Clinical trial NCT03614728
Conditions: Neoplasms
Keywords: Acute myeloid leukemia Myelodysplastic syndrome Chronic myelomonocytic leukemia GSK3326595 5-Azacitidine
Sponsor: GlaxoSmithKline
Start date: 2018-10-16; Completion date: 2022-01-11
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will evaluate the safety, tolerability, and clinical activity of GSK3326595 in participants with relapsed and refractory MDS, chronic myelomonocytic leukemia (CMML), and AML. The study will be conducted in 2 parts: Part 1 will determine the clinical benefit rate (CBR) of GSK3326595 in monotherapy and Part 2 will be expanded to study GSK3326595 in combination with 5-Azacitidine which will be composed of a dose escalation phase followed by dose expansion cohort of GSK3326595.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: GSK3326595 intervention 2: 5-Azacitidine
Intervention descriptions: intervention 1: GSK3326595 will be administered. intervention 2: 5-Azacitidine will be administered.

Protocol documents:
Prot_000.pdf: 
TMF-11785988 
CONFIDENTIAL 
GlaxoSmithKline group of companies 
208809 
1
TITLE PAGE 
Protocol Title: A Phase I/II study to investigate the safety and clinical activity of 
GSK3326595 and other agents in participants with myelodysplastic syndrome and acute 
myeloid leukaemia. 
Protocol Number: 208809/Amendment 3 
Compound Number: 
GSK3326595 
Study Phase: Phase I/ Phase II 
Short Title: Phase I/II Study of GSK3326595 and other agents to treat myelodysplastic 
syndrome (MDS) and acute myeloid leukaemia (AML) 
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: 151531 
Approval Date: 15-FEB-2021 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
2 
 
SPONSOR SIGNATORY 
Protocol Title:  A Phase I/II study to investigate the safety and clinical activity of 
GSK3326595 and other agents in participants with myelodysplastic syndrome and acute 
myeloid leukaemia. 
Protocol Number: 208809/Amendment 3 
Compound Number 
or Name: 
GSK3326595  
 
 
Eleftherios Zografos, MD/PhD  
Program Physician Lead 
 
Date 
The signed page is a separate document. 
 
 
 
 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
 
 
 
 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
3 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 03 
15-FEB-2021 
TMF-11785988 
Amendment 02 
21-APR-2020 
2017N345622_05 
Amendment 01 
12-JUN-2019 
2017N345622_04 
Republishing 
16-JUL-2018 
2017N345622_03 
Republishing 
22-JUN-2018 
2017N345622_02 
Republishing 
22-MAY-2018 
2017N345622_01 
Original Protocol 
09-MAY-2018 
2017N345622_00 
 
Amendment 3: 15-FEB-2021 
Overall Rationale for the Amendment:  
The primary driver for the protocol amendment is to discontinue further development 
with monotherapy GSK3326595 based on clinical activity meeting pre-specified futility 
criteria as specified in the Protocol (Part 1), while continuing to explore GSK3326595 in 
combination with 5-Azacitidine in the Part 2 Dose Escalation and Dose Expansion 
cohorts.  The Part 2 Dose Escalation design of GSK3326595 with 5-Azacitidine is 
amended to include intermittent dose schedules of GSK3326595 in relapsed / refractory 
MDS, CMML and AML participants.  Part 2 Dose Expansion cohorts will include 
treatment naïve MDS and CMML participants.  
The other main driver for this protocol amendment is the inclusion of additional 
prohibited medications (strong / moderate inhibitors or inducers of MATE2-K, OAT3 
and OCT2 transporters) listed in the latest supplement to the Investigator Brochure (cut 
off date 04 February 2020), as it has been identified that GSK3326595 is a substrate of 
MATE2-K, OAT3 and OCT2 uptake transporters; therefore, there is potential for drug-
drug interactions.  
Some non-clinical and clinical risk assessment and mitigation strategies (Section 2.3.2) 
for GSK3326595 have been updated. 
Other changes are detailed below. 
Updated literature with additional information for combination approaches with 
5-Azacitidine in the front line setting and preclinical models and response to PRMT5. 
Data from Interim Analysis of 300 mg Part 1 cohort has been added. 
Explanation for starting dose in Part 1 Dose Confirmation cohort and clarification for 
dose change has been added. 
Clarification on the N-CRM design for Part 1 has been added. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
4 
 
Clarification of definition of DLT and Clinical Benefit Rate has been added. 
Clarification with regards to population, number of participants and endpoint in Part 2 
has been added. 
Statistical design and futility criteria in Part 2 has been revised. 
Inclusion of 25 mg capsules given doses potentially to be explored in Part 2 Dose 
Escalation. 
Clarification for tumor sample collection at baseline (14 days prior to first dose) has been 
added. 
Correction that Laboratory assessments collected until 30 days post last dose. 
Correction that all AE/SAE collected until 30 days post last dose. 
Clarification added: ‘for genomic testing done locally, any results and type of test to be 
recorded and provided’. 
Thyroid function tests (TSH, free T3 and free T4) has been added to Clinical Laboratory 
Tests (Appendix 2). 
Ophthalmology assessments and folate / B12 levels have been added to safety testing. 
The assessment of Patient Reported Outcomes (PROs) has been removed from the study. 
Clarification of IWG criteria as per Cheson 2006 has been added. 
Updates to inclusion of Appendix 13 outlining clinical study delivery under 
circumstances of pandemic caused by COVID19 in future. 
The Assessment of Intensity has been modified to remove mild/moderate/severe AE/SAE 
grading and replaces with NCI-CTCAE Version 4.0 criteria. 
Typographical errors have been corrected and minor editorial changes have been made. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
IND: 151531 
Regulatory agency identifying 
number has been updated. 
Sponsor Signatory 
Eleftherios Zografos, MD 
To update sponsor signatory. 
Section 1.1 Synopsis: 
Objective and Endpoints, 
Rationale, Overall Design 
2.1 Study Rationale, 4.1 
Overall Design, 4.1.3 Part 2: 
No further evaluation of 
GSK3326595 monotherapy 
will be explored in Study 
208809. Part 2A and Part 2C 
will not be progressed. Part 
2B (now referred to as Part 2) 
Given prespecified criteria 
(described in body of the 
protocol) were met, futility was 
declared for GSK3326595 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
5 
 
Section # and Name 
Description of Change 
Brief Rationale 
Further Exploration of Efficacy 
in Myeloid Neoplas, 4.3 
Scientific Rationale for study 
design 
will explore combination with 
GSK3326595 and 5-
Azacitidine in Dose Escalation 
with intermittent dosing in 
myeloid neoplasms as 
described in Section 5 and 
Dose Expansion cohorts in 
participants with newly 
diagnosed MDS or CMML.  
Explanation added regarding 
doses explored in study 
204653 in the study rationale. 
monotherapy in 
MDS/AML/CMML population.  
Intermittent dosing of 2 weeks 
on and 2 weeks off is 
introduced instead of 
continuous dosing in Part 2 as 
guided by data from safety, 
tolerability, PK, PD and given 
overlapping toxicities with 
GSK326595 and 5-
Azacitidine. 
Clarification of text, based on 
updated information 
 
Section 1.1 Synopsis, Number 
of Participants for Part 2;  
Section 4.1.3.1 Part 2: 5-
Azacitidine plus GSK3326595, 
Section 4.2 Number of 
Participants 
In Part 2 approximately 24 
participants will be enrolled in 
each dose escalation cohort 
(QD or BID) in schedule of 2 
weeks on and 2 weeks off. In 
Part 2 Dose Expansion, 
approximately 35 participants 
will be enrolled. 
Part 2A and Part 2C will not 
be progressed 
Part 2 design changes: Dose 
Escalation for each QD or BID 
will follow N-CRM design. Part 
2 Dose Expansion is based on 
Bayesian decision making 
approach. 
 
Section 1.1 Synopsis and 
Section 3: Objectives and 
Endpoints, Part 2  
 
• Removal of Part 2A and 
Part 2C Objectives as per 
decision to discontinue 
monotherapy development 
with GSK3326595 in Study 
208809. 
• Split of Part 2B objectives 
for Part 2 Dose Escalation 
and Part 2 Dose 
Expansion objectives 
• Change to primary 
endpoint for Part 2  Dose 
Expansion to Complete 
Remission Rate  
• Removal of PFS, OS, TTR 
from Part 2 Dose 
As explained above. 
In the pivotal AZA001 study in 
treatment naïve participants 5-
Azacitidine demonstrated 
significant improvement in OS 
compared to conventional 
care (Fenaux 2009). In 
addition 5-Azacitidine yielded 
improvement in ORR 
including CR rate. In an ad 
hoc analysis of AZA001 using 
the 2006 IWG criteria 
participants who achieved CR 
had the best OS compared to 
mCR or PR, and hence CR 
can be considered as a 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
6 
 
Section # and Name 
Description of Change 
Brief Rationale 
Escalation cohort 
exploratory objectives ( 
• In Part 2 Dose Expansion 
cohort objectives, PFS 
moved from secondary to 
exploratory endpoint 
• Inclusion of frequency of 
dose interruptions, dose 
reductions and treatment 
discontinuations due to 
adverse events as part of 
primary endpoint in Dose 
Escalation or secondary 
endpoint in Dose 
Expansion. 
• Removal of PROs 
surrogate endpoint for OS in 
higher-risk MDS pts 
(Komrokji, 2015). 
Frequency of dose 
interruptions, reductions and 
treatment discontinuations is 
an additional measure to 
determine safety, tolerability 
and recommended 
combination dose in Part 2. 
To reduce participant burden, 
hence exclusion of PRO 
1.2 Schema and Figure 3 
Part 2A and Part 2C will not 
be progressed. 
Part 2  will continue in 
combination with 5-Azacitidine 
in Dose Escalation Part as 
daily (QD) and twice daily 
(BID) cohorts in schedule of 2 
weeks on and 2 weeks off 
with GSK3326595. 5-
Azacitidine is administered as 
per prescribed information. 
Starting dose at QD cohort is 
200 mg, and at BID cohort 
100 mg. Once Recommended 
Combination dose and 
regimen is determined, dose 
expansion will be initiated in 
up to 35 participants. 
Rationale of Part 2A and Part 
2C as above. 
Proposed Dose Escalation 
schedule will explore both 
daily and twice daily dosing in 
a N-CRM design until 
maximum tolerated dose 
(MTD) is confirmed.  
Choice of patient population is 
explained in Section 5 of the 
Protocol and below. 
1.3 Schedule of Activities 
(SoA), Part 2  
Part 2A and Part 2C SoA is 
removed. 
Part 2 SoA is adapted to 
schedule of intermittent 
dosing of 2 weeks on and 2 
weeks off including additional 
PK and PD samples, PD 
samples collected at Week 9 
moved to Week 7 instead and 
Rationale of Part 2A and Part 
2C as above. 
Intermittent dosing rational as 
explained above. 
Additional PK samples 
collected as required for 
analysis. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
7 
 
Section # and Name 
Description of Change 
Brief Rationale 
footnote clarifications 
included. 
TSH, free T3 and free T4 is 
included as additional 
assessment at screening, 
Week 5 Day 1 and Week 9 
Day 1, every 8 weeks 
thereafter and EOT. 
Inclusion of ocular 
assessments and folate 
testing at BSL and on 
treatment. 
PROs are removed. 
Collection of diary from Day 1 
instead from Day 8 
AE/SAE and laboratory 
assessments collected until 
30 days post treatment  
Inclusion of requirement for 
Investigators to ask 
participants about vision 
symptoms at each routine visit 
and document responses 
Additional PD samples 
collected as required for 
analysis. 
It is hypothesized thyroid 
function may be related to 
fatigue observed as common 
adverse event, hence 
introduction for TSH, free T3 
and free T4 measurements. 
Ocular assessments and 
folate testing introduced to 
monitor a safety event 
observed. 
 
Section 2.2.1 Clinical 
Background: MDL and AML 
Inclusion of additional data 
and literature for combination 
approaches with 5-Azacitidine 
in front line setting 
Updated literature included 
Section 2.2.2.2 Spliceosomal 
Mutations and Potential 
Biomarkers for PRMT5 
Inhibition in Myeloid 
Neoplasms 
Inclusion of additional data 
from literature on preclinical 
models and response to 
PRMT5 
Updated literature included  
Section 2.2.3 Clinical 
experience with PRMT5 
inhibitors 
Addition of section to 
summarize experience with 
other clinical studies 
evaluating GSK3326595 and 
other PRMT5 inhibitors. 
Includes explanation of 
Additional information is 
available. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
8 
 
Section # and Name 
Description of Change 
Brief Rationale 
ophthalmology findings 
potentially related to 
GSK3326595. 
2.3.2 Preclinical and clinical 
risk assessment 
Table divided into two tables 
listing either Identified or 
Potential risks separately  
• Inclusion of statement on 
conclusions from GLP 
genotoxicity study and 
embryofetal development 
risks  
• Removal of Cardiac 
Effects risks 
• Inclusion of statement for 
the preclinical data for 
hepatic event risks  
• Addition of statement to 
the preclinical data for 
damage to exocrine tissue 
• Addition of ophthalmology 
adverse event findings in 
clinical study and 
mitigation approaches 
• Addition of fatigue 
Update as required per 
updated information 
Section 2.3.3 Pharmacokinetic 
Risk Assessment 
Inclusion of MATE2-K, OAT3 
and OCT2 as potential 
substrate of GSK3326595 
 
Alignment with latest IB data 
cut off 04 February 2020 
Section 2.3.4 Benefit 
Assessment and 2.3.5 Overall 
Benefit: Risk Conclusion 
Inclusion of data from Interim 
Analysis of 300 mg Part 1 
cohort and explanation of 
patient population for Part 2   
Justification added given new 
patient population is enrolled 
in Part 2  
Section 4.1.1.1 Part 1 Dose 
Confirmation and Section 
4.1.1.1.2 Starting dose, 
planned dose level, and 
alternative dosing schedules 
Explanation regarding starting 
dose in Part 1 Dose 
Confirmation cohort of Study 
208809.   
And explanation added to 
clarify dose in Study 204653 
have changed to 300 mg 
Updated information included 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
9 
 
Section # and Name 
Description of Change 
Brief Rationale 
during the study as well due to 
safety and tolerability.  
Section 4.1.1.1.3 Dose 
confirmation 
Text clarification on the N-
CRM design for Part 1. 
Clarification included. 
Section 4.1.1.1.4 Dose limiting 
toxicities, Table 5 and Section 
4.1.3.1.1 Part 2 Dose 
escalation 
Clarification of DLT definition 
included in ‘’other’’ category 
and in text in Section 4.1.3.1.1 
Clarification included 
Section 4.1.1.5 Statistical 
Design, Table 6 
Clarification of definition of 
Clinical Benefit Rate as 
inclusive of mCR, PR, SD>=8 
weeks or HI 
Clarification included 
Section 4.1.2 Decision 
whether to proceed to Part 2 
Explanation on decision to 
proceed to Part 2 
Explanation as above 
Section 4.1.3 Part 2: Further 
Exploration of Efficacy in 
Myeloid Neoplasms 
Part 2 high level objectives 
outlines and Part 2A and 2C 
outline of objectives deleted 
Explanation as above 
Section 4.1.3.1 Part 2: 5-
Azacitidine plus GSK3326595 
and Section 4.1.3.1.1 Part 2 
Dose Escalation 
Explanation on design of part 
2 Dose Escalation and 
Expansion and Patient 
numbers and starting dose, 
dosing steps and dose 
reductions guidance. 
Statement included that the 
recommended combination 
Dose and Regimen will be 
based on safety, tolerability, 
and available PK and PD data 
Changes in line with proposed 
design for Part 2 
Starting dose at 200mg QD 
and 100mg BID at respective 
cohorts which is two dose 
levels lower than RP2D for 
Monotherapy given 
continuously. 
Clarification included on data 
required to guide decision for 
Recommended Combination 
Dose and Regimen 
Section 4.1.3.1.2 Part 2, Dose 
Expansion: Clinical Efficacy in 
Newly Diagnosed MDS and 
CMM, Table 8 
Clarification with regards to 
population, number of 
participants and endpoint 
used 
Revised statistical design and 
futility criteria 
Explanation above. 
Revised statistical design and 
the futility criteria given the 
change in the primary 
endpoint and decision making 
approach. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
10 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 4.2 Number of 
Participants 
Change in number of 
participants 
Explanation above 
Section 4.3 Scientific 
Rationale for Study Design, 
4.3.2 Part 2 
Explanation of patient 
population added and 
corrected 
Explanation above 
Section 4.4 Justification for 
dose, Section 4.4.1.1 
GSK3326595 
Change to align with updated 
status of doses explored in 
204653 and 208809 studies. 
Inclusion of starting dose in 
Part 2 and rationale 
Explanation above 
Section 4.5 End of Study 
definition 
End of Study definition 
clarification 
Clarification to align to design 
where Part 1 and Part 2 
included, no Part 2A or Part 
2C 
Section 5.1 Inclusion criteria 
Part 2A and 2C population 
deleted  
 
Part 2 population in Dose 
Escalation and Dose 
Expansion cohort listed out 
Circumstances under which 
HIV and HepB participants 
may be enrolled included in 
Section 5,2 
Patient population in Dose 
Escalation selected to include 
patients with unmet medical 
need and with no additional 
options for standard therapy.  
R/R AML that has exhausted 
all treatment option with WBC 
<20,000 cells/µL (so not just 
AML evolving from 
MDS/MPN) enrolled to 
broaden the population 
covering additional area of 
unmet medical need where 5-
Azacitidine is part of SoC) 
Section 5.2 Exclusion criteria 
Updated notes to include 
HIV/Hep B participants into 
study 
To include HIV/Hep B 
participants 
Section 5.3.1.1 Female 
Participants of Childbearing 
Potential 
Section 5.3.1.3 Male 
Participants 
Clarification regarding use of 
contraception after last dose 
of GSK3326595 and 5-
Azacitidine has been added. 
Clarification added. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
11 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1 Study Intervention 
administered 
Participants can be 
administered either tablets or 
capsules in Part 2. 
Inclusion of 25 mg capsules  
 
Clarification to administration 
of 5-Azacitidine as based on 
prescribed information in 
registered label 
Clarification that 5-Azacitidine 
may be obtained from 
registered manufacturers 
Allow to take drug with food 
on Cycle 1 Day 8 in part 2 
dose escalation 
Change the GSK3326595 
intake to 2 h pre dose and 1 h 
post dose 
Relative bioavailability sub-
study in study 204653 has 
enabled the use of tablets. 
Inclusion of 25 mg capsules 
given doses potentially to be 
explored in Part 2 Dose 
Escalation. 
Clarification of language 
 
Clarification of language 
 
 
Allows exploration of food 
effect on PK 
Clarification of food intake 
timing. 
Section 6.2 Method of 
Treatment Assignment,  
Section 6.3 Blinding, Section 
8.1 Visit Windows 
Removal of Part 2A and Part 
2C 
As explained above 
Section 6.6.1.2. Cautionary 
Medications 
Perpetrator risk of 
GSK3326595 has been 
identified as a CYP1A2 
inducer and therefore co-
administration of 
GSK3326595 and substrates 
of CYP1A2 should be avoided 
in order to prevent inadvertent 
under-exposure to these 
agents. 
Alignment with latest IB cut off 
04 February 2020 
Section 6.6.1.3. Prohibited 
Medications 
GSK3326595 is a substrate of 
MATE2-K, OAT3 and OCT2 
uptake transporters; therefore, 
GSK3326595 should not be 
co- administered with strong 
Alignment with latest IB cut off 
04 February 2020 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
12 
 
Section # and Name 
Description of Change 
Brief Rationale 
and moderate inhibitors or 
inducers of MATE2-K, OAT3 
and OCT2.  
The warning for GSK3326595 
not to be co-administered with 
strong or moderate inhibitors 
of Breast Cancer Resistance 
Protein (BCRP) has been 
removed. 
Section 8.2.2 Tumor Sample 
Tumor sample collection 
within 14 days prior to the first 
dose of study drug(s) 
Clarification in language 
Section 8.3.1 Disease 
Assessment 
Removal of Part 2A and Part 
2C 
As explained above 
Section 8.4.4 
Electrocardiograms 
Clarification that single 12-
lead ECG are collected on 
treatment and additional 
details of triplicate ECG 
measurements to be moved to 
SRM. 
Locally collected ECGs may 
be read centrally.  
Clarification added 
Section 8.4.5 Bone Mineral 
Density 
Clarification added that locally 
collected DEXA scans may be 
read centrally 
Clarification added 
Section 8.4.6 Clinical Safety 
Laboratory Assessments 
Correction that Laboratory 
assessments collected until 
30 days post last dose 
Alignment with AE/SAE 
collection post last dose 
Section 8.4.7 Adverse Events 
and Serious Adverse Events 
Correction that all AE/SAE 
collected until 30 days post 
last dose 
Clarification added 
Section 8.7 
Pharmacodynamics and 
Biomarker 
Clarification for genomic 
testing done locally, any 
results and type of test to be 
recorded and provided. 
Additional collection of results 
and type of tests from locally 
generated genomic testing 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
13 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.8 Patient Reported 
Outcomes 
PRO assessments have been 
removed. 
PRO assessments have been 
removed from Part 2 to 
reduce participant burden 
during the Dose Escalation 
phase. 
Section 9 Statistical 
Consideration 
Part 1 text clarifications.  
 
Part 2 Dose Escalation N-
CRM design details and 
simulations were added for 
each QD and BID.  
Part 2 Dose Expansion 
revised statistical design 
including changes to the 
decision making framework 
and the futility time points. 
Removal of duplicated 
information.  
Part 2 Dose Escalation 
operating characteristics 
assessment of the N-CRM 
design. 
Part 2 Dose Expansion 
changes due to the primary 
endpoint change and 
refinement of the decision 
making framework. 
Section 10 References 
Additional references are 
included 
As above  
Section 11.2 Appendix 2 
Inclusion of TSH, free T3 and 
free T4 
Explanation above 
Section 11.9 Appendix 9 
Clarification regarding IWG 
criteria as per Cheson 2006 
included 
Clarification needed  
Section 11.11 Appendix 11 
Clarification that Appendix 11 
lists dose modification criteria 
for GSK3326595, 5-
Azacitidine shall follow dose 
adjustments as per registered 
label 
Clarification needed 
Section 11.12 Appendix 12 
Rationale for Response 
Assumptions included CR 
rate. 
Removal of Part 2A and Part 
2C related information. 
Due to change in Part 2 
primary endpoint explanation 
and literature included 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
14 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 11.13 Appendix 13 
COVID 19 Appendix included  
Guidance under COVID19 
pandemic as per GSK 
requirements included  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
15 
 
TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY ........................................................................................ 20 
1.1. 
Synopsis ..................................................................................................... 20 
1.2. 
Schema ...................................................................................................... 27 
1.3. 
Schedule of Activities (SoA) ........................................................................ 27 
1.3.1. 
Part 1: Single Agent in Relapsed/Refractory Myeloid 
Disease ....................................................................................... 28 
1.3.2. 
Part 2: GSK3326595 in combination with 5-Azacitidine ................ 31 
1.3.3. 
Part 2: GSK3326595 in combination with 5-Azacitidine ................ 35 
2. 
INTRODUCTION .................................................................................................... 39 
2.1. 
Study Rationale .......................................................................................... 39 
2.2. 
Background ................................................................................................ 40 
2.2.1. 
Clinical Background: MDS and AML ............................................ 40 
2.2.2. 
PRMT5 as a Target in Myeloid Neoplasms .................................. 41 
2.2.2.1. 
PRMT5 in MDS and AML ........................................... 41 
2.2.2.2. 
Spliceosomal Mutations and Potential 
Biomarkers for PRMT5 Inhibition in Myeloid 
Neoplasms ................................................................. 42 
2.2.3. 
Clinical Experience with PRMT5 inhibitors ................................... 44 
2.2.3.1. 
GSK3326595 - Study 204653 ..................................... 44 
2.2.3.2. 
Other PRMT5 inhibitors .............................................. 44 
2.3. 
Benefit/Risk Assessment ............................................................................ 44 
2.3.1. 
Overlapping Toxicities (Part 2) ..................................................... 45 
2.3.2. 
Preclinical and Clinical Risk Assessment ..................................... 46 
2.3.3. 
Pharmacokinetic Risk Assessment .............................................. 53 
2.3.4. 
Benefit Assessment ..................................................................... 53 
2.3.5. 
Overall Benefit: Risk Conclusion .................................................. 54 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 54 
4. 
STUDY DESIGN .................................................................................................... 58 
4.1. 
Overall Design ............................................................................................ 58 
4.1.1. 
Part 1: Single Agent Activity in Relapsed/Refractory MDS 
and Hypoproliferative AML ........................................................... 59 
4.1.1.1. 
Part 1 Dose Confirmation ........................................... 59 
4.1.1.1.1. 
Type and number of participants ............ 60 
4.1.1.1.2. 
Starting dose, planned dose 
levels, and alternative dosing 
schedules ............................................... 60 
4.1.1.1.3. 
Dose confirmation ................................... 61 
4.1.1.1.4. 
Dose limiting toxicities ............................ 61 
4.1.1.1.5. 
Dose escalation decisions ...................... 62 
4.1.1.1.6. 
Intra-participant dose escalation ............. 62 
4.1.1.1.7. 
Identification of the recommended 
myeloid monotherapy dose ..................... 63 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
16 
 
4.1.1.2. 
Part 1 Dose Expansion: Clinical Efficacy in 
Relapsed/Refractory MDS and 
Hypoproliferative AML ................................................ 63 
4.1.1.2.1. 
Type and number of participants ............ 63 
4.1.1.3. 
Treatment Arms and Duration .................................... 64 
4.1.1.4. 
Dose Selection ........................................................... 64 
4.1.1.5. 
Statistical Design ........................................................ 64 
4.1.2. 
Decision Whether to Proceed to Part 2 ........................................ 65 
4.1.3. 
Part 2: Further Exploration of Efficacy in Myeloid 
Neoplasms ................................................................................... 66 
4.1.3.1. 
Part 2: 5-Azacitidine plus GSK3326595 ...................... 66 
4.1.3.1.1. 
Part 2 Dose Escalation ........................... 67 
4.1.3.1.2. 
Part 2, Dose Expansion: Clinical 
Efficacy in Newly Diagnosed MDS 
and CMML .............................................. 68 
4.2. 
Number of Participants ............................................................................... 70 
4.3. 
Scientific Rationale for Study Design .......................................................... 70 
4.3.1. 
Part 1 ........................................................................................... 70 
4.3.2. 
Part 2 ........................................................................................... 70 
4.4. 
Justification for Dose .................................................................................. 71 
4.4.1. 
Starting Doses ............................................................................. 71 
4.4.1.1. 
GSK3326595 .............................................................. 71 
4.4.1.2. 
5-Azacitidine ............................................................... 72 
4.5. 
End of Study Definition ............................................................................... 72 
4.5.1. 
Participants Completion ............................................................... 72 
4.5.2. 
Study completion ......................................................................... 72 
5. 
STUDY POPULATION ........................................................................................... 73 
5.1. 
Inclusion Criteria ......................................................................................... 73 
5.2. 
Exclusion Criteria ........................................................................................ 76 
5.3. 
Lifestyle Considerations .............................................................................. 78 
5.3.1. 
Gender-Specific Restrictions........................................................ 78 
5.3.1.1. 
Female Participants of Childbearing Potential ............ 78 
5.3.1.2. 
Female Participants of Non-Childbearing 
Potential ..................................................................... 79 
5.3.1.3. 
Male Participants ........................................................ 79 
5.3.2. 
Meals and Dietary Restrictions .................................................... 79 
5.4. 
Screen Failures........................................................................................... 79 
6. 
STUDY INTERVENTION ........................................................................................ 80 
6.1. 
Study Intervention(s) Administered ............................................................. 80 
6.2. 
Method of Treatment Assignment ............................................................... 81 
6.3. 
Blinding ....................................................................................................... 81 
6.4. 
Preparation/Handling/Storage/Accountability .............................................. 81 
6.5. 
Study Intervention Compliance ................................................................... 82 
6.6. 
Concomitant Therapy.................................................................................. 82 
6.6.1. 
Concomitant Medications ............................................................. 82 
6.6.1.1. 
Permitted Medications ................................................ 83 
6.6.1.2. 
Cautionary Medications .............................................. 83 
6.6.1.3. 
Prohibited Medications ............................................... 83 
6.6.2. 
Concomitant Non-Drug Therapies ............................................... 84 
6.7. 
Dose Modification ....................................................................................... 84 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
17 
 
