, study 
#15469), exemestane/everolimus (breast cancer, study #17096 ), standard of care hormonal 
treatment (breast cancer, study # 16298) as well as bortezomib/dexamethasone (multiple 
myeloma, study #18987). 
In addition, in a clinical trial in prostate cancer evaluating the combination of standard doses of 
atezolizumab plus radium-223 dichloride (NCT02814669), no dose-limiting toxicities, safety 
signals, or changes in serum biomarkers were observed beyond the known safety profiles of
either drug (Morris et al. 2020). 
No safety signal has been identified in these studies and none of these studies has been stopped 
for safety.
A detailed description of the chemistry, pharmacology, efficacy, and safety of radium-223 
dichloride is provided in the investigator’s brochure (IB).
Pembrolizumab (Keytruda®) is a potent humanized immunoglobulin G4 monoclonal antibody 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with PD-L1 and PD ligand 2 (PD-L2). Based on the preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an 
intravenous immunotherapy for advanced malignancies. Pembrolizumab is indicated for the 
treatment of patients across a number of indications. For more details on specific indications 
refer to the IB.


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In the first-line setting, pembrolizumab is approved for the treatment of NSCLC, both as a 
single agent (for PD-L1 tumor protein score [TPS] 50%) and in combination with cisplatin or
carboplatin+pemetrexed (non-squamous only, regardless of PD-L1 TPS) as well as in 
combination with carboplatin-nab-paclitaxel or carboplatin-paclitaxel (squamous NSCLC,
regardless of PD-L1 TPS). In the second line setting after failure of platinum-based 
chemotherapy, single agent pembrolizumab is indicated for treatment of NSCLC with a PD-L1 
TPS 1%. There are no comprehensive data regarding the efficacy of pembrolizumab in 
patients treated after progression on an immune checkpoint inhibitor.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab.
2.3
Benefit/Risk Assessment
Radium-223 dichloride has a favorable safety profile. The anticipated risks attributed to 
radium-223 dichloride include the following AEs: GI (constipation, transient but treatable 
diarrhea, nausea, and vomiting); hematological (transient reduction in neutrophil count, mild to 
moderate myelosuppression, low grade thrombocytopenia). Due to its radioactive nature, 
radium-223 dichloride has the potential of inducing long-term toxicities such as other primary 
cancers.
There is extensive clinical experience available with pembrolizumab in monotherapy and in 
combination with various agents. Pembrolizumab 200mg every 3 weeks has been shown to be 
active and tolerable in NSCLC in different treatment settings. Overall, the safety profile is well-
characterized as immune-mediated, and considered manageable and acceptable. The immune-
related AEs may be fatal and may occur after discontinuation of pembrolizumab.
Overlapping side effects of pembrolizumab and radium-223 dichloride such as GI toxicities are 
possible and specific guidance for patient monitoring and dose modifications has been included 
in Section 6.6.1. GI toxicity in the form of diarrhea could be a very common and potentially 
serious event caused by radium-223 dichloride and pembrolizumab combination therapy. 
Diarrhea could be either the only presenting symptom of GI toxicity, potentially self-limiting, 
or part of immune-checkpoint inhibitor-induced colitis that could require hospitalization and 
intensive treatment. As such, it is important to distinguish among different types of diarrhea 
and exclude alternative etiology (e.g., disease progression, other medications, infections).
Special attention should be given to participants who have undergone prior pelvic radiation 
therapy, as cases of pelvic radiation disease (characterized by symptoms such as diarrhea, 
tenesmus, incontinence and rectal bleeding) have been reported.
In addition, a potential increase (severity and/or incidence) in reproductive toxicity for the 
combination of radium-223 dichloride and pembrolizumab should be taken into consideration. 
Precautions will be strictly applied to prevent pregnancy. 
While no overlapping bone toxicity is expected for the combination of pembrolizumab and 
radium-223 dichloride, precautionary safety measures have been implemented. All patients 
must be on a BHA treatment (such as bisphosphonates or denosumab) unless such treatment is 
contraindicated or not recommended per investigator’s judgement (in line with available local
guidelines). Patients with history of osteoporotic fracture will be excluded from the study.  
Based on the potential effect of radium-223 dichloride on the cancer immunity pathway and the 
known activity of pembrolizumab in NSCLC, the combination of radium-223 dichloride and 
pembrolizumab might provide additional clinical benefit to participants.


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A positive benefit/risk for the combination treatment of radium-223 dichloride and 
pembrolizumab is expected since potential antitumor activity is anticipated with a manageable 
AE profile while the unmet medical need remains high in patients with NSCLC.
3.
Objectives and Endpoints
Objectives and Endpoints:
Phase 1
Objectives
Endpoints
Primary

To assess the safety of the combination of 
radium-223 dichloride and pembrolizumab 
and to determine the recommended Phase 2 
dose (RP2D) 

AE assessments using NCI CTCAE v.5.0 
and Incidence of DLTs
Secondary

To assess the efficacy of the combination of 
radium-223 dichloride and pembrolizumab

ORR per RECIST v1.1 

DoR per RECIST v1.1 

DCR per RECIST v1.1 
Tertiary/Exploratory

To evaluate predictive, prognostic and 
pharmacodynamic biomarkers

PD-L1, TMB, bone markers, immune cell 
analysis and circulating protein markers

To assess the pharmacokinetics (PK) and 
immunogenicity of pembrolizumab in 
combination with radium-223 dichloride (if 
applicable)

To explore additional indicators of efficacy 
of the combination of radium-223 dichloride 
and pembrolizumab

Trough PK Concentrations and Titers for 
ADAs and nABs for pembrolizumab (if 
applicable)

ORR per iRECIST

DoR per iRECIST

DCR per iRECIST

PFS per v1.1 RECIST and iRECIST

OS
Phase 2 (Cohort 1 and 2)
Objectives
Endpoints
Primary

To assess the efficacy of the combination of 
radium-223 dichloride and pembrolizumab 
(for Cohort 1: compared to pembrolizumab 
alone)

ORR per RECIST v1.1
Secondary

To assess the efficacy of the combination of 
radium-223 dichloride and pembrolizumab 
(for Cohort 1: compared to pembrolizumab 
alone)

DoR per RECIST v1.1 

DCR per RECIST v1.1 

PFS per RECIST v1.1 

OS

To evaluate the safety of the combination of 
radium-223 dichloride and pembrolizumab 
(for Cohort 1: compared to pembrolizumab 
alone)

AE assessments using NCI CTCAE (v.5.0)
Tertiary/Exploratory

To assess the efficacy of the combination of 
radium-223 dichloride and pembrolizumab 
(for Cohort 1: compared to pembrolizumab 

SSE-FS

ORR per iRECIST

DoR per iRECIST


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Objectives
Endpoints
alone)

DCR per iRECIST

PFS per iRECIST

To evaluate predictive prognostic and 
pharmacodynamics biomarkers

PD-L1, TMB, bone markers, immune cell 
analysis and circulating protein markers

To assess patient reported outcome (PRO) 
(only applicable to Cohort 1)

Time to deterioration in global health status

Time to deterioration in dyspnea

Change from baseline in EORTC QLQ-C30 
quality of life scale score and item scores

Change from baseline inEORTC QLQ-
LC13 scale scores and item scores

To assess the PK and immunogenicity of 
pembrolizumab in combination with 
radium-223 dichloride (if applicable)

PK trough concentrations and titers for 
ADAs and nABs for pembrolizumab (if 
applicable)
4.
Study Design
4.1
Overall Design
This is an open-label, multicenter, Phase 1/2 study which includes a safety run-in as well as two 
distinct cohorts to assess the efficacy of the combination of radium-223 dichloride and 
pembrolizumab.
The study schema is provided in Section 1.2, and the Schedule of Activities (SoA) is provided 
in Section 1.3. For details of treatments given during the study, see Section 6.1. For details on 
study assessments, see Section 8.


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Figure 4-1: Overall Study Design: Phase 1/ 2
Abbreviations: IO = immune oncology; kBq = kilo Becquerel; NSCLC = non-small cell lung cancer; PD = 
progressive disease; PD-L1 = programmed cell death protein ligand 1; TPS = tumor protein score
* For 2nd line pretreated with appropriate tyrosine kinase inhibitor (TKI)) in case of EGFR/ALK/ROS1/BRAF
genomic tumor aberrations
4.1.1
Screening Phase
Screening examinations will only be performed after the participant has signed the informed 
consent form (ICF). Participants with NSCLC will be screened for eligibility for up to 21 days 
prior confirmation of eligibility (Phase1, Phase 2 Cohort2) or randomization (Phase 2 Cohort 1). 
During this period, the inclusion and exclusion criteria will be evaluated and all screening 
procedures will be performed. Results of all screening evaluations must be reviewed by the 
investigator or his/her designee prior to enrollment of each participant into the study to ensure 
that all inclusion and exclusion criteria have been satisfied (Section 5).
After eligibility has been confirmed and documented (Phase1, Phase 2 Cohort2) or 
randomization has been performed (Phase 2 Cohort 1), an additional period of up to 21 days 
may take place before the administration of the first treatment dose, to account for all logistical 
needs related to radium-223 dichloride dose preparation and transportation. All efforts will be 
made to shorten this period as much as possible.
4.1.2
Treatment Phase
4.1.2.1
Phase 1 Part
The purpose of the Phase 1 part of the study is to determine the Recommended Phase 2 Dose 
(RP2D) of radium-223 dichloride in combination with the standard dose of pembrolizumab 
(200 mg pembrolizumab every 3 weeks [Q3W]) and establish the safety of the combination.
The starting dose of radium-223 dichloride will be the monotherapy dose approved for 
castration resistant prostate cancer (55 kBq/kg body weight). Radium-223 dichloride will be 
administered every 6 weeks (every 2nd cycle of pembrolizumab) for a total of 6 administrations. 
All participants must be evaluated for the occurrence of DLTs during the DLT observation 
window, which is defined as 6 weeks from the first dose of pembrolizumab. Participants not 
evaluable for DLT due to early discontinuation (i.e., who have not completed 1 dose of radium-
223 dichloride and 2 cycles of pembrolizumab) for reasons other than DLT will be replaced 
until the RP2D has been determined, additional participants may be recruited until at least 10 
radium-223 dichloride + 
pembrolizumab
radium-223 55 kBq/kg every 6 
weeks for a total of 6 administrations
+ 200 mg pembrolizumab every 3 
weeks for up to 35 cycles
dose de-escalation
(only if needed)
all comers (1st and 2nd line as in 
expansion cohorts) NSCLC*
~ 10-20 pts
COHORT 2 
single arm
radium-223 dichloride
+pembrolizumab
2nd line NSCLC* PD on IO
(irrespective PD-L1 TPS)
~ 40 pts
COHORT 1
randomized
1st line NSCLC
(PD-L1 TPS 50%)
~ 104 pts
radium-223 
dichloride +
pembrolizumab
pembrolizumab
1:1
randomization


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evaluable participants have been treated with the RP2D. In case of toxicities, the radium-223 
dichloride dose may be reduced to 33 kBq/kg body weight every 6 weeks. The dose de-
escalation will follow a 3+3 design.
Decisions on whether to step down to the lower dose level of 33 kBq/kg body weight for 
radium-223 dichloride will follow the rules described below:

If 0 out of 3 participants experience a DLT: the dose level will then enroll to a total of
up to 10 evaluable participants 

If 1 out of 3 participants experience a DLT: 3 more participants will be enrolled at this 
dose level

If 1 out of the 6 participants experience a DLT: the dose level will then enroll a total of 
up to 10 evaluable participants 

If 2 or more out of 6 participants experience a DLT: step-down to the lower dose level
will be implemented.
If during enrollment of the 10 participants, 3 participants experience a DLT, this dose level will 
be considered not tolerable and a step down from 55 kBq/kg to 33 kBq/kg will be implemented. 
If no more than 2 out of 10 participants experience a DLT, 55 kBq/kg radium-223 dichloride 
will then be recommended for the Phase 2 part of the study. 
In case of dose de-escalation, the rules as outlined above will be followed with the exception 
that further dose de-escalation will not be allowed. If 2 or more out of 6 participants or 3 out of 
10 participants experience a DLT at the lower dose level of 33 kBq/kg, the study will be 
terminated. If no more than 2 out of 10 participants experience a DLT, 33 kBq/kg radium-223 
dichloride will then be recommended for the Phase 2 part of the study.
Phase 1 should include a minimum of three participants meeting Cohort 2 eligibility criteria at 
each dose level, if applicable. As participants who already failed prior therapy with an immune 
checkpoint inhibitor may behave differently in terms of safety than participants receiving first 
line treatment, the determination of the RP2D might be done separately for the two patient 
populations, if needed.
Regular safety calls will be implemented with participation of the investigators and sponsor.
The decision on potential dose de-escalation and the recommended Phase 2 dose will be made 
by the sponsor in consultation with the investigators during the dose decision meetings and will 
be made based on the incidence of DLTs, clinical assessment and all available safety data. The 
dose decision meeting will be held after 3, 6 and/or 10 evaluable participants have completed 
the DLT observation period (at each dose level, if applicable). Details of the dose decision 
meeting will be described in a separate document.
Additional participants may be treated at the RP2D in Phase 1.
All Phase 1 participants will stay in the study and continue receiving study drug at the assigned 
dose level until withdrawal criteria are met. No intra participant dose escalation or de-
escalation is allowed.
4.1.2.2
Phase 2 Part
In Cohort 1 participants with treatment naïve stage IV NSCLC will be randomized 1:1 to 
receive either radium-223 dichloride plus pembrolizumab or pembrolizumab monotherapy. In 
Cohort 2 (single arm) participants with stage IV NSCLC who have progressed on prior therapy 
with immune checkpoint inhibitors will receive radium-223 dichloride plus pembrolizumab. 
Participants in both cohorts will be treated every 6 weeks with the RP2D of radium-223 


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dichloride as determined in the Phase 1 part of the study plus 200 mg pembrolizumab every 3 
weeks.
4.1.2.3
End of Treatment
Participants will be followed up to 30 days (+ 7 days) after the last treatment. If the treatment 
was permanently discontinued after dose interruption/delay per protocol and the decision to 
withdraw the participant occurred more than 30 days after last dose of study treatment, the EoT 
visit should be performed within 14 days of the permanent discontinuation. During the end of 
treatment (EoT) visit, procedures to monitor participant’ health, to identify potential toxicities, 
to assess efficacy and to evaluate biomarkers will be performed. 
4.1.3
Follow-up
4.1.3.1
Active Follow-up
Participants, who discontinue study treatment due to any reason other than locally confirmed 
radiological or clinical PD, will be monitored every 3 months (±14 days) for general safety and 
for efficacy according to the schedule defined in Section 8.1, until any withdrawal criterion for 
active FU is met.
During active FU participants will be followed for:

Response according to the protocol defined tumor assessment schedule (see 
Section 8.1).

SSEs (Phase 2 only):
o
use of external beam radiotherapy (EBRT) to relieve skeletal symptoms
o
new symptomatic pathological bone fractures (vertebral and 
nonvertebral)
o
tumor-related orthopedic surgical intervention
o
spinal cord compression

Treatment related AEs/serious AEs (SAEs).

SAEs regardless of the investigator’s causality assessment, per pembrolizumab 
requirements with an onset up to 90 days after cessation of study intervention or 
up to EoT visit ( 30 [+ 7] days following cessation of study intervention) if the 
participant initiates new anticancer therapy, whichever is earlier, need to be 
documented 

New primary malignancy (including acute myeloid leukemia [AML]) or 
hematological conditions (e.g., myelodysplastic syndrome [MDS], aplastic 
anemia, myelofibrosis) must be reported as SAEs at any time and regardless of 
the investigator’s causality assessment.

Radium-223 dichloride-related occurrences of febrile neutropenia or 
hemorrhage.

Bone fractures and bone associated events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of the 
investigator’s causality assessment. 

Any anti-cancer treatment and BHA.


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4.1.3.2
Long-Term FU
All participants who completed the active FU, will be contacted every 6 months (±28 days) up 
to at least 2 years after the last dose of radium-223 dichloride to determine survival and long-
term safety. This visit may be done by telephone call or on site. Note: participants with 
confirmed PD during the treatment period enter long-term FU immediately after the EoT visit.
During long-term FU participants will be followed for 

Survival status.

Treatment related AEs/SAEs. 

SAEs regardless of the investigator’s causality assessment, per pembrolizumab 
requirements with an onset up to 90 days after cessation of study intervention 
or up to EoT visit ( 30 [+ 7] days following cessation of study intervention) if 
the participant initiates new anticancer therapy, whichever is earlier, need to be 
documented.

New primary malignancy (including AML) or hematological conditions (e.g., 
MDS, aplastic anemia, myelofibrosis) must be reported as SAEs at any time 
and regardless of the investigator’s causality assessment.

Radium-223 dichloride-related occurrences of febrile neutropenia or 
hemorrhage.

Bone fractures and bone associated events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of 
the investigator’s causality assessment. 

Any anti-cancer treatment and BHA.
Participants may transition into a separate FU study to complete this long-term FU. 
4.2
Scientific Rationale for Study Design
Numerous novel combinations with immunotherapy as backbone are being investigated in 
clinical trials for metastatic NSCLC. Although checkpoint blockade overcomes many immune-
suppressive mechanisms in the tumor microenvironment, most patients do not benefit from this 
strategy or progress after an initial response. Based on a different and potentially synergistic 
mechanism of action, combining radium-223 dichloride with pembrolizumab in bone-
metastatic NSCLC participants might enhance and consolidate the antitumor response in the 
first-line clinical setting, leading to durable responses and prolonged survival, and overcome 
immune suppression and resistance in participants progressing on or after an immune 
checkpoint therapy. 
The study is a combined Phase1/2 study investigating radium-223 dichloride in combination 
with pembrolizumab which is approved in the treatment of patients with NSCLC. Based on the 
approval of pembrolizumab, PD-L1 expression ≥ 50% has been chosen as an inclusion criterion 
for the first line setting whereas participants who have progressed on prior immune checkpoint 
therapy can be enrolled regardless of PD-L1 expression of their tumor. 
The participants are not expected to be exposed to undue risk as major overlapping toxicities 
are not expected to be observed. Overlapping side effects such as (GI) toxicities are possible.
The sample size and the design of the safety run in Phase 1 part is a standard approach intended 
to investigate the safety profile and tolerability of new combinations of drugs. Regular safety 


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calls with participation of the sponsor and the investigators will be held to evaluate and discuss 
the safety of the participants. 
Once the dose of radium-223 dichloride has been determined, the Phase 2 part of the study will 
start to enable further exploration of tumor responses in participants with NSCLC. This Phase 2 
part consists of 2 independent cohorts. Both cohorts will include interim analyses to ensure a 
minimum benefit is observed before exposing more participants to the new drug combination. 
An open label approach is considered justified for this signal generating Phase 2 due to the 
complex handling of the study drug radium-223 dichloride. 
4.3
Justification for Dose
Radium-223 dichloride and pembrolizumab are both marketed products. The starting dose of 
radium-223 dichloride chosen for the study is the monotherapy dose approved for CRPC (55 
kBq/kg body weight).
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the pembrolizumab development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type. As 
outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W)

Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK analysis) at 200 mg 
Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All 
of these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 
mg fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, 
flat dose-exposure-response relationships were also observed in other tumor types including 
head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These findings 
are consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
Physiologically Based Pharmacokinetic Modeling (PBPK) analysis was conducted to predict 
tumor PD-1 saturation over a wide range of tumor penetration and PD-1 expression. This 
evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both 
blood and tumor.


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Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected 
for evaluation across all pembrolizumab protocols.
4.4
End of Study Definition
The end of the study is defined as the date when the last participant has been followed for at 
least 2 years after the last dose of radium-223 dichloride or died or withdrew consent.
In the event participants roll over to a separate study for long-term FU, the present study will 
end when all participants have transitioned into the rollover-study or discontinued from this 
study for another reason (e.g., consent withdrawn, lost to FU, death). Until the transition to the 
rollover-study, participants will continue to follow all the procedures and visits required in the 
current version of the protocol.
The sponsor has the right to close this study or individual sections of this study (e.g., treatment 
arms; dose cohorts; centers) at any time. 
Reasons for closure may include: 

If risk-benefit ratio becomes unacceptable owing to, for example,
o
Safety findings from this study (e.g., SAEs) 
o
Results of parallel clinical studies or emerging data from literature
o
Results of parallel animal studies (on e.g., toxicity, teratogenicity, carcinogenicity or 
reproduction toxicity).

If the study conduct (e.g., recruitment rate; dropout rate; protocol compliance) does not 
suggest a proper completion of the trial within a reasonable time frame.

