Clinical trial NCT05424380
Conditions: Leukemia, Myeloid, Acute
Keywords: GSK3745417 Acute myeloid leukemia AML high-risk myelodysplastic syndrome HR-MDS
Sponsor: GlaxoSmithKline
Start date: 2022-09-20; Completion date: 2024-03-04
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1, open label, two-part study to determine recommended phase 2 dose (RP2D) and schedule of GSK3745417 administration in participants with relapsed/refractory AML or HR-MDS.

Detailed description:

Arms: arm 1: Part 1 will evaluate a dosing schedule for a total of 28 days in each cycle. The starting dose for Cycle 1 will be escalated in the next dose escalation cohort until MTD is reached. arm 2: Part 2 will evaluate efficacy after an induction phase. The induction phase consists of a treatment regimen at RP2D determined in Part 1.
Interventions: intervention 1: GSK3745417
Intervention descriptions: intervention 1: GSK3745417 will be administered

Protocol documents:
Prot_000.pdf: 
Protocol
Study ID:  209809
Official Title of Study: A Phase 1, Open Label Study of Intravenous 
GSK3745417 to Evaluate Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Determine RP2D and Schedule in Participants 
With Relapsed or Refractory Myeloid Malignancies Including Acute 
Myeloid Leukemia (AML) and High-risk Myelodysplastic Syndrome 
(HR-MDS)
NCT ID: NCT05424380
Date of Document: 25-Jan-2022


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GlaxoSmithKline group of companies 
 
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TITLE PAGE 
Protocol Title: A Phase 1, open label study of intravenous GSK3745417 to evaluate 
safety, tolerability, pharmacokinetics, pharmacodynamics and determine RP2D and 
schedule in participants with relapsed or refractory myeloid malignancies including acute 
myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) 
Protocol Number: 209809/Version 1.0 
Compound Number 
or Name: 
GSK3745417 
 
Brief Title: A Phase 1, open label study of intravenous GSK3745417 to evaluate safety, 
tolerability, pharmacokinetics, pharmacodynamics and determine RP2D & schedule in 
participants with relapsed or refractory Myeloid Malignancies including AML and 
HR-MDS 
Study Phase: Phase 1 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information  
Can be found in the Study Reference Manual. 
Regulatory Agency Identifying Number(s): 
IND: 159056 
EudraCT Number: 2021-005234-41 
Approval Date: 25-JAN-2022 
©2022 GSK group of companies or its licensor. All rights reserved.  Unauthorised 
copying or use of this information is prohibited. 
 


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SPONSOR SIGNATORY: 
Protocol Title: A Phase 1, open label study of intravenous GSK3745417 to evaluate 
safety, tolerability, pharmacokinetics, pharmacodynamics and determine RP2D and 
schedule in participants with relapsed or refractory myeloid malignancies including acute 
myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) 
Protocol Number: 209809/Version 1.0 
Compound Number 
or Name: 
GSK3745417 
 
 
 
 
Ivan Diaz-Padilla, MD, PhD 
VP, Oncology Clinical Development 
 
Date 
 
The signed page is a separate document. 
 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual. 
 
 


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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY .......................................................................................... 7 
1.1. 
Synopsis ....................................................................................................... 7 
1.2. 
Schema ...................................................................................................... 12 
1.3. 
Schedule of Activities (SoA) ........................................................................ 13 
1.3.1. 
Part 1 – Dose Escalation ............................................................. 15 
1.3.2. 
Part 2 – Induction Cycle ............................................................... 27 
1.3.3. 
Part 1 and Part 2 – GSK3745417 Maintenance Once 
Weekly ......................................................................................... 39 
1.3.5. 
Part 2 – GSK3745417 Maintenance Every 3 Weeks .................... 47 
2. 
INTRODUCTION .................................................................................................... 53 
2.1. 
Study Rationale .......................................................................................... 53 
2.2. 
Background ................................................................................................ 53 
2.3. 
Benefit/Risk Assessment ............................................................................ 54 
2.3.1. 
Risk Assessment ......................................................................... 54 
2.3.2. 
Benefit Assessment ..................................................................... 59 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 59 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 59 
4. 
STUDY DESIGN .................................................................................................... 62 
4.1. 
Overall Design ............................................................................................ 62 
4.1.1. 
Dose Limiting Toxicities (DLT) ..................................................... 66 
4.1.2. 
Dose Escalation Decisions .......................................................... 67 
4.2. 
Number of Participants ............................................................................... 68 
4.3. 
Scientific Rationale for Study Design .......................................................... 68 
4.4. 
Justification for Dose .................................................................................. 69 
4.4.1. 
Human Experience with GSK3745417 Dosing in 
Participants with Solid Tumors ..................................................... 69 
4.4.2. 
Selected Human Starting Dose and Discussion ........................... 69 
4.5. 
End of Study Definition ............................................................................... 70 
5. 
STUDY POPULATION ........................................................................................... 70 
5.1. 
Inclusion Criteria ......................................................................................... 70 
5.2. 
Exclusion Criteria ........................................................................................ 72 
5.3. 
Lifestyle Considerations .............................................................................. 75 
5.3.1. 
Meals and Dietary Restrictions .................................................... 75 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 75 
5.3.3. 
Activity ......................................................................................... 75 
5.4. 
Screen Failures........................................................................................... 76 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 76 
6.1. 
Study Intervention(s) Administered ............................................................. 76 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 77 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 78 
6.4. 
Dose Modification ....................................................................................... 78 
6.4.1. 
Participant-Level Dose Modifications due to Adverse 
Events ......................................................................................... 78 
6.4.1.1. 
Intra-Patient Dose Escalation ..................................... 79 


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6.4.1.2. 
Tumor Lysis Syndrome ............................................... 79 
6.4.1.3. 
Infusion Reaction ........................................................ 80 
6.4.1.4. 
Cytokine Release Syndrome ...................................... 80 
6.4.1.5. 
Cardiac Monitoring ..................................................... 83 
6.4.1.6. 
Cardiac Monitoring and Dose Modification 
Guidelines .................................................................. 83 
6.4.1.7. 
Immune mediated events on study ............................. 84 
6.5. 
Continued Access to Study Intervention after the End of the Study ............ 89 
6.6. 
Treatment of Overdose ............................................................................... 89 
6.7. 
Concomitant Therapy.................................................................................. 89 
6.7.1. 
Permitted Medications ................................................................. 89 
6.5.2. Prohibited Medications and Non-Drug Therapies .............................. 90 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 91 
7.1. 
Discontinuation of Study Intervention .......................................................... 91 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 91 
7.1.2. 
Renal Stopping and Increased Monitoring Guidelines .................. 92 
7.1.3. 
QTc Stopping Criteria .................................................................. 92 
7.1.4. 
Temporary Discontinuation .......................................................... 93 
7.1.5. 
Rechallenge ................................................................................. 93 
7.1.5.1. 
Study Intervention Restart After Liver Stopping 
Criteria Met ................................................................. 93 
7.1.5.2. 
Study Intervention Restart When Renal 
Toxicity Stopping Criteria Met ..................................... 93 
7.1.5.3. 
Study Intervention Restart When QTc Stopping 
Criteria Met ................................................................. 94 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 94 
7.3. 
Lost to Follow-Up ........................................................................................ 94 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 95 
8.1. 
Efficacy Assessments ................................................................................. 95 
8.2. 
Safety Assessments ................................................................................... 95 
8.2.1. 
Physical Examinations ................................................................. 96 
8.2.2. 
Performance Status ..................................................................... 96 
8.2.3. 
Vital Signs .................................................................................... 96 
8.2.4. 
Electrocardiograms ...................................................................... 96 
8.2.5. 
Holter Monitoring ......................................................................... 96 
8.2.6. 
Clinical Safety Laboratory Assessments ...................................... 97 
8.2.7. 
Pregnancy Testing ....................................................................... 97 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 98 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 98 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 99 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 99 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 99 
8.3.5. 
Pregnancy ................................................................................... 99 
8.3.6. 
Cardiovascular and Death Events .............................................. 100 
8.3.7. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs............................................. 101 
8.3.8. 
Adverse Events of Special Interest ............................................ 101 


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8.4. 
Pharmacokinetics ..................................................................................... 101 
8.5. 
Genetics and Pharmacogenomics ............................................................ 102 
8.6. 
Biomarkers ............................................................................................... 102 
9. 
STATISTICAL CONSIDERATIONS ...................................................................... 104 
9.1. 
Statistical Hypotheses............................................................................... 104 
9.2. 
Sample Size Determination ...................................................................... 104 
9.3. 
Analysis Sets ............................................................................................ 110 
9.4. 
Statistical Analyses ................................................................................... 110 
9.4.1. 
Efficacy Analyses ....................................................................... 110 
9.4.2. 
Safety Analyses ......................................................................... 111 
9.4.2.1. 
Extent of Exposure ................................................... 111 
9.4.2.2. 
Adverse Events ........................................................ 111 
9.4.2.3. 
Clinical Laboratory Evaluations ................................ 112 
9.4.2.4. 
Other Safety Analyses .............................................. 112 
9.4.3. 
Other Analyses .......................................................................... 112 
9.4.3.1. 
Pharmacokinetic Analyses ........................................ 112 
9.4.3.2. 
Pharmacokinetic/Pharmacodynamic Analyses ......... 113 
9.4.3.3. 
Exploratory Biomarker Analyses ............................... 113 
9.5. 
Interim Analysis ........................................................................................ 113 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 114 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .......................................................................................... 114 
10.1.1. 
Regulatory and Ethical Considerations ...................................... 114 
10.1.2. 
Financial Disclosure ................................................................... 114 
10.1.3. 
Informed Consent Process ........................................................ 115 
10.1.4. 
Data Protection .......................................................................... 115 
10.1.5. 
Committees Structure ................................................................ 115 
10.1.6. 
Dissemination of Clinical Study Data ......................................... 116 
10.1.7. 
Data Quality Assurance ............................................................. 116 
10.1.8. 
Source Documents .................................................................... 117 
10.1.9. 
Study and Site Start and Closure ............................................... 117 
10.1.10. Publication Policy ....................................................................... 118 
10.2. 
Appendix 2: Clinical Laboratory Tests ....................................................... 119 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 121 
10.3.1. 
Definition of AE .......................................................................... 121 
10.3.2. 
Definition of SAE ........................................................................ 123 
10.3.3. 
Definition of Cardiovascular Events ........................................... 124 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................. 124 
10.3.5. 
Reporting of SAE to GSK ........................................................... 126 
10.4. 
Appendix 4: Adverse Events of Special Interest ........................................ 128 
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ..................................... 130 
10.5.1. 
Definitions: ................................................................................. 130 
10.5.2. 
Contraception Guidance: ........................................................... 131 
10.6. 
Appendix 6: Genetics ................................................................................ 133 
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10.7. 
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Restart/Rechallenge 
Guidelines ................................................................................................. 134 
10.7.1. 
Study Treatment Restart or Rechallenge ................................... 135 
10.7.2. 
Restart Following Transient Resolving Liver Stopping 
Events Not Related to Study Treatment ..................................... 136 
10.8. 
Appendix 8: IWG Criteria for Response for Participants with MDS ............ 138 
10.9. 
Appendix 9: Response Criteria for Participants with AML ......................... 139 
10.10. Appendix 10: ECOG Performance Statusa ................................................ 140 
10.11. Appendix 11: Cairo-Bishop Clinical Tumor Lysis Syndrome 
Definition and Grading .............................................................................. 141 
10.12. Appendix 12: Abbreviations and Definitions and Trademarks ................... 142 
11. REFERENCES ..................................................................................................... 143 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
A Phase 1, open-label study of intravenous GSK3745417 to evaluate safety, tolerability, 
pharmacokinetics, pharmacodynamics and determine RP2D and schedule in participants 
with relapsed or refractory myeloid malignancies including acute myeloid leukemia 
(AML) and high-risk myelodysplastic syndrome (HR-MDS).  
Rationale: 
GSK3745417 is an intravenously delivered STING (STimulator of Interferon Genes) 
agonist currently under evaluation in solid tumors in the FTIH 208850 dose escalation 
study. Recent evidence has shown that in addition to immune-mediated activity, 
GSK3745417 exhibits a cytolytic effect, a second mechanism of action, in AML cells in 
nonclinical studies. STING is expressed at a higher level on AML cells compared with 
other tumor types [The Cancer Genome Atlas (TCGA) - National Cancer Institute]. The 
high level of STING expression combined with preclinical evidence of antitumor activity 
makes AML a suitable indication to establish proof of mechanism and evaluate the 
clinical activity of GSK3745417. The goal of the study is to identify an RP2D and 
schedule with a manageable safety profile. Study 209809 is proposed to evaluate safety, 
pharmacokinetics, pharmacodynamics, and preliminary clinical activity of GSK3745417 
in relapsed or refractory AML and high-risk myelodysplastic syndrome (HR-MDS). 
Objectives and Endpoints 
Dose Escalation (Part 1) 
 
Objectives 
Endpoints 
Primary 
• 
To determine the safety, tolerability, 
and RP2D of a daily dosing schedule 
(induction) of GSK3745417.   
• 
Frequency and severity of 
Adverse Events (AEs), Serious 
Adverse Events, (SAEs), Dose 
Limiting Toxicity (DLT), 
withdrawals due to AEs  
Secondary 
• 
To characterize the pharmacokinetics 
(PK) of GSK3745417, and relevant 
metabolites, as applicable, after single 
and repeat-dose administration. 
• 
GSK3745417 concentrations in 
plasma or PK parameters 
Exploratory 
 
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Dose Escalation (Part 1) 
 
Objectives 
Endpoints 
 
 
 
 
 
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Dose Expansion (Part 2)  
 
Objectives 
Endpoints 
Primary 
• 
To evaluate clinical efficacy following 
the daily dosing “induction” period of 
GSK3745417 in participants with 
relapsed/refractory AML and HR-MDS. 
• 
To determine the safety, tolerability, 
and recommended Phase 2 dose 
(RP2D) for “maintenance”  
• 
Objective response rate (ORR) 
after the daily dosing “induction” 
period of GSK3745417 
 
• 
Frequency and severity of 
Adverse Events (AEs), Serious 
Adverse Events, (SAEs), Dose 
Limiting Toxicity (DLT), 
withdrawals due to AEs during 
“maintenance” dosing 
Secondary 
• 
To further evaluate the safety, 
tolerability of one or more RP2D for 
maintenance 
 
The following may be included based 
on the availability of data and 
appropriateness: 
• 
AEs, SAE, AESIs leading to dose 
modifications or delays 
 
• 
To characterize the pharmacokinetics 
(PK) of GSK3745417, and relevant 
metabolites, as applicable, after single 
and repeat-dose administration. 
• 
GSK3745417 concentrations in 
plasma or PK parameters 
Exploratory 
 
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Dose Expansion (Part 2)  
 
Objectives 
Endpoints 
 
 
 
 
Overall Design and Brief Summary: 
This is a Phase 1, open label, dose escalation study to evaluate safety, pharmacokinetics, 
and pharmacodynamics of intravenous GSK3745417 in participants with relapsed or 
refractory AML or high risk MDS.  
The study will be conducted in a staged approach consisting of 2 parts. Part 1 will 
evaluate a dosing schedule of a 5 days on/2 days off schedule for 2 weeks, and then have 
an additional 2 weeks off dose for observation for a total of 28 days in each cycle (5 / 2/ 5 
q28d). Once a maximum tolerated dose (MTD) has been established, additional cohorts 
may be opened to refine dosing frequency optimization. Each cohort will include at least 
3 participants and dosing of participants entering the study will be staggered by at least 
5 days from D1 of previous patient for the first cohort only. Part 1 will include 
intra-patient dose escalation for 3 cycles, according to safety and tolerability parameters. 
The starting dose for Cycle 1 will be escalated in the next dose-escalation cohort until a 
cohort level starting dose-based MTD is reached. Individual patients may titrate above 
the starting dose-based MTD based on tolerability. Dose escalation cohorts will start with 
Cycle 1 at 12.5 µg GSK3745417. Within a cohort for an individual subject the dose may 
double for Cycle 2, and double again for Cycle 3 based on individual tolerability. The 
starting dose of subsequent cohorts will increase by 2-fold from Cycle 1 of the previous 
cohort. Patients may be dose reduced for subsequent cycles if there is lack of tolerability 
in the previous cycle (Section 6.4). The DLT period will be 28 days starting at Day 1 of 
Cycle 1 of each cohort. After 3 induction cycles, if a complete response (CR) or partial 
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response (PR) (IWG) is observed (See Appendix 9) each patient will continue with 
maintenance weekly dosing at the Cycle 3 dose level until disease progression or 
unacceptable toxicity. Participants with progressive disease after 3 induction cycles will 
be withdrawn from study. Participants with stable disease or PR after 3 cycles might 
receive additional cycles if the assessment by the investigator determined a benefit and 
GSK Medical Monitor agrees.    
For Part 1, approximately 22 participants will receive dosing in the hospital on a 5 days 
on/2 days off schedule for 2 weeks, and then have an additional 2 weeks off dose for 
observation. The participant will be observed for at least 24 hours after the final dose in 
each cycle. All participants will be hospitalized the day before a new dosing cycle starts 
to receive tumor lysis syndrome (TLS) prophylaxis in line with institutional guidelines 
(all participants should receive IV fluids ± allopurinol as well as alkalinization of urine 
with renal consult if this is in line with institutional guidance). TLS prophylaxis will 
continue alongside daily dosing as clinically indicated. To further reduce the risk of TLS, 
guidance in Section 6.4.1.2 must be followed to determine when daily dosing should be 
held.  
A 5 / 2 / 5 q28d dosing regimen is being evaluated in Part 1 since it is hypothesized that 
increased dosing frequency of GSK3745417 will enhance the direct cell killing effect by 
more constantly engaging target. After 3 cycles, if a CR or PR (IWG) is observed, each 
patient will continue with maintenance weekly dosing at the Cycle 3 dose level until 
disease progression or unacceptable toxicity. Participants with PR after 3 induction cycles 
might receive additional cycles if the assessment by the investigator determined a benefit 
and GSK Medical Monitor agrees. 
For Part 2, efficacy will be evaluated after an induction phase in approximately 
50 participants, 25 AML participants and 25 HR-MDS participants. The induction phase 
consists of a treatment regimen cycles at the dose/doses determined to be safe in Part 1 
(RP2D). The number of cycles, number of doses investigated in the induction phase, 
and/or dosing schedule of 5 / 2 / 5 q28d treatment will be determined and may be 
modified based on a review of safety and PK data generated from Part 1. After the 
induction phase, patients will continue to either a weekly (Q1W), every three weeks 
(Q3W), or less frequent dosing schedule for maintenance treatment, if a CR or PR is 
observed (See Response Criteria for Participants with AML Appendix 9; See IWG 
Criteria for Response for Participants with MDS Appendix 8). Participants with stable 
disease or PR after 3 induction cycles might receive additional cycles if the assessment 
by the investigator determined a benefit and GSK Medical Monitor agrees. Up to three 
dose levels for maintenance treatment will be evaluated in the maintenance dose 
escalation. The DLT period for the maintenance dose escalation portion of Part 2 will be 
28 days starting at Day 1 of each cycle. Dose escalation for the maintenance schedule 
will start at the highest dose cleared for safety in Part 1. Part 2 will evaluate the efficacy 
of the induction regimen separately for AML and HR-MDS as well as the tolerability and 
duration of response of the Q1W or Q3W maintenance schedules to determine the best 
dose and schedule for further studies.  


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Number of Participants: 
Approximately 22 participants may be enrolled in Part 1, and approximately 
50 participants may be enrolled in Part 2. The total number of participants to be enrolled 
is an estimate and will depend on the number needed to adequately characterize the DLT 
and PD profile and determine the MTD(s)/RP2D(s). All participants who take at least one 
dose of study intervention will be considered evaluable for analysis. 
Intervention Groups and Duration: 
The study includes a screening period, a treatment period (consisting of - 3-cycle 
induction phase and a maintenance phase), and a follow-up period. Participants will be 
screened for eligibility beginning up to 4 weeks before the start of treatment. 
GSK3745417 will be centrally administered IV according to the dosing schedule in the 
corresponding cohort the participant is enrolled.  
Participants will be assessed for response according to the IWG response criteria for 
AML or MDS at end of each induction cycle including (at 28 days [after Cycle 1], at 
56 days [after Cycle 2], and at 84 days [after Cycle 3]). Within the maintenance phase, 
assessment will be at 3 weeks and then every 6 weeks thereafter. Participants will be 
treated until disease progression, unacceptable toxicity, withdrawal of consent, or 
termination of the study by GSK. 
Data Monitoring/ Other Committee: No 
1.2. 
Schema 
Part 1: Dose Escalation Cohorts for Daily Dosing MTD  
Figure 1 
Part 1 Induction Intra-patient Dose-Escalation Study    
 
* Patients in C3 dose level in all cohorts will be continuing dosing Q1W at C3 dose level  
 


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Figure 2 
Part 1: Dosing and Observation Timeline for Each Cycle    
 
 
Figure 3 
Part 2: Expansion Study: Induction and Maintenance Dose 
Escalation  
 
1.3. 
Schedule of Activities (SoA) 
• The schedule of activities for each Part of the study may be found on the 
following pages. For all parts, the following apply: 
• The timing of planned study assessments may change during the study based on 
emerging data/in-stream data review to ensure appropriate monitoring.  
• Any changes in the timing of time points for any planned study assessments as the 
result of emerging pharmacokinetic/pharmacodynamic data from this study 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 
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• The Competent Authority (CA) and ethics committee (EC) will be informed of 
any safety issues that constitute a substantial amendment and require alteration of 
the safety monitoring scheme or amendment of the informed consent form (ICF). 
The changes will be approved by the CA and the EC before implementation. 
• For Part 1, Table 1 applies to Cycles 1, 2, and 3 in the Dose Escalation Cohort 
After completing the assessments in Cycle 3, participants would proceed to 
complete the assessments in Table 3 for the maintenance phase. 
• For Part 2, after completing the assessments in Table 2, participants would 
proceed to complete the assessments in either Table 3 or Table 4 for the 
maintenance phase. 


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1.3.1. 
Part 1 – Dose Escalation  
Table 1 
Schedule of Activities: Part 1 - Dose Escalation Cohort(s)  
DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion and 
Exclusion criteria 
X 
 
 
 
 
 
 
Demographics, 
Medical History, Prior 
Medications, Disease 
Characteristics 
X 
 
 
 
 
 
Include use of antibiotics, probiotics and 
anti-infectives taken 60 days prior to study 
intervention. 
Anticancer Therapy 
and Response to Prior 
Anticancer Therapy 
X 
 
 
 
 
 
 
Participant 
Registration 
X 
 
 
 
 
 
 
Safety Assessments 
 
In-House Monitoring 
 
X 
X 
 
 
 
Participants should be monitored in a medically 
qualified unit/clinic/hospital starting on Day -1 
through Day 13 (24 hours after the administration of 
GSK3745417 on Day 12) of each cycle.  
Physical Exam  
X 
 
X 
 
X 
 
A complete physical exam is required at screening, 
including cardiac and neurological examinations; 
brief or targeted physical exams will be performed 
on Day 1 at predose (within 1h prior to dosing) and 


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DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Day 13 of each cycle, and as clinically indicated. 
Refer to Section 8.2.1 for physical examination 
details. 
ECOG PS 
X 
 
X 
 
X 
 
Should be assessed at each cycle  
Vital Signs 
X 
X 
X 
 
X 
 
Should be collected at each cycle at least 6 times on 
Day -1 within 24 hours prior to dosing, Day 1, 5, 8, 
and 12 at predose (within 1h prior to dosing), end of 
injection (EOI)+30m, +1h, +2h, +4h, +6h, +8h, +12h, 
+24h and, at least four times every day until 
discharge or more frequently if clinically indicated.  
Weight 
X 
X 
 
 
X 
 
Should be collected at each cycle. 
Echocardiogram 
X 
Week 1 and then Q8W. Additional echocardiography 
may occur as clinically indicated 
 
If available, a 3D ECHO is preferred, otherwise a 2D 
ECHO may be performed. Where the quality of the 
ECHO examination is sub-optimal, MUGA scans 
may be used. The modality used at baseline should 
be repeated throughout the study to ensure 
comparison to baseline. At TDV, ECHO/MUGA does 
not need to be performed if an on-study ECHO has 
been conducted within the 4 weeks prior to visit. 
ECHO should be performed in the final week of the 
observation period. 
IV Contrast-enhanced 
Brain MRI (preferred) 
or IV Contrast-
X 
Repeat if clinically indicated 
 
Scans performed as standard of care prior to study 
consent will be acceptable as long as assessment is  
Brain imaging to be performed only if clinically 
indicated. 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
enhanced Brain CT 
Scan 
12-lead ECG 
X 
 
X 
 
X 
 
Triplicate ECGs should be performed at screening. 
Single ECGs should be obtained at each cycle on 
Day 1 and Day 4 at predose (within 1h prior to 
dosing) and EOI+2h. In cases of TLS, triplicate 
ECGs will be obtained at screening. Single ECGs 
should be obtained prior to GSK3745417 dosing, 
within 5 min EOI, and within 2 hours prior to 
completion of clinic visit. Post Week 6, next ECG 
should be on Week 9 and then Q3W thereafter. 
Patients with new onset symptoms consistent with 
immune-mediated pericarditis or myocarditis should 
have additional ECGs as clinically indicated. 
Holter Monitoring 
 
X 
X 
 
 
 
Baseline and Day -1 and Day 1 of Cycle 1 after 
dosing, starting at least -24h predose, followed by 
normal activity (ambulatory) until -30 min predose, 
when participant will be lying supine until time 0. 
Postdose, the participant will by lying supine for at 
least 3 minutes to align with the PK plasma sampling 
at EOI +5m, +15m, +30m, +45m, +1h, +2h, +4h, 
+6h, +8h, +12h and +24h. Holter monitoring will end 
at 24h after the first study intervention. The Holter 
will remain with the participant until 24h post-dose 
and then will be removed. The requirement for Holter 


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209809 
 
Protocol 
 
 
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Clinical Study Protocol template V15 dated 21-Dec-2020 
DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
monitoring may be waived for individual participants 
upon approval from GSK. 
Neurological 
Assessment including 
ICE scoring 
X 
Conduct if clinically indicated 
 
Refer to Section 6.4.1 for neurological assessment 
details. 
AE/SAE Review 
 
Assess at each visit from first dose until the TDV for AEs and until 90 days after the last dose for AESI and SAEs 
Concomitant 
Medication Review 
 
Continuous: Assess at each visit from first dose of study intervention 
Follow-Up Phone Call 
 
 
 
X 
 
 
Participants should be contacted by phone 
24-72 hours and 1 week (+24 hours) following 
discharge from clinic to assess for any AEs or 
cytokine related events.  
Safety Laboratory Assessments 
Human 
Immunodeficiency 
Virus (HIV), Hepatitis 
B Surface Antigen 
(HBsAg), Hepatitis C 
Virus (HCV) Antibody 
X 
 
 
 
 
 
 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Pregnancy Test 
X 
 
≤72 
hours 
(serum) 
X 
X 
Q12W 
Negative serum pregnancy test required at 
screening and within 72 hours prior to date of first 
dose of study treatment for females of childbearing 
potential. Urine pregnancy test will be conducted 
every 4 weeks for duration of study, on last day of 
treatment (if possible), at TDV, and at the Follow-Up 
visit. 
CBC with differential 
X 
X 
X 
X 
X 
 
Sample collection times: Single sample from Day -1 
to Day 13, prior to each administration of 
GSK3745417. At least every 6 hours for the first 
48 hours following initiation of daily dosing period, 
then at least twice daily up to an including Day 5 
dosing of each daily dosing period, and more 
frequently as clinically indicated. On the days when 
GSK3745417 is not administered, samples will be 
collected at approximately the same times as on the 
days of GSK3745417 administration. A sample will 
also be taken between Day 20 and Day 22 during 
the outpatient period of the cycle. 
Clinical Chemistry 
(including laboratory 
parameters for TLS 
diagnosis and 
management) 
X 
X 
X 
X 
X 
 
Sample collection times:  
Cycle 1, and any cycle with a dose increase:  
single sample on Day –1; Days 1 and 2 at predose, 
EOI+6h, +12h, +18h and +24h; Days 3 - 5 – at 
predose and EOI+6hrs; Days 6 and 7 – single daily 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
sample, Days 8 - 12 – at EOI+6hrs: Day 13 – single 
sample prior to discharge. 
Clinical chemistry including uric acid and phosphate 
will be measured at least every 6 hours for the first 
48 hours following initiation of daily dosing period, 
then at least twice daily up to an including Day 5 
dosing of each daily dosing period, and more 
frequently as clinically indicated. 
Clinical chemistry samples should be collected more 
frequently if clinically indicated (such as cases of 
TLS). A sample will also be taken between Day 20 
and Day 22 during the outpatient period of the cycle.  
See Section 10.2 for complete list of required 
laboratory assessments. 
C-Reactive Protein 
X 
 
X 
X 
X 
 
Sample collection times: Day 1 at predose, EOI+8h 
and +24h for first dose, then pre dose at Day 5 and 
Day 12 of each cycle.  
Thyroid functionc 
X 
 
X 
 
X 
 
Sample collection times: Day 1 at predose of Cycles 
1 and 3. 
Troponin I and T 
X 
 
X 
 
X 
 
See Section 6.4.1.5 for management of cardiac 
events. Samples will be collected on Day 13. 
BNP (or NTproNBNP) 
X 
Repeat as clinically indicated 
 
 
Repeat test as outlined in management of cardiac 
events (Section 6.4.1.5) 
eGFR 
X 
 
 
 
 
 
See Section 7.1.2 for management of renal events (if 
needed).  