6.8. 
Intervention after the End of the Study ........................................................ 85 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 85 
7.1. 
Discontinuation of Study Intervention .......................................................... 86 
7.1.1. 
Disease Progression .................................................................... 86 
7.1.2. 
Liver Chemistry Stopping Criteria ................................................ 87 
7.1.3. 
QTc Stopping Criteria .................................................................. 88 
7.1.4. 
Other Stopping Criteria ................................................................ 89 
7.1.5. 
Temporary Discontinuation .......................................................... 89 
7.1.6. 
Rechallenge ................................................................................. 89 
7.1.6.1. 
Study Intervention Restart or Re-challenge ................ 89 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 90 
7.3. 
Lost to Follow Up ........................................................................................ 90 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 90 
8.1. 
Visit Windows ............................................................................................. 91 
8.2. 
Critical Baseline Assessments .................................................................... 92 
8.2.1. 
Disease Characteristics ............................................................... 92 
8.2.2. 
Tumor Sample ............................................................................. 93 
8.3. 
Efficacy Assessments ................................................................................. 93 
8.3.1. 
Disease Assessment ................................................................... 93 
8.3.2. 
Survival Assessments .................................................................. 93 
8.4. 
Safety Assessments ................................................................................... 93 
8.4.1. 
Physical Examinations ................................................................. 93 
8.4.2. 
Performance Status ..................................................................... 93 
8.4.3. 
Vital Signs .................................................................................... 93 
8.4.4. 
Electrocardiograms ...................................................................... 94 
8.4.5. 
Bone Mineral Density ................................................................... 94 
8.4.6. 
Ophthalmic Assessment .............................................................. 94 
8.4.7. 
Clinical Safety Laboratory Assessments ...................................... 95 
8.4.7.1. 
Urine and Serum Safety Studies................................. 95 
8.4.8. 
Adverse Events and Serious Adverse Events .............................. 96 
8.4.8.1. 
Time Period and Frequency for Collecting AE 
and SAE Information .................................................. 96 
8.4.8.2. 
Method of Detecting AEs and SAEs ........................... 96 
8.4.8.3. 
Follow-up of AEs and SAEs ........................................ 97 
8.4.8.4. 
Regulatory Reporting Requirements for SAEs ............ 97 
8.4.8.5. 
Pregnancy .................................................................. 97 
8.4.8.6. 
Cardiovascular and Death Events .............................. 97 
8.4.9. 
Treatment of Overdose ................................................................ 98 
8.5. 
Pharmacokinetics ....................................................................................... 98 
8.6. 
Genetics ..................................................................................................... 99 
8.7. 
Pharmacodynamics and Biomarkers ........................................................... 99 
8.7.1. 
Immunogenicity Assessments .................................................... 100 
8.7.2. 
RNA Transcriptome Research ................................................... 100 
8.7.3. 
RNA Expression Research of a Subset of RNA Species ............ 100 
8.7.4. 
Circulating Cell Free DNA (cfDNA) Analysis .............................. 101 
8.7.5. 
Proteome Research ................................................................... 101 
8.8. 
Patient Reported Outcomes ...................................................................... 101 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics ................................................................................................ 101 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
18 
 
9. 
STATISTICAL CONSIDERATIONS ...................................................................... 101 
9.1. 
Sample Size Determination ...................................................................... 101 
9.1.1. 
Part 1 ......................................................................................... 102 
9.1.2. 
Part 2 ......................................................................................... 102 
9.1.2.1. 
Dose escalation ........................................................ 102 
9.1.2.2. 
Dose Expansion ....................................................... 103 
9.2. 
Populations for Analyses .......................................................................... 104 
9.3. 
Statistical Analyses ................................................................................... 105 
9.3.1. 
Efficacy Analyses ....................................................................... 105 
9.3.1.1. 
Efficacy Endpoints .................................................... 105 
9.3.1.2. 
Part 1 ....................................................................... 106 
9.3.1.3. 
Part 2 ....................................................................... 107 
9.3.2. 
Safety Analyses ......................................................................... 107 
9.3.2.1. 
Extent of Exposure ................................................... 107 
9.3.2.2. 
Adverse Events ........................................................ 107 
9.3.2.3. 
Clinical Laboratory Evaluations ................................ 108 
9.3.2.4. 
Other Safety Measures ............................................. 108 
9.3.3. 
Other Analyses .......................................................................... 108 
9.3.3.1. 
Pharmacokinetic Analyses ........................................ 108 
9.3.3.2. 
Pharmacokinetic/Pharmacodynamic Analyses ......... 110 
9.3.3.3. 
Pharmacodynamic/Biomarker Analyses ................... 110 
9.3.4. 
Interim Analyses ........................................................................ 110 
9.3.4.1. 
Part 1 ....................................................................... 110 
9.3.4.2. 
Part 2 ....................................................................... 110 
10. REFERENCES ..................................................................................................... 111 
11. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 115 
11.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .......................................................................................... 115 
11.1.1. 
Regulatory and Ethical Considerations ...................................... 115 
11.1.2. 
Financial Disclosure ................................................................... 115 
11.1.3. 
Informed Consent Process ........................................................ 116 
11.1.4. 
Data Protection .......................................................................... 116 
11.1.5. 
Dissemination of Clinical Study Data ......................................... 117 
11.1.6. 
Data Quality Assurance ............................................................. 117 
11.1.7. 
Source Documents .................................................................... 118 
11.1.8. 
Study and Site Closure .............................................................. 118 
11.2. 
Appendix 2: Clinical Laboratory Tests ....................................................... 119 
11.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 122 
11.3.1. 
Definition of AE .......................................................................... 122 
11.3.2. 
Definition of SAE ........................................................................ 123 
11.3.3. 
Definition of Cardiovascular Events ........................................... 124 
11.3.4. 
Recording and Follow-Up of AE and SAE .................................. 124 
11.3.5. 
Reporting of SAE to GSK ........................................................... 126 
11.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................................ 128 
11.4.1. 
Definitions: ................................................................................. 128 
11.4.2. 
Contraception Guidance: ........................................................... 129 
11.4.3. 
Collection of Pregnancy Information: ......................................... 130 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
19 
 
11.5. 
Appendix 5: Genetics ................................................................................ 132 
11.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Rechallenge Guidelines .................. 133 
11.7. 
Appendix 7: IPSS-R Scoring System for MDS .......................................... 139 
11.8. 
Appendix 8: CMML Scoring System .......................................................... 140 
11.8.1. 
CPSS Scoring System (Such, 2013) .......................................... 140 
11.8.2. 
CPSS-mol Scoring System (Elena, 2016) .................................. 141 
11.9. 
Appendix 9: IWG Criteria for Response for Participants in Part 1 
and Part 2 ................................................................................................. 143 
11.10. Appendix 10: ECOG Performance Status ................................................. 145 
11.11. Appendix 11: Guidelines for Management of Toxicity ............................... 146 
11.12. Appendix 12: Rationale for Response Assumptions .................................. 150 
11.13. Appendix 13: Overall Rationale for this Appendix ..................................... 152 
11.14. Appendix 14: Abbreviations and Trademarks ............................................ 155 
11.15. Appendix 15: Protocol Amendment History ............................................... 160 
 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
20 
 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase I/II study to investigate the safety and clinical activity of 
GSK3326595 and other agents in participants with myelodysplastic syndrome and acute 
myeloid leukaemia. 
Short Title: Phase I/II Study of GSK3326595 and other agents to treat myelodysplastic 
syndrome (MDS) and acute myeloid leukaemia (AML) 
Rationale: 
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 (as a consequence of 
ineffective hematopoiesis), molecular and/or karyotypic abnormalities, and an expansion 
of immature myeloid cells. It is the quantitation of these immature myeloblasts (“blasts”) 
that, in part, differentiates AML from MDS, with a 20% blast percentage marking the 
transition from MDS to AML. While multiple new targeted agents have been approved to 
treat AML in patients harbouring a limited number of mutations, the majority of patients 
with both MDS and AML are not eligible for these therapies. Current therapies for most 
patients are inadequate: a newly diagnosed MDS patient may expect only to live for one 
to two years before dying of the disease, and the lifespan of someone diagnosed with 
AML would be even shorter, despite modern therapy. Disease that relapses after standard 
treatment, or which fails to respond to therapy, confers an even more dismal prognosis. 
The median overall survival (OS) for relapsed MDS is approximately six months, and 
there is no generally accepted standard of care for these patients. As such, new therapies 
to prolong survival are desperately needed.   
Protein arginine methyltransferases (PRMTs) are a family of enzymes that methylate 
arginines in proteins involved in various cellular processes, including precursor 
messenger ribonucleic acid (pre-mRNA) splicing, transcription factors, kinases and 
histones. One family member, PRMT5, is responsible for the majority of symmetric 
dimethylation of arginine in vivo. PRMT5 is overexpressed in a number of tumors, 
including myeloid malignancies [Tarighat, 2016]. Inhibition of PRMT5 leads to 
decreased proliferation and cell death in preclinical models of AML.  
GSK3326595 is a potent, selective, reversible inhibitor of PRMT5 currently under 
investigation in solid and hematologic tumors in the first-in-human study 204653 
evaluating subjects with solid tumors and non-Hodgkin’s lymphoma (NHL). In Part 1 of 
the dose escalation phase, the QD dose escalation population consisted of 8 cohorts 
(12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, and 600 mg) and the twice 
daily (BID) dose-escalation population consisted of 4 cohorts (50 mg, 100 mg, 150 mg, 
and 200 mg). The starting dose in Part 2 was 400 mg daily; however, it was subsequently 
agreed to start participants at a dose of 300 mg daily due to safety and tolerability. 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
21 
 
Study 208809 is a Phase I/II study to evaluate the safety, tolerability, and clinical activity 
of GSK3326595 in participants with relapsed and refractory MDS, chronic 
myelomonocytic leukaemia (CMML), and hypoproliferative AML that has evolved from 
an antecedent MDS (Part 1, “MDS cohort”).  At the end of Part 1,  pre-specified criteria 
(as described in the body of the protocol) for futility were met for GSK3326595 
monotherapy.  Therefore no further investigation of GSK3326595 monotherapy will be 
conducted in this patient population, but the study will be expanded to study 
GSK3326595 in combination with 5-Azacitidine in Part 2. Part 2 consists of a Dose 
Escalation phase where intermittent dosing schedule (2 weeks on, 2 weeks off), two 
regimens (daily and twice daily) of GSK3326595 will be administered in combination 
with 5-Azacitidine in participants with MDS, CMML or AML, followed by a Dose 
Expansion cohort using the Recommended Combination Dose and Regimen determined 
in the Dose Escalation phase. The inclusion of any additional agents will require a 
protocol amendment prior to implementation. 
Objectives and Endpoints: 
Part 1 
Objectives 
Endpoints 
Primary 
• 
To determine the clinical activity of 
GSK3326595 in participants with myeloid 
neoplasms 
• Clinical Benefit Rate (CBR), as defined as 
the percentage of participants achieving a 
complete remission (CR), complete 
marrow remission (mCR), partial remission 
(PR), stable disease (SD) lasting at least 8 
weeks, or hematologic improvement (HI), 
per International Working Group (IWG) 
criteria. 
Secondary 
• 
To determine the safety, tolerability, and 
recommended myeloid monotherapy 
dose of orally-administered GSK3326595 
in participants with relapsed and/or 
refractory myeloid neoplasms 
• 
Frequency and severity of adverse events 
• 
Frequency of dose limiting toxicities 
(DLTs) 
• 
To further describe the clinical activity of 
GSK3326595 in participants with relapsed 
and/or refractory myeloid neoplasms 
• 
Overall response rate (ORR), defined as 
the percentage of participants achieving a 
CR, mCR, or PR, per IWG criteria. 
• 
Progression free survival (PFS), defined 
as time from first dose to disease 
progression, as defined by IWG criteria, 
or death due to any cause, whichever 
occurs earlier 
• 
Overall survival (OS), defined as time 
from first dose to death due to any cause 


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
2 2  
 
P art 1  
O bj e cti ve s  
E n d p oi nt s  
•  
T o c h ar act eriz e th e p h ar mac oki n etics 
( P K) of G S K 33 2 65 95 i n p artici p a nts wit h 
r el a ps e d a nd/ or r efr act ory my el oi d 
n e opl as ms  
•  
G S K 33 2 65 95 P K p ar a m et ers i n pl as m a 
f oll o wi n g si ngl e- ( Day 1) a nd r e p eat-dos e 
a d mi nistr ati o n of G S K3 3 265 9 5  
E x pl or at or y  
 
 
C CI


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
2 3  
 
P art 2  D o se Es c al ati o n  
O bj e cti ve s  
E n d p oi nt s  
Pri m ary  
•  
T o d eter mi n e th e saf ety, t oler a bility, an d 
r ec o m m e n d ed c o m bin ati on d os e a nd 
r e gi m e n of or ally -a d mi nist ere d 
G S K 33 2 65 95 w h en a d mi nist er e d i n 
c o m bi n ati on wit h 5-Az aciti din e  i n 
p artici p a nts wit h my el oid n eo pl as ms  
•  
Fr e q u ency a nd s everity of adv ers e eve nts  
•  
Fr e q u ency of DL Ts  
•  
Fr e q u ency of d ose i nterru ptio ns, d os e 
r e d ucti ons, an d tr e at m ent disc o nti nu ati on 
d u e t o a dv ers e ev ents  
S e c o n d ary  
•  
T o d eter mi n e th e cli nic al activity of 
G S K 33 2 65 95 pl us 5 -Az acitidi n e  i n 
p artici p a nts wit h  my el oid n eo pl as ms   
•  
C o m pl et e R e missi o n ( C R) r at e, d efin e d 
as t he p erc e nta g e of p articip a nts 
ac hi evi n g a C R per I W G criteria  
•  
T o d escri b e t he p h ar mac okin etics  ( P K) of 
G S K 33 2 65 95 a n d 5 -Azacitidi n e  aft er 
si n gl e- a nd r e pe at -d os e a d mi nistr ati o n  
•  
G S K 33 2 65 95 a n d 5 -Azacitidi n e  P K 
p ar a m eters i n pl as m a f oll o wi n g si n gl e - 
( Day 1) a nd r e pe at-dos e a d mi nistr ati o n of 
G S K 33 2 65 95  i n c o mbi n ati on wit h 
5 -Az aciti di n e . 
•  
T o f urt her d escri be t he cli nic al activity of 
G S K 33 2 65 95 pl us 5 -Az acitidi n e  i n 
p artici p a nts wit h my el oid n eo pl as ms  
•  
O R R, d efi ne d as t he p erc e nt a g e of 
p articip a nts achi evi n g a C R, m C R, or P R, 
p er I W G crit eria.  
E x pl or at or y  
C CI


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
2 4  
 
P art 2  D o se Ex p a n si o n  
O bj e cti ve s  
E n d p oi nt s  
Pri m ary  
•  
T o d eter mi n e th e cli nic al activity of 
G S K 33 2 65 95 pl us 5 -Az acitidi n e  i n 
p artici p a nts wit h hi g h risk ne wly di a g n os ed 
M D S or C M M L  
•  C o m pl et e R e missi o n ( C R) r at e, d efin e d 
as t he perc e nta g e of p articip a nts 
ac hi evi n g a C R per I W G criteria  
S e c o n d ary  
•  
T o d eter mi n e th e saf ety  a nd  t ol er a bility, of 
or ally -a d mi nist er e d G S K3 32 6 59 5 w he n 
a d mi nist er e d i n c o m bin ati on wit h 5 -
Az aciti di n e  i n partici p a nts wit h hi gh risk 
n e wly di ag n ose d M D S or C M M L  
•  
Fr e q u ency a nd s everity of adv ers e 
ev e nts  
•  
Fr e q u ency of d ose i nterru ptio ns, d os e 
r e d ucti ons, an d tr e at m ent disc o nti nu ati on 
d u e t o a dv ers e ev ents  
•  
T o d escri b e t he p h ar mac okin etics of 
G S K 33 2 65 95 a n d 5 -Azacitidi n e  aft er 
si n gl e- a nd r e pe at -d os e a d mi nistr at i o n 
•  
G S K 33 2 65 95 a n d 5 -Azacitidi n e  P K 
p ar a m eters i n pl as m a f oll o wi n g si n gl e - 
( Day 1) a nd r e pe at-dos e a d mi nistr ati o n 
of G S K 3 32 65 9 5  i n c o m bin ati o n wit h 
5 -Az aciti di n e.  
•  
T o f urt her d escri be t he cli nic al activity of 
G S K 33 2 65 95 pl us 5 -Az acitidi n e  i n 
p artici p a nts wit h hi g h risk ne wly di a g n os ed 
M D S or C M M L  
•  
O R R, d efi ne d as t he p erc e nt a g e of 
p articip a nts achi evi n g a C R, m C R, or 
P R, p er I W G crit eria.  
E x pl or at or y  
C CI
C CI


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
2 5  
 
O ver all Desi g n:  
St u d y 2 0 8 8 0 9 is a n o pe n -la bel, m ultice ntre, m ulti-part st u d y of G S K 3 3 2 6 5 9 5 as 
m o n ot hera p y a n d i n c o m bi nati o n wit h 5 -Azaciti di ne  i n partici pa nts wit h m yel oi d 
mali g na n cies. Refer t o Secti o n  1. 2  f or t he o verall st u d y sc he m atic. 
A d diti o nal a ge nt(s) ma y be a d de d, eit her as si n gle a ge nt or i n c o m bi nati o n, t o a n y of t he 
p arts of t his st u d y bas e d o n e mer gi n g cli nical a n d precli nical dat a. A pr ot oc ol a me n d me nt 
will be re q uire d t o i ncl u d e t he a d diti o nal a ge nts t o be use d i n t his st u d y.  
Part 1 is c o m p ose d of a s afet y e v al uati o n, f oll o we d b y  a si n gle -ar m d ose e x pa nsi o n 
c o h ort t o deter mi ne t he C B R of G S K 3 3 2 6 5 9 5 i n p artici pa nts wit h rela ps e d a n d/ or 
refract or y M D S, C M M L, a n d h y p o pr oliferati ve A M L t hat has e v ol ve d fr o m a n 
a ntece d e nt M D S.  At t he e n d of Part 1, pre -s pecifie d criteri a (as d escri be d i n t he b o d y of 
t he pr ot oc ol) f or f utilit y were met f or G S K 3 3 2 6 59 5  m o n ot hera p y.  T heref ore , n o f urt her 
i n vesti gati o n of G S K 3 3 2 6 5 9 5 m o n ot hera p y will be c o n d ucte d, b ut t he st u d y will be 
e x pa n de d t o st u d y G S K 3 3 2 6 5 9 5 i n c o m bi nati o n wit h 5 -Azaciti di ne  i n Part 2. Part 2 is 
c o m p ose d of t w o d ose escalati o n  c o h orts of i nter mitte nt d osi n g of G S K 3 3 2 6 5 9 5 
(Re gi me n  1 : O nce d ail y d osi n g [Q D ] wit h 2 wee ks o n, 2 wee ks off G S K 3 3 2 6 5 9 5 i n 
c o m bi nati o n wit h 5 -Azaciti di ne  a d mi nistere d as per pres cri bi n g i nf or mati o n a n d 
Re gi m en  2 : T wice d ail y d osi n g [BI D ] wit h 2 wee ks o n, 2 wee ks off G S K 3 3 2 6 5 9 5, wit h 
5 -Azaciti di ne  a d mi nistere d as per prescri be d i nf or mati o n . P artici pa nts  e nr ol le d i n t he 
D ose Escalati o n p or ti o n of P art 2 will i ncl u de  patie nts wit h m yel oi d ne o plas ms.  
O nce  t he Rec o m me n de d C o m bi nati o n D ose a n d Re gi me n  is det er mi ne d bas e d o n data 
fr o m D ose Escalati o n  c o h orts, t he D ose E x pa nsi o n c o h ort  i n hi g h ris k tr eat me nt naï ve 
M D S  or  C M M L  partici p a nt s will be i nitiate d  t o deter mi ne t he C R rate of t he c o m bi nati o n 
of G S K 3 3 2 6 5 9 5 pl us 5 -A zaciditi ne.   
C CI


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
26 
 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Reference Manual (SRM). The SRM will provide 
the site personnel with administrative and detailed technical information that does not 
impact participant safety. 
Disclosure Statement: This is a sequential treatment study with study arms that is not 
masked. 
Number of Participants: 
Participants enrolled in Part 1 of this study will have a diagnosis of relapsed / refractory 
(R/R) MDS, CMML, or AML for which no standard therapy is expected to provide a 
significant response. Part 2 Dose Escalation will enroll participants with myeloid 
neoplasms.  Participants in the Part 2 Dose Expansion cohort will have newly diagnosed, 
high-risk MDS, CMML. Participants in both Part 2 Dose Escalation and Dose Expansion 
will receive IP in combination with the approved first-line agent 5-Azacitidine. It is 
estimated that a maximum of 113 participants will be enrolled in the study, divided as 
follows: in Part 1 30 participants were enrolled; in Part 2 Dose Escalation cohorts 
approximately 24 participants in each of the two dose regimens (QD and BID) and 
approximately 35 participants in Dose Expansion cohort.  
Intervention Groups and Duration: 
All participants will receive GSK3326595, either as a single agent (Part 1) or in 
combination with 5-Azacitidine (Part 2 Dose Escalation and Dose Expansion). 
Participants will begin therapy on Day 1 of the study and continue until unacceptable 
toxicity, progression of disease, withdrawal of consent, death, or termination of the study 
by the sponsor. The total duration of study will depend on recruitment rates, withdrawals 
due to toxicity or progression or death, with an approximate duration of 5-6 years. 
Once daily administration of GSK3326595 as monotherapy was explored in Part 1. 
Intermittent dosing schedule (2 weeks on, 2 weeks off),once daily and twice daily 
regimen will be explored in Part 2. The intermittent dosing schedule above was selected 
based on the available safety, tolerability, PK and PD data. More specifically: 1) the need 
to allow for sufficient bone marrow recovery as GSK3326595 and 5-Azacitidine both can 
induce sever cytopenias, 2) data on time to achieve maximum reduction of SDMA in 
plasma (nadir of SDMA achieved after day 14), 3) median time of onset of most common 
adverse events related to GSK3326595 (unpublished data). 
Dose reductions for individual participants may be required, based on toxicity observed 
during the study, and the frequency and duration of dose reductions will be reported.  
There will not be any pre-planned dose reductions. In Part 2, participants who require 
permanent discontinuation of either one of the study treatments in the combination may 
continue on the second agent. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
27 
 
1.2. 
Schema 
 
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: 
• 
Permissible windows for visits and study assessments are provided in Section 8.1. 
• 
The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker, or efficacy assessments may be 
altered during the course of the study based on newly available data (e.g., to obtain 
data closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring.  
• 
Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member 
and then archived in the sponsor and site study files but will not constitute a 
protocol amendment. The Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) will be informed of any safety issues that require alteration 
of the safety monitoring scheme or amendment of the Informed Consent Form 
(ICF). 
• 
Whenever vital signs, 12-lead ECG, and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: 12-lead ECG, 
vital signs, and blood draws. Whenever vital signs and blood draws are scheduled 
for the same nominal time, vital signs should be performed prior to blood draws.  
The timing of the assessments should allow the blood draw to occur at the exact 
nominal time. Detailed procedures for obtaining each assessment are provided in 
the SRM.  
• 
Unless otherwise stated in the SOA all assessments shall be performed pre dose. 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
28 
 
1.3.1. 
Part 1: Single Agent in Relapsed/Refractory Myeloid Disease 
Table 1 
Schedule of Activities, Part 1 
Procedure1 
Screening 
DLT Observation 
Period 
Week 
5 
Week 
7 
Week 9 and thereafter 
Week 13 
and 
thereafter 
End of 
Treatment 
(EOT) 
Survival 
Follow-
up 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 1 
Day 1 
Week 9 
Day 1 
only 
Every 4 
Weeks1 
Every 8 
Weeks 
Every 12 
Weeks 
Screening 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Register Participant 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drug 2 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Safety 
Physical Examination3 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
12-lead Electrocardiogram (ECG) 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
Pregnancy test4 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Follicle Stimulating Hormone (FSH)/Estradiol5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Human Immunodeficiency virus HIV, Hepatitis 
B Surface Antigen (HBsAg), Hepatitis C Virus 
(HCV) Antibody Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
DEXA Bone Densitometry6 
X 
 
 
 
 
 
 
 
 
X 
 
X7 
 
Clinical Laboratory Assessments8 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
29 
 
Procedure1 
Screening 
DLT Observation 
Period 
Week 
5 
Week 
7 
Week 9 and thereafter 
Week 13 
and 
thereafter 
End of 
Treatment 
(EOT) 
Survival 
Follow-
up 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 1 
Day 1 
Week 9 
Day 1 
only 
Every 4 
Weeks1 
Every 8 
Weeks 
Every 12 
Weeks 
Study Intervention  
Administer Study Drug 
 
================================ [Daily Dosing]==================→ 
 
 
Adverse Events (AE)/ Serious Adverse Event 
(SAE) review 
======================== [Continuous from Signing of Informed Consent to EOT Visit] =============→ 
 
 
Concomitant medication review 
======================= [Continuous from Signing of Informed Consent to EOT Visit] ================→ 
 
Review Diary Card  
====================================== [Continuous from Day 8 to EOT Visit] ==================→ 
 
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx) 
PK Plasma Samples9  
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
Plasma Samples (Symmetric 
Dimethylarginine(SDMA) and Circulating 
Biomarkers)10 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Whole Blood Samples (Transcriptomics)10 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Serum Sample (Translational Studies)10 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Bone Marrow Biopsy (SDMA and 
Translational Studies)11 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Genetic Sample (Saliva)12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
Bone Marrow Biopsy 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Survival Follow-up13 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
30 
 
1. After Week 49, the assessment frequencies may be reduced to every 8 weeks at the discretion of the Investigator. Refer to Section 8.1 of the full protocol for visit/procedure 
windows 
2. Study drug (GSK3326595) will be dispensed every 4 weeks at the clinic. If after Week 49, the assessment frequencies are reduced to every 8 weeks, then the study drug would 
then be dispensed every 8 weeks 
3. Refer to Section 8.4.1 for components of physical examination that must be performed at each visit 
4. Pregnancy testing only required for female participants of childbearing potential; see Section 5.3.1.1 for details.  Must be within 7 days of first dose. 
5. FSH/Estradiol testing only required for perimenopausal women whose childbearing potential is questionable; see Section 5.3.1.2 for details 
6. If possible, DEXA to be performed on same machine for particular participant (see SRM) 
7. Only if EOT is > 8 weeks from prior DEXA 
8. Refer to Appendix 2: Clinical Laboratory Tests for list of required laboratory assessments.  Note that routine serum and urinalysis studies are required for all participants 
enrolled; additional serum and urine tests for participants with a baseline creatinine clearance < 60 ml/min/1.73 m2 should be performed as described in Appendix 2: Clinical 
Laboratory Tests. 
9. PK samples following Day 1 and Day 15 dose will be collected at pre-dose (within 1 hour prior to dosing), 5 min±2 min, 30m±5min, 1h±5min, 2h±5min, 3h±5min, 4h±10 min, 
6h±10 min, 8h± 15min, 12h±2h, 24h±2h. PK samples on days of subsequent visits should be collected within 1 hour Pre-dose 
10. Plasma, serum, and whole blood samples should be collected Pre-dose on Day 1 and 6h (±3h) after dosing with GSK3326595 on the other days indicated.  Unscheduled 
samples for translational studies (see Section 8.7) should also be collected 6h (±3h) after dosing with GSK3326595 
11. Bone marrow (BM) biopsies for translational studies should be collected at screening and then 6h (±3h) on the days indicated, after dosing with GSK3326595.  Unscheduled 
biopsies for translational studies (see Section 8.7) should also be collected 6h (±3h) after dosing with GSK3326595 
12. Informed consent for optional genetics research should be obtained before collecting a sample. The sample will be collected at the first opportunity after a participant has met all 
eligibility requirements on Day 1 (pre- or post-dose) 
13. Survival Follow-Up may be via telephone, email, or other form of communication 
 
 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
31 
 
1.3.2. 
Part 2: GSK3326595 in combination with 5-Azacitidine  
Table 2 
Schedule of Activities, Part 2 Dose Escalation  
Procedure1 
Screening 
DLT Observation Period 
Week 5 
Week 7 
Week 9  
Week 9 and 
thereafter 
Week 13 
and 
thereafter 
Every 26 
weeks 
End of 
Treatment2  
 
 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 1 
Day 1 
Day 1 
Every 4 
Weeks1 
Every 8 
Weeks 
Every 12 
Weeks 
 
 
Screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Register Participant 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination3 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
12-lead ECG4 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
Pregnancy test5 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
FSH/Estradiol6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBsAg, HCV 
Antibody Screening7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Assessments8 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
Folate and selected 
vitamins8 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
TSH, free T3, free T4  
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
Opthalmic Assessment9 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
DEXA Bone Densitometry10 
X 
 
 
 
 
 
 
 
 
X 
 
 
X11 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
32 
 
Procedure1 
Screening 
DLT Observation Period 
Week 5 
Week 7 
Week 9  
Week 9 and 
thereafter 
Week 13 
and 
thereafter 
Every 26 
weeks 
End of 
Treatment2  
 
 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 1 
Day 1 
Day 1 
Every 4 
Weeks1 
Every 8 
Weeks 
Every 12 
Weeks 
 
 
Study Intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer GSK332659512 
 
X 
X 
 
 
X 
 
X 
X 
 
 
 
 
Dispense Study Drug 
(GSK3326595)13 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
Administer 5-Azacitidine14 
 
X 
(X)14 
 
 
X 
 
X 
X 
 
 
 
 
Vision Symptom Review15 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
AE review 
 