For strategic reasons (e.g., the clinical development of the treatment combination is 
stopped)
If the trial is stopped but benefits are observed for ongoing participants, options for treatment 
continuation will be discussed and agreed between the investigator, sponsor and the 
participants.
Primary completion will be reached for each cohort respectively, when all participants in each 
cohort have been followed up for 36 weeks tumor assessment, prematurely discontinued the 
study for any reasons or have progressed before 36 weeks.


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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be ≥18 years of age (or age of legal maturity) at the time of signing the 
informed consent.
Disease Characteristics
2. Histologically or cytologically confirmed diagnosis of stage IV NSCLC.
Phase 1 includes participants meeting either Cohort 1 or Cohort 2 inclusion criteria as 
outlined below.
a. Phase 2 Cohort 1:
No Epidermal Growth Factor Receptor (EGFR)/v-Raf murine sarcoma 
viral oncogene homolog B (BRAF) mutation or anaplastic lymphoma 
kinase (ALK)/ROS1 rearrangement. Testing is required for all 
participants with a tumor of non-squamous or not otherwise specified 
(NOS) histology and for participants with squamous cell carcinoma 
(SCC) if testing is clinically recommended. Additional genomic tumor 
aberrations may be assessed per local standard of care
Treatment naïve (no prior systemic therapy) for their metastatic NSCLC. 
Completion of treatment with chemotherapy as part of 
neoadjuvant/adjuvant therapy is allowed as long as the therapy was 
completed at least 6 months prior to the diagnosis of metastatic disease
PD-L1 TPS ≥ 50% as per local assessment 
b. Phase 2 Cohort 2:
Progression on prior treatment with an immune checkpoint inhibitor to 
be documented within 12 weeks from the last dose (see Section 10.10). 
Only one prior treatment line with an immune checkpoint inhibitor is 
permitted unless it is part of an adjuvant or consolidation therapy and the 
participant did progress more than 9 months after completion of therapy. 
Prior treatment with platinum-based chemotherapy in combination or in 
sequence in line with local standard of care 
BRAF/EGFR sensitization (activating) mutation or ALK/ROS1 
rearrangement
Testing is required for all participants with a tumor of non-squamous or 
not otherwise specified (NOS) histology and for participants with 
squamous cell carcinoma (SCC) if testing is clinically recommended.

If no EGFR/BRAF mutation or ALK/ROS1 rearrangement: One 
or 2 prior lines of therapies for metastatic NSCLC

If EGFR/BRAF mutation or ALK/ROS 1 rearrangement: Prior 
treatment with an appropriate tyrosine kinase inhibitor and at 


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least one and not more than 3 prior lines of therapy for metastatic 
NSCLC. Participants with more than 3 prior lines of therapy for 
metastatic NSCLC, may be enrolled after prior discussion with 
the Sponsor. Additional genomic tumor aberrations may be 
assessed per local standard of care.
Availability of tumor specimen for determination of PD-L1 status.
3. Measurable disease per RECIST v1.1 as assessed by the local site 
investigator/radiologist. Lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions. 
4. At least 2 skeletal metastases identified at baseline confirmed by magnetic resonance 
imaging (MRI) (preferable) or computed tomography (CT).
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
6. Adequate bone marrow and organ function as assessed by the following laboratory 
tests:
a.
Hemoglobin ≥ 9 g/dL without transfusion or erythropoietin within the last 
4 weeks 
b. Absolute neutrophil count (ANC) ≥ 1500/mm3
c.
Platelet count ≥ 100000/mm3 without platelet transfusion within the last 4 weeks 
d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
upper limit of normal (≤ 5 X ULN in case of liver metastases)
e.
Total bilirubin ≤ 1.5 X ULN
f.
Creatinine ≤ 1.5 X ULN or estimated creatinine clearance ≥30 mL/min as 
calculated using the Cockcroft-Gault equation
g. Prothrombin International normalized ratio or prothrombin time and activated 
partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving 
anticoagulant therapy (as long as PT or aPTT is within therapeutic range of 
intended use of anticoagulants)
Participants being treated with anticoagulant will be allowed to 
participate provided no prior evidence of an underlying abnormality in 
these parameters exists. For anticoagulants that require monitoring, 
standards should be considered and controlled by the investigator. For 
new oral anticoagulants, an individual risk benefit in accordance with the 
applicable labels and/or local guidelines should be carefully assessed.
Contraception
7. Female participants of child-bearing potential must have a negative serum pregnancy 
test within 7 days before the start of study drug administration. Post-menopausal 
females and surgically sterilized females (please refer to 10.4) are exempt from a 
pregnancy test.
8. Females of childbearing potential and males must agree to use highly effective methods 
of birth control (i.e., failure rate <1% per year) from signing of the ICF until at least 120 
days after the last administration of pembrolizumab or 6 months after last 
administration of radium-223 dichloride, whatever comes later, when sexually active 
(plus an additional 30 days [a menstruation cycle] for female participants and plus an 
additional 75 days [a spermatogenesis cycle] for male participants who must refrain 


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from donating sperm during this period). 
Highly effective methods of contraception for female participants include: (i) combined 
hormonal contraception associated with inhibition of ovulation; (ii) progestogen-only 
hormonal contraception associated with inhibition of ovulation; (iii) intra-uterine device 
(IUD); intra-uterine hormone-releasing system (IUS); bilateral tubal occlusion; sexual 
abstinence. Abstinence is only considered an effective method if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment and when this is the preferred and usual lifestyle of the participant. Male 
participants are required to use condoms unless they have had vasectomy, bilateral 
orchiectomy and continuous androgen deprivation therapy (total serum testosterone 
should be less than 50 ng/mL or 1.7 nmol/L). The male participants’ partner should use 
an adequate contraception as described above. Male participants with partners who are 
pregnant must use a condom during sexual intercourse. Male participants should be 
advised on the conservation of sperm as there is a potential risk that radiation from 
radium-223 dichloride could cause adverse effects on fertility. 
The investigator or a designated associate is requested to advise the participants how 
achieve highly effective birth control. 
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for participants in clinical studies.
Informed Consent
9. Capable of giving informed consent as described in Appendix 1 (Section 10.1.3) which 
includes compliance with the requirements and restrictions listed in the ICF and in this 
protocol before performing any screening assessment.
Other Criteria
10. Participants must be on a BHA treatment, such as bisphosphonates or denosumab 
treatment unless such treatment is contraindicated or not recommended per 
investigator’s judgement and inclusion is agreed to by the medical monitor.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Previous or concurrent cancer within 3 years prior to enrollment except for curatively 
treated carcinoma in situ (e.g., breast carcinoma, cervical cancer, prostate carcinoma, 
non-melanoma skin cancer, and superficial bladder tumors).
2. Condition by Cohort and Phase:
a.
Phase 2 Cohort 1 (and participants eligible for 1st line treatment in Phase 1): Has 
received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor 
(e.g., cytotoxic T-lymphocyte antigen 4 [CTLA-4], OX40, cluster of 
differentiation [CD]137).
b. Phase 2 Cohort 2 (and participants eligible for ≥ 2nd line treatment in Phase 1):
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent 
or with an agent directed to another stimulatory or co-inhibitory T-cell receptor 


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(e.g., CTLA-4, OX40, CD137) and was discontinued from that treatment due to 
a Grade 3 or higher irAE.
3. Known active central nervous system metastases and/or carcinomatous meningitis. 
Participants with previously treated brain metastases may participate provided they are 
radiologically stable (i.e., without evidence of progression for at least 4 weeks by repeat 
imaging) (note that the repeat imaging should be performed during study screening), 
clinically stable, and without requirement of steroid treatment for at least 14 days prior 
to first dose of study treatment.
4. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e.,
with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
5. History of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
6. Major surgical procedure or significant traumatic injury within the last 28 days. Note: If 
participants received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. Central line 
surgery is not considered major surgery.
7. Non-healing wound, non-healing ulcer, or non-healing bone fracture.
8. Evidence or history of any bleeding diathesis, irrespective of severity.
9. Known history or presence of osteonecrosis of jaw.
10. Known hypersensitivity to the active substance or to any of the excipients of 
radium-223 dichloride or pembrolizumab 
11. Seizure disorder requiring medication.
12. Ongoing infection >Grade 2 NCI-CTCAE v.5.0 requiring systemic therapy
13. Significant acute GI disorders with diarrhea as a major symptom e.g., Crohn’s disease, 
malabsorption, or ≥ NCI-CTCAE v.5.0 Grade 2 diarrhea of any etiology.
14. Pregnant or breast-feeding participants.
15. Congestive heart failure ≥ New York Heart Association (NYHA) class 2. See 
Section 10.8.
16. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 
3 months).
17. Myocardial infarction in the last 6 months 
18. Uncontrolled cardiac arrhythmias (≥ grade 3 CTC version 5.0).
19. History of osteoporotic fracture
Diagnostic assessments
20. Known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive 
or detectable [qualitative] HBV DNA) or known active Hepatitis C virus (defined as 
HCV Ribonucleic Acid [RNA] [qualitative] is detected) infection. 
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
authority.


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21. Known human immunodeficiency virus (HIV). No HIV testing is required unless 
mandated by local authority.
Prior/Concomitant Therapy
22. Previous (within the last 4 weeks of the planned first dose of study treatment) or 
concomitant participation in another clinical study with investigational medicinal 
product(s). Note: Participants must have recovered from all AEs due to previous 
therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be 
eligible.
23. Systemic steroid therapy within 3 days of the planned first dose of study treatment or 
chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone 
equivalent). Participants with asthma that require intermittent use of bronchodilators, 
inhaled steroids, or local steroid injections would not be excluded from the study.
24. Previous treatment with live vaccine within 30 days of planned start of study treatment 
(seasonal flu vaccines that do not contain a live virus are permitted).
25. Transfusion of blood products (including platelets or red blood cells) or administration 
of colony stimulating factors (including granulocyte-colony stimulating factor [G-CSF], 
granulocyte-macrophage-colony stimulating factor [GM-CSF] or recombinant 
erythropoietin) within 4 weeks prior to planned start of study treatment.
26. Prior treatment with radium-223 dichloride or any therapeutic radiopharmaceutical.
27. Prior radiotherapy within 21 days of planned start of study treatment. Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not 
have had radiation pneumonitis. 
28. Prior transplantation of human cells, tissues and organs (e.g., liver transplant) or 
candidates for any type of transplantation.
Other Criteria
29. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial or interfere with the participation for the full 
duration of the trial
30. Known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
5.3
Lifestyle Considerations
There are no lifestyle considerations for participants’ eligibility for the study.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
who did not subsequently enter in the study. 
If one or more screening laboratory tests do not support eligibility, laboratory re-test is 
permitted only once without the need of re-consent. Only the laboratory tests which are out of 
range need to be repeated. The laboratory re-tests must be performed within 21 days of the 
original ICF signature. If the tests cannot be performed or their results will not available within 
21 days of the original ICF signature, participant is considered a screening failure. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials publishing 


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requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened with the following exceptions:

The participant had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule, e.g., due to logistical reasons.

The inclusion/exclusion criteria preventing the participant’s initial attempt to participate 
have been changed (via protocol amendment).
In any case, the investigator has to ensure that the repeated screening procedures do not expose 
the participant to an unjustifiable health risk. 
Diagnostic testing performed as part of the original screening or standard of practice (e.g., 
CT/MRI scans and bone scintigraphy) will not need to be repeated if performed within 4 weeks 
of confirmation of eligibility (Phase 1, Phase 2 Cohort 2) or randomization (Phase 2 Cohort 2). 
However, if CT/MRI scans fall outside of the 28 days allowed period, they will need to be 
newly acquired.
Re-screening of participants who have failed screening is only allowed once after discussion 
with the sponsor’s designated medical representative and after approval by the sponsor. 
Sponsor approval of re-screening for a participant must be documented.
The screening failure will be registered to close the patient identification number (PID), and re-
screening will start again by signing a new ICF and being assigned a new PID. 
6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Participants who satisfy all selection criteria (see Section 5.1 and Section 5.2) will be eligible to 
start study intervention.
The start of intervention period is defined by the first administration of study intervention. 
Participants will receive radium-223 dichloride and pembrolizumab combination treatment. If 
pembrolizumab and radium-223 dichloride are not administered on the same day, the date of 
pembrolizumab administration is considered start of intervention. 
6.1
Study Interventions Administered
A cycle is defined as 3-week interval and starts with every new administration of 
pembrolizumab. 
Pembrolizumab will be administered using IV infusion on Day 1 of each 3-week treatment 
cycle after all procedures and assessments have been completed. Pembrolizumab will be 
administered as a dose of 200 mg using a 30-minute IV infusion. Sites should make every effort 
to target infusion timing to be as close to 30 minutes as possible. However, given the variability 
of infusion pumps from site to site, a window between -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes [-5 min/+10 min]).
Pembrolizumab may be administered up to 3 days before or after the scheduled day of dosing 
due to administrative reasons. 


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Dosing interruptions are permitted:

Up to 3 weeks in the case of medical / surgical events or logistical reasons (i.e. elective 
surgery, unrelated medical events, participant vacation, holidays) not related to 
pembrolizumab. Participants should be placed back on pembrolizumab therapy within 3 
weeks of the scheduled interruption, unless otherwise discussed with the sponsor. The 
reason for interruption should be documented in the participant's study record. 

Up to 12 weeks due to treatment related toxicity or need for corticosteroid treatment
that cannot be reduced to ≤ 10 mg prednisone or equivalent per day 
Pembrolizumab will be administered for a maximum of up to 35 cycles or until PD, death, or 
withdrawal of consent (whichever occurs first).
Participants who discontinue pembrolizumab due to any reason will also be discontinued from 
radium-223 dichloride treatment.
Radium-223 dichloride will be administered as a slow bolus IV injection every second cycle of 
pembrolizumab (every 6 weeks) after initial administration in Cycle 1 for a total of up to 6 
administrations or until PD, death, or withdrawal of consent (whichever occurs first). The time 
window between two radium-223 dichloride administrations should not be less than 4 weeks. 
Radium-223 dichloride administration may be delayed by no more than 6 weeks from the date 
of intended dose (maximum of 12 weeks between 2 doses) for recovery of radium-223 related 
AEs or any other reason. Continuation of pembrolizumab after stopping radium-223 dichloride 
can be considered, if this is judged by the investigator to be in the best interest of the 
participant.
Pembrolizumab and radium-223 should be given on the same day. Radium-223 dichloride must 
be administered at least 30 minutes post administration of pembrolizumab when study drugs are 
given on the same day. If not possible, radium-223 dichloride may be administered on a 
different day following administration of pembrolizumab. The time window between both drug 
administrations should be as short as possible and not longer than +14 days in C1 and + 7 days 
thereafter if pembrolizumab and radium-223 are being administered as scheduled. In case of 
dose delays required for any of the two study drugs, the other study drug can be continued as 
planned with the aim to again synchronize both drug administrations as soon as possible.
Table 6-1: Study Intervention Administered
Study Intervention 
Radium-223 dichloride
(BAY 88-8223)
Pembrolizumab
Type 
Drug 
Drug
Dose Formulation
Aqueous solution of radium-223 
dichloride
Concentrate for solution for 
infusion
4ml vial (25mg/mL)
Dosage Level(s)
Phase1: RP2D will be determined in 
Phase 1 part
Starting dose is 55 kBq/kg body weight 
every second cycle after Cycle 1 for 6 
injections
In case of toxicities, starting dose may 
be reduced to 33 kBq/kg body weight 
every 6 weeks
200 mg pembrolizumab Q3W 
for a maximum of 35 cycles 


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Table 6-1: Study Intervention Administered
Study Intervention 
Radium-223 dichloride
(BAY 88-8223)
Pembrolizumab
No intraindividual dose de-escalation or 
escalation is allowed
Phase 2: RP2D will be administered to 
all participants
Route of 
Administration
slow bolus IV injection (generally up to 
one minute)
IV infusion
Sourcing
Provided by the sponsor 
Provided by the sponsor 
Packaging and 
Labeling
Vial in lead container and Type A 
radioactive package. Each vial will be 
labeled as required per country 
requirement.
Two vials in a kit box. Each 
vial will be labeled as required 
per country requirement.
Abbreviations: IV = intra-venous; kBq = kilo Becquerel; Q3W = every three weeks; RP2D = recommended 
Phase 2 dose
Details on the dose calculation, preparation and administration are provided in the Pharmacy 
Manual. 
6.1.1
Radium-223 Dichloride
The sponsor will provide radium-223 dichloride. Radium-223 dichloride is produced according 
to good manufacturing practice (GMP) and will be delivered with a certified activity. This 
alpha particle emitting radiopharmaceutical is shipped in a lead container and a Type A 
radioactive package according to international transportation guidelines for radioactive 
materials. 
Radium-223 dichloride should be received, used and administered only by authorized personnel 
in designated clinical settings. The receipt, storage, use, transfers and disposal of radium-223 
dichloride is subject to the regulations and/or appropriate licenses of the competent official 
organization. 
The volume per vial is 6 mL, corresponding to 6.6 Mega Becquerel (MBq), at the calibration 
reference day. Radium-223 dichloride has a shelf life of 28 days from production day, when 
stored at ambient temperature. The shelf life is valid for all climate zones I to IV. In addition, it 
has been shown that the product quality is not jeopardized upon freezing. 
The dose should be ordered through IxRS preferably 3 weeks prior to the planned date of 
administration. The participant’s weight taken 3 to 5 days (for US sites) or within 3 days (for ex 
US sites) before radium-223 dichloride dosing will be submitted with the dose request. The site 
is not required to perform safety laboratory assessments prior to placing the order.
It is important to note that, in general, in all cases where study drug has been ordered, the time 
window for administration should be within 3 days of the scheduled radium-223 dichloride 
dosing day. If administration must be postponed more than 3 days after the scheduled radium-
223 dichloride dosing day, replacement of the drug order may be required.
For more details please refer to the Pharmacy Manual. 
Written information about radium-223 dichloride and instruction about storage, handling, and 
injection of radioactive material will be provided to study personnel. 


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In general, the administration of radioactive drugs involves a potential risk for third parties, due 
to radiation from the participant and due to possible contamination by spilling urine or feces or 
vomit. When radium- 223 dichloride has been injected intravenously into a participant, the risk 
for external radiation exposure to third parties is extremely low, due to the short range of the 
alpha particles (<100 μm) and the low portion of beta and gamma radiation. For these reasons 
the product can be administered on an outpatient basis. 
To minimize the risk of contamination, the participant and her/his caregivers will be provided 
with instructions regarding hygiene precautions to abide by after receiving the radioactive drug 
according to the investigational study site radiation protection guidelines. 
6.1.1.1
Dose Calibration
Radium-223 dichloride can be measured in a normal dose calibrator instrument. When all the 
required written approvals for the use and handling of radium-223 dichloride from the 
Radiation Protection Agency/Agencies for the specific site have been received by the sponsor, 
a vial of radium-223 dichloride for technical use may be sent to the study site, if the site is not 
already a qualified user of radium-223 dichloride.
Different clinical study sites possess dose calibrators from various suppliers; thus, the isotope 
calibration factor may differ from site to site. Consequently, each site must perform the radium-
223 dial setting on their relevant dose calibrator(s) if no isotope calibration factor for radium-
223 is being provided by the vendor of the dose calibrator. For dial setting, the clinical study 
site will receive a sealed vial or a prefilled syringe containing a radium-223 solution for 
calibration only. The vial or syringe is identical to the vials/syringes used for study treatment. 
The amount of radium-223 in the vial/syringe will be stated on the label. Instructions for the 
dial setting, including the calibration log form, will be enclosed with the dispatch of the 
calibration sample.
For clinical study sites in Japan: A radium-223 calibration factor (traceable to the Japanese 
national radium-223 standard provided by JRIA/AIST) is generally provided by the vendor of 
the dose calibrator and must be used. If this radium-223 calibration factor cannot be provided 
by the vendor, the clinical study site needs to perform the dial setting using a sealed calibration-
vial containing a radium-223 solution for dial-setting (traceable to National Institute of 
Standards and Technology [NIST]). This sealed vial will be provided from the sponsor. The 
investigator must report immediately all non-approved medical device failures which could 
cause health damage, as well as any health damage that may be causally associated with a non-
approved medical device failure. For this reporting, the forms provided are to be used and sent 
to the designated recipient.
6.1.1.2
Dose Handling
Radium-223 dichloride should be handled by individuals who are qualified by training and 
experience in the safe handling of radionuclides.
The radium-223 dichloride vials or patient ready doses (PRDs) must be stored inside their lead 
container in a secure facility. The study drug should be used within 28 days of production or 
prior to the expiry date specified for PRDs. 
Control measurements of both the radium-223 dichloride vial (before and after dispensing) and 
syringes (before and after administration) are performed as part of the clinical trial 
documentation. Since PRDs will be prepared at the country depot, relevant procedures are 
recorded by the country depot staff. All administrations of radium-223 dichloride will be based 
on the certified activity of radium-223 at the reference date. 