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Clinical Study Protocol template V15 dated 21-Dec-2020 
DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Urinalysisc 
X 
 
X 
 
X 
 
Sample collection times: Days 1, 8 and 13 of each 
cycle. If urinalysis is abnormal, a microscopy should 
be performed. 
Coagulationc 
X 
 
X 
 
 
 
Sample collection times: at screening and prior to 
administration of first dose of GSK3745417 and at 
Day 8 of each cycle. Additional coagulation samples 
should be collected in the event of CRS (see 
Section 6.4.1.4) 
Study Intervention 
Administer 
GSK3745417 
 
 
X 
 
 
 
GSK3745417 will be administered the same dose 
within each cycle on Days 1 – 5 and Days 8 - 12 QD. 
Participants will receive up to 3 cycles of treatment 
before moving to Q1W or Q3W dosing (Section 6.1). 
See Section 4.1 for maximum duration of study 
intervention. See Section 4.1 for safety and 
tolerability parameters to be reviewed prior to each 
daily dose 
Non-Azole Antifungal 
 
X 
X 
X 
 
 
Non-azole antifungals should be administered if 
indicated, per local standard, on Day -1 through 
Day 28 of each cycle. 
Tumor Lysis 
Syndrome Prophylaxis 
 
X 
 
 
 
 
All participants should receive tumor lysis syndrome 
(TLS) prophylaxis prior to date of first dose of each 
cycle on Day -1 according to institutional guidelines 
(e.g., participants should receive IV fluids ± 
allopurinol and consider alkalization of urine and 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
renal consult). TLS prophylaxis and fluids should be 
continued over each dosing cycle as clinically 
indicated. Refer to Section 6.4.1.2 for prophylaxis 
and management of TLS. 
Efficacy Assessments 
BM Sample for 
Disease Assessment 
X 
 
D40 
(i.e.D12 
of Cycle 
2) 
D84 (i.e. D28 of 
Cycle 3) 
X 
 
BM aspirate and core biopsy samples are required 
at Screening, Day 12 of Cycle 2 (within EOI+24hr), 
and D28 of Cycle 3 (+2 days is allowed, but must be 
before Day 1 of next cycle). The collection time point 
is mandatory after the last cycle of intense dosing 
(i.e. D28 of Cycle 3) before moving into maintenance 
+2 days is allowed for BM sample collection at each 
time point provided it occurs before next treatment 
cycle starts. 
Both BM aspirate and core biopsy samples should 
be used for Disease Assessment and 
pharmacodynamics.  
Pharmacokinetics (PK), Pharmacodynamics, and Genomics 
BM Samples 
X 
 
D40 
(i.e.D12 
of Cycle 
2) 
D84 (i.e. D28 of 
Cycle 3) 
 
 
BM aspirate and core biopsy samples are required 
at Screening, Day 12 of Cycle 2 (within EOI+24hr), 
and Day 28 of Cycle 3 (+2 days is allowed, but must 
be before Day 1 of next cycle). Consult GSK Medical 
Monitor if bone marrow samples could not be 
obtained for any reason during these time points. 


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Protocol 
 
 
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Clinical Study Protocol template V15 dated 21-Dec-2020 
DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Alternative on-treatment biopsy timings may be 
explored, as discussed with GSK Medical Monitor. 
Additional unscheduled BM aspirate and/or biopsies 
may be performed any time during the treatment 
period upon participant consent for this optional 
procedure. 
Progressive Disease 
BM Sample  
 
 
 
 
X 
 
Although not required, BM aspirate and core biopsy 
at the time of disease progression is highly 
encouraged. 
Whole blood (flow 
cytometry) 
 
 
X 
X 
X 
 
Sample collection should occur on Days 1, 5,  9, 12, 
13 and 28 of each cycle.  
On Days 1 and 9: predose, EOI+4h, EOI+8h, 
EOI+12h, and EOI+24h time points will be collected; 
On Day 5: predose and EOI+8h will be collected; 
On Day12: predose, EOI+8h, and EOI+24h time 
points will be collected; 
For Days 13 & 28: only one time point (any time) will 
be collected. 
Collection of samples at disease progression is 
optional. 
Serum (cytokines) 
 
 
X 
X 
X 
 
Sample collection should occur on Days 1, 5, 9, and 
12 of each cycle.  
On Days 1 and 9: predose, EOI+4h, EOI+8h, 
EOI+12h, and EOI+24h time points will be collected; 


TMF- 14199778 
 
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209809 
 
Protocol 
 
 
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Clinical Study Protocol template V15 dated 21-Dec-2020 
DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
On Day 5 and 12: predose and EOI+8h will be 
collected. 
Collection of serum samples at disease progression 
is optional. 
GSK3745417 plasma 
PK 
 
 
X 
 
 
 
Cycle 1: PK sample collection times: Day 1 at 
predose (within 1h prior to dosing), EOI +5m, +15m, 
+30m, +45m, +1h, +2h, +4h, +6h, +8h, +12h and 
+24h; Day 4 at predose; Day 5 at predose and 
EOI+5m, +4h, +8h, +24h; Days 8 at predose (within 
1h prior to dosing) and EOI+4h, EOI+8h, EOI+12h 
and EOI+24h; and Day 12 at predose (within 1h 
prior to dosing) and EOI+8h and EOI+24h. 
Cycle 2: PK sample collection times: Day 1 at 
predose (within 1h prior to dosing) and EOI +5m, 
+1h, +4h, +8h, +12h and +24h; Day 4 at predose; 
Day 5 at predose and EOI +5m, +4h, +8h, +24h and 
Days 8 and Day 12 at predose (within 1h prior to 
dosing) and EOI +8h 
Cycle 3: PK sample collection times: Days 1 and 5 at 
predose (within 1h prior to dosing) and EOI +5m, 
+1h, +4h, +8h, 12h and +24h; Day 4 at predose; and 
Days 8 and Day 12 at predose and EOI +5m, +4h, 
+8h, and +24h. 


TMF- 14199778 
 
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Clinical Study Protocol template V15 dated 21-Dec-2020 
DE Cohort 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of injection; h=hour; ICF=informed consent form; m=min; 
Q1W=Every 1 week; Q3W=Every 3 weeks; Q6W=Every 6 weeks; Q9W=Every 9 weeks; Q12W=Every 12 weeks; SAE=serious adverse event; W=week; TLS = Tumor Lysis Syndrome; 
TDV=treatment discontinuation visit 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
Predose = within 60 minutes before the start of the GSK3745417 injection 
EOI+5m = at 5 minutes ±2 minutes from the end of the GSK3745417 injection 
EOI+15m = at 15 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+30m = at 30 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+45m = at 45 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+1h = at 1 hour ±15 minutes from the end of the GSK3745417 injection  
EOI+2h = at 2 hours ±30 minutes from the end of the GSK3745417 injection  
EOI+4h = at 4 hours ±30 minutes from the end of the GSK3745417 injection  
EOI+6h = at 6 hours ±30 minutes from the end of the GSK3745417 injection   
EOI+8h = at 8 hours ±1 hours from the end of the GSK3745417 injection 
EOI+12h = at 12 hours ±1 hour from the end of the GSK3745417 injection 
EOI+18h = at 18 hours ±2 hours from the end of the GSK3745417 injection 
EOI+24h = at 24 hours ±2 hours from the end of the GSK3745417 injection and before the next infusion 
CCI


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Clinical Study Protocol template V15 dated 21-Dec-2020 
  
a. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
b. 
The assessments required at the study treatment discontinuation visit must be completed within 30 days from the date study treatment was discontinued and must occur prior to 
the start of subsequent anti-cancer therapy; the window for this visit is +10 days.  
c. 
Procedures scheduled on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
 
 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
1.3.2. 
Part 2 – Induction Cycle 
Table 2 
Schedule of Activities: Part 2 – Induction Cycles 
 
 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion and 
Exclusion criteria 
X 
 
 
 
 
 
 
Demographics, 
Medical History, Prior 
Medications, Disease 
Characteristics 
X 
 
 
 
 
 
Include use of antibiotics, probiotics and 
anti-infectives taken 60 days prior to study 
intervention. 
Anticancer Therapy 
and Response to Prior 
Anticancer Therapy 
X 
 
 
 
 
 
 
Participant 
Registration 
X 
 
 
 
 
 
 
Safety Assessments 
 
In-House Monitoring 
 
X 
X 
 
 
 
Participants should be monitored in a medically 
qualified unit/clinic/hospital starting on Day -1 
through Day 13 (24 hours after the administration of 
GSK3745417 on Day 12) of each cycle.  
Physical Exam  
X 
 
X 
 
X 
 
A complete physical exam is required at screening, 
including cardiac and neurological examinations; 
brief or targeted physical exams will be performed 
on Day 1 at predose (within 1h prior to dosing) and 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Day 13 of each cycle, and as clinically indicated. 
Refer to Section 8.2.1 for physical examination 
details. 
ECOG PS 
X 
 
X 
 
X 
 
Should be assessed at each cycle  
Vital Signs 
X 
X 
X 
 
X 
 
Should be collected at each cycle at least 6 times on 
Day -1 within 24 hours prior to dosing, Day 1, 5, 8, 
and 12 at predose (within 1h prior to dosing), end of 
injection (EOI)+30m, +1h, +2h, +4h, +6h, +8h, +12h, 
+24h and, at least four times every day until 
discharge or more frequently if clinically indicated.   
Weight 
X 
X 
 
 
X 
 
Should be collected at each cycle. 
Echocardiogram 
X 
Week 1 and then Q8W except for the Part 2 Every 
three weeks daily dosing cohort where 
echocardiography will occur at Week 1 and then Q9W 
per protocol. Additional echocardiography may occur 
as clinically indicated 
 
If available, a 3D ECHO is preferred, otherwise a 2D 
ECHO may be performed. Where the quality of the 
ECHO examination is sub-optimal, MUGA scans 
may be used. The modality used at baseline should 
be repeated throughout the study to ensure 
comparison to baseline. At TDV, ECHO/MUGA does 
not need to be performed if an on-study ECHO has 
been conducted within the 4 weeks prior to visit. 
ECHO should be performed in the final week of the 
observation period. 
IV Contrast-enhanced 
Brain MRI (preferred) 
or IV Contrast-
enhanced CT Scan 
X 
Repeat if clinically indicated 
 
Brain imaging to be performed only if clinically 
indicated. 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
12-lead ECG 
X 
 
X 
 
X 
 
Triplicate ECGs should be performed at screening. 
Single ECGs should be obtained at each cycle on 
Day 1 and Day 4 at predose (within 1h prior to 
dosing) and EOI+2h. In cases of TLS, triplicate 
ECGs will be obtained at screening. Single ECGs 
should be obtained prior to GSK3745417 dosing, 
within 5 min EOI, and within 2 hours prior to 
completion of clinic visit. Post Week 6, next ECG 
should be on Week 9 and then Q3W thereafter. 
Patients with new onset symptoms consistent with 
immune-mediated pericarditis or myocarditis should 
have additional ECGs as clinically indicated. 
Holter Monitoring 
 
X 
X 
 
 
 
Baseline and Day -1 and Day 1 of Cycle 1 after 
dosing, starting at least -24h predose, followed by 
normal activity (ambulatory) until -30 min predose, 
when participant will be lying supine until time 0. 
Postdose, the participant will by lying supine for at 
least 3 minutes to align with the PK plasma sampling 
at EOI +5m, +15m, +30m, +45m, +1h, +2h, +4h, 
+6h, +8h, +12h and +24h. Holter monitoring will end 
at 24h after the first study intervention. The Holter 
will remain with the participant until 24h post-dose 
and then will be removed. The requirement for Holter 
monitoring may be waived for individual participants 
upon approval from GSK. 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Neurological 
Assessment including 
ICE scoring 
X 
Conduct if clinically indicated 
 
Refer to Section 6.4.1 for neurological assessment 
details. 
AE/SAE Review 
 
Assess at each visit from first dose until the TDV for AEs and until 90 days after the last dose for AESI and SAEs 
Concomitant 
Medication Review 
 
Continuous: Assess at each visit from first dose of study intervention 
Follow-Up Phone Call 
 
 
 
X 
 
 
Participants should be contacted by phone 
24-72 hours and 1 week (+24 hours) following 
discharge from clinic to assess for any AEs or 
cytokine related events.  
Safety Laboratory Assessments 
Human 
Immunodeficiency 
Virus (HIV), Hepatitis 
B Surface Antigen 
(HBsAg), Hepatitis C 
Virus (HCV) Antibody 
X 
 
 
 
 
 
 
Pregnancy Test 
X 
 
≤72 
hours 
(serum) 
X 
X 
Q12W 
Negative serum pregnancy test required at 
screening and within 72 hours prior to date of first 
dose of study treatment for females of childbearing 
potential. Urine pregnancy test will be conducted 
every 4 weeks for duration of study, on last day of 
treatment (if possible), at TDV, and at the Follow-Up 
visit. 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
CBC with differential 
X 
X 
X 
X 
X 
 
Sample collection times: Single sample from Day -1 
to Day 13, prior to each administration of 
GSK3745417. At least every 6 hours for the first 48 
hours following initiation of daily dosing period, then 
at least twice daily up to an including Day 5 dosing 
of each daily dosing period, and more frequently as 
clinically indicated. On the days when GSK3745417 
is not administered, samples will be collected at 
approximately the same times as on the days of 
GSK3745417 administration. A sample will also be 
taken between Day 20 and Day 22 during the 
outpatient period of the cycle. 
Clinical Chemistry 
(including laboratory 
parameters for TLS 
diagnosis and 
management) 
X 
X 
X 
X 
X 
 
Sample collection times:  
Cycle 1, and any cycle with a dose increase:  
single sample on Day –1; Days 1 and 2 at predose, 
EOI+6h, +12h, +18h and +24h; Days 3 - 5 – at 
predose and EOI+6h; Days 6 and 7 – single daily 
sample, Days 8 - 12 – at EOI+6hrs: Day 13 – single 
sample prior to discharge. 
Clinical chemistry including uric acid and phosphate 
will be measured at least every 6 hours for the first 
48 hours following initiation of daily dosing period, 
then at least twice daily up to an including Day 5 
dosing of each daily dosing period, and more 
frequently as clinically indicated. 


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Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Clinical chemistry samples should be collected more 
frequently if clinically indicated (such as cases of 
TLS). A sample will also be taken between Day 20 
and Day 22 during the outpatient period of the cycle.  
See Section 10.2 for complete list of required 
laboratory assessments. 
C-Reactive Protein 
X 
 
X 
X 
X 
 
Sample collection times: Day 1 at predose, EOI+8h 
and +24h for first dose, then pre dose at Day 5 and 
Day 12 of each cycle.  
Thyroid functionc 
X 
 
X 
 
X 
 
Sample collection times: Day 1 at predose of 
Cycles 1 and 3. 
Troponin I and T 
X 
 
X 
 
X 
 
See Section 6.4.1.5 for management of cardiac 
events. Samples will be collected on Day 13. 
BNP (or NTproNBNP) 
X 
Repeat as clinically indicated 
 
 
Repeat test as outlined in management of cardiac 
events (Section 6.4.1.5) 
eGFR 
X 
 
 
 
 
 
See Section 7.1.2 for management of renal events (if 
needed).  
Urinalysisc 
X 
 
X 
 
X 
 
Sample collection times: Days 1, 8 and 13 of each 
cycle. If urinalysis is abnormal, a microscopy should 
be performed. 
Coagulationc 
X 
 
X 
 
 
 
Sample collection times: at screening and prior to 
administration of first dose of GSK3745417 and at 
Day 8 of each cycle. Additional coagulation samples 
should be collected in the event of CRS (see 
Section 6.4.1.4) 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Study Intervention 
Administer 
GSK3745417 
 
 
X 
 
 
 
GSK3745417 will be administered each cycle on 
Days 1 – 5 and Days 8 - 12 QD. Participants will 
receive up to 3 cycles of treatment before moving to 
Q1W, Q3W, or less frequent dosing schedule 
(Section 6.1). See Section 4.1 for maximum duration 
of study intervention. See Section 4.1 for safety and 
tolerability parameters to be reviewed prior to each 
daily dose 
Non-Azole Antifungal 
 
X 
X 
X 
 
 
Non-azole antifungals should be administered if 
indicated, per local standard, on Day -1 through 
Day 28 of each cycle. 
Tumor Lysis 
Syndrome Prophylaxis 
 
X 
 
 
 
 
All participants should receive tumor lysis syndrome 
(TLS) prophylaxis prior to date of first dose of each 
cycle on Day -1 according to institutional guidelines 
(e.g., participants should receive IV fluids ± 
allopurinol and consider alkalization of urine and 
renal consult). TLS prophylaxis and fluids should be 
continued over each dosing cycle as clinically 
indicated. Refer to Section 6.4.1.2 for prophylaxis 
and management of TLS. 
Efficacy Assessments 
Follow-up for survival 
 
 
 
 
 
Q12W 
Participants will be followed Q12W (2 weeks) for 
survival and subsequent anticancer therapy. The 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
survival follow-up visit will commence after 
discontinuation of study intervention.  
BM Sample for 
Disease Assessment 
X 
 
D40 
(i.e.D12 
of Cycle 
2) 
D84 (i.e. D28 of 
Cycle 3) 
X 
 
BM aspirate and core biopsy samples are required 
at Screening, Day 12 of Cycle 2 (within EOI+24hr), 
and Day 28 of Cycle 3 (+2 days is allowed but must 
be before Day 1 of next cycle). The collection time 
point is mandatory after the last cycle of intense 
dosing (i.e. Day 28 of Cycle 3) before moving into 
maintenance. +2 days is allowed for BM sample 
collection at each time point provided it occurs 
before next treatment cycle starts. 
Both BM aspirate and core biopsy samples should 
be collected for Disease Assessment and 
pharmacodynamics. 
Pharmacokinetics (PK), Pharmacodynamics and Genomics 
BM Sample 
X 
 
D40 
(i.e.D12 
of 
Cycle2) 
D84 (i.e. D28 of 
Cycle 3) 
X 
 
BM aspirate and core biopsy samples are required 
at Screening, Day 12 of Cycle2 (within EOI+24hr), 
and Day 28 of Cycle 3 (+2 days is allowed but must 
be before Day 1 of next cycle). Consult GSK Medical 
Monitor if bone marrow samples could not be 
obtained for any reason during these time points. 
Alternative on-treatment biopsy timings may be 
explored, as discussed with GSK Medical Monitor. 
Additional unscheduled BM aspirate and/or biopsies 
may be performed any time during the treatment 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
period upon participant consent for this optional 
procedure. 
Progressive Disease 
BM biopsy  
 
 
 
 
X 
 
Although not required, BM aspirate and core biopsy 
at the time of disease progression is highly 
encouraged. 
Whole blood (flow 
cytometry) 
 
 
X 
X 
X 
 
Cycle 1: Sample collection should be done on Days 
1, 5, 9, 12, 13 and 28. 
• 
On Days 1 and 9: predose, EOI+4h, EOI+8h, 
EOI+12h, and EOI+24h time points will be 
collected.  
• 
On Days 5 & 12: predose and EOI+8h will be 
collected. 
• 
For Days 13 & 28: only one time point (any 
time) will be collected. 
Cycle 2: Sample collection should be done on D12 
only (predose, EOI+4h, EOI+8h, EOI+12h, and 
EOI+24h) 
Cycle 3: D28 (anytime)  
Sample collection at disease progression is optional. 
Serum (cytokines) 
 
 
X 
X 
X 
 
Cycle 1: Sample collection should be done on Days 
1, 5,  9, and 12.  


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Clinical Study Protocol template V15 dated 21-Dec-2020 
 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
• 
On Days 1 and 9: predose, EOI+4h, EOI+8h, 
EOI+12h, and EOI+24h time points will be 
collected;  
• 
On Days 5 & 12: predose and EOI+8h time 
points will be collected.  
Cycle 2: Sample collection should be done on D1 
(predose, EOI+8h) and D12 (predose, EOI+4h, 
EOI+8h, EOI+12h, and EOI+24h) 
Cycle 3: Sample collection should be done on D1 
(predose, EOI+8hr) and D12 (predose, EOI+8hr). 
Sample collection at disease progression is optional. 
GSK3745417 plasma 
PK 
 
 
X 
 
 
 
Cycle 1: PK sample collection times: Day 1 at 
predose (within 1h prior to dosing), EOI +5m, +15m, 
+30m, +45m, +1h, +2h, +4h, +6h, +8h, +12h and 
+24h; Day 4 at predose; Day 5 at predose and 
EOI+5m, +4h, +8h, +24h; Days 8 at predose (within 
1h prior to dosing) and EOI+4h, EOI+8h, EOI+12h 
and EOI+24h; and Day 12 at predose (within 1h 
prior to dosing) and EOI+8h and EOI+24h. 
Cycle 2: PK sample collection times: Day 1 at 
predose (within 1h prior to dosing), EOI +1h, +4h, 
+8h; Day 12 at predose (within 1h prior to dosing) 
and EOI +1h, +4h, +8h, +12h and +24 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
 
Screeninga 
Cycle (Induction Period) 
Follow-Up  
(post-final dose 
administered) 
 
Study Procedure 
 
Intervention Period 
(In-Patient-Day1 of 
cycle 1) 
Observation 
Period 
(Outpatient) 
TDVb 
Follow-
Up 
Notes 
Week 
≤4 
1 - 2 
3 - 4 
+4 
 
 
Day 
28 
-1 
1 - 13 
14 - 28 
+30d 
 
 
Cycle 3: PK sample collection times: Day 1 predose 
(within 1h prior to dosing), EOI +1h, +4h, +8h; and 
Day 12 at predose (within 1h prior to dosing) and 
EOI +1h, +4h, +8h; and on Day 28 anytime 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of injection; h=hour; ICF=informed consent form; m=min; 
Q1W=Every 1 week; Q3W=Every 3 weeks; Q6W=Every 6 weeks; Q9W=Every 9 weeks; Q12W=Every 12 weeks; SAE=serious adverse event; W=week; TLS = Tumor Lysis Syndrome; 
TDV=treatment discontinuation visit 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
Predose = within 60 minutes before the start of the GSK3745417 injection 
EOI+5m = at 5 minutes ±2 minutes from the end of the GSK3745417 injection 
EOI+15m = at 15 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+30m = at 30 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+45m = at 45 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+1h = at 1 hour ±15 minutes from the end of the GSK3745417 injection  
EOI+2h = at 2 hours ±30 minutes from the end of the GSK3745417 injection  
EOI+4h = at 4 hours ±30 minutes from the end of the GSK3745417 injection  
EOI+6h = at 6 hours ±30 minutes from the end of the GSK3745417 injection   
CCI


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EOI+8h = at 8 hours ±1 hours from the end of the GSK3745417 injection 
EOI+12h = at 12 hours ±1 hour from the end of the GSK3745417 injection 
EOI+18h = at 18 hours ±2 hours from the end of the GSK3745417 injection 
EOI+24h = at 24 hours ±2 hours from the end of the GSK3745417 injection and before the next infusion 
 
a. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
b. 
The assessments required at the study treatment discontinuation visit must be completed within 30 days from the date study treatment was discontinued and must occur prior to 
the start of subsequent anti-cancer therapy; the window for this visit is +10 days.  
c. 
Procedures scheduled on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
 
 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
1.3.3. 
Part 1 and Part 2 – GSK3745417 Maintenance Once Weekly  
Table 3 
Schedule of Activities (GSK3745417 Maintenance Once Weekly- Part 1 & Part 2) 
Q1W Cohort 
Study Maintenance Period 
 
 
Study Procedure 
GSK417 Weekly (Q1W) 
TDVa 
Follow-Up 
(post-final 
dose 
administer
ed 
Notes 
Week 
 
1 and Thereafter 
+4 
 
 
Day 
-1 
1 and Thereafter 
+30d 
 
 
Safety Assessments 
In-House Monitoring 
X 
Q1W 
 
 
Participants should be monitored in a medically 
qualified unit/clinic/hospital starting on Day -1 
and 24 hours following the administration of 
GSK3745417. This requirement may be 
eliminated as safety data emerge.  
Physical Exam  
 
Q1W 
X 
 
Brief or targeted physical exams will be 
performed on Day 1 at predose (within 1h prior 
to dosing) and as clinically indicated. Refer to 
Section 8.2.1 for physical examination details. 
ECOG PS 
 
Q1W 
X 
 
If available, a 3D ECHO is preferred, otherwise 
a 2D ECHO may be performed. Where the 
quality of the ECHO examination is sub-optimal, 
MUGA scans may be used. The modality used 
at baseline should be repeated throughout the 
study to ensure comparison to baseline. 
Vital Signs 
 
Q1W 
X 
 
Vital signs should be collected at least 6 times 
on Day -1 within 24 hours prior to dosing and on 
Day 1 at EOI+30m, +1h, +2h, +4h, +6h, +8h, 
+12h and +24h.  
Weight 
 
Q1W 
X 
 
 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
Q1W Cohort 
Study Maintenance Period 
 
 
Study Procedure 
GSK417 Weekly (Q1W) 
TDVa 
Follow-Up 
(post-final 
dose 
administer
ed 
Notes 
Week 
 
1 and Thereafter 
+4 
 
 
Day 
-1 
1 and Thereafter 
+30d 
 
 
Echocardiogram 
 
Week 1, then Q8W 
X 
 
If available, a 3D ECHO is preferred, otherwise 
a 2D ECHO may be performed. Where the 
quality of the ECHO examination is sub-optimal, 
MUGA scans may be used. The modality used 
at baseline should be repeated throughout the 
study to ensure comparison to baseline. At 
TDV, ECHO/MUGA does not need to be 
performed if an on-study ECHO has been 
conducted within the 4 weeks prior to visit. 
IV Contrast-
enhanced Brain MRI 
(preferred) or IV 
Contrast-enhanced 
CT Scan 
Conduct if clinically indicated 
 
Brain scans must be performed with IV contrast. 
12-lead ECG 
 
Q1W 
X 
 
Single ECGs should be obtained at predose 
(within 1h prior to dosing), within 5 min EOI, and 
within 2 hours prior to completion of clinic visit. 
Triplicate ECG should be obtained in case of 
TLS and participants should have continuous 
cardiac monitoring. Patients with new onset 
symptoms consistent with immune-mediated 
pericarditis or myocarditis should have 
additional ECGs as clinically indicated. 
Holter Monitoring 
X 
 
 
 
12-lead Holter monitoring will be conducted at 
Baseline and as clinically indicated on Day -1 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
Q1W Cohort 
Study Maintenance Period 
 
 
Study Procedure 
GSK417 Weekly (Q1W) 
TDVa 
Follow-Up 
(post-final 
dose 
administer
ed 
Notes 
Week 
 
1 and Thereafter 
+4 
 
 
Day 
-1 
1 and Thereafter 
+30d 
 
 
and Day 1 of Week 3 starting at least -24h 
predose. Holter monitoring will end 24hQ after 
the first dose followed by normal activity 
(ambulatory) until -30 min predose, when 
participant will be lying supine until time 0. 
Postdose, the participant will by lying supine for 
at least 3 minutes to align with the PK plasma 
sampling at EOI +5m, +15m, +30m, +45m, +1h, 
+2h, +4h, +6h, +8h, +12h, +24h. Holter 
monitoring will end at 24h after the first study 
intervention. The Holter will remain with the 
participant until 24h post-dose and then will be 
removed. The requirement for Holter monitoring 
may be waived for individual participants upon 
approval from GSK. 
Neurological 
Assessment 
Conduct if clinically indicated 
 
Refer to Section 6.4.1 for neurological 
assessment details. 
AE/SAE Review 
Assess at each visit from first dose until the TDV for AEs and until 90 days after the last dose for AESI and SAEs 
Concomitant 
Medication Review 
Continuous: Assess at each visit from first dose of study intervention 
Follow-Up Phone 
Call 
 
X 
 
 
Participants should be contacted by phone 
24-72 hours following discharge from clinic to 
assess for any AEs or cytokine related events  


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Clinical Study Protocol template V15 dated 21-Dec-2020 
Q1W Cohort 
Study Maintenance Period 
 
 
Study Procedure 
GSK417 Weekly (Q1W) 
TDVa 
Follow-Up 
(post-final 
dose 
administer
ed 
Notes 
Week 
 
1 and Thereafter 
+4 
 
 
Day 
-1 
1 and Thereafter 
+30d 
 
 
Safety Laboratory Assessments 
Pregnancy Test 
 
X 
X 
X 
Urine pregnancy test will be conducted every 
4 weeks for duration of study, on last day of 
treatment (if possible), at TDV, and at the 
Follow-Up visit. 
CBC with differential 
X 
Q1W 
X 
 
Sample collection times: Day –1 (single sample) 
and Day 1 at predose, EOI+4h and EOI+24h. At 
least every 6 hours for the first 48 hours 
following initiation of daily dosing period, then at 
least twice daily up to an including Day 5 dosing 
of each daily dosing period, and more 
frequently as clinically indicated. 
Clinical Chemistry 
and TLS labs 
X 
Q1W 
X 
 
Sample collection times: Day –1 (single sample) 
and Day 1 at predose, EOI+6h, +12h, +18h and 
+24h; see Section 10.2 for complete list of 
required laboratory assessments. 
C-Reactive Protein 
 
Q1W 
X 
 
Sample collection times: predose, EOI+8h, and 
EOI+24h.  
Thyroid functionb 
 
Day 1, then Q8W 
X 
 
The first assessment should be done at Week 1 
and then Q8W. 
Troponin I and T 
 
Q2W 
X 
 
Sample will be collected predose and every 
2 weeks.  
BNP (or 
NTproNBNP) 
X 
Repeat as clinically indicated 
 
 
Repeat test as outlined in management of 
cardiac events (Section 6.4.1.5) 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
Q1W Cohort 
Study Maintenance Period 
 
 
Study Procedure 
GSK417 Weekly (Q1W) 
TDVa 
Follow-Up 
(post-final 
dose 
administer
ed 
Notes 
Week 
 
1 and Thereafter 
+4 
 
 
Day 
-1 
1 and Thereafter 
+30d 
 
 
Urinalysisb 
 
Q1W 
X 
 
If urinalysis is abnormal, a microscopy should 
be performed. 
Coagulationb 
 
Day 1, then Q3W 
 
 
The first assessment should be done at Day 1 
and then Q3W. Additional coagulation samples 
should be collected in the event of CRS (see 
Section 6.4.1.4) 
Study Intervention 
Administer 
GSK3745417 
 
Q1W 
 
 
GSK3745417 must be administered with ±1 day 
of scheduled visit unless otherwise indicated. 
Each subsequent dose in a participant should 
be administered at least 5 days apart. See 
Section 4.1 duration of study intervention. 
Non-Azole 
Antifungal 
X 
X 
X 
 
Non-azole antifungals should be administered if 
indicated, per local standard, on Day -1 through 
Day 28 of each cycle. 
Tumor Lysis 
Syndrome 
Prophylaxis 
X 
 
 
 
All participants should receive tumor lysis 
syndrome (TLS) prophylaxis prior to date of 
GSK3745417 administration starting on Day -1 
and continuing over 24 hours according to 
institutional guidelines (e.g., participants should 
receive IV fluids ± allopurinol and consider 
alkalization of urine and renal consult). Refer to 
Section 6.4.1.2 for prophylaxis and 
management of TLS. 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
Q1W Cohort 
Study Maintenance Period 
 
 
Study Procedure 
GSK417 Weekly (Q1W) 
TDVa 
Follow-Up 
(post-final 
dose 
administer
ed 
Notes 
Week 
 
1 and Thereafter 
+4 
 
 
Day 
-1 
1 and Thereafter 
+30d 
 
 
Efficacy Assessments 
Follow-up for 
survival 
 
 
 
Q4W 
Participants will be followed Q4W (2 weeks) 
for survival and subsequent anti-cancer 
therapy. The survival follow-up visit will 
commence after discontinuation of study 
intervention.  
BM Sample for 
Disease Assessment 
 
Q6W during the 1st three 
months, then Q12W 
 
 
Both BM aspirate and core biopsy samples 
should be collected for Disease Assessment 
every 6 weeks during the first three months (2 
time points) and then Q12W thereafter until 
disease progression or initiating another cancer 
treatment. 
Pharmacokinetics (PK), Pharmacodynamics and Genomics 
BM Biopsy 
 
Q6W during the 1st three 
months, then Q12W 
 
 
On-treatment BM aspirate and core biopsies 
are both required during the maintenance 
phase until disease progression. Sample 
collection should be performed within 
EOI+48 hours but allowed window is +7 days 
after the scheduled visit.  
Alternative on-treatment biopsy timings may be 
explored, as discussed with GSK Medical 
Monitor. Unscheduled BM biopsies may be 
performed any time during the treatment period 
upon participant consent for this optional 
procedure.  