=====================[Continuous from Start of Treatment to 30 days after last treatment] =========→ 
SAE review 
=====================[Continuous from Signing of Informed Consent to 30 days after last treatment] =========→ 
Concomitant medication 
review 
============================== [Continuous from Signing of Informed Consent to EOT Visit] ============→ 
Review Diary Card  
 
=============================== [Continuous from Day 1 to EOT Visit] ====================→ 
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx) 
PK Plasma Samples16 
 
X 
X17 
X18 
 
X 
X18 
X 
X 
 
 
 
 
Plasma Samples (SDMA 
and Circulating 
Biomarkers)19 
 
X 
X 
X 
 
X 
X 
 
 
 
X 
 
 
Plasma Sample for 
cfDNA20 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Whole Blood Samples 
(Transcriptomics)19 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
Serum Sample 
(Translational Studies)19 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
Bone Marrow Biopsy 
(SDMA and Translational 
Studies)21 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Genetic Sample (Saliva)22 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Biopsy 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
33 
 
1. After Week 49, the assessment frequencies will be reduced to every 8 weeks. Refer to Section 8.1 of the full protocol for visit/procedure windows 
2. EOT visit to occur within 30 days from the last dose of the study treatment 
3. Refer to Section 8.4.1 for components of physical examination that must be performed at each visit 
4. On Day 1 and Day 8 triplicate ECGs will be obtained at or about the time of PK sample collection as described in the SRM 
5. Pregnancy testing only required for female participants of childbearing potential; see Section 5.3.1.1 for details. Must be within 7 days prior to the first dose. 
6. FSH/Estradiol testing only required for perimenopausal women whose childbearing potential is questionable; see Section 5.3.1.2 for details 
7. If test performed within 3 months prior to first dose of study treatment, testing at screening may not be required. Discuss with Medical Monitor if unclear 
8. Refer to Appendix 2: Clinical Laboratory Tests for list of required laboratory assessments.  Note that routine serum and urinalysis studies are required for all participants 
enrolled; additional serum and urine tests for participants with a baseline creatinine clearance < 60 ml/min/1.73 m2 should be performed as described in Appendix 2: Clinical 
Laboratory Tests. Clinical labs performed during screening within 72 hours prior to first dose do not need to be repeated on Day 1. Folate and selected vitamins to be drawn at 
Screening, Week 5, Week 9, and every 8 weeks thereafter and at EOT. If a participant’s folate or selected vitamins result(s) remain borderline or low at EOT visit, further 
testing may be requested until no longer deemed necessary in the opinion of the Investigator and Medical Monitor. 
9. Refer to Section 8.4.6 for description of components of ocular assessment.  If a participant’s ocular result(s) remain abnormal at EOT visit, further testing may be requested 
until no longer deemed necessary in the opinion of the Investigator and Medical Monitor.  
10. DEXA scheduling should allow for a 7 day washout period of CT IV and/or oral contrast agents. DEXA must be performed on the same machine for all evaluations on a 
particular participant.  On Week 8 and every 8 weeks thereafter DEXA scan can be collected within ±1 week. DEXA scans should be performed prior to CT scans, as both 
examination are to be done every 8 weeks. 
11. Only if EOT is >8 weeks from prior DEXA 
12. GSK3326595 will be administered for 2 weeks, followed by 2 weeks off in a 4 week cycle.  This SoA will be the same for alternative dosing schedules, assuming cycle is 4 
weeks long. In Dose Escalation cohorts participants will receive GSK3326595 either daily or twice daily. GSK3326595 will be administered orally with water (approximately 
200 mL) at approximately the same time of day (±4 hours for QD dosing and ±1 hour for BID dosing) with no food or antacids for 2h before and 1h after each dose. On serial 
PK day D1 participants should fast from 8 h prior to dose until 2 h after dose.  On serial PK days and for two days prior participants should attempt to take GSK3326595 within 
a 2 hour window (i.e. 10-12 hours for BID or 23-25 hours for continuous QD dosing after the last dose).Only for Cycle 1 Day 8 visit participants should take the drug with food 
(within 30 minutes).(in case of BID dosing participants, both Day 8 doses must be taken with food). 
13. Study drug (GSK3326595) will be dispensed every 4 weeks at the clinic. If after Week 49, the assessment frequencies are reduced to every 8 weeks, then the study drug 
would then be dispensed every 8 weeks 
14. 5-Azacitidine should be administered according to registered label, dose frequency can be as per local standard, for seven doses per cycle starting on the days indicated.  
Doses may be administered on seven consecutive days or, to allow for clinic scheduling and eliminate weekend dosing, once daily for 5 consecutive days starting on day 1, 
with no treatment on days 6-7, and then once daily for 2 consecutive days starting on Day 8 (e.g., Monday through Friday followed by the next Monday and Tuesday) 
15. At each visit, the investigator should specifically ask the participant about any changes in vision since their last visit/contact (Section 8.4.8.2).  The investigator should 
document the response, consider if there are any reported events which meet the definition of an AE or SAEs, and intervene as clinically appropriate following discussion with 
the Medical Monitor if necessary. 
16. PK samples for GSK3326595 and 5-Azacitidine following Day 1 and Day 8 dose will be collected at pre-dose (within 1 hour prior to dosing), 5 min±2 min, 30min±5min, 
1h±5min, 2h±5min, 3h±5min, 4h±10 min, 6h±10 min, 8h± 15min, 12h±2h (to be analyzed for GSK3326595 only, for BID GSK3326595 this will be prior to evening dose 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
34 
 
administration), 24h±2h (to be analyzed for GSK3326595 only, for BID GSK3326595 this sample will be post second dose administration). PK samples on days of subsequent 
visits should be collected within 1 hour Pre-dose.  If 5-Azacitidine is administered on a schedule that does not include dosing on Day 8 (e.g., Monday through Sunday), then 
steady-state PK collection should be obtained on a day (last dosing day of cycle 1) when both 5-Azacitidine and GSK3326595 are administered (e.g., on Day 7 or on Day 9). 
17. Serial PK samples for GSK3326595 and 5-Azacitidine will be collected on the last dosing day of cycle 1 for 5-Azacitidine 
18. PK pre-dose sample will be analysed for GSK3326595 only (not 5-Azacitidine) 
19. Plasma, serum, and whole blood samples should be collected Pre-dose on Day 1 and 4h (±0.5h) after dosing with GSK3326595 on the other days indicated. Day 8 sample 
collections may be performed 4h (±0.5h) after the last dose of 5-Azacitidine (Day 8 ±1 Day). Unscheduled samples for translational studies (see Section 8.7) should also be 
collected 4h (±0.5h) after dosing with GSK3326595 
20. Plasma for cfDNA will be collected on pre-dose on Day 1 and 4 hours post dose (±0.5h), Week 5 Day 1, Week 13 Day 1 and every 12 weeks thereafter for the duration of the 
study. 
21. Bone marrow biopsies for translational studies should be collected at screening and then 4h (±0.5h) on the days indicated, after dosing with GSK3326595.  Unscheduled 
biopsies for translational studies (see Section 8.7) should also be collected 4h (±0.5h) after dosing with GSK3326595 
22. Informed consent for optional genetics research should be obtained before collecting a sample. The sample will be collected at the first opportunity after a participant has met 
all eligibility requirements on Day 1 (pre- or post-dose) or later. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
35 
 
1.3.3. 
Part 2: GSK3326595 in combination with 5-Azacitidine 
Table 3 
Schedule of Activities, Part 2 Dose Expansion 
Procedure1 
Screening 
Week 1 - Week 4 
Week 5 Week 7 Week 9  
Week 9 and 
thereafter 
Week 13 
and 
thereafter 
Every 
26 
Weeks 
End of 
Treatment2 
Survival 
Follow-
up 
Day 1 
Day 8 
Day 
15 
Day 
22 
Day 1 
Day 1 
Day 1  Every 4 
Weeks1 
Every 8 
Weeks 
Every 12 
Weeks 
Screening 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Register Participant 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
Physical Examination3 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
12-lead ECG4 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
Pregnancy test5 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
FSH/Estradiol6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBsAg, HCV Antibody 
Screening7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Assessments8 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
Folate and selected vitamins8 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
TSH, free T3, free T4  
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
Ophthalmic Assessment9 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
DEXA Bone Densitometry10 
X 
 
 
 
 
 
 
 
 
X 
 
 
X11 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
36 
 
Procedure1 
Screening 
Week 1 - Week 4 
Week 5 Week 7 Week 9  
Week 9 and 
thereafter 
Week 13 
and 
thereafter 
Every 
26 
Weeks 
End of 
Treatment2 
Survival 
Follow-
up 
Day 1 
Day 8 
Day 
15 
Day 
22 
Day 1 
Day 1 
Day 1  Every 4 
Weeks1 
Every 8 
Weeks 
Every 12 
Weeks 
Study Intervention  
Administer GSK332659512 
 
X 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
Dispense Study Drug 
(GSK3326595)13 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
Administer 5-Azacitidine14 
 
X 
(X)14 
 
 
X 
 
X 
X 
 
 
 
 
 
Vision Symptom Review15 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
AE Review 
 
=====================[Continuous from Start of Treatment to 30 days after last treatment] =========→ 
 
SAE review 
========================= [Continuous from Signing of Informed Consent to 30 days after last treatment] =========→ 
 
Concomitant medication 
review 
============================== [Continuous from Signing of Informed Consent to EOT Visit] ===========→ 
 
Review Diary Card  
 
=============================== [Continuous from Day 1 to EOT Visit] ====================→ 
 
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx) 
PK Plasma Samples16 
 
X 
X17 
X18 
 
X 
X18 
X 
X 
 
 
 
 
 
Plasma Samples (SDMA and 
Circulating Biomarkers)19 
 
X 
X 
X 
 
X 
X 
 
 
 
X 
 
 
 
Plasma Sample for cfDNA20 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Whole Blood Samples 
(Transcriptomics)19 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
Serum Sample (Translational 
Studies)19 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
Bone Marrow Biopsy (SDMA 
and Translational Studies)21 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Genetic Sample (Saliva)22 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
Bone Marrow Biopsy 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Survival Follow-up23 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
37 
 
1. After Week 49, the assessment frequencies will be reduced to every 8 weeks. Refer to Section 8.1 of the full protocol for visit/procedure windows 
2. EOT visit to occur within 30 days from the last dose of the study treatment 
3. Refer to Section 8.4.1 for components of physical examination that must be performed at each visit 
4. On Day 1 and Day 8 triplicate ECGs will be obtained at or about the time of PK sample collection, as described in the SRM 
5. Pregnancy testing only required for female participants of childbearing potential; see Section 5.3.1.1 for details. Must be within 7 days prior to the first dose. 
6. FSH/Estradiol testing only required for perimenopausal women whose childbearing potential is questionable; see Section 5.3.1.2 for details 
7. If test performed within 3 months prior to first dose of study treatment, testing at screening may not be required. Discuss with Medical Monitor if unclear 
8. Refer to Appendix 2: Clinical Laboratory Tests for list of required laboratory assessments. Note that routine serum and urinalysis studies are required for all participants 
enrolled; additional serum and urine tests for participants with a baseline creatinine clearance < 60 ml/min/1.73 m2 should be performed as described in Appendix 2: Clinical 
Laboratory Tests. Clinical labs performed during screening within 72 hours prior to first dose do not need to be repeated on Day 1. Folate and selected vitamins to be drawn at 
Screening, Week 5, Week 9, and every 8 weeks thereafter and at EOT. If a participant’s folate or selected vitamins result(s) remain low or borderline at EOT visit, further testing 
may be requested until no longer deemed necessary in the opinion of the Investigator and Medical Monitor. 
9. Refer to Section 8.4.6 for description of components of ocular assessment. If a participant’s ocular result(s) remain abnormal at EOT visit, further testing may be requested until 
no longer deemed necessary in the opinion of the Investigator and Medical Monitor 
10. DEXA scheduling should allow for a 7 day washout period of CT IV and /or oral contrast agents. DEXA must be performed on the same machine for all evaluations on a 
particular participant (see SRM). 
11. Only if EOT is >8 weeks from prior DEXA 
12. GSK3326595 will be administered for 2 weeks, followed by 2 weeks off in a 4 week cycle. This SoA will be the same for alternative dosing schedules, assuming cycle is 4 
weeks long.  In Dose Expansion cohort participants will receive Recommended Combination Dose and Regimen. GSK3326595 will be administered orally with water 
(approximately 200 mL) at approximately the same time of day (± 4 hours) with no food or antacids for 2h before and 1h after each dose 
13. Study drug (GSK3326595) will be dispensed every 4 weeks at the clinic. If after Week 49, the assessment frequencies are reduced to every 8 weeks, then the study drug would 
then be dispensed every 8 weeks. 
14. 5-Azacitidine should be administered according to registered label, dose frequency can be as per local standard, for seven doses per cycle starting on the days indicated.  
Doses may be administered on seven consecutive days or, to allow for clinic scheduling and eliminate weekend dosing, once daily for 5 consecutive days starting on day 1, with 
no treatment on days 6-7, and then once daily for 2 consecutive days starting on Day 8 (e.g., Monday through Friday followed by the next Monday and Tuesday) 
15. At each visit, the investigator should specifically ask the participant about any changes in vision since their last visit/contact (Section 8.4.8.2).  The investigator should document 
the response, consider if there are any reported events which meet the definition of an AE or SAEs, and intervene as clinically appropriate following discussion with the Medical 
Monitor if necessary. 
16. PK samples for GSK3326595 and 5-Azacitidine following Day 1 and Day 8 dose will be collected at pre-dose (within 1 hour prior to dosing), 5 min±2 min, 30min±5min, 
1h±5min, 2h±5min, 3h±5min, 4h±10 min, 6h±10 min, 8h± 15min, 12h±2h (to be analyzed for GSK3326595 only, for BID GSK3326595 this will be prior to evening dose 
administration), 24h±2h (to be analyzed for GSK3326595 only, for BID GSK3326595 this sample will be post second dose administration). PK samples on days of subsequent 
visits should be collected within 1 hour Pre-dose.  If 5-Azacitidine is administered on a schedule that does not include dosing on Day 8 (e.g., Monday through Sunday), then 
steady-state PK collection should be obtained on a day (last dosing day of cycle 1) when both 5-Azacitidine and GSK3326595 are administered (e.g., on Day 7 or on Day 9). 
17. Serial PK samples for GSK3326595 and 5-Azacitidine will be collected on the last dosing day of cycle 1 for 5-Azacitidine 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
38 
 
18. PK pre-dose sample will be analysed for GSK3326595 only (not 5-Azacitidine) 
19. Plasma, serum, and whole blood samples should be collected Pre-dose on Day 1 and 4h (± 0.5h) after dosing with GSK3326595 on the other days indicated.  Day 8 sample 
collections may be performed 4h (± 0.5h) after the last dose of 5-Azacitidine (Day 8 ± 1 Day). Unscheduled samples for translational studies (see Section 8.7) should also be 
collected 4h (± 0.5h) after dosing with GSK3326595 
20. Plasma for cfDNA will be collected on pre-dose on Day 1 and 4 hours (±0.5h) post-dose Week 5 Day 1, Week 13 Day 1 and every 12 weeks thereafter for the duration of the 
study. 
21. Bone marrow biopsies for translational studies should be collected at screening and then 4h (± 0.5h) on the days indicated, after dosing with GSK3326595.  Unscheduled 
biopsies for translational studies (see Section 8.7) should also be collected 4h (± 0.5h) after dosing with GSK3326595 
22. Informed consent for optional genetics research should be obtained before collecting a sample. The sample will be collected at the first opportunity after a participant has met all 
eligibility requirements on Day 1 (pre- or post-dose) or later. 
23. All participants will be followed for survival approximately every 6 months  2 weeks until the study is completed  (See Section 4.5.2 for definition of Study completion) 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
39 
 
2. 
INTRODUCTION 
GSK3326595 is a potent, selective, reversible inhibitor of the protein arginine 
methyltransferase 5 (PRMT5) that is being tested as an oral treatment for human 
participants with cancer. Myelodysplastic syndrome (MDS) and acute myeloid leukaemia 
(AML) are bone marrow neoplasms for which novel, effective therapies are desperately 
needed. Study 208809 aims to test the safety, tolerability, and clinical activity of 
GSK3326595 in participants with MDS, chronic myelomonocytic leukemia (CMML) and 
AML. While GSK3326595 (either as a single agent or in combination with the standard 
of care drug 5-Azacitidine) will be the only investigational agent initially under 
investigation in study 208809, additional agents such as other investigational compounds 
or standards of care may be added at a later date. The inclusion of additional agents will 
require a protocol amendment. 
2.1. 
Study Rationale 
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 (as a consequence of 
ineffective hematopoiesis), molecular and/or karyotypic abnormalities, and an expansion 
of immature myeloid cells.  It is the quantitation of these immature myeloblasts (“blasts”) 
that, in part, differentiates AML from MDS, with a 20% blast percentage marking the 
transition from MDS to AML.  While multiple new targeted agents have been approved 
to treat AML in patients harbouring a limited number of mutations, the majority of 
patients with both MDS and AML are not eligible for these therapies.  Current therapies 
for most patients are inadequate: a newly diagnosed MDS patient may expect only to live 
for one to two years before dying of the disease, and the lifespan of someone diagnosed 
with AML would be even shorter, despite modern therapy.  Disease that relapses after 
standard treatment, or which fails to respond to therapy, confers an even more dismal 
prognosis.  The median OS for relapsed MDS is approximately six months, and there is 
no generally accepted standard of care for these patients.  As such, new therapies to 
prolong survival are desperately needed.   
Protein arginine methyltransferases (PRMTs) are a family of enzymes that methylate 
arginines in proteins involved in various cellular processes, including precursor 
messenger ribonucleic acid (pre-mRNA) splicing, transcription factors, kinases and 
histones [Karkhanis, 2011; Wang, 2008; Pal, 2007].  One family member, PRMT5, is 
responsible for the majority of symmetric dimethylation of arginine in vivo.  PRMT5 is 
overexpressed in a number of tumors, including myeloid malignancies [Tarighat, 2016].  
Inhibition of PRMT5 leads to decreased proliferation and cell death in preclinical models 
of AML.  GSK3326595 is a potent, selective, reversible inhibitor of PRMT5 currently 
under investigation in solid and hematologic tumors.  The first-in-human clinical study, 
204653 is evaluating subjects with solid tumors and non-Hodgkin’s lymphoma (NHL). In 
Part 1 of the dose escalation phase, the QD dose escalation population consisted of 
8 cohorts (12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, and 600 mg) and 
the twice daily (BID) dose-escalation population consisted of 4 cohorts (50 mg, 100 mg, 
150 mg, and 200 mg). The starting dose in Part 2 was 400 mg daily; however, it was 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
40 
 
subsequently agreed to start subjects at a dose of 300 mg daily due to safety and 
tolerability. 
Study 208809 is a Phase I/II study to evaluate the safety, tolerability, and clinical activity 
of GSK3326595 in participants with relapsed and refractory MDS and hypoproliferative 
AML that has evolved from an antecedent MDS (Part 1, “MDS cohort”).  Based on the 
interim analysis results of 300 mg cohort, further development in monotherapy setting is 
discontinued. Based on unmet medical need in MDS, CMML and AML patients, the 
modest clinical benefit seen in monotherapy setting and preclinical data showing 
combination activity and increased cytotoxicity of GSK3326595 with 5-Azacitidine in 
AML cell lines (data not published) further development in combination setting with 
5-Azacitidine will be explored in Part 2. Part 2 consists of a Dose Escalation phase where 
intermittent dosing schedule, two regimens of GSK3326595 will be administered in 
combination with 5-Azacitidine in participants with MDS, CMML or AML followed by a 
Dose Expansion cohort using the Recommended Combination Dose and Regimen 
verified within the Dose Escalation phase. While GSK3326595 (Part 1) and 5-Azacitidine 
in combination with GSK3326595 (Part 2) are initially the only agents to be tested in this 
trial, other agents may be added at a later date. The inclusion of any additional agents will 
require a protocol amendment prior to implementation.  
2.2. 
Background 
2.2.1. 
Clinical Background: MDS and AML 
MDS and AML are closely related neoplastic diseases of hematopoietic myeloid 
progenitors. In the United States in 2017, approximately 21,000 new cases of AML 
(Surveillance, Epidemiology and End Results (SEER) data) and 15,000 new cases of 
MDS (Leukemia and Lymphoma Society ([LLS ]) data) were reported; the incidence rate 
is similar in other developed nations including Western Europe and Australia [Deschler, 
2006].  This incidence is expected to rise in coming decades due to an aging population; 
the majority of cases of both diseases are diagnosed in patients greater than the age of 60.  
While curative approach to both diseases is possible via allogeneic stem cell transplant, 
the reality is that most patients will not be transplant eligible due to advanced age, lack of 
a suitable stem cell donor, or medical comorbidity. 
Patients with MDS and CMML are typically treated with a hypomethylating agent (either 
5-Azacitidine or decitabine).  Patients with AML who are ineligible for intensive therapy 
or who fail intensive therapy, may also be treated with either Azacitidine or decitabine 
[Almeida, 2016].  However, both agents are associated with a low ORR (15-30% in 
studies of MDS, per Vidaza and Dacogen package inserts).  Moreover, only 5-
Azacitidine improves OS in patients with high-risk MDS [Fenaux, 2009] and low-blast 
percentage AML [Fenaux, 2010]; while decitabine has failed to improve OS in either 
population [Kantjarian, 2006; Kantjarian, 2012].   
For patients with MDS who fail to respond to first-line therapy, or who progress on the 
therapy, there are currently no approved options.  Many proceed onto clinical trials, while 
others are treated with low-dose cytotoxic agents or with best supportive care (e.g., 
transfusion and growth factors). Recent data with the multi-kinase inhibitor rigosertib in 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
41 
 
high-risk MDS patients with relapsed and refractory disease demonstrated clinical benefit 
(including an ORR of 27%), though this clinical response did not result in improved OS 
[Garcia-Manero, 2016]. Increasingly, clinical trials have been conducted to evaluate the 
combination of novel agents with 5-Azacitidine with some promising early results. These 
combinations have been pursued in the relapsed setting, as well as in the front-line setting 
as the sole approved agents have an underwhelming rate of response and clinical benefit 
[Ball, 2017].  In front line setting, Magrolimab (monoclonal antibody against CD47) in 
Phase 1b study (NCT03248479) showed  91% ORR and 42% Complete Response in 
participants with Higher-Risk MDS Treated with Magrolimab Plus Azacitidine [Sallman, 
2020]. In addition, in front line setting of MDS combinations of Azacitidine are studied 
in Phase 3 with Venetoclax, BCL-2 Inhibitor (NCT04401748); with MBG453, 
anti-TIM-3 monoclonal antibody (NCT04266301); with pevonedistat, inhibitor of 
NEDD8-activating enzyme (NCT03268954) and with APR-246 molecule 
(NCT03745716). Often, these combinations are designed based on clinical considerations 
– utilizing an agent with some single-agent activity and evaluating it in combination with 
the only agent with proven efficacy, as a way of improving response rates in the front 
line. 
While treatment of MDS is currently limited to hypomethylating agents and intensive 
chemotherapy, the approach towards AML has become more complicated following 
recent advances in understanding the genetic and genomic landscape of the disease.  
Recent papers have characterized recurrent mutations and analysed them as they relate to 
one another [The Cancer Genome Atlas Research Network (TCGA), 2013]. Additional 
work has attempted to cluster these mutations into a novel classification scheme driven 
by the presence or absence of key genetic drivers of disease [Papaemmanuil, 2016].  
While a limited number of these mutations have yielded therapeutic benefit to date [Perl, 
2017], it raises the possibility that agents targeting other driver pathways may result in 
effective therapy of myeloid diseases. 
2.2.2. 
PRMT5 as a Target in Myeloid Neoplasms 
2.2.2.1. 
PRMT5 in MDS and AML 
Due to the poor overall prognosis for patients with myeloid neoplasms, and the lack of 
generally accepted therapies, novel targets are under investigation.  One such target is 
PRMT5, an enzyme that catalyzes the symmetric dimethylation of arginines in target 
proteins.  These targets include splicing factors, transcription factors, kinases and others 
[Karkhanis, 2011].  PRMT5 also methylates histone arginine residues (H3R8, H2AR3 
and H4R3), and these histone marks are associated with transcriptional silencing of tumor 
suppressor genes such as Retinoblastoma Protein 1(RB1) and Suppressor of 
Tumorigenicity 7(ST7) [Wang, 2008; Pal, 2007].  Additionally, symmetric dimethylation 
of H2AR3 has been implicated in the silencing of differentiation genes in embryonic 
stem cells [Tee, 2010]. PRMT5 plays a critical role in the cell-cycle and pro-apoptotic 
effects of p53 via two mechanisms: direct inhibition of p53 activity via methylation of 
arginine residues on p53 itself and degradation of p53 via differential splicing of MDM4, 
a p53 ubiquitin ligase [Berger, 2008; Bezzi, 2013]. Finally, PRMT5 plays a role in 
cellular signaling through the methylation of epithelial growth factor receptor (EGFR) 
and phosphoinositol-3 kinase (PI3K) [Hsu, 2011; Wei, 2012]. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
42 
 
PRMT5 has been implicated in the pathogenesis of AML and PRMT5 inhibition leads to 
cell growth inhibition in several preclinical models of AML (Serio, 2017; Kaushik, 2017; 
Tarighat, 2016).  GSK3326595 is a potent, selective, reversible inhibitor of PRMT5 
currently under investigation for use in multiple oncology indications.  GSK3326595 and 
related PRMT5 inhibitor (GSK3203591) attenuate growth and induce cell death in 
preclinical models of AML (Figure 1).  This suggests that PRMT5 is an appropriate novel 
target for therapy in AML and related diseases, including MDS.   
The first-in-class clinical compound, GSK3326595, is currently in the first-in-human trial 
204653 in solid tumors and non-Hodgkin’s lymphoma.  Study 208809 is the first 
evaluation of safety and efficacy of GSK3326595 in myeloid neoplasms. 
Figure 1 
Apoptosis and cell death evident in a panel of AML cell lines after 
treatment with PRMT5 inhibitor (GSK3203591) 
 
2.2.2.2. 
Spliceosomal Mutations and Potential Biomarkers for PRMT5 Inhibition 
in Myeloid Neoplasms 
PRMT5 plays an important role in the splicing of messenger Ribonucleic Acid (mRNA) 
via methylation of proteins in the spliceosome [Prusty, 2017; Gonsalvez, 2007].  This 
leads to differential expression of multiple proteins, including p53, that are critical for 
cell growth and death and can lead to tumorigenesis if dysregulated [Bezzi, 2013].  
Overall, PRMT5 is thought to be necessary for correct splicing, as conditional knockouts 
that are deficient for PRMT5 have selective retention of introns and skipping of exons 
with weak 5′ donor sites [Bezzi, 2013]. An identical splicing phenotype is observed in 
cancer cell lines treated with GSK3326595.  Therefore, pharmacologic inhibition of 
PRMT5 (e.g., via GSK3326595) acts as a splicing inhibitor.  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
43 
 
Mutations in genes (especially Splicing Factor 3B subunit 1 [SF3B1], Serine and 
Arginine Rich Splicing Factor 2 [SRSF2], U2 Small Nuclear RNA Auxiliary Factor 1 
[U2AF1], and Zinc Finger CCCH-Type, RNA Binding Motif and Serine/Arginine Rich 2 
(ZRSR2)) are relatively common in some myeloid malignancies.  They are more 
common in MDS and CMML, where up to 60% of patient samples have been 
demonstrated to harbour a mutation in these genes [Dvinge, 2016].  Mutations are less 
commonly identified in de novo AML, though they still rank among the most common 
recurrent mutations identified [Dvinge, 2016; TCGA, 2013].  Spliceosomal mutations 
have been shown to confer a poor prognosis in both AML [Papaemmanuil, 2016] and 
MDS [Taskesen, 2014].  Intriguingly, mutations in the different genes are mutually 
exclusive.  This has given rise to the hypothesis that cells may tolerate only a single ‘hit’ 
to the spliceosome, and therefore inhibiting mRNA splicing (e.g., via pharmacologic 
inhibition of the spliceosomal machinery) may confer therapeutic benefit to the subset of 
patients whose disease harbour underlying spliceosomal mutations. Recent work 
demonstrated increased sensitivity to PRMT5 inhibition in an Srsf2-mutant mouse AML 
tumor model compared to an isogenic Srsf2-wildtype control [Fong, 2019].  In-house 
preclinical studies have confirmed the sensitivity of splicing-factor mutant AML tumor 
models to inhibition of PRMT5. This research has shown increased growth inhibition and 
cell death in AML cell lines following treatment with a tool PRMT5 inhibitor 
GSK3203591. Interestingly, AML cell lines without splicing factor mutations were 
similarly sensitive, suggesting that, in addition to activity in splicing-factor mutant AML, 
PRMT5 activity in AML may also be more widespread (Figure 2).  
Figure 2 
Sensitivity of AML Cell Lines to PRMT5 Is Not Dependent on 
Spliceosome Mutational Status 
 
Study 208809 will enroll participants in a mutation-agnostic fashion.  Evaluation of the 
role of spliceosomal mutations will be performed retrospectively, and any changes in 
enrollment requirements will be made via protocol amendment. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
44 
 