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6.1.1.3
Dose calculation 
For this study, two dose levels of radium-223 dichloride may be tested:

55 kBq/kg body weight 

33 kBq/kg body weight 
The total activity to be injected will be calculated volumetrically using the participant’s body 
weight (kg) within 3 days prior to the dose for ex-US sites or 3 to 5 days prior to the dose for 
US sites, the dosage level, and the decay correction factor (DK) to correct for physical decay of 
radium-223 (ex-US sites only). A table with DKs according to physical decay of the study 
medication will be provided with each vial of radium-223 dichloride (ex-US sites only). The 
total amount (volume to be drawn into the syringe) to be administered to a participant should be 
calculated according to the recommended formula below for each dose group: 

55 kBq/kg 
Body Weight (kg) x 55 kBq/kg
= volume to be injected (mL)
DK x 1,100 kBq/mL
In case of de- escalation:

33 kBq/kg 
Body Weight (kg) x 33 kBq/kg
= volume to be injected (mL)
DK x 1,100 kBq/mL
Site specific volume calculation methods are acceptable as well, provided that the participant
dose is as indicated above. 
Data regarding activity, calculations (ex-US sites only), and volume to be injected must be 
recorded in the Investigational medicinal product (IMP) preparation log and in the study 
electronic data capture (EDC) tool. This applies to both doses that are prepared at the study site 
and doses that are prepared by an off-site vendor. 
In the US, applicable documentation is required for the country PRD depot. The participant’s 
weight will be obtained only once for each dose. To ensure time for the country PRD depot to 
prepare and deliver the PRDs to the sites:

The participant’s weight will be obtained 3 to 5 days before the planned dosing date

This weight will be communicated to the country PRD depot for preparation of the 
current dose along with a prescription and any other details required by the PRD depot; a 
record of this information transfer will be retained at the site

Documentation by the PRD depot of the required activity and volume in the syringe will 
be retained at the depot with a copy provided to the site
Participants at ex-US sites should be reweighed on the day of dose administration; the final 
dose to be administered should be determined using that weight. Participants should not be 
weighed more than once or at different departments on the day of the administration to avoid 
the potential use of different weights. Participants in the US will receive patient-ready doses 
based on the participant weight 3 to 5 days before the day of administration. Therefore, no 
other weight measurement is needed.


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6.1.1.4
Dose preparation 
Personnel should use appropriate protective clothing and equipment during syringe filling and 
application to prevent contamination with the radioactive solution (lab coats, medical gloves, 
protective glasses) and to reduce radiation exposure. Sites should adhere to all relevant 
radiation safety regulations as prescribed by local authorities administering their site radiation 
license, including as low as reasonably achievable principles. 
Filling of the syringe should take place in a safety bench or similar cabinet in the 
Radiopharmacy/Nuclear Medicine Department. The individual responsible for study drug 
preparation will draw the correct volume of study drug into a syringe. The size of the syringe 
should be chosen according to the applied volume to reach the required dosing accuracy. In 
some countries/study sites, a third party vendor will be used to prepare the injections to be used 
by the study site. 
Radium-223 dichloride should not be diluted or mixed with any solutions. If the vials have 
been stored in a refrigerator, they should be left at room temperature for 1 hour prior to use, 
since cold material should not be injected in a participant.
It is important to note that, in general (unless otherwise agreed, e.g., for sites using PRD depots 
[Section 6.1.1.2]), in cases where study drug has been ordered, the time window for 
administration should be within 3 days of the scheduled treatment visit. If administration must 
be postponed more than 3 days after the scheduled treatment visit, replacement of the drug 
order may be required. 
The study intervention will be administered as a slow bolus IV injection. The actual 
radioactivity administered must be within the tolerance limits of 10% of the calculated 
radioactivity. After administration, the equipment used in connection with the preparation and 
administration of drug, are to be treated as radioactive waste and should be disposed in 
accordance with hospital procedures for the handling of radioactive material and according to 
local laws. Written information about radium-223 dichloride and instructions for the handling 
and injection of radioactive material will be provided to study personnel.
For additional information regarding dose preparation, please refer to the Pharmacy Manual.
6.1.2
Dose Limiting Toxicities
In Phase 1, dose-limiting toxicities, using CTCAE version 5.0 for the severity grading, will be 
monitored for each participant during 6 weeks after the first administration of pembrolizumab 
(DLT window).
The occurrence of any of the following toxicities during the DLT window will be considered a 
DLT, if assessed by the investigator to be possibly, probably, or definitely related to study 
treatment administration, excluding toxicities clearly not related to the any of study drugs, i.e.
radium-223 dichloride or pembrolizumab, such as disease progression, environmental factors, 
unrelated trauma, etc.:
1. Grade 4 non-hematologic toxicity.
2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia:

Grade 4 thrombocytopenia of any duration

Grade 3 thrombocytopenia associated with clinically significant bleeding
3. Any non-hematologic AE (excluding laboratory) ≥Grade 3 in severity should be 
considered a DLT, with the following exceptions: Grade 3 fatigue lasting ≤ 3 days; 


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Grade 3 diarrhea, nausea, or vomiting despite use of anti-emetics or anti-diarrheals per 
standard of care lasting ≤ 3 days; Grade 3 rash without use of systemic corticosteroids 
or anti-inflammatory agents per standard of care.
4. Any Grade 3 non-hematologic laboratory value if:

Clinically significant medical intervention is required to treat the participant, or

The abnormality leads to hospitalization, or

The abnormality persists for >1 week.
5. Liver function tests:

Grade 3 abnormality in AST, ALT, or bilirubin in a participant without liver 
metastases at screening

The abnormality results in a Drug-induced Liver Injury (DILI) (see Section 8.3.6)
6. Febrile neutropenia Grade 3 or Grade 4:

Grade 3 is defined as absolute neutrophil count (ANC) <1000/mm3 with a single 
temperature of >38.3 degrees Celsius [°C] (101 degrees Fahrenheit [°F]) or a 
sustained temperature of ≥38 degrees C (100.4 degrees F) for more than 1 hour

Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 
°F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for more than 1 
hour, with life-threatening consequences and urgent intervention indicated.
7. Prolonged delay (>2 weeks) in initiating Cycle 2 of pembrolizumab due to treatment-
related toxicity
8. Any treatment-related toxicity that causes the participant to discontinue treatment 
during Cycle 1 or 2.
9. Missing >25% of pembrolizumab doses as a result of drug-related AE(s) during the first 
cycle.
10. Grade 5 toxicity.
For details on dose cohort management and dose de-escalation, please refer to Section 4.1.2.1.
6.2
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received and any discrepancies are reported 
and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e.,
receipt, reconciliation, and final disposition records).


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Further guidance and information for the final disposition of unused study interventions are 
provided in the Clinical Trial Supply Plan (CTSP) /Pharmacy Manual.
6.3
Measures to Minimize Bias: Randomization and Blinding
In Phase 1 and Phase 2 Cohort 2 all participants who meet the inclusion/exclusion criteria will 
receive radium-223 dichloride plus pembrolizumab. Phase 1 as well as Phase 2 Cohort 2 are 
uncontrolled and all participants will receive pembrolizumab which is approved for the 
treatment of NSCLC. 
Participants in Phase 2 Cohort 1 will be randomized in a 1:1 ratio to receive either radium-223 
dichloride plus pembrolizumab combination or pembrolizumab alone. Pembrolizumab which is 
approved for the treatment of NSCLC will be given to participants in both arms. 
The study is open label, however potential bias will be reduced by central randomization. The 
specific intervention(s) to be administered to a participant will be assigned using an IxRS. The 
site will contact the IxRS prior to the start of study intervention administration for each 
participant. The site will record the intervention assignment on the applicable case report form, 
if required.
In order to ensure participants' safety and the integrity of trial, the study will include the same 
regular safety examinations for all participants as well as appropriate dose modifications.
6.4
Study Intervention Compliance
The administration of radium-223 dichloride and pembrolizumab will be performed at the site 
as indicated in Section 1.3 and must be recorded in the source data and electronic case report 
form (eCRF).
Reasons for dose delay, interruption, or discontinuation will also be recorded in the source data 
and in the eCRF.
Participant compliance with study intervention will be assessed at each visit. Deviation(s) from 
the prescribed dosage regimen should be recorded in the eCRF.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study till EoT (for BHAs until end of long term FU) must be recorded on eCRF 
along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
All participants must be on a BHA treatment, such as bisphosphonates or denosumab treatment 
unless contraindicated or not recommended per investigator’s judgement.
Administration of contrast media for protocol-specified radiological procedures does not need 
to be reported, unless there is an AE related to the contrast medium injection (e.g., allergic 
reaction).
All medication and therapies which are considered necessary for the participant’s welfare, and 
which are not expected to interfere with the evaluation of the study intervention, may be given 


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at the discretion of the investigator. The sponsor or representative should be contacted if there 
are any questions regarding concomitant or prior therapy.
6.5.1
Prohibited Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required. The investigator should discuss any questions regarding this with the sponsor.
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant's primary physician. However, the decision to continue the participant on trial 
therapy or vaccination schedule requires the mutual agreement of the investigator, the sponsor 
and the participant.
Listed below are specific restrictions for concomitant therapy or vaccination during the course 
of the study:

The use of systemic corticosteroid or immunosuppressant before starting 
pembrolizumab should be avoided because of their potential interference with the 
pharmacodynamic activity and efficacy of pembrolizumab. Note: replacement therapy 
such as physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency (in dosing not exceeding 10 mg daily of prednisone equivalent) is not 
considered a form of systemic treatment as well as inhaled steroids are allowed for 
management of asthma. Moreover, systemic corticosteroids or other 
immunosuppressants can be used after starting pembrolizumab to treat immune-related 
adverse reactions as well as allergy to contrast media.

Anti-neoplastic therapies, including immunotherapy, chemotherapy, biological therapy 
or experimental therapies other than radium-223 dichloride and pembrolizumab.

Radiation therapy 
Note: Radiation therapy to a symptomatic lesion may be allowed after discussion with 
the sponsor. 

Live vaccines within 30 days prior to the first dose of trial treatment and while
participating in the trial. Live vaccines must not be administered for 90 days after the 
last dose of study intervention. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus 
Calmette-Guérin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed. However, intranasal 
influenza vaccines (e.g., Flu - Mist®) are live attenuated vaccines, and are not allowed

Excessive intake of biotin above the recommended daily dose of 30 μg. Biotin is found 
in multivitamins, including prenatal multivitamins, biotin supplements, and dietary 
supplements for hair, skin, and nail growth at levels that may interfere with laboratory
tests.
6.5.2
Permitted Concomitant Therapy
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. 

Participants who are therapeutically treated with an agent such as warfarin or heparin or 
novel oral anticoagulants (NOACs) such as dabigatran or rivaroxaban will be allowed to 


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participate provided that no prior evidence of underlying abnormality in coagulation 
parameters exists. 

Palliative or supportive care for any underlying illness (e.g., Megestrol acetate 
(Megace®) as supportive care). 

Palliative and supportive care for the other disease-related symptoms and for toxicity 
associated with treatment will be offered to all participants on this trial. The use of anti-
diarrheal or anti-emetics according to standard practice is strongly encouraged.
All medication and therapies which are considered necessary for the participant’s welfare, and 
which are not expected to interfere with the evaluation of the study intervention, may be given 
at the discretion of the investigator.
6.5.3
Drug-Drug Interactions Relevant for Pembrolizumab
No formal PK drug interaction studies have been conducted with pembrolizumab. Since 
pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug 
interactions are expected.
6.6
Dose Modification
6.6.1
Toxicity Management and Dose Modifications Recommendations for 
Radium-223
Decisions on whether to step down to the lower dose level for radium-223 dichloride of 
33 kBq/kg body weight based on DLT are explained in Section 4.1.2.1. Otherwise, intra-
participant dose reduction of radium-223 dichloride is not allowed (Section 6.1.1). The dose of 
pembrolizumab will remain constant at 200 mg Q3W for each dose level, in each cohort and in 
each participant.
Based on a participant’s AE, the investigator will determine which study drug may be related to 
the toxicity and, therefore, apply the respective dose modification. In case an attribution to 
radium-223 dichloride or pembrolizumab cannot be determined and conflicting 
recommendations are provided, the most conservative approach should be followed.
Prior to each dose of radium-223 dichloride, participants must meet the following criteria for 
study treatment administration:

Hemoglobin (Hb) level ≥8.0 g/dL

Platelet count ≥50 x 109/L

ANC ≥1 x 109/L

All non-hematological toxicities resolved to Grade ≤2 or baseline
Every effort will be made to administer the full dosing regimen (6 doses of radium-223 
dichloride). Dose adjustment of radium-223 dichloride is not permitted. The minimum time 
window between 2 doses of radium-223 dichloride must be 4 weeks.
GI toxicity in the form of diarrhea could be very common and potentially serious event caused 
by radium-223 dichloride and pembrolizumab combination therapy.
The below guidance should be considered in addition to the guidance outlined in Table 6-2.:

Monitor all patients for signs and symptoms of enterocolitis (i.e., diarrhea, abdominal 
pain, blood or mucus in stool with or without fever) and bowel perforation (e.g.,
peritoneal signs and ileus)


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
For diarrhea G1 and G2:
o
Consider oral fluids, loperamide, avoid high fiber/lactose diet 

For diarrhea ≥ G2, please consider per local institutional guidelines: 
o
Blood tests (e.g., hematology and general chemistry including liver function 
tests (AST, ALT, Bilirubin))
o
Stool examination (e.g., culture, Clostridium difficile, cytomegalovirus or other 
viral etiology, ova and parasite)
o
GI consultation and Imaging (e.g., CT scan of abdomen and pelvis and GI 
endoscopy with biopsy)
o
Administer corticosteroids (initial dose of 1-2 mg/kg prednisone or equivalent) 
followed by taper upon AE improving to ≤ G1 and continue to taper over at least 
4 weeks

For severe and life-threatening diarrhea/colitis:
o
Consider hospitalization or outpatient facility for patients with dehydration or 
electrolyte imbalance 
o
Fluid and electrolytes should be administered via IV infusion.
o
Urgent GI consultation and Imaging (e.g., CT scan of abdomen and pelvis and 
GI endoscopy with biopsy)
o
IV corticosteroid should be initiated first followed by oral steroid. 
6.6.2
Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than one body system
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids, and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification and 
toxicity management guidelines for irAEs associated with pembrolizumab are provided in
Table 6-2.


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Table 6-2: Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with 
Pembrolizumab
General instructions:
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced 
to ≤10 mg prednisone or equivalent per day within 12 weeks.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-
related AEs
Toxicity grade 
or conditions 
(CTCAE v.5.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and FU
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms of 
pneumonitis.
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment.
Add prophylactic antibiotics for opportunistic 
infections.
Grade 3 or 4, or 
recurrent Grade 2
Permanently discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (i.e., diarrhea, abdominal pain, blood
or mucus in stool with or without fever) and of 
bowel perforation (i.e., peritoneal signs and 
ileus).
Participants with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion
(see Section 6.6.1).
Recurrent Grade 3 
or Grade 4
Permanently discontinue
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold
Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone 
or equivalent) followed by taper
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable)
Grade 3 or 4 
Permanently discontinue
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
Newly onset 
T1DM or 
Withholda
Initiate insulin replacement 
therapy for participants with 
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes.


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Table 6-2: Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with 
Pembrolizumab
or Hyperglycemia
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
T1DM.
Administer anti-hyperglycemic in 
participants with hyperglycemia.
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated.
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency).
Grade 3 or 4 
Withhold or permanently 
discontinuea
Hyperthyroidism 
Grade 2
Continue 
Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate.
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently discontinuea
Hypothyroidism
Grade 2-4
Continue 
Initiate thyroid replacement 
hormones (e.g., levothyroxine or 
liothyroinine) per standard of 
care.
Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis: grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 2
Withhold 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.
Monitor changes of renal function.
Grade 3 or 4 
Permanently discontinue
Myocarditis
Grade 1 or 2
Withhold
Based on severity of AE 
administer corticosteroids.
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes.
Grade 3 or 4
Permanently discontinue
All other immune-
related AEs
Intolerable/ 
persistent Grade 2
Withhold
Based on type and severity of 
AE administer corticosteroids. 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes.
Grade 3
Withhold or discontinue 
based on the type of 
event. Events that require 
discontinuation include 
and not limited to: 
Guillain-Barre Syndrome, 
encephalitis and
Stevens-Johnson 
Syndrome 


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Table 6-2: Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with 
Pembrolizumab
Grade 4 or 
recurrent Grade 3 
Permanently discontinue
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = common terminology criteria for adverse 
events; GI = gastrointestinal; irAE = immune-related AE; IV = intravenous; T1-DM = type-1 diabetes mellitus
a Withhold or permanently discontinue pembrolizumab at the discretion of the investigator or treating physician.
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).


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6.6.3
Dose Modification and Toxicity Management of Infusion-Reactions Related 
to Pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 6-3.
Table 6-3: Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤ 24 hours.
Stop Infusion.
Additional appropriate medical therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, 
the infusion may be restarted at 50% of the original infusion 
rate (e.g., from 100 mL/hr to 50 mL/hr). Otherwise dosing will 
be held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment
Participant may be 
premedicated 1.5 hours 
(± 30 minutes) prior to 
infusion with:
Diphenhydramine 50 
mg orally (or equivalent 
dose of antihistamine).
Acetaminophen 500-
1000 mg orally (or 
equivalent dose of 
analgesic).
Grade 3
Prolonged (i.e., not rapidly 
responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates)
Grade 4
Life-threatening; pressor 
or ventilator support 
indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not 
limited to:
Epinephrine**                   
IV fluids
Antihistamines                 
NSAIDs
Acetaminophen               
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used 
immediately.
Participant is permanently discontinued from further study 
drug treatment.
No subsequent dosing
Abbreviations: CTCAE = common terminology criteria for adverse events; IV = intravenous; NCI = National 
Cancer Institute; NSAID = nonsteroidal anti-inflammatory drug 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration. For further information, please refer to the CTCAE v.5.0 


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6.7
Intervention after the End of the Study
After the end of study, further therapy is at the discretion of the investigator.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention for abnormal liver function should be considered by the 
investigator when a participant meets one of the conditions outlined in Section 6.6 or if the 
investigator believes that it is in best interest of the participant.
If a clinically significant finding is identified (including, but not limited to changes from 
baseline in QT interval after enrollment), the investigator or qualified designee will determine 
if the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation 
and FU and for any further evaluations that need to be completed.
7.1.1
Temporary Discontinuation
Temporary discontinuation of pembrolizumab may be considered for participants who have 
attained a confirmed complete response (CR), have received at least 8 infusions (24 weeks) of 
pembrolizumab treatment and had at least 2 infusions with pembrolizumab beyond the date 
when the initial CR was declared.
No temporary discontinuation of radium-223 is allowed.
7.2
Participant Discontinuation/Withdrawal from the Study
A participant must be withdrawn from the study at any time at his/her own request.
A participant may be withdrawn from the study at any time at the discretion of the 
investigator for safety, behavioral, compliance, or administrative reasons. This is expected to 
be uncommon.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, and additionally requests destruction of her/his 
samples taken but not yet tested, the investigator must document this (either destruction by 
site or request to central lab, as applicable) in the site study records.
In all cases, the reason for withdrawal must be recorded in the eCRF and in the participant’s 
medical record.
Withdrawal from Study Intervention Period
Participants must be withdrawn from the intervention period if any of the following occurs:

If, in the investigator’s opinion, continuation of the study intervention would be 
harmful to the participant’s well-being.


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
Confirmed radiological disease progression (using iRECIST), unless the investigator
in consultation with the sponsor or representative deems that continued treatment is 
appropriate.

Clinical progression per investigator judgement.

Substantial noncompliance with the requirement of the study.

Pregnancy as confirmed by a urine dipstick test or serum test. Pregnancy will be 
reported under the same timelines as an SAE.

Use of illicit drugs or other substances that may, in the opinion of the investigator or 
their designated associate(s), have a reasonable chance of contributing to toxicity or 
otherwise confound the results.

Development of any intercurrent illness or situation which may, in the judgment of the 
investigator, affect assessment of clinical status and study endpoints to a relevant 
degree.

Development of a second primary malignancy that requires a different treatment

Start of a new systemic anti-cancer treatment.

Unacceptable toxicity, i.e. event requiring permanent discontinuation of 
pembrolizumab according to dose modification guidance in Section 6.6.2.

Participants who experience a delay of more than 12 weeks to receive the subsequent 
pembrolizumab infusion due to treatment related toxicity or need for corticosteroid
treatment that cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 
12 weeks.