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Clinical Study Protocol template V15 dated 21-Dec-2020 
Q1W Cohort 
Study Maintenance Period 
 
 
Study Procedure 
GSK417 Weekly (Q1W) 
TDVa 
Follow-Up 
(post-final 
dose 
administer
ed 
Notes 
Week 
 
1 and Thereafter 
+4 
 
 
Day 
-1 
1 and Thereafter 
+30d 
 
 
Progressive Disease 
BM biopsy 
 
 
X 
 
Although not required, a BM aspirate and core 
biopsy at the time of disease progression is 
highly encouraged. 
Whole blood (flow 
cytometry) 
 
Weeks 1, 2, 3, 4  
X 
 
Sample collection time points: Day 1 (Predose, 
EOI+4h, EOI+8h, EOI+12h, and EOI+24h), 
Day 8 (Predose, EOI+8h), Day 15 (Predose, 
EOI+8h), and Day 22 (Predose only). 
Collection of samples at disease progression is 
optional. 
Serum (cytokines) 
 
Weeks 1, 2, 3, 4, then Q3W 
X 
 
Sample collection time points: Day 1 (Predose, 
EOI+4h, EOI+8h, EOI+12h, and EOI+24h), 
Day 8 (Predose, EOI+8h), Day 15 (Predose, 
EOI+8h), and Day 22 (Predose only). After 
Day 22, samples will be collected Q3W 
(predose, EOI+8hr) until disease progression.  
Collection of serum samples at disease 
progression is optional. 
GSK3745417 
plasma PK 
 
Weeks 1, 2, 3, 4, then Q3W 
 
 
PK sample collection times: Week 3 at predose, 
EOI +5m, +15m, +30m, +45m, +1h, +2h, +4h, 
+6h, +8h, +12h, +24h; All other weeks at 
predose, EOI+1h, EOI +4h, and EOI +8h.  
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of injection; h=hour; ICF=informed consent form; 
m=minQ1W=Every 1 week; Q3W=Every 3 weeks; Q6W=Every 6 weeks; Q9W=Every 9 weeks; Q12W=Every 12 weeks; SAE=serious adverse event; W=week; TLS = Tumor Lysis 
Syndrome; TDV=treatment discontinuation visit. 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
Predose = within 60 minutes before the start of the GSK3745417 injection 
EOI+5m = at 5 minutes ±2 minutes from the end of the GSK3745417 injection 
EOI+15m = at 15 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+30m = at 30 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+45m = at 45 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+1h = at 1 hour ±15 minutes from the end of the GSK3745417 injection  
EOI+2h = at 2 hours ±30 minutes from the end of the GSK3745417 injection  
EOI+4h = at 4 hours ±30 minutes from the end of the GSK3745417 injection  
EOI+6h = at 6 hours ±30 minutes from the end of the GSK3745417 injection   
EOI+8h = at 8 hours ±1 hours from the end of the GSK3745417 injection 
EOI+12h = at 12 hours ±1 hour from the end of the GSK3745417 injection 
EOI+18h = at 18 hours ±2 hours from the end of the GSK3745417 injection 
EOI+24h = at 24 hours ±2 hours from the end of the GSK3745417 injection and before the next infusion 
 
a. 
The assessments required at the study treatment discontinuation visit must be completed within 30 days from the date study treatment was discontinued and must occur prior to 
the start of subsequent anti-cancer therapy; the window for this visit is +10 days.  
b. 
Procedures scheduled on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
 
 
 


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Clinical Study Protocol template V15 dated 21-Dec-2020 
1.3.5. 
Part 2 – GSK3745417 Maintenance Every 3 Weeks  
Table 4 
Schedule of Activities (GSK3745417 Maintenance Every 3 Weeks- Part 2 only) 
Q3W Cohort 
Study Maintenance 
Period 
 
 
Study Procedure 
GSK417 Every 3 
Weeks (Q3W) 
TDVb 
Follow-Up (post-
final dose 
administered 
Notes 
Week 
 
1 and 
Thereaftera 
+4 
Q4W 
 
Day 
-1 
1 and 
Thereafter 
+30d 
 
 
Safety Assessments 
In-House Monitoring 
X 
Q3W 
 
 
Participants should be monitored in a medically qualified unit/clinic/hospital starting 
on Day -1 and 24 hours following the administration of GSK3745417 on Day 1. This 
requirement may be eliminated as safety data emerge.  
Physical Exam  
 
Q3W 
X 
 
Brief or targeted physical exams will be performed on Day 1 at predose (within 1h 
prior to dosing), and as clinically indicated. Refer to Section 8.2.1 for physical 
examination details. 
ECOG PS 
 
Q3W 
X 
 
 
Vital Signs 
X 
Q3W 
X 
 
Vital signs should be collected at least 6 times on Day -1 within 24 hours prior to 
dosing and on Day 1 at predose (within 1 hour prior to dosing) and at EOI+30m, 
+1h, +2h, +4h, +6h, +8h, +12h and +24h.  
Weight 
 
Q3W 
X 
 
 
Echocardiogram 
 
Week 1, then 
Q9W 
X 
 
If available, a 3D ECHO is preferred, otherwise a 2D ECHO may be performed. 
Where the quality of the ECHO examination is sub-optimal, MUGA scans may be 
used. The modality used at baseline should be repeated throughout the study to 
ensure comparison to baseline. At TDV, ECHO/MUGA does not need to be 
performed if an on-study ECHO has been conducted within the 4 weeks prior to 
visit. 


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Q3W Cohort 
Study Maintenance 
Period 
 
 
Study Procedure 
GSK417 Every 3 
Weeks (Q3W) 
TDVb 
Follow-Up (post-
final dose 
administered 
Notes 
Week 
 
1 and 
Thereaftera 
+4 
Q4W 
 
Day 
-1 
1 and 
Thereafter 
+30d 
 
 
IV Contrast-
enhanced Brain MRI 
(preferred) or IV 
Contrast-enhanced 
CT Scan 
Conduct if clinically indicated 
 
Brain scans must be performed with IV contrast. 
12-lead ECG 
 
Q3W 
X 
 
Single ECGs should be obtained at predose (within 1h prior to dosing), within 5 min 
EOI, and within 2 hours prior to completion of clinic visit. Triplicate ECG should be 
obtained in case of TLS. Patients with new onset symptoms consistent with 
immune-mediated pericarditis or myocarditis should have additional ECGs as 
clinically indicated. 
Holter Monitoring 
Day 
-1 
Day 1 
 
 
12-lead Holter monitoring will be conducted at Baseline on Day-1 and Day 1 of 
Week 7 starting at least -24h pre-dose. Holter monitoring will end 24h after the first 
dose, followed by normal activity (ambulatory) until -30 min predose, when 
participant will be lying supine until time 0. Postdose, the participant will by lying 
supine for at least 3 minutes to align with the PK plasma sampling at EOI +5m, 
+15m, +30m, +45m, +1h, +2h, +4h, +6h, +8h, +12, and +24. Holter monitoring will 
end at 24h after the first study intervention. Holter will remain with the participant 
until the end of Day 1 and will be removed prior to end of clinic visit. The 
requirement for Holter monitoring may be waived for individual participants upon 
approval from GSK. 
Neurological 
Assessment 
including ICE scoring 
 
Conduct if clinically 
indicated 
 
Refer to Section 6.4.1 for neurological assessment details. 
AE/SAE Review 
 
Assess at each visit from first dose until the TDV for AEs and until 90 days after the last dose for AESI and SAEs 


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Q3W Cohort 
Study Maintenance 
Period 
 
 
Study Procedure 
GSK417 Every 3 
Weeks (Q3W) 
TDVb 
Follow-Up (post-
final dose 
administered 
Notes 
Week 
 
1 and 
Thereaftera 
+4 
Q4W 
 
Day 
-1 
1 and 
Thereafter 
+30d 
 
 
Concomitant 
Medication Review 
 
Continuous: Assess at each visit from first dose of study intervention 
Follow-Up Phone 
Call 
 
X 
 
 
Participants should be contacted by phone 24-72 hours following discharge from 
clinic to assess for any AEs or cytokine related events  
Safety Laboratory Assessments 
Pregnancy Test 
 
X 
X 
X 
Urine pregnancy test will be conducted every 3 weeks for duration of study, on last 
day of treatment (if possible), at TDV, and at the Follow-Up visit. 
CBC with differential 
X 
Q3W 
X 
 
Sample collection times: Day –1 (single-sample) and Day 1 at predose, EOI+4h 
and EOI+24h. At least every 6 hours for the first 48 hours following initiation of daily 
dosing period, then at least twice daily up to an including Day 5 dosing of each 
daily dosing period, and more frequently as clinically indicated. 
Clinical Chemistry 
and TLS labs 
X 
Q3W 
X 
 
Sample collection times: Day –1 (single-sample) and Day 1 at predose, EOI+6h, 
+12h, +18h and +24h; see Section 10.2 for complete list of required laboratory 
assessments. 
C-Reactive Protein 
 
Q3W 
X 
 
Sample collection times: Predose, EOI+8h, and EOI+24h.  
Thyroid functionb 
 
Day 1, then 
Q6W 
X 
 
The first assessment should be done at Week 1 and then Q6W. 
Troponin I and T 
 
Q3W 
X 
 
Sample will be collected predose and every 3 weeks.  
BNP (or 
NTproNBNP) 
X 
Repeat as 
clinically 
indicated 
 
 
Repeat test as outlined in management of cardiac events (Section 6.4.1.5) 
Urinalysisb 
 
Q3W 
X 
 
If urinalysis is abnormal, a microscopy should be performed. 
Coagulationb 
 
Day 1, then 
Q3W 
 
 
The first assessment should be done at Day 1 and then Q3W. 


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Q3W Cohort 
Study Maintenance 
Period 
 
 
Study Procedure 
GSK417 Every 3 
Weeks (Q3W) 
TDVb 
Follow-Up (post-
final dose 
administered 
Notes 
Week 
 
1 and 
Thereaftera 
+4 
Q4W 
 
Day 
-1 
1 and 
Thereafter 
+30d 
 
 
Study Intervention 
Administer 
GSK3745417 
 
Q3W 
 
 
GSK3745417 must be administered with ±3 day of scheduled visit unless 
otherwise indicated. Each subsequent dose in a participant should be administered 
at least 5 days apart. See Section 4.1 duration of study intervention. 
Non-Azole Antifungal 
X 
X 
X 
 
Non-azole antifungals should be administered if indicated, per local standard, on 
Day -1 through Day 28 of each cycle. 
Tumor Lysis 
Syndrome 
Prophylaxis 
X 
 
 
 
All participants should receive tumor lysis syndrome (TLS) prophylaxis prior to date 
of GSK3745417 administration starting on Day -1 and continuing over 24 hours 
according to institutional guidelines (e.g., participants should receive IV fluids ± 
allopurinol and consider alkalization of urine and renal consult). Refer to 
Section 6.4.1.2 for prophylaxis and management of TLS. 
Efficacy Assessments 
Follow-up for survival 
 
 
 
Q4W 
Participants will be followed Q4W (2 weeks) for survival and subsequent 
anti-cancer therapy. The survival follow-up visit will commence after discontinuation 
of study intervention.  
BM Sample for 
Disease Assessment 
 
Q6W during the 
1st three 
months, then 
Q12W 
 
 
Both BM aspirate and core biopsy samples should be collected for Disease 
Assessment every 6 weeks during the first three months (2 time points) and then 
Q12W thereafter until disease progression or initiating another cancer treatment.  
Pharmacokinetics (PK), Pharmacodynamics and Genomics 
BM Biopsy 
 
Q6W during the 
1st three 
months, then 
Q12W 
 
 
On-treatment BM aspirate and core biopsies are both required every 6 weeks 
during the first three months (2 time points) and then Q12W thereafter until disease 
progression. Sample collection during the maintenance phase should be performed 
within EOI+48 hours but allowed window is +7 days after the scheduled visit.  


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Q3W Cohort 
Study Maintenance 
Period 
 
 
Study Procedure 
GSK417 Every 3 
Weeks (Q3W) 
TDVb 
Follow-Up (post-
final dose 
administered 
Notes 
Week 
 
1 and 
Thereaftera 
+4 
Q4W 
 
Day 
-1 
1 and 
Thereafter 
+30d 
 
 
Alternative on-treatment biopsy timings may be explored, as discussed with GSK 
Medical Monitor. Unscheduled BM biopsies may be performed any time during the 
treatment period upon participant consent for this optional procedure.  
Progressive Disease 
BM biopsy 
 
 
X 
 
Although not required, a BM aspirate and/or biopsy at the time of disease 
progression is highly encouraged. 
Whole blood (flow 
cytometry) 
 
Weeks 1, 2, 3, 4  
X 
 
Sample collection time points: Day 1 (Predose, EOI+4h, EOI+8h, EOI+12h, and 
EOI+24h), Day 8 (any time), Day 15 (any time), and Day 22 (Predose only).  
Collection of samples at disease progression is optional. 
Serum (cytokines) 
 
Weeks 1, 2, 3, 
4, then Q3W 
X 
 
Sample collection time points: Day 1 (Predose, EOI+4h, EOI+8h, EOI+12h, and 
EOI+24h), Day 8 (any time), Day 15 (any time), and Day 22 (Predose only). After 
Day 22, samples will be collected Q3W (predose, EOI+8hr) until disease 
progression.  
Collection of serum samples at disease progression is optional. 
GSK3745417 plasma 
PK 
 
Weeks 1, 4, 7, 
10, then Q3W 
 
 
PK sample collection times: Week 7 at predose, EOI +5m, +15m, +30m, +45m, 
+1h, +2h, +4h, +6h, +8h, +12, and +24; All other weeks at predose, EOI+1h, EOI 
+4h, and EOI +8h. 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of injection; h=hour; ICF=informed consent form; m=min; 
Q1W=Every 1 week; Q3W=Every 3 weeks; Q6W=Every 6 weeks; Q9W=Every 9 weeks; Q12W=Every 12 weeks; SAE=serious adverse event; W=week; TLS = Tumor Lysis Syndrome; 
TDV=treatment discontinuation visit. 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
Predose = within 60 minutes before the start of the GSK3745417 injection 
EOI+5m = at 5 minutes ±2 minutes from the end of the GSK3745417 injection 


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EOI+15m = at 15 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+30m = at 30 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+45m = at 45 minutes ±5 minutes from the end of the GSK3745417 injection  
EOI+1h = at 1 hour ±15 minutes from the end of the GSK3745417 injection  
EOI+2h = at 2 hours ±30 minutes from the end of the GSK3745417 injection  
EOI+4h = at 4 hours ±30 minutes from the end of the GSK3745417 injection  
EOI+6h = at 6 hours ±30 minutes from the end of the GSK3745417 injection   
EOI+8h = at 8 hours ±1 hours from the end of the GSK3745417 injection 
EOI+12h = at 12 hours ±1 hour from the end of the GSK3745417 injection 
EOI+18h = at 18 hours ±2 hours from the end of the GSK3745417 injection 
EOI+24h = at 24 hours ±2 hours from the end of the GSK3745417 injection and before the next infusion 
  
a. The assessments required at the study treatment discontinuation visit must be completed within 30 days from the date study treatment was discontinued and must occur prior to the 
start of subsequent anti-cancer therapy; the window for this visit is +10 days.  
b. Procedures scheduled on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale  
GSK3745417 is an intravenously delivered STING (STimulator of Interferon Genes) 
agonist currently under evaluation in solid tumors in the FTIH 208850 dose escalation 
study. Recent evidence has shown that in addition to immune-mediated activity, 
GSK3745417 exhibits a cytolytic effect, a second mechanism of action, in AML cells in 
nonclinical studies. STING is expressed at a higher level on AML cells compared with 
other tumor types [The Cancer Genome Atlas (TCGA) - National Cancer Institute]. The 
high level of STING expression combined with preclinical evidence of antitumor activity 
makes AML a suitable indication to establish proof of mechanism and evaluate the 
clinical activity of GSK3745417. The goal of the study is to identify an RP2D and 
schedule with a manageable safety profile. Study 209809 is proposed to evaluate the 
safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of 
GSK3745417 in relapsed or refractory AML and high-risk myelodysplastic syndrome 
(HR-MDS). 
2.2. 
Background 
Clinical Background: AML and MDS 
MDS and AML are clonal neoplasms of myeloid progenitors that arise within the bone 
marrow. They are typically manifested by peripheral cytopenias (neutropenia, anemia, 
and/or thrombocytopenia), hypercellularity of the bone marrow (because of ineffective 
hematopoiesis), molecular and/or karyotypic abnormalities, and an expansion of 
immature myeloid cells. It is the quantitation of these immature myeloblasts that, in part, 
differentiates AML from MDS, with a 20% blast percentage marking the transition from 
MDS to AML. In the US, the estimate for new cases of AML in 2020 was approximately 
20,000 and the estimate for deaths from AML was approximately 11,000. For MDS, 
some estimates indicate around 10,000 cases per year [from American Cancer Society 
website]. While multiple new targeted agents have been approved to treat AML in 
patients that have a limited number of genetic mutations, most patients with both MDS 
and AML are not eligible for these therapies. Despite modern therapies, patients 
eventually relapse and may become refractory to treatment and have a poor prognosis. 
Currently, for relapsed/refractory AML patients, there is no standard of care and clinical 
trial participation is recommended. The median overall survival for relapsed/refractory 
AML and for high-risk MDS is short, generally less than 6 months. Therefore, new 
therapies to prolong survival are desperately needed. 
GSK3745417 Background:  
Preclinical data support the use of STING agonists for the treatment of AML. STING is 
the key adaptor molecule in the cGAS-STING-TBK1 pathway that mediates the sensing 
of cytosolic DNA (Chen, 2017; Sun, 2013). Activation of STING generates a distinctive 
set of type I interferons (IFNα and IFNβ) and pro-inflammatory cytokines that instigate 
T-cell dependent tumor immunity and tumor vascular collapse (Ishikawa, 2009; 
Mahadevan, 1990; Woo, 2014). Preclinical studies support the hypothesis that the STING 


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activation pathway has the potential to boost tumor antigen presentation and tumor 
immunogenicity. In animal models of AML, STING agonists have demonstrated some 
activity by improving survival and inducing immune responses via induction of type I 
interferons and proinflammatory cytokines, suggesting that they may play a role in 
immune therapy for leukemia and possibly other hematologic malignancies (Curran, 
2016). Data demonstrated a second mechanism of action of direct induction of apoptosis 
in AML cells treated with GSK3745417. Published literature also support a role for 
STING activation in driving human myeloid and AML cell death (Baba, 2021; Gaidt, 
2017). These reports and others suggest cell death driven by a range of mechanisms 
including lysosomal cell death (Gaidt, 2017), reactive oxygen species (Baba, 2021), and 
apoptosis (Gulen, 2017). 
GSK3745417 is a synthetic STING agonist that is being developed by GlaxoSmithKline 
as an immune stimulatory agent for the treatment of cancer. It is currently being studied 
in a Phase 1 first in human trial, 208850, to assess the safety, PK, PD, and preliminary 
clinical activity of GSK3745417 administered alone and in combination with other 
immunotherapies in participants with advanced solid tumors. Preliminary data from the 
208850 study have shown that administration of GSK3745417 results in increased 
proinflammatory cytokine production after dosing in participants with solid tumors 
(GSK3745417 IB). This study is ongoing and clinical activity has not yet been evaluated.  
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of GSK3745417 may be found in the IB and 
Informed Consent document. Table 5 presents an overview of the potential risks 
associated with GSK3745417 dosing in participants with AML, and the risk mitigation 
strategies.  


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Table 5 
Risk Assessment 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) GSK3745417  
Cytokine release 
syndrome (CRS) 
Nonclinical: 
The severity of cytokine related symptoms/signs observed in an AML 
population is not expected to be more severe than that observed to 
date in the solid tumor population of Study 2008850 and based on the 
non-clinical data. 
 
Clinical:  
In Study 208850, dose dependent cytokine-related symptoms and 
CRS were observed. Symptoms reported with CRS commonly 
comprised pyrexia, chills/rigors, tachycardia, hypotension, hypoxia, 
and headache; these were all Grade 1 or 2 events, with none of the 
cases being life threatening or fatal.  
 
Preliminary analyses suggest that cytokine-related AEs may be more 
likely associated with drug exposure (AUC-related) than measured 
cytokine levels.   
 
  
General Measures: 
• 
Sites selected based on cytokine release syndrome (CRS) 
management capabilities (i.e. ICU proximity, staff 
experience, resuscitation measures, central line placement 
and medication administration capability). 
• 
CRS events are categorized as Adverse Events of Special 
interest (AESIs) which must be reported to the Medical 
Monitor within 24 hours regardless of study drug 
relationship. 
 
Monitoring: 
• 
Careful observation with continuous in-hospital monitoring 
throughout the 2-week induction daily-dosing period of the 
cycle, and 24hr hospital observation post-dose for 
maintenance dosing.  
 
Mitigation: 
• 
Use a starting dose of 12.5 µg that is 1/32nd of the 400 µg 
MTD (refer to Section 4.4.2). 
• 
Dose staggering of participants to allow assessment initial 
safety data before enrolling next participant. 
• 
Guidelines on the management of CRS symptoms is 
provided in Table 11 and dose modifications in 
Section 6.4.1. 
Tumor Lysis 
syndrome 
In vitro, GSK3745417 shows direct cell killing of AML cells. AML 
population typically has a high risk for TLS with additional risk factors 
General measures: 
• 
Admission to hospital 24hrs prior to each dose for prophylaxis 
against TLS (Refer to Section 4.1.1). 


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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
of large tumor burden (high blast count in AML), impaired renal 
function and inadequate hydration.  
• 
TLS events are categorized as adverse events of special 
interest (AESIs) which must be reported to the Medical Monitor 
within 24 hours regardless of study drug relationship. 
 
Monitoring: 
• 
Careful observation with continuous in-hospital monitoring 
throughout the 2-week induction daily-dosing period of the 
cycle, and 24hr hospital observation post-dose for the 
maintenance dosing. 
• 
Frequent monitoring of clinical chemistry including uric acid and 
phosphate as per schedule of activities (SOA), Section 1.3. 
 
Mitigation: 
• 
Participants must have: 
▪ 
white cell counts <25,000/µL 
▪ 
eGFR (CKD-EPI) >60 ml/min/1.73m2 
• 
Guidelines on the management of TLS symptoms is provided in 
Table 11, holding of dosing and stopping criteria outlined in 
Section 6.4.1. 
Renal toxicity 
Nonclinical: In monkeys given doses of GSK3745417 renal changes 
considered secondary to significant cytokine release, were observed in 
some animals (refer to IB). 
 
Clinical: No significant renal adverse events have been observed in 
the first 3 dose levels of Study 208850.  
 
The risk of TLS may potentially lead to additional renal toxicity. 
Monitoring: 
• 
Frequent monitoring of clinical chemistry including serum 
creatinine and eGFR as per schedule of activities (SOA), 
Section 1.3. 
 
Mitigation: 
• 
Inclusion criteria of eGFR (CKD-EPI) >60 ml/min/1.73m2 
• 
Specific renal stopping criteria and dose modification 
management guidelines outlined in Section 7.1.2 


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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Cardiac effects 
Nonclinical: There were dose-related increases in the heart rate 
(26-114 bpm) observed in monkeys given ≥0.6 mg/kg/dose of 
GSK3745417 (fourth weekly dose) between 1- and 20-hour post-dose, 
and in the number of ventricular ectopic arrhythmia in monkeys given 
1 mg/kg/dose (second administration of this dose). Inflammatory 
cytokines have been shown to contribute to increased heart rate and 
ventricular arrhythmias. 
 
Clinical: Tachycardia and changes in blood pressure associated with 
cytokine release have been observed in Study 208850 in solid tumors.  
One likely immune-mediated event of myocarditis has been observed 
in Study 208850 to date and therefore cardiac monitoring on study is 
required. 
Monitoring: 
• 
Frequent study cardiac monitoring with EKG, ECHO, and 
troponin (see SOA and Section 6.4.1.5). 
• 
Holter monitoring per SOA. 
 
Mitigation: 
• 
Inclusion of those with adequate LF function (Section 5.1) 
• 
Exclusion of patients with a history or evidence of 
cardiovascular risk including a history of immune myocarditis 
and/or pericarditis (Section 5.2). 
• 
Specific dose modification and management guidelines, 
including when cardiac consult needed outlined in Section 7.1.3. 
Immune-related 
AEs 
Inflammatory AEs such as diarrhea/colitis, pneumonitis, nephritis, and 
hepatotoxicity are well established as treatment emergent AEs with 
immune-modulating agents and are a potential risk for GSK3745417 
based on the immune-stimulatory mechanism of action.  
Clinical: One likely immune mediated event of myocarditis has been 
observed in Study 208850 to date.  
General measures: 
• 
AEs are categorized as AESIs which must be reported to the 
Medical Monitor within 24 hours regardless of study drug 
relationship. 
 
Mitigation: 
• 
Exclusion of patients with active immune disease or unresolved 
immune-related toxicity from prior treatment as per Section 5.2. 
• 
Guidelines on the management of potential immune-related AEs 
is provided in Section 6.4.1.7. 
Hepatic toxicity 
Nonclinical: Hepatic toxicity considered secondary to high cytokine 
levels was observed after repeat dosing in mice and monkeys (Refer to 
the IB of GSK3745417).   
 
Clinical: No participants have met liver stopping criteria in 
Study 208850 over the first 3 dose levels. There have been a small 
General measures: 
• 
Inclusion criteria for ALT≤2.5x ULN and bilirubin≤1.5x ULN. 
 
Mitigation: 
• 
Inclusion criteria for ALT 2.5x ULN and bilirubin 1.5x ULN. 
• 
Guidelines on the management of potential immune-related AEs 
is provided in Section 6.4.1.7. 


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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
number of transient mild ALT and AST elevations though cases are 
generally confounded by liver metastases.  
• 
Standard phase 1 oncology Liver Chemistry Stopping Criteria. 
(See Section 7.1.5). 
Hematologic 
Toxicity 
 
 
Nonclinical: Nonclinical models showed a transient and dose 
dependent decrease in red blood cells after dosing.  
Clinical: Drug-related anemia was observed in Study 208850. 
AML risks to pancytopenia manifesting as anemia, neutropenia, and 
thrombocytopenia.  
Measures 
• 
Full supportive care including transfusions are permitted. on 
study. There are no Hb or platelet inclusion criteria in the 
protocol as AML patients are generally dependent on regular 
red blood cell and platelet transfusions. Haemato-oncologists 
are well experienced in managing hematological toxicity.  
Reproductive 
toxicity 
 
No reproductive organ toxicity was observed with GSK3745417 in mice 
and monkeys. Based on the immune activation mechanism of action, 
GSK3745417 may affect establishment or maintenance of a 
pregnancy. There is also a potential risk for embryofetal toxicity. 
Mitigation: 
• 
Exclusion of lactating and pregnant women  
• 
Contraception guidelines will be included as inclusion criteria for 
females (Section 5.1). 
• 
Additional male and female contraceptive requirements if 
patients are taking a permitted concomitant medication, 
hydroxyurea, to control blast count (Section 10.5.2). 
 