2.2.3. 
Clinical Experience with PRMT5 inhibitors 
PRMT5 inhibitors, including GSK3326595, are currently being evaluated in the treatment 
of both solid tumors and hematologic malignancies. 
2.2.3.1. 
GSK3326595 - Study 204653 
Phase I Study 204653 is a FTIH study in relapsed and/or refractory solid tumors and 
non-Hodgkin’s lymphoma (NHL). In Part 1 (Dose Escalation Phase), participants have 
received doses up to 600 mg once daily (QD), or up to 200 mg twice daily (BID) and no 
maximum tolerated dose (MTD) has been established.  In Part 2 of the study, 
disease-specific expansion cohorts are being evaluated to further explore clinical activity 
of GSK3326595 in participants with selected solid tumors and NHL.  The starting dose in 
Part 2 in May 2018 was 400 mg QD; however, it was subsequently reduced to 300 mg 
QD after assessment of the safety and tolerability data in September 2019. 
The most common adverse events observed with GSK3326595 in Study 204653 at a 
starting dose of 400 mg/day (seen in at least 10% of participants) were fatigue/asthenia, 
anemia, nausea, alopecia, dysgeusia, thrombocytopenia/decreased platelet count, 
decreased appetite, stomatitis, dry skin, vomiting and diarrhea. Further information can 
be found in the latest IB.  In addition, within Study 204653, there have been two 
observations of optic neuropathy in participants treated with study drug over a prolonged 
period (>12 months exposure).  Although no causal relationship has been established, in 
order to ensure appropriate ongoing monitoring of participants within this study, all those 
treated will undergo ophthalmic assessments as described in Section 8.4.6. 
In addition to ophthalmic assessments, folate and selected vitamin levels will be 
monitored at baseline, Week 5, Week 9 and then every 8 weeks until EOT. 
2.2.3.2. 
Other PRMT5 inhibitors 
Apart from GSK3326595, four other PRMT5 inhibitors entered clinical trial 
development, including JNJ-64619178 (NCT03573310), PF-06939999 (NCT03854227), 
PRT543 (NCT03886831) and PRT 811 (NCT04089449).  Top-line safety data reported 
from Phase I studies of JNJ-64619178 and PRT543 reveal a similar profile of adverse 
events (fatigue, hematologic, and gastrointestinal [GI] effects). 
2.3. 
Benefit/Risk Assessment 
A summary of single-agent toxicities of agents under investigation in this study are listed 
below. More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of GSK3326595 may be found in the latest 
Investigator’s Brochure (IB) (GlaxoSmithKline Document Number 2017N314773_04).  
More detailed information about 5-Azacitidine may be found in the prescribing 
information (e.g., package insert). Section 2.3.2 outlines the risk assessment and 
mitigation strategy for this protocol. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
45 
 
2.3.1. 
Overlapping Toxicities (Part 2) 
Based on the clinical evidence to date, participants in Part 2 receiving both GSK3326595 
and 5-Azacitidine may be at increased risk of cytopenias compared to participants 
receiving either agent alone. Based on preclinical studies of GSK3326595 and preclinical 
and clinical experience with 5-Azacitidine, there is also the potential for overlapping 
gastrointestinal, hepatic, and reproductive toxicity. The potential for additive severity and 
incidence of these AEs exists. Refer to Section 7.1.2 for hepatic stopping criteria, to 
Section 11 for reproductive risk management guidelines, and to Appendix 12 for 
recommended toxicity management guidelines of GSK3326595. For toxicity 
management of 5- Azacitidine, refer to prescribing information.  
In addition, risks and mitigation strategies related to the COVID-19 pandemic are 
included in Appendix 13. 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
46 
 
2.3.2. 
Preclinical and Clinical Risk Assessment 
Identified Risks of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
GSK3326595 
Bone marrow: hematologic/lymphoid effects 
Preclinical Effects: 
Central and peripheral hematopoietic toxicity occurred in 
rats and dogs: Bone marrow - decreased cellularity, fibrosis 
(rats), asynchronous maturation and shift to immaturity with 
increased blasts; Peripheral - decreases in erythroid, 
myeloid and platelet counts; Lymphoid tissues - lymphoid 
depletion in thymus,  gut associated lymphoid tissue 
(GALT), lymph nodes and spleen. Complete or ongoing 
recovery following cessation of dosing. 
Clinical Effects: 
Based on the review of safety data as of the IB update (cut 
off date 04 February 2020) [GlaxoSmithKline Document 
Number 2017N314773_04], hematologic adverse events of 
anemia, thrombocytopenia/ decreased platelet count and 
neutropenia/decreased neutrophil count have been reported 
across all GSK3326595 clinical trials to date. Some of these 
events were SAEs and led to treatment withdrawal. 
ICF includes the risk of bone marrow/hematologic effects.  
Protocol includes exclusion criteria for recent bleeding 
events or uncontrolled thrombocytopenia.   
Protocol includes laboratory assessments (complete 
blood count [CBC], coagulation factors [international 
normalized ratio (INR), prothrombin time (PT), partial 
thromboplastin time (PTT)] and reticulocytes), monitoring 
for bruising/infection. 
Protocol includes dose stopping/modifications criteria for 
suspected Investigational Product (IP)-related 
hematologic toxicity. 
Gastrointestinal (GI) effects 
 
Preclinical Effects: 
Gastrointestinal toxicity was dose limiting in rats and dogs 
and included:  decreased body weight and food 
consumption;  emesis and abnormal stools (dogs: unformed, 
watery, mucoid, with red or black exudate); microscopic 
erosions, ulcers, hemorrhage, edema, inflammation, 
epithelial cell apoptosis/ degeneration/ regeneration, villous 
atrophy, decreased goblet cells, and crypt dilatation. Rats 
had epithelial hyperkeratosis/ hyperplasia of the tongue, 
esophagus and non-glandular stomach. These effects were 
reversible following discontinuation.  
ICF includes the risk of gastrointestinal effects.  
Protocol includes medical history, physical examination 
(including weight) and clinical laboratory assessments to 
assess toxicity in the GI tract.  
Protocol includes specific dose adjustment/stopping 
safety criteria for gastrointestinal toxicity. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
47 
 
Identified Risks of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Clinical Effects: 
Based on the review of safety data as of the IB update (cut 
off date 04 February 2020) [GlaxoSmithKline Document 
Number 2017N314773_04], GI adverse events of nausea, 
diarrhea, dysgeusia, vomiting and decreased appetite are 
among the most commonly reported treatment related 
adverse events in all GSK3326595 clinical trials to date.  
Fatigue/Asthenia 
Clinical data: 
Based on the review of safety data as of the IB update (04 
February 2020)[GlaxoSmithKline Document Number 
2017N314773_04] among the 183 participants in Study 
204653 of Part 2, the most frequent AE considered related 
to GSK3326595 was fatigue (42% of participants). Asthenia 
was noted in 21% of participants in Part 2.  For Study 
208809 of Part 1, fatigue was reported for 29% of 14 
participants in 400 mg cohort and 0% of 8 participants in 
300 mg cohort.  
Informed Consent Form (ICF) includes the risk of 
fatigue/asthenia. 
5-Azacitidine 
Hematologic Toxicity 
5-Azacitidine causes anemia, neutropenia and 
thrombocytopenia. 
Monitor complete blood counts frequently for response 
and/or toxicity, at a minimum, prior to each dosing cycle. 
After administration of the recommended dosage for the 
first cycle, adjust dosage for subsequent cycles based on 
nadir counts and hematologic response 
Liver 
Because 5-Azacitidine is potentially hepatotoxic in patients 
with severe pre-existing hepatic impairment, caution is 
needed in patients with liver disease. Patients with extensive 
tumor burden due to metastatic disease have been reported 
to experience progressive hepatic coma and death during 5-
Azacitidine treatment, especially in such patients with 
baseline albumin <30 g/L. 5-Azacitidine is contraindicated in 
patients with advanced malignant hepatic tumors.   
Monitor liver chemistries prior to initiation of therapy and 
with each cycle.  
Safety and effectiveness of 5-Azacitidine in patients with 
MDS and hepatic impairment have not been studied as 
these patients were excluded from the clinical trials. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
48 
 
Identified Risks of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Renal 
Renal toxicity ranging from elevated serum creatinine to 
renal failure and death have been reported in patients 
treated with intravenous 5-Azacitidine in combination with 
other chemotherapeutic agents for non-MDS conditions. In 
addition, renal tubular acidosis, defined as a fall in serum 
bicarbonate to <20 mEq/L in association with an alkaline 
urine and hypokalemia (serum potassium <3 mEq/L) 
developed in 5 patients with CML treated with 5-Azacitidine 
and etoposide. 
Monitor serum creatinine and electrolytes prior to initiation 
of therapy and with each cycle. If unexplained reductions 
in serum bicarbonate <20 mEq/L or elevations of Blood 
Urea Nitrogen (BUN) or serum creatinine occur, reduce or 
hold the dose. 
Patients with renal impairment may be at increased risk 
for renal toxicity. Also, 5-Azacitidine and its metabolites 
are primarily excreted by the kidney. Therefore, monitor 
these patients closely for toxicity.  Patients with MDS and 
renal impairment were excluded from the clinical studies. 
Tumor Lysis Syndrome 
5-Azacitidine may cause fatal or serious tumor lysis 
syndrome, including in patients with MDS. Tumor lysis 
syndrome may occur despite concomitant use of allopurinol 
Assess baseline risk and monitor and treat as 
appropriate. 
Differentiation Syndrome 
5-Azacitidine may cause life threatening or serious 
differentiation syndrome. Differentiation syndrome usually 
occurs within 1 to 2 weeks after starting treatment, but it can 
occur later. Signs and symptoms of differentiation syndrome 
include fever; cough; dyspnea; weight gain; edema; 
pericardial or pulmonary effusion; hypotension; and acute 
renal failure. 
Assess baseline risk and monitor and treat as appropriate 
Reproductive 
Based on the mechanism of action and findings in animals, 
5-Azacitidine can cause fetal harm when administered to a 
pregnant woman. 5-Azacitidine administered to pregnant 
rats via a single intraperitoneal (IP) dose approximating 8% 
of the recommended human daily dose caused fetal death 
and anomalies. 
Advise females with reproductive potential to avoid 
pregnancy during treatment with 5-Azacitidine. Men 
should be advised to not father a child while receiving 
treatment with 5-Azacitidine. For male and female 
contraception and pregnancy guidelines, please refer to 
the local prescribing information for 5-Azacitidine. 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
49 
 
Potential Risks of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
GSK3326595 
Hepatic events 
Preclinical Effects: 
Hepatocellular single cell necrosis and Kupffer cell 
hyperplasia were present in rats but not dogs treated for 4 
weeks; these changes were still present in animals held 
without dosing for 4-weeks after the dosing period ended. 
This did not correlate with transaminase activities as these 
values were decreased rather than increased. There was 
minimal to moderate centrilobular hepatocellular 
degeneration/necrosis in early decedent rats on the 13 week 
study that were generally consistent with hypoxia secondary 
to cardiac damage/insufficiency. There were no hepatic 
effects in rats at the end of the 17-week off dose period. 
Clinical Effects: 
Based on the overall review of hepatic events as of the 
latest IB update (cut-off date 04 February 2020) 
[GlaxoSmithKline Document Number 2017N314773_04], 
there is no clinical evidence of drug-induced hepatic toxicity. 
ICF includes the risk of hepatic effects. 
Protocol includes hepatic eligibility criteria, laboratory 
assessments during the study, and dose 
stopping/modifications criteria for the management of 
hepatic events. 
Damage to Exocrine Tissues 
Preclinical Effects: 
Degeneration or apoptosis of acinar epithelial cells was 
present in rats treated for 4 or 13 weeks in pancreas, 
salivary gland, male mammary gland and/or Harderian 
gland.  Degeneration of male mammary and Harderian 
glands were recovering in animals held without dosing for 
4-weeks after the 4 week dosing period ended, but had fully 
recovered after a 17-week off dose period on the 13-week 
study. 
Clinical Effects: 
Based on the overall review of AE safety data as of the IB 
cut-off (4 February 2020) [GlaxoSmithKline Document 
ICF includes the risk of damage to exocrine tissues.  
Protocol includes laboratory assessment of pancreatic 
enzymes. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
50 
 
Potential Risks of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Number 2017N314773_04], there was no clinical evidence 
of drug induced pancreatic exocrine toxicity. 
Reproductive toxicity 
Preclinical Effects: 
Male dogs and rats had testicular changes (degeneration of 
germ cells within seminiferous tubules or tubular epithelial 
degeneration) with associated epididymal changes (luminal 
cell debris and reduced luminal sperm); reversibility was 
observed in rats after a 17 week off dose period. 
Female rats had atrophy of ovaries, uterus, cervix and 
vagina. A single high-dose female dog had follicular atresia 
on the 4-week study. GSK3326595 may impact male and 
female fertility. 
In an embryofetal development study in rats, GSK3326595 
was embryotoxic (increased pre- and post-implantation loss) 
and teratogenic (cardiac and skeletal malformations.  
Genotoxicity studies: in vivo rat micronucleus studies, Ames 
and mouse lymphoma studies (all GLP studies) were all 
negative. 
Clinical Effects: 
There have been no pregnancies reported as of the IB cut-
off, 04 February 2020 [GlaxoSmithKline Document Number 
2017N314773_04]. No reproductive toxicity has been 
reported, as of 04 February 2020. 
ICF includes the risk of reproductive effects. 
Protocol requires pregnancy testing for women of 
childbearing potential. 
Male contraception for at least 5 half-lives plus 90 days 
(95 days) after the last dose of GSK3326595, as 
recommended by June 2015 Food and Drug 
Administration (FDA) draft guidance document. 
Female contraception for at least 5 half-lives (5 days) plus 
one menstrual cycle after the last dose of GSK3326595. 
Bone and teeth effects 
Preclinical Effects: 
Bone (rats): sternebrae and femur/tibia had intramedullary 
woven bone deposition and/or fibrosis, with decreased 
mature or lamellar bone manifested as variable loss of 
primary and secondary spongiosa, premature growth plate 
closure and marrow hematopoietic hypocellularity. These 
findings were reversible after a 17 week off-dose period. 
Similar bone changes were not observed in dogs.  
Informed Consent Form (ICF) includes preclinical finding 
and the potential risk to humans.  
Protocol includes baseline and periodic dual energy x-ray 
absorptiometry (DEXA) for all participants on study 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
51 
 
Potential Risks of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Teeth (rats): pale, broken and/or missing incisors; 
ameloblast and odontoblast degeneration/necrosis and 
dental tubular degeneration. Rodent incisors grow 
continuously throughout their lifetime; currently only adults 
are included in ongoing clinical trials; potential concern for 
pediatric participants. 
Clinical Effects: 
A few participants were reported with bone adverse events 
(hypercalcemia, pathological fracture, osteoporosis) in Study 
204653 as of the IB cut-off (04 February 2020) 
[GlaxoSmithKline Document Number 2017N314773_04].  
and were attributable to underlying risk factors including 
bone metastasis (pathological fracture), advanced age and 
chronic renal failure. As there are insufficient data from 
participants previously treated or receiving ongoing 
GSK3326595 treatment, an association with these bone 
events and GSK3326595 cannot be determined. 
Evaluation of the non-clinical finding and any potential 
correlation to clinical studies continues. 
Ocular toxicity 
Preclinical data: 
There have been no eye findings in rats and dogs treated up 
to 13 weeks. Procedures conducted include indirect 
ophthalmoscopy and slit lamp biomicroscopy and histologic 
evaluation of the eye including optic nerve.  After a single 
dose of [14C]-GSK3326595, radioactivity (study method 
cannot determine parent vs. metabolite) was retained in the 
uveal tract of the eye in rats out to 14 days (last sampling 
timepoint). This is not unexpected since this indicates that 
drug-related material binds to melanin (radioactivity also 
detected in pigmented skin), a common property of many 
small molecule drugs. 
ICF will include the risk for optic neuropathy 
Protocol requires the investigator to ask participants 
about any changes in vision at every visit and document 
responses.  Ocular exams will be conducted at baseline 
and every 6 months, or sooner if a participant develops 
any new or evolving ophthalmic symptoms in the interval 
period (comprehensive ophthalmic exam with visual 
acuity, visual field assessment, OCT, and colour vision 
assessment). In addition, folate/B12 and selected 
vitamins level will be checked at Baseline, Week 5, 
Week 9 and then every 8 weeks until end of treatment 
(EOT). 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
52 
 
Potential Risks of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Clinical data:  
There have been reports of 2 participants in Study 204653 
with optic neuropathy related to study treatment. Based on 
GSK’s assessment of the overall data in these participants, 
there appears to be a link between GSK3326595 and optic 
neuropathy, as well as between low folate levels and the 
event. The events improved or fully resolved after 
discontinuation of GSK3326595 and with folic acid 
supplementation. 
At the present time there is insufficient evidence of a causal 
relationship between GSK3326595 and folate deficiency. 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
53 
 
2.3.3. 
Pharmacokinetic Risk Assessment  
Currently limited information on metabolism and elimination of GSK3326595 exists. The 
isozymes catalyzing metabolism of GSK3326595 have not yet been identified. From in 
vitro microsome, hepatocyte data oxidation and deacetylation of GSK3326595 are the 
primary pathways of metabolism. Based on preclinical information of DDI potential of 
GSK3326595, it is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6. GSK3326595 is also a potential P-glycoprotein (Pgp), MATE2-K, 
OAT3 and OCT2 substrate. 
As per the prescribing information and product monograph of VIDAZA, the 
pharmacokinetics of 5-Azacitidine were studied in 6 MDS patients following a single 
75 mg/m2 intravenous (IV) dose and a single 75 mg/m2 subcutaneous (SC) dose. 
5-Azacitidine is rapidly absorbed after SC administration; the peak plasma 5-Azacitidine 
concentration of 750 ± 403 ng/mL occurred in 0.5 hour. The bioavailability of SC 
5-Azacitidine relative to IV 5-Azacitidine is approximately 89% with mean half-life of 
41± 8 minutes. Published studies indicate that urinary excretion is the primary route of 
elimination of 5-Azacitidine and its metabolites, with mean elimination half-life of total 
radioactivity (5-Azacitidine and its metabolites) of about 4 hours. Based on in vitro data, 
Azacitidine metabolism does not appear to be mediated by cytochrome P450 isoenzymes. 
Therefore, CYP inhibitors and inducers are unlikely to have any impact on the 
metabolism of 5-Azacitidine. Metabolism of 5-Azacitidine is by spontaneous hydrolysis 
and by deamination mediated by cytidine deaminase. Clinically significant inhibitory or 
inductive effects of 5-Azacitidine on cytochrome P450 enzymes are unlikely. 
For participants enrolled in Part 2, the risk of a pharmacokinetic drug-drug interaction 
between GSK3326595 and 5-Azacitidine is low to moderate.  Untested effect of 5-
Azacitidine as a Pgp/BCRP/MATE2-K/OAT3/OCT2 inhibitor and unknown effects of 
GSK3326595 on cytosolic enzymes responsible for metabolism of 5-Azacitidine 
contribute to some of pharmacokinetic drug interaction risk. Therefore, Day1 and Day 8 
PK sampling will be done to monitor levels of GSK3326595 and 5-Azacitidine following 
the start of combination therapy.   
2.3.4. 
Benefit Assessment 
Study 208809 is an open-label study and the first to explore the clinical activity of 
PRMT5 inhibition in myeloid malignancies. As of the clinical data cut-off date of 30 
June 2020, 30 participants have been treated with GSK3326595 in Part 1 of Study 
208809 (n=13 at 400 mg and n=17 at 300 mg) and there were a total of 5 participants 
with clinical benefit events, 2 participants in 400 mg and 3 participants in 300 mg cohort. 
All participants enrolled in Part 1 have disease for which no standard of care therapy is 
available. These individuals are generally accepted as appropriate for clinical trials. 
Participants enrolled in Part 2 Dose Escalation will have either AML, MDS, CMML 
which has relapsed or is refractory to the standard of care, MDS or CMML that have 
neither responded nor progressed on 5-Azacitidine after 4 cycles, or are treatment naïve 
MDS, CMML. For patients with R/R disease or patients who have not responded to 5-
Azacitidine after 4 cycles, there is no standard of care established. While 5-Azacitidine is 
established as the front-line treatment for many patients with myeloid neoplasms, 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
54 
 
response rates with 5-Azacitidine monotherapy are low (17% CR rate, Fenaux, 2009). 
There are many ongoing clinical trials investigating 5-Azacitidine in combination with 
other agents in treatment naïve patients, aiming to improve on 5-Azacitidine 
monotherapy.  Participants enrolled in Part 2 Dose Expansion will be treatment naïve 
MDS or CMML. All participants in Part 2 will receive 5-Azacitidine, an active agent that 
is considered the appropriate front-line therapy for newly diagnosed MDS and CMML 
patients in combination with GSK3326595. In Part 2, the study will assess whether both 
agents in combination result in enhanced efficacy compared to historical responses to 
5-Azacitidine alone.  Refer to Appendix 12 for a full description of the response 
assumptions utilized in the study. 
2.3.5. 
Overall Benefit: Risk Conclusion 
Based on available data from preclinical and clinical development, these data indicate 
GSK3326595 inhibits PRMT5, and that this inhibition have some clinical utility in the 
treatment of myeloid malignancies. Taking into account the measures taken to minimize 
risk to participants in this clinical trial, the potential risks identified in association with 
GSK3326595 are justified by the anticipated benefits that may be afforded to participants 
in Part 1 (monotherapy) or in Part 2 in combination with an active standard-of-care 
therapy (5-Azacitidine). 
3. 
OBJECTIVES AND ENDPOINTS 
Part 1 
Objectives 
Endpoints 
Primary 
• 
To determine the clinical activity of 
GSK3326595 in participants with myeloid 
neoplasms 
• Clinical Benefit Rate (CBR), as defined as 
the percentage of participants achieving a 
complete remission (CR), complete 
marrow remission (mCR), partial remission 
(PR), stable disease (SD) lasting at least 8 
weeks, or hematologic improvement (HI), 
per International Working Group (IWG) 
criteria. 
Secondary 
• 
To determine the safety, tolerability, and 
recommended myeloid monotherapy 
dose of orally-administered GSK3326595 
in participants with relapsed and/or 
refractory myeloid neoplasms 
• 
Frequency and severity of adverse events 
• 
Frequency of dose limiting toxicities 
(DLTs) 
• 
To further describe the clinical activity of 
GSK3326595 in participants with relapsed 
and/or refractory myeloid neoplasms 
• 
Overall response rate (ORR), defined as 
the percentage of participants achieving a 
CR, mCR, or PR, per IWG criteria. 
• 
Progression free survival (PFS), defined 
as time from first dose to disease 


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
5 5  
 
P art 1  
O bj e cti ve s  
E n d p oi nt s  
pr o gr essi o n, as d efin e d by I W G crit eria, 
or d e at h d u e t o a ny ca us e, w hic h ev er 
occ urs e arli er  
•  
Ov er all s urviv al ( O S), defi ne d as ti me 
fr o m first d os e t o d eat h d u e t o a ny c a us e 
•  
T o c h ar act eriz e th e p h ar mac oki n etics 
( P K) of G S K 33 2 65 95 i n partici p a nts  wit h 
r el a ps e d a nd/ or r efr act ory my el oi d 
n e opl as ms  
•  
G S K 33 2 65 95 P K p ar a m et ers i n pl as m a 
f oll o wi n g si ngl e- ( Day 1) a nd r e p eat-dos e 
a d mi nistr ati o n of G S K3 3 265 9 5  
E x pl or at or y  
 
C CI


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
5 6  
 
P art 2  D o se Es c al ati o n  
O bj e cti ve s  
E n d p oi nt s  
Pri m ary  
•  
T o d eter mi n e th e saf ety, t oler a bility, an d 
r ec o m m e n d ed c o m bin ati on d os e a nd 
r e gi m e n of or ally -a d mi nist ere d 
G S K 33 2 65 95 w h en a d mi nist er e d i n 
c o m bi n ati on wit h 5-Az aciti din e  i n 
p artici p a nts wit h  my el oi d n eo pl as ms  
•  
Fr e q u ency a nd s everity of adv ers e eve nts  
•  
Fr e q u ency of DL Ts  
•  
Fr e q u ency of d ose i nterru ptio ns, d os e 
r e d ucti ons, an d tr e at m ent disc o nti nu ati on 
d u e t o a dv ers e ev ents  
S e c o n d ary  
•  
T o d eter mi n e th e cli nic al activity of 
G S K 33 2 65 95 pl us 5 -Az acitidi n e  i n 
p artici p a nts wit h my el oid n eo pl as ms  
•  
C o m pl et e R e missi o n ( C R ) r at e, d efin e d 
as t he p erc e nta g e of p articip a nts 
ac hi evi n g a C R per I W G criteria  
•  
T o d escri b e t he p h ar mac okin etics  ( P K) of 
G S K 33 2 65 95 a n d 5 -Azacitidi n e  aft er 
si n gl e- a nd r e pe at -d os e a d mi nistr ati o n  
•  
G S K 33 2 65 95 a n d 5 -Azacitidi n e  P K 
p ar a m eters i n pl as m a f oll o w i n g si n gl e- 
( Day 1) a nd r e pe at-dos e a d mi nistr ati o n of 
G S K 33 2 65 95  i n c o mbi n ati on wit h 
5 -Az aciti di n e . 
•  
T o f urt her d escri be t he cli nic al activity of 
G S K 33 2 65 95 pl us 5 -Az acitidi n e  i n 
p artici p a nts wit h my el oid n eo pl as ms  
•  
O R R, d efi ne d as t he p erc e nt a g e of 
p artici p a nts achi evi n g a C R, m C R, or P R, 
p er I W G crit eria.  
E x pl or at or y  
C CI


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
5 7  
 
P art 2 D o se Ex p a n si o n  
O bj e cti ve s  
E n d p oi nt s  
Pri m ary  
•  
T o d eter mi n e th e cli nic al activity of 
G S K 33 2 65 95 pl us 5 -Az acitidi n e  i n 
p artici p a nts wit h hi g h risk ne wly 
di a g nos ed M D S a nd C M M L  
•  C o m pl et e R e missi o n ( C R ) r at e, d efin e d as 
t h e p erc e nt a ge of particip a nts ac hi evi ng a 
C R p er I W G crit eria  
S e c o n d ary  
•  
T o d eter mi n e th e saf ety  a nd  t ol er a bility of 
or ally -a d mi nist er e d G S K3 32 6 59 5 w he n 
a d mi nist er e d i n c o m bin ati on wit h 5 -
Az aciti di n e  i n partici p a nts wit h hi g h risk 
n e wly di ag n ose d M D S a n d C M M L  
•  
Fr e q u ency a nd s everity of adv ers e eve nts  
•  
Fr e q u ency of d ose i nterru ptio ns, d os e 
r e d ucti ons, an d tr e at m ent disc o nti nu ati on 
d u e t o a dv ers e ev ents  
•  
T o d escri b e t he p h ar mac okin etics of 
G S K 33 2 65 95 a n d 5 -Azacitidi n e  aft er 
si n gl e- a nd r e pe at -d os e a d mi nistr ati o n  
•  
G S K 33 2 65 95 a n d 5 -Azacitidi n e  P K 
p ar a m eters i n pl as m a f oll o wi n g si n gl e - 
( Day 1) a nd r e pe at-dos e a d mi nistr ati o n of 
G S K 33 2 65 95  i n c o mbi n ati on wit h 
5 -Az aciti di n e.  
•  
T o f urt her d escri be t he cli nic al activity of 
G S K 33 2 65 95 pl us 5 -Az acitidi n e  i n 
p artici p a nts wit h hi g h risk ne wly 
di a g nos ed M D S a nd C M M L  
•  
O R R, d efi ne d as t he p erc e nt a g e of 
p articip a nts achi evi n g a C R, m C R, or P R, 
p er I W G crit eria.  
E x pl or at or y  
C CI
C CI