Participants who complete 35 infusions of pembrolizumab (after approximately 2 
years of treatment).

Participants who experience a delay of more than 3 weeks to receive the subsequent 
pembrolizumab infusion due to medical / surgical events or logistical reasons (i.e.
elective surgery, unrelated medical events, participant vacation, holidays) not related 
to pembrolizumab. Note: participants should be placed back on pembrolizumab 
therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with 
the sponsor. 

Lost to FU

Withdrawal of consent for study intervention

Death

Withdrawal of radium-223 only:
o
Participants who experience a delay of more than 6 weeks to receive the 
subsequent radium-223 injection due to any reason (more than 12 weeks 
between 2 doses)
Withdrawal from active follow-up
Participants must be withdrawn from active FU if any of the following occurs:

Radiologically (using iRECIST) or clinically confirmed PD is observed. 

Start of subsequent anti-cancer treatment


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
Lost to FU

Withdrawal of consent to efficacy FU visits

Death
Participants may be withdrawn from active FU if any of the following occurs:

At the specific request of the sponsor and in liaison with the investigator (e.g., obvious 
non-compliance).
Withdrawal from long-term FU
Participants must be withdrawn from long-term FU if any of the following occurs:

Lost to follow-up

Withdrawal of consent to long-term FU

Death
Participants may be withdrawn from long-term FU if any of the following occurs:

At the specific request of the sponsor and in liaison with the investigator (e.g., obvious 
non-compliance).
7.3
Lost to Follow-up
A participant will be considered lost to FU if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to FU, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered lost to 
FU.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1).
8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers 
or exemptions are not allowed. Adherence to the study design requirements, including those 
specified in the SoA, is essential and required for study conduct.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.


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All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
8.1
Efficacy Assessments
The RECIST v1.1 and iRECIST criteria will be used for efficacy evaluation of response and 
disease control (for details see 10.7). Participants who show evidence of radiological PD by 
RECIST 1.1 and are clinically stable may continue on study treatment until repeat imaging is 
obtained and confirmation of progression is documented according to iRECIST criteria. For 
further guidance please refer to Section 10.7.2. Participants who continue to receive study 
drug after confirmed disease progression as defined by iRECIST must sign a written informed 
consent prior to receiving any additional dose of study drug. In addition, treatment beyond 
progression should not delay an imminent intervention to prevent serious complications of 
disease progression (i.e. central nervous system [CNS] metastases).
Radiological tumor assessments will be performed locally by the investigator/radiologist.
Tumor imaging should be performed by CT or MRI with contrast enhancement. At FU CT or 
MRI can be done, as an exception, without use of contrast media if this is contraindicated. For 
chest examination, CT is strongly recommended and preferred. A bone scan (i.e. whole-body 
technetium-99m bone scan) is mandatory at baseline only. If in the opinion of the investigator, 
the bone scan is not considered appropriate, whole-body FDG-PET or FDG-PET/CT scan is 
acceptable. Bone metastases detected by bone scan should be confirmed by MRI (preferable) 
or CT. All scans should be interpreted by the same radiologist/investigator during the study, 
where at all possible.
The first radiological tumor evaluation will be conducted during the screening period. Images 
that were obtained prior to the signing the ICF as part of normal clinical FU of the 
participant’s tumor can be used as long as they were performed within 28 days of 
randomization or confirmation of eligibility and meet the requirements for the study.
Tumor evaluation must include chest, abdomen and pelvis, and bone. Head CT or MRI will be 
done in participants with known active or suspected central nervous system metastases and/or 
carcinomatous meningitis at baseline (screening) and throughout the study treatment period. 
Tumor assessments during the study intervention and active follow-up periods include the 
same anatomic areas as baseline and will be done until radiological disease progression or the 
end of the study.
Evaluations are to be performed at screening, and every 6 weeks (± 7 days) following Cycle 1 
Day 1 for the first 36 weeks, thereafter every 9 weeks (±7 days) up to 2 years, after 2 years 
every 3 months (±14 days). The evaluations will end when confirmed disease progression by 
iRECIST is documented.
For participants who discontinue study intervention without radiological disease progression, 
subsequent tumor assessments will be obtained during active FU.
All scans should be done with the same modality (CT or MRI) and the equivalent technique 
(e.g., slice thickness, field of view) to those obtained at baseline.


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Scan data should be stored in DICOM (Digital Imaging and Communications in Medicine) 
format until the end to the trial (either in the radiology department or in the investigator site 
file on applicable storage media, e.g., CD/DVD and made available to the sponsor upon 
request.
8.2
Safety Assessments
Safety will be assessed by monitoring and recording all AEs and SAEs, cardiac, hematologic,
and blood chemistry parameters, vital signs, ECOG PS, and any abnormal findings observed 
during the performance of physical examinations.
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical Examinations
A complete physical examination will include, at minimum, assessments of the 
Cardiovascular, Respiratory, GI, and Neurological systems. Height and weight will also be 
measured and recorded (Section 1.3).
Investigators should pay special attention to clinical signs related to previous serious illnesses.
8.2.2
Vital Signs

Body temperature, pulse rate, and blood pressure will be assessed.

Vital signs will be measured after 5 minutes rest and will include temperature, systolic 
and diastolic blood pressure, and pulse 
8.2.3
Electrocardiograms (ECGs)

Single12-lead ECG will be obtained as outlined in the SoA (see Section 1.3).
8.2.4
Clinical Safety Laboratory Assessments

See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed 
and to the SoA (Section 1.3) for the timing and frequency.
o
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant's condition.

If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory are considered clinically significant by the 
investigator, then these also need to be reported as SAE or AE.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within the EoT visit after the last dose of study 
intervention should be repeated until the values return to normal or baseline or are no 
longer considered clinically significant by the investigator.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the protocol and the SoA.


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8.2.5
ECOG Performance Status
An ECOG PS score of 0 or 1 is required for study inclusion (see Section 5.1). Assessment of 
ECOG performance is carried out during screening, on Day 1 of each cycle, and at the EoT 
visit as indicated in the SoA (Section 1.3).
Grading definitions for ECOG PS are given in Table 8-1 below.
Table 8-1: Definitions for ECOG PS Grading
Grade
Description
0
Fully active, able to carry on all pre-diseases 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.
Abbreviations: ECOG = Eastern Cooperative Oncology Group; PS = performance status
8.2.6
Patient Reported Outcome
Patient reported outcomes are administered to both Cohort 1 and Cohort 2 in Phase 2 to assess 
health condition of the participants. For participants in Cohort 1, PROs are administered 
within 7 days before study intervention and thereafter, on Day 1 of every second cycle. It is 
strongly recommended that PROs are completed prior to study drug administration, adverse 
event evaluation, and disease status assessment. For participants in Cohort 2, PROs are 
administered only within 7 days before study intervention.
EORTC QLQ-C30 (version 3.0) and a supplementary questionnaire module (EORTC 
QLQ-LC13) are administered to participants. The EORTC QLQ-C30 was developed to assess 
the quality of life of cancer subjects and is the most widely used cancer-specific Health 
Related Quality of Life (HRQoL) instrument.  It contains 30 items and measures five 
functional dimensions (physical, role, emotional, cognitive, and social), three symptom items 
(fatigue, nausea/vomiting, and pain), six single items (dyspnea, sleep disturbance, appetite 
loss, constipation, diarrhea, and financial impact) and global health and quality of life.  The 
global health and quality of life scale uses a 7 point scale scoring with anchors (1=very poor 
and 7=excellent); the other items are scored on a 4 point scale (1=not at all, 2=a little, 3= quite 
a bit, 4=very much). 
The EORTC QLQ-LC13 (Bergman et al. 1994) , a supplemental lung cancer-specific module 
used in combination with QLQ-C30 (Aaronson et al. 1993), comprises multi-item and single-
item measures of lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and site 
specific pain) and treatment-related symptoms (sore mouth, dysphagia, peripheral neuropathy 
and alopecia).  It is scored on a 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very 
much).
Detailed scoring approach for the PROs is presented in Section 10.5 (Appendix 5).
8.2.7
Pregnancy Test
A serum pregnancy test is performed at screening. From Cycle 1 onwards, either a urine or 
serum pregnancy test may be used. The frequency of pregnancy tests may be higher, if 
required by local regulations. 


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8.2.8
Baseline Characteristics
Demographics
Baseline participant data pertaining to demographic information should be documented 
accordingly in the appropriate eCRF including the following:

Date of birth (year, age) if allowed according to local law

Gender

Race, if legally allowed

Ethnicity, if legally allowed

Weight (weight is also measured at other time points indicated in the SoA, 
Section 1.3)

Height
Medical History
Medical history findings (including co-existing disease, prior non cancer related surgery, and 
allergy history) and smoking history meeting all criteria listed below will be collected as 
available to the investigator.

Started before signing the ICF

Considered relevant for the participant’s study eligibility.
Other Baseline Characteristics
Other baseline characteristics will be collected, including but not limited to:

Baseline cancer characteristics, including cancer type, date of initial diagnosis, 
histology, tumor stage, and tumor mutations, date of most recent progression, prior 
cancer therapies and procedures, and radiotherapy

ECOG-PS

All medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the participant within 21 days 
prior to the study intervention.
All the population characteristic data should be recorded in the eCRF. Detailed instructions on 
baseline characteristics can be found in the eCRF completion guidelines.


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8.3
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative or health care professional not involved in the 
study).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up SAEs, or AEs, considered related to the study intervention or study procedures, 
or those that caused the participant to discontinue the study intervention or the study (see 
Section 7). Events of Special Interest have to be followed up regardless of causality or 
relationship to study intervention.
Investigators should refer to the current radium-223 dichloride and pembrolizumab IB for the 
expected side effects. As with any agent, there is always the potential for unexpected AEs, 
including hypersensitivity reactions.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs/SAEs, whether or not related to the study drugs, will be collected from the signing of 
the ICF until the EoT visit after the last dose of the study intervention at the time points 
specified in the SoA (Section 1.3); all AE/SAEs must be fully documented in the participant’s 
records and on the respective CRF pages by the investigator. 
An AE/SAE (irrespective of causal relationship) not completely resolved at the EoT visit must 
be followed up until resolution (chronicity, baseline grade or complete resolution) or until the 
investigator considers the event will not improve further. 
In addition, during the FU period participants will be followed for:

Study intervention related AEs/SAEs

All SAEs regardless of the investigator’s causality assessment, per 
pembrolizumab requirements, with an onset up to 90 days after cessation of 
study intervention or up to EoT visit ( 30 [+ 7] days following cessation of 
study intervention) if the participant initiates new anticancer therapy, 
whichever is earlier, need to be documented.

All occurrences of leukemia, myelodysplastic syndrome, aplastic anemia, and 
primary bone cancer or any other new primary malignancy; regardless of the 
investigator’s causality assessment. 

Any anti-cancer treatment and BHA

All bone fractures and bone associated events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of 
the investigator’s causality assessment. 

Radium-223 dichloride-related occurrences of febrile neutropenia or 
hemorrhage will also be collected.

Only during Active FU of Phase 2: SSEs need to be collected as either AEs or 
SAEs regardless of the investigator’s causality assessment.


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Medical occurrences that begin before obtaining informed consent will be recorded on the 
medical history section of the eCRF.
Medical findings (e.g., ECG or radiological findings), that conceivably started before
signing of informed consent, will be recorded as medical history.
Medical conditions that started before signing of informed consent and for which 
symptoms or treatment are present after signing of informed consent, at unchanged 
intensity, are recorded as medical history (e.g., allergic pollinosis).
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the AE section of the eCRF.
Medical occurrences that started before but deteriorated after obtaining informed consent will 
be recorded as AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in 
Section 8.3.6), will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to FU (as defined in Section 7.3). Further information on FU
procedures is given in Appendix 3 (Section 10.3).
8.3.4
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators.


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Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.5
Pregnancy
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected at least 6 months after the last dose of study intervention 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). The participant will be withdrawn from the study.
If a participant becomes pregnant while on treatment, the participant will be immediately 
discontinued from study treatment. The site will contact the participant at least monthly and 
document the participant’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the sponsor without delay and within 24 hours if 
the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or 
other disabling or life-threatening complication to the mother or newborn). The study 
investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the sponsor.
Radium-223 dichloride and pembrolizumab may have adverse effects on a fetus in utero. 
Furthermore, it is not known if pembrolizumab has transient adverse effects on the 
composition of sperm.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (from the day of study medication initiation (or 14 days prior to the initiation of 
study medication for oral contraception) throughout the study period and up to 6 months after 
the last dose of radium-223 dichloride or up to 120 days after the last dose of pembrolizumab, 
whichever is later. If there is any question that a participant of childbearing potential will not 
reliably comply with the requirements for contraception, that participant should not be entered 
into the study.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs.
For a pregnancy in the partner of a male study participant, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.
8.3.6
Adverse Events of Special Interest
Selected non-serious and serious AEs are also known as AEs of Special Interest (AESI) and 
must be reported to the sponsor (within 24 hours of the investigator’s awareness): 


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AESI - Pembrolizumab

Pembrolizumab overdose defined as ≥1000 mg (5 times the study dose) of 
pembrolizumab. 

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing (per DILI criteria).
AESI – Radium-223

All bone fractures (including asymptomatic radiologic fractures) 

Osteonecrosis of the jaw (ONJ)
8.4
Treatment of Overdose
Radium-223 dichloride
There have been no reports of inadvertent overdose of radium-223 dichloride solution during 
clinical studies. 
There is no specific antidote. In the event of an inadvertent overdose, general supportive 
measures, including monitoring for potential hematological and GI toxicity should be 
undertaken. 
Single doses up to 276 kBq (0.00746 milli Curie [mCi]) per kg b.w. were evaluated in a 
Phase 1 clinical trial and no dose-limiting toxicities were observed. 
Pembrolizumab
An overdose of pembrolizumab will be defined as any dose of 1000 mg or ≥5 times the 
indicated dose.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
General guidance
In the event of an overdose, the investigator should:
1. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study intervention can no longer be detected systemically (at least 120 days for 
pembrolizumab).
2. Obtain a serum sample for PK analysis (for pembrolizumab PK in case of a 
pembrolizumab overdose) within 3 days from the date of the last dose of study 
intervention if requested by the sponsor (determined on a case-by-case basis). In case 
the overdose is identified during a clinical visit, then a serum PK sample should be 
collected during that visit (if no scheduled PK sampling is planned).
3. Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration eCRF.
4. AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the AE eCRF.
5. Appropriate supportive treatment should be provided if clinically indicated.


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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
For detailed guidance on overdosing please refer to the most current version of the IBs for 
radium-223 dichloride and pembrolizumab.
8.5
Pharmacokinetics
In all participants enrolled, serial blood (serum) samples will be collected at the time points 
shown in the SoA Table 1-2, to assess PK of pembrolizumab.
Wherever possible, all efforts should be made to adhere to the blood sampling schedule as 
given in Section 1.3. Samples for PK will be collected at pre-dose on Cycles 1, 2, 4, 6, 8 and 
every 4 cycles thereafter and at EoT. The PK sampling beyond Cycle 8 might be discontinued
after sponsor agreement, if no additional benefit or knowledge will be expected.
A decision to analyze PK samples for pembrolizumab will be made during the course of the 
study. Until that time, samples will be held by the central lab.
When the PK assessments coincide with the ECG recording and/or the measurement of vital 
signs (blood pressure and heart rate), participants’ ECG and vital signs will be measured 
before collection of the PK sample. If this sequence is not feasible, then the investigating site 
should obtain the PK sample at the planned time, followed by 5-10 minutes period of quiet 
rest in supine or semi-recumbent position, then the ECG and finally the vital signs.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/IEC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF.
The date and time of actual blood sampling will have to be documented in the eCRF. The 
actual dosing start and stop date and time will have to be documented in the eCRF.
Instruction for the collection, processing, storage, and shipment of PK samples will be 
provided separately by the sponsor (sample handling sheets and Biosample Management 
Plan).
For this trial, PK parameters will not be calculated/reported by the sponsor; the samples may
be used for separate PK analyses under separate cover.
8.6
Pharmacodynamics
Refer to Section 8.8.
8.7
Genetics
Refer to Section 8.8.
8.8
Biomarkers
8.8.1
Biomarker Overview
For all participants, archival or fresh tumor material has to be collected during screening. For 
participants eligible for first line treatment and enrolled in Phase 1 or Phase 2 Cohort 1, PD-
L1 expression has be determined prior to enrollment to confirm eligibility. If a PD-L1 testing 
result is available (based on an approved or appropriately validated test) at screening and has 


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been performed in line with the protocol requirements, this can be used to confirm eligibility 
of the participant and does not need to be repeated. For all other participants (Phase 1 ≥ 2nd 
line treatment and Phase 2 Cohort 2) , the PD-L1 test result is not required to be available 
before enrollment and will be determined retrospectively in a central laboratory.
Tumor samples are to be collected for all participants and will further be used to determine 
TMB by Next Generation Sequencing (NGS) as well as to determine the inflammatory status 
of a tumor.
Pharmacodynamic biomarker evaluations will be conducted for all participants enrolled in the 
study using circulating markers. Biomarker samples will be collected from participants as 
specified in the SoA and as described below, and will include the following:

Serum/urine samples will be used to assess baseline and post-dose levels of bone 
formation (e.g., B-ALP, PINP) or bone resorption markers (e.g., bCTX , NTX).

Plasma will be used for evaluations of circulating tumor DNA, and circulating protein 
markers such as cytokines

Whole blood will be collected for immune cell analysis.
Blood, serum/urine, and plasma samples will be collected on Day 1 (predose) and Day 15 of 
Cycle 1, thereafter on Day 1 (predose) of subsequent cycles, and during the EoT visit.
Samples will be tested for bone biomarkers and circulating proteins or tumor DNA.
Details on collection, processing, storage and shipment of samples are described in a separate 
document (e.g., sample handling sheets or laboratory manual). 
Samples may be stored for a maximum of 15 years (or according to local regulations) 
following the last participant’s last visit for the study at a facility selected by the sponsor to 
enable further analysis of biomarker responses to pembrolizumab.
8.8.2
Immunogenicity Assessments
Antibodies to pembrolizumab will be evaluated in serum samples collected from all 
participants according to the SoA. Samples will be collected at pre-dose on Cycles 1, 2, 4, 6, 8 
and every 4 cycles thereafter and at EoT. Immunogenicity sampling beyond Cycle 8 might be 
discontinued after sponsor agreement, if no additional benefit or knowledge will be expected
(Section 8.5). 
A decision to analyze immunogenicity samples for pembrolizumab will be made during the 
course of the study. Until that time, samples will be held by the central lab.
Serum samples will be screened for antibodies binding to pembrolizumab and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify the 
stability of antibodies to pembrolizumab and/or further characterize the immunogenicity of 
pembrolizumab.
Instructions for the collection, processing, storage and shipment of IM samples will be 
provided separately by the sponsor (e.g., sample handling sheets or laboratory manual).
For this trial Immunogenicity results will not be reported by the sponsor; the samples may be 
used for separate analyses and reported under a separate report.
8.9
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.


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9.
Statistical Considerations
9.1
Statistical Hypotheses
9.1.1
Phase 1 
No formal statistical hypotheses will be tested. Analysis will be descriptive and exploratory. 
All data will be pooled, and descriptive analyses will be summarized and listed by dosing 
cohort at the end of Phase 1.
9.1.2
Phase 2 Efficacy
The primary objective of Phase 2 is to assess the efficacy of the combination of radium-223 
dichloride and pembrolizumab (compared with pembrolizumab alone in Cohort 1 only).
The primary endpoint, ORR as determined by RECIST 1.1, will be tested using the chi-square
test in Cohort 1, and the exact binomial test in Cohort 2. 
In Cohort 1, the population of inference is patients with treatment-naïve Stage IV non-small 
cell lung cancer with PD-L1 TPS ≥ 50%.  The null and alternative hypotheses for Cohort 1 are:
H0: p1≤p2 versus H1:p1>p2
where p1 is the true response rate fto treatment with pembrolizumab and radium-223 in this 
population, and p2 is the true response rate to treatment with pembrolizumab monotherapy in 
this population.
In Cohort 2, the population of inference is patients with Stage IV non-small cell lung cancer
of any PD-L1 status who progressed following a prior line of treatment with an immune 
checkpoint inhibitor. The null and alternative hypotheses for Cohort 2 are:
H0: p≤0.1 versus Ha: p>0.1
Where p is the true response rate to treatment with the pembrolizumab and radium-223 
combination in this population, and 0.1 is the assumed historical ORR for patients in this 
population. 
Both hypotheses will be tested at the one-sided α 0.1 level. 
The tests for Cohorts 1 and 2 are assumed independent. There will be no adjustment for 
multiplicity in this Phase 2 study. There will be no other formal statistical testing in this study.
9.1.3
Phase 2 Safety
There will be no formal hypothesis testing of safety in either cohort of Phase 2. 
9.2
Sample Size Determination
9.2.1
Phase 1
Phase 1 is designed to determine the tolerable dose of radium-223 dichloride in combination 
with standard dose of pembrolizumab (200 mg pembrolizumab Q3W) in participants with 
NSCLC. The dose de-escalation will follow ‘3+3” design. No formal sample size calculation 
was performed. It is planned to treat up to 10 participants evaluable for DLT at each dose
level, and it expected that 10 to 20 participants will be treated in Phase 1, not including 
replacements for those who do not complete the DLT assessment window.