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2.3.2. 
Benefit Assessment 
The high level of STING expression combined with sensitivity to dual mechanisms of 
action of direct cell killing and immune activation as well as intravenous (IV) 
administration of GSK3745417 make AML a suitable indication to establish proof of 
mechanism and clinical activity of GSK3745417 with possible benefit that may include 
complete/partial remission, independence from transfusion, and competent immune 
function for an indication with unmet medical need. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Upon review of the nonclinical and available clinical safety data from the ongoing 
208850 solid tumor study, there are currently no known risks associated with 
GSK3745417 which would preclude further development. Given the disease under study 
(relapsed/refractory AML with no other effective treatment options) and the mitigation 
measures specified in the protocol to reduce the potential risks, the benefit:risk for 
commencing development of GSK3745417 in AML is considered favorable. 
3. 
OBJECTIVES AND ENDPOINTS 
Dose Escalation (Part 1) 
 
Objectives 
Endpoints 
Primary 
• 
To determine the safety, tolerability, 
and RP2D of a daily dosing schedule 
(induction) of GSK3745417   
• 
Frequency and severity of 
Adverse Events (AEs), Serious 
Adverse Events, (SAEs), Dose 
Limiting Toxicity (DLT), 
withdrawals due to AEs  
Secondary 
• 
To characterize the pharmacokinetics 
(PK) of GSK3745417, and relevant 
metabolites, as applicable, after single 
and repeat-dose administration. 
• 
GSK3745417 concentrations in 
plasma or PK parameters 
Exploratory 
 
CCI


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Dose Escalation (Part 1) 
 
Objectives 
Endpoints 
 
 
 
 
 
Dose Expansion (Part 2)  
 
Objectives 
Endpoints 
Primary 
• 
To evaluate clinical efficacy following 
the daily dosing “induction” period of 
GSK3745417 in participants with 
relapsed/refractory AML and HR-MDS. 
• 
Objective response rate (ORR) 
after the daily dosing “induction” 
period of GSK3745417 
 
CCI


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Dose Expansion (Part 2)  
 
Objectives 
Endpoints 
• 
To determine the safety, tolerability, 
and recommended Phase 2 dose 
(RP2D) for “maintenance”  
• 
Frequency and severity of 
Adverse Events (AEs), Serious 
Adverse Events, (SAEs), Dose 
Limiting Toxicity (DLT), 
withdrawals due to AEs during 
“maintenance” dosing 
Secondary  
• 
To further evaluate the safety, 
tolerability of one or more RP2D for 
maintenance 
 
The following may be included based 
on the availability of data and 
appropriateness: 
• 
AEs, SAE, AESIs leading to dose 
modifications or delays 
Secondary 
• 
To characterize the pharmacokinetics 
(PK) of GSK3745417, and relevant 
metabolites, as applicable, after single 
and repeat-dose administration. 
• 
GSK3745417 concentrations in 
plasma or PK parameters 
Exploratory 
 
CCI


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Dose Expansion (Part 2)  
 
Objectives 
Endpoints 
 
 
 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 1 open-label study of intravenous GSK3745417 to evaluate safety, 
tolerability, pharmacokinetics, pharmacodynamics and determine RP2D and schedule in 
participants with relapsed or refractory acute myeloid leukemia (AML) and high-risk 
myelodysplastic syndrome (HR-MDS).  
The study will be conducted in a staged approach consisting of 2 parts. Part 1 represents 
dose escalation to determine a cohort level MTD and incorporates intra-patient dose 
escalation within cohorts to minimize the potential for a participant to be exposed to a 
non-efficacious sub-therapeutic dose. Dosing in Part 1 will include 3 initial cycles 
followed by “maintenance” at a weekly dosing schedule. Part 2 represents an expansion 
cohort at the recommended induction dose/doses and schedule from Part 1 for 3 cycles, 
followed by either a weekly, every 3 weeks, or less frequent dosing schedule for 
“maintenance.” Approximately 72 participants will be enrolled: approximately 
22 participants in Part 1 and 50 participants in Part 2.   
Part 1 
Part 1 will evaluate a dosing schedule of a 5 days on/2 days off schedule for 2 weeks, and 
then have an additional 2 weeks off dose for observation for a total of 28 days in each 
cycle (5 / 2 / 5 q28d). Once an MTD has been established, additional cohorts may be 
opened to refine dosing frequency optimization. Each cohort will include at least 
CCI


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3 participants. Part 1 will include intra-patient dose escalation for 3 cycles, according to 
safety and tolerability parameters. The starting dose for Cycle 1 will be escalated in the 
next dose escalation cohort until a cohort level MTD is reached. The first participant at 
the starting dose level(s) of each cohort will begin treatment after review of safety data 
and DEM to allow assessment of initial safety data before beginning the next 
participant’s treatment. The dosing of subsequent participants will be staggered by 
≥5 days. 
Table 6 
Dosing and Hospitalization Schedule for Cycles 1 - 3 
Day 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14-28 
GSK3745417 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
In-patient 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Non-azole 
antifungal  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dose escalation will initiate with Cycle 1 at 12.5 µg GSK3745417 as the first cohort and 
the Cycle 1 dose will increase by 2-fold between cycles (3 dose levels). The starting dose 
of subsequent cohorts will increase by 2-fold from Cycle 1 of the previous cohort. 
Patients may be dose reduced for subsequent cycles if there is lack of tolerability in the 
previous cycle (Section 6.4). The DLT period will be 28 days starting at Day 1 of Cycle 1 
of each cohort. After 3 induction cycles, if a CR or PR (IWG) is observed (See 
Appendix 9), each patient will continue with maintenance weekly dosing at the Cycle 3 
dose level until disease progression or unacceptable toxicity. Participants with 
progressive disease after 3 induction cycles will be withdrawn from study. Participants 
with stable disease or PR after 3 cycles might receive additional cycles if the assessment 
by the investigator determined a benefit and GSK Medical Monitor agrees.   
In Part 1, participants will receive dosing in the hospital on a 5 days on/2 days off 
schedule for 2 weeks, and then have an additional 2 weeks off dose for observation. The 
participant will be observed for at least 24 hours after the final dose in each cycle. All 
participants will be hospitalized the day before a new dosing cycle starts to receive tumor 
lysis syndrome (TLS) prophylaxis in line with institutional guidelines (all participants 
should receive IV fluids ± allopurinol as well as alkalinization of urine with renal consult 
if this is in line with institutional guidance). TLS prophylaxis will continue alongside 
daily dosing as clinically indicated. To further reduce the risk of TLS, guidance in 
Section 6.4.1.2 must be followed to determine when daily dosing should be held.  


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Figure 4 
Part 1 Intense Dosing Regimen (Intra-patient Dose-Escalation Study) 
 
* Patients in C3 dose level in all cohorts will be continuing dosing Q1W at C3 dose level  
 
Part 2 
Part 2: Efficacy will be evaluated after an induction phase in approximately 50 
participants, 25 AML participants and 25 HR-MDS participants. The induction phase 
consists of a treatment regimen at the dose/doses determined to be safe in Part 1 (RP2D). 
The number of cycles, number of doses investigated in the induction phase, and/or dosing 
schedule of 5 / 2 / 5 q28d treatment will be determined and may be modified based on a 
review of safety and PK data generated from Part 1. After the induction phase, patients 
will continue to either a weekly (Q1W), every 3 weeks (Q3W), or less frequent dosing 
schedule for maintenance treatment, if a CR or PR is observed (See Response Criteria for 
Participants with AML Appendix 9; See IWG Criteria for Response for Participants with 
MDS Appendix 8). Participants with stable disease or PR after 3 induction cycles might 
receive additional cycles if the assessment by the investigator determined a benefit and 
GSK Medical Monitor agrees. Up to three dose levels for maintenance treatment will be 
evaluated in the maintenance dose escalation. The DLT period for the maintenance dose 
escalation portion of Part 2 will be 28 days starting at Day 1 of each cycle. Dose 
escalation for the maintenance schedule will start at the highest dose cleared for safety in 
Part 1. Part 2 will evaluate the efficacy of the induction regimen separately for AML and 
HR-MDS as well as the tolerability and duration of response of the Q1W or Q3W 
maintenance schedules to determine the best dose and schedule for further studies.  


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Figure 5 
Part 2 Dose Escalation for Maintenance Dosing MTD and Expansion 
 
Each part of the study includes a screening period, a treatment period, and a follow up 
period. Participants will be screened for eligibility beginning 4 weeks (or 28 days) before 
the start of treatment. 
Dose Escalation 
To complete dose escalation in Part 1, it is estimated that up to 22 participants will be 
enrolled. Dose escalation for Part 1 will use the N-CRM. This method utilizes a 
2parameter logistic model, with parameters α and β, to describe the relationship between 
DLT and dose (12.5, 25, 50, 100, 200 µg). The N-CRM estimates, for each potential 
dose, the posterior probabilities that the DLT rate lies in each of 4 toxicity intervals:  
• [0%,16%)=Underdosing range; 
• [16%,33%)=Target toxicity range; 
• [33%,50%)=Excessive toxicity range;  
• [50%,100%)=Unacceptable toxicity range. 
Additionally, the following constraints for the recommended dose will be maintained:  
 
The posterior probability of the DLT rate lying in the Excessive Toxicity or 
 
Unacceptable Toxicity range is less than 25%.  
Dose escalation will continue until:  
i. 
An MTD is found:  
At least 9 participants have been treated at the current target dose  
AND  
The posterior probability that the DLT rate for the current dose lies in either the 
excessive toxicity or unacceptable toxicity range is less than 25%.  
AND  


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The posterior probability that the DLT rate for the next higher dose lies in either 
the excessive toxicity or unacceptable toxicity range is greater than or equal to 
25%.  
OR  
ii. 
The RP2D has been reached and at least 9 participants have been dosed at that 
dose level.  
OR  
iii. 
All doses have a posterior probability of lying in either the excessive toxicity or 
unacceptable toxicity range of greater than or equal to 25%  
AND  
 
At least 2 DLTs have been observed.  
All available data, including safety, PK, and pharmacodynamic data from current and 
prior cohorts will be reviewed at dose escalation meetings after each cohort in Part 1. 
Clinical judgment by the Medical Monitor, recommendation from GSK clinical 
pharmacologist, GSK scientist and GSK statistician, and in consultation with the 
investigators can decide dose escalation or reduce the recommended dose as deemed 
appropriate at any time during the trial. 
Maximum Tolerated Dose: The MTD will be defined as the dose within cycle that has 
the highest probability of having a DLT rate within the target toxicity interval, and for 
which the probability that the DLT rate lies within the excessive toxicity, or the 
unacceptable toxicity window is less than 25%. The DLT observation period will be 
28 days. 
Recommended Phase 2 Dose: RP2D of GSK3745417 will be determined after review of 
all available safety, PK, pharmacodynamics, and clinical efficacy data. The RP2D will be 
equivalent with the MTD or a lower GSK3745417 dose and regimen that provides 
adequate PK exposure and biologic activity with acceptable safety and tolerability. 
Maintenance dose escalation for Part 2 will use the mTPI method as described in 
Section 9.2. Dose escalation will proceed until the MTD for GSK3745417 for a specific 
maintenance dosing schedule is determined.  
4.1.1. 
Dose Limiting Toxicities (DLT) 
All toxicities will be graded using National Cancer Institute – Common Toxicity Criteria 
for AEs (NCI-CTCAE), version 5.0. 
An AE is considered to be a DLT if it is considered by the investigator to be clinically 
relevant and attributed (definitely, probably, or possibly) to the study intervention and 
meets at least 1 of the criteria listed in the table below. If an AE is considered related to 
the underlying disease it is not a DLT. The DLT period is 28 -days starting at Day 1 of 
each cycle. Participants unable to receive at least 70% of scheduled doses within the DLT 


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period for reasons other than toxicity (e.g., acute illness, disease progression) will not be 
considered evaluable.  
Table 7 
Dose-Limiting Toxicities 
Toxicity 
DLT Definition 
Cytokine Release 
Syndrome (CRS) 
Grade 3 or 4 (See Section 10.4) 
TLS 
• 
Grade 3 or Grade 4 TLS (Cairo Bishop criteria, Appendix 11) that 
cannot be managed/ is not resolved within 72 hours 
Liver Toxicity 
ALT 3x upper limit of normal (ULN), plus bilirubin 2x ULN (>35% direct) 
or plus international normalized ratio (INR)>1.5 (Possible Hy’s law) 
Other 
Grade 3 non-hematologic toxicity of any duration with the following 
exceptions: 
• 
Transient ( 72 hours) abnormal laboratory value without 
associated clinically significant signs or symptoms 
• 
Individual parameters of CRS which collectively constitute 
<Grade 3 CRS  
• 
Nausea, vomiting, or diarrhea that improves with supportive care 
within 72 hours 
• 
Alopecia of any grade 
• 
Grade 3 fatigue with duration <7 days 
• 
Grade 3 headache that resolves with supportive treatment to 
Grade 2 within 24 hours 
• 
G3 acute renal injury considered related to TLS which improves 
or resolves with appropriate fluids and management of TLS  
Grade 3 immune-related toxicity that does not resolve to Grade 1 or 
baseline within 8 days despite adequate immune suppressive therapy. 
Any other event which in the judgment of the investigator and GSK 
Medical Monitor is considered to be a DLT. 
 
Participants who withdraw from the study before completing DLT period for reasons 
other than DLT may be replaced. If a participant experiences a DLT during the DLT 
period of treatment, the participant will be discontinued from study treatment unless the 
investigator considers it in the best interest of the participant to continue on study (e.g., in 
case of symptomatic disease improvement, and/or if the DLT is viewed as preventable in 
subsequent doses/visits, etc.) and the sponsor approves of the decision. 
Guidance for the management of toxicity, including dose modification algorithms, is 
provided in Section 6.4. 
4.1.2. 
Dose Escalation Decisions 
The Dose Escalation committee, in joint discussion with the participating investigators, 
will be responsible for determining whether cohort level dose escalation or de-escalation 
during the study should continue as recommended by the N-CRM approach for Part 1 and 
the mTPI approach for Part 2. Prior to the dose escalation/de-escalation decision, the 
medical monitor, clinical scientist, safety physician/scientist, clinical pharmacologist, 


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statistician, and investigators will review critical safety data defined in the Dose 
Escalation Plan, including data on all adverse events including non-DLT toxicities, 
laboratory assessments and other safety evaluations, as well as any available PK and/or 
PD data. The quality review of critical safety data will be described in the Dose 
Escalation Plan, which includes ongoing study monitoring visits along with data review 
of the clinical database. 
The dose-escalation/de-escalation decision and rationale for each cohort will be discussed 
with investigators during teleconference(s) and documented in writing with copies 
maintained at each study site and in the GSK trial master file. 
Intra-patient dose escalation  
In Part 1, participants are permitted to dose escalate between the 2-3 induction 5 / 2 / 5 
q28d cycles based on discussion and agreement with Medical Monitor and the 
Investigator after reviewing available safety and laboratory data, and in line with the 
following safety and tolerability parameters:  
• Investigator and MM must both consider that dose escalation is in the best 
interests of the participant 
• Participant must have received at least 7 of the 10 doses in the prior cycle  
• Participant must not have experienced: 
o Any Grade ≥3 adverse event 
o Grade ≥3 TLS 
o A DLT (which includes Grade 3 CRS, all non-hematologic Grade 3 events 
with a few exceptions as per Table 7) 
o More than 1 episode of Grade 2 CRS in the previous cycle 
o Evidence of ongoing immune related AEs during the observation period 
(sustained or intermittent Grade ≥2 fever ongoing after the first week of 
the observation period, in which infectious cause is ruled out).  
4.2. 
Number of Participants 
Approximately 22 participants may be enrolled in Part 1, and approximately 
50 participants may be enrolled in Part 2. The total number of participants to be enrolled 
is an estimate and will depend on the number needed to adequately characterize the DLT 
and PD profile and determine the MTD(s)/RP2D(s). All participants who take at least one 
dose of study intervention will be considered evaluable for analysis. See the statistical 
considerations, Section 9.2, for justification of the sample size. 
4.3. 
Scientific Rationale for Study Design 
Preclinical data support the use of STING agonists for the treatment of AML. A study 
evaluating the effect of a STING agonist on 144 different cancer cell lines spanning 14 
different histologies revealed that GSK3745417 induced cell growth inhibition in two out 
of two AML cell lines tested and one large cell lymphoma cell line. In a subsequent study 
focused on 12 additional AML cell lines, GSK3745417 induced cytotoxicity in 3 of 12 
cell lines, cytostaticity in 5 of 12 cell lines, or modest to no effect in 4 of 12 cell lines. 


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Even with these "cytostatic" lines, apoptosis was induced. Over both studies, 
GSK3745417 induced cytotoxicity or cytostaticity in 64% (9 of 14) of all AML cell lines 
tested. Mechanistically, GSK3745417 activates caspases 3/7 in highly sensitive AML cell 
lines, suggesting a role for STING mediated apoptosis in driving AML cell death. In 
addition to STING driven cytotoxicity or cytostaticity of AML, a recent publication also 
suggests STING agonists stimulate potent anti-AML immunity in a mouse model via 
induction of type I interferons and proinflammatory cytokines (Curran, 2016). A 5 / 2 / 5 
q28d dosing regimen is being evaluated in Part 1 since it is hypothesized that increased 
dosing frequency, and therefore average concentration, of GSK3745417 will enhance the 
direct cell killing effect. 
The proposed Phase 1 study will evaluate the safety and tolerability, PK, PD, and 
preliminary clinical activity of increasing doses of GSK3745417 administered IV in adult 
participants with relapsed or refractory AML or high-risk MDS and will determine a dose 
and schedule of GSK3745417 for future clinical studies. 
4.4. 
Justification for Dose 
4.4.1. 
Human Experience with GSK3745417 Dosing in Participants with 
Solid Tumors 
For the ongoing first time in human study (Study 208850), the minimally anticipated 
biological effect level (MABEL) approach was used in conjunction with the ICH S9 
guidance on selection of starting dose for a biopharmaceutical with immune agonistic 
properties to select a safe starting dose of GSK3745417 for use in cancer patients with 
advanced tumors with due consideration of relevant in vitro, ex vivo, and in vivo 
nonclinical data. A dose level of 100 µg QW was used as a starting dose following a 
10-fold safety factor from the identified MABEL dose of 1000 µg and was tolerated in 
humans. The 100 µg was considered safe and tolerated as no DLTs were observed during 
the DLT determination period of 21 days. To date, three dose levels (100, 200, and 
400 µg) have been investigated in the solid tumor population, with further detail in the 
human PK section below. MTD was identified as 400 ug for Q1W mono therapy. Study 
208850 is ongoing with further investigations into Q3W dosing of GSK3745417 
monotherapy, and eventually Q1W or Q3W in combination therapy with dostarlimab. 
4.4.2. 
Selected Human Starting Dose and Discussion 
It is unclear how the observed solid tumor effects of GSK3745417 in BALB/c mice will 
translate into the human AML disseminated tumor setting or the current human 
experience in solid tumors, though it is noted that the Cmax in the 200 and 400 µg dose 
levels in human approximates the 3 h concentration in the BALB/c tumor model where 
tumor regression was observed. Regarding the direct cell killing mechanism, to match the 
geometric mean of the gIC50 values of 5.14 ng/mL for growth inhibition, and assuming 
linear PK, a predicted dose level of ~16 µg would be required to achieve a Cmax of 
~5.14 ng/mL.  


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Therefore, with the lower dose goal of achieving direct cell killing, the recommended 
starting dose in the AML population is 12.5 µg, which is approximately 1× of the 
geometric mean of the gIC50 in AML cell lines, 1/8th of the lowest dose studied to date in 
the solid tumor population (Study 208850), and 1/16nd of the maximum tolerated dose in 
the solid tumor population (Study 208850). The 100-µg starting dose in the solid tumor 
study was dosed weekly; 12.5 µg daily for 5 days is still cumulatively a lower dose than 
the 100-µg single dose used in the solid tumor study. This starting dose would be 
predicted to result in a Cmax of ~4 ng/mL and an AUC of ~8 hr*ng/mL. This approach 
relies on the finding in bone marrow that the AML population would have no higher 
cytokine induction through the innate immune system response, and therefore represents 
an additional three low-dose cohorts compared to the solid tumor study (Study 208850). 
This low starting dose of 12.5 µg also provides an important safety margin given the 
preliminary non-clinical data which suggest that there may be some accumulation of 
cytokine related symptoms/immune system activation with daily dosing. Given the 
available safety profiles with human dosing in 21 participants in Study 208850, and 
absence of significant cytokine related symptoms at the starting dose of 0.1 mg in 
Study 208805 this would appear to be a reasonable risk/benefit trade-off because of the 
potential benefit of cell killing at lower dose levels. 
4.5. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the Schedule of Activities (SoA) for the last 
participant in the trial globally. 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit or the last scheduled procedure shown in the 
Schedule of Activities. In addition, if the sponsor decides to close the study, participants 
who are receiving study intervention or are in the follow-up period will be considered to 
have completed the study. 
Participant would be considered off study in the event of death, withdrew consent, or lost 
to follow-up. 
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 for inclusion in this study if all the following criteria apply: 
1.  Must be ≥18 years of age and ≤75 years of age at the time of signing the 
informed consent for dose escalation and >18 years of age at the time of signing 
the informed consent for the dose expansion.  


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2. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in the 
protocol. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
4. Participants with AML/High Risk MDS are eligible for participation in Part 1 and 
Part 2 if they have:  
• A diagnosis of AML according to the World Health Organization 2016 
criteria (Arber, 2016) with relapsed or refractory disease and ineligible for or 
have exhausted standard therapeutic options. 
• Have high-risk or high/very high by IPSS-Revised [IPSS-R] criteria 
[Greenberg] MDS (restricted to Part 1) that has relapsed after or been 
refractory to prior therapy with hypomethylating agent. 
5. Adequate organ function:  
Organ system 
Laboratory Values 
Hematologic 
 
White blood cell count (absolute) 
≤25,000/µL (both at screening and prior to study 
drug administration on Day 1) (hydroxyurea is 
permitted to reduce white cell count prior to 
screening). Hydroxyurea or leukapheresis may 
be used prior to and throughout study to control 
white cell count 
PT/INR and PTT in patients not receiving 
therapeutic anticoagulants  
≤1.5 x ULN 
PT/INR and PTT in patients receiving therapeutic 
anticoagulants   
Within the intended therapeutic range of the 
anticoagulant 
Hepatic 
 
Total bilirubin 
For participants with Gilbert’s Syndrome (only if 
direct bilirubin 35%) 
≤1.5 x ULN 
≤3.0 x ULN 
ALT 
≤2.5 x ULN 
Renal 
 
eGFR by CKD-EPI 
≥50mL/min/1.73m2 
Endocrine 
 
TSH1 
WNL 
Cardiac  
 
Ejection fraction 
≥Lower limit of normal (LLN) (minimum of 50%) 
1. 
If TSH is not within normal limits at baseline, the participant may still be eligible if total T3 or free T3 and free 
T4 are within the normal limits 
 
6. Participants with a prior history of stem cell transplant (autologous and/or 
allogeneic) are allowed if:  


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• No clinical signs or symptoms of graft versus host disease (other than 
Grade 1 GVHD (<25% skin surface affected) and the participant is off all 
systemic immunosuppression. (Note: topical steroids for G1 skin GVHD 
are permitted on study) 
7. Agree to abide by the gender specific contraceptive requirements below:  
• Female participants are eligible to participate if they are not either 
pregnant or breastfeeding, and at least one of the following conditions 
applies:  
o Is not a woman of childbearing potential (WOCBP), or 
o Is a WOCBP and using a contraceptive method that is highly 
effective (with a failure rate of <1% per year), with low user 
dependency during the study treatment period and for at least 
7 days after the last dose of study treatment and agrees not to 
donate eggs (ova, oocytes) for the purpose of reproduction during 
this period. The investigator should evaluate the effectiveness of 
the contraceptive method in relationship to the first dose of study 
treatment. 
o A WOCBP must have a negative highly sensitive pregnancy test 
(urine or serum) as required by local regulations) within 7 days 
before the first dose of study intervention. If a urine test cannot be 
confirmed as negative (e.g., an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is 
positive. 
o Additional requirements for pregnancy testing during and after 
study treatment will be described in the protocol. 
o The investigator is responsible for a review of medical history, 
menstrual history, and recent sexual activity to decrease the risk 
for inclusion of a woman with an early undetected pregnancy.  
• Male participants and WOCBP taking hydroxyurea during the study must 
follow contraceptive guidance in the hydroxyurea prescribing information  
5.2. 
Exclusion Criteria 
1. Diagnosis of acute promyelocytic leukemia (APML or t(15;17) PML-RARA 
fusion). Patients with biphenotypic disease are excluded.  
2. Active central nervous system involvement or disorder: 
a. Participants with a history of CNS disease are permitted to enroll if they 
have previously received appropriate therapy and CNS remission has been 


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documented and are symptom/progression free and off therapies that are 
controlling symptoms for at least 4 weeks prior to enrollment. Note: In the 
absence of CNS symptoms, a lumbar puncture is not required for study 
entry. 
b. Active CNS disorder, such as seizure, cerebrovascular 
ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune 
disease with CNS involvement, unless considered stable and 
well-controlled with ongoing treatment   
3. Immediate life-threatening, severe complications of leukemia (sepsis, 
hemorrhage). 
4. Participants with extramedullary disease as the sole site of AML 
5. Active severe or uncontrolled infection, known human immunodeficiency virus 
infection, or presence of hepatitis B surface antigen (HBsAg) or positive hepatitis 
C antibody test at screening. Note: Participants with positive hepatitis C antibody 
due to prior resolved disease can be enrolled only if a confirmatory negative 
hepatitis C RNA polymerase chain reaction (PCR) (or comparable test) is 
obtained.  
6. Participants with signs/symptoms suggestive of COVID-19 within 14 days of 
study entry, or with known exposure to COVID-19 within 14 days prior to study 
entry 
7. Active autoimmune disease that has required systemic disease modifying or 
immunosuppressive treatment within the last 2 years.  
8. Concurrent medical condition requiring the use of systemic immunosuppressive 
treatment within 28 days before the first dose of study treatment. 
Note: Physiologic doses of corticosteroids for treatment of endocrinopathies or 
steroids with minimal systemic absorption, including topical, inhaled, or 
intranasal corticosteroids may be continued if the participant is on a stable dose. 
9. History of vasculitis at any time prior to study treatment. 
10. Participant has a history of other malignancies less than 2 years prior to study 
entry, with the exception of: 
• Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of 
breast; 
• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the 
skin; 
11. QTcF >450 msec for male participants, >470 msec for female participants, or 
>480 msec for participants with bundle branch block. QTcF is QT corrected for 


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heart rate according to Fridericia’s formula and can be machine calculated or 
manually over-read. 
12. Recent history of allergen desensitization therapy within 4 weeks of starting study 
treatment. 
13. History or evidence of cardiovascular (CV) risk including any of the following: 
• Clinically significant uncontrolled hypertension 
• Recent (within the past 6 months) history of serious uncontrolled cardiac 
arrhythmia or clinically significant ECG abnormalities including second 
degree (Type II) or third-degree atrioventricular block. 
• Cardiomyopathy, myocardial infarction, acute coronary syndromes 
(including unstable angina pectoris), coronary angioplasty, stenting, or 
bypass grafting within the past 6 months before enrollment. 
• Congestive heart failure (Class II, III, or IV) as defined by the New York 
Heart Association functional classification system [NYHA, 1994]. 
• History of immune myocarditis or pericarditis. 
14. Prior STING therapy.  
15. Prior solid organ transplantation. 
16. Recent prior therapy defined as follows:  
• Any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, 
whichever is longer, prior to start of study treatment  
• Prior therapy with biological agents (including monoclonal antibodies) 
within 28 days prior to start of study treatment 
• Any radiotherapy or major surgery within 14 days prior to start of study 
treatment 
• Currently receiving investigational therapy in a clinical trial  
Note: Hydroxyurea may be used prior to and throughout study to control 
white cell count.  
17. Receipt of any live vaccine within 30 days of start of study treatment. Inactivated 
vaccines such as the inactivated flu intramuscular vaccine are permitted. Live 
attenuated vaccines including herpes zoster, nasal flu, and coronavirus vaccines 
should be avoided. Recombinant human or non-human primate adenoviral vector 
vaccines are also excluded. 


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18. Immune-related toxicity related to prior treatment that has not resolved to 
Grade ≤1 (except alopecia, hearing loss or Grade ≤2 neuropathy or 
endocrinopathy managed with replacement therapy). 
19. Concomitant administration of drugs that are sensitive substrates or narrow 
therapeutic range substrates for cytochrome p450 (CYP)3A4 enzyme, P-gp, 
BCRP, OATP1B1 and OATP1B3 transporter, and moderate to strong inducers 
and inhibitors of CYP3A4, P-gp, OATP1B1 and OATP1B3 should be excluded 
during the study and for 7 days prior to and following treatment with 
GSK3745417 (14 days for itraconazole). Note: any medications (including 
antibacterials, antifungals, and antivirals) which are necessary for the health, 
well-being, or standard clinical care of patients with hematologic malignancies 
are exempt from this restriction. Any medications potentially interacting with 
GSK3745417 will require a pause in GSK3745417 dosing unless allowed through 
consultation with Sponsor.  
20. Ongoing drug or alcohol abuse. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• 
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from at least 
7 days before the start of study intervention until after the final dose. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
• During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 4 hours 
before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample. 
• During each dosing session, participants will abstain from alcohol for 24 hours before 
the start of dosing until after collection of the final PK and/or pharmacodynamic 
sample.  
• Participants who use tobacco products will be instructed that use of 
nicotine-containing products (including nicotine patches and other delivery devices 
such as vaporizers) will not be permitted while they are in the clinical unit.  
5.3.3. 
Activity 
• 
Participants will abstain from strenuous exercise for 8 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading). 