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
5 8  
 
4.  
S T U D Y D E SI G N  
4. 1.  
O v er all D e si g n  
St u d y 2 0 8 8 0 9 is a n o pe n -la bel, m ultice ntre, m ulti-part st u d y of G S K 3 3 2 6 5 9 5 as 
m o n ot hera p y a n d i n c o m bi nati o n wit h 5 -Azaciti di ne  i n partici pa nts  wit h m yel oi d 
mali g na n cies. Refer t o Fi g ure 3  f or t he o verall st u d y sc h e matic. 
A d diti o nal a ge nt(s) ma y be a d de d, eit her as si n gle a ge nt or i n c o m bi nati o n, t o a n y of t he 
Parts of t his st u d y base d o n e mer gi n g cli nical a n d precli nical dat a. A pr ot oc ol a me n d me nt 
will  be re q uire d t o i ncl u d e t he a d diti o nal a ge nts t o be use d i n t his st u d y.  
Part 1 ( Secti o n 4. 1. 1 ) is c o m p ose d of a safet y e val uati o n, f oll o we d b y a sin gle -ar m d ose 
e x pa nsi o n c o h ort t o deter mi ne t he C B R of G S K 3 3 2 6 5 9 5 i n partici pa nts  rela pse d a n d/ or 
refract or y M D S, C M M L, a n d h y p o pr oliferati ve A M L t hat has e v ol ve d fr o m a n 
a ntece d e nt M D S. Part 2 is c o m p ose d of t w o d ose escalati o n c o h orts of i nter mitte nt 
d os i n g of G S K 3 3 2 6 5 9 5 (Re gi me n 1 : 2  wee ks o n a n d 2  wee k s off Q D a n d Re gi me n  2: 
2  wee ks o n a n d 2 wee ks off  BI D ) i n c o m bi nati o n wit h 5 -Azaciti di ne  f oll o we d b y a 
si n gle-ar m d ose e x pa nsi o n c o h ort t o deter mi ne t he C R  rate of t he c o m bi nati o n of 
G S K 3 3 2 6 5 9 5 pl us 5 -Azaciti di ne  i n hi g h ris k ne wl y  dia g n os e d M D S  or C M M L . 
Partici pa nts  ma y c o nti n ue treat me nt i n t he st u d y u ntil disease pr o gressi o n, u nacce pta ble 
t o xicit y, wit h dra w al of c o nse nt, or ter mi nati o n of t he st u d y b y t he s p o ns or ( Secti o n 7 ).  
Partici pa nts  w h o c o nti n ue t o recei ve be n efit u p o n ter mi nati o n of a c o h ort (e. g., f or 
f utilit y) ma y c o nti n ue t o re mai n o n st u d y pr o vi de d t hat st o p pi n g criteri a i n Secti o n 7  are 
n ot met.  
S u p ple me ntar y st u d y c o n d uct i nf or mati o n n ot ma n date d t o be pres e nt i n t his pr ot oc ol is 
pr o vi de d i n t he acc o m pa n yi n g St u d y Refere nce Ma n ual ( S R M). T he S R M will pr o vi de 
t he site pers o n nel wit h a d mi nistrati ve a n d detaile d tec h nical i nf or mati o n t hat d oes n ot 
i m pact partici pa nt  safet y. 
C CI


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
59 
 
Figure 3 
Study Schematic 
 
4.1.1. 
Part 1: Single Agent Activity in Relapsed/Refractory MDS and 
Hypoproliferative AML 
The primary objective of Part 1 is to assess the clinical activity of GSK3326595 when 
administered as a single agent in participants with relapsed and/or refractory MDS (and 
related disorders) and hypoproliferative AML that has evolved from an antecedent MDS.  
Part 1 will consist of an abbreviated safety assessment to confirm a Recommended 
Myeloid Monotherapy Dose, followed by a single-arm dose expansion cohort to evaluate 
efficacy in this disease population. As described in Section 4.1.1.1.2, dosing will start at 
the solid tumor Part 2 Dose, as determined in Study 204653 (400 mg daily dose). Six 
participants will initially be enrolled, and the dose may be modified based on emerging 
toxicity in the myeloid population (in which case, additional participants will be enrolled 
at a different dose or schedule).  Once the recommended dose for myeloid malignancies 
is determined, additional participants (for a total of up to 35 participants treated at the 
Recommended Myeloid Monotherapy Dose) will be enrolled to assess the clinical 
activity of GSK3326595 in relapsed and/or refractory MDS and hypoproliferative AML 
that has evolved from an antecedent MDS (please refer to Section 5 for definitions of the 
study population).  Overall, up to 41 participants will be enrolled in Part 1: up to 
12 participants during dose confirmation, and approximately 29 participants in dose 
expansion. If 6 participants will be enrolled during dose confirmation and treated at the 
Recommended Myeloid Monotherapy Dose, only 29 additional participants need be 
enrolled in expansion cohort for a total of 35 participants to be treated at the 
Recommended Myeloid Monotherapy Dose.  
4.1.1.1. 
Part 1 Dose Confirmation  
Part 1 will incorporate a safety run-in cohort in order to confirm that the solid tumor 
Part 2 Dose, as identified in study 204653 (400 mg QD), does not confer unacceptable 
toxicity in a population of participants with myeloid malignancies.  The Neuenschwander 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
60 
 
continual reassessment method (N-CRM) [Neuenschwander, 2009] will be utilized to 
guide dose escalation/de-escalation decisions, based on the rate of dose-limiting toxicities 
(DLTs) observed in participants.  The dose of 300 mg QD was the starting dose for the 
dose expansion cohort due to tolerability issues (primarily fatigue) observed with the 
400 mg dose in the dose confirmation cohort and in 204653 study. 
4.1.1.1.1. Type and number of participants 
It is estimated that at least 6 and up to 12 participants will be enrolled into Part 1 Dose 
Confirmation.  The study population will be adults with a diagnosis of relapsed or 
refractory MDS, CMML, and hypoproliferative AML as described in Section 5. 
If a participants fails to receive at least 75% of the planned doses within the 28-day DLT 
observation period for reasons other than toxicity (e.g., concurrent illness or disease 
progression), the participant will be replaced by additional participant(s) assigned to the 
same dose level. 
4.1.1.1.2. Starting dose, planned dose levels, and alternative dosing schedules 
The starting dose for Part 1 will be the dose and schedule identified as the solid tumor 
Part 2 Dose in the FTIH Study 204653. At the time of publication of the 208809 original 
protocol, this dose and schedule is 400 mg QD. No dose escalation is planned beyond this 
dose, unless emerging data (e.g., PK or PD data) indicate that a higher dose is appropriate 
for participants with myeloid malignancies.   
In the possibility that the solid tumor Part 2 Dose is modified prior to initiation of the 
208809 study, then the starting dose for 208809 may be modified without requiring 
protocol amendment.  In this case, documentation (e.g., Note To File) will be provided 
detailing the change in dose, including the data and rationale for the dosing modification.  
The change will subsequently be reflected in the next scheduled 208809 protocol 
amendment. The solid tumor Part 2 dose was modified to 300 mg QD due to safety and 
tolerability during enrollment into Part 2 of Study 204653. Similarly in Study 208809 the 
starting dose was amended from 400 mg to 300 mg due to safety and tolerability issues.  
If participant-to-participant dose modification is required (e.g. for emerging toxicity in 
the 208809 study) in Part 1 of the protocol, the following dose levels will be utilized: 
Note that if the starting dose is altered, a modified version of Table 4 will be provided for 
reference in the documentation provided. 
Table 4 
Pre-planned dose levels 
DL+2 
800 mg QD 
DL+1 
600 mg QD 
DL0 
400 mg QD 
DL-1 
300 mg QD 
DL-2 
200 mg QD 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
61 
 
Alterations to the dosing schedule (including incorporation of intermittent dosing [e.g., 
3 weeks on, 1 week off]) may be made to the schedule of administration based on the 
results of emerging PK and safety data.  Any changes to the dosing schedule may be 
made only after review of all available data by the study team and investigators as 
described in the Dose Escalation Plan (Section 4.1.1.1.5), and clearance by the GSK 
medical monitor and an amendment submitted as required by national regulations. Any 
planned changes will apply to a cohort of participants and not an individual participant. 
Changes will be communicated to the site in writing along with justification and data 
supporting the change. 
4.1.1.1.3. Dose confirmation  
Approximately six participants will initially be enrolled at the dose described in Section 
4.1.1.1.2.  In the absence of DLTs, the dose escalation rules are deterministic. If DLTs 
are observed, an N-CRM model will be implemented to guide dose escalation/de-
escalation decisions. A 28-day dose limiting toxicity window will be utilized as described 
in Section 4.1.1.1.4.  Cohorts will be recruited in blocks of approximately three 
participants. The maximum number of participants assigned to any single dose will be at 
the discretion of the Sponsor in consultation with the investigators.  
N-CRM is a Bayesian model‐based adaptive dose finding approach. The design classifies 
the posterior distributions of probability DLT into four categories and makes dose 
recommendations: 
• Under-dosing: DLT rate<16% 
• Target toxicity: 16%<=DLT rate<33% 
• Excessive toxicity: 33%<=DLT rate<60% 
• Unacceptable toxicity: DLT rate>=60% 
At the end of the DLT observation period for each dose level, the posterior distribution of 
DLT rate will be summarized by the posterior probability of the DLT rate falling into the 
interval of under-dosing, target toxicity, excessive toxicity, and unacceptable toxicity 
respectively. If the probability of excessive or unacceptable toxicity is more than 25%, a 
dose de-escalation will be required. Planned dose levels for escalation/de-escalation are 
described in Section 4.1.1.1.2. 
4.1.1.1.4. Dose limiting toxicities  
An event is considered to be a dose-limiting toxicity (DLT) if the event occurs within the 
first 28 days of treatment and meets the criteria listed in Table 5, unless it can be clearly 
established that the event is unrelated to treatment. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
62 
 
Table 5 
Dose-Limiting Toxicity Criteria 
Toxicity 
DLT Definition 
Non-hematologic 
• 
Hepatic toxicity that meets Liver Stopping Criteria as defined in Section 
7.1.2. 
• 
Grade 3 nausea, vomiting or diarrhea that does not improve within 72h 
despite appropriate supportive treatment(s) 
• 
Grade 4 or greater nausea, vomiting, or diarrhea of any duration 
• 
Any other Grade 3 or greater clinically significant non-hematologic toxicitya 
Hematologic 
• 
Grade 4 or greater treatment-emergent neutropenia, anemia, or 
thrombocytopenia, lasting for ≥14 days in the absence of IP, that cannot be 
attributed to underlying disease 
Other 
• 
Inability to receive all seven planned doses of 5-Azacitidine (in Part 2) as 
well as at least 75% of the planned doses of GSK3326595 (Part 1 and 
Part 2) within the 28-day DLT observation period due to toxicity 
• 
Dose interruption, starting at any time in the DLT observation period, due to 
toxicityb, that lasts 7 days or prolongs scheduled interruption for 7 days or 
greater 
• 
Grade 2 or higher toxicity that occurs beyond 28 days which in the 
judgment of the investigator and GlaxoSmithKline (GSK) Medical Monitor is 
considered to be a DLT 
Toxicity Grading based on National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 4 
a. Except electrolyte imbalance or other laboratory abnormalities controlled without sequelae within 24h.  Discuss 
with Medical Monitor if there is a question regarding “clinically significant” 
b. Participants with prolonged dose interruption for reasons other than toxicity (e.g., acute illness, disease 
progression) will not be evaluable for DLT purposes and will be replaced in the cohort. 
4.1.1.1.5. Dose escalation decisions  
The GSK medical monitor, in joint discussion with the participating investigators, will be 
responsible for determining whether dose escalation or de-escalation during Part 1 should 
continue as recommended by the N-CRM approach. Prior to the dose escalation/de-
escalation decision, the medical monitor, clinical scientist, safety physician, clinical 
pharmacologist, 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 master study files at GlaxoSmithKline (GSK). 
4.1.1.1.6. Intra-participant dose escalation  
If the dose is escalated beyond the solid tumor Part 2 Dose, defined in study 204653, 
intra-participant dose escalations may be considered on a case-by-case basis, provided 
that the participant has completed the DLT observation period, that all participants at the 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
63 
 
next higher dose level have completed the DLT observation period, and that prior 
approval has been obtained from the GSK Medical Monitor. Participants may be dose-
escalated to the highest cleared dose. Individual participants may dose-escalate multiple 
times provided that the above criteria are met at each intra-participant dose escalation 
step. 
Safety assessments from these participants will be included in the determination of the 
Recommended Myeloid Monotherapy Dose. 
Participants approved for intra-participant dose escalation may require additional PK 
sampling on Day 15 at the higher dose, as specified in the SRM. Additional safety 
assessments may be specified at the time of dose escalation or schedule modification 
based on the safety profile in previous participants at the higher dose level. Intra-
participant dose escalations or schedule modification will be discussed with investigators 
and approved by the GSK Medical Monitor and safety monitoring required will be 
specified in writing. 
4.1.1.1.7. Identification of the recommended myeloid monotherapy dose  
The Recommended Myeloid Monotherapy Dose will be confirmed only if the posterior 
probability of excessive or unacceptable toxicity is no more than 25%. The excessive or 
unacceptable toxicity is defined as DLT rate exceeding 33%. 
Participants treated in dose confirmation cohort(s) at the Recommended Myeloid 
Monotherapy Dose will be included in the dose expansion cohort analysis. 
4.1.1.2. 
Part 1 Dose Expansion: Clinical Efficacy in Relapsed/Refractory MDS 
and Hypoproliferative AML 
Once the Recommended Myeloid Monotherapy Dose is identified, additional participants 
will be enrolled in a single-arm cohort (Part 1 Dose Expansion) at the Recommended 
Myeloid Monotherapy Dose to better characterize the clinical activity (as well as safety, 
PK, and PD profile) of GSK3326595 in relapsed and/or refractory MDS (and related 
diseases). Plasma samples for PK evaluation will be collected in all participants. PD and 
translational samples from blood and from bone marrow will be collected pre- and on-
study drug treatment at timepoints as defined in the SoA. The primary endpoint will be 
CBR, defined as the percentage of participants with CR, PR, complete marrow response, 
SD lasting at least 8 weeks, or HI, per IWG criteria (Appendix 9: IWG Criteria for 
Response for Participants in Part 1 and Part 2).  
4.1.1.2.1. Type and number of participants  
In Part 1 Dose Expansion, the cohort may be composed of up to 35 participants with 
MDS, CMML or hypoproliferative AML that failed to respond to standard therapy, or 
that progressed after responding to standard therapy, as described in Section 5.  The total 
number of participants enrolled in the expansion cohort will be smaller than 35, as 
participants enrolled in the dose confirmation cohort and treated at the Recommended 
Myeloid Monotherapy Dose will be included in dose expansion cohort analysis.  If 6 
participants are enrolled during dose confirmation and treated at the Recommended 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
64 
 
Myeloid Monotherapy Dose, only 29 additional participants need be enrolled in 
expansion cohort for a total of 35 participants to be treated at the Recommended Myeloid 
Monotherapy Dose. Refer to Section 9.1.1 for the statistical rationale for the number of 
participants to be enrolled. 
In Part 1 Dose Expansion, participants will not be replaced if they prematurely 
discontinue study intervention or withdraw from study. 
4.1.1.3. 
Treatment Arms and Duration 
All participants in Part 1 Dose Expansion will receive GSK3326595 as a single agent 
until progression, unacceptable toxicity, or withdrawal of consent. 
4.1.1.4. 
Dose Selection  
Participants will start dosing on Day 1 with the dose and schedule selected in Part 1 Dose 
Confirmation. 
4.1.1.5. 
Statistical Design  
Part 1 Dose Expansion will employ a Bayesian design that allows the trial to be 
monitored with the constraint of both Type I and Type II error rates. Clinical response 
will be assessed by bone marrow biopsy and defined per IWG criteria (see Appendix 9: 
IWG Criteria for Response for Participants in Part 1 and Part 2).  The evaluation is 
designed to exclude a 30% CBR representing best available therapy in favour of a 50% 
CBR. The rational for the historical control assumption is provided in Appendix 12: 
Rationale for Response Assumptions. The first interim futility analysis will be conducted 
after a minimum of 8 evaluable participants have completed at least two post-baseline 
efficacy assessments, have progressed or died, or have permanently discontinued from 
study intervention. The subsequent interim futility analysis will be performed every 2-3 
months depending on enrollment with minimum additional 5 evaluable participants. The 
decision rules, specifying the number of participants with a clinical response needed for 
continuing enrolment or, stopping for futility, are indicated in Table 6. The methodology 
is based on the predictive probability of success if enrolment continues to 35 [Lee, 2008].   


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
65 
 
Table 6 
Part 1 Expansion Cohort Stopping Criteria for Futility 
 Number of Evaluable 
Participants  
  This Number of CR, mCR, 
PR, SD ≥8 weeks or HI to 
Stop Early for Futility  
Probability of continuing 
enrolling when Clinical 
Benefit Rate (CBR)=0.3 
 Probability of continuing 
enrolling when CBR=0.5  
8 
0 
0.9424 
0.9961 
9 
1 
0.8040 
0.9805 
10 
1 
0.8040 
0.9805 
 11 
1 
0.8040 
0.9805 
 12 
1 
0.8040 
0.9805 
 13 
2 
0.7399 
0.9761 
 14 
2 
0.7399 
0.9761 
 15 
3 
0.6547 
0.9691 
 16 
3 
0.6547 
0.9691 
 17 
3 
0.6547 
0.9691 
 18 
4 
0.5924 
0.9648 
 19 
4 
0.5924 
0.9648 
 20 
5 
0.5202 
0.9588 
 21 
5 
0.5202 
0.9588 
 22 
5 
0.5202 
0.9588 
 23 
6 
0.4702  
0.9553 
 24 
6 
0.4702 
0.9553 
 25 
7 
0.4134 
0.9505 
 26 
7 
0.4134 
0.9505 
 27 
8 
0.3578 
0.9450 
 28 
8 
0.3578 
0.9450 
 29 
9 
0.3064 
0.9389 
 30 
10 
0.2407 
0.9259 
 31 
10 
0.2407 
0.9259 
 32 
11 
0.1968 
0.9156 
 33 
12 
0.1468 
0.8960 
 34 
13 
0.1035 
0.8677 
 35  
14 
0 
0 
These rules are intended as a guideline. Actual decisions will depend on the totality of the 
data. The decision to terminate the cohort will not depend solely on the results of the 
statistical model but will take all factors into account, including the results of the model, 
safety, tolerability, PK, and PD data. In some cases (e.g., under-representation of a given 
predictive biomarker in the participants treated at the time of interim analysis), additional 
participants may be enrolled even if the model suggests a low likelihood of activity. 
4.1.2. 
Decision Whether to Proceed to Part 2 
A formal interim futility data analysis was performed with data cut off 30th June 2020 for 
participants who have undergone at least two post-baseline disease assessments, have 
progressed or died, or permanently discontinued from study intervention. As of data cut 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
66 
 
off  30th June 2020, 30 participants have been enrolled to Part 1, 13 participants at 
400 mg dose and 17 participants cohort at  300 mg dose. As per Protocol, the design 
recommends to stop early for futility if number of clinical benefit events is ≤ 3 out of 
17 participants in the dose expansion cohort. Based on the interim analysis results 
reported of 300 mg cohort with data cut off 30th June 2020 further development in 
monotherapy setting is discontinued. Irrespective of the outcome of this analysis, any Part 
1 participants still receiving therapy with GSK3326595 may continue receiving study 
drug until progression, death, withdrawal of consent, unacceptable toxicity, or 
termination of the study by the Sponsor, as described in Section 7.1. Clinic visits and 
efficacy analysis should continue as described in the SoA. 
The decision to discontinue monotherapy development in myeloid malignancies is based 
on an evaluation of the efficacy (defined by the design in Table 6), and totality of safety, 
tolerability, PK, and PD data (including data from participants who prematurely 
discontinue therapy). The criteria to progress with monotherapy development required 
demonstrating single-agent efficacy in Part 1, during which both of the following criteria 
must have been met: 
• 
GSK3326595 can be safely and tolerably administered to the study population at a 
dose expected to achieve therapeutic concentrations, and 
• 
GSK3326595 demonstrated preliminary clinical activity based on clinical benefit 
rate, as defined by the design in Table 6. 
4.1.3. 
Part 2: Further Exploration of Efficacy in Myeloid Neoplasms  
Part 2 will be opened to   
• determine a safe and tolerable combination dose and regimen of GSK3326595 in 
combination with standard-of-care therapy, 5-Azacitidine, in patients with 
myeloid neoplasms (Part 2 Dose Escalation phase); and 
• to explore the clinical efficacy of the combination of GSK3326595 in 
combination with 5-Azacitidine, in treatment-naïve patients with MDS or CMML 
(Part 2 Dose Expansion phase) 
4.1.3.1. 
Part 2: 5-Azacitidine plus GSK3326595 
Part 2 will consist of two dose escalation cohorts with intermittent dosing (such as 
Regimen 1: 2 weeks on, 2 week off QD and Regimen 2: 2 weeks on, 2 weeks off BID)  to 
select a safe and tolerable GSK3326595 dose and regimen in combination with 
5-Azacitidine (the Recommended Combination Dose and Regimen). Dosing of 
GSK3326595 will start at 200 mg QD in cohort 1 and 100 mg BID in cohort 2 and 
escalate up to the Recommended Myeloid Combination Dose.  Once the Recommended 
Combination Dose and Regimen is determined, additional participants (for a total of up to 
35) will be enrolled to assess the clinical activity of GSK3326595 plus 5-Azacitidine in 
newly-diagnosed MDS and CMML participants.  Overall, approximately 83 participants 
will be enrolled in Part 2: approximately 24 participants in each dose escalation cohort 
and up to 35 participants in Dose Expansion cohort.  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
67 
 
4.1.3.1.1. Part 2 Dose Escalation  
Part 2 will incorporate two dose escalation cohorts with intermittent dosing in order to 
select a safe and tolerable dose and regimen of GSK3326595 when administered in 
combination with 5-Azacitidine. An N-CRM model will be utilized to guide dose 
escalation decisions, based on the rate of dose-limiting toxicities (DLTs) observed in 
participants. The final dose and regimen for evaluation of efficacy will be decided based 
on all available data, including safety, tolerability, PK, PD, and efficacy. 
Type and number of participants 
It is estimated that approximately 48 participants will be enrolled into Part 2 Dose 
Escalation. The study population will be adults with a diagnosis of myeloid neoplasms as 
described in Section 5.  
In order to be eligible for DLT determination, a participant must meet one of the 
following three criteria: 
• Have received all seven planned doses of 5-Azacitidine as well as at least 75% of 
the planned doses of GSK3326595 within the 28-day DLT observation period, or 
• Have received less than this minimum dose requirement due to toxicity in which 
case DLT should be recorded, or 
• Have received less than this minimum dose requirement for reasons other than 
toxicity but already experienced a DLT 
Any participant who does not meet this minimum dose requirement for reasons other than 
toxicity (e.g., concurrent illness or disease progression) will be replaced by additional 
participant(s) assigned to the same dose level. 
Starting dose, planned dose levels, and alternative dosing schedules 
Dose escalation will commence with the approved dose of 5-Azacitidine (75 mg/m2 dose 
for seven days in a 28-day cycle, as detailed in the registered label in combination with 
GSK3326595 administered,  at a starting dose of 200 mg QD (Regimen 1, cohort 1) and 
100 mg BID (Regimen 2, cohort 1) at schedule of 2 weeks on, 2 weeks off. 
Dosing will then escalate or de-escalate, using the dosing steps shown in Table 7. The 
dose of GSK3326595 administered in combination with 5-Azacitidine will not exceed the 
Recommended Myeloid Monotherapy Dose unless emerging data suggest that a 
therapeutic dose in combination requires a higher daily dose of GSK3326595 (e.g., if 
exposure is decreased due to drug-drug interaction). The 5-Azacitidine regimen will not 
be altered beyond the approved dose and schedule.  
Table 7 
Dose Escalation/De-escalation Dosing Steps in Part 2 
Dose levels 
QD dosing 
BID dosing 
D+1 
300 mg 
150 mg 
D0 
200 mg 
100 mg 
D-1 
100 mg 
75 mg 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
68 
 
If a dose reduction is warranted for a specific participant, participants may have two dose 
reductions as follows: a) For the QD regimen dose reductions will happen by 100 mg 
increments down to a dose 100 mg QD and by 25 mg increments down to a dose of 
50 mg for participants reducing below 100 mg QD. b) For the BID regimen, dose 
reductions will happen by 25 mg increments down to a dose level of 25 mg BID. Any 
further dose reductions (greater than two) will need to be discussed with the GSK 
medical monitor.  
Based on relative bioavailability substudy in study 204653, comparable plasma exposures 
of GSK3326595 were observed between tablets and capsules. As a result, participants can 
be administered either tablets/capsules in Part 2.  Alterations to the GSK3326595 dosing 
schedule (including intermittent dosing [e.g., 3 weeks on, 1 week off]) may be made to 
the schedule of administration based on the results of emerging PK and safety data. Any 
changes to the dosing schedule may be made only after review of all available data by the 
Study team and Investigators as described in the Dose Escalation Plan and clearance by 
the GSK medical monitor and an amendment submitted as required by national 
regulations. Any planned changes will apply to a cohort of participants and not an 
individual participant. Changes will be communicated to the site in writing along with 
justification and data supporting the change. 
Dose Escalation, Dose-Limiting Toxicities, and the Determination of the 
Recommended Combination Dose 
Participants will be enrolled in cohorts of approximately 3, starting at the dose level 
described in Section 4.1.3.1, using the dosing steps described in Section 4.1.3.1.1.  Dose 
escalation will use the N-CRM method described in Section 4.1.1.1.3.  Part 2 Dose 
Escalation will use the same DLT criteria described in Section 4.1.1.1.4.  Dose escalation 
decisions will all be made as described in Section 4.1.1.1.5.  Recommended Combination 
Dose will be the dose that maximizes the posterior probability of target toxicity interval 
as defined in Section 4.1.1.1.3 while controlling the posterior probability of excessive or 
unacceptable toxicity no more than 25%, or a lower dose that provides adequate PK 
exposure and biologic/clinical activity with superior tolerability. The Recommended 
Combination Dose and Regimen selection will be based on safety and tolerability and 
available PK and PD data.  
4.1.3.1.2. Part 2, Dose Expansion: Clinical Efficacy in Newly Diagnosed MDS and 
CMML 
Once the Recommended Combination Dose and Regimen is identified, additional 
participants will be enrolled in a single-arm, open-label, single cohort (Part 2 Dose 
Expansion) in order to better characterize the clinical activity (as well as safety, PK, and 
PD profile) of GSK3326595 in combination with 5-Azacitidine in newly diagnosed MDS 
and CMML participants. Plasma samples for PK evaluation will be collected in all 
participants. PD samples from plasma and from bone marrow will be collected pre- and 
on-study drug treatment at timepoints as defined in the SoA (Part 2 Dose Expansion). 
The primary endpoint will be CR rate, defined as the percentage of participants with CR 
per IWG criteria. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
69 
 
Type and Number of Participants 
In Part 2 Dose Expansion, the cohort will be composed of approximately 35 participants 
with newly diagnosed MDS and CMML, as described in Section 5.1. Participants will not 
be replaced if they prematurely discontinue study intervention or withdraw from study.   
Treatment Arms and Duration 
All participants in Part 2 Dose Expansion will receive GSK3326595 plus 5-Azacitidine 
until progression, unacceptable toxicity, withdrawal of consent, or termination of the 
study by the Sponsor, as described in Section 7.   
Dose Selection 
Participants will start dosing on Day 1 with the dose and schedule selected as the 
Recommended Combination Dose and Regimen in Part 2 Dose Escalation (Section 
4.1.3.1.1). 
Statistical Design 
A Bayesian approach has been designed to set up the decision-making framework for the 
study and is detailed in Section 9.1.2  including the operating characteristics of the 
overall trial design. The rational for the historical control assumption from 17% and the 
meaningful improvement to 32% is provided in Appendix 12. The first interim futility 
analysis will be conducted after 8 evaluable participants have had at least two post-
baseline efficacy assessments, have progressed or died, or have permanently discontinued 
from study intervention. The subsequent interim futility analysis will be performed every 
additional 9 evaluable participants. The decision rules, specifying the number of 
participants with a complete remissions needed for continuing enrolment or, stopping for 
futility, are displayed in Table 8. For example, if in the first 17 participants there is one or 
fewer complete remissions observed, the study can be stopped for futility. The interim 
analysis will be for futility only, i.e., the Dose Expansion cohort will not stop early for 
efficacy. All evaluable population will be used for the interim futility analyses. 
Table 8 
Part 2 Expansion Cohort Stopping Criteria for Futility 
Number of Evaluable 
Participants  
This Number of 
Confirmed Complete 
Remissions to Stop 
Early for Futility  
Probability of 
Continuing Enrolling 
When CR Rate=0.17 
Probability of 
Continuing Enrolling 
When CR Rate=0.32 
8 
0 
0.7753 
0.9546 
17 
1 
0.7059 
0.9496 
26 
3 
0.5733 
0.9417 
35 
7 
0.2151 
0.8803 
These rules are intended as a guideline. The decision to terminate the cohort will not 
depend solely on the Bayesian predictive probability of study failure but will take into 
account, safety, tolerability, available PK and PD data.  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
70 
 