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9.2.2
Phase 2
In both Cohort 1 and 2, sample size is calculated based on the primary endpoint: ORR, which 
is determined by RECIST v1.1 (as defined in Section 9.4.1).
Cohort 1:
Assuming the control group (pembrolizumab alone) ORR is 45%, in order to detect a 25% 
increase in ORR in the experimental group (radium-223 dichloride + pembrolizumab), a total 
of 104 participants are required to achieve 90% power, based on a test with 1-sided α = 0.1 
and a randomization ratio of 1:1 between the 2 groups (experimental and control groups).
Cohort 2:
The null hypothesis of the true ORR is 0.10 will be tested against a 1-sided alternative 
hypothesis of the true ORR is greater than 0.1. By utilizing Simon’s 2-stage Min-Max design, 
a total of 40 participants are required to achieve 90% power with 1-sided α=0.1 when the true 
ORR is 0.25. In the first stage, 27 participants will be accrued. If there are 2 or fewer 
responses in these 27 participants, the cohort will be stopped early for futility. Otherwise, 
another 13 participants will be accrued to reach the total number of 40 participants in the 
second stage. The null hypothesis will be rejected if 7 or more responses are observed in the 
40 participants.
9.3
Populations for Analyses
9.3.1
Phase 1
The DLT Population will be used for evaluation of the number of participants experiencing 
DLTs in Phase 1. The DLT analysis population will include all the following participants:

Participants who experienced a DLT during the DLT observation window, which is 
defined as the time from the first dose of study treatment through 6 weeks after 
administration of the first dose of pembrolizumab.

Participants who did not experience a DLT, and who were compliant with treatment 
administration during the DLT observation window.
The Safety Population (SAF) will be used for summaries of safety data. The Safety 
Population will consist of all participants who received at least 1 administration of study 
treatment. Participants who were replaced for evaluation of DLT in Phase 1 will still be 
included in the Safety Population, if they received at least 1 administration of any study 
treatment (any component of the combination).
The Efficacy population (EFF) will be used for assessment of antitumor activity. The 
efficacy population will include all participants who received at least 1 administration of 
planned dose of any study treatment. 
9.3.2
Phase 2
The Full Analysis Set (FAS) will include all participants treated in Cohort 2 or randomized in 
Cohort 1 regardless of whether any study treatment was received. Participants in Cohort 1 will 
be analyzed for efficacy in the treatment groups they were randomized to even if a participant
received, partially or completely, the wrong study treatment. Participants in Cohort 2 must 
have received at least 1 administration of planned dose of any study treatment. This is the 
primary analysis population for efficacy. The FAS definition for Cohort 1 is identical to the 
traditional definition for an Intent-to-Treat population.


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The Safety Population (SAF) will be used for summaries of safety data. The Safety 
Population will consist of all participants who received at least 1 administration of any study 
treatment. The analysis will be performed using actual treatment received. For patients in 
Cohort 1, to be assigned to the combination arm, a participant must have received at least one 
administration (any non-zero amount) of any study treatment. 
9.4
Statistical Analyses
The statistical analysis plan (SAP) will be developed and finalized before database lock and 
will describe the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints.
9.4.1
Efficacy Analyses
9.4.1.1
Phase 1 Efficacy Variables
Secondary efficacy variables in the Phase 1 will include ORR, DCR, DoR.
Exploratory efficacy variables in the Phase 1 will include PFS, OS, iORR, iDCR, iPFS, and 
iDoR.
Phase 1 efficacy variables will have the same definition as described for the corresponding 
Phase 2 efficacy variables. See Section 9.4.1.2.
9.4.1.2
Phase 2 Efficacy Variables
The efficacy objectives in the Phase 2 will be demonstrated by the following endpoints:
Primary endpoint:

ORR, as determined by RECIST v1.1, is defined as the proportion of participants in 
the analysis population who have best overall response of CR or partial response (PR) 
during the course of the study. A CR or PR must be confirmed by a second assessment 
of CR/PR at least 4 weeks apart. 
Secondary endpoints:

PFS is defined as the time from the Reference Date (see below) to the date of earliest 
radiological progression per RECIST 1.1 or death due to any cause, whichever occurs 
first. Additional details including censoring rules will be defined in the SAP. 

OS is defined as the time from the Reference Date (see below) to death due to any 
cause. Participants who are alive at the time of database cut-off will be censored at the 
last date known to be alive.

DoR is defined as the time interval from the date of first response (CR or PR) to the 
date of disease progression (as determined by RECIST 1.1 response criteria) or death, 
whichever comes first. Only responders (participants with confirmed CR or PR per 
RECIST 1.1) will be included in the analysis. 

DCR is defined as the proportion of participants in the analysis population who have 
CR or PR, or SD per RECIST 1.1 for at least 6 weeks from the first study treatment. 
Tertiary/Exploratory endpoints:

iORR as determined by iRECIST, is defined as the proportion of participants in the 
analysis population who have best overall response (iBOR) of iCR or iPR during the 
course of the study. iCR or iPR must be confirmed by a second assessment of iCR/iPR 
at least 4 weeks apart.


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
iPFS is defined as the time from the Reference Date (see below) to the date of 
radiological progression per iRECIST criteria or death, whichever occurs first. 
Additional details including censoring rules will be defined in the SAP. 

iDoR is defined as the time interval from the date of first response (iCR or iPR) to the 
date of disease progression per iRECIST  or death, whichever comes first. Only 
responders (participants with confirmed iCR or iPR per iRECIST) will be included in 
the analysis. Additional details including censoring rules will be defined in the 
SAP.iDCR is defined as the proportion of participants in the analysis population who 
have iCR or iPR, or iSD per iRECIST for at least 6 weeks from the first study 
treatment. Assessments of iCR, iPR, or iSD occurring following unconfirmed 
progression per iRECIST will count as continuous disease control for purposes of this 
endpoint.

SSE-FS is defined as the time from the Reference Date (see below) to the earliest 
occurrence of one of the following:
o
the use of EBRT to relieve skeletal symptoms 
o
the occurrence of new symptomatic pathological bone fractures (vertebral or 
non-vertebral)
o
the occurrence of spinal cord compression
o
a tumor related orthopedic surgical intervention 
o
Death from any cause

Patient reported outcome (PRO) (Phase 2 Cohort 1 only):
The EORTC QLQ-C30 was developed to assess the quality of life of cancer subjects 
and is the most widely used cancer-specific HRQoL instrument.  It contains 30 items 
and measures five functional dimensions (physical, role, emotional, cognitive, and 
social), three symptom items (fatigue, nausea/vomiting, and pain), six single items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact) 
and global health and quality of life.  The global health and quality of life scale uses a 
7 point scale scoring with anchors (1=very poor and 7=excellent); the other items are 
scored on a 4 point scale (1=not at all, 2=a little, 3= quite a bit, 4=very much). 
The EORTC QLQ-LC13 (Bergman et al. 1994), a supplemental lung cancer-specific 
module used in combination with QLQ-C30 (Aaronson et al. 1993), comprises multi-
item and single-item measures of lung cancer-associated symptoms (cough, 
hemoptysis, dyspnea, and site specific pain) and treatment-related symptoms (sore 
mouth, dysphagia, peripheral neuropathy and alopecia). It is scored on a 4 point scale 
(1=not at all, 2=a little, 3=quite a bit, 4=very much) and has been translated and 
validated into more than 60 languages.
o
Time to deterioration of Global heath (TTDGH) is defined, as time from the 
Reference Date (see below) to deterioration from the baseline EORTC QLQ-
C30 global/health quality of life scale score or death, whichever occurs first. 
Details included the score change required for deterioration and censoring rules 
will be defined in the SAP.
o
Time to deterioration of dyspnea (TTDD) is defined, as time from the 
Reference Date (see below) to deterioration from the baseline EORTC QLQ-
LC13 dyspnea scale score or death, whichever occurs first. Details included the 
score change required for deterioration and censoring rules will be defined in
the SAP.


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o
Change from baseline in EORTC QLQ-C30 symptom scale scores (fatigue, 
nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, 
diarrhea, financial difficulties) and item scores is defined, for each symptom 
scale and each item score at each post-baseline assessment timepoint, as the 
change in the applicable score from baseline to the timepoint. 
o
Change from baseline in EORTC QLQ-LC13 symptom scale scores (dyspnea, 
pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and 
hemoptysis) and item scores is defined, for each symptom scale and each item 
score at each post-baseline assessment timepoint, as the change in the 
applicable score from baseline to the timepoint.
The Reference Date is defined as the date of randomization (Phase 2 Cohort 1) or date of first 
dose of pembrolizumab (Phase 1 and Phase 2 Cohort 2). 
9.4.1.3
Statistical Methods for Phase 1 Efficacy Analyses
The analysis of Phase 1 efficacy variables will be descriptive. 
The ORR and DCR will be summarized in the EFF by dose cohort and overall. Confidence 
intervals (CI) will be provided overall and for each dose cohort with at least 10 participants. 
The number and types of responses will be listed and summarized separately, as appropriate.
DoR will be summarized descriptively for each dose cohort (if there will be dose de-
escalation), if data warrant, using Kaplan-Meier medians and quartiles.
Details will be described in the SAP
9.4.1.4
Statistical Methods for Phase 2 Efficacy Analyses 
The ORR in Cohort 1 will be tabulated based on the number and percentage of participants 
attaining either a CR or PR for each treatment group in the FAS. The chi-square test will be 
performed for differences between treatment groups. The observed treatment difference and 
its 80% and 95% CIs will be reported. Binomial exact 80% and 95% CIs for ORR will be 
provided for each treatment group.
The ORR in Cohort 2 will be tabulated based on the number of percentage of participants 
attaining either a CR or PR in the SAF. An exact binomial test will be performed. The null 
hypothesis will be rejected if at least 7 responders are observed. Binomial exact 80% and 95% 
CIs for ORR will be provided.
Additional details, including details for calculating the p-value, will be described in the SAP.
Secondary endpoints:
PFS will be summarized descriptively, by treatment group in Cohort 1 and overall in Cohort 2, 
using Kaplan-Meier quantile estimates and graphic displays. Details will be described in the 
SAP including rules for censoring. DoR will be summarized descriptively for by treatment 
group in Cohort 1 and overall in Cohort 2, if data warrant, using Kaplan-Meier medians and 
quartiles. Details on rules for censoring will be provided in the SAP.
The DCR will be analyzed as specified for ORR, except that no hypothesis test will be 
performed. 
OS will be summarized, by treatment group in Cohort 1 and overall in Cohort 2, using 
Kaplan-Meier quantile estimates and graphic displays. For the analysis of OS, the last date of 
known contact will be used for those participants who have not died at the time of analysis; 
such participants will be considered censored. Further details on rules for censoring will be 
provided in the SAP.


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Tertiary/Exploratory endpoints:
iORR and iDCR will be analyzed as specified for ORR.
iDoR will be summarized in the same manner as DoR. 
iPFS, SSE-FS, TTDGH, and TTDD will be summarized in the same manner as PFS.
Change in baseline in EORTC QLQ-C30 and EORTC QLQ-LC13 symptom scale and item 
scores will be summarized with descriptive statistics at baseline and each post-baseline 
timepoint. Plots of change over time may be provided for selected scores. Details will be 
provided in the SAP. 
9.4.2
Safety Analyses
All safety analyses for Phase 1 and Phase 2 will be performed on the Safety Population. 
Safety data will be presented in tabular and/or graphical format and summarized descriptively.
All collected safety endpoints (e.g., laboratory tests, vital signs, ECG) will be summarized 
according to the scheduled, nominal visits at which they were collected. Complete details will 
be provided in the SAP.
AEs will be coded using the latest Medical Dictionary for Drug Regulatory Affairs (MedDRA)
version. AEs will be graded by the investigator according to the NCI-CTCAE v.5.0.
Events will be summarized by frequency and proportion of total participants, by system organ 
class and preferred term. Separate summaries will be given for all AEs, treatment-related AEs, 
SAEs and AEs leading to discontinuation of study treatment and dose modification. AEs, if 
listed in the NCI-CTCAE v.5.0, will be summarized by the maximum grade.
DLTs will be listed for Phase 1 participants and summarized by dose cohort (if there is dose 
de-escalation).
Any AEs of special interest will be summarized. An analysis of time to bone fracture will be 
performed. Details will be described in the SAP.
The incidence of deaths and primary cause of death will be summarized and listed.
Laboratory abnormalities will be summarized by severity and, where applicable, by dose 
cohort or treatment group. Frequency and incidence rates will be provided. Frequency tables 
will also be provided for changes in severity from baseline to worst value post-baseline. 
Laboratory test results outside the reference ranges will be summarized using proportions. 
Summaries by visit will include data from scheduled assessments only, and all data will be 
reported according to the nominal visit date for which it was recorded (i.e., no visit windows 
will be applied). Unscheduled data will be included in ‘worse case post baseline’ summaries 
which will capture a worst case across all scheduled and unscheduled visits after the first dose 
of study treatment. Further details will be provided in the SAP.
Data for vital signs and ECGs will be summarized based on predetermined criteria identified 
to be of potential clinical concern. Further details will be provided in the SAP.
9.4.3
Other Analyses
The pharmacodynamic, and biomarker exploratory analyses will be described in the statistical 
analysis plan finalized before database lock, Additional exploratory analyses may be 
described in documents separate from the study SAP. The pharmacodynamic analyses will be 
presented separately from the main clinical study report. In case the PK samples are going to 
be analyzed, the analyses will be described and results will be presented separately from the 
main clinical study report.


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9.5
Interim Analyses 
In Phase 2 Cohort 1, an interim analysis will be performed when 52 participants are 
randomized and then treated for at least 12 weeks or have PD. The analysis will be delayed 
pending confirmation of response if a participant has unconfirmed response at 12 weeks. A 
Hwang-Shih-DeCani (Hwang et al. 1990) futility boundary with γ=-2 will be used for interim 
efficacy assessment and the type II error spent at the interim analysis is about 2.7%. If the 
futility boundary is crossed based on the interim analysis results, Cohort 1 will be stopped for 
futility. 
At the time of interim analysis, Cohort 1 is stopped for futility if the difference in ORR 
(radium-223 dichloride plus pembrolizumab - pembrolizumab) is < -0.8% or 1-sided P-value 
is > 0.524. This actual threshold for P-value or treatment difference might change based on 
the actual number of participants at the time of interim analysis. There is no plan to stop the 
study at the interim analysis due to superiority of the combination arm. Accrual will not be 
paused for the interim analysis.
In Phase 2 Cohort 2, a look will be performed when 27 participants are enrolled. If there are 
2 or fewer responses at the time the 27th participant is treated, accrual will be paused until all 
participants have the Week 12 tumor assessment or have PD. If at the Week 12 assessment 
there are 2 or fewer confirmed responses and a participant has unconfirmed response, the 
analysis will be delayed pending confirmation of response. If there are still 2 or fewer 
responses, then Cohort 2 will be stopped for futility.
9.5.1
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be instituted for this study in order to ensure 
ongoing safety of study participants in the Phase 2 portion of this study, and to conduct the 
planned formal futility analysis of Cohort 1. 
Safety data will be monitored by DMC periodically and the DMC may recommend that the 
study can be stopped for any safety findings. The DMC will conduct risk/benefit assessments
during each periodic data review meeting and provide a formal recommendation for 
continuation/termination of each cohort of the study.
An independent unblinded Statistical Analysis Center will conduct the planned formal Cohort 
1 futility analysis. The DMC will review results and provide a formal recommendation for 
continuation/termination of the Cohort 1 portion of the study. 
Only the DMC and the independent Statistical Analysis Center will have access to unblinded
study results of Phase 2 Cohort 1 prior to the study database being locked for the final analysis. 
Details on the responsibilities and operations of the DMC will be given in a separate DMC 
charter.


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10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g.,
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations.
10.1.2
Financial Disclosure
All relevant documentation will be filed in the trial master file.
10.1.3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative1 and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative1 (if acceptable per local law) will be required to sign 
a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.
                                                
1 Note: For Germany, participants who are not capable of providing informed consent will not
be included in this study. 


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
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative1.
Participants who are rescreened are required to sign a new ICF (Section 5.4).
10.1.4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred.

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.1.5
Dissemination of Clinical Study Data
Result Summaries of Bayer’s sponsored clinical trials in drug development Phases II, III, and 
IV and Phase I trials in patients are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the “Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases.” In addition, results of clinical drug 
trials will be provided on the publicly funded website www.ClinicalTrials.gov and European 
Union (EU) Clinical Trials Register in line with the applicable regulations.
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials 
in patients for medicines and indications approved in the US and EU on or after 
January 01, 2014 as necessary for conducting legitimate research.
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative.
10.1.6
Data Quality Assurance

All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.


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
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (e.g.,
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH for good clinical practice 
(GCP), and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor.
10.1.7
Source Documents

Source Documents Source documents provide evidence for the existence of the 
participant and substantiate the integrity of the data collected. Source documents are 
filed at the investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in a separate document. 
10.1.8
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines


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
Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
10.1.9
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments.
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10-1 will be performed by the local laboratory at time 
points specified in the SoA (Section 1.3).

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy testing is detailed in Section 8.2.7.
Table 10-1: Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular volume 
(MCV) 
Mean cell Hb (MCH)
Reticulocytes
White blood cell (WBC) count 
with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell 
(RBC) Count
Hb
Hematocrit
Clinical 
Chemistry
Blood urea 
nitrogen (BUN) or 
urea
Potassium
AST/ Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT)
Lipase
Total bilirubin
Creatinine
Sodium
ALT/ Serum Glutamic-
Pyruvic Transaminase 
(SGPT)
Total Protein
Albumin
Glucose (non-
fasting) 
Calcium
Alkaline phosphatase
Chloride
Magnesium
Phosphorus
Coagulation

International Normalized Ratio (INR) or Prothrombin time (PT)

Activated partial thromboplastin time (aPTT)
Calculation of 

By Cockcroft Gault


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Table 10-1: Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
eGFR
GFR [ml/min per 1.73 m²] = 
(140-age) x weight (kg) [x 0.85 if female] / (72 x serum creatinine [mg/dl])
Thyroid 
Function

Thyroid stimulating hormone (TSH)

Free T3

Free T4
Other 
Screening 
Tests

At screening: highly sensitive serum human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)a

From cycle 1 onwards: either urine or serum pregnancy test
The results of each test must be entered into the eCRF.
Abbreviations: ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; eCRF = electronic case report form; eGFR =estimated glomerular 
filtration rate; Hb = hemoglobin; hCG = human chorionic gonadotropin; INR = international normalized ratio; MCV 
= mean corpuscular volume; PT = prothrombine time; RBC = red blood cell count; SGOT = serum glutamic-
oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; TSH = thyroid stimulating hormone; 
WBC = white blood cell count
a Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC.
Investigators must document their review of each laboratory safety report.
10.3
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after signature of informed consent even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.


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
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as an AE or SAE if they fulfil the definition of an 
AE or SAE.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or 
SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication prolongs 


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hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Recording and FU of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records in lieu of completion of the AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by Bayer (the sponsor). In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to the sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and grade each event using NCI-CTCAE, version 5.0.


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
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Action taken with study intervention
The study intervention action should be recorded separately for each study intervention as 
detailed in the eCRF.

Drug withdrawn

Drug interrupted

Dose reduced

Dose not changed

Not applicable

Unknown
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of FU information 
and send an SAE FU report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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FU of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized FU
period, the investigator will provide the sponsor with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
10.3.4
Reporting of SAEs
SAE Reporting to Bayer via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to the sponsor will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see below) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
below) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the investigator file.
SAE Reporting to Bayer via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the investigator file.


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10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal (see 
below) unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy.
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered women of childbearing potential:
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above (e.g., mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
o
A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). However, 
in the absence of 12 months of amenorrhea, confirmation with more than 
one FSH measurement is required. 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance:
Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in this 
study. This applies only to male participants who receive study intervention.


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
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the FU will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure. 
Female Participants who become pregnant

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect FU information on the participant and the neonate, after 
obtaining the signed informed consent from both parents of the neonate, unless local 
law or specific circumstances of the respective case allow otherwise, and the 
information will be forwarded to the sponsor. Generally, FU will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy-related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting.