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5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. 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 (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations, and any 
serious adverse events (SAEs). 
Individuals identified as Screen Failures may be rescreened once if the failure was based 
on elements of eligibility that may change, e.g., laboratory test results. 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
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. 
6.1. 
Study Intervention(s) Administered 
GSK3745417 will be administered to participants at each study site under medical 
supervision of an investigator or designee. Cytokine-related AEs including changes in 
vital signs may begin within several hours of administration of GSK3745417. 
Participants must be monitored in the clinic/hospital throughout dosing in the initial 
cycles and for up to 24 hours after administration of the Q1W or Q3W maintenance 
doses, or longer as clinically indicated. Guidelines for monitoring cytokine-related AEs 
and tumor lysis syndrome are summarized in Section 6.4. 
For Part 1, the dosing schedule each Cycle from 1 – 3 is 5 days on / 2 days off / 5 days on 
followed by observation for 2 weeks. After 3 cycles, participants will move to a dosing 
schedule of once every week (Q1W). For Part 2, after the induction regimen determined 
from Part 1, participants will enter a maintenance phase at a dose and schedule 
determined by emerging FIH data.   
The specific time of study treatment administration (e.g., time of the week for first 
administration; time of the day for each administration) should take into consideration PK 
sampling time points and study visit procedures and will be recorded in the source 
documents and in the eCRF. 
Weekly dosing may be done 24 hours and Q3W dosing may be done 72 hours.  
ARM Name 
Intervention 
Intervention Name 
GSK3745417 
Type  
Drug 
Dose Formulation  
To be provided in the study reference manual 
Dosage Form 
Powder for Solution for Injection 
Unit Dose Strength(s)  
2 mg/vial 


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Dosage Level(s) 
12.5 µg – 800 µg (to be determined) 
Route of Administration 
IV injection through a central or PICC line 
Use 
experimental 
IMP and NIMP 
GSK3745417 
Sourcing 
Provided centrally by the Sponsor 
Packaging and Labeling 
Study Intervention will be provided as 1 vial in a 
carton. Each vial and carton will be labeled as 
required per country requirement. 
Current/Former Name(s) or Alias(es) 
N/A 
 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions 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. 
3. 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). 
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual.  
• Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or GSK 
study contact. 
• A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK. 
Precaution will be taken to avoid direct contact with the study intervention. A Material 
Safety Data Sheet (MSDS)/equivalent document describing occupational hazards and 
recommended handling precautions either will be provided to the investigator, where this 
is required by local laws, or is available upon request from GSK. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or GSK 
study contact. 


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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. Investigators and study team will have direct access to 
individual participant’s study intervention. All screened participants will be identified by 
a unique participant number that will remain consistent for the duration of the study.  
In Part 1, at least 3 participants will be enrolled at a particular dose level. For the first 
cohort, the first participant will be enrolled, treated with 10 planned doses, and observed 
for 2 more days before subsequent participants are enrolled into that cohort to allow 
assessment of initial safety data. The next 2 participants in the first cohort will receive 
study treatment at least 5 days apart. Study Intervention Compliance 
• When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff.  
• When participants are dosed at the site, they will receive study intervention directly 
from the investigator or designee, under medical supervision. The date and time of 
each dose administered in the clinic will be recorded in the source documents. The 
dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering 
the study intervention. 
6.4. 
Dose Modification 
6.4.1. 
Participant-Level Dose Modifications due to Adverse Events 
GSK3745417 dose reduction or alternative dosing schedules at a participant or cohort 
level may be considered based on emerging data. 
Holding daily dosing 
Daily dosing will be continued unless there is evidence of ongoing TLS or immune 
activation in line with the criteria below.  
Daily dosing held if: 
• Ongoing Grade 3 TLS (see Appendix 11 for Cairo Bishop grading) or Grade 3 
electrolyte abnormalities that are not responding to treatment    
• Failure of any CRS, fevers, or chills to resolve to Grade ≤1 (with supportive 
treatment) within 24 hours 
• Any new neurological adverse events (except for Grade ≤2 headache which 
responds to analgesia), until assessment and cause of neurological event is 
identified 
• Investigator judgement that dosing should be held based on the clinical status of 
patient 


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Dose reduction for CRS 
In the event of Grade 2 CRS, further dosing can be given with prophylaxis against CRS 
with steroids, paracetamol/acetaminophen, and antihistamines (as agreed between 
investigator and MM). Patients with more than one episode of Grade 2 CRS within the 
same cycle despite prophylaxis should be dose reduced to the next dose level down once 
dosing resumes. Participants will come off study if more than 2 dose reductions required, 
or if they require dose reduction below the lowest study dose of 12.5 µg. 
In participants who develop CRS requiring holding of daily dosing, Investigators should 
perform additional LFT and clinical chemistry tests during the dose hold as clinically 
indicated, and perform the additional investigations outlined in Section 6.4.1.4. 
6.4.1.1. 
Intra-Patient Dose Escalation 
Intra-patient dose escalation is permitted for induction treatment cycles 2 and 3 
depending on safety and tolerability of the first dosing cycle. To allow intra patient dose 
escalation for the next dosing cycle: 
• Investigator and MM must both consider that dose escalation is in the best 
interests of the participant 
• Participant must have received at least 7 of the 10 doses in the prior cycle  
• Participant must not have experienced: 
o Any Grade ≥3 AE 
o Grade ≥3 TLS 
o A DLT (which includes Grade 3 CRS, all non-hematologic Grade 3 events 
with a few exceptions as per Table 7) 
o More than 1 episode of Grade 2 CRS in the previous cycle 
o Evidence of ongoing immune activation during the observation period 
(sustained or intermittent Grade ≥2 fever ongoing after the first week of 
the observation period)   
6.4.1.2. 
Tumor Lysis Syndrome 
Tumor lysis syndrome (TLS) may occur in participants treated with GSK3745417 as it 
has demonstrated a direct cell killing mechanism in AML cells. Laboratory or Clinical 
TLS should be diagnosed according to the Cairo Bishop criteria (Cairo, 2004). In the 
event of TLS, Investigators should use clinical judgement and follow institutional 
guidelines for prophylaxis and symptom management of TLS. 
Participants should be assessed for TLS risk prior to each dose, including evaluation of 
tumor burden, comorbidities, and renal function, and prior to each dosing with 
GSK3745417 should be admitted to hospital the day before first dose of each induction 
cycle or maintenance dose, and receive prophylaxis for TLS in line with institutional 
guidance. Blood clinical chemistry must be monitored every 6 hours for the first 48 hours 
of the first dosing cycle, and each cycle with a dose increase. Participants are hospitalized 
throughout the 2-week dosing period of each induction treatment cycle and TLS 
prophylaxis should continue alongside daily dosing of GSK3745417 as clinically 
indicated.  


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Table 8 
Cairo Bishop Definition of Laboratory TLS 
Assessment 
Result Range 
Uric acid 
≥476 µmol/L (≥8.0 mg/dL) or 25% increase from baseline 
Potassium 
≥6.0 mmol/L or 25% increase from baseline 
Phosphorus 
≥1.45 mmol/L (≥4.5 mg/dL; adults) or 25% increase from baseline 
Calcium 
≤1.75 mmol/L (≤7.0 mg/dL) or 25% decrease from baseline 
 
Table 9 
Cairo Bishop Definition of Clinical TLS 
Creatinine: x ≥1.5 ULN  
Cardiac arrythmia/sudden death 
Seizure 
 
For grading of TLS, refer to Cairo Bishop grading in Appendix 11. 
6.4.1.3. 
Infusion Reaction 
Infusion reactions typically develop within 30 minutes to two hours after initiation of 
drug infusion, although symptoms may be delayed for up to 48 hours. There are multiple 
mechanisms known to lead to infusion-related reactions including both IgE-dependant 
anaphylactic and non-IgE dependent anaphylactoid hypersensitivities. Infusion reactions 
may affect any organ system in the body. Most are mild in severity, although severe and 
fatal reactions can occur. As a group, infusion reactions (including both 
cytokine-mediated and allergic) usually occur during or within a few hours of drug 
infusion. Occasionally, a reaction may occur one to two days after administration. The 
NCI-CTCAE (version 5.0) [NCI, 2017] for grading adverse reactions during the infusion 
of a pharmacological or biological substance has a term for grading the severity of 
infusion reactions and separate terms for grading allergic reactions, anaphylaxis, and 
cytokine release syndrome. The use of these separate terms in grading severity of the 
event may be useful for classifying the nature of an infusion reaction for research 
purposes; they are less useful for clinical care, since it may not be obvious if the 
participant is having an allergic infusion reaction or a non-allergic infusion reaction. 
Clinically, infusion reactions may present with fever, chills, flushing, itching, urticaria, 
and/or angioedema, repetitive cough, sudden nasal congestion, shortness of breath, chest 
tightness, wheeze, sensation of throat closure or choking, and/or change in voice quality, 
faintness, tachycardia (or less often bradycardia), hypotension, hypertension and/or loss 
of consciousness, nausea, vomiting, abdominal cramping, and/or diarrhea, sense of 
impending doom, tunnel vision, dizziness, and/or seizure, severe back, chest, and pelvic 
pain. 
6.4.1.4. 
Cytokine Release Syndrome 
Cytokine release syndrome, and severe, cytokine “storm”, has been identified as a 
sequelae of immune system activation associated with infusion reactions. 


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Prophylaxis for CRS is not mandated. However, if a participant experiences CRS, 
prophylaxis with antihistamines and paracetamol is permitted on subsequent infusions. 
Steroids may also be considered after discussion with the Medical Monitor.  
Table 11 provides the recommended management of CRS according to grade, which has 
been further adapted from CTCAE for use with immunotherapy and should be 
implemented in accordance with institutional guidelines. Symptoms can mimic those 
seen with infection. The diagnosis of CRS is clinical and is supported by the exclusion of 
infection as well as the presence of increased cytokine levels and other biomarkers. 
Assessment and treatment guidelines are provided below in alignment with (the Society 
for Immunotherapy of Cancer SITC) guidelines (Maus, 2020). In the event of CRS, 
Investigators may also follow institutional guidelines for symptom management; 
additional guidance can be found in the published literature (Lee, 2019).  
If CRS is suspected, in addition to assessment for infection, the following tests should be 
conducted every day for the first week and approximately every other day thereafter 
until symptoms are improving or an alternative diagnosis is confirmed: 
- 
Local tests: 
o Clinical chemistry including LFTs, hematology, ferritin and coagulation, 
as well as C-reactive protein (CRP) labs; 
o Troponin, and N-terminal pro B-type natriuretic peptide (NT-proBNP) / 
BNP tests; 
- 
Central tests: See Table 10 for central or local biomarker testing 
o cytokine-profiling as described in Section 8.6. 
CCI


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Table 11 
Management Guidelines for Cytokine Release Syndrome 
Grade 
Clinical Presentation for Grading 
Assessment1,2 
Management Guidelines 
1 
Temperature ≥38.0 °C 
Vigilant supportive care4 
Assess for infection and treat5 
2 
Temperature ≥38.0 °C with hypotension not 
requiring vasopressors and/or hypoxia 
requiring the use of oxygen delivered by low-
flow nasal cannula (≤6 L/minute) or blow-by. 
Monitor cardiac and other organ function 
Vigilant supportive care4 
Assess for infection and treat5 
Treat hypotension with fluid  
Administer O2 for hypoxia6 
Consider administering tocilizumab ± 
corticosteroids7  
3 
Temperature ≥38.0 °C with hypotension 
requiring a vasopressor with or without 
vasopressin and/or hypoxia requiring high-
flow nasal cannula (>6 L/minute), facemask, 
non-rebreather mask, or venturi mask not 
attributable to any other cause3 
Monitor participant very closely for 
cardiac and other organ dysfunction. 
Most likely will require monitoring in an 
intensive care unit (ICU). 
Vigilant supportive care4 
Assess for infection and treat5 
Treat hypotension with fluid and 
pressors6. Administer O2 for hypoxia. 
Administer tocilizumab ± corticosteroids7 
4 
Temperature ≥38.0 °C with hypotension 
requiring multiple vasopressors (excluding 
vasopressin) and/or hypoxia requiring 
positive pressure (eg: CPAP, BiPAP, 
intubation and mechanical ventilation) 
Manage participant in ICU 
Intensive supportive care including 
mechanical ventilation, fluids, pressors, 
antibiotics and other measures as 
required6 
Administer tocilizumab ± corticosteroids7 
5 
Death 
 
1. 
Fever is defined as temperature 38°C not attributable to any other cause. In patients who have CRS then 
receive antipyretic or anti-cytokine therapy such as tocilizumab or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
2. 
CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. 
For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring 
low-flow nasal cannula is classified as grade 3 CRS. 
3. 
Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
4. 
Supportive care includes monitor fluid balance, maintain adequate hydration and blood pressure  
5. 
Assessment and treatment to include history and physical, blood and urine cultures, imaging studies, 
administration of antimicrobial agents for concurrent bacterial infections, and for treatment of fever and 
neutropenia as per institutional practice; and antipyretics, analgesics as needed.  
6. 
Given that prolonged fluid resuscitation without pressor use is associated with worse outcome and because early 
and aggressive supportive care, early use of vasopressors, and timely anti-cytokine therapy are paramount to 
mitigating life-threatening CRS. 
7. 
Other immunosuppressor agents may be used, including TNFα and IL-1R inhibitors.  
Source: (Lee, 2019) 
 


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6.4.1.5. 
Cardiac Monitoring  
6.4.1.6. 
Cardiac Monitoring and Dose Modification Guidelines  
In Study 208850 examining GSK3745417 in participants with advanced solid organ 
tumors, one case of immune-mediated perimyocarditis has been observed, with a likely 
causal relationship to GSK3745417. On-study monitoring of cardiac symptoms 
(myocarditis or pericarditis), troponins and cardiac function (using ECHO or MUGA) 
will be therefore required in this study.  
BNP will be measured at screening and then on study as clinically indicated. Troponin 
should be measured at baseline and then every 2-3 weeks on study as per the schedule in 
Section 1.3. Troponin T will be assessed at a central laboratory as a means of consistent 
evaluation across all subjects. A second troponin sample will be assessed at a local 
laboratory for purposes of subject management. Whenever possible, troponin T will be 
assayed by the local laboratory. However, troponin I may be assessed at a local 
laboratory if troponin T is not available. The same local laboratory test (troponin I or 
troponin T) should be used consistently for an individual subject throughout the study.  
Participants should receive a screening ECHO which should be a 3D ECHO if available. 
If not, a 2D ECHO should be used, and MUGA may be used where ECHO is considered 
sub-optimal e.g., large body habitus. The same modality should then be used throughout 
the study to enable comparison to baseline (ideally by the same reader at study center). 
Global longitudinal strain will be assessed via ECHO. All ECHO/MUGA data will be 
transferred and reviewed by an independent cardiologist. 
GSK3745417 should be withheld, and participant referred for cardiology consult if: 
• 
Troponin is elevated ≥2× ULN  
• 
patient experiences symptoms consistent with pericarditis or myocarditis 
• 
ECHO – on-study decrease in left ventricular ejection fraction ≥ 10% AND falling 
below the LLN, OR 
• 
Absolute decrease in left ventricular ejection fraction ≥ 15%, even if LVEF remains 
in the normal range for the institution 
Elevation of troponin ≥2× ULN without symptoms requires withholding GSK3745417 
while awaiting repeat troponin value. A repeat troponin ≥2× ULN requires withholding 
GSK3745417 and awaiting cardiology consult. In participants with asymptomatic 
troponin elevations, GSK3745417 may be restarted in discussion with medical monitor, 
depending on benefit/risk. 
Participants with suspected myocarditis should be diagnosed and managed in line with 
institutional guidelines and cardiology advice. For a detailed review of diagnosis and 
management of myocarditis, and to guide treatment principles, the ASCO guidelines 
(Brahmer, 2018) and a recent review of myocarditis in patients treated with checkpoint 


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inhibitors (Palaskas, 2020) may be used, which include treatment principles around use of 
high dose steroids with a slow, monitored taper.  
6.4.1.7. 
Immune mediated events on study 
In Study 208850 examining GSK3745417 in participants with advanced solid organ 
tumors, one case of immune-mediated perimyocarditis has been observed, with a likely 
causal relationship to GSK3745417. Participants with new cardiac or respiratory 
symptoms should be assessed for potential pericarditis or myocarditis, with cardiology 
consult and cardiac imaging as clinically indicated. Other immune-mediated events may 
be a potential risk of GSK3745417 based on the anticipated pharmacology.   


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Table 12 
Dose Modification and Toxicity Management Guidelines for Immune Related- Aes  
General instructions: 
1. 
Corticosteroid taper may be initiated upon AE improving to Grade 1 or less as per investigator judgement and institutional treatment guidelines 
2. 
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 
(CTCAEv5.0) 
Action taken 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
 
 
 
Pneumonitis  
Grade 2 
Restart dosing when toxicity resolves to Grade 
0-1. If Grade 2 recurs, permanently discontinue. 
• Administer corticosteroids (initial dose of 
1-2 mg/kg methylprednisolone 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 
Restart dosing when toxicity resolves to Grade 
0-1. 
• Administer corticosteroids (initial dose of 
1-2 mg/kg methylprednisolone 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. 
Grade 4 
Permanently discontinue 
AST / ALT elevation or 
increased bilirubin 
Grade 2 
Restart dosing when toxicity resolves to Grade 
0-1. 
• Administer corticosteroids (initial dose of 
0.5- 1 mg/kg methylprednisolone 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 
• 
See Section 10.7 for additional details on Liver 
Event Follow-Up Assessments 
Grade 3 or 4  
Permanently discontinue3 
• Administer corticosteroids (initial dose of 
1-2 mg/kg methylprednisolone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
Grade 3-4 
hyperglycemia or 
T1DM 
(associated with 
Restart dosing in appropriately managed, 
clinically and metabolically stable patients; 
insulin replacement therapy is required. 
• Initiate insulin replacement therapy for 
participants with T1DM  
• Administer antihyperglycemic in 
participants with hyperglycemia  
• 
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes. 


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General instructions: 
1. 
Corticosteroid taper may be initiated upon AE improving to Grade 1 or less as per investigator judgement and institutional treatment guidelines 
2. 
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 
(CTCAEv5.0) 
Action taken 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
 
 
 
metabolic 
acidosis or 
ketonuria) 
Hypophysitis 
Grade 2 or 3 
For Grade 2-3, hold until administration of 
hormonal therapy results in return to adequate 
hormone levels based on laboratory values and 
restart dosing when toxicity 
resolves to Grade 0-1. For recurrence or 
worsening of ≥ Grade 2 hypophysitis after 
steroid taper has been completed and patient is 
on adequate hormone replacement therapy, 
permanently discontinue. 
• 
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated.   
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 4  
Permanently discontinue 
Hyperthyroidism  
Grade 3 
Hold until administration of hormonal therapy 
results in return to adequate hormone levels 
based on laboratory values and restart dosing 
when toxicity resolves to Grade 0-1. 
• Treat with non-selective beta-blockers 
(e.g., propranolol) or thionamides as 
appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 4  
Permanently discontinue1 
Hypothyroidism 
Grade 2-4 
Grade 3: Hold until administration of hormonal 
therapy results in return to adequate hormone 
levels based on laboratory values and restart 
dosing when toxicity resolves to Grade 0-1. 
• 
Initiate thyroid replacement hormones 
(e.g., levothyroxine or liothyroinine) per 
standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
• 
Monitor TFTs 
• 
Ensure adequate evaluation (eg., endocrine 
consultation) 
• 
Exclude concomitant adrenal insufficiency (AM 
cortisol level) 
Grade 3-4 
Grade 4: Permanently discontinue 
Myocarditis or 
pericarditis 
Grade 1 or 2 
Withhold. Seek cardiology consult. Ensure 
complete resolution after steroid treatment 
before considering re-start of GSK3745417 
depending on benefit/risk of further study drug 
• 
Based on severity of AE administer 
corticosteroids. Consider high dose 
steroids with slow taper, as per 
cardiology advice / institutional 
guidelines for myocarditis.  
• 
Treat until cardiac function returns to 
baseline 
• 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 or 4 
Permanently discontinue 


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General instructions: 
1. 
Corticosteroid taper may be initiated upon AE improving to Grade 1 or less as per investigator judgement and institutional treatment guidelines 
2. 
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 
(CTCAEv5.0) 
Action taken 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
 
 
 
Adrenal insufficiency 
Grade 2 or 3 
Hold until administration of hormonal therapy results 
in return to adequate hormone levels based on 
laboratory values and restart dosing when toxicity 
resolves to Grade 0-1. For recurrent or worsening ≥ 
Grade 2 adrenal insufficiency while adequate 
hormonal replacement is continuing, permanently 
discontinue study drug. 
• Start treatment with corticosteroids before 
other hormone replacement to avoid 
adrenal crisis (hydrocortisone slowly 
titrating doses down according to 
symptoms OR prednisone and 
fludrocortisone titrating up or down based 
on BP, other symptoms, and labs); patient 
with severe symptoms may require 
additional fluids (e.g., saline >2 L). 
• Monitor for cortisol level (AM), comprehensive 
metabolic panel (Na, K, CO2, glucose) and renin.   
Grade 4 
Permanently discontinue 
Uveitis 
Grade 2  
Withhold 
• Urgent ophthalmology consultation 
• Administer treatment with ophthalmic and 
systemic prednisone/methylprednisolone 
• Ensure adequate evaluation (e.g., urgent 
ophthalmology consultation)  
Immune-related 
Encephalitis 
Any grade 
Permanently discontinue 
• Consider IV acyclovir until PCR results 
obtained 
• Trial with methylprednisolone; if severe, 
treatment with methylprednisolone 
• If positive for autoimmune encephalopathy 
antibody or no improvement after 7-14 
days, consider rituximab  
• Ensure adequate evaluation to confirm etiology 
and/or exclude other causes. 
Rash 
Grade 3 
Withhold 
• Treat with high potency topical steroids to 
affected areas 
• Treat with prednisone 
• Ensure adequate evaluation (eg., urgent 
dermatology consultation) to confirm etiology 
and/or exclude other causes. 
Grade 4 
Permanently discontinue 
 
Renal failure or 
nephritis 
Grade 2 
Restart dosing when toxicity resolves to Grade 0-1. 
• Start treatment with prednisone; if 
persistent G2 beyond 1 week, 
prednisone/methylprednisone 
 
• Monitor participants for signs and symptoms, 
including monitoring of creatinine and urine protein 
every 3-7 days. 
• Ensure adequate evaluation (eg., nephrology 
consultation) to confirm etiology and/or exclude 
other causes. 


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General instructions: 
1. 
Corticosteroid taper may be initiated upon AE improving to Grade 1 or less as per investigator judgement and institutional treatment guidelines 
2. 
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 
(CTCAEv5.0) 
Action taken 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
 
 
 
Grade 3 or 4 
Permanently discontinue 
• Start treatment with prednisone; if 
persistent G2 beyond 1 week, 
prednisone/methylprednisone 
• Consider adding one of the following after 
1 week of steroids: azathioprine, 
cyclosporine, cyclophosphamide, 
infliximab, mycophenolate 
• Ensure adequate evaluation (eg., nephrology 
consultation, renal biopsy) to confirm etiology 
and/or exclude other causes. 
• Consider inpatient care  
Recurrence of Aes 
after resolution to 
≤Grade 1 
Grade 1 or 2 
Withhold 
• Based on severity of Aes, administer 
appropriate treatment until symptoms 
improve to ≤Grade 2 
Grade 3 or 4 
Permanently discontinue 
NOTES:  
1. 
The decision whether to withhold or permanently discontinue GSK3745417 is at the discretion of the investigator or treating physician.   
2. 
For participants with Grade 3 or 4 immune-related endocrinopathy where interruption of GSK3745417 is required, treatment with GSK3745417 may be resumed when the event resolves to 
Grade ≤2 and is controlled with hormonal replacement therapy or, for T1DM, metabolic control has been achieved.  
 


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6.5. 
Continued Access to Study Intervention after the End of the 
Study 
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the participant’s medical condition. 
Refer to the Schedule of Assessments for follow-up assessments of participants who are 
to be followed for disease progression and/or survival after they permanently discontinue 
from study intervention. 
6.6. 
Treatment of Overdose 
For this study, any dose of GSK3745417 greater than 50% within a 24-hour period will 
be considered an overdose. 
GSK does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE, vital signs, and laboratory 
abnormalities for at least 24 hours, and longer if clinically indicated or recommended 
by the medical monitor based on safety data obtained from the study  
3. Obtain a blood sample for PK analysis as soon as possible following the study 
intervention if requested by the Medical Monitor (determined on a case-by-case 
basis) 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
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. 
6.7. 
Concomitant Therapy 
6.7.1. 
Permitted Medications 
Participants considered to have an increased risk of thrombosis (e.g., history of catheter 
related clots, DVT) can be considered for prophylactic anticoagulation per local practice 
and/or clinical judgement. 
Prophylaxis for CRS is not mandated. However, if a participant has CRS, prophylaxis 
with antihistamines and paracetamol /acetaminophen is permitted on subsequent 
infusions. NSAIDs for fever or symptoms control should be avoided due to risk of renal 
injury.  


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Participants receiving hormonal therapy for a definitively treated malignancy (e.g., 
adjuvant therapy of localized breast or prostate cancer) may continue to receive therapy 
during study, after discussion with the medical monitor. 
Erythropoiesis-stimulating agents and colony-stimulating factors like filgrastim and 
pegfilgrastim may be used as clinically indicated for treatment of cytopenias. If used, 
these agents should be held for a period prior to disease assessment, per local institutional 
practice or guidelines. 
6.5.2. Prohibited Medications and Non-Drug Therapies 
The following medications are prohibited before the first dose of study treatment (see 
Section 5.2 for specific time requirements) and while on treatment in this study: 
• Any investigational drug(s) 
• Other anticancer therapy (chemotherapy, radiation therapy [unless administered 
palliatively], immunotherapy, biologic therapy, or hormone therapy other than for 
replacement).  
o Note: participants receiving hormonal therapy for a definitively treated 
malignancy (e.g., adjuvant therapy of localized breast or prostate cancer) may 
continue to receive therapy during study, after discussion with the medical 
monitor. 
• Live vaccines or live attenuated vaccines including herpes zoster, nasal flu, and 
coronavirus vaccines, as well as recombinant human or non-human primate 
adenoviral vector vaccines. 
Concomitant administration of drugs that are sensitive substrates or narrow therapeutic 
range substrates for cytochrome p450 (CYP) 3A4 enzyme, P-gp, BCRP, OATP1B1 and 
OATP1B3 transporter, and moderate to strong inducers and inhibitors of CYP3A4, P-gp, 
OATP1B1 and OATP1B3 should be excluded during the study and for 7 days prior to 
and following treatment with GSK3745417 (14 days for itraconazole),. Note: any 
medications (including antibacterials, antifungals, and antivirals) which are necessary for 
the health, wellbeing, or standard clinical care of patients with hematologic malignancies 
are exempt from this restriction. Any medications potentially interacting with 
GSK3745417 will require a pause in GSK3745417 dosing unless allowed through 
consultation with the Sponsor. Refer to the Study Reference Manual for a detailed list of 
excluded drugs. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
In some instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for disease status / progression and survival. See the 
SOA for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
7.1. 
Discontinuation of Study Intervention 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study intervention for abnormal liver tests is required when a 
participant meets one of the conditions outlined in Figure 6.  
Figure 6 
Liver Stopping and Monitoring Event Algorithm 
 
Refer to Section 10.7 for required Liver Safety Actions and Follow up Assessments and 
for required process for study intervention restart/rechallenge if considered for the 
participant. 
Continue Study Treatment 
Discontinue Study Treatment 
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5*
Possible
Hy’s Law
ALT≥3xULN
Both
ALT≥5xULN 
and ≥2X 
baseline 
value
Both 
ALT≥3xULN 
and ≥1.5X 
baseline value  
Plus
Symptoms of 
liver injury or 
hypersensitivity
Both
ALT≥3xULN 
and ≥1.5X 
baseline 
value but 
able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
Both
ALT≥3xULN
and ≥1.5X 
baseline value 
persist for
4 weeks or 
other stopping 
criteria met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
➢If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix


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7.1.2. 
Renal Stopping and Increased Monitoring Guidelines 
Renal events are to be managed as outlined in Table 13. 
Table 13 
Guidelines for Dose Modification and Management of Renal Events 
Adverse Event 
Management 
Serum Creatinine Increase 
by >0.3 mg/dL or 
26.5 mol/L Compared to 
Baseline 
• 
Hold Study Treatment unless considered related to TLS (see 
Section 6.4.1.2) 
• 
Repeat serum creatinine levels at least every 24 hours, monitor 
urine output 
• 
Perform diagnostics to identify root cause 
• 
Nephrology consultation is highly recommended 
• 
Discuss with Sponsor/Medical Monitor if considering resuming study 
drug treatment after initial hold 
• 
If serum creatinine is Grade 2 or higher for more than 7 days without 
a known cause, permanently discontinue treatment (unless 
continued dosing is approved by Medical Monitor) 
• 
If renal injury is considered secondary to TLS (for example, an 
increase in creatinine in association with increasing blood phosphate 
and uric acid levels), treatment may be continued (without hold) with 
the agreement of the Medical Monitor. In such cases, consider close 
monitoring of urine output and urinary pH, and early nephrology 
consultation 
Abnormal urinalysis 
findings, including 
hematuria 
• 
Perform diagnostics to identify root cause 
• 
Consider holding study treatment (though patients with abnormal 
findings consistent with TLS such as urate crystals may continue 
dosing as agreed by investigator and Medical Monitor)  
• 
Nephrology consultation is highly recommended if cause is not 
known 
 
7.1.3. 
QTc Stopping Criteria 
The QTcF correction formula will be used for each individual participant to determine 
eligibility for and discontinuation from the study. This formula may not be changed or 
substituted once the participant has been enrolled. If an ECG demonstrates a prolonged 
QTcF interval, then obtain 2 more ECGs over a brief period and then use the averaged 
QTcF values of the 3 ECGs to determine whether the participant should be discontinued 
from the study. 
If a participant meets either of the following criteria, they must be discontinued from 
study treatment.  
• 
QTcF >500 msec 
OR 
• 
Change from baseline of QTcF >60 msec 


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For participants with underlying bundle branch block, proceed with the following 
discontinuation criteria: 
Baseline QTcF with Bundle Branch Block 
Discontinuation QTcF with Bundle Branch Block 
<450 msec 
500 msec 
450 – 480 msec 
530 msec 
QTcF = QT duration corrected for heart rate by Fridericia’s formula 
 
If a clinically significant finding is identified (including, but not limited to changes 
from baseline in QT interval corrected using [Bazett’s formula [QTcB] or Fridericia’s 
formula [QTcF]]) 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. 
7.1.4. 
Temporary Discontinuation 
Please refer to Section 7.1.5 for information on rechallenge following a liver stopping 
event.  
7.1.5. 
Rechallenge 
7.1.5.1. 
Study Intervention Restart After Liver Stopping Criteria Met 
Study intervention restart after liver chemistry stopping criteria are met is allowed in this 
study. Study intervention rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
If participant meets liver chemistry stopping criteria, do not restart participant with study 
intervention unless: 
• GSK Medical Governance approval is granted 
• Ethics and/or IRB approval is obtained, if required, and 
• Separate consent for intervention restart is signed by the participant and 
participant is informed of any associated risks Refer to Appendix 7 for details on 
restart process.  
• 
If GSK Medical Governance approval to restart participant with study intervention is 
not granted, then participant must permanently discontinue study intervention and 
should continue in the study for protocol-specified follow up assessments. 
7.1.5.2. 
Study Intervention Restart When Renal Toxicity Stopping Criteria Met 
If the patient meets renal toxicity stopping criteria (serum creatinine is Grade ≥2 for 
>7 days without a known cause), permanently discontinue treatment unless the benefits 
of therapy outweigh the risk of rechallenge in the opinion of the investigator, the Medical 
Monitor, as well as GSK medical governance. In this situation, rechallenge may be 
permitted. 