4.2. 
Number of Participants  
It is estimated that a maximum of 113 participants will be enrolled in the study, divided 
as follows: 30 participants were enrolled in Part 1, 24 participants in each of the Part 2 
Dose Escalation Cohorts and approximately 35 in Part 2 Dose Expansion.  Further details 
of the type and number of participants are available in Section 4.1.1.1.1, Section 
4.1.1.2.1, Section 4.1.3.1.1, Section 4.1.3.1, and Section 4.1.3.1.2. 
4.3. 
Scientific Rationale for Study Design 
Given the unmet medical need of myeloid malignancies, a Phase I/II study (208809) is 
proposed. The study comprises multiple Parts to efficiently evaluate the safety and 
efficacy of GSK3326595) in relapsed/refractory MDS, CMML and AML, and 
GSK3326595 and 5-Azacitidine in myeloid neoplasms as described in Section 5. 
4.3.1. 
Part 1 
Part 1 is a dose escalation/expansion study in participants with relapsed/refractory MDS 
(and low-grade AML that has evolved from an antecedent MDS) to determine the 
recommended myeloid monotherapy dose, as well as whether to proceed with 
monotherapy development. Decisions will be based on both efficacy as well as safety. 
Efficacy will be monitored via interim analyses. A Bayesian design that allows the trial to 
be frequently monitored with the constraint of both Type I and Type II error rates will be 
used. Clinical response will be defined as CBR, per standard evaluation criteria (see 
Appendix 12 for definitions of response assessments and criteria).  The design is based 
on a historical CBR of 30% versus a clinically meaningful CBR of 50%; the rationales 
for these response assumptions are described in Appendix 12. 
Dose escalation/de-escalation decisions will be based primarily on the N-CRM, a well-
validated method for identifying the maximum tolerated dose (MTD) of oncology 
therapeutics. Dose re-escalation after a de-escalation step may be permitted based on the 
results of the N-CRM model. 
4.3.2. 
Part 2 
Part 2 consists of a dose escalation and dose expansion cohorts in participants with 
myeloid neoplasms (See Section 5) treated with GSK3326595 in combination with 
5-Azacitidine. The dose escalation part has been designed in order to explore a number of 
doses, intermittent schedule (2 weeks on, 2 weeks off) and regimens of GSK3326595 to 
determine the Recommended Combination dose and regimen. The Part 2 Dose Expansion 
cohort will explore clinical activity in newly diagnosed MDS or CMML.  
5-Azacitidine was chosen as a combination partner as it is a widely-used epigenetic agent 
that demonstrates an OS benefit in first-line high-risk MDS (Fenaux, 2009).  It is 
generally well-tolerated, with an acceptable incidence primarily of gastrointestinal and 
hematologic adverse events and can be administered to patients who would not otherwise 
be fit for intensive cytotoxic chemotherapy. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
71 
 
In Part 2, decisions will be based on both efficacy as well as safety. Safety and efficacy 
will be monitored as discussed in Section 4.3.1.  
4.4. 
Justification for Dose 
GSK3326595 has been previously administered to participants with myeloid 
malignancies and solid tumors, and GSK3326595 and 5-Azacitidine have not been 
previously administered in combination in any tumor type. 5-Azacitidine is currently 
approved as a single agent for use in MDS and CMML. 
4.4.1. 
Starting Doses  
4.4.1.1. 
GSK3326595 
A Phase I study (204653) with GSK3326595 (as a single agent) is currently underway in 
participants with advanced solid tumors and non-Hodgkin’s lymphoma. Doses of 12.5 to 
600 mg once daily (QD) and doses of 50 mg to 200 mg BID have been evaluated. Based 
on safety, tolerability, PK, PD, and efficacy data, 400 mg QD was selected as the solid 
tumor Part 2 Dose, however, it was subsequently agreed to start participants at a dose of 
300 mg daily due to safety and tolerability.  Refer to Section 2.3.2 for a summary of key 
preclinical and clinical risks, as well as to the latest GSK3326595 Investigator’s Brochure 
(GlaxoSmithKline Document Number 2017N314773_04) for full details of the clinical 
experience to date with GSK3326595. 
The doses explored in Part 1 of this study were 400 mg and 300 mg. 
Starting dose for the Part 2 combination with 5-Azacitidine has been lowered to 2 dose 
levels below 300 mg QD to manage overlapping toxicity with 5-Azacitidine, 100 mg QD 
continuous which is equivalent to 200 mg QD 2 weeks on/2 week off (same total dose of 
drug over a 4-week cycle). The equivalent dose for the BID regiment would be 100 mg 
BID 2 weeks on/ 2 week off.  
The maximum QD dose that will be investigated in combination with 5-Azacitidine is 
300 mg and for BID regimen it is 150 mg (2 weeks on, 2 weeks off). 
The rationale for further exploration of BID regimen at 100 mg BID is supported by 
PK/PD modeling of plasma cfSDMA suppression (unpublished data), predicted to 
achieve more optimal cfSDMA suppression across participants than 300 mg QD.  Similar 
decrease in plasma cfSDMA suppression was observed in patients treated with QD and 
BID regimen in Part 1 of study 204653.  The maximum decrease observed to date is 74% 
and 80% at day 15 of dosing 200 mg BID or 600 mg QD, respectively.  Similarly, 
analysis of plasma in 27 participants with MDS and AML revealed an average 77.7 % 
(±5 SD) and 75.6 % (±15 SD) decrease in cfSDMA after 15 days of treatment with 
300 mg QD and 400 mg QD of GSK3326595, respectively (unpublished data). 
The rationale for the intermittent dosing schedule (2 weeks on, 2 week off) was selected 
based on the available safety, tolerability, PK and PD data. More specifically: 1) the need 
to allow for sufficient bone marrow recovery as GSK3326595 and 5-Azacitidine can 
induce severe cytopenias, 2) data on time to achieve maximum reduction of cfSDMA in 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
72 
 
plasma (nadir of cfSDMA achieved at day 14), 3) median time of onset of most common 
adverse events related to GSK3326595 (unpublished data).  
4.4.1.2. 
5-Azacitidine 
The currently approved dose of 5-Azacitidine is 75 mg/m2 daily for 7 days (either 
7 continuous days or including 2-day interruptions to allow for weekends [e.g., Monday 
through Friday, then the following Monday and Tuesday]) to be administered by 
subcutaneous (SC) injection or intravenous (IV) infusion.  Dose reductions (up to 50%, 
administered on the same schedule) are recommended for participants experiencing 
hematologic toxicity as well as for treatment-emergent renal impairment.  While the 
inclusion/exclusion criteria (Section 5.1 and Section 5.2) exclude patients with significant 
kidney dysfunction at baseline, emerging toxicity may warrant a dose reduction as 
described in Appendix 11.  For Part 2 of this study, 5-Azacitidine will be administered at 
the 75 mg/m2 dose for seven days in a 28-day cycle, as detailed in the registered label. 
Refer to Section 6.1 of this protocol or Section 2 of the package insert for details of 
administration. 
4.5. 
End of Study Definition 
4.5.1. 
Participants Completion 
In Part 1, a participant is considered to have completed the study if he/she has been 
followed until death or completed Part 1 of the study. 
In Part 2 dose escalation a participant is considered to have completed the study if they 
have discontinued study treatment (either due to disease progression or reasons listed in 
Section 7) and completed the EoT visit and 30-day AE/SAE follow up after last dose of 
study drug, or withdrawn consent to further treatment/study participation. 
In Part 2 dose expansion a participant is considered to have completed the study if they 
have discontinued study treatment for reasons listed in Section 7, if they die while 
receiving study treatment, or are receiving ongoing study treatment at the time of the 
Sponsor’s decision to close the study.  
Participants who have not died and are no longer being followed up for survival are 
considered to have discontinued the study 
4.5.2. 
Study completion 
The study will be considered completed for purposes of a final analysis for Part 1 or 
Part 2 when participants have completed treatment as outlined in Section 4.5.2 and 70% 
of the participants enrolled in Part 1 have died and 70% of the participants enrolled in 
Part 2 dose expansion have died.  Survival follow up for remaining participants may not 
be needed.  However, the study or a particular part of the study may be stopped prior to 
completion (e.g., for toxicity or futility) as described in Section 4.1.  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
73 
 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
1. Males and females ≥18 years of age (at the time consent is obtained) 
2. Capable of giving signed informed consent as described in Appendix 1: Regulatory, 
Ethical, and Study Oversight Considerations which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
3. Able to swallow, retain, orally-administered medication 
4. Eastern cooperative oncology group (ECOG) performance status (defined in 
Appendix 10) of 0, 1, or 2 
5. Diagnosis of one of the following: 
• Part 1:  
o MDS classified as intermediate, high, or very high risk by International 
Prognostic Scoring System-Revised [IPSS-R] criteria, as described in 
Appendix 7: IPSS-R Scoring System for MDS [Greenberg, 2012]), OR 
o CMML classified as intermediate-2 or high risk per CMML-specific 
prognostic scoring system (CPSS) or clinical/molecular CPSS (CPSS-mol) 
criteria, as described in Appendix 8: CMML Scoring System  (Such, 2013; 
Elena, 2016), OR 
o MDS/CMML secondary to prior anti-neoplastic therapy, of any risk score, 
OR 
o AML, which has evolved from an antecedent MDS/Myeloproliferative 
neoplasms (MPN) of any risk score, provided that the myeloblast 
percentage in the marrow is ≤ 30% or the peripheral white blood cell 
count is less than 20,000 cells/µL in the absence of leukoreducing therapy 
(e.g., hydroxyurea, leukapheresis) 
▪ NOTE: Participants without a documented history of antecedent 
MDS/MPN must have AML with myelodysplasia-related changes 
or recurrent cytogenetic abnormalities per World Health 
Organization (WHO) criteria 
• Part 2 Dose Escalation:  
o MDS classified as intermediate, high, or very high risk by International 
Prognostic Scoring System-Revised [IPSS-R] criteria, as described in 
Appendix 7: IPSS-R Scoring System for MDS [Greenberg, 2012]), OR 
o CMML classified as intermediate-2 or high risk per CMML-specific 
prognostic scoring system (CPSS) or clinical/molecular CPSS (CPSS-mol) 
criteria, as described in Appendix 8: CMML Scoring System  (Such, 2013; 
Elena, 2016), OR 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
74 
 
o MDS/CMML secondary to prior anti-neoplastic therapy, of any risk score, 
OR 
o AML, with relapsed or refractory disease and ineligible for or have 
exhausted standard therapeutic options, provided the peripheral white 
blood cell count is less than 20,000 cells/µL in the absence of 
leukoreducing therapy (e.g., hydroxyurea, leukapheresis) 
 
• Part 2 Dose Expansion: 
o MDS Treatment naïve classified as high/very high by IPSS-Revised 
[IPSS-R] criteria, as described in Appendix 7: IPSS-R Scoring System for 
MDS [Greenberg, 2012]), OR 
o CMML Treatment naïve classified as intermediate-2 or high risk per 
CMML-specific prognostic scoring system (CPSS) or clinical/molecular 
CPSS (CPSS-mol) criteria, as described in Appendix 8: CMML Scoring 
System  
 
6. Prior therapy 
• Part 1: Participants must have disease that failed to respond to, or progressed 
despite, treatment at least one systemic therapy 
• Part 2 Dose Escalation:  
o Participants with MDS or CMML may: 
▪ have disease that failed to respond to, or progressed despite, treatment 
at least one systemic therapy 
OR 
▪ be treatment naïve; 
OR 
▪ have completed minimum 4 cycles of 5-Azacitidine and have not 
reported response or progression 5-Azacitidine 
o Participants with AML must have disease that failed to respond to, or 
progressed, despite treatment with at least one systemic therapy 
 
• Part 2 Dose Expansion Participants must have received no prior therapy for their 
disease of MDS or CMML, OR have completed no more than one cycle of a 
hypomethylating agent   
 
7. Molecular markers 
• Part 1: At least 12 participants must have documented loss-of-function 
mutation(s) at least one of the following genes/proteins: SF3B1, SRSF2, U2AF1, 
or ZRSR2; in addition, at least 12 participants must have documented wild type 
status of all of these genes/proteins.  While enrolment will initially proceed 
without consideration of mutational status, enrolment may be limited to one group 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
75 
 
or the other as the study proceeds based on the enrolment rates in each group, in 
order to ensure this minimum number of mutated and wild type participants. 
• Part 2:  30% of total participants in Dose Escalation on MTD for each Regimen 
and at least 14 participants in the Dose Expansion should have documented 
mutation(s) at least one of the following genes/proteins: SF3B1, SRSF2, U2AF1, 
or ZRSR2. While enrolment will initially proceed without consideration of 
mutational status, enrolment may be limited to one group or the other as the study 
proceeds based on the enrolment rates in each group, in order to ensure this 
minimum number of mutated participants. 
8. Participants with a prior history of stem cell transplant (autologous and/or 
allogeneic) are allowed if: 
• At least 3 months has elapsed from the time of transplant and 
• the participant has recovered from transplant-associated toxicities prior to the first 
dose of GSK3326595 and 
• For participants with a prior history of allogeneic transplant, 
o the participant has been off systemic immunosuppressive medications 
(including but not limited to: cyclosporine, tacrolimus, mycophenolate 
mofetil, or corticosteroids) for at least 1 month prior to the first dose of 
GSK3326595. Topical steroids are permitted 
o there are no signs or symptoms of acute graft versus host disease, other 
than Grade 1 skin involvement. 
o there are no signs or symptoms of chronic graft versus host disease 
requiring systemic therapy 
9. All prior treatment-related toxicities must be NCI-CTCAE v4 ≤ Grade 1 (except 
alopecia [permissible at any Grade] and peripheral neuropathy [which must be ≤ 
Grade 2]) at the time of treatment allocation. 
• Note: Participants with treatment-related toxicities that are unlikely to resolve per 
the investigator may be enrolled on a case-by-case basis after discussion with the 
medical monitor 
10. Adequate organ system functions (at both screening and where applicable pre-first 
dose) as defined in Table 9. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
76 
 
Table 9 
Definitions for Adequate Organ Function 
System 
Laboratory Values 
Hematologic 
 
Platelets 
10 X 109/L (participants may receive transfusion to 
ensure adequate platelet counts) 
PT/INR and PTT 
1.5 X upper limit of normal (ULN), unless 
participant is receiving systemic anticoagulation 
Hepatic 
 
Albumin 
2 g/dL 
Total bilirubin 
1.5 x ULN 
NOTE: Isolated bilirubin >1.5 X ULN is acceptable if: 
• 
bilirubin is fractionated and direct bilirubin 
<35% OR 
• 
participant has a diagnosis of Gilbert’s 
syndrome 
Alanine aminotransferase (ALT)  
2.5 x ULN 
Renal 
 
Estimated glomerular filtration rate (eGFR)a 
 50 mL/min/1.73 m2 
NOTE: Participants with eGFR of <60 
mL/min/1.73 m2 will require additional monitoring as 
described in Appendix 2: Clinical Laboratory Tests. 
a. 
EGFR should be calculated using the Chronic Kidney Disease Epidemiology Collaborative 
(CKD-Epi) method:- 
Females, serum creatinine >62 μmol/L: 144 x (serum creatinine x 0.0113/0.7)−1.209 x 0.993age 
Females, serum creatinine ≤62 μmol/L: 144 x (serum creatinine x 0.0113/0.7)−0.329 x 0.993age 
Males, serum creatinine >80 μmol/L: 141 x (serum creatinine x 0.0113/0.9)−1.209 x 0.993age 
Males, serum creatinine ≤80 μmol/L: 141 x (serum creatinine x 0.0113/0.9)−0.411 x 0.993age 
[Levey, 2009] 
NOTE:  Laboratory results obtained during Screening should be used to determine eligibility criteria.  In 
situations where laboratory results are outside the permitted range, the investigator may opt to retest the 
participant and the subsequent within range screening result may be used to confirm eligibility. 
11.  Agree to abide by the gender-specific contraceptive requirements described in 
Section 5.3.1. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. History of prior solid organ transplant 
2. History of a second malignancy, excluding non-melanoma skin cell cancer, within 
the last three years 
• Participants with second malignancies that were indolent, in situ or definitively 
treated may be enrolled even if less than three years have elapsed since treatment.  
Participants with a recent history of ductal carcinoma in situ (DCIS) that has been 
definitively treated may be enrolled irrespective of the time since diagnosis.  
Consult the GSK Medical Monitor if second malignancies meet the requirements 
specified above. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
77 
 
3. Active severe or uncontrolled infection.  Controlled infections are permitted. 
4. Symptomatic or untreated Central Nervous System (CNS) disease 
• Note that lumbar puncture (LP) is not required for study enrollment unless there is 
clinical suspicion for CNS disease 
• Participants with a history of CNS disease are permitted to enroll if they have 
previously received appropriate therapy and CNS remission has been 
documented. Participants on maintenance intrathecal chemotherapy may be 
enrolled and continue to receive therapy. 
5. Recent prior therapy, defined as follows: 
• Any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, 
whichever is longer, prior to the first dose of IP.  
o Participants in Part 2 may enroll during the first cycle of 5-Azacitidine and 
continue cycle 1 in combination with IP, after discussion between the 
investigator and the medical monitor 
• Prior therapy with biologic agents (including monoclonal antibodies) within 28 
days prior to the first dose of IP 
• Any radiotherapy within 14 days or major surgery within 28 days prior to the first 
dose of IP.  
• Note: participants receiving hormonal therapy for a definitively-treated 
malignancy (e.g., adjuvant therapy of localized breast or prostate cancer) may 
continue to receive adjuvant therapy during study, after discussion with the 
medical monitor 
6. Prior therapy with any PRMT5 inhibitor 
7. Current use of a prohibited medication or planned use of any forbidden medications 
during treatment with study drug(s) (see Section 6.6.1.3 for the list of medications). 
8. History of known human immunodeficiency virus (HIV) infection, or positive HIV 
test result at screening. NOTE: HIV – Patients may be eligible if they fullfill all of 
the requirements below: Have started on antiviral therapy for at least 4 weeks prior 
to start of study drug treatment, Not be taking HIV related therapy (antivirals, 
antibiotics) that is on the prohibited list per protocol, Have a CD4 count 
350 cells/uL, Have a HIV viral load <400 copies/ml  
9. Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test 
result at screening.  
Note: Participants with chronic HBV infection, who meet the criteria for anti HBV 
therapy may be eligible if patient is on a suppressive antiviral therapy prior to 
initiation of cancer therapy. 
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) is obtained. Also Hep C - Patients may be eligible if they have both: 
completed curative antiviral therapy, have a HCV viral load <quantifiable limit 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
78 
 
10. Any of the following cardiac abnormalities: 
• History, within the past 6 months prior to first dose of study drug(s), of acute 
coronary syndromes (including myocardial infarction and unstable angina), 
coronary angioplasty, or stenting 
• Baseline Corrected QT (Fridericia’s formula) interval (QTcF) 480 msec 
• Uncontrolled arrhythmias. Participants with rate-controlled atrial fibrillation prior 
to first dose of study drug(s) may be eligible. 
• Class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system. 
11. History of sensitivity to any of the study medications, or components thereof, or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation 
12. History of optic nerve neuropathy or neuritis. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Gender-Specific Restrictions  
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
5.3.1.1. 
Female Participants of Childbearing Potential 
A female participant of childbearing potential (woman of childbearing potential 
[WOCBP]) is eligible to participate if: 
• 
She is not pregnant, and 
• 
Not breastfeeding, and 
• 
Agrees to follow the contraceptive guidance in Appendix 4: Contraceptive Guidance 
and Collection of Pregnancy Information from the first dose of study intervention 
until at least 5 days plus one menstrual cycle after the last dose of GSK3326595 and 
at least the time period described in the current prescribing information after the last 
dose of 5-Azacitidine, whichever is longer (in Part 2).  The investigator should 
evaluate the effectiveness of the contraceptive method in relationship to the first dose 
of study intervention. 
A WOCBP must have a negative highly sensitive serum pregnancy test within 7 days 
before the first dose of study intervention. 
• 
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information. 
• 
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
79 
 
5.3.1.2. 
Female Participants of Non-Childbearing Potential  
Refer to Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information 
for definitions of “non-childbearing potential”.  Female participants of non-childbearing 
potential have no requirements for contraception.  If there is any question by the 
investigator and/or medical monitor regarding the child-bearing potential of a female 
participant, then an FSH and estradiol may be required at screening. 
5.3.1.3. 
Male Participants 
A male participant with a female partner of childbearing potential must agree to use 
contraception as detailed in Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information of this protocol from the first dose of study intervention of 
GSK3326595 until at least 95 days after the last dose of study intervention and at least 
the time period described in the current prescribing information after the last dose of 5-
Azacitidine, whichever is longer (in Part 2). 
All male participants must refrain from donating sperm from the first dose of study 
intervention until at least 95 days after the last dose of study intervention. 
5.3.2. 
Meals and Dietary Restrictions 
• 
Participants should be instructed to refrain from consumption of Seville oranges, 
grapefruit or grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit 
juices for at least 24 hours before the start of study intervention until after the final 
dose. 
• 
During each serial PK sampling day (e.g., Days 1 and 15 in Part 1, Day 1 and Day 8 
in Part 2), participants should be instructed to abstain from ingesting alcohol, 
tobacco products, caffeine- or xanthine-containing products (e.g., coffee, tea, cola 
drinks, and chocolate) for 24 hours before the start of dosing until after collection of 
the final PK sample. 
5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but 
who 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, and any serious adverse 
events (SAEs). 
Individuals identified as Screen Failures may be rescreened if the failure was based on 
elements of eligibility that may change, e.g., laboratory test results. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
80 
 
6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study Intervention(s) Administered 
Study 
Intervention 
Name: 
GSK3326595 
5-Azacitidine 
Dosage 
formulation: 
Hydroxypropyl 
methylcellulose 
(HPMC) Capsules 
Tablets 
Lyophilized powder in 
100 mg single-dose vials 
Unit dose 
strength(s)/ 
Dosage level(s): 
25 and 100 mg 
strengths as free-
base drug substance 
100 mg 
75 mg/m2 
Route of 
Administration  
Oral 
Subcutaneous or 
intravenous 
Dosing 
instructions: 
 
GSK3326595 is to be administered orally with 
water (approximately 200 mL) at 
approximately the same time of day (±4 
hours for QD dosing and ±1 hours for BID 
dosing) with no food or antacids for 2 h 
before and 1 h after each dose. Only for cycle 
1 day 8 visit in Part 2 Dose escalation 
participants should take the drug with food 
within 30 minutes (if BID, dosing cohort, both 
doses taken with food). If a dose is delayed 
by more than 4 hours, the participant should 
not take that dose and should mark the dose 
as “not taken”. On serial PK days and for two 
days prior, participants should attempt to take 
GSK3326595 within a 1 h window (i.e., 23-25 
hours after the last dose). Capsules/tablets 
should not be chewed or crushed. If dose 
regimen requires more than one 
capsule/tablet per dose, the capsules/tablets 
should be taken one at a time. 
Based on relative bioavailability substudy in 
study 204653, comparable plasma exposures 
of GSK3326595 were observed between 
tablets and capsules. As a result, participants 
can be administered either tablets or 
capsules in Part 2. Participants who started 
on capsules may be switched to tablets for 
Administer 75 mg/m2 
subcutaneously or 
intravenously for 7 days out 
of a 28 day cycle, as per 
prescribed information in 
registered label  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
81 
 
Study 
Intervention 
Name: 
GSK3326595 
5-Azacitidine 
the remainder of the study, once they have 
been notified by the Sponsor. 
Physical 
description 
Capsules of Opaque 
White (size 00) for 
100 mg, capsules of 
Opaque Light Green 
(size 1) for 25 mg  
White to almost white 
film coated tablets 
with no markings  
See dosage formulation 
Packaging and 
Labelling 
Study intervention will be provided in bottles. 
Each bottle will be labelled as required per 
country requirement.  
5-Azacitidine will be 
commercially available and 
will be stored, packaged, 
prepared, and labelled as 
per local standard. 
Manufacturer 
GSK 
Celgene or other 
manufacturers registered 
NOTE: These formulation details are current at the time of protocol finalization and may be 
updated in other documents (e.g., SRM and/or informed consent form) without requiring protocol 
amendment 
6.2. 
Method of Treatment Assignment  
Part 1, Part 2 
Upon signing informed consent, participants will be 
assigned a unique number in ascending numerical order at 
each study site. This number will remain consistent for 
the duration of the study. 
For all participants enrolled in the study, study intervention will be 
dispensed/administered at the study visits summarized in the SOA.  Returned study 
intervention should not be re-dispensed to the participants. 
6.3. 
Blinding  
This is an open-label study. Investigators and study team will have direct access to 
individual participant’s study intervention 
6.4. 
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 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
82 
 
(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 SRM.  
5. Precautionary action to limit exposure (example: wearing gloves, washing hands post 
exposure) should be taken by site staff during dispensing GSK3326595.  A Material 
Safety Data Sheet (MSDS) describing occupational hazards and recommended 
handling precautions will be provided to the investigator. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study 
contact.  
6.5. 
Study Intervention Compliance 
• 
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 
• 
When participants self-administer study intervention(s) at home, compliance with 
GSK3326595 will be assessed through review of dosing diaries during site visits and 
documented in the source documents and Case Report Form (CRF).  A record of the 
number of GSK3326595 capsules/tablets dispensed to and taken by each participant 
must be maintained and reconciled with study intervention and compliance records.  
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the CRF. 
• 
5-Azacitidine will be subcutaneously or intravenously administered to participants at 
the site.  Administration will be documented in the source documents and reported in 
the CRF. 
6.6. 
Concomitant Therapy 
6.6.1. 
Concomitant Medications  
Participants will be instructed to inform the investigator prior to starting any new 
medications from the Screening Visit until the end of the study (Final Study Visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF. The minimum requirement is that drug name, route of 
administration, dose and frequency of dosing, along with start and stop dates of 
administration should be recorded. Additionally, a complete list of all prior cancer 
therapies will be recorded in the eCRF. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
83 
 
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification. 
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter. 
6.6.1.1. 
Permitted Medications  
Participants should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, as appropriate. 
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. 
Hydroxyurea may be used as per local practice for control of leukocytosis, except as 
prohibited at time of enrollment in Part 1 and Part 2 (Section 5.1). 
6.6.1.2. 
Cautionary Medications  
The following paragraphs describe potential interactions between GSK3326595 and other 
medications.  While co-administration is not prohibited, these medications should be used 
with caution and additional monitoring for adverse effects should be utilized. 
 Perpetrator risk of GSK3326595 has been identified as a CYP1A2 inducer. Co-
administration of GSK3326595 and substrates of CYP1A2 (e.g., alosetron, duloxetine, 
melatonin, ramelteon, tasimelteon, tizanidine) should be avoided in order to prevent 
inadvertent under-exposure to these agents.  GSK3326595 is a substrate for P-gp.  Other 
P-gp substrates include medications such as 3-hydroxy-3-methylglutaryl-coenzyme A 
(HMGCoA) reductase inhibitors (statins) and digoxin, which may have a narrow 
therapeutic index.  While co-administration of other P-gp substrates with GSK3326595 is 
not prohibited, they should be used with caution and additional monitoring for adverse 
effects should be utilized.   
Though QT prolongation was not identified in pre-clinical animal studies of 
GSK3326595, medications that are associated with a risk of torsades de pointes (as per 
crediblemeds.org or similar database) should be used with caution.  If co-administration 
with GSK3326595 is necessary, additional ECG monitoring should be implemented until 
the medication is at steady state, as per standard clinical practice. 
6.6.1.3. 
Prohibited Medications  
Participants should not receive other systemic anti-cancer therapy for their myeloid 
disorder while on treatment in this study.  Any participant requiring new therapy for their 
myeloid neoplasm (e.g., chemotherapy, targeted therapy, immunotherapy, etc.) must be 
discontinued from study.  Participants previously on adjuvant hormonal therapy for 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
84 
 
definitively-treated tumors (e.g., localized breast or prostate carcinoma) may continue to 
receive their hormone therapy after discussion with the investigator and medical monitor. 
Note: with the exception of other systemic anti-cancer therapies, any medication 
(including antibacterials, antifungals, or antivirals) which are necessary for the health, 
well-being, and standard clinical care of participants with myeloid neoplasms are exempt 
from the restrictions below. 
No in vitro CYP phenotyping data are available for GSK3326595. In the absence of these 
data, strong and moderate inhibitors or inducers of CYP isoenzymes should not be 
coadministered with GSK3326595, except for those medications necessary for the health 
of the participant as noted in the paragraph above.  If administered (e.g., azole antifungals 
for treatment and/or prophylaxis of systemic fungal infection), then the date, dose, and 
duration of therapy with these concomitant medications should be recorded in the CRF. 
GSK3326595 was found to be a substrate for P-gp in bidirectional permeability assays 
using Continuous cell of heterogeneous human epithelial colorectal adenocarcinoma cells 
(Caco-2) and Madine-Darby canine kidney (MDCK)-II monolayers. GSK3326595 should 
not be co-administered with strong and moderate inhibitors of Pgp Such inhibitors 
include cyclosporine, tacrolimus, and ketoconazole. 
In addition, GSK3326595 is a substrate of MATE2-K, OAT3 and OCT2 uptake 
transporters; therefore, GSK3326595 should not be co-administered with strong and 
moderate inhibitors or inducers of MATE2-K, OAT3 and OCT2.  Such inhibitors 
include, but are not limited to, cimetidine, probeneacid, metformin, pyrimethamine, and 
benzylpenicillin (penicillin G). 
6.6.2. 
Concomitant Non-Drug Therapies  
Non-drug anti-cancer therapies (e.g., radiation therapy, surgery, and/or tumor 
embolization) will not be permitted from the screening visit through the End of 
Treatment visit. 
NOTE: Participants may receive focal palliative intervention during this study (e.g., 
radiation therapy for local management of leukemia cutis).  Any proposed focal 
therapy must be approved by the investigator and the medical monitor prior to 
intervention. 
Participants will abstain from using herbal preparations/medications throughout the study 
until the final study visit. Herbal products include, but are not limited to: St. John’s Wort, 
kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, 
saw palmetto, ginseng, and marijuana. 
6.7. 
Dose Modification 
In the dose escalation cohorts of Part 1 and Part 2, participants will be assigned to a dose 
level as described in Section 4.1.1.1.2 and Section 4.1.3.1.1, respectively. The 
participant’s dose may be escalated as described in Section 4.1.1.1.3 and Section 
4.1.3.1.1. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
85 
 