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study.


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10.5
Appendix 5: Patient Reported Outcome: EORTC QLQ-C30 and 
EORTC QLQ-C13
EORTC QLQ-C30
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" 
answers. The information that you provide will remain strictly confidential.
Not At 
All
A 
Little
Quite 
a Bit
Very 
Much
1.
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a short walk outside of the 
house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the day?
1
2
3
4
5.
Do you need help with eating, dressing, washing yourself or 
using the toilet?
1
2
3
4
During the past week:
Not At 
All
A 
Little
Quite 
a Bit
Very 
Much
6.
Were you limited in doing either your work or other daily 
activities?
1
2
3
4
7.
Were you limited in pursuing your hobbies or other leisure 
time activities?
1
2
3
4
8.
Were you short of breath?
1
2
3
4
9.
Have you had pain?
1
2
3
4
10.
Did you need to rest?
1
2
3
4
11.
Have you had trouble sleeping?
1
2
3
4
12.
Have you felt weak?
1
2
3
4
13.
Have you lacked appetite?
1
2
3
4
14.
Have you felt nauseated?
1
2
3
4
15.
Have you vomited?
1
2
3
4
16.
Have you been constipated?
1
2
3
4
Please go on to the next page


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During the past week:
Not At 
All
A 
Little
Quite 
a Bit
Very 
Much
17.
Have you had diarrhea?
1
2
3
4
18.
Were you tired?
1
2
3
4
19.
Did pain interfere with your daily activities?
1
2
3
4
20.
Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television?
1
2
3
4
21.
Did you feel tense?
1
2
3
4
22.
Did you worry?
1
2
3
4
23.
Did you feel irritable?
1
2
3
4
24.
Did you feel depressed?
1
2
3
4
25.
Have you had difficulty remembering things?
1
2
3
4
26.
Has your physical condition or medical treatment interfered 
with your family life?
1
2
3
4
27.
Has your physical condition or medical treatment interfered 
with your social activities?
1
2
3
4
28.
Has your physical condition or medical treatment caused you 
financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that 
best applies to you
29.
How would you rate your overall health during the past week?
             1               2               3              4              5              6              7
Very poor                                                                                         Excellent
30.
How would you rate your overall quality of life during the past week?
             1               2               3              4              5              6              7
Very poor                                                                                         Excellent


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EORTC QLQ-LC13
Patients sometimes report that they have the following symptoms or problems. Please indicate the
extent to which you have experienced these symptoms or problems during the past week. Please 
answer by circling the number that best applies to you.
During the past week:
Not At 
All
A 
Little
Quite 
a Bit
Very 
Much
31.
How much did you cough?
1
2
3
4
32.
Did you cough up blood?
1
2
3
4
33.
Were you short of breath when you rested?
1
2
3
4
34.
Were you short of breath when you walked?
1
2
3
4
35.
Were you short of breath when you climbed stairs?
1
2
3
4
36.
Have you had a sore mouth or tongue?
1
2
3
4
37.
Have you had trouble swallowing?
1
2
3
4
38.
Have you had tingling hands or feet?
1
2
3
4
39.
Have you had hair loss?
1
2
3
4
40.
Have you had pain in your chest?
1
2
3
4
41.
Have you had pain in your arm or shoulder?
1
2
3
4
42.
Have you had pain in other parts of your body? 
If yes, where ___________________________
1
2
3
4
43.
Did you take any medicine for pain?
1             No                              2                   Yes
If yes, how much did it help?
1
2
3
4
10.6
Appendix 6: Participant Identification Number
The Participant Identification Number is a 9-digit number consisting of:
Digit 1 to 5 = Unique center number
Digit 6 to 9 = Current participant number with the center


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10.7
Appendix 7: Response Evaluation Criteria in Solid Tumors 
(RECIST) and iRECIST
10.7.1
RECIST
The RECIST v1.1 criteria, based on the measurement of the longest diameter of tumor lesions, 
were designed and validated to assess treatment response in solid tumors (Eisenhauer et al. 
2009).
Measurable Disease:
Non-nodal tumor lesions: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) with a minimum size of:

10 mm by CT scan or MRI (slice thickness no greater than 5 mm). If scans with slice 
thicknesses greater than 5mm are used, the minimum size should be twice the slice 
thickness.

20 mm by chest x-ray

10 mm calliper measurement by clinical examination will not qualify as target lesion 
in this study, but can be considered as non-target lesions 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan or MRI (slice thickness 
recommended to be no greater than 5 mm). At baseline and in FU, only the short axis will be 
measured and followed.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that 
can be evaluated by CT or MRI, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability. 
Tumor lesions situated in a previously irradiated area are not considered measurable unless 
there has been demonstrated progression in the lesion.
Non-Measurable Disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to < 15mm short axis) are 
considered non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitic involvement of skin or lung, inflammatory breast disease, abdominal 
masses/ abdominal organomegaly identified by physical examination that are not measurable 
by reproducible imaging techniques and blastic bone lesions are all non-measurable.
Target Lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs should be identified as target lesions and be 
recorded and measured at baseline. These 5 lesions should be selected on the basis of their 
size (lesion with the longest diameter), be representative of all involved organs and should be 
suitable for reproducible repeated measurements. A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression of the measurable dimension of the disease. If 
there are > 5 measurable lesions, those not selected as target lesions will be considered 
together with non-measurable disease as non-target lesions.
Non-target Lesions: All non-measurable lesions (or sites of disease) plus any measurable 
lesions over and above the 5 listed as target lesions, including pathological lymph nodes (with 


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short axis ≥10 mm and < 15 mm), should be identified as non-target lesions and should also 
be recorded at baseline. Measurements are not required but these lesions should be noted at 
baseline and should be followed as “present”, “absent” or in rare cases “unequivocal 
progression”. In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the CRF (e.g.; ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
Best Response
The best overall response is the best response recorded from the start of the study treatment 
until the end of active FU. The participant’s best overall response assignment will depend on 
the findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. 
All participants will have their BEST RESPONSE on study classified as outlined below: 
Complete Response: Disappearance of all clinical and radiological evidence of tumor (both 
target and non-target). Any pathological lymph nodes (whether target or non-target) must 
have a reduction in short axis to < 10mm.
Partial Response: At least a 30% decrease in the sum of diameters of target lesions taking as 
reference the baseline sum, no unequivocal progression of existing non target lesions and no 
appearance of new lesions.
Stable Disease: Steady state of disease. Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, no unequivocal progression of existing non target lesions 
and no appearance of new lesions.
Progressive Disease: At least a 20% increase in the sum of diameters of target lesions taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5mm. Unequivocal progression of existing non target lesions or the 
appearance of one or more new lesions will also constitute PD. Ascites or pleural effusion will 
be recorded as disease progression only if proven malignant.
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response 
criteria are met, since a normal lymph node is defined as having a short axis of <10mm.
To achieve unequivocal progression in participants with measurable disease on the basis of 
the non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR 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.


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Table 10-2: RECIST v1.1: Response for participants with target and non-target 
lesions
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Response for this
category also requires
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
documented at least 6 weeks 
from start of treatment 
Not all 
evaluated
Non-PD
no
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR = complete response; NE = not evaluated; PD = progressive disease; PR = partial response; 
RECIST = response evaluation criteria in solid tumors; SD = stable disease
Participants with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. Every effort 
should be made to document the objective progression even after discontinuation of treatment.
Response duration
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study).
Stable disease duration
Stable disease is measured from treatment allocation until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is 
the reference for calculation of PD).
Methods of Measurement
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during FU. All measurements must be recorded 
in millimeters (or decimal fractions of centimeters), if applicable.
Clinical Lesions - Clinical lesions will not be considered measurable disease in this study. 
Chest X-ray - Lesions on chest X-ray will not be considered measurable disease in this study.
If new lesions are identified by chest X-ray in the course of the study, confirmation by CT or 
MRI is advised.
CT / MRI - CT scans and MRI should be performed with cuts of 5 mm or less in slice 
thickness. When slice thickness are greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness. This applies to all anatomical regions. 
Ultrasound - Ultrasound is not useful in assessment of lesion size and should not be used as 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. 
Endoscopy / Laparoscopy - The utilization of these techniques for objective tumor 
evaluation is not advised. 


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Cytology / Histology - These techniques can be used to differentiate between PR and CR in 
rare cases. When effusions are known to be a potential adverse effect of treatment, the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response (or stable disease) and PD.
10.7.2
iRECIST
iRECIST is RECIST v1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs (Table 10-3). iRECIST will be used by site 
investigator/local radiology review to make treatment decisions. This data will be collected in 
the clinical database
Description of the iRECIST Process for Assessment of Disease Progression
Assessment at screening and Prior to RECIST v1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST v1.1 Progression
For participants who show evidence of radiological PD by RECIST v1.1, the investigator will 
decide whether to continue a participant on study treatment until repeat imaging is obtained 
using iRECIST for participant management (see Table 10-3). This decision by the investigator 
should be based on the participant’s overall clinical condition.
Clinical stability is defined as the following: 

Evidence of clinical benefit (defined as the stabilization or improvement of disease 
related symptoms) as assessed by the investigator 

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status 

Absence of tumor progression at critical anatomical sites (i.e., leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions.

No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated at least 4 weeks, but no longer than 8 
weeks later to confirm PD by iRECIST, per investigator assessment.
Tumor flare may manifest as any factor causing radiographic progression per RECIST v1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir


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
Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original RECIST 
1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD and iCPD (confirmed PD). For 
purposes of iRECIST assessment, the first visit showing progression according to RECIST 
v1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors caused 
the progression.
At this visit, target and non-target lesions identified at baseline by RECIST v1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST v1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively as 
New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed (with 
an overall response of iCPD), or as showing persistent unconfirmed progression (with an 
overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the initial iUPD show worsening

For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared with any prior iUPD time point

For non-target lesions, worsening is any significant growth in lesions overall, 
compared with any prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point 

Visible growth of new non-target lesions 

The appearance of additional new lesions
Any new factor appears that would have triggered PD by RECIST v1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND


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
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST v1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. The assessment of the subsequent confirmation imaging proceeds in an 
identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion 
for progression is “reset”. This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered following consultation with the sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the intervals
as outlined in this protocol (see Section 8.1) 
Detection of Progression at Visits after Pseudo-progression Resolves
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
Target lesions

Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir is 
always the smallest sum of diameters seen during the entire trial, either before or after 
an instance of pseudo-progression.
Non-target lesions

If non-target lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.

If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of non-
target lesions, taken as a whole.


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New lesions

New lesions appear for the first time

Additional new lesions appear

Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum

Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with one 
exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to 
iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication (Seymour et al. 
2017).


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Page 91 of 98
Table 10-3: Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD by 
RECIST 1.1 
Repeat 
imaging 4 -8 
weeks later at 
site to confirm 
PD
May continue 
study treatment 
at the local site 
investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging 
by site by 
iRECIST.
Repeat imaging 
4-8 weeks later 
to confirm PD 
per physician 
discretion only
Discontinue 
treatment
Repeat tumor imaging 
confirms PD (iCPD) 
by iRECIST at the 
local site
No additional 
imaging 
required
Discontinue
treatment 
(exception is 
possible upon 
consultation with 
sponsor)
No additional 
imaging required
N/A
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
investigator 
assessment
Repeat 
imaging 4 -8 
weeks later to 
confirm PD.
Continue study 
treatment at the 
investigator’s 
discretion.
Repeat imaging 
4-8 weeks later
to confirm PD 
per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor imaging 
shows iSD, iPR, or 
iCR by iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at the 
local site 
investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion provided 
criteria for dose 
delay per protocol 
are met. 
Abbreviations: iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = 
modified response evaluation criteria in solid tumors 1.1 for immune-based therapeutics; iPR = iRECIST partial 
response; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; N/A = not 
applicable; PD = progressive disease; RECIST v1.1 = response evaluation criteria in solid tumors, version 1.1


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Page 92 of 98
10.8
Appendix 8: New York Heart Association Functional Classification
NYHA Class
Symptoms
I
No symptoms and no limitation in ordinary physical activity, e.g., shortness 
of breath when walking, climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g., walking short distances (20–100 m).
Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients.
Abbreviations: NYHA = New York Heart Association
Source (National Heart Lung and Blood Institute 2004)
10.9
Appendix 9: Line of Treatment
Line of treatment: A line of treatment is defined as 1 or more cycles of a planned treatment 
program. This may consist of 1 or more cycles of single-agent therapy or combination 
therapy, as well as a sequence of treatments administered in a planned manner. A new line of 
treatment starts when a planned course of therapy is modified to include other treatment 
agents (alone or in combination) as a result of disease progression, relapse, or toxicity. A new 
line of treatment also starts when a planned period off treatment is interrupted by a need for 
additional treatment for the disease (Rajkumar et al. 2011).
10.10
Appendix 10: Definition of PD/L1 refractory
This is only applicable to participants eligible for ≥2nd line treatment in Phase 1 and in Phase 2 
Cohort 2. 
Participants must have progressed on treatment with an anti-PD-1/L1 monoclonal antibody 
(mAb) administered either as monotherapy, or in combination with other checkpoint 
inhibitors or other therapies. PD/L1 treatment progression is defined by meeting all of the 
following criteria:
a) Has received at least 2 doses of an approved anti-PD-1/L1 mAb. 
b)
Has demonstrated disease progression after PD-1/L1 as defined by RECIST 
v1.1. The initial evidence of PD is to be confirmed by a second assessment no 
less than four weeks from the date of the first documented PD, in the absence 
of rapid clinical progression. 
c) PD has been documented within 12 weeks from the last dose of anti-PD-1/L1 
mAb. 
1. iRECIST: Guidelines for response criteria for use in trials testing 
immunotherapeutics (Seymour et al. 2017).
2. This determination is made by the investigator. Once PD is confirmed, 
the initial date of PD documentation will be considered the date of 
disease progression.


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Page 93 of 98
10.11
Appendix 11: Abbreviations
AAP
abiraterone acetate plus prednisone/prednisolone
ADA
anti-drug antibodies
AE
adverse event
AESI
adverse event of special interest
AIST
National Institute of Advanced Industrial Science and Technology
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AQA
analgesic quantification algorithm
AST
aspartate aminotransferase
B-ALP
bone alkaline phosphatase
BCG
Bacillus Calmette-Guérin
bCTX
B-carboxyl-terminal cross-linking telopeptide of type I collagen
BHA
bone health agent
BRAF
v-Raf murine sarcoma viral oncogene homolog B
BUN
blood urea nitrogen
C
cycle
°C
degree Celsius
CD
cluster of differentiation
CFR
code of federal regulations
CI
confidence interval
CIOMS
council for international organizations of medical sciences
CNS
central nervous system
CR
complete response
CRPC
castration resistant prostate cancer
CT
computed tomography
CTCAE 
common terminology criteria for adverse events (v.5.0)
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte associated protein 4
CTSP
clinical trial supply plan
DCR
disease control rate
DICOM
digital imaging and communications in medicine
DILI
drug induced Liver Injury
DK
decay correction factor
DL
dose level
DLT
dose limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DoR
duration of response
EBRT
external beam radiotherapy
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group 
(e)CRF
(electronic) case report form
EDC
electronic data capture
e.g.
exempli gratia / for example
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
EORTC 
European Organization for Research and Treatment of Cancer 
EoT
end of treatment
EU
European Union
°F
degree Fahrenheit
FACS
fluorescence activated cell sorting
FAS
full analysis set
FDG
2-deoxy-[18F]fluoro-D-glucose
FSH
follicle-stimulating hormone


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Page 94 of 98
FU
follow-up
GCP
good clinical practice
G-CSF
granulocyte colony-stimulating factor
GI
gastrointestinal
GM-CSF
granulocyte- macrophage colony-stimulating factor
GMP
good manufacturing practice
Hb
hemoglobin
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormonal replacement therapy
IB
investigator’s brochure
iBOR
immune best overall response
ICF
informed consent form
ICH
International Council for Harmonisation
iCPD
immune confirmed progressive disease
iCR
immune complete response
ICTP
C-telopeptide pyridinoline crosslinks of type I collagen
iDCR
immune disease control rate
iDoR
immune duration of response
i.e.
Id est (that is)
IEC
independent ethics committee 
IMP
investigational medicinal product
INR
international normalized ratio
IO
immune oncology
iPFS
immune progression-free survival
iPR
immune partial response
irAEs
immune-related AEs
IRB
institutional review board
iRECIST
immune response evaluation criteria in solid tumors, version 1.1
iSD
immune stable disease
ITT
intent-to-treat (population)
IUD
Intrauterine device
iUPD
immune unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous
IxRS
interactive voice/web response system
JRIA
Japan Radioisotope Association
kBq
kilo Becquerel
LET
linear energy transfer
mAb
monoclonal antibody
MBq
mega Becquerel
MCH
mean cell hemoglobin
mCi
milli Curie
mCRPC
metastatic castration resistant prostate cancer
MCV
mean corpuscular volume
MDS
myelodysplastic syndrome 
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRI
magnetic resonance imaging
nABs
neutralizing antibodies
NCI
National Cancer Institute
NE
not evaluated
NGS
next generation sequencing
NIST
National Institute of Standards and Technology
NOAC
novel oral anticoagulants
NSAIDs
nonsteroidal anti-inflammatory drugs


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Clinical Study Protocol BAY 88-8223 / 19781
Global AMD 2, 18 Sep 2020
Page 95 of 98
NSCLC
non-small cell lung cancer
NTX
amino-terminal cross-linking telopeptide of type I collagen
NYHA
New York Heart Association
OME
oral morphine equivalents
ONJ
osteonecrosis of the jaw
ORR
objective response rate
OS
overall survival
PBPK
Physiologically Based Pharmacokinetic Modeling
PD-1
programmed cell death protein 1
PD
progressive disease
PD-L1
programmed cell death protein ligand 1
PD-L2
programmed cell death protein ligand 2
PET
positron emission tomography
PFS
progression-free survival
PID
patient identification number
PINP
procollagen-type-Ι-N-terminal propeptide
PK
pharmacokinetics
PR
partial response
PRD
patient-ready dose
PRO
patient reported outcome
PS
performance status
PT
prothrombin time
Q2W
every 2 weeks
Q3W
every 3 weeks
QLQ
Quality of Life Questionnaire
RBC
red blood cell count
RECIST
response evaluation criteria in solid tumors, version 1.1
RNA
ribonucleic acid
ROS
reactive oxygen species
RP2D
recommended Phase 2 dose
rPFS
radiological progression free survival
SAE
serious adverse event
SAP
statistical analysis plan 
SD
stable disease
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SoA
schedule of activities
SSE
symptomatic skeletal event
SSE-FS
symptomatic skeletal event-free survival
T
thyroxine 
T1-DM
type 1 diabetes mellitus
T1/2
half-life
T3
triiodothyronine
T4
thyroxine
TKI
tyrosine kinase inhibitor
TMB
tumor mutational burden
TMDD
target-mediated drug disposition
TPS
tumor protein score
TSH
thyroid stimulating hormone
TTDD
time to deterioration of dyspnea
TTDGH
time to deterioration of global heath
ULN
upper limit of normal
US(A)
United States of America
WBC
white blood cell count


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Global AMD 2, 18 Sep 2020
Page 96 of 98
10.12
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 1 (29 OCT 2019)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall rationale for the amendment
Overall rationale: This protocol amendment was prepared to clarify and strengthen guidance 
on tumor assessment, eligibility criteria, toxicity management and DLT criteria, in line with 
Health Authorities’ requests. 
Section # and name
Description of change
Brief rationale
1.3 Schedule of Activities, 8.1
Efficacy Assessments
Clarification was made on bone 
scan requirement at screening.
Change made to ensure the 
extent of bone disease is 
accurately 
diagnosed/documented at 
screening.
5.1 Inclusion Criteria, 6.5 
Concomitant Therapy
Bisphosphonates or 
denosumab usage was made 
mandatory.
Precautionary measure to 
align with other radium-223 
studies.
5.2 Exclusion Criteria
History of osteoporotic fracture 
was added to the exclusion 
criteria.
Precautionary measure to 
align with other radium-223 
studies.
6.1.2 Dose Limiting Toxicities
Addition of DLT criterion for 
grade 3 liver toxicity in 
participants without liver 
metastases at screening.
To extend DLT criteria for liver 
toxicity in participants without 
liver metastases at screening.
6.1.2 Dose Limiting Toxicities
The DLT criterion for non-
hematologic toxicities was 
modified to also include any 
grade 4 laboratory event.
Update made since the 
CTCAE definition for most 
grade 4 laboratory 
abnormalities includes “life-
threatening consequences.”