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7.1.5.3. 
Study Intervention Restart When QTc Stopping Criteria Met 
• 
If the patient meets the QTc stopping criteria, patient should not be rechallenged. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, or compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See the SoA for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
• 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, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up 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 the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow up, 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 to 
have withdrawn from the study.  
• Site personnel, or an independent third party, will attempt to collect the vital 
status of the participant within legal and ethical boundaries for all participants 
randomized, including those who did not get study intervention. Public sources 
may be searched for vital status information. If vital status is determined as 
deceased, this will be documented, and the participant will not be considered lost 


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to follow-up. Sponsor personnel will not be involved in any attempts to collect 
vital status information. 
Discontinuation of specific sites or of the study are handled as part of Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA.  
• Protocol waivers or exemptions are not allowed  
• 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. 
• Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
• 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 ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the time frame defined in the SoA. 
• The maximum amount of blood collected from each participant over the duration 
of the study, including any extra assessments that may be required, will not 
exceed 275 mL in a 4-week period. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Efficacy Assessments 
Bone marrow biopsies for response assessments will be performed as outlined in the SoA 
tables. Participants will have responses graded per IWG criteria, as described in 
Appendix 8. Note that for clear cases of progression (e.g., emergence of blasts in the 
peripheral blood) that bone marrow biopsy may not be needed to document progression.  
Participants will be followed every 12 weeks (±2 weeks) for survival and subsequent 
anticancer therapy. The survival follow-up visit will commence after discontinuation of 
study intervention. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 


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8.2.1. 
Physical Examinations 
Each physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal (including abdominal examination), and 
neurological systems as well as the skin. Height should be measured and recorded at 
screening. Weight should be measured and recorded at screening and at each visit as 
detailed in the SoA. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses or abnormal physical examinations. 
8.2.2. 
Performance Status 
The performance status will be assessed using the ECOG scale in Section 10.10 at the 
timepoints specified in the SoA. 
8.2.3. 
Vital Signs 
• Vital sign measurements to be measured, in a consistent fashion, per institutional 
standard (e.g., in a seated or semi-supine position after 5 minutes rest), will 
include temperature, systolic and diastolic blood pressure, pulse rate, and 
respiratory rate.  
• In case of an abnormal first reading, three readings of blood pressure and pulse 
rate should be taken and averaged to give the measurement to be recorded in the 
CRF. 
• Vital signs will be measured more frequently if warranted by clinical condition of 
the participant.  
Refer to the SRM for further details. 
8.2.4. 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically or manually calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. Refer to Section 7.1.2 for QTc withdrawal criteria and 
additional QTc readings that may be necessary. 
8.2.5. 
Holter Monitoring 
Digital Holter ECG data will be obtained from 12-lead continuous Holter monitoring 
device supplied by the Sponsor. ECG acquisition via the Holter monitoring device will be 
performed (Section 1.3) and may be waived for individual participants upon approval 
from GSK. 
Analysis of intervals and morphology from the continuous digital ECG data will be 
acquired and stored electronically and may be manually over-read by an external central 
validated ECG laboratory. 
Refer to the Study Reference Manual (SRM) for details regarding Holter monitoring 
procedures. 


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8.2.6. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.  
• The investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents.  
• Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant, unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
intervention should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor.  
o If clinically significant 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. 
• All protocol-required laboratory tests, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
• If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.2.7. 
Pregnancy Testing 
• Refer to Section 5.1 for pregnancy testing entry criteria. 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during study intervention period. 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure plus an additional 30 days and 
correspond with the time frame for female participant contraception in 
Section 5.1. 
• Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s participation in the 
study. 


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8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of adverse events (AE) or serious adverse events (SAEs) can be found in 
Section 10.3. 
The definitions of unsolicited and solicited AEs can be found in Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up all OR AEs that are serious, considered related to the study intervention or 
the study, or that caused the participant to discontinue the study intervention study (see 
Section 7).  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All SAEs will be collected from the signing of the informed consent form (ICF) OR 
start of intervention until the follow-up visit at the time points specified in the SoA 
(Section 1.3). However, any SAEs assessed as related to study participation (e.g., 
study intervention, protocol-mandated procedures, invasive tests, or change in 
existing therapy) or related to a GSK product will be recorded from the time a 
participant consents to participate in the study.  
• All AEs will be collected from the signing of the ICF OR start of intervention until 
the follow-up visit at the time points specified in the SoA (Section 1.3). 
• Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions not 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. 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 information on AEs or SAEs after the 
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. 


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8.3.2. 
Method of Detecting AEs and SAEs 
• 
Care will be taken not to introduce bias when detecting AE and/or SAE. 
Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.  
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 non-serious AEs of special 
interest (as defined in Section 8.3.8]), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 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. 
• 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 Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study intervention and until time 
for reporting pregnancies should align with the time for post-intervention 
contraception determined in Section 5.1. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy. While pregnancy itself is not 
considered to be an AE or SAE, any pregnancy complication or elective termination 
of a pregnancy for medical reasons will be reported as an AE or SAE. 


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• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• The participant/pregnant female partner will be followed to determine the outcome of 
the pregnancy. The investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate, and the information will be 
forwarded to the sponsor. 
• 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 /pregnant female partner, 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 OR may request 
continuation of study intervention. 
Prior to continuation of study intervention following pregnancy, the following must 
occur: 
The sponsor and the relevant IRB/IEC give written approval. 
The participant gives signed informed consent. 
The investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and her offspring. 
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events and all deaths, whether they are considered SAEs, specific 
Cardiovascular (CV) and Death sections of the CRF will be required to be completed. 
These sections include questions regarding cardiovascular (including sudden cardiac 
death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.   
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 


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8.3.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
The following disease related events (DREs) are common in participants with AML and 
can be serious/life threatening: 
• 
Disease Progression 
Disease progression does not need to be reported as a serious adverse event (SAE). Death 
due to disease under study is to be recorded on the Death form of the electronic case 
report form (eCRF). Because these events are typically associated with the disease under 
study, they will not be reported according to the standard process for expedited reporting 
of SAEs to GSK (even though the event may meet the definition of an SAE). These 
events will be recorded within 7 days and monitored by the GSK study team.   
Note: However, if either of the following conditions apply, then the event must be 
recorded and reported as an AE/SAE (instead of a DRE):  
• The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, 
OR 
• The investigator considers that there is a reasonable possibility that the event was 
related to intervention with the investigational product 
8.3.8. 
Adverse Events of Special Interest  
Adverse events of special interest designated in this protocol include events that may be 
immune-related or related to CRS or TLS. AESIs must be reported to the GSK medical 
monitor within 24 hours regardless of relationship to study treatment. The severity of 
AEs will be graded utilizing the NCI-CTCAE, version 5.0. Guidelines for dose 
modifications and interruptions for management of common toxicities associated with the 
study treatment are provided in Section 6.4. Please also refer to Appendix 4 for AEs of 
special interest. 
8.4. 
Pharmacokinetics 
Blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of GSK3745417 as specified in the SoA (Section 1.3). 
• A maximum of 10 samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor. The 
timing of sampling may be altered during the study based on newly available data 
to ensure appropriate monitoring. 
• Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded. 


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• Samples will be used to evaluate the PK of GSK3745417. Each plasma sample 
will be divided into 2 aliquots (1 each for [PK, other analyses, and a back-up]). 
Samples collected for analyses of GSK3745417 plasma concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or 
after the study. 
• 
• Plasma samples may be analyzed for other compound-related metabolites and the 
results reported under a separate DMPK, GlaxoSmithKline protocol. 
• Details on PK blood sample collection, processing, storage, and shipping 
procedures are provided in the SRM. 
8.5. 
Genetics and Pharmacogenomics 
8.6. 
Biomarkers 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
With respect to the primary objectives and endpoints of Part 1 and the maintenance 
dosing of Part 2, no specific statistical hypotheses are being tested. The primary focus of 
Part 1 and maintenance dosing of Part 2 will be on determining the RP2D for both 
induction and maintenance for further exploration based upon the safety, PK, and 
anticancer activity profiles of GSK3745417 alone.  
The primary efficacy objective of the expansion cohort in Part 2 is to demonstrate that 
GSK3745417 is clinically active at the proposed induction RP2D(s) in participants with 
R/R AML and separately in participants with HR-MDS.  
Specifically, the first half of Part 2 is designed to provide evidence with regards to ORR 
to support the null hypothesis:  
H0: p≤10% 
or to reject it in favor of the alternative hypothesis: 
HA: p≥30% 
where p is the overall response rate. 
9.2. 
Sample Size Determination 
Approximately 72 participants will be enrolled to receive study intervention. The planned 
sample size for the study was chosen to allow adequate characterization of safety, clinical 
activity, PK, and PD profile based on the study objectives. For Part 1 dose escalation, the 
total sample size will depend on the number needed to adequately characterize the DLT 
profile and determine the MTD. For Part 2 dose expansion, approximately 50 participants 
will be recruited. 
Part 1: 
To complete dose escalation, it is estimated that up to approximately 22 participants will 
be enrolled in Part 1, assuming scenario 2 (described below) is most likely to occur. 
Dose escalation for Part 1 will use the N-CRM. This method utilizes a 2-parameter 
logistic model, with parameters α and β, to describe the relationship between DLT and 
dose. The N-CRM estimates, for each potential dose, the posterior probabilities that the 
DLT rate lies in each of 4 toxicity intervals:  
• [0%,16%)=Underdosing range; 
• [16%,33%)=Target toxicity range; 
• [33%,50%)=Excessive toxicity range;  
• [50%,100%)=Unacceptable toxicity range. 


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The following dose levels were used in statistical simulations: 12.5, 25, 50, 100, 200 µg. 
The proposed doses of GSK3745417 may be adjusted, as appropriate, based on the 
safety, tolerability, and PK data obtained in preceding cohorts. 
The N-CRM uses a Bayesian framework where the parameters  and  are assumed to 
have a bivariate normal prior distribution. Using Fixed and Adaptive Clinical Trial 
Simulator (FACTS) software (version 6.1; Berry Consultants [Austin, TX]), the 
parameters (mean [standard deviation {SD}]) of the bivariate normal prior for (, ln()) 
were derived. The parameters (SD) of the explicit distribution are α = -1.7907 (1.6787), 
ln(β) = 0.1961 (0.1706), and ρ = -0.7729 where α and ln(β) are distributed as bivariate 
normal with correlation ρ. 
Simulations were conducted to determine the average sample size and percentage of 
times each dose would be selected under three different scenarios, assuming the projected 
dose levels and N-CRM dose recommendations are followed. Simulations assumed 
cohorts of three participants would be enrolled starting with dose level 1. Three scenarios 
were considered for this simulation: scenario 1 (low-dose DLT) representing target 
toxicity at relatively low dose(s); scenario 2 (mid-dose DLT) representing target toxicity 
at intermediate dose(s); scenario 3 (high-dose DLT) representing target toxicity at 
relatively high dose(s). The toxicity curves for these three scenarios are shown in Figure 
7. 


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Figure 7 
Dose Toxicity Scenarios (with dose strength shown in units of mg) 
Low-dose DLT 
 
 
Mid-dose DLT 
 
 
High-dose DLT 
 
 
For each scenario, 10000 clinical trials were simulated. The average sample sizes over 
the 10000 clinical trials simulated under the three scenarios were 14, 20, 22, respectively. 


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Details of the simulation results are provided in Table 14. For the simulations, the 
selected reference dose was the median (0.05 mg).  
Table 14 
Summary of Simulation Results 
Scenario 
% of Trials 
Selecting Correct 
Dose(s) as MTD 
% of Trials 
Selecting 
Underestimating 
MTD 
% of Trials 
Selecting 
Overestimating 
MTD 
Average Sample 
Size 
Low-dose DLT 
92.69% 
- 
2.88% 
~14 
Mid-dose DLT 
85.72% 
13.76% 
0.52% 
~20  
High-dose DLT 
87.01% 
12.99% 
- 
~22 
 
Maximum Tolerated Dose: The MTD will be defined as the dose that has the highest 
probability of having a DLT rate within the target toxicity interval, and for which the 
probability that the DLT rate lies within the excessive toxicity, or the unacceptable 
toxicity window is less than 25%. The DLT observation period will be 28 days. 
Part 2: 
Approximately 50 participants will be recruited for Part 2, 25 AML participants and 25 
HR-MDS participants. Part 2 cohort expansion is designed based on predictive 
probability methodology of Lee and Liu (Lee, 2008). A test that the overall response rate 
[ORR] (p) is less than or equal to the null hypothesis rate versus the response rate is 
greater than or equal to the alternative rate is being performed separately in each 
indication using the stopping rules shown in Table 15.   
For Part 2 the hypotheses in terms of overall response rate (p) are detailed below.  
The null hypothesis is: 
H0: p≤10% 
The alternative hypothesis is: 
HA: p≥30% 
The null hypothesis of p=10% was specified given low likelihood of response following 
failure of standard therapies. The alternative hypothesis of p≥30% was specified to 
ensure robust evidence for efficacy to support advancement of a novel drug. 
GSK3745417 will be evaluated for efficacy in approximately 13 to 25 participants with 
AML and separately in 13 to 25 HR-MDS participants in the expansion cohorts.  
The futility evaluation will occur after 13 participants have completed induction and 
allow for a maximum number of 25 participants. This design will have a type I error rate 
(α) of 0.09 and a power of 0.88. A cohort (AML and/or MDS) can be terminated early for 
futility if the predictive posterior probability of the response rate greater than the null 
hypothesis of 10% being above 80% is very low, i.e., below 10% (θL) for this design. 
The type I error rate and power were derived by explicitly stating null and alternative 


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hypotheses of response rate, the minimum and maximum sample size, boundaries of 
predictive probability for futility criteria and the selection of the optimizing criterion as 
the maximization of power under the alternative hypothesis. The Bayesian prior used in 
determining the design was Beta (0.01, 0.09), a distribution with a mean response rate of 
10%. Under the null hypothesis, that is, if the true response rate is less than 10%, the 
expected sample size of the design is 17.5 participants per cohort and probability of early 
termination is 62.1%. Under the alternative hypothesis, that is, if the true response rate is 
at least 30%, the expected sample size of the design is 24.2 participants and probability of 
early termination is 6.4%. 
Table 15 
Stopping Rules for Part 2 Cohort Expansion 
Number of Evaluable Participantsa  
Stop for Futility if No. of Responders Less Than or Equal to This 
Numberb 
13 
1 
25 
4 
a. 
Evaluable participants for response assessment are defined by any or all of the following criteria: 
• 
Participants who have at least one post-baseline disease assessment. 
• 
Participants who have progressed or have died or have withdrawn from study treatment due to any reason. 
b. 
The specific criteria for stopping an expansion cohort due to futility. For instance, if 13 participants are enrolled, 
then the cohort may be stopped for futility if number of Responders ≤1. 
Note: These rules will be applied to both AML and HR-MDS cohorts in Part 2. 
 
Enrollment into AML and/or HR-MDS cohorts in Part 2 may be stopped according to the 
rules in Table 15 once all enrolled participants in the expansion cohort have met criteria 
for evaluability (as defined in the footnote to Table 15) after induction. The futility 
stopping rules are intended as a guideline only. Actual decisions will depend on the 
totality of the data. 
Up to 18 of these (AML and HR MDS) participants who respond to induction will 
continue to maintenance dosing. The maintenance dosing schedule will be determined 
based on data from the FTIH 208850 study. If enrollment into one of the cohorts (AML 
or HR MDS) is stopped early, additional participants in the other cohort may be enrolled 
to have a sufficient number of participants for maintenance dosing evaluation. Fewer 
doses in maintenance therapy are expected to be studied for dose escalation; therefore, 
the modified Toxicity Probability Interval (mTPI) procedure (Ji, 2013) (and not N-CRM) 
will be used to identify the MTD of GSK3745417 during maintenance dosing after 2 to 3 
cycles of daily dosing at the induction MTD determined from Part 1. Part 2 will evaluate 
3 increasing dose levels starting at the MTD determined from Part 1. The DLT period for 
Part 2 will be 28 days starting at Day 1 of each cycle. Dose escalation will target 3 
participants up to a target maximum of 6 at each dose level. Dose escalation will proceed 
until the MTD for GSK3745417 in maintenance dosing is determined.  
The rules guiding dose escalation based on the mTPI procedure are provided in Figure 8. 
Columns provide the number of participants treated at the current dose level, and rows 
provide the corresponding numbers of participants experiencing toxicity. The 
recommended decision (E = escalate to next higher dose, S = stay at current dose, 
D = de-escalate, DU = unacceptably toxic dose) is determined by taking the row showing 
the total number of participants with DLT at the current dose and finding the cell that 


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corresponds to the column showing total number of participants in the current dose level. 
For example, when one of three participants experiences a DLT at the current dose, the 
decision can be located at row indicating 1 and column indicating 3, which is S (to stay at 
the current dose level). All dose escalation decisions will be assessed by the GSK study 
team and investigators. 
Figure 8 
Dose Finding Spreadsheet of the Modified Toxicity Probability 
Interval (mTPI) Method 
 
The spreadsheet was generated based on a beta/binomial model and precalculated before 
trial initiation. The letters in different colors are computed based on the decision rules 
under the mTPI method and represent different dose-finding actions. In addition to 
actions de-escalate the dose (D), stay at the same dose (S), and escalate the dose (E), the 
table includes action unacceptable toxicity (DU), which is defined as the execution of the 
dose-exclusion rule in mTPI. 


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9.3. 
Analysis Sets 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Analyses Evaluated 
All screened 
All participants who sign the ICF to 
participate in the clinical study. 
Participants in this population will be 
used for the screen failure summary. 
Study Population 
Safety 
All participants who take at least 1 dose 
of study intervention. Participants will be 
analyzed according to the intervention 
they actually received. 
Study Population, Safety, Efficacy 
DLT-evaluable 
All participants who take at least 1 dose 
of study intervention and are followed for 
the DLT observation period or are 
withdrawn within the DLT observation 
period due to meeting the DLT criteria.  
Summary/Listing of Dose-Limiting 
Toxicities during the Determinative 
Period 
PK population 
All participants from the safety population 
for whom a PK sample is obtained and 
analyzed. 
PK 
PD population 
All participants who contribute a predose 
and at least one on-treatment 
PD/biomarker sample(s). 
PD 
 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to FSFV and it will include a 
more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. 
Data will be listed and summarized according to the GSK reporting standards, where 
applicable. Complete details will be documented in the SAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the SAP and clinical study report (CSR). 
9.4.1. 
Efficacy Analyses 
The safety population will be used for anticancer activity analyses. Since this is a Phase 1 
study, anticancer activity will be evaluated based on clinical evidence and response 
criteria.  
Overall response rate (ORR) for AML is defined as the percentage of participants with a 
complete remission (CR), CRp, CRi, or a partial remission (PR) as per response criteria 
for AML (Cheson, 2003) and HR MDS (Cheson, 2006), respectively. Participants with 
unknown or missing response will be included in the denominator when calculating the 
percentage. 
The estimate of ORR along with 95% exact confidence interval (CI) will be provided. 


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Duration of response (DOR) for AML is defined as the time from first evidence of 
response to earlier date of disease progression or death due to any cause, for participants 
with a complete remission (CR), CRp, CRi, or a partial remission (PR) as per response 
criteria for acute myeloid leukemia. Participants who have not progressed or died at the 
data cut-off, will be censored at the date of last adequate disease assessment. In addition, 
participants with an extended time without adequate assessment or who start a new 
anticancer therapy prior to a DOR event will be censored at the date of last adequate 
disease assessment (assessment where visit level response is CR, CRp, CRi, or PR) prior 
to the extended time without adequate assessment or initiation of new anti-cancer 
therapy, respectively. Further details on rules for censoring will be provided in the 
Statistical Analysis Plan. DOR will be summarized using Kaplan-Meier quantile 
estimates along with 95% CIs. 
Event-free survival (EFS) is defined as the time from first dose of study intervention to 
disease progression, failure to achieve CR, or relapse from CR, or death resulting from 
any cause, whichever occurs earliest. Participants who achieve induction treatment 
success and are alive and in remission at the data cut-off, will be censored at the date of 
last adequate disease assessment. In addition, participants with an extended time without 
adequate assessment or who start a new anticancer therapy prior to an EFS event will be 
censored at the date of last adequate disease assessment (assessment where visit level 
response is CR, CRp, CRi, PR, or SD) prior to the extended time without adequate 
assessment or initiation of new anti-cancer therapy, respectively. Further details on rules 
for censoring will be provided in the SAP. The milestone EFS at 6 months will be 
summarized using Kaplan-Meier quantile estimates along with 95% CIs. 
9.4.2. 
Safety Analyses 
The safety population will be used for the analysis of safety data. All serially collected 
safety endpoints (e.g., laboratory tests, vital signs, ECGs) will be summarized according 
to the scheduled, nominal visit at which they were collected and across all on-treatment 
time points using a “worst-case” analysis. Complete details of the safety analyses will be 
provided in the SAP. 
9.4.2.1. 
Extent of Exposure 
The number of participants administered study intervention will be summarized 
according to the duration of therapy. 
9.4.2.2. 
Adverse Events 
AEs will be coded using the standard MedDRA and grouped by system organ class. AEs 
will be graded by the investigator according to the NCI-CTCAE (version 5.0). Events 
will be summarized with frequency and percentage by preferred term. Separate 
summaries will be provided for all AEs regardless of grade, treatment-related AEs, 
treatment-related AEs by maximum grade, serious adverse events (SAEs), 
treatment-related SAEs, AEs leading to discontinuation of study intervention, AEs 
leading to dose reductions and AEs leading to dose interruptions/delays. Details will be 
provided in the statistical analysis plan (SAP). Dose-limiting toxicities (DLTs) will be 
listed and summarized by dose cohort based on the DLT Evaluable Population. Any AEs 


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of special interest will be summarized as detailed in the SAP. The incidence of deaths and 
the primary cause of death will be summarized. 
9.4.2.3. 
Clinical Laboratory Evaluations 
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE v5. Laboratory test results outside the reference 
ranges that do not have associated NCI-CTCAE v5 criteria will be summarized using 
proportions. Further details will be provided in the SAP.  
9.4.2.4. 
Other Safety Analyses 
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 
PK, PD, , and biomarker exploratory analyses will be described in the SAP. The 
population PK, PD, analyses may be presented separately from the main CSR.  
9.4.3.1. 
Pharmacokinetic Analyses 
PK analysis of GSK3745417 will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation (CPMS) Department, GSK.  
• PK analysis of GSK3745417 drug concentration-time data will be conducted by 
noncompartmental methods under the direction of CPMS, GSK. The following 
PK parameters will be determined if data permit:  
o Cmax  
o area under the plasma concentration-time curve (AUC(0-t), AUC(0-τ), 
[repeat dosing] and/or AUC(0-∞) [single dose])  
o apparent terminal phase elimination rate constant (z)  
o apparent terminal phase half-life (t1/2) (single dose)  
o systemic clearance of parent drug (CL)  
o volume of distribution (V) 
o Other parameters and analyses as appropriate and data permits, such as 
dose proportionality and time-invariance.  
Statistical analyses of the PK parameters data will be the responsibility of Clinical 
Statistics, GSK. All PK analyses will be performed on the PK population. 
Drug concentration-time data will be listed for each participant and summarized by 
descriptive statistics at each time point by cohort. PK parameter data will be listed for 
each participant and summarized by descriptive statistics by cohort and dosing day. 
The data from this study may be combined with the data from other studies for a 
population PK analysis and/or exposure-response analysis, which will be reported 
separately. 


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9.4.3.2. 
Pharmacokinetic/Pharmacodynamic Analyses 
Data obtained from the pharmacodynamic samples may be descriptively and/or 
graphically summarized, 
 
. Results may be reported 
separately.  
9.4.3.3. 
Exploratory Biomarker Analyses 
9.5. 
Interim Analysis 
The primary driver for the dose-escalation decision(s) will be safety and tolerability of 
each dose cohort. For Part 1 induction and Part 2 maintenance, dose escalation and 
de-escalation decisions will be guided by an N-CRM model and mTPI, respectively. 
Predicted DLT rates will be provided with the aim of escalating to doses with small 
probability of excessive or unacceptable toxicity. Preliminary safety and available PK/PD 
data will be reviewed by the GSK study team and investigators after completion of each 
dose cohort. This review will support the decision on the dose level in the next dose 
cohort.  
After the last cohort of participants completes the DLT observation period for induction 
in Part 1, a formal interim analysis will be performed to support the initiation of Part 2 
and the recommended dose level for induction. Data considered to support these 
decisions will include, but are not limited to, safety, PK profile, PD, and observed signs 
of clinical activity. Details of the interim analysis will be provided in the SAP. 
For Part 2, assessment of efficacy and safety will be performed after the first futility 
assessment based upon a minimum of 13 participants with available unconfirmed overall 
response data, separately for the AML and HR-MDS cohorts. If the stopping criteria for 
futility are met in either the AML or MDS cohort, further enrollment in that cohort may 
be stopped. 
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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: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 
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 IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
• 
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/EC 
• 
Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study. 


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10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study.  
• Participants must be informed that their participation is voluntary. 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.  
• 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.  
• 
Participants who are rescreened are required to sign a new ICF. 
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorized designee 
will inform each participant of the possibility of further research not related to the 
study/disease. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate signature will be required to document a participant's agreement to allow any 
participant data and/or remaining specimens to be used for further research. Participants 
who decline further research will tick the corresponding “No” box in the ICF. 
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 who will be required to give 
consent for their data to be used as described in the informed consent.  
• 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. 
Committees Structure 
Not applicable. 


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10.1.6. 
Dissemination of Clinical Study Data 
• Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually agreeable location. 
• GSK will also provide all investigators who participated in the study with a 
summary of the study results and will tell the investigators what treatment their 
participants received. The investigator(s) is/are encouraged to share the summary 
results with the study subjects, as appropriate. 
• Under the framework of the SHARE initiative, GSK intends to make anonymized 
participant-level data from this trial available to external researchers for scientific 
analyses or to conduct further research that can help advance medical science or 
improve patient care. This helps ensure the data provided by trial participants are 
used to maximum effect in the creation of knowledge and understanding. 
Requests for access may be made through www.clinicalstudydatarequest.com. 
10.1.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRF 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 CRF.  
• Guidance on completion of CRFs will be provided in the eCRF Completion 
Guidelines. 
• Quality tolerance limits (QTLs) will be pre-defined in the Data Quality Plan to 
identify systematic issues that can impact participant safety and/or reliability of 
study results. These pre-defined parameters will be monitored during and at the 
end of the study and all deviations from the QTLs and remedial actions taken will 
be summarized in the clinical study report. 
• 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 including definition of study critical data 
items and processes (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 study specific 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). 


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• Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary 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.  
10.1.8. 
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 CRF 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, and its origin can be found in [Source 
Data Acknowledgment]. 
• The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF 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 GCP, and all 
applicable regulatory requirements.  
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site Termination 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. 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. 