Dose modifications will be permitted on a case-by-case basis for management of toxicity 
or other adverse events.  Toxicity management guidelines for GSK3326595 may be 
found in Appendix 11.  Toxicity management guidelines for 5-Azacitidine may be found 
in the package insert.   
6.8. 
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 Section 8.3.2 and 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. 
If available, participants continuing on treatment at the time of final analysis may be 
offered the option to continue in a separate rollover trial, if available, based on the 
investigators’ discretion. 
For participants who discontinue on study treatment, any post study treatment will not be 
provided as part of the protocol. Upon discontinuation from assigned study treatment, 
participants may receive additional (non-protocol) therapy at the discretion of the treating 
physician. New therapy should be documented on the eCRF. Every effort should be made 
to complete the required withdrawal and follow up evaluations prior to initiating further 
therapy or dosing of an investigational agent (see Section 7 for follow-up assessments 
and procedures). 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not GSK is providing 
specific post-study treatment. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Participants will receive study intervention until disease progression, death or 
unacceptable adverse event.  In addition, study intervention may be permanently 
discontinued for any of the following reasons: 
• Deviation(s) from the protocol 
• Request of the participant or proxy 
• Investigator’s discretion 
• Participant is lost to follow-up 
• Study is closed or terminated. 
In all cohort(s), unless the cohort is closed early, survival follow-up will continue until 
the study is completed.  At such time, the cohort will be closed and any further follow-up 
on participants enrolled in that cohort will cease. Participants with lack of disease 
progression who are still receiving study intervention at the time of study completion 
may continue treatment through a separate mechanism (e.g., roll-over protocol). 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
86 
 
7.1. 
 Discontinuation of Study Intervention 
The primary reason study intervention was permanently discontinued must be 
documented in the participant’s medical records and electronic case report form (eCRF).  
If the participant voluntarily discontinues from intervention due to toxicity, ‘adverse 
event’ will be recorded as the primary reason for permanent discontinuation on the eCRF.  
Once a participant has permanently discontinued from study intervention, the participant 
will not be allowed to be retreated. 
All participants who discontinue from study intervention will have safety assessments at 
the time of discontinuation and during post study intervention follow-up as specified in 
the Schedule of Activities (Section 1.3). 
Participants who discontinue study intervention without disease progression should 
continue to be followed for disease assessment until disease progression or initiation of 
new anti-cancer therapy.  All participants who permanently discontinue study 
intervention will be followed for survival and new anti-cancer therapy (including 
radiotherapy) every 6 months until death or termination of the study by the sponsor. If 
participants are unable or unwilling to attend clinic visits during follow-up, contact to 
assess survival may be made via another form of communication (e.g., telephone, email, 
etc.). 
7.1.1. 
Disease Progression 
Participants with equivocal progression (e.g., mild increase in myeloblast content in the 
marrow without significant change in hematologic parameters in the periphery) may 
continue on study therapy provided that safety-related stopping criteria are not met.  
Participants whose disease assessment demonstrates progressive disease (PD) per 
standard criteria may continue to receive study intervention until progression is 
confirmed at a follow-up assessment at least 4 weeks after the first assessment 
demonstrating PD. These considerations should be balanced by clinical judgment (e.g., 
whether the participant is clinically deteriorating and unlikely to receive any benefit from 
continued treatment). 
If confirmed at least 4 weeks later, participants with PD should discontinue therapy with 
study drug(s).  However, participants with confirmed PD may remain on study on a case-
by-case basis (e.g., as long as the Investigator and the GSK Medical Monitor concur that 
the participant could continue to receive benefit, the participant is not experiencing 
serious toxicity, and there is no alternative treatment that is likely to benefit the 
participant). Discussion between the Investigator and the Medical Monitor must occur in 
order for a participant to continue study intervention once PD has been confirmed. 
Participants who continue on study beyond confirmed progression should continue to 
undergo all assessments described in the Schedule of Activities tables (Section 1.3).  
Participants who demonstrate continued progression at subsequent scheduled disease 
assessments may be required to discontinue therapy at the discretion of the Investigator 
and the Medical Monitor. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
87 
 
7.1.2. 
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 4 or Figure 5 , OR 
• when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant.  
Figure 4 
Liver Chemistry Stopping and Increased Monitoring 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
88 
 
Figure 5 
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm including Participants WITH documented liver 
metastases/tumor infiltration at baseline AND entry criteria 
ALT>2.5xULN but ≤5xULN 
 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6: Liver Safety: Required Actions and Follow-up Assessments and Study 
Intervention Rechallenge Guidelines. 
Refer to Section 7.1.6 for rechallenge guidelines after a liver safety event. 
7.1.3. 
QTc Stopping Criteria 
If a participant meets the corrected QT (QTc) interval duration criteria below, study 
intervention(s) will be withheld. 
• QTcF interval ≥500  msec OR interval increase from baseline ≥60 msec: Study 
drug(s) will be permanently discontinued unless the benefits of therapy outweigh 
the risk of rechallenge in the opinion of the investigator, the GSK Medical 
Monitor, as well as the GSK medical governance. In this situation, rechallenge 
may be permitted (see Section 7.1.6 for rechallenge guidelines). 
NOTE: QT interval duration criteria should be based on the average QTc value of 
triplicate electrocardiograms (ECGs) to include manual over-read. For example, if 
an ECG demonstrates a prolonged QT interval, obtain 2 additional ECGs over a 
brief period (e.g., within approximately 10 minutes of the abnormal ECG, if 
possible, and approximately 2 minutes apart from each other), and then use the 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
89 
 
averaged QTc values of the 3 ECGs to determine whether the participants should 
have study intervention discontinued. 
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF; defined as [QT/(RR1/3)]). 
• For eligibility and withdrawal, QTcF will be used for all participants. 
• For purposes of data analysis, QTcF will be used. 
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed. 
7.1.4. 
Other Stopping Criteria  
Stopping criteria for other toxicities (including nausea, diarrhea, and thrombocytopenia 
unable to be rescued by platelet transfusion) are detailed in Table 20. 
Safety will be reviewed on an ongoing basis by the Safety Review Team (SRT) which 
will be compromised of, at a minimum, a GSK medical monitor, GSK Global Safety 
representative, and GSK clinical study representative (including a representative from 
Biostatistics). Deaths, SAEs, and Grade 3/4 adverse events will be carefully evaluated for 
the possibility of causality. 
If clinically significant adverse events or toxicities are observed in more than one third of 
the participants, and/or if deaths related to study drug are observed, enrollment may be 
terminated, and/or a lower-dose cohort may be opened or expanded. 
7.1.5. 
Temporary Discontinuation 
Participants who require temporary withdrawal of study intervention s) (e.g., for 
toxicity), may be permitted to restart therapy as described in Table 20. 
7.1.6. 
Rechallenge 
7.1.6.1. 
Study Intervention Restart or Re-challenge  
If participant meets liver chemistry or QTc stopping criteria, do not restart/rechallenge 
participant with study intervention unless: 
• 
GSK Medical Governance approval is granted 
• 
Ethics and/or Institutional Review Board (IRB) approval is obtained, if required, and 
• 
Separate consent for treatment restart/rechallenge is signed by the participant 
Refer to Appendix 6: Liver Safety: Required Actions and Follow-up Assessments and 
Study Intervention Rechallenge Guidelines for full guidance.  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
90 
 
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, behavioural, 
compliance or administrative reasons.  
• 
An end of treatment (EOT) visit should be performed as detailed in the SoA 
• 
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 and report to the sponsor. 
• 
Refer to 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. 
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 or not 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 with a primary reason of lost to follow up.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations. 
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. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
91 
 
• 
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 during any 12 month 
period, including any extra assessments that may be required, will not usually exceed 
650 mL. 
• 
Whenever vital signs, 12-lead ECG, and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: 12-lead ECG, 
vital signs, and blood draws.  Whenever vital signs and blood draws are scheduled 
for the same nominal time, vital signs should be performed prior to blood draws.  
The timing of the assessments should allow the blood draw to occur at the exact 
nominal time. Detailed procedures for obtaining each assessment are provided in the 
SRM. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Visit Windows  
Screening (baseline to pre-dose):  
• Informed consent must be obtained prior to any study-specific evaluations or 
procedures.  However, there is no maximum time after which informed consent 
must be re-obtained. If a participant is re-screened, the informed consent does not 
need to be re-signed. 
• All other screening assessments should be completed within 14 days prior to first 
dose.  
• For females of childbearing potential, pregnancy testing should be performed 
within 7 days prior to first dose. 
Week 1: Visits during Week 1 must be performed on the day indicated.  All subsequent 
visits following Week 1 Day 1 (first day of dosing) must refer back to the Week 1 Day 1 
visit (i.e. all time windows that are allowed around each visit are relative to the Week 1 
Day 1 visit). 
Week 2 Day 1 (Day 8) to Week 9:  
• Based on participant and clinic schedule, assessments can be ± 2 days. 
• The Day 15 PK collection (for Part 1) and the Day 8 PK collection (for Part 2) is 
timed to permit evaluation of PK at steady-state dosing. Part 1 will evaluate PK of 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
92 
 
GSK3326595 alone; Part 2 will evaluate PK of both GSK3326595 as well as 
5-Azacitidine.  If a participant is not receiving drug on the steady state collection 
date (either as a consequence of a planned drug holiday or due to toxicity), then 
this PK collection should be rescheduled for a later timepoint when the participant 
is again being dosed at steady state, and the alternate collection date noted in the 
eCRF.  If a participant in Part 2 is receiving 5-Azacitidine in a fashion that does 
not administer dose on Day 8, then the steady-state PK collection should be 
obtained on the last day of 5-Azacitidine dosing. 
• The bone marrow biopsy at week 5 (for tumor PD and efficacy) should be 
performed ± 2 days.  
Every 4-week, 8-week, and 12-week visits after Week 9 until Week 49:  
• Based on participant and clinic schedule, assessments (including efficacy 
assessments at Weeks 13, 25, 26, 37, and 49) can be ± 5 days. 
Every 4-week, 8-week, 12-week and 26-week visits after Week 49:  
• After week 49, the every 4-week visits will change frequency to every 8 weeks.   
5 Azacitidine administration will remain on a 4 week cycle 
• For the every 8-12 and 26 -week visits, clinic visits can be scheduled  ± 7 days. 
• After week 49, bone marrow biopsies are only required as clinically indicated 
(e.g., for changing blood counts or other signs of clinical progression) 
End of treatment visit:  
• Should be within 30 days from last dose of study drug. If a participant is unable to 
return to the clinic due to hospitalization, site staffs are encouraged to telephone 
the participant for assessment of adverse events. 
Long term survival follow-up (not applicable to Part 2 dose escalation): 
• All participants who discontinue therapy should be followed for survival as 
described in Section 8.3.2.  Contact should be attempted every 6 months ± 2 
weeks. 
8.2. 
Critical Baseline Assessments  
8.2.1. 
Disease Characteristics  
The following information, as available, should be provided for all participants: 
• Cytogenetic and mutational evaluation of tumor sample at screening and/or 
following the most recent prior line of therapy 
• Information regarding prior lines of therapy, best response, duration of response 
(if any) 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
93 
 
8.2.2. 
Tumor Sample  
For all participants enrolled on study, a fresh baseline bone marrow biopsy (or biopsy of 
extramedullary disease, if bone marrow biopsy is not feasible or likely to be negative) is 
required and should be obtained within 14 days prior to the first dose of study drug(s). 
8.3. 
Efficacy Assessments 
8.3.1. 
Disease Assessment  
Bone marrow biopsies for response assessments will be performed as outlined in the 
Schedule of Assessments. Participants enrolled in Part 1 (including those with AML, 
CMML and MDS), and Part 2 will have responses graded per IWG criteria, as described 
in Appendix 9: IWG Criteria for Response for Participants in Part 1 and Part 2.  Note that 
for clear-cut cases of progression (e.g., new-onset leukemia cutis or emergence of 
myeloblasts in the peripheral blood) that bone marrow biopsy may not be necessary to 
document progression. 
8.3.2. 
Survival Assessments 
For the Part 2 dose expansion, all participants who discontinue therapy will be followed 
for survival every 6 months as outlined in the Schedule of Assessments.  Follow-up 
should be made by telephone, email, or other appropriate form of communications.  
8.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.4.1. 
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. 
8.4.2. 
Performance Status  
The performance status will be assessed using the ECOG scale (Appendix 10) as 
specified in the SoA. 
8.4.3. 
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.  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
94 
 
• 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. On days where vital signs are measured multiple times, 
temperature does not need to be repeated unless clinically indicated. 
Refer to the SRM for further details. 
8.4.4. 
Electrocardiograms 
• Triplicate 12-lead ECG will be obtained prior to dosing and single 12-lead ECG 
on days outlined in the SoA using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTcF intervals. Refer to Section 
7.1.3 for QTc withdrawal criteria and to Table 20 for management strategies for 
QTcF prolongation. Local ECG may be collected and read centrally. 
8.4.5. 
Bone Mineral Density 
In order to assess the clinical bone safety of GSK3326595, DEXA scans will be 
performed on all participants at baseline and approximately every 8 weeks thereafter 
(Section 1.3). This evaluation has been deemed most relevant as it is the clinical gold 
standard to detect any unexpected changes in bone mineral density (BMD), which may 
suggest an increased risk of fracture. Locally collected scans may be read centrally. 
For consistency in the assessment, wherever possible, DEXA scans should be performed 
on the same machine for all evaluations on a particular participant, if this is not possible, 
it should be discussed with the GSK Medical Monitor DEXA scans should be performed 
prior to CT scans, as both examinations are to be done every 8 weeks. 
DEXA scheduling should allow for a 7 day washout of CT IV and/or oral contrast agents, 
as these can interfere with the results of the analysis. Please refer to the SRM for more 
details. 
8.4.6. 
Ophthalmic Assessment 
Study sites must establish a close collaboration with an appropriately qualified eye-care 
specialist (ophthalmologist/optometrist) who in conjunction with the Investigator will be 
responsible for carrying out the schedule of ophthalmic assessments, and managing / 
referring any participant who develops visual symptoms and / or signs potentially 
associated with GSK3326595 exposure. 
Management of participants with potential treatment-related changes in vision must be 
performed in close collaboration with the Investigator, appropriately qualified eye-care 
specialist, and the GSK Medical Monitor. 
Participants will have listed below assessments performed by a qualified eye-care 
specialist at screening/baseline, then every 6 months and at EOT. The assessments may 
be expedited in the event that a participant develops any new or evolving ophthalmic 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
95 
 
symptoms and / or signs in the interval period between assessments. If an abnormal result 
is recorded at the EOT visit, additional assessment will be required as deemed necessary 
by the Investigator, appropriately qualified eye-care specialist and the GSK Medical 
Monitor.  
• Full comprehensive exam with best corrected visual acuity (BCVA) at distance 
for each eye 
• Humphrey Visual field assessment (or equivalent as agreed with the Sponsor) 
• Optical coherence tomography (OCT) of the optic nerve retinal nerve fibre layer 
(RNFL) with ganglion complex analysis 
• OCT of the macula 
• Assessment of color vision by Ishihara method 
Primary outputs of the Humphrey Visual Field and OCT assessments will be held 
centrally by GSK in the event that central or independent evaluation of these is deemed 
beneficial to support on-going safety evaluation.  
Additional examinations, if deemed necessary, may be performed at the discretion of the 
treating eye-care specialist, and in discussion with the Investigator and Medical Monitor. 
Further details can be found in the Ocular Manual. 
8.4.7. 
Clinical Safety Laboratory Assessments 
• Refer to Appendix 2: Clinical Laboratory Tests 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 relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant’s condition. 
• 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.  
• If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
• All protocol-required laboratory assessments, as defined in Appendix 2: Clinical 
Laboratory Tests must be conducted in accordance with the laboratory manual 
and the SoA. 
8.4.7.1. 
Urine and Serum Safety Studies 
All participants with eGFR at baseline of <60 mL/min/1.73 m2 should have additional 
urinary and serum tests performed as part of the clinical safety assessments.  These 
additional tests are included in Appendix 2: Clinical Laboratory Tests. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
96 
 
8.4.8. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3: Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
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 AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention(s) (see 
Section 7).  
8.4.8.1. 
Time Period and Frequency for Collecting AE and SAE Information 
• 
All SAEs will be collected from the signing of the ICF until 30 days post last dose at 
the time points specified in the SoA (Section 1.3).   
• 
All AEs will be collected from start of study treatment until 30 days post last dose 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 on the Medical History/Current Medical 
Conditions section of the CRF not the AE section. 
• 
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: 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of 
the study participation. However, if the investigator learns of any AE or 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. 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting. 
8.4.8.2. 
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.  
• 
One line of solicited questioning will be followed for the vision symptom review.  At 
each visit, the investigator should ask the participant “Have you had any changes in 
your vision since your last visit/contact?”. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
97 
 
8.4.8.3. 
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 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: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting. 
8.4.8.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a 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. 
• 
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. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information e.g., summary or listing of SAE) 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. 
8.4.8.5. 
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 
90 days after the last dose of GSK3326595 or as otherwise specified in package 
insert of 5-Azacitidine. 
• 
If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4: 
Contraceptive Guidance and Collection of Pregnancy Information. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.4.8.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting and all deaths, whether 
or not 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.  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
98 
 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities Medical Dictionary for Regulatory Activities 
(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. 
8.4.9. 
Treatment of Overdose 
For this study, any dose of study drug(s) greater than the protocol-specified dose within a 
24-hour time period  4 hours will be considered an overdose. 
GSK does not recommend specific treatment for an overdose of GSK3326595. 
In the event of a 5-Azacitidine overdose, the patient should be monitored with 
appropriate blood counts and should receive supportive treatment, as necessary. There is 
no known specific antidote for 5-Azacitidine overdose.  
In the event of any overdose, the investigator (or treating physician) should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
drug(s) can no longer be detected systemically and the duration of effect has been 
exceeded (at least 28 days). 
3. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of 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. 
8.5. 
Pharmacokinetics 
• Blood samples of approximately 2 mL will be collected for measurement of 
GSK3326595 (in all Parts). In Part 2, an additional 2 mL will be collected to 
characterize 5-Azacitidine as specified in the SoA. A maximum of 6 additional 
samples may be collected at additional time points during the study if warranted 
and agreed upon between the investigator and the sponsor. 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. 
Details of PK blood sample collection, processing, storage and shipping 
procedures will be provided in the Lab Manual. 


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
9 9  
 
•  Ge netic a n al ys es will n ot be perf or me d o n t hese w h ole bl o o d sa m ples u nless 
c o nse nt f or t his was i ncl u de d i n t he i nf or me d c o ns e nt. Partici pa nt c o nfi de ntialit y 
will be mai ntai ne d.  
•  O nce t he plas ma h as bee n a nal yze d f or G S K 3 3 2 6 5 9 5 a n y re mai ni n g plas m a ma y 
be a nal yz e d f or ot h er c o m p o u n d -relate d met a b olites a n d t he res ults re p orte d u n der 
a se parate pr ot oc ol . 
8. 6.  
G e n eti c s  
A 2 m L sali va s a m ple f or D N A i s olati o n will be c ollecte d fr o m partici pa nts w h o ha ve 
c o nse nte d t o partici p ate i n t he ge netics a n al ysis c o m p o ne nt of t he st u d y. Partici pati o n is 
o pti o nal. Partici pa nts w h o d o n ot wis h t o partici pate i n t he ge netic researc h ma y still 
partici pate i n t he st u d y.  
I n t he e ve nt of D N A e xtr acti o n fail ure, a re pl ace m e nt ge netic sa m ple ma y b e re q uest e d 
fr o m t he partici pa nt. Si g ne d i nf or me d c o ns e nt will be re q uire d t o o btai n a re place m e nt 
sa m ple u nless it was i ncl u de d i n t he ori gi n al c o ns e nt. 
See A p pe n di x  5 : Ge netics f or inf or mati o n re gar di n g ge n etic res earc h. Det ails o n 
pr ocesses f or c ollecti o n a n d s hi p me nt a n d destr ucti o n of t hese sa m ples ca n be f o u n d i n 
t he La b Ma n ual  
8. 7.  
P h ar m a c o d y n a mi c s a n d Bi o m ar k er s  
All partici pa nts will ha ve P D a n d bi o mar ker sa m pli n g perf or me d o n t he d a ys i n dicate d i n 
t he S o A.  A d diti o nal P D a n d/ or bi o mar ker assess me nts ma y be re q u este d o n a case-b y -
case basis i n a n u ns c he d ule d fas hi o n as dee me d a p pr o p riate bas e d o n e mer gi n g cli nical 
data (e. g., at ti me of res p o nse).  
 
. C ha n ge fr o m baseli ne le vels will be meas ure d. W h ole bl o o d sa m ples 
ma y b e utilize d f or t he  i de ntificati o n a n d/ or vali dati o n of a si n gle ge ne or gr o u p of ge nes 
i n dicati ve of m o d ulati o n i n res p o nse t o G S K 3 3 2 6 5 9 5. T his ge n e or ge n es ma y ser ve as a 
n o vel P D bi o mar ker of P R M T 5 i n hi biti o n b y G S K 3 3 2 6 5 9 5. T he P D o utc o me ma y b e 
c orrel ate d t o cli nical o u tc o me.  Bl o o d or t u m or sa m ples ma y als o b e use d t o disc o ver a n d 
vali date bi o mar kers i n dicati ve of resista nce or se nsiti vit y t o t he st u d y dr u g, 
G S K 3 3 2 6 5 9 5.  
W hile sa m ples c ollecte d f or t his st u d y will be pri maril y use d t o assess M D S, C M M L , 
A M L, a n d t he acti v it y of t he st u d y i nter ve nti o n, sa m ples ma y als o b e use d f or researc h t o 
de vel o p met h o ds, assa ys, pr o g n ostics a n d/ or c o m p a ni o n dia g n ostics relate d t o P R M T 5 
i n hi biti o n, disease pr ocess, pat h wa ys ass ociat e d wit h disease state, a n d/ or mec ha nis m of 
acti o n of t h e st u d y i nter ve nti o n or ot her treat me nts c urre ntl y u n der i n vesti gati o n.  
Bl o o d S a m ple C ollecti o n  
Plas ma sa m ples will be c ollecte d fr o m all partici pa nts i n Part 1 acc or di n g t o t he S R M f or 
t he p ur p ose of assessi n g p har mac o d y n a mic, pre di cti ve, a n d/ or diseas e-relate d 
bi o mar kers.  
C CI


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
100 
 
Peripheral whole blood samples will be collected as described in the Schedule of 
Activities (Section 1.3) and according to the SRM for the purpose of transcriptomic 
studies to assess pharmacodynamic, predictive, and/or disease-related biomarkers. 
Serum samples will be collected according to the SRM for the purpose of proteomics 
studies to assess pharmacodynamic, predictive, and/or disease-related biomarkers.  
Tumor Biopsy Collection 
A fresh bone marrow biopsy (or biopsy of extramedullary disease, if bone marrow biopsy 
is not feasible or likely to be negative) is required from all participants at screening and 
on the days indicated in the SoA.  When possible, bone marrow biopsy for PD and 
biomarker evaluation should be collected 6 hours (± 3 hours) after dosing with 
GSK3326595. If genomic testing (eg splicing factor mutations) of bone marrow biopsies 
was performed prior to enrollment, results and type of test used should be provided.  
Samples may also be used for research to develop methods, assays, prognostics and/or 
companion diagnostics related to PRMT5 inhibition, disease process, pathways 
associated with disease state, and/or mechanism of action of the study intervention or 
other treatments currently under investigation. 
8.7.1. 
Immunogenicity Assessments  
Immunogenicity or immunophenotyping studies may be conducted using multiplex 
Immunohistochemistry (IHC), gene expression, and/or alternative equivalent 
technologies.  This assessment may help identify possible combinations with immune 
therapies. 
8.7.2. 
RNA Transcriptome Research 
Transcriptome studies will be conducted using microarray, RNAseq, and/or alternative 
equivalent technologies, which facilitates the simultaneous measurement of the relative 
abundances of thousands of Ribonucleic Acid (RNA) species resulting in a transcriptome 
profile for a subset of blood and/or tumor biopsy samples. This will enable the evaluation 
of changes in transcriptome profiles that may correlate with biological response relating 
to MDS, CMML, AML, or the action of GSK3326595.  The same samples may also be 
used to confirm findings by application of alternative technologies. 
8.7.3. 
RNA Expression Research of a Subset of RNA Species 
RNA expression studies may be conducted using quantitative reverse transcription 
polymerase chain reaction (RT-PCR), and/or alternative equivalent technologies, which 
can facilitate the simultaneous measurement of the relative abundances of hundreds of 
RNA species resulting in a RNA expression profile for a subset of blood and tumor 
biopsy samples. The RNAs assayed may be those involved with the pathogenesis of 
MDS, CMML, AML, and/or the absorption, distribution, metabolism, or excretion of 
GSK3326595, or in the participant’s response to GSK3326595. In addition, continuing 
research may identify other proteins or regulatory RNAs that may be involved in 
response to GSK3326595 or the pathogenesis of MDS, CMML or AML. The RNAs that 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
101 
 
code for these proteins and/or regulatory RNAs may also be studied. This will enable the 
evaluation of changes in RNA expression profiles that may correlate with biological 
response relating to MDS, CMML, AML, or the action of GSK3326595. 
8.7.4. 
Circulating Cell Free DNA (cfDNA) Analysis  
Tumor-specific circulating nucleic acid (cfDNA) levels detected in plasma or serum have 
been found to correlate with increasing tumor burden. Furthermore, cfDNA in cancer 
participants can harbor many genetic alterations (mutations, microsatellite alterations, 
aberrant methylation), which are generally consistent with the tumor. Thus, tumor 
specific circulating cfDNA has the potential to be a useful biomarker of therapeutic 
response as well as offering a less invasive blood based technique for identifying and 
selecting participants for certain treatments. Given the promise of cfDNA blood based 
test for participant selection, this test will be explored to determine whether mutations in 
cfDNA correlate with that in the tumor tissue from which it is derived. This test may also 
be explored to correlate increasing cfDNA levels with increasing tumor burden. 
8.7.5. 
Proteome Research  
Proteomic studies will be conducted using any of a variety of mass spectrometry methods 
and/or alternative equivalent technologies which facilitates the simultaneous 
measurement of the relative abundances of hundreds to thousands of protein species 
resulting in a proteome profile for a subset of blood and/or tumor biopsy samples. This 
will enable the evaluation of changes in proteome profiles that may correlate with 
biological response relating to MDS, CMML, AML, or the action of GSK3326595.  The 
same samples may also be used to confirm findings by application of alternative 
technologies. 
8.8. 
Patient Reported Outcomes  
Patient Reported Outcomes (PROs) are not evaluated in this study. 
8.9. 
Health Economics OR Medical Resource Utilization and 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Sample Size Determination 
The sample size for each part of the trial was chosen to adequately characterize the 
safety, clinical activity, PK, and pharmacodynamic marker data based on the objectives 
of each part of the study. The references for the control assumption and rationale for 
meaningful improvement over the historical control are provided in the Appendix 12: 
Rationale for Response Assumptions. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
102 
 