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Global AMD 2, 18 Sep 2020
Page 97 of 98
11.
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Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life 
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Mar 3;85(5):365-76.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after 
Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 
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Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall Survival with 
Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018 Dec 
13;379(24):2342-50.
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: a 
modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) 
for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J 
Cancer. 1994;30A(5):635-42.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009 Jan;45(2):228-47.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence 
and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. 
Int J Cancer. 2015 Mar 1;136(5):E359-86.
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med. 1990 Dec;9(12):1439-45.
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Jan;46 Suppl 1:4S-12S.
Kuchuk M, Addison CL, Clemons M, Kuchuk I, Wheatley-Price P. Incidence and 
consequences of bone metastases in lung cancer patients. J Bone Oncol. 2013 
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Malamas AS, Gameiro SR, Knudson KM, Hodge JW. Sublethal exposure to alpha radiation 
(223Ra dichloride) enhances various carcinomas' sensitivity to lysis by antigen-
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Morris MJ, Fong L, Petrylak DP, Sartor AO, Higano CS, Pagliaro LC, et al. Safety and 
clinical activity of atezolizumab (atezo) + radium-223 dichloride (r-223) in 2L 
metastatic castration-resistant prostate cancer (mCRPC): Results from a phase Ib 
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High Blood Pressure Education Program. 2004.
Nilsson S, Cislo P, Sartor O, Vogelzang NJ, Coleman RE, O'Sullivan JM, et al. Patient-
reported quality-of-life analysis of radium-223 dichloride from the phase III 
ALSYMPCA study. Ann Oncol. 2016 May;27(5):868-74.
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SAP_001.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
An open-label, multicenter, Phase 1/2 study of radium-223 
dichloride in combination with pembrolizumab in participants 
with stage IV non-small cell lung cancer 
NCT Number: 
NCT03996473 
Document Date: 
31 JAN 2023 
 
 


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 1 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Title page 
An open-label, multicenter, Phase 1/2 study of radium-223 dichloride in 
combination with pembrolizumab in participants with stage IV 
non-small cell lung cancer 
Phase 1/2 study of radium-223 dichloride in combination with pembrolizumab in 
non-small cell lung cancer 
Bayer study drug 
BAY 88-8223 / radium-223 dichloride / Xofigo® 
Study purpose: 
dose finding and expansion 
Clinical study 
phase: 
1/2 
Date: 
31 JAN 2023 
Study No.: 
 
BAY 88-8223 / 
19781 
Version: 
Final 4.0 
Author: 
 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended 
solely for the guidance of the clinical investigation. Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) are not 
displayed. Hence, the appearance of product names without these symbols does not 
imply that these names are not protected. 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no 
signatures. 
The approval of the Statistical Analysis Plan is documented in a separate Signature 
Document. 
 
 
PPD


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 2 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Table of Contents 
Title page ............................................................................................................................... 1 
Table of Contents ................................................................................................................. 2 
Table of Tables ..................................................................................................................... 3 
Abbreviations ........................................................................................................................ 4 
1. 
Introduction ................................................................................................................... 6 
2. 
Study Objectives ............................................................................................................ 6 
2.1 
Primary objective ......................................................................................................... 6 
2.2 
Secondary objective ..................................................................................................... 6 
2.3 
Exploratory objectives ................................................................................................. 7 
3. 
Study Design .................................................................................................................. 7 
4. 
General Statistical Considerations .............................................................................. 9 
4.1 
General principles ........................................................................................................ 9 
4.2 
Handling of dropouts ................................................................................................... 9 
4.2.1 
Screen failures and rescreening ................................................................................ 9 
4.2.2 
Dropout ..................................................................................................................... 9 
4.2.3 
Replacement ............................................................................................................. 9 
4.3 
Handling of missing data ........................................................................................... 10 
4.3.1 
Efficacy variables ................................................................................................... 10 
4.3.2 
Safety variables....................................................................................................... 10 
4.3.3 
Laboratory values ................................................................................................... 10 
4.4 
Interim analyses and Data Monitoring Committee .................................................... 11 
4.5 
Data rules ................................................................................................................... 11 
4.6 
Final data review ........................................................................................................ 11 
5. 
Analysis Sets ................................................................................................................ 11 
5.1 
Assignment of analysis sets required by protocol ..................................................... 11 
5.2 
Assignment of other analysis sets .............................................................................. 12 
6. 
Statistical Methodology .............................................................................................. 12 
6.1 
Population characteristics .......................................................................................... 12 
6.1.1 
Disposition .............................................................................................................. 12 
6.1.2 
Demographic and baseline disease characteristics ................................................. 12 
6.1.3 
Treatment duration of study drug ........................................................................... 13 
6.2 
Efficacy ...................................................................................................................... 13 
6.2.1 
Objective response rate ........................................................................................... 13 
6.2.2 
Duration of response ............................................................................................... 14 
6.2.3 
Disease control rate ................................................................................................ 15 
6.2.4 
Progression free survival ........................................................................................ 16 
6.2.5 
Overall survival ...................................................................................................... 16 
6.3 
Pharmacokinetics/pharmacodynamics ....................................................................... 16 
6.4 
Safety ......................................................................................................................... 16 
6.4.1 
Dose limiting toxicities ........................................................................................... 16 
6.4.2 
Adverse events ........................................................................................................ 16 
6.4.3 
Deaths ..................................................................................................................... 18 
6.4.4 
Clinical laboratory evaluations ............................................................................... 18 


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 3 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
6.4.5 
Biomarkers.............................................................................................................. 21 
6.4.6 
Other safety endpoints ............................................................................................ 21 
7. 
Document history and changes in the planned statistical analysis ......................... 21 
8. 
References .................................................................................................................... 22 
 
Table of Tables 
Table 3–1: Planned dose Levels ................................................................................................. 8 
Table 6–1: Duration of response and progression free survival censoring rules ..................... 14 
Table 6–2: Two consecutive missed tumor assessments ......................................................... 15 
 
 


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 4 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
Abbreviations 
ADA 
anti-drug antibodies 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
ALK 
anaplastic lymphoma kinase 
BOR 
best objective response 
BRAF 
v-RAF murine sarcoma viral oncogene homolog B 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CSP 
clinical study protocol 
CTC 
Common Terminology Criteria 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DoR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
EFF 
efficacy population 
EGFR 
epidermal growth factor receptor 
EoT 
end of treatment 
GCP 
good clinical practice 
iBOR 
immune best objective response 
ICH 
International Council for Harmonisation 
iDCR 
immune disease control rate 
iDoR 
immune duration of response 
iPFS 
immune progression-free survival 
irAE 
immune-related adverse event 
iRECIST 
Modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics 
IRR 
infusion related reaction 
kBq 
kilo Becquerel 
LKAD 
last known alive date 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
nABs 
neutralizing antibodies 
NCI 
National Cancer Institute 
NE 
not evaluated 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death protein ligand 1 
PFS 
progression free survival 
PID 
participant identification number 
PK 
pharmacokinetics 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS 
reactive oxygen species 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
System Organ Class 


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 5 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
 
 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TMB 
tumor mutational burden 
TNM 
TNM Classification of Malignant Tumors 
TPS 
tumor protein score 
ULOQ 
upper limit of quantification 


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 6 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
1. 
Introduction 
This Statistical Analysis Plan (SAP) is based on the Phase 1 part for Clinical Study Protocol 
(CSP) BAY 88-8223 / 19781, Global Amendment 2 dated 18 SEP 2020. 
The purpose of the study is to determine the safety and assess the efficacy of the combination 
of radium-223 dichloride and pembrolizumab in participants with stage IV non-small cell lung 
cancer (NSCLC) with bone metastases who are either treatment naïve or have progressed on 
prior anti-programmed cell death protein (ligand) 1 (PD-L1/PD-1) therapy. 
The study consists of two phases, including a safety run-in as well as two distinct cohorts to 
assess the efficacy of the combination of radium-223 dichloride and pembrolizumab. 
The purpose of the Phase 1 part of the study is to determine the Recommended Phase 2 Dose 
(RP2D) of radium-223 dichloride in combination with the standard dose of pembrolizumab 
(200 mg pembrolizumab every 3 weeks) and establish the safety of the combination. 
In JAN 2021, Bayer decided to not further pursue the NSCLC study. At the time of the decision 
10 participants were enrolled in the treatment refractory group and none in the treatment naïve 
group; 7 of the 10 participants were treated. This decision was mainly based on strategic 
considerations, also acknowledging the recruitment challenges for the first line population 
encountered during the Phase 1 part of the study. No safety issues were observed for the 
combination and data observed so far are consistent with the known safety profile of both drugs. 
As a consequence of this decision, some analyses are not being done and some data are being 
displayed in listings rather than summarized. 
2. 
Study Objectives 
2.1 
Primary objective 
The primary objective of Phase 1 of this study is: 
 To assess the safety of the combination of radium-223 dichloride and pembrolizumab 
and to determine the RP2D: 
o Adverse event (AE) assessments using National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) (v 5.0) and 
incidence of dose limiting toxicities (DLT) 
2.2 
Secondary objective 
The secondary objective of Phase 1 of this study is: 
 To assess the efficacy of the combination of radium-223 dichloride and 
pembrolizumab: 
o Objective response rate (ORR) per Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 
o Duration of response (DoR) per RECIST v1.1 
o Disease control rate (DCR) per RECIST v1.1 


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2.3 
Exploratory objectives 
The exploratory objectives of Phase 1 of this study are: 
 To evaluate predictive, prognostic and pharmacodynamic biomarkers: 
o Programmed cell death protein ligand 1 (PD-L1), tumor mutational burden 
(TMB), bone markers, immune cell analysis and circulating protein markers 
 To assess the pharmacokinetics (PK) and immunogenicity of the combination of 
radium-223 dichloride and pembrolizumab (if applicable): 
o Trough PK concentrations and titers for anti-drug antibodies (ADAs) and 
neutralizing antibodies (nABs) for pembrolizumab (if applicable) 
 To explore efficacy of the combination of radium-223 dichloride and pembrolizumab 
o ORR per a modified RECIST 1.1 for immune-based therapeutics (iRECIST) 
[iORR] 
o DoR per iRECIST (iDoR) 
o DCR per iRECIST (iDCR) 
o Progression-free survival (PFS) per RECIST 1.1 and iRECIST 
o Overall survival (OS) 
3. 
Study Design 
This is an open-label, multicenter, Phase 1/2 study consisting of a Phase 1 part to determine the 
RP2D of radium-223 dichloride in combination with pembrolizumab and a Phase 2 part to 
evaluate the efficacy and safety of radium-223 dichloride in combination with pembrolizumab. 
The Phase 1 part consists of 4 phases: screening, treatment, active-follow-up and long-term 
follow-up periods: 
 The screening period is defined as the period from informed consent to start of any 
study treatment. 
 The treatment period is defined as the period from start of any study treatment to end 
of treatment visit. 
 The active follow-up period is defined as the period from end of treatment visit to day 
of last protocol stipulated procedure. 
 The long-term follow period is defined as the period from the day after the last 
protocol stipulated procedure (in case of completion of active follow-up) to at least 2 
years after last dose of radium-223. 
Participants receiving treatment beyond progression will still be classed as being in the 
treatment period until the end of treatment visit. 
The Phase 1 part of the study will include participants with stage IV NSCLC either treatment 
naïve (PD-L1 tumor protein score [TPS] ≥ 50%) or after progression on prior therapy with 
immune checkpoint inhibitors (irrespective of PD-L1 TPS). It is designed to determine the 
tolerable dose of radium-223 dichloride in combination with standard dose of pembrolizumab 
(200 mg pembrolizumab every 3 weeks for a maximum of 35 cycles). 
Radium-223 dichloride will be administered every 6 weeks for up to 6 administrations. All 
participants will be evaluated for occurrence of DLTs during the DLT observation window 
(6 weeks after first dose of pembrolizumab). 


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All Phase 1 participants will stay in the study and continue receiving study drug at the assigned 
dose level until withdrawal criteria are met. No intra-participant dose escalation or de-escalation 
is allowed. 
In Phase 1, approximately 10 to 20 participants will be treated for a total of at least 10 evaluable 
participants at the RP2D. 
Dose de-escalation decision 
The starting dose will be the monotherapy dose approved for castration resistant prostate cancer, 
55 kilo Becquerel (kBq)/kg body weight of radium-223 dichloride. In case of DLTs, the 
radium-223 dichloride dose may be reduced by one dose level to 33 kBq/kg body weight (see 
Table 3–1). 
Table 3–1: Planned dose Levels 
Dose Sequence 
Dose Level 
1 
55 kBq/kg (starting dose) 
2 
33 kBq/kg (lowest planned dose) 
The dose de-escalation will follow a 3 + 3 design. 
Decisions on whether to step down to the lower dose level of 33 kBq/kg body weight for 
radium-223 dichloride will follow the rules described below: 
 If 0 out of 3 participants experience a DLT: the dose level will then enroll to a total of 
up to 10 evaluable participants 
 If 1 out of 3 participants experience a DLT: 3 more participants will be enrolled at this 
dose level 
 If 1 out of the 6 participants experience a DLT: the dose level will then enroll a total 
of up to 10 evaluable participants 
 If 2 or more out of 6 participants experience a DLT: step-down to the lower dose level 
will be implemented. 
If during enrollment of the 10 participants, 3 participants experience a DLT, this dose level will 
be considered not tolerable and a step-down from 55 kBq/kg to 33 kBq/kg will be implemented. 
If no more than 2 out of 10 participants experience a DLT, 55 kBq/kg radium-223 dichloride 
will then be recommended for the Phase 2 part of the study. 
In case of dose de-escalation, the rules as outlined above will be followed with the exception 
that further dose de-escalation will not be allowed. If 2 or more out of 6 participants or 3 out of 
10 participants experience a DLT at the lower dose level of 33 kBq/kg, the study will be 
terminated. If no more than 2 out of 10 participants experience a DLT, 33 kBq/kg radium-223 
dichloride will then be recommended for the Phase 2 part of the study. 
Additional participants may be treated at the RP2D in Phase 1. 
Phase 1 should include a minimum of 3 participants refractory to prior therapy with immune 
checkpoint inhibitors (irrespective of PD-L1 TPS) at each dose level, if applicable. As 
participants who already failed prior therapy with an immune checkpoint inhibitor may behave 
differently in terms of safety than participants receiving first line treatment, the determination 
of the RP2D might be done separately for the 2 patient populations, if needed. 
Regular safety calls will be implemented with participation of the investigators and sponsor. 
The decision on potential dose de-escalation and the RP2D will be made by the sponsor in 


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consultation with the investigators during the dose decision meetings and will be made based 
on the incidence of DLTs, clinical assessment, and all available safety data. The dose decision 
meeting will be held after 3, 6 and/or 10 evaluable participants have completed the DLT 
observation period (at each dose level, if applicable). 
4. 
General Statistical Considerations 
4.1 
General principles 
The statistical evaluation will be performed using the software package SAS release 9.4 or 
higher (SAS Institute Inc., Cary, NC, USA). 
Unless otherwise specified: 
 Continuous variables will be summarized using amount of available data (n), mean, 
standard deviation, minimum, median, maximum and missing (provided it exceeds 0). 
 Categorical variables will be summarized using n and percentages. 
 For the time to event endpoints, the product limited estimates of the survival distribution 
function using Kaplan-Meier will be presented for each dose cohort: N, total failed, total 
censored, time to event (medians) with the associated 80% and 95% CIs), range (with 
or without censored), probability of event-free survival at pre-specified months, such as 
3, 6, 9, etc. months. Kaplan-Meier curves will be generated by dose, if necessary. 
4.2 
Handling of dropouts 
4.2.1 
Screen failures and rescreening 
Screen failures are defined as participants who consent to participate in the clinical study but 
do not meet the eligibility criteria. Participants may be rescreened under the following criteria: 
 The participant had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule, e.g., due to logistical reasons. 
 The inclusion/exclusion criteria preventing the participant’s initial attempt to participate 
have been changed (via protocol amendment). 
Screen failures will be registered to close the participant identification number (PID). After 
Sponsor approval of re-screening a new informed consent form will be signed and the 
participant will be assigned a new PID. A map between the original and the new PID will be 
maintained. For other reporting purposes, the participant will be identified by the rescreened 
PID, and the reported date of the rescreened informed consent. Rescreened participants will 
appear once in disposition summaries utilizing the rescreened PID. 
4.2.2 
Dropout 
Dropouts are eligible participants who withdraw during the DLT observation window (see 
Section 6.4.1) for reasons other than experiencing a DLT and who have not completed both 
1 dose of radium-223 dichloride and 2 cycles of pembrolizumab. Dropouts will be replaced. 
Dropouts will not be included in the DLT analysis set but will be included in the Safety and 
efficacy population (see Section 5). 
4.2.3 
Replacement 
In this study, “replacement” indicates the enrollment and treatment of additional participants to 
ensure that the required number of participants are eligible for the DLT population.  


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According to the protocol, subjects not completing the DLT observation window will be 
replaced if they discontinued for a reason other for a DLT.  Replaced subjects will be included 
in all other analyses for which they meet validity criteria. I.e., All treated subjects will be 
included in the safety analysis regardless of replacement for other purposes.  
4.3 
Handling of missing data 
In order to achieve the goal of a well-conducted clinical trial according to International Council 
for Harmonisation Good Clinical Practice (ICH-GCP), every effort should be made to collect 
all data. However, despite best efforts, it may be inevitable that missing or incomplete data are 
reported. 
All missing or partially missing data will be presented in the participant data listings as they are 
recorded on the case report form (CRF). Such listings will include reasons that data was not 
collected, was invalid, etc. where it has been collected in the eCRF. 
Except as otherwise specifically noted, missing data will not be imputed or carried forward in 
any statistical analysis. 
When appropriate, the following rules will be implemented so as not to exclude participants 
from summaries due to missing or incomplete data: 
4.3.1 
Efficacy variables 
Last known alive date (LKAD) and death date for efficacy variables will be imputed 
according to the following rules: 
 If partial date has day and month missing, then the date will not be imputed. 
 If partial date has missing day only, then the first day of the month will be assigned to 
the missing day. 
 If the imputed first of the month is before the treatment start date, then the date will be 
imputed as the treatment start date. 
4.3.2 
Safety variables 
When only partial dates are available, the following rules will be used for the derivation of 
treatment-emergence: 
 If AE partial date has day and month missing, date will not be imputed. Such events, 
recorded on the AE CRF, will be deemed treatment-emergent with indeterminable 
start and duration. 
 If partial date has missing day only, then the first day of the month will be assigned to 
the missing day. 
 If the imputed first of the month is before the treatment start date, then the date will be 
imputed as the treatment start date. 
 If the imputed first of the month places stop date before start date, then use start date. 
4.3.3 
Laboratory values 
For laboratory values below the lower limit of quantification (LLOQ) like “< xxx” or 
“≤ xxx”, or above the upper limit of quantification (ULOQ) like “> xxx” or “≥ xxx”, LLOQ 
or ULOQ (xxx) as applicable will be imputed for purposes of calculating descriptive statistics. 
The original laboratory values (“< xxx”, “≤ xxx”, “> xxx” or “≥ xxx”) will be presented in a 
listing. 


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4.4 
Interim analyses and Data Monitoring Committee 
Except for the dose de-escalation decisions described in Section 3 of this SAP, neither interim 
analysis nor a data monitoring committee are planned for Phase 1 of this study. The safety of 
study participants will be monitored regularly by investigators and sponsor experts. Monitoring 
activities, including dose decision meetings described in Section 3, will be based on clinical 
data management reports. 
4.5 
Data rules 
Generally, for each date stored in the database, a set of organizational variables will be 
derived in order to describe the temporal context of that date in the specific study: phase of 
study treatment (radium-223 dichloride or pembrolizumab) (screening, treatment or 
follow-up), day relative to the start of study treatment, day relative to the end of study 
treatment. Additional contextual variables may be created in analysis datasets. 
Unless otherwise specified, the baseline value for safety or efficacy data is defined as the last 
non-missing value on or prior to first administration date of any study treatment (radium-223 
dichloride or pembrolizumab). Any unscheduled (repeated) assessments/evaluations will be 
included in the determination of the baseline value. 
The duration for the time-to-event variables in days is calculated by (event/censoring date – 
reference date + 1). Time-to-event analysis reference date is the start of any study treatment 
date. Time-to-event variables may be converted to months for reporting as specified in this 
SAP. The unit will be noted in the Tables, Figures and Listings specifications. Conversion to 
months will divide by 30.4375. 
4.6 
Final data review 
The results of the final data assessment will be documented in the final list of important 
deviations, validity findings and assignment to analysis set(s). Any changes to the statistical 
analysis prompted by the results of the review of study data will be documented in an 
amendment and, if applicable, in a supplement to this SAP. 
5. 
Analysis Sets 
5.1 
Assignment of analysis sets required by protocol 
Dose Limiting Toxicity (DLT) population 
The DLT population will be used for evaluation of the number of participants experiencing 
DLTs. The DLT population will include all the following participants: 
 Participants who experienced a DLT during the DLT observation window (see 
Section 6.4.1) 
 Participants who did not experience a DLT, and who were not dropouts as defined in 
Section 4.2. 
Safety population (SAF) 
The SAF will be used for summaries of safety data. The SAF will consist of all participants 
who received at least 1 administration of study treatment. Participants who were replaced for 
evaluation of DLT will still be included in the SAF, if they received at least 1 administration of 
the study treatment. 