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Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• 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 
• Inadequate or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the subject and should assure appropriate 
participant therapy and/or follow-up. 
10.1.10. 
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. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
All safety laboratory assessments, as defined in Section 1.3, will be performed 
by local laboratory unless otherwise noted.  
• 
Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be recorded.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 16 
Protocol-Required Safety Laboratory Tests 
Local Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Clinical 
Chemistry1 
BUNa 
Creatinine 
Fasting Glucose 
Potassium 
Sodium 
Calcium 
AST (SGOT) 
ALT (SGPT) 
Alkaline Phosphatase 
 
eGFR 
 
Total Protein 
Albumin 
Total and direct bilirubin 
Lactate dehydrogenase (LDH) 
Phosphate, uric acid,  
Thyroid Function 
Thyroid Stimulating Hormone, free T4 
Cardiac Function 
Troponin I or T  
Routine 
Urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Other Screening 
Tests 
Hepatitis B (HBsAg) 
Quantitative HBsAg 
Hepatitis C (Hep C antibody) 
 
Serum Pregnancy test (as needed for WOCBP) 
 
Hematology 
Platelet Count 
RBC Count 
Hemoglobin 
Hematocrit 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Myeloblasts (if present) 
Central Safety Laboratory Assessments 
Coagulation 
PTT, PT/NR, fibrinogen 
Cardiac Function 
Troponin T  
Other 
C-Reactive Protein 
 


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a Required if local lab testing does not include BUN standards. 
NOTES : 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1.1 and Appendix 7. All events of ALT 3 × upper limit of normal 
(ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) 
>1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). 
2. 
If the local laboratory is unable to perform any assessment, the central laboratory may be utilized. 
 


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10.3. 
Appendix 3: AEs and SAEs: 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 clinical study participant, 
temporally associated with the use of a 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 a study intervention. 
 
Definition of Unsolicited and Solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a 
Participant Diary and that is communicated by a participant who has signed the 
informed consent. Unsolicited AEs include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, or emergency room visit, or visit to/by a health care 
provider). The participant will be instructed to contact the site as soon as possible 
to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant’s concern. Detailed information about 
reported unsolicited AEs will be collected by qualified site personnel and 
documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by 
participant will be collected during interview with the participants and by review of 
available medical records at the next visit. 
• Solicited AEs are predefined local at the injection site and systemic events for 
which the participant is specifically questioned, and which are noted by the 
participant in their diary.  
 
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. 


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• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• 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 AE or SAE if they fulfill the definition of 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. 
 


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10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
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 admitted 
(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 AE. If a complication prolongs 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 or significant 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. Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
g. Other situations: 
• Possible Hy’s Law case: ALT≥3×ULN AND total bilirubin ≥2×ULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported 
as SAE 
• Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 


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medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias, 
convulsions, or development of intervention dependency or intervention 
abuse. 
 
10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 
10.3.4. 
Recording and Follow-Up of AE and 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, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, except for the participant 
number, will be redacted on the copies of the medical records before submission to 
GSK. 


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• 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 assess severity for each AE and SAE reported during the study 
and assign it to 1 of the following categories:  
• 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 AE and SAE 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. 
 
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 Investigator’s Brochure (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 GSK. However, it is very 
important that the investigator always assess causality for every event before 
the initial transmission of the SAE data to GSK. 
• The investigator may change his/her opinion of causality considering follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 


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• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK 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 follow-
up period, the investigator may be requested to provide GSK with a copy of any 
postmortem findings including histopathology. 
• New or updated information will be recorded in the originally submitted 
documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
postmortem receipt of the information. 
 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to GSK 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 next section) 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 
next section) or to the SAE coordinator by telephone. 
• 
Contacts for SAE reporting can be found in the Study Reference Manual. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the SAE coordinator. 


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• 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 data collection tool within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the Study Reference Manual. 


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10.4. 
Appendix 4: Adverse Events of Special Interest 
The list of terms and reporting requirements for AESI are provided below. These are 
selected non-serious AEs and SAEs that must be reported to the GSK medical monitor 
within 24 hours regardless of relationship to study treatment. Any event that meets the 
criteria described below must be reported regardless of investigator-determined 
relationship to study treatment or if considered immune-related (unless otherwise 
specified). Investigators/study coordinators/designated site personnel are required to 
record these experiences in the eCRF (as described in the eCRF completion guidance 
document) and to provide supplemental information (such as medical history, 
concomitant medications, investigations, etc.) about the event. 
Cytokine-related AEs 
Cardiopulmonary or hemodynamic toxicity starting within 24 hours of study treatment 
that requires >40% FiO2, vasopressor administration, antiarrhythmic agent or other 
significant medical intervention. Asystole, as measured by ECG, or bradycardia that is 
symptomatic and requires medical intervention. 
Immune-related AEs 
Pneumonitis (reported as AESI if ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as AESI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as AESI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of 
systemic steroids to treat the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or 
metabolic acidosis (DKA) 
Endocrine (reported as AESI) 
Type 1 diabetes mellitus (if new onset) 
 
 
Hematologic (reported as AESI if ≥ Grade 3 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Autoimmune hemolytic anemia  
Aplastic anemia  
Thrombotic 
Thrombocytopenic Purpura 
(TTP) 
Idiopathic (or immune) Thrombocytopenia 
Purpura (ITP) 
Disseminated Intravascular 
Coagulation (DIC) 
Hemolytic Uremic Syndrome 
(HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as AESI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Hepatitis  
Autoimmune hepatitis  
Transaminase elevations 
(ALT and/or AST) 
Infusion Reactions (reported as AESI for any grade) 
Allergic reaction 
Anaphylaxis 
CRS 
Serum sickness 
Infusion reactions 
Infusion-like reactions 


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Neurologic (reported as AESI for any grade) 
Autoimmune neuropathy 
Guillain-Barré syndrome 
Demyelinating 
polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as AESI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as AESI if ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as AESI if ≥Grade 3 or any 
grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Skin (reported as AESI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as AESI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment  
Other (reported as AESI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
Any grade of hemophagocytic lymphohistiocytosis 
 
 
 


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10.5. 
Appendix 5: Contraceptive and Barrier Guidance  
10.5.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
• 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 >40 IU/L or mIU/mL is required.  
o 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 
enrolment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
• 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), 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. 
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. 


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10.5.2. 
Contraception Guidance: 
Participants are required to agree to abide by the gender specific contraceptive 
requirements below:  
• Female participants are eligible to participate if they are not either pregnant or 
breastfeeding, and at least one of the following conditions applies:  
• Is not a woman of childbearing potential (WOCBP), or 
• Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), with low user dependency during the study 
treatment period and for at least 7 days after the last dose of study treatment and 
agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during 
this period. The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study treatment. 
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) 
as required by local regulations) within 7 days before the first dose of study 
intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous 
result), a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive. 
• Additional requirements for pregnancy testing during and after study treatment 
will be described in the protocol. 
• The investigator is responsible for a review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.  
• Male participants and WOCBP taking hydroxyurea during the study must follow 
contraceptive guidance in the hydroxyurea prescribing information. 
 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 


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• 
Highly Effective Methods b That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
• 
Sexual abstinence 
• 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction) 
 
 


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10.6. 
Appendix 6: Genetics 
CCI


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10.7. 
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Restart/Rechallenge 
Guidelines 
• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM174090.pdf 
• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM174090.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianc
eRegulatoryInformation/Guidances/UCM174090.pdf 
• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM174090.pdf 
• https://doi.org/10.1016/j.jhep.2019.02.014  
Phase 1 oncology liver chemistry stopping criteria have been designed to assure 
participant safety and to evaluate liver event etiology. 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
ALT absolute 
Both ALT  5xULN and 2x baseline value 
ALT Increase 
Both ALT  3xULN and ≥ 1.5x baseline value that persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5 
Cannot Monitor 
Both ALT  3xULN and ≥ 1.5x baseline value that cannot be monitored for 
4 weeks 
Symptomatic3 
 
Both ALT  3xULN and ≥ 1.5x baseline value associated with symptoms (new 
or worsening) believed to be related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping Event 
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment  
• Report the event to GSK within 24 hours 
• Complete the liver event CRF and complete SAE 
data collection tool if the event also meets the 
criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline (see 
MONITORING below) 
• Do not restart/rechallenge participant with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (refer to 
Appendix 7) 
• If restart/rechallenge not allowed per protocol or 
not granted, permanently discontinue study 
treatment and may continue participant in the 
study for any protocol specified follow up 
assessments MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin, and INR) and 
• Viral hepatitis serology4 
• Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend 
• Blood sample for pharmacokinetic (PK) 
analysis, obtained within 48h of the last dose6 
• Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin2xULN 
• Obtain complete blood count with differential to 
assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over 
the counter medications 
• Record alcohol use on the liver event alcohol 
intake case report form 


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perform liver event follow up assessments within 
24 hr 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilize, or return to within 
baseline 
• A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 
perform liver event follow up assessments within 
24-72 hr 
• Monitor participants weekly until liver chemistries 
resolve, stabilize, or return to within baseline 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total 
immunoglobulin G (IgG or gamma globulins) 
• Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: not 
required in China  
• Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) and 
/or liver biopsy to evaluate liver disease; 
complete Liver Imaging and/or Liver Biopsy 
CRF forms 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT  3xULN and bilirubin  2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. 
All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the threshold value stated will not apply to participants receiving anticoagulants 
3. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash, or 
eosinophilia) 
4. 
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody  
5. 
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal , 2005]. 
6. 
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.  Not required for single-dose studies 
 
10.7.1. 
Study Treatment Restart or Rechallenge 
If participant meets liver chemistry stopping criteria do not restart participant with study 
treatment unless: 
• GSK Medical Governance approval is granted (as described below), 
• Ethics and/or IRB approval is obtained, if required, and 
• Separate consent for treatment restart/rechallenge is signed by the 
participant 
If GSK Medical Governance approval to restart participant with study treatment is not 
granted, then participant must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments for overall survival.  


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10.7.2. 
Restart Following Transient Resolving Liver Stopping Events Not 
Related to Study Treatment 
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g., biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, restart is not permitted 
following liver stopping event when the underlying cause was alcoholic hepatitis. 
Approval by GSK for study treatment restart can be considered where: 
• 
Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 × baseline and ALT 
<3×ULN). 
• 
Possible study treatment-induced liver injury has been excluded by the investigator 
and the study team. This includes the absence of markers of hypersensitivity 
(otherwise unexplained fever, rash, eosinophilia). Where a study treatment has an 
identified genetic marker associated with liver injury (e.g., lapatinib, abacavir, 
amoxicillin/clavulanate), the presence of the marker should be excluded. If study 
treatment-related liver injury cannot be excluded, the guidance on rechallenge in 
Section 10.7.2 will apply. 
• 
There is no evidence of alcoholic hepatitis. 
• 
Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required. 
• 
If restart of study treatment is approved by GSK Medical Governance in writing, the 
participant must be provided with a clear description of the possible benefits and 
risks of study treatment administration, including the possibility of recurrent, more 
severe liver injury or death.   
• 
The participant must also provide signed informed consent specifically for the study 
treatment restart. Documentation of informed consent must be recorded in the study 
chart.   
• 
Study treatment must be administered at the dose specified by GSK. 
• 
Participants approved by GSK Medical Governance for restarting study treatment 
must return to the clinic once a week for liver chemistry tests until stable liver 
chemistries have been demonstrated and then laboratory monitoring may resume as 
per protocol.  
• 
If after study treatment re-start, participant meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions. 


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• 
GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study treatment 
restart.  
• 
GSK to be notified of any adverse events, as per Section 10.3.  


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10.8. 
Appendix 8: IWG Criteria for Response for Participants with 
MDS 
Category 
Response Criteria 
Complete Remission 
Bone marrow: ≤5% myeloblasts with normal maturation of all cell linesa 
Persistent dysplasia will be noteda,b 
Peripheral blood (Response must be maintained for at least 4 weeks) 
Hgb ≥11 g/dL 
Platelets ≥100 Gi/L 
Neutrophils ≥ 1.0 Gi/Lb 
Blasts 0% 
Partial Remission 
All CR criteria if abnormal before treatment except: 
Bone marrow blasts decreased by ≥ 50% over pre-treatment but still > 5% 
Cellularity and morphology not relevant 
Marrow CRb 
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pre-treatmentb 
Peripheral blood: if HI responses, they will be noted in addition to marrow CRb 
Hematologic 
improvement (HI) 
Erythroid (HI-E): 
Hgb increase of > 1.5 g/dL 
decrease of > RBC transfusions/8 weeks versus pretreatment requirement in 
previous 8 weeks; only RBC transfusions given for a pretreatment Hgb of 
< 9.0 g/dL count 
Platelet (HI-P): 
increase of > 30,000/mL (starting with > 20,000/mL) 
increase from < 20,000/mL to > 20,000/mL by > 100% 
Neutrophil (HI-N): 
increase of > 100% and > 500/µL 
Stable Disease 
Failure to achieve at least PR, but no evidence of progression > 8 wks 
Disease Progression 
For participants with: 
• 
Less than 5% BM blasts: ≥ 50% increase in blasts to > 5% blasts 
• 
5%-<10% BM blasts: ≥ 50% increase to > 10% blasts 
• 
10%-<20% BM blasts: ≥ 50% increase to > 20% blasts 
• 
20%-30% BM blasts: ≥ 50% increase to > 30% blasts 
Any of the following: 
• 
At least 50% decrement from maximum remission/response in 
granulocytes or platelets 
• 
Reduction in Hgb by ≥ 2 g/dL 
• 
Transfusion dependence 
Non-evaluable 
Participant does not meet any of the above criteria 
BM = bone marrow; CR = complete remission; Hgb = hemoglobin; PR = partial remission 
d. 
Dysplastic changes should consider the normal range of dysplastic changes (modification). 
e. 
Modification to IWG response criteria for MDS [Cheson, 2006]. 
 
 
 


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10.9. 
Appendix 9: Response Criteria for Participants with AML 
[Modified Cheson, 2003] 
Complete remission (CR): The subject must achieve a morphologic leukemia-free state 
(≤ 5% blasts) and have no evidence of extramedullary disease. The subject must be free 
of all symptoms related to leukemia, have an absolute neutrophil count ≥ 1 × 109/L and 
platelet count ≥ 100 × 109/L, and be transfusion independent. 
CRp: Marrow response as per CR but platelet count <100 × 109/L. 
CRi: Marrow response as per CR but platelet count <100 × 109/L or neutrophil count 
<1 × 109/L. 
Partial remission (PR): A decrease from baseline of at least 50% in the number of bone 
marrow blasts, to between 5% and 25% of the bone marrow aspirate. 
No response: Subject does not meet criteria for CR, CRp, CRi, or PR. 
Recurrence: Morphologic relapse, defined as the reappearance of peripheral blasts or 
increase in bone marrow blasts ≥ 5% not attributable to any other cause (e.g., infection, 
growth factor support, bone marrow regeneration). 
References 
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH. Revised 
recommendations of the International Working Group for diagnosis, standardisation of 
response criteria, treatment outcomes, and Reporting Standards for therapeutic trials in 
Acute Myeloid Leukemia. Journal of Clinical Oncology 2003 Dec 15; 21 (24):4642-9. 
 
 


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10.10. 
Appendix 10: ECOG Performance Statusa 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. 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 
In bed <50% of the time. 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 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Dead. 
a. 
Oken, 1982. 


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10.11. 
Appendix 11: Cairo-Bishop Clinical Tumor Lysis Syndrome 
Definition and Grading  
 
 


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10.12. 
Appendix 12: Abbreviations and Definitions and Trademarks 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
AST 
Aspartate aminotransferase 
CNS 
Central nervous system 
CRP 
C-reactive protein 
CRS 
Cytokine Release Syndrome 
CV 
Cardiovascular 
CYP 
Cytochrome P450 
 
 
DMPK 
Drug Metabolism and Pharmacokinetics 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
EU 
European Union 
FTIH 
First Time in Humans 
GSK 
GlaxoSmithKline 
HPLC/MS/MS 
High performance liquid chromatography with tandem mass 
spectrometry 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IFN 
Interferon 
IL 
Interleukin 
IV 
Intravenous 
MABEL 
Minimum anticipated biological effect level 
MC 
Multicenter 
ND 
Not determined 
OATP 
Organic anion transporter polypeptide 
OL 
Open label 
PD 
Pharmacodynamic 
PD-1 
Programmed death receptor 1 
PEG 
Polyethylene glycol 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SD 
Standard deviation 
SOC 
System organ class 
STING 
STimulator of InterferoN Genes 
TBK1 
TANK binding kinase-1 
TK 
Toxicokinetic 
TNF 
Tumor necrosis factor 
Treg 
T-regulatory 
WBC 
White blood cell 


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11. 
REFERENCES 
Arber DA, Orazi A, Hasserjian R, Jurgen T, Borowitz M, Le Beau M, et al. The 2016 
revision to the World Health Organization classification of myeloid neoplasms and acute 
leukemia. Blood. 2016;127(20):2391-2405.  
Baba T, Yoshida T, Tanabe Y, Nishimura T, Morishita S, Gotoh N, et al. Cytoplasmic 
DNA accumulation preferentially triggers cell death of myeloid leukemia cells by 
interacting with intracellular DNA sensing pathway. Cell Death Dis. 2021;12(4):322. 
Published 2021 Mar 26.  
Brahmer JR, Lacchetti C, Schneider BJ, Atkins M, Brassil K, Caterino J, et al. 
Management of Immune-Related Adverse Events in Patients Treated With Immune 
Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice 
Guideline. J Clin Oncol. 2018;36(17):1714-1768.  
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and 
classification. Br J Haematol. 2004 Oct;127(1):3-11. 
Chen DS and Mellman I. Elements of cancer immunity and the cancer-immune set point. 
Nature, 2017;541:321-30. 
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH. Revised 
recommendations of the International Working Group for diagnosis, standardisation of 
response criteria, treatment outcomes, and Reporting Standards for therapeutic trials in 
Acute Myeloid Leukemia. Journal of Clinical Oncology 2003 Dec 15; 21 (24):4642-9. 
Cheson BD, Greenberg PL, Bennett JM, Lowenberg R, Wijermans PW, Nimer SD, et al. 
Clinical application and proposal for modification of the International Working Group 
(IWG) response criteria in myelodysplasia. Blood. 2006 July 15;108, Number 2: 419-
425. 
Curran E, Chen X, Corrales L, Kline DE, Dubensky TW Jr, Duttagupta P, et al. STING 
Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia. Cell 
Rep. 2016 Jun 14;15(11):2357-66. 
Gaidt MM, Ebert TS, Chauhan D, Ramshorn K, Pinci F, Zuber S, et al. The DNA 
inflammasome in human myeloid cells is initiated by a STING-cell death program 
upstream of NLRP3. Cell. 2017;171(5):1110-1124.e18.  
GSK Document Number 2018N357563_03, Investigator’s Brochure for GSK3745417. 
Version 03. 2020. 
Gulen MF, Koch U, Haag SM, Schuler F, Apetoh F, Villunger A, et al. Signalling 
strength determines proapoptotic functions of STING. Nat Commun. 2017;8(1):427. 
Published 2017 Sep 5.  
Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I 
interferon-dependent innate immunity. Nature. 2009;461(7265):788-792.  


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James LP, Letzig L, Simpson PM, Capparelli E, Roberts D, Hinson J, et al. 
Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metab Dispos. 2009 Aug;37(8):1779-84. 
Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable 
method than the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013 May 
10;31(14):1785-91. 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Deny P, et al. Quantification of 
hepatitis delta virus RNA in serum by consensus real-time PCR indicates different 
patterns of virological response to interferon therapy in chronically infected patients. J 
Clin Microbiol. 2005 May;43(5):2363-9. 
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT 
Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated 
with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25:625-638. 
Lee, J. J., & Liu, D. D. A predictive probability design for phase II cancer clinical trials. 
Clinical Trials, (2008). 5(2), 93-106. 
Mahadevan V, Malik ST, Meager A, Fiers W, Lewis GP, Hart I. Role of tumor necrosis 
factor in flavone acetic acid-induced tumor vasculature shutdown. R. Cancer Res. 1990 
Sep 1;50(17):5537-42. 
Maus MV, Alexander S, Bishop MR, Brudno J, Callahan C, Davila M, et al. Society for 
Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector 
cell-related adverse events. J Immunother Cancer. 2020 Dec;8(2):e001511. 
NCI (2017) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
Nov, 2017. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_5x7.pdf 
NYHA: The Criteria Committee of the New York Heart Association (NYHA). 
Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th Ed. 
Boston, Mass: Little, Brown & Co.; 1994:253-256. 
Oken, MM, Creech, RH, Tormey, DC, Horton, J, Davis, TE, McFadden, ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982; 5:649-655.   
Palaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A. Immune Checkpoint 
Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment. J 
Am Heart Assoc. 2020;9(2):e013757.  
Schwartz LB. Diagnostic Value of Tryptase in Anaphylaxis and Mastocytosis. Immunol 
Allergy Clin. 2006, 26(3):451-463. 
Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA 
sensor that activates the type I interferon pathway. Science. 2013;339(6121):786-791.  


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Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna M, Leung M, et al. 
STING-dependent cytosolic DNA sensing mediates innate immune recognition of 
immunogenic tumors [published correction appears in Immunity. 2015 Jan 20;42(1):199]. 
Immunity. 2014;41(5):830-842.  

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  209809
Official Title of Study: A Phase 1, Open Label Study of Intravenous 
GSK3745417 to Evaluate Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics and Determine RP2D and Schedule in Participants 
With Relapsed or Refractory Myeloid Malignancies Including Acute 
Myeloid Leukemia (AML) and High-risk Myelodysplastic Syndrome 
(HR-MDS)
NCT ID: NCT05424380
Date of Document: 24-Feb-2025


 
 
 
CONFIDENTIAL 
 
209809 
Page 1 of 29 
 
Information Type: 
Statistical Analysis Plan (SAP) 
 
TITLE PAGE 
Protocol Title: 
A Phase 1, open label study of intravenous GSK3745417 to 
evaluate safety, tolerability, pharmacokinetics, 
pharmacodynamics and determine RP2D and schedule in 
participants with relapsed or refractory myeloid malignancies 
including acute myeloid leukemia (AML) and high-risk 
myelodysplastic syndrome (HR-MDS) 
 
 
Study Number: 
209809 
 
Compound Number: GSK3745417 
Abbreviated Title: 
PH1, GSK3745417, Open Label, safety, tolerability, PK and 
PD study in Participants with AML and HR-MDS 
 
 
Sponsor Name: GlaxoSmithKline Research & Development Limited  
Regulatory Agency Identifier Number(s)  
Registry 
ID 
IND 
EudraCT 
159056 
2021-005234-41 
 
XBU Statistical Analysis Plan (SAP) Template v2.0 17 January 2022 
Copyright 2024  the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


 
 
CONFIDENTIAL 
 
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Page 2 of 29 
 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
VERSION HISTORY ....................................................................................................... 5 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
Objectives, Estimands and Endpoints ........................................................... 6 
1.2. 
Study Design ................................................................................................ 8 
2. 
STATISTICAL HYPOTHESES ................................................................................. 9 
2.1. 
Multiplicity Adjustment .................................................................................. 9 
3. 
ANALYSIS SETS ................................................................................................... 10 
4. 
STATISTICAL ANALYSES ..................................................................................... 10 
4.1. 
General Considerations .............................................................................. 10 
4.1.1. 
General Methodology .................................................................. 10 
4.1.2. 
Baseline Definition ....................................................................... 11 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 11 
4.2.1. 
Definition of endpoint(s) ............................................................... 11 
4.2.2. 
Main analytical approach ............................................................. 11 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 13 
4.3.1. 
Key secondary endpoint(s) .......................................................... 13 
4.3.1.1. 
Definition of endpoint(s) .............................................. 13 
4.3.1.2. 
PK Evaluation ............................................................. 13 
4.3.2. 
Supportive secondary endpoint(s) ............................................... 14 
4.4. 
Exploratory Endpoint(s) Analyses ............................................................... 16 
4.4.1. 
Exploratory Efficacy Analyses ...................................................... 16 
4.5. 
Other Safety Analyses ................................................................................ 17 
4.5.1. 
Extent of Exposure ...................................................................... 17 
4.5.2. 
COVID-19 .................................................................................... 17 
4.5.2.1. 
COVID-19 Assessment and COVID-19 AEs ............... 17 
4.5.2.2. 
Impact of COVID-19 Pandemic on Safety 
Results ....................................................................... 18 
4.5.3. 
Additional Safety Assessments .................................................... 18 
4.5.4. 
Deaths ......................................................................................... 18 
4.5.5. 
Pregnancies ................................................................................. 18 
4.6. 
Other Analyses ........................................................................................... 18 
4.7. 
Interim Analyses ......................................................................................... 18 
4.8. 
Changes to Protocol Defined Analyses ....................................................... 18 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 19 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 20 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 20 
6.1.1. 
Participant Disposition ................................................................. 20 
6.1.2. 
Demographic and Baseline Characteristics .................................. 20 
6.1.3. 
Protocol Deviations ...................................................................... 21 
6.1.4. 
Prior and Concomitant Medications ............................................. 21 


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6.1.5. 
Prior Anti-cancer Therapy ............................................................ 21 
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic .................. 21 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 22 
6.2.1. 
Criteria for Potential Clinical Importance ...................................... 22 
6.2.1.1. 
ECG ........................................................................... 22 
6.2.1.2. 
Vital Signs .................................................................. 22 
6.2.2. 
Study Period ................................................................................ 23 
6.2.2.1. 
Treatment Emergent Flag for Adverse Events ............ 23 
6.2.3. 
Study Day and Reference Dates .................................................. 23 
6.2.4. 
Assessment Window ................................................................... 24 
6.2.5. 
Multiple measurements at One Analysis Time Point .................... 24 
6.2.6. 
Handling of Partial Dates ............................................................. 25 
6.2.7. 
Trademarks ................................................................................. 28 
7.
REFERENCES ....................................................................................................... 29 


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LIST OF TABLES 
PAGE 
No table of figures entries found. 


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VERSION HISTORY 
SAP Version 
Approval Date 
Protocol 
Version 
(Date) 
on which 
SAP is 
Based 
Change 
Rationale 
SAP 
13-JUN-2022
1.0 (25-
JAN-
2022) 
Not 
Applicable 
Original version 
Amendment 1 16-FEB-2024
1.0 (25-
JAN-
2022) 
Removal of 
Part 2 
analysis and 
adjustments 
to Part 1 
analysis to 
algin with 
study 
termination 
Study termination 
Amendment 2 24-FEB-2025
1.0 (25-
JAN-
2022) 
Correct data 
error in 
version 
history 
table 
Study Closure 


 
 
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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report (CSR) for Study 209809.  Due to the termination of this study, only the 
planned Part 1 analyses described in the protocol will be produced for a synoptic CSR.  
Additional details with regards to data handling conventions and the specification of data 
displays will be provided in the Output and Specification (OPS) document. Additional 
data will be available to view via RAPIDO DV (for more details see OPS). 
1.1. 
Objectives, Estimands and Endpoints 
Dose Escalation  
 
Objectives 
Endpoints 
Primary 
• 
To determine the safety, tolerability, 
and RP2D of a daily dosing schedule 
(induction) of GSK3745417   
• 
Frequency and severity of 
Adverse Events (AEs), Serious 
Adverse Events, (SAEs), Dose 
Limiting Toxicity (DLT), 
withdrawals due to AEs  
Secondary 
• 
To characterize the pharmacokinetics 
(PK) of GSK3745417, and relevant 
metabolites, as applicable, after single 
and repeat-dose administration. 
• 
GSK3745417 concentrations in 
plasma or PK parameters 
Exploratory 
 
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Dose Escalation  
 
Objectives 
Endpoints 
 
 
 
 
 
Estimands will not be considered for this first-time-in-human (FTIH) study. 
 
CCI


 
 
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1.2. 
Study Design 
Overview of Study Design and Key Features 
Part 1 Induction Intra-patient Dose-Escalation Study   
 
Part 1: Dosing and Observation Timeline for Each Cycle    
 
Design 
Features 
• 
This is a Phase 1 open-label study of intravenous GSK3745417 to evaluate 
safety, tolerability, pharmacokinetics, pharmacodynamics and determine 
RP2D and schedule in participants with relapsed or refractory acute myeloid 
leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS).  
 
• 
The study will be conducted in a staged approach consisting of 2 parts. Part 
1 represents dose escalation to determine a cohort level MTD and 
incorporates intra-patient dose escalation within cohorts to minimize the 
potential for a participant to be exposed to a non-efficacious sub-therapeutic 
dose. Due to termination of this asset, Part 2 of this study will not be 
conducted. 
 
• 
The total duration of study participation begins with the signing of the 
informed consent form (ICF) and continues through the final protocol-defined 
follow-up assessment period. The maximum duration of study participation 
will depend on the participant’s duration of study intervention.  
  


 
 
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Overview of Study Design and Key Features 
Study 
intervention 
• 
Part 1 will evaluate a dosing schedule of a 5 days on/2 days off schedule for 
2 weeks, and then have an additional 2 weeks off dose for observation for a 
total of 28 days in each cycle (5 / 2 / 5 q28d). Once an MTD has been 
established, additional cohorts may be opened to refine dosing frequency 
optimization. Each cohort will include at least 3 participants. Part 1 will 
include intra-patient dose escalation for 3 cycles, according to safety and 
tolerability parameters. The starting dose for Cycle 1 will be escalated in the 
next dose escalation cohort until a cohort level MTD is reached.  
 