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Efficacy population (EFF) 
The EFF will be used for assessment of antitumor activity. In Phase 1, the EFF will include all 
participants who received at least 1 administration of planned dose of any study treatment. 
5.2 
Assignment of other analysis sets 
Enrolled population 
All participants who signed informed consent will be considered part of the enrolled population. 
Rescreened participants will be included in the enrolled population once and identified by the 
rescreened PID. 
6. 
Statistical Methodology 
No formal statistical hypotheses will be tested in the Phase 1 portion of the study. Analysis will 
be descriptive and exploratory. Descriptive analyses at the end of Phase 1 will be summarized 
and listed by dosing cohort. In the event that the RP2D is determined separately for the 2 patient 
populations (treatment naïve and treatment refractory participants), the analysis will be 
presented by dosing cohort for each patient population, as applicable. 
6.1 
Population characteristics 
6.1.1 
Disposition 
The number and percentage of enrolled participants who did not complete screening, assigned 
to treatment, were never treated, and who started treatment, and treated participants who 
terminated treatment, and who are ongoing with treatment will be presented. The number and 
percentage of treated participants who started, completed or are ongoing with active follow-up, 
and long-term follow-up will also be presented. The number and percentage of participants with 
each reason for terminating screening, treatment, terminating active follow-up, and terminating 
long-term follow-up, will also be presented. The number and percentage of participants in each 
analysis set together with reasons for non-inclusion will be tabulated. 
Participants who discontinued will also be listed. 
The number and percentage of participants in each protocol required analysis set together with 
reasons for non-inclusion will be tabulated. 
6.1.2 
Demographic and baseline disease characteristics 
Descriptive summaries of demographics and baseline disease characteristics will be presented 
by dosing cohort and overall for the SAF. 
The following demographic data will be summarized: 
 Sex (Female, Male, Not reported) 
 Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Not reported, Multiple) 
 Age at Screening (years) 
 Age group (< 65, ≥ 65, 65 – 74, 75 – 84, ≥ 85 years) 
 Weight at Baseline (kg) 


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The following baseline disease characteristics will be summarized: 
 Cigarette smoking status (never, former, current) 
 Patient population (treatment naïve, treatment refractory) 
 Prior systemic lines of therapy 
 PD-L1 TPS treatment refractory (< 1%, 1 – 19%, 20 – 49%, ≥ 50%) 
 Any of EGFR, ALK, or ROS mutation (Yes, No) 
 Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score (0 vs 1) 
 NSCLC histology (squamous cell carcinoma, large cell carcinoma, non-squamous cell 
carcinoma) 
 Stage at initial diagnosis (TNM classification) 
 Stage at study entry (TNM classification) 
 Grading (American Joint Committee on Cancer [AJCC]) at initial diagnosis 
 Time from initial diagnosis to first study treatment (months) (simple summary 
statistics, standard means) 
 Time from most recent progression/ relapse to first study treatment (months) (simple 
summary statistics, standard means) 
Demographics and baseline disease characteristics will be listed. 
6.1.3 
Treatment duration of study drug 
Treatment duration of radium-223 dichloride and pembrolizumab respectively will be 
summarized by presenting descriptive statistics of overall time under treatment (including 
interruptions/delays), number of injections of radium-223 dichloride (6-week interval) and 
number of cycles of pembrolizumab (3-week interval). Number of injections of radium-223 
dichloride and number of cycles will be presented using both descriptive statistics and 
categorically. Cycles for pembrolizumab will be split into the following categories (0, 1 to < 3, 
3 to < 5, 5 to < 9, 9 to ≤ 12, and > 12). 
Overall time under treatment (weeks) will be calculated as: 
day of last dose − day of first dose +  1
7
 
A cycle is defined as 3-week interval and starts with every new administration of 
pembrolizumab. 
Exposure to radium-223 dichloride and pembrolizumab will be listed. 
6.2 
Efficacy 
Efficacy data will be listed for participants in the EFF. 
6.2.1 
Objective response rate 
Objective response rate, as determined by RECIST v1.1, accessed by investigator, is defined as 
the proportion of participants in EFF who have best overall response of complete response (CR) 
or partial response (PR) during the course of the study.  Participants whose best overall tumor 
response is CR or PR will be considered as responders while other participants will be 
considered as non-responders. 


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Best objective response (BOR) is defined as the best timepoint response per RECIST v1.1 
(ordered CR, PR, stable disease [SD], progressive disease [PD], non-evaluated [NE]) over all 
post-treatment assessments on or prior to first progression or any new systemic anticancer 
therapy, subject to the following additional rules: 
 Time point responses of CR require confirmation by a consecutive CR at least 4 weeks 
later, with no intervening assessment of PR, SD or PD. 
 Time point responses of PR require confirmation by a subsequent PR or CR at least 
4 weeks later with no intervening SD or PD. 
 Time point assessments of SD must occur at least 6 weeks following first treatment. A 
time point assessment of SD occurring prior to 6 weeks will be classified as NE for 
purposes of calculating BOR. 
 Unconfirmed assessments of CR or PR, if meeting the timing requirements for SD, 
will be classified as SD. 
 If the requirements of CR, PR, SD or PD are not met, the BOR is NE. 
RECIST response assessments over time and best overall response will be listed. 
6.2.2 
Duration of response 
Duration of response is defined as the time interval from the date of first response (CR or PR) 
to the date of disease progression (as determined by RECIST 1.1 response criteria) or death due 
to any cause, whichever comes first. Only responders will be included in the analysis. Details 
of censoring rules have been provided in Table 6–1 and details for two consecutive missed 
tumor assessments have been provided in Table 6–2. 
Duration of response will not be provided due to study termination. 
Table 6–1: Duration of response and progression free survival censoring rules 
Situation 
End date  
Outcome 
Reason for censoring 
Applicable 
analysis 
PD (without two or more 
consecutive missing or 
inadequate tumor 
assessments a) 
Date of first PD 
Event b 
Not applicable 
DoR and PFS 
Death (without two or 
more consecutive 
missing or inadequate 
tumor assessment) 
without radiological PD 
assessment before death 
Date of death 
Event b  
Not applicable 
DoR and PFS 
No baseline or post-
baseline radiological 
tumor assessment   
Treatment start date 
Censored 
No baseline or post-
baseline radiological 
assessment. 
PFS 
Death during the study 
before first 
radiological assessment 
Treatment start date 
Censored 
No 
radiological progression 
observed 
PFS 


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Table 6–1: Duration of response and progression free survival censoring rules 
Situation 
End date  
Outcome 
Reason for censoring 
Applicable 
analysis 
Death or PD after more 
than 1 missed 
radiological assessment 
Date of last adequate 
radiological assessment 
before missed 
assessment 
Censored 
Missed more than 1 
tumor assessment 
DoR and PFS 
Participant 
discontinuation from 
study due to a reason 
other than PD  
Last adequate 
radiological assessment 
date without PD 
Censored 
Participant discontinued 
from study due to a 
reason other than PD 
DoR and PFS 
Participant discontinued 
from study due to PD, 
but no documented date 
of PD 
Date of last adequate 
radiological assessment 
before discontinuation 
Censored 
Participant discontinued 
from study due to PD, 
but no documented date 
of PD 
DoR and PFS 
Participants still on study 
at the time of data cutoff 
without PD 
Last adequate 
radiological assessment 
before data cutoff 
Censored 
Participant is still alive 
without PD 
DoR and PFS 
New anticancer 
treatment started 
Date of last adequate 
radiological assessment 
before starting new 
systemic anticancer 
treatment 
Censored 
New systemic 
anticancer treatment 
started 
DoR and PFS 
PFS or DoR = (End Date – treatment start date +1)/30.4375 
a Two consecutive missing radiological assessments are defined as being when the time interval between last 
adequate tumor assessment to either event date or cut-off date is more than the allowed time frame. 
b The earliest end date in the table is used in calculating the PFS or DoR. 
Table 6–2: Two consecutive missed tumor assessments 
Scheduled tumor assessments 
Scheduled data from treatment 
start date 
Time windows for two 
consecutive missed tumor 
assessments 
Before Week 36 
Every 6 weeks 
2 * (6 + 1) = 14 weeks 
Week 45 to Week 108 
Every 9 weeks 
2 * (9 + 1) = 20 weeks 
After Week 108  
Every 3 months 
7 months 
6.2.3 
Disease control rate 
DCR, as determined by RECIST v1.1, is defined as the proportion of participants in the EFF 
who have CR, PR or SD for at least 6 weeks from the start of study treatment. 
DCR will not be reported due to study termination. 


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6.2.4 
Progression free survival 
PFS is defined as the time from start of any study treatment to the date of radiological 
progression per RECIST 1.1 and iRECIST or death due to any cause, whichever occurs first. 
Details of censoring have been provided in Table 6–1 and details for two consecutive missed 
tumor assessments have been provided in Table 6–2. 
PFS will not be reported due to study termination. 
6.2.5 
Overall survival 
Overall survival is defined as the time from start of any study treatment to the date of death due 
to any cause. Participants who are alive at the time of database cut-off will be censored at the 
last date known to be alive or the database cut-off date, whichever occurs first. 
Overall survival analysis will not be reported due to study termination. 
6.3 
Pharmacokinetics/pharmacodynamics 
Not applicable. 
6.4 
Safety 
With the exception of DLTs, all safety analyses will be performed on the SAF. DLTs will be 
presented using the DLT analysis set. 
6.4.1 
Dose limiting toxicities 
A DLT is defined as any AE listed in Section 6.1.2 of the CSP, occurring within 6 weeks after 
the first administration of pembrolizumab (DLT observation window), if assessed by the 
investigator to be possibly, probably, or definitely related to study treatment administration. 
Section 3 of this SAP describes the dose de-escalation process as well as rules for finding the 
RP2D.  
Participants experiencing DLTs will be presented by System Organ Class (SOC) and Preferred 
Term (PT). Dose limiting toxicities will be presented in participant listings. 
6.4.2 
Adverse events 
6.4.2.1 
Adverse event definitions 
Adverse events will be coded using the latest version of Medical Dictionary for Drug 
Regulatory Affairs (MedDRA). Adverse events will be graded by the investigator according to 
the NCI CTCAE v.5.0. 
Treatment-emergent Adverse Events 
The treatment period for this study for reporting purposes of AEs, extends from the initiation 
of study treatment until: 
 90 days after the cessation of study treatment for serious adverse events (SAE) 
(regardless of causality) or until the end of treatment (EoT) visit if the participant 
initiates new anti-cancer therapy, whichever is earlier. 
 EoT visit for all other AEs. 
 Participants with treatment beyond progression will still be classed as treatment 
emergent if it is within the treatment period. 


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All AEs starting or worsening within the treatment period will be considered 
treatment-emergent adverse events (TEAE), for example: 
 Events that started on or after the first dose and within the treatment period and are not 
a continuation of a pre-treatment event. 
 Events that started before the first dose and worsened on or after the first dose and on 
or before the end of the treatment period. 
Pre-treatment AEs 
Pre-treatment AEs will be defined as AEs that started and either stopped before the first dose 
of study treatment or continued after and did not worsen in intensity (i.e. increase in CTCAE 
grade or became serious) during the treatment period. 
Post-treatment AEs 
Post-treatment AEs will be defined as AEs that started or worsened after the treatment period. 
6.4.2.2 
Adverse event summaries 
An overall summary of TEAEs will be provided by dose cohort and overall presenting the 
number and percentage of participants with: 
 Any TEAE, 
 Any TEAE by maximum CTCAE grade, 
 Any study treatment-related TEAE, 
 Any study treatment-related TEAE by maximum CTCAE grade, 
 Any TEAE related to procedures required by the CSP, 
 Any TEAE leading to discontinuation of study treatment, 
 Any TEAE leading to discontinuation of radium-223 dichloride, 
 Any TEAE leading to discontinuation of pembrolizumab, 
 Any TEAE leading to dose modification of radium-223 dichloride, 
 Any TEAE leading to dose modification of pembrolizumab, 
 Any treatment-emergent SAE (TESAE), 
 Any study treatment-related TESAE, 
 Any TESAE related to procedures required by the CSP, 
 Any TESAE leading to discontinuation of study treatment, 
 Any TESAE leading to discontinuation of radium-223 dichloride, 
 Any TESAE leading to discontinuation of pembrolizumab, 
 Any TESAE leading to dose modification of radium-223 dichloride,  
 Any TESAE leading to dose modification of pembrolizumab, 
 Any TEAE of special interest, 
 Any treatment-emergent bone fractures, and 
 TEAEs with outcome death, 
where study treatment refers to either radium-223 dichloride or pembrolizumab. 


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 18 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
TEAEs will be summarized by presenting frequency and percentage of participants by SOC, 
PT, and worst CTCAE grade. For each participant, multiple occurrences of the same event will 
be counted once at their maximum severity within an SOC and PT. Tables will be sorted 
alphabetically by SOC. Preferred terms will be sorted by descending overall total frequency 
within an SOC. 
 All TEAEs 
Data listings will be produced for all AEs recorded in the study. 
6.4.3 
Deaths 
Deaths will be reported in participant listings. 
6.4.4 
Clinical laboratory evaluations 
Selected laboratory abnormalities will be summarized by severity (based on the most abnormal 
result during the treatment period including any unscheduled visits) and by dose cohort (and 
overall). Frequency and incidence rates will be provided. 
The following laboratory parameters will be summarized: 
Hematology: 
 Hemoglobin (g/dL) 
o Increase 
 > 0 – 2 g/dL change from upper limit of normal (ULN) 
 > 2 – 4 g/dL change from ULN 
 > 4 g/dL change from ULN 
 Total increased change from ULN 
o Decrease 
 < lower limit of normal (LLN) – 10.0 g/dL 
 < 10.0 – 8.0 g/dL 
 < 8.0 g/dL 
 Total decreased 
 All (participants with at least one non-missing post-baseline value) 
 Neutrophils (GIGA/L) 
o Decrease 
 < LLN – 1.5 GIGA/L 
 < 1.5 – 1.0 GIGA/L 
 < 1.0 – 0.5 GIGA/L 
 < 0.5 GIGA/L 
 Total decreased 
 All (participants with at least one non-missing post-baseline value) 
 Platelets (GIGA/L) 
o Decrease 
 < LLN – 75.0 GIGA/L 
 < 75.0 – 50.0 GIGA/L 


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 19 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 < 50.0 – 25.0 GIGA/L 
 < 25.0 GIGA/L 
 Total decreased 
 All (participants with at least one non-missing post-baseline value) 
Chemistry: 
 Alanine aminotransferase (U/L) 
o Increase (Baseline Normal) 
 > ULN – 3.0 x ULN 
 > 3.0 – 5.0 x ULN 
 > 5.0 – 20.0 x ULN 
 > 20.0 x ULN 
 Total Increased with Baseline Normal 
 All with Baseline Normal (participants who have a normal baseline and 
at least one non-missing post baseline value) 
o Increase (Baseline Abnormal) 
 ≥ 1.5 – 3.0 x Baseline 
 > 3.0 – 5.0 x Baseline 
 > 5.0 – 20.0 x Baseline 
 > 20.0 x Baseline 
 Total Increased with Baseline Abnormal 
 All with Baseline Abnormal (participants who have an abnormal 
baseline and at least one non-missing post baseline value) 
 All with Baseline (participants with non-missing baseline and at least 
one non-missing post-baseline result) 
 Alkaline phosphatase (U/L) 
o Increase (Baseline Normal) 
 > ULN – 2.5 x ULN 
 > 2.5 – 5.0 x ULN 
 > 5.0 – 20.0 x ULN 
 > 20.0 x ULN 
 Total Increased with Baseline Normal 
 All with Baseline Normal (participants who have a normal baseline and 
at least one non-missing post baseline value) 
o Increase (Baseline Abnormal) 
 2.0 – 2.5 x Baseline 
 > 2.5 – 5.0 x Baseline 
 > 5.0 – 20.0 x Baseline 
 > 20.0 x Baseline 
 Total Increased with Baseline Abnormal 


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 20 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 All with Baseline Abnormal (participants who have an abnormal 
baseline and at least one non-missing post baseline value) 
 All with Baseline (participants with non-missing baseline and at least 
one non-missing post-baseline result) 
 Aspartate aminotransferase (U/L) 
o Increase (Baseline Normal) 
 > ULN – 3.0 x ULN 
 > 3.0 – 5.0 x ULN 
 > 5.0 – 20.0 x ULN 
 > 20.0 x ULN 
 Total Increased with Baseline Normal 
 All with Baseline Normal (participants who have a normal baseline and 
at least one non-missing post baseline value) 
o Increase (Baseline Abnormal) 
 1.5 – 3.0 x Baseline 
 > 3.0 – 5.0 x Baseline 
 > 5.0 – 20.0 x Baseline 
 > 20.0 x Baseline 
 Total Increased with Baseline Abnormal 
 All with Baseline Abnormal (participants who have an abnormal 
baseline and at least one non-missing post-baseline value) 
 All with Baseline (participants with non-missing baseline and at least 
one non-missing post-baseline result) 
 Bilirubin (mg/dL) 
o Increase (Baseline Normal) 
 > ULN – 1.5 x ULN 
 > 1.5 – 3.0 x ULN 
 > 3.0 – 10.0 x ULN 
 > 10.0 x ULN 
 Total Increased with Baseline Normal 
 All with Baseline Normal (participants who have a normal baseline and 
at least one non-missing post baseline value) 
o Increase (Baseline Abnormal) 
 1.0 – 1.5 x Baseline 
 > 1.5 – 3.0 x Baseline 
 > 3.0 – 10.0 x Baseline 
 > 10.0 x Baseline 
 Total Increased with Baseline Abnormal 
 All with Baseline Abnormal (participants who have an abnormal 
baseline and at least one non-missing post baseline value) 


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 21 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 All with Baseline (participants with non-missing baseline and at least 
one non-missing post-baseline result) 
 Creatinine (mg/dL) 
o Increase 
 > ULN – 1.5 x ULN 
 > 1.5– 3.0 x ULN 
 > 3.0 – 6.0 x ULN 
 > 6.0 x ULN 
 Total Increased 
 All (participants with at least one non-missing post-baseline value) 
Other laboratory parameters (TSH, T3 and T4) not included in the above list will be presented 
using shifts from baseline to worst post-baseline value based on normal range categories (low, 
normal, high). 
6.4.5 
Biomarkers 
Not applicable. 
6.4.6 
Other safety endpoints 
Not applicable. 
7. 
Document history and changes in the planned statistical analysis 
 Approval of the SAP for Phase 1 version 4.0 dated 31 JAN 2023. 
Rationale for updates: 
o Section on patient replacement added to Section 4.2.3 
o Prior systemic lines of therapy added to baseline characteristics 
o Removed analysis on treatment related AEs for pembrolizumab and 
radium-223 dichloride and kept the combinations 
o Separated AEs leading to dose modification to include radium-223 dichloride 
and pembrolizumab 
 Approval of the SAP for Phase 1 version 3.0 dated 22 FEB 2021. 
Rationale for updates: 
o Strategic considerations and recruitment challenges has led to the study no 
longer being pursued. This SAP update contains adjustments for the synopsis 
CSR. 
 Approval of the SAP for Phase 1 version 2.0 dated 11 DEC 2020. 
Rationale for updates: 
o Protocol amendment 2 updates impacting the SAP 
o Study objectives updated to include the endpoints 
o Study design updated to include the study periods 
o Enrolled set included in the analysis set section 
o Demographic and baseline characteristics updated 


Statistical Analysis Plan 
(Phase 1 Part) 
BAY 88-8223 / 19781 
Page: 22 of 22
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
o Treatment duration updated with the details of the categories for 
pembrolizumab 
o Description added for time to event analysis, response rates and rescreened 
participants 
o Listing added for rescreened participants 
o Censoring rules added for DoR and PFS 
o Overall AEs now include irAE, IRR, additional primary malignancy and bone 
fractures. 
 Approval of the SAP for Phase 1 version 1.0 dated 02 JUN 2020 
8. 
References 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika. 1934;26(4):404-13. https://doi.org/10.1093/biomet/26.4.404