• 
After 3 induction cycles, if a CR or PR (per appropriate response criteria) is 
observed, each patient will continue with maintenance weekly dosing at the 
Cycle 3 dose level until disease progression or unacceptable toxicity. 
Participants with progressive disease after 3 induction cycles will be 
withdrawn from study. Participants with stable disease or PR after 3 cycles 
might receive additional cycles. 
Study 
intervention 
Assignment 
• 
This is a FTIH, open-label, non-randomized study. 
2. 
STATISTICAL HYPOTHESES  
With respect to the primary objectives and endpoints of the dose escalation (Part 1), no 
specific statistical hypotheses are being tested. The primary focus will be on determining 
the RP2D for induction for further exploration based upon the safety, PK, and anticancer 
activity profiles of GSK3745417 alone.  
2.1. 
Multiplicity Adjustment 
Not applicable. 


 
 
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3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Screened 
• All participants who were screened for eligibility.  
• Study 
Population 
Enrolled 
• All participants who entered the study (who received 
GSK3745417 or underwent a post-screening 
procedure). Note: Screening failures (who never 
passed screening even if rescreened) and 
participants screened but never enrolled into the 
study (met eligibility but not needed) are excluded 
as they did not enter the study. 
• Study 
Population 
Safety 
• All participants who take at least 1 dose of study 
intervention. Participants will be analysed according 
to the intervention they actually received. 
• Study 
Population 
• Safety 
• Efficacy 
 
DLT-evaluable 
• All participants who take at least 1 dose of study 
intervention and are followed for the DLT 
observation period or are withdrawn within the DLT 
observation period due to meeting the DLT criteria. 
• Participants unable to receive at least 70% of 
scheduled doses within the DLT period for other 
reasons other than toxicity will not be considered 
evaluable 
• Safety 
PK  
• All participants from the Safety Analysis Set for 
whom a PK sample is obtained and analysed. 
• PK 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
The Safety Analysis Set will be used for all study population, efficacy, and safety 
analyses, unless otherwise specified. AE and PK related tables, listings and figures will 
be summarized by dose level. Study population and efficacy tables and listings will be 
summarized by treatment sequence. 
The DLT-evaluable Analysis Set will be used for assessment of dose-limiting toxicities.  
Confidence intervals will use 95% confidence levels unless otherwise specified.  


 
 
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Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (std), median, minimum, and maximum. 
Categorical data will be summarized as the number and percentage of participants in each 
category. 
4.1.2. 
Baseline Definition 
For all endpoints (except as noted in baseline definitions), the baseline value will be the 
latest pre-dose of GSK3745417 assessment with a non-missing value, including those 
from unscheduled visits, if available. If time is not collected, Day 1 assessments are 
assumed to be taken prior to first dose and used as baseline.  
 
For laboratory data, baseline will be the latest non-missing pre-dose value.  
 
For ECG analyses, if the latest, non-missing pre-dose values is from triplicate, the subject 
level baseline is defined as the mean of triplicate baseline assessments.  
 
Unless otherwise stated, if baseline data are missing, no derivation will be performed, and 
baseline will be set to missing. 
 
4.2. 
Primary Endpoint(s) Analyses 
4.2.1. 
Definition of endpoint(s) 
An AE is considered a DLT if it is considered by the investigator to be clinically relevant 
and attributed (definitely, probably, or possibly) to the study intervention and meets at 
least 1 of the criteria listed in Table 7 of the protocol. If an AE is considered related to the 
underlying disease, it is not a DLT. The DLT period is 28 days starting at Day 1 of each 
cycle. The analysis of DLTs will be based on the DLT-Evaluable Analysis Set, unless 
otherwise specified. 
The definitions of an AE or Serious Adverse Event (SAE) can be found in Appendix 3 of 
the protocol. AEs will be reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant's legally authorized representative). The analysis 
of AEs and SAEs will be based on the Safety Analysis Set, unless otherwise specified.  
4.2.2. 
Main analytical approach 
Adverse events analyses including the analysis of AEs, SAEs, and other significant AEs 
will be based on GSK Core Data Standards. Summary tables will focus on treatment-
emergent AEs (TEAE) only. Details on treatment-emergent AEs are provided in Section 
6.2.2. AEs will be coded using the standard MedDRA and grouped by system organ class 


 
 
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(SOC). AEs will be graded by the investigator according to the NCI-CTCAE (version 
5.0). 
A summary of treatment-emergent adverse events by system organ class and preferred 
term and maximum grade will be produced. A summary of common non-serious TEAEs 
that occurred in strictly 10% of the participants or above will be provided (no rounding 
for the percentage will be used in terms of 10% threshold, e.g., events with 9.9% 
incidence rate should not be included in this table). A summary of common (>=10%) 
TEAEs by overall frequency. The summary of common non-serious AEs will be grouped 
by SOC and PT. A summary of common adverse events by overall frequency will be 
produced. 
 
The summary will use the following algorithms for counting the participant: 
 
Preferred term row: Participants experiencing the same AE preferred term several times 
with different grades will only be counted once with the maximum grade. 
 
Any event row: Each participant with at least one adverse event will be counted only 
once at the maximum grade no matter how many events they have. 
The date of the first occurrence of an AE will be used to indicate which dose level an AE 
should be reported in.  
A study treatment-related AE is defined as an AE for which the investigator classifies the 
relationship to study treatment as “Yes”. A worst-case scenario approach will be taken to 
handle missing relatedness data, i.e., the summary table will include events with the 
relationship to study treatment as ‘Yes’ or missing. Study treatment-related AEs will be 
summarized by SOC, PT, and maximum grade. An overall frequency summary of non-
serious drug related treatment emergent adverse events will also be produced.  
 
Serious TEAEs will be summarized by SOC, PT, and maximum grade, as well as a 
separate summary of serious TEAEs by SOC and PT (Number of subjects and 
Occurrences). A separate summary of serious fatal and non-fatal drug-related treatment 
emergent by overall frequency will be created for disclosure requirements to regulatory 
agencies, displayed by PT. 
Additionally, a summary of the number of patients experiencing DLTs in each cohort will 
be provided for the dose escalation period. DLTs will be summarized according to GSK 
Oncology Data Standards. 
 
All AEs (including SAEs and subject IDs for each individual AE) will be listed. A listing 
of reasons for considering as a serious adverse event will be generated.  


 
 
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4.3. 
Secondary Endpoint(s) Analyses 
4.3.1. 
Key secondary endpoint(s) 
4.3.1.1. 
Definition of endpoint(s) 
The following PK parameters will be determined if data permit:  
• Cmax, Cmin, and Tmax 
• Area under the plasma concentration-time curve (AUC(0-t), AUC(0-τ), [repeat 
dosing]])  
• Apparent terminal phase elimination rate constant (z) (single dose) 
• Apparent terminal phase half-life (t1/2) (single dose)  
• Systemic clearance of parent drug (CL)  
• Volume of distribution (V)  
• Other parameters and analyses as appropriate and data permits, such as dose 
proportionality and time-invariance.  
 
4.3.1.2. 
PK Evaluation 
Pharmacokinetic parameters for GSK3745417 administered IV in this study will be 
calculated by standard non-compartmental analysis according to current working 
practices and using the currently supported version of Phoenix WinNonlin. 
 
Analysis procedures will follow GSK VQD-REF-015788 unless otherwise noted below. 
All calculations of non-compartmental parameters will be based on actual sampling 
times. PK analysis of GSK3745417 will be the responsibility of the Clinical 
Pharmacology Modeling and Simulation (CPMS) Department, GSK. PK analysis of 
GSK3745417 drug concentration-time data will be conducted by noncompartmental 
methods under the direction of CPMS, GSK. 
Statistical analyses of the PK parameters data will be the responsibility of Clinical 
Statistics, GSK. All PK analyses will be performed on the PK Analysis Set. 
 
Drug concentration-time data will be listed for each participant and summarized by 
descriptive statistics at each time point by dose. PK parameter data will be listed for each 
participant and summarized by descriptive statistics by dose and visit.  
All derived PK parameters will be summarised using descriptive statistics, graphically 
presented (where appropriate) and listed. For each of these parameters, except Tmax, the 
following summary statistics will be calculated for each dose level and treatment day: 
median, minimum, maximum, arithmetic mean, 95% CI for the arithmetic mean, std, 
coefficient of variation (%CV = 100*(sqrt (exp(SD2) - 1))) (where SD = SD of natural 
log transformed data), geometric mean, 95% confidence interval for the geometric mean 
and std of natural logarithmically transformed data. For Tmax, median, maximum, 
minimum, arithmetic mean, 95% CI, and std will be calculated. The first point, last point 


 
 
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and number of points used in the determination of λz will be included on the listing of the 
derived parameters. 
All PK parameters will be reported to at least 3 significant digits, but to no more 
significant digits than the precision of the original data. 
The data from this study may be combined with the data from other studies for a 
population PK analysis and/or exposure-response analysis, which will be reported 
separately. 
The following PK statistical analyses will only be performed if sufficient data are 
available (i.e., if participants have well defined serum profiles). Analyses may not be 
performed on Cmax or AUC if the team considers there are a large amount of data either 
below the limit of quantification or non-calculable; alternatively, if the dose with limited 
data is at the lower end of the dose range, the data of this dose will be excluded, and the 
appropriate analysis conducted on the rest of the data. However, if there are non-
calculable PK parameter data at intermittent doses no statistical analyses will be 
performed. A minimum of 3 doses will be required to assess dose proportionality. 
Dose proportionality of GSK3745417 will be assessed by visual inspection of: 
• Scatter plots (+geometric mean and 95% confidence intervals, as appropriate) of 
GSK3745417 dose-normalized PK parameter vs dose will be produced for [or 
AUC(0-t) and Cmax. 
• Scatter plots of GSK3745417 log10 PK parameter vs log10 dose will be produced for 
AUC(0-t) and Cmax. 
The PK parameters will be dose-normalized by the actual dose that each patient received 
(i.e., Cmax/actual dose). 
Other PK figures may be produced if deemed appropriate.  
4.3.2. 
Supportive secondary endpoint(s) 
The list of terms for adverse events of special interest (AESI) is in Appendix 4 of the 
protocol and includes events that may be immune-related or related to cytokine release 
syndrome (CRS) or tumor lysis syndrome (TLS). AESIs and the type of event will be 
recorded in the CRF.  
The list of AESIs is provided below and may be updated at the time of database lock 
based on the MedDRA version in use at the time of reporting and/or any additional safety 
information available from GSK that may determine a need to consider additional events 
of interest.  


 
 
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Cytokine-related AEs  
Cardiopulmonary or hemodynamic toxicity starting within 24 hours of study treatment 
that requires >40% FiO2, vasopressor administration, antiarrhythmic agent, or other 
significant medical intervention. Asystole, as measured by ECG, or bradycardia that is 
symptomatic and requires medical intervention. Some of the MedDRA preferred terms 
relevant to cytokine-related AEs include cytokine release syndrome, cytokine storm, 
cytokine increased and systemic inflammatory response syndrome. 
Immune-related AEs 
Pneumonitis (reported as AESI if  ≥ Grade 2) 
Acute interstitial 
pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as AESI if ≥ Grade 2 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis 
hemorrhagic 
Gastrointestinal 
perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as AESI if  ≥ Grade 3 or ≥ Grade 2 and resulting in dose 
modification or use of systemic steroids to treat the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with 
ketosis or metabolic acidosis (DKA) 
Endocrine (reported as AESI) 
Type 1 diabetes mellitus (if 
new onset) 
 
 
Hematologic (reported as AESI if  ≥ Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
Autoimmune hemolytic 
anemia  
Aplastic anemia  
Thrombotic 
Thrombocytopenic 
Purpura (TTP) 
Idiopathic (or immune) 
Thrombocytopenia Purpura  
(ITP) 
Disseminated 
Intravascular 
Coagulation (DIC) 
Hemolytic Uremic 
Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as AESI if  ≥ Grade 2, or any grade resulting in dose modification 
or use of systemic steroids to treat the AE) 
Hepatitis  
Autoimmune hepatitis  
Transaminase elevations 
(ALT and/or AST) 
Infusion Reactions (reported as AESI for any grade) 
Allergic reaction 
Anaphylaxis 
CRS 
Serum sickness 
Infusion reactions 
Infusion-like reactions 


 
 
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Neurologic (reported as AESI for any grade) 
Autoimmune neuropathy 
Guillain-Barré syndrome 
Demyelinating 
polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as AESI if  ≥ Grade 2 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as AESI if  ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as AESI if ≥Grade 3 or 
any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Skin (reported as AESI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson 
syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as AESI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment  
Other (reported as AESI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
Summaries of the number and percentage of subjects with treatment-emergent AESIs will 
be provided for each type of event separately by PT and maximum grade. A summary of 
the number of participant and occurrences of treatment-emergent cytokine release 
syndrome adverse events and infusion related reactions will be produced. These 
summaries will be based on data as recorded in the eCRF.  
4.4. 
Exploratory Endpoint(s) Analyses 
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4.5. 
Other Safety Analyses 
The safety analyses will be based on the Safety Analysis Set, unless otherwise specified. 
4.5.1. 
Extent of Exposure 
Exposure to GSK3745417 will be summarized according to cumulative actual dose, 
number of cycles, time on study treatment (weeks) with separate sections for induction 
dosing and maintenance dosing in one table. Descriptive statistics including mean, 
median, standard deviation, minimum, and maximum will be calculated.  
The cumulative dose, converted to and displayed in mg, is the sum of the actual dose 
administered in micrograms during each infusion for a subject throughout the study. For 
induction dosing, cumulative dose will be summarized by cycle. For induction cycles, the 
number of cycles will be calculated by the number of GSK3745417 doses received 
during the induction phase divided by 10. For subsequent maintenance cycles, the 
number cycles will be calculated by (last maintenance infusion date – first maintenance 
infusion date + 7)/28. 
Subject level details for extent of exposure to study treatment will be listed. The listing 
will include cycle, total dose taken per cycle, cycle day, start and stop dates, scheduled 
dose, actual dose, and cumulative dose. Exposure data will be listed in both units (mg and 
μg). 
4.5.2. 
COVID-19 
4.5.2.1. 
COVID-19 Assessment and COVID-19 AEs 
A standardized MedDRA Query (SMQ) will be used to identify all COVID-19 AEs. 
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4.5.2.2. 
Impact of COVID-19 Pandemic on Safety Results 
Since all subjects are dosed after the pandemic started, the outputs showing the incidence 
rates for events occurring before or after the start of the COVID-19 pandemic are not 
applicable. 
 
4.5.3. 
Additional Safety Assessments 
Any additional safety data will be produced using listings via RAPIDO data viewer. This 
includes a listing of liver monitoring/stopping event reporting, liver stopping event 
profile, ECOG performance status, and LVEF.  
4.5.4. 
Deaths 
All deaths will be summarized based on the number and percentage of participants. This 
summary will classify participants by time of death relative to the last dose of medication 
(>30 days or 30 days) and primary cause of death in the order listed in the eCRF. A 
supportive listing will be generated to provide participant-specific details on participants 
who died. 
4.5.5. 
Pregnancies 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE.  
4.6. 
Other Analyses 
Data from all participating centres will be integrated and no controlling for center-effect 
will be considered in the statistical analyses.   
4.7. 
Interim Analyses 
Due to study termination, no interim analyses will be conducted.  
4.8. 
Changes to Protocol Defined Analyses 
Study termination occurred just as Part 1 (dose escalation) had finished recruitment. 
Therefore, no participants will be recruited to Part 2 of study design mentioned within the 
protocol (Dated: 25-Jan-2022) and hence no data will be collected or analysed. 
Additionally, no interim analyses will occur as there is no need to initiate Part 2.  


 
 
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5. 
SAMPLE SIZE DETERMINATION 
Approximately 72 participants were planned to be enrolled to receive study intervention. 
The planned sample size for the study was chosen to allow adequate characterization of 
safety, clinical activity, PK, and PD profile based on the study objectives. For Part 1 dose 
escalation, the total sample size will depend on the number needed to adequately 
characterize the DLT profile and determine the MTD. For Part 2 dose expansion, 
approximately 50 participants were planned to be recruited. Refer to Section 9.2 of the 
protocol for details regarding sample size determination, statistical design, and operating 
characteristics.   


 
 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the study population analyses will be based on the Safety 
Analysis Set.  
In this multicentre global study, enrolment will be presented by country and site. 
6.1.1. 
Participant Disposition 
A summary of the number and percentage of participants who completed the study as 
well as those who prematurely withdrew from the study or died will be provided. 
Reasons for study withdrawal will be listed. For those who have neither completed, died, 
nor withdrawn, they will be categorized as on study intervention or in follow up.  
A participant is considered to have completed the study if they have completed all phases 
of the study including the last visit or the last scheduled procedure shown in the Schedule 
of Activities (Section 1.3 of the protocol). In addition, if the sponsor decides to close the 
study, participants who are receiving study intervention or are in the follow-up period 
will be considered to have completed the study. 
A summary of study intervention status will be provided. This display will show the 
number and percentage of participants who have completed the scheduled study 
intervention, are ongoing with study intervention, died, or have discontinued study 
intervention prematurely, as well as primary reasons for discontinuation of study 
intervention. Reasons for study treatment discontinuation will be listed.  
A listing of reasons for screen failure will be provided using the screened population. A 
listing of subjects excluded from any population, and a listing of subjects with 
inclusion/exclusion criteria deviations will be reported.  
 
6.1.2. 
Demographic and Baseline Characteristics 
The demographic characteristics including age, gender, ethnicity, height/weight at 
screening and race will be summarized with descriptive statistics using the Safety 
population. In addition, the following age categories will be summarized: 18-64, 65-84 
and >=85 based on the Enrolled Analysis Set. 
Disease characteristics at screening including primary tumor type, time since initial 
diagnosis, disease classification (WHO classification of AML or MDS and IPSS-R 
category), blast count percentage, and cytogenetics and molecular alterations will be 
summarized and listed. The following genetic markers have been identified by the study 
team for inclusion in displays: IDH1, IDH2, NPM1, FTL3, NRAS, c-KIT, TP53, 
CEBPA. 


 
 
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6.1.3. 
Protocol Deviations 
Important protocol deviations will be listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
• 
Data will be reviewed prior to freezing the database to ensure all important 
deviations (where possible without knowing the study intervention details) are 
captured and categorised in the protocol deviations dataset.  
• 
This dataset will be the basis for the summaries of important protocol deviations. 
 
6.1.4. 
Prior and Concomitant Medications 
Concomitant medications will be coded using the WHO Drug dictionaries. A listing of 
concomitant medications using ingredient will be produced.   
Concomitant medications include any medication that was taken at some point during the 
on-intervention period as defined in Section 6.2.1.1. 
6.1.5. 
Prior Anti-cancer Therapy 
The number and percentage of participants that received any prior anti-cancer therapy or 
stem cell transplant will be summarized. Prior anti-cancer therapy will be summarized by 
ingredient.  
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic 
The incidence of AEs and SAEs (fatal and non-fatal) of COVID-19, COVID-19 AEs 
leading to study drug discontinuation or study withdrawal, and COVID-19 AEs by 
severity, will be obtained from standard AE and SAE summaries. 
Since all subjects are dosed after the pandemic started and the outputs showing the 
incidence rates for events occurring before or after the start of the COVID-19 pandemic 
are not applicable. 
 


 
 
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6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Criteria for Potential Clinical Importance 
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory. A laboratory value that is outside the reference range is 
considered either high abnormal (value above the upper limit of the reference range) or 
low abnormal (value below the lower limit of the reference range). Note: a high abnormal 
or low abnormal laboratory value is not necessarily of clinical concern.  
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE v4.0.3) will be used to assign grades to the relevant laboratory parameters, 
including clinical chemistry, hematology, coagulation, liver function tests, QTc 
(Fridericia’s) values, and vital signs (heart rate, blood pressure, temperature, respiratory 
rate). 
6.2.1.1. 
ECG 
ECG Parameter 
Units 
 
Clinical Concern Range 
 
Lower 
Upper 
 
Absolute 
Absolute QTcF Interval 
msec 
Grade 1 
≥ 450 
< 481  
Grade 2 
≥ 481  
< 501 
Grade 3 
≥ 501  
 
 
Change from Baseline 
Increase from Baseline 
QTcF 
msec 
 
> 30   
≤ 60   
msec 
 
> 60   
 
 
6.2.1.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
 
Clinical Concern Range 
 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
Grade 1 
≥120   
<140 
 
mmHg 
Grade 2 
≥140   
<160 
 
mmHg 
Grade 3 
≥160  
 
Diastolic Blood 
Pressure 
mmHg 
Grade 1 
≥ 80   
< 90 
 
mmHg 
Grade 2 
≥ 90  
< 100 
 
mmHg 
Grade 3 
≥ 100  
 
Heart Rate 
bpm 
L/H 
< 60 
> 100 
Temperature 
Degrees C 
L/H 
≤ 35 
≥ 38 
Respiratory Rate 
Breaths/min 
L/H 
<12 
≥ 25 
 


 
 
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6.2.2. 
Study Period 
Assessments and events will be classified according to the time of occurrence relative to 
the study intervention period.  
Pre-Intervention is defined as time prior to the first dose of study intervention. 
On-Intervention is defined as time from first dose to last date plus 30 days. If time of 
assessment or study intervention is not collected, the following assessment on the first 
dose date will be assumed to be taken prior to the first dose and therefore considered pre-
intervention: ECOG, ECG, Lab, and vital signs, and first dose date is considered on-
intervention for AE and concomitant medication. 
Post-Intervention is defined as any time post on-intervention window, i.e. > last dose 
date + 30 days. 
Anti-cancer therapy will be classified as either prior to screening or following study 
treatment as per GSK Display Standards. 
6.2.2.1. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
For AEs: 
• 
Study Treatment Start Date ≤ AE Start Date ≤ Treatment Discontinuation 
Visit or Study Treatment Stop Date + 30 Days if TDV is missing 
• 
AE Start Date is missing 
 
For SAEs/AESIs: 
• 
Study Treatment Start Date ≤ AE Start Date or pre-existing (prior to 
exposure) AE Worsening Date ≤ Study Treatment Stop Date + 90 days or 
Start of Anti-Cancer Therapy, whichever occurs first 
• 
AE Start Date is missing 
 
• 
Missing AE Start Date will be imputed following rules in Appendix 2 for 
determining Treatment Emergent AEs. 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
 
 
6.2.3. 
Study Day and Reference Dates 
The safety reference date is the study intervention start date and will be used to calculate 
study day for safety measures.  
The efficacy reference date is the study intervention start date and will be used to 
calculate study day for efficacy measures and baseline characteristics, as well as efficacy 
durations.  


 
 
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The study day is calculated as below: 
• 
Assessment Date = Missing              → Study Day = Missing  
• 
Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• 
Assessment Data ≥ Reference Date → Study Day = Assessment Date – Ref Date + 1     
6.2.4. 
Assessment Window  
For data summaries by visit, the nominal visit description will be used.  
For PK data, the data from unscheduled visits will be slotted as follows: 
Elapsed time from dose to start of PK sample collection(ARELTM) in hours is calculated 
as = (start datetime of PK sample collection – reference dose datetime) /3600.  
 
Elapsed time from dose to start of PK sample collection(ARELTM) in minutes is 
calculated as = (start datetime of PK sample collection – reference dose datetime) /60. 
 
 Slotting algorithm if elapsed time(ARELTM) is in minutes: 
• 0 < ARELTM <= 1, ARELTM = 1 min 
• 1< ARELTM < =5, ARELTM = 5 min 
• 5 < ARELTM <=15, ARELTM = 15 min 
• 25 <= ARELTM <=35, ARELTM = 30 min 
• 40<=ARELTM<=50, ARELTM = 40 min 
 
Slotting algorithm if elapsed time (ARELTM) is in hours: 
• 0.75 <= ARELTM <=1.25, ARELTM = 1 hr 
• 1.50 <= ARELTM <=2.50, ARELTM = 2 hrs 
• 3 <= ARELTM < =5, ARELTM = 4 hrs 
• 7 <= ARELTM < =9, ARELTM = 8 hrs 
• 22 <= ARELTM < =26, ARELTM = 24 hrs 
 
6.2.5. 
Multiple measurements at One Analysis Time Point 
Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented (including the mean). For PK data, if there 
are multiple records observed at the same date and time for a subject, those data will be 
excluded from the WNL file and will not be used for the derivation of PK parameters. 
 
Participants having both High and Low values for Normal Ranges at any post-baseline 
visit for safety parameters will be counted in both the High and Low categories of “Any 
visit post-baseline” row of related summary tables. This will also be applicable to 
relevant Potential Clinical Importance summary tables. 


 
 
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6.2.6. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays.   
• 
However, where necessary, display macros may impute dates as temporary variables 
for sorting data in listings only. In addition, partial dates may be imputed for ‘slotting’ 
data to study phases or for specific analysis purposes as outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to onset or duration 
(e.g., time to onset or duration of adverse events), or elapsed time variables (e.g., time 
since diagnosis). In addition, imputed dates are not used for deriving the last contact 
date in overall survival analysis dataset. 
Adverse 
Events 
• 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
Missing start day 
If study intervention start date is missing (i.e., participant did 
not start study intervention), then set start date = 1st of month. 
Else if study intervention start date is not missing: 
• 
If only a single dose level was given in the same month, 
then AE start date = 1st of the month or treatment start 
date (whichever is later). 
• 
If more than one dose level was given in the same month 
as the AE start date, then, 
− If AE end date contains a full date and AE end date is 
earlier than study intervention start date of the 
highest dose given that month, then set AE start 
date= 1st of month. 
− If AE end date contains a full date and AE end date is 
later than the study intervention start date of the 
highest dose given that month, then AE start date = 
study intervention start date of highest dose given 
that month. 
− If AE end date is missing, then set AE start date as 
the study intervention start date of the highest dose 
given that month. 
Else set start date = 1st of month. 
Missing start day 
and month 
If study intervention start date is missing (i.e., participant did 
not start study intervention), then set AE start date = January 
1. 
Else if study intervention start date is not missing: 
• 
If year of AE start date = year of study intervention start 
date, then 


 
 
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Element 
Reporting Detail 
− If AE stop date contains a full date and AE stop date 
is earlier than study intervention start date, then set 
AE start date = January 1. 
− If AE stop date contains a full date and AE stop date 
is later than study intervention start date, then set 
start date = study intervention start date of most 
recent dose level given prior to the AE stop date.   
Else set AE start date = January 1. 
Missing end day  
A '28/29/30/31' will be used for the day (dependent on the 
month and year). 
Missing end day 
and month 
No Imputation 
Completely 
missing start/end 
date 
No imputation. Consequently, time to onset and duration of 
such events will be missing. 
Concomitant 
Medications/
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
Missing start day 
If study intervention start date is missing (i.e., participant did 
not start study intervention), then set start date = 1st of month. 
Else if study intervention start date is not missing: 
• 
If month and year of start date = month and year of 
study intervention start date, then 
− If stop date contains a full date and stop date is 
earlier than study intervention start date, then set 
start date= 1st of month. 
− Else set start date = study intervention start date. 
Else set start date = 1st of month. 
Missing start day 
and month 
If study intervention start date is missing (i.e., participant did 
not start study intervention), then set start date = January 1. 
Else if study intervention start date is not missing: 
• 
If year of start date = year of study intervention start 
date, then 
− If stop date contains a full date and stop date is 
earlier than study intervention start date, then set 
start date = January 1. 
− Else set start date = study. intervention start 


 
 
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Element 
Reporting Detail 
date.       
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the 
month and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for the 
month. 
Completely 
missing start/end 
date 
No imputation 
Prior Anti-
cancer 
Therapy/Radi
othe 
rapy/Surgical 
Procedures/S
tem Cell 
Transplant 
Start and end dates are generally not imputed. If start or end dates need to be imputed for 
an analysis (e.g., to calculate duration of prior therapy or elapsed time as covariates for 
efficacy analyses), following rules will be applied. Imputed dates are not used for summary 
of anti-cancer therapy or radiotherapy. 
• 
If start/end date is completely missing or both day and month are missing, no 
imputation will be applied 
• 
If day is missing for start date, first of the month will be used 
• 
If day is missing for stop date,  
o If first dosing date is the first of the month, minimum of dates (impute last 
day of the partial date month to partial date, first dosing date) will be 
used 
• 
Else minimum of dates (impute last day of the partial date month to partial date, 
first dosing date - 1) will be used 
New Anti-
cancer 
Therapy/ 
Radiotherapy/ 
Surgical 
Procedures/C
ross over for 
Efficacy 
Evaluation 
(e.g., 
response 
rate, time to 
event) 
Start dates for follow-up anti-cancer therapy, radiotherapy (where applicable), stem cell 
transplant, and surgical procedures (where applicable) will be imputed in order to define 
event and censoring rules for progression-free survival, response rate, or duration of 
response (i.e. start date for new anti-cancer therapy). Dates will only be imputed when a 
month and year are available, but the day is missing. The following rules will be used to 
impute the date when partial start dates are present on anti-cancer therapy, radiotherapy, 
stem cell transplant, and/or surgical procedures dataset[s]: 
• 
Completely missing start dates will remain missing, with no imputation applied;  
• 
Partial start dates will be imputed using the following convention: 
o If both month and day are missing, no imputation will be applied;  
o If only day is missing:  
▪ 
If the month of partial date is the same as the month of last dosing 
date, minimum of dates (last dosing date + 1, impute last day of the 
partial date month to partial date) will be used for the day;  
▪ 
If the month of partial date is the same as the month of last disease 
assessment and the last disease assessment is PD for MDS 
(Recurrences for AML), minimum of dates (last date of disease 
assessment + 1, impute last day of the partial date month to partial 
date) will be used for the date;  
▪ 
If both conditions above are met, the later date will be used for the 
day;  
▪ 
Otherwise, a ‘01’ will be used for the day;  


 
 
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Element 
Reporting Detail 
• 
Completely or partial missing end dates will remain missing, with no imputation 
applied. 
 
6.2.7. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 


 
 
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7. 
REFERENCES 
NA