9.1.1. 
Part 1 
Part 1 will evaluate safety and clinical activity of GSK3326595 in participants with 
relapsed or refractory MDS and low-grade AML that has evolved from an antecedent 
MDS. 
The Part 1 dose confirmation will be guided by the N-CRM model. No formal statistical 
hypotheses will be tested. The design classifies the DLT rate into four categories and 
makes dose recommendations based on posterior distribution of the four categories 
detailed in the Section 4.1.1.1.3. 
CRM model may not be employed until the first DLT occurs. It is estimated that at least 6 
and up to 12 participants will be enrolled into Part 1 dose escalation. The prior 
distribution assumptions will use the information from the GSK3326595 first time in 
human study 204653. Details on the model will be provided in the Reporting and 
Analysis Plan (RAP). 
The Part 1 expansion cohort will employ a Bayesian design that allows the trial to be 
monitored frequently with the constraint of both Type I and Type II error rates. The 
evaluation is designed to exclude a 30% clinical benefit rate (CBR) representing best 
available therapy in favour of a 50% clinical benefit rate. A close to non-informative 
prior will be used. Let p denote the CBR, the prior distribution used is p ~ Beta (0.05, 
0.05). The cohort will be stopped early due to futility if the predictive probability of 
success is less than 1%. The success is defined as posterior probability of CBR > 30% at 
the end of the cohort is larger than 89.1%. The first interim analysis will be performed 
when at least 8 participants become evaluable. The maximum sample size is 35 
participants, and the design will have type I error of 0.07 and power of 83%. 
9.1.2. 
Part 2 
Part 2 will evaluate safety and clinical activity of GSK3326595 in combination with 5-
Azacitidine in newly diagnosed MDS, CMML. 
9.1.2.1. 
Dose escalation  
The Part 2 dose escalation will employ N-CRM design, similar to what is used for Part 1 
dose escalation. The goal is to identify the MTD of GSK3326595 when combined with 
approved dose of 5-Azacitidine for each Regimen. It is estimated that approximately 
24 participants will be enrolled in each Part 2 dose escalation cohorts. The MTD is 
defined in Section 4.1.3.1.1. 
For each Regimen, simulations were conducted to determine the average sample size and 
percentage of times each dose would be selected as an MTD under different scenarios, 
assuming the N-CRM dose recommendations are followed. The simulations assume 
3 dose levels starting at the second dose level, recruiting in cohort size of approximately 
3 DLT evaluable participants, with maximum of 6 participants at each dose level 
(6 needed to declare an MTD) with further 6 for MTD confirmation, resulting in 
approximately 24 participants per dose escalation. The prior distribution assumptions for 
the combination treatment incorporates the information from the GSK3326595 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
103 
 
monotherapy first time in human study 204653 and results from Part 1 of this study. The 
minimally informative prior for each parameter (α, β) for the N-CRM two parameter 
logistic model are specified via a bivariate normal distribution with a separate mean and 
standard deviation (SD) for α and ln(β) and a correlation term, ρ, using reference dose 
level 2. The parameters of the model are: 
QD schedule: = -1.7681 (2.5018), ln() = -5.7972 (0.0012), ρ = -0.9975 
BID schedule: = -1.4373 (2.2972), ln() = -0.1725 (0.4273), ρ = -0.9964 
Further details on the model will be provided in the RAP. The simulation results are 
shown in Table 10. For each scenario a dose with a true DLT rate falling in the target 
toxicity interval are highlighted. The average sample sizes over the 1000 clinical trials 
simulated under the four simulation scenarios were 10.4, 9.4, 8.0 and 7.1 for QD and it is 
10.1, 8.6, 7.5 and 6.8 for BID schedule. The percent of trials with all toxic dose were 6%, 
23% 60% and 72% for QD and these were 9%, 38%, 65% and 75% for BID schedule. 
Table 10 
Operating Characteristics 
GSK3326595 
Dose and 
Regimen in 
combination 
with 
5-Azacitidine 
Scenario 1: 
Low Toxicity 
Scenario 2: 
Target Toxicity 
Scenario 3: 
Two Target Toxicity 
Scenario 4: 
High Toxicity 
True DLT 
Rate (%) 
Percent 
of Times 
Selecting 
Dose as 
MTD (%) 
True DLT 
Rate (%) 
Percent 
of Times 
Selecting 
Dose as 
MTD (%) 
True DLT 
Rate (%) 
Percent 
of Times 
Selecting 
Dose as 
MTD (%) 
True DLT 
Rate (%) 
Percent 
of Times 
Selecting 
Dose as 
MTD (%) 
300 mg QD 
20 
81.3 
20 
65.0 
40 
20.7 
45 
12.2 
200 mg QD 
10 
12.0 
15 
10.8 
30 
15.2 
35 
13.0 
100 mg QD 
0 
6.7 
10 
24.2 
20 
64.1 
25 
74.8 
150 mg BID 
20 
78.5 
25 
47.5 
40 
19.7 
45 
11.5 
100 mg BID 
10 
12.3 
20 
14.3 
30 
15.3 
35 
13.5 
50 mg BID 
0 
9.2 
15 
38.2 
20 
65.0 
25 
75.0 
 
9.1.2.2. 
Dose Expansion  
Part 2 Dose Expansion will treat approximately 35 participants and will employ a 
Bayesian approach that allows the trial to be monitored frequently as detailed in Table 8. 
The evaluation is designed to exclude a 17% CR rate for 5-Azacitidine in favour of a 
32% CR rate. The decision making framework was set up based on the positive and 
negative guideline. Positive guideline is set as at least 90% probability that the true CR 
rate with combination treatment is > 17%, or Pr (true CR rate > 17% | data) > 90%, and 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
104 
 
the negative guideline is set as at least 90% probability that the true CR rate is < 32%, or 
Pr(true CR rate < 32% | data) > 90%; if neither guidelines are met, ORR and safety will 
be taken in the decision making. A vague prior was used to assess the operating 
characteristics of the design with the prior distribution for the CR rate of Beta (0.017, 
0.036). The minimum observed value that meets the criteria for the positive guideline is 
10 or more CR out of 35 participants, the maximum observed value that meets the criteria 
for the negative guidelines is 7 or less CR out of 35 participants. Predictive probability 
(which is the probability of achieving failure at the end of study with 35 participants 
given the data observed) will be used to guide the interim decision-making, starting with 
8 evaluable participants.  The futility threshold is the predictive probability of negative 
guideline is more than 95%.  With such decision making framework, taking into account 
the interim analyses the operating characteristics are presented in Table 11.   
Table 11 
Operating Characteristics  
True CR Rate (%) 
Probability of 
continuing (%) 
Probability of stopping 
(%) 
Probability of making a 
decision based on other 
endpoints (%) 
17% 
5.9 
78.5 
15.6 
25% 
36.5 
36.1 
27.4 
32% 
71.2 
12.0 
16.8 
9.2. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled  
All participants who sign the ICF 
DLT Evaluable 
For DLT assessment (Part 1 Dose Confirmation and Part 2 Dose 
Escalation): defined as participants who received at least 75% of 
the planned doses of GSK3326595 and all seven planned doses 
of 5-Azacitidine (Part 2) within the 28-day DLT observation period 
or those who have had a DLT. 
Response Evaluable 
Defined as participants who have had two post baseline disease 
assessments, have progressed or died, or permanently 
discontinued from the study intervention 
All Treated 
Participants who receive at least one dose of GSK3326595 as 
monotherapy or at least one dose of both combination drugs as 
combination treatment. 
PK 
Participants from the All Treated Population for whom a PK 
sample is obtained and analyzed. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
105 
 
9.3. 
Statistical Analyses 
9.3.1. 
Efficacy Analyses 
9.3.1.1. 
Efficacy Endpoints  
Clinical benefit rate (CBR):  
• Part 1 and Part 2: defined as the percentage of participants with CR, mCR, PR, 
SD lasting at least 8 weeks, and HI, as per IWG criteria (Appendix 9: IWG 
Criteria for Response for Participants in Part 1 and Part 2). Participants with 
unknown or missing response will be included in the denominator when 
calculating the percentage. 
Complete remission rate (CR):  
• Part 2: defined as the percentage of participants with CR as per IWG criteria 
(Appendix 9: IWG Criteria for Response for Participants in Part 1 and Part 2). 
Participants with unknown or missing response will be included in the 
denominator when calculating the percentage.  
Overall Response Rate (ORR): 
• Part 1 and Part 2: defined as the percentage of participants with CR, mCR, or PR 
as per IWG criteria (Appendix 9: IWG Criteria for Response for Participants in 
Part 1 and Part 2). Participants with unknown or missing response will be 
included in the denominator when calculating the percentage. 
Progression Free Survival (PFS): 
• Part 1 and Part 2 Dose Expansion: defined as the time from the first dose of study 
intervention to disease progression per IWG criteria or death due to any cause, 
whichever occurs earlier. Participants who have not progressed or died at the time 
of the PFS analysis, 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 anti-cancer therapy prior to a PFS event will be 
censored at the date of last adequate disease assessment (assessment where visit 
level response is CR, mCR, PR, HI, 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 RAP. 
Overall Survival (OS):  
• Part 1 and Part 2 Dose Expansion: defined as the time from the first dose of study 
intervention to the death due to any cause. Participants who are alive at the time 
of OS analysis will be censored at the last date of known contact. 


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 0 6  
 
: 
•  
 
 
 (A p pe n di x 9 : I W G Criteria f or Res p o ns e f or Partici pa nts i n Part 1 a n d 
Part 2 ). 
 
•  
 
 
 (A p pe n di x 9 : I W G Criteria f or Res p o ns e f or 
Partici pa nts i n Part 1 a n d Part 2 ). F or p artici pa nts w h o ha ve n ot pr o gresse d or 
die d at t he ti me of t he D O R a nal ysis, t he s a me ce ns ori n g r ul e as f or P F S a nal ysis 
will be use d.  
9. 3. 1. 2.  
P art 1  
All efficac y a n al ys es i n Part 1 will be perf or me d b ase d o n All Treate d p o p ulati o n u nless 
ot her wise s pecifie d. Parti ci pa nts  e nr olle d i n Part 1 d ose escal ati o n will be i ncl u de d i n t he 
d ose e x pa nsi o n c o h ort a n al ysis gi ve n t he p artici pa nt  was treate d at t he sa m e d ose as t he 
d ose e x pa nsi o n c o h ort.  
Pri m ar y Effic ac y E n d p oi nt –  C B R  
T he  esti mate of C B R al o n g wit h 9 5 % e x act CI will be pr o vi de d. T he i nteri m f utilit y 
a nal ys es f or t h e d ose e x pa nsi o n c o h orts will be base d o n t he All E val ua ble p o p ulati o n 
a n d pri mar y/fi nal effic ac y a n al ysis will be b ase d o n t he All Treate d p o p ul ati o n.  
Sec o n d ar y  Effic ac y E n d p oi nt - O R R  
T he esti mate of O R R al o n g wit h 9 5 % e x act CI will be pr o vi de d.  
Sec o n d ar y Effic ac y E n d p oi nt - P F S  
P F S will be s u m mariz e d usi n g Ka pl a n -Meier q ua ntile esti mates al o n g wit h 9 5 % CIs, if 
data warra nt.  
Sec o n d ar y Effic ac y E n d p oi nt - O S  
If data warra nt, O S will be s u m marize d usi n g Ka pl a n -Meier q u a ntile esti mates al o n g 
wit h 9 5 % CIs.  
E x pl or at or y Effic ac y E n d p oi nt - 
 
 
E x pl or at or y Effic ac y E n d p oi nt - 
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 0 7  
 
9. 3. 2.  
S af et y A n al y s e s  
All safet y a nal yses will be perf or me d o n t he All Treate d P o p ulati o n. U nless ot her wise 
s pecifie d, safet y s u m maries will be c o n d ucte d b y d ose f or Part 1 a n d Part 2 d ose 
escalati o n c o h orts res pecti vel y.  
9. 3. 2. 1.  
E xt e nt of E x p o s ur e  
T he treat me nt e x p os ure will be s u m marize d wit h treat me nt d urati o n a n d d ose i nte nsit y 
( dail y d os e f or oral dail y d osi n g) as well as t he d ose m o dificati o ns i ncl u di n g d ose 
re d ucti o ns, d ose i nterr u pti o ns/ dela ys a n d d os e escalati o ns. T he s u m maries will be 
pr o vi de d f or G S K 3 3 2 6 5 9 5 a n d 5 -Azaciti di ne  se paratel y i n Part 2 A a nal yses. Details will 
be s pecifie d i n t he R A P.  
9. 3. 2. 2.  
A d v er s e E v e nt s  
A d verse e ve nts will be c o de d usi n g t he sta n d ar d Me d D R A a n d gr o u pe d b y s yste m or ga n 
class. A d vers e e ve nts will be gra de d b y t he i n v esti gat or acc or di n g t o t he N CI -C T C A E 
v 4.  
C CI


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
108 
 
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, 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 RAP.  
DLTs will be listed and summarized by dose cohort for Part 1 dose escalation and Part 2 
dose escalation based on DLT Evaluable Population. 
The incidence of deaths and the primary cause of death will be summarized. 
9.3.2.3. 
Clinical Laboratory Evaluations  
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE v4. Laboratory test results outside the reference 
ranges that do not have an associated NCI-CTCAE criterion will be summarized using 
proportions. Summaries by visit will include data from scheduled assessments only, and 
all data will be reported according to the nominal visit date for which it was recorded 
(i.e., no visit windows will be applied). Unscheduled data will be included in ‘worse case 
post baseline’ summaries which will capture a worst case across all scheduled and 
unscheduled visits after the first dose of study intervention.  Further details will be 
provided in the RAP. 
9.3.2.4. 
Other Safety Measures  
Data for vital signs, ECGs, and cardiac output evaluation (e.g., echocardiogram) will be 
summarized based on predetermined criteria identified to be of potential clinical concern. 
Further details will be provided in the RAP. 
9.3.3. 
Other Analyses 
9.3.3.1. 
Pharmacokinetic Analyses 
The plasma concentrations for individual participants will be determined using a 
validated analytical method for GSK3326595. For participants participating in serial 
sampling, plasma GSK3326595 concentration-time data will be analyzed by non-
compartmental methods with Phoenix WinNonlin. The following pharmacokinetic 
parameters will be determined, as data permit:  
• maximum observed plasma concentration (Cmax) 
• time to Cmax (tmax) 
• area under the plasma concentration-time curve (AUC(0-t), AUC(0-∞) and 
AUC(0-)) 
• apparent terminal phase half-life (t½). 
• oral clearance (CL/F) 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
109 
 
• time invariance (TI) and accumulation ratio (AR) as calculated by the following 
equations: 
 
 
For Part 2, additionally plasma concentration of 5-Azacitidine will be determined using a 
validated analytical method. Plasma 5-Azacitidine concentration-time data will be 
analyzed by non-compartmental methods with Phoenix WinNonlin and similar 
pharmacokinetic parameters as above will be determined, as data permit. 
Plasma concentration-time data will be summarized using descriptive statistics (n, mean, 
SD, median, minimum and maximum) by planned relative assessment time and by dose. 
Mean and median values will be plotted over time. Individual plasma pharmacokinetic 
parameter values as well as a descriptive summary (mean, standard deviation, median, 
minimum, maximum, geometric mean, and the standard deviation, CV% and 95% CI of 
log-transformed parameters [if applicable]) by dose cohort will be reported.  
Cmax and AUC (AUC(0-∞), single dose; and AUC(0-), steady state) will be plotted as a 
function of the dose administered. If more than 2 dose cohorts are required to reach MTD 
(or the recommended dose based on available safety, PK and response data),dose 
proportionality of AUC and Cmax for GSK3326595 following single dose administration 
and AUC(0-) and Cmax following repeat dose administration will be assessed 
graphically and using the power model as described below: 
log (pharmacokinetic parameter) = a + b * log(dose) 
where a is the intercept and b is the slope. 
The power model will be fitted by restricted maximum likelihood (REML) using 
Statistical Analysis System (SAS) Proc Mixed. Both the intercept and slope will be fitted 
as fixed effects. If there is sufficient data, the model may also be fit with the intercept 
and/or slope as random effects depending on the ability of the model to converge and on 
estimation of variance-covariance matrix. The mean slope and corresponding 90% CI 
will be estimated from the power model. 
A nonlinear mixed effects model may be used to determine population pharmacokinetic 
parameters and identify important covariates (e.g., age, weight, or disease related 


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 1 0  
 
c o variates). F urt her det ails of p o p ulati o n P K a nal ysis will be descri be d i n t he R A P; 
res ults of s uc h a n a nal ysis ma y be i n cl u de d i n a re p ort se parat e fr o m t he cli nical st u d y 
re p ort. 
9. 3. 3. 2.  
P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c A n al y s e s  
 
 I nitiall y, 
t he relati o ns hi ps will be e x pl ore d gra p hicall y. If t hese gra p hi cal a nal ys es s u g gest a 
relati o ns hi p bet wee n s afet y/efficac y/ P D e n d p oi nts an d G S K 3 3 2 6 5 9 5 P K para meters, 
P K/ P D m o dels ma y be d eri ve d a n d e val uate d usi n g t he n o nli near mi x e d effect m o deli n g 
a p pr oac h. F urt h er details of P K/ P D a nal ys es will be descri b e d i n t he R A P; res ults of 
t hese a nal yses ma y b e i n cl u de d i n a re p ort se parat e fr o m the cli nical st u d y re p ort.  
9. 3. 3. 3.  
P h ar m a c o d y n a mi c/ Bi o m ar k er A n al y s e s  
If data p er mit, t he relati o ns hi ps bet wee n vari o us P D e n d p oi nts a n d bi o mar kers will be 
e x pl ore d si milarl y t o Secti o n  9. 3. 3. 2 . 
9. 3. 4.  
I nt eri m A n al y s e s 
F ull details of t he i nteri m a nal ys es will be s pecifie d i n t he R A P.  
9. 3. 4. 1.  
P art 1  
T he pri mar y dri v er f or t h e d ose -es calati o n decisi o n(s) will be safet y a n d t olera bilit y of 
eac h d ose c o h ort.  
F or Part 1 d ose escal ati o n a n d de -es calati o n decisi o ns will be g ui de d b y a n N -C R M 
m o del.  Pre dicte d D L T rates will be pr o vi de d wit h t he ai m of escalati n g t o d oses wit h 
s mall pr o ba bilit y of e x cessi ve or u nacce pta ble t o xicit y .   
F or Part 1 d ose e x pa nsi o n c o h ort, t he first i nteri m a nal ysis will be p erf or m e d w he n at 
least 8 partici pa nts bec o me e val ua ble. Partici pa nts  w h o were e nr olle d d uri n g d ose 
escalati o n b ut treat e d at t he sa me d ose as e x pa nsi o n c o h ort will be i ncl u de d i n t he 
a nal ysis. T h e c o h ort will be st o p pe d earl y d u e t o f utilit y if t he pre dicti ve pr o ba bilit y of 
s uccess is less t ha n 1 %. T he i nteri m f utilit y a nal ysis will be perf or me d e v er y 2 -3 m o nt hs 
de pe n di n g o n e nr oll me nt wit h mi ni m u m a d diti o nal 5 e val ua ble partici pa nts . All 
e val ua ble p o p ulati o n will be  use d f or t h e i nteri m f utilit y a n al ys es.  T he c o h ort ma y b e 
st o p pe d earl y f or f utilit y b ut n ot f or efficac y. 
9. 3. 4. 2.  
P art 2  
T he i nteri m a nal ys es f or t he D ose E x pa nsi o n are s pecifie d i n Secti o n 4. 1. 3. 1. 2 .  
C CI


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
111 
 
10. 
REFERENCES 
Almeida AM and Ramos F. Acute Myeloid Leukemia in the older adults. Leukemia 
Research Reports. 2016; 6: 1–7. 
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MML. The 2016 
revision to the World Health Organiation classification of myeloid neoplasms and acute 
leukemia. Blood.  2016 127:2391-2405 
Ball B, Zeidan A, Gore SD and Prebet T. Hypomethylating agent combination strategies 
in myelodysplastic syndromes: hopes and shortcomings.  2017. Leukemia Lymphoma. 
2017 May;58(5):1022-1036.  
Berger SL. Out of the jaws of death: PRMT5 steers p53. Nature Cell Biology. 2008 
Dec;10(12):1389-90  
Bezzi M, Teo SX, Muller J, Mok WC, Sahu SK, Vardy LA. Regulation of constitutive 
and alternative splicing by PRMT5 reveals a role for MDM4 pre-mRNA in sensing 
defects in the spliceosomal machinery. Genes and Development. 2013 Sep 
1;27(17):1903-16.   
Cheson BD, Bennett JM, Kopecky KJ. International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for 
Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec15;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. http://www.bloodjournal.org/content/bloodjournal/108/2/419.full.pdf?sso-
checked=true 
Deschler B and Lubbert M. Acute myeloid leukemia : epidemiology and etiology. 
Cancer. 2006;107:2099–107. 
Dvinge H, Kim E, Abdel-Wahab O and Bradley RK. RNA splicing factors as 
oncoproteins and tumour suppressors Nature Reviews Cancer. 2016 Jul;16(7):413-30.  
Elena C, Galli A, Such E, Meggendorfer M, Ulrich G, Rizzo E. Integrating clinical 
features and genetic lesion in the risk assessment of patients with chronic 
myelomonocytic leukemia. Blood. 2016;128(10):1408-1417 
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A. Efficacy 
of azacitidine compared with that of conventional care regimens in the treatment of 
higher-risk myelodysplatic syndromes : a randomised, open-label, phase III study.   
Lancet Oncology. 2009 Mar;10(3):223-32 
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U. 
Azacitidine prolongs overall survival compared with conventional care regimens in 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
112 
 
elderly patients with low bone marrow blast count acute myeloid leukemia. Journal of 
Clinical Oncology 28, no. 4 (February 2010) 562-569.  
Fong JY, Pignata L, Goy PA, Kawabata KC, Chun-Wei Lee S, Koh CM, et al. 
Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine 
methylation. 2019, Cancer Cell 36:194-209 
Garcia-Manero G, Fenaux P, Al-Kali A, Baer MR, Sekeres MA, Roboz GJ. Rigosertib 
versus best supportive care for patients with high-risk myelodysplastic syndromes after 
failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. 
Lancet Oncology 2016; 17: 496–508 
Gonsalvez GB, Tian L, Ospina JK, Boisvert FM, Lamond AI, Matera G. Two distinct 
arginine methyltransfereases are required for biogenesis of Sm-class ribonucleoproteins. 
Journal of Cell Biology 2007 178(5):733–740. 
Gordon Lan KK and Demets D. Discrete sequential boundaries for clinical trials. 
Biometrika. Volume 70, Issue 3, 1 December 1983, Pages 659–663, 
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F. Revised 
international prognostic scoring system for myelodysplastic syndromes. Blood. 2012 Sep 
20 ; 120(12) : 2454-65.  
GSK Document ID No. 2015N237263_04. 204653. A phase I, open-label, dose 
escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and 
clinical activity of GSK3326595 in patients with solid tumors and nonHodgkin’s 
lymphoma. Effective date : 11 September 2018. 
GSK Document ID No. 2017N314773_04. GSK3326595: Investigator’s Brochure. 
Effective date:  April 2020 
Hsu JM, Chen CT, Chou CK, Kuo HP, Li LY, Lin CY. Crosstalk between ARG1175 
methylation and TYR1173 phosphorylation negatively modules EGFR-mediated ERK 
activation. Nature Cell Biology. 2011 Feb; 13(2):174-81.  
Kantjarian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J. Decitabine 
improves patient outcomes in myelodysplastic syndromes: results of a phase III 
randomised study. Cancer. 2006 Apr 15;106(8):1794-803. 
Kantjarian H, Thomas X, Dmoszynska A, Wierbowska A, Mazur G, Mayer J. 
Multicentre, randomised, open-label, Phase III trial of Decitabine versus patient choice, 
with physician advice, of either supportive care or low dose cytarabine for the treatment 
of older patients with newly diagnosed acute myeloid leukaemia. Journal of Clinical 
Oncology 30, no. 21 (July 2012) 2670-2677 
Karkhanis V, Hu YJ, Baiocchi RA, Imbalzano AN, Sif S. Versatility of PRMT5-induced 
methylation in growth control and development. Trends Biochem Sci. 2011 Dec; 36 (12): 
633-41. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
113 
 
Kaushik S. Genetic deletion or small molecule inhibition of the Arginine 
Methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-
rearranged AML. Leukemia, 2017, 32(2);499-509 
Komrokji, RS, DeZern AE, Zell K, Al Ali NH, Estling C, Zimmerman C, et al. 
Validation of International Working Group (IWG) Response Criteria in Higher-Risk 
Myelodysplastic Syndromes (MDS): A Report on Behalf of the MDS Clinical Research 
Consortium (MDS CRC) . Blood. 2015, 126 (23):909 
Lee JJ and Liu DD. A predicitive probability design for phase II cancer clinical trials. 
Clinical trials. 2008:5(2):93-106. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150 (9): 604–612 
LLS data Available at:  https://www.lls.org/http%3A/llsorg.prod.acquia-sites.com/facts-
and-statistics/facts-and-statistics-overview/facts-and-statistics  
Neuenschwander B, Branson M and Gsponer T. Critical aspects of the Bayesian approach 
to Phase I cancer trials. Statistics in Medicine. 2009 Jun 15; 27(13): 1420-39. 
Oken MM; Creech RH; Tormey DC; Horton J; Davis TE; McFadden ET; et al. Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. American Journal 
of Clinical Oncology. 1982; 5: 649-655. 
Pal S, Baiocchi RA, Byrd JC, Grever MR, Jacob ST, Sif S. Low levels of miR-92b/96 
induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma. 
EMBO J. 2007; 26 (15): 3558-69. 
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, ROberts ND. 
Genomic classification and prognosis in acute myeloid leukemia. New England Journal 
of Medicine. 2016;374:2209-21. 
Perl AE. The role of targeted therapy in the management of patients with AML. Blood 
advances. 2017 Nov 14;1(24):2281-2294. 
Prusty AB, Meduri R, Prusty BK, Vanselow J, Schlosser A and Fischer U. Impaired 
spliceosomal UsnRNP assembly leads to Sm mRNA down-regulation and Sm protein 
degradation. The Journal of Cell Biology. 2017 Aug 7;216(8):2391-2407. 
Sallman DA, Malki MA, Lee DJ, Kambhampati 2, Donnellan WB. Tolerability and 
efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine 
in MDS and AML patients: Phase Ib results. 2020 American Society of Clinical 
Oncology (ASCO) Annual Meeting (Abstract #7507). 
SEER data.  Available at https://seer.cancer.gov/statfacts/html/amyl.html  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
114 
 
Serio J, Ropa J, Chen W, Mysliwski M, Saha N, Chen L. The PAF complex regulation of 
PRMT5 facilitates the progression and maintenance of MLL fusion leukaemia. 
Oncogene, 2017;37;450-460 
Such E, Germing U, Malcovati L, Cervera J, Kuendgen A, Della Porta MG. Development 
and validation of a prognostic scoring system for patients with chronic myelomonocytic 
Leukemia. Blood. 2013 Apr ``:121 (15):3005-15. 
Tarighat SS, Santhanam R, Frankhouser D, Radomska HS, Lai H, Anghelina M. The dual 
epigenetic role of PRMT5 in acute myeloid leukaemia: gene activation and repression via 
histone arginine methylation. Leukemia, 2016. 30(4):789-799 
Taskesen E, Havermans M, van Lom K, Sanders MA, van Norden Y, Bindels E. Two 
splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML 
using combined gene expression and DNA-methylation profiling. Blood. 2014 May 
22;123(21):3327-35.  
Tee WW, Pardo M, Theunissen TW, Yu L, Choudhury JS, Hajkova P. PRMT5 is 
essential for early mouse development and acts in the cytoplasm to maintain ES cell 
pluripotency. Genes and Development. 2010 Dec 15; 24 (24):2772-7. 
The Cancer Genome Atlas Research Network (TCGA). Genomic and Epigenomic 
Landscapes of Adult De Novo Acute Myeloid Leukemia. The New England Journal of 
Medicine. 2013;368:2059-74. 
Wang L, Pal S, Sif S. Protein arginine methyltransferase 5 suppresses the transcription of 
the RB family of tumor suppressors in leukemia and lymphoma cells. Mol Cell Biol. 
2008; 28 (20): 6262-77. 
Wang Y, Li Q, Liu C, Han F, Chen M, Zhang L, et al. Protein Arginine 
Methyltransferase 5 (Prmt5) Is Required for Germ Cell Survival During Mouse 
Embryonic Development. Biol Reprod. 2015; 92 (4): 104, 1–10 
Wei TY, Juan CC, Hisa JY, Su LJ, Lee YC, Chou HY. Protein arginine methyltransferase 
5 is a potential oncoprotein that upregulated G1 cyclin/cyclin dependent kinases and the 
phosphoinositide-3 kinase/AKT signalling cascade. Cancer Science. 2012 Sep; 
103(9):1640-50. 
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring Fatigue and Other 
Anemia-Related Symptoms with the Functional Assessment of Cancer Therapy (FACT) 
Measurement System. Journal of Pain and Management. 1997;13:63-74. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
115 
 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
11.1.1. 
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 International Council for Harmonisation (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.  
• 
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), and all other 
applicable local regulations 
11.1.2. 
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 
course of the study and for 1 year after completion of the study. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
116 
 
11.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the 
study to the participant or his/her legally authorized representative and 
answer all questions regarding the study.  
• Participants must be informed that their participation is voluntary. 
Participants or their legally authorized representative 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 or the 
participant’s legally authorized representative.  
• Participants who are rescreened are required to sign a new ICF. 
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with Standard Operating 
Procedure (SOP)-GSKF-410. The investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. 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 remaining specimens to be used for exploratory 
research. Participants who decline to participate will not provide this separate signature. 
11.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any 
participant records or datasets that are transferred to the sponsor will 
contain the identifier only; participant names or any information which 
would make the participant identifiable will not be transferred.  
• The participant must be informed that his/her personal study-related data 
will be used by the sponsor in accordance with local data protection law. 
The level of disclosure must also be explained to the participant.  
• The participant must be informed that his/her medical records may be 
examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
117 
 
11.1.5. 
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 the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate. 
• 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy. 
• 
GSK may 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 participant care. This helps ensure 
the data provided by the trial participants are used to maximum effect in the 
creation of knowledge and understanding.  
11.1.6. 
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.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the 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.  
• 
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 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
118 
 
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.  
11.1.7. 
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 can be found in the SRM 
11.1.8. 
Study and Site Closure 
GSK or its 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. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
119 
 
11.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 12 will be performed by a local laboratory, with the 
following exceptions: The additional urine and serum renal biomarker testing,  
will be performed at the central laboratory. Testing for homocysteine and 
methylmalonic acid levels may be performed either locally or centrally. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 12 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
Mean 
Corpuscular 
Volume (MCV) 
Mean 
Corpuscular 
Haemoglobin 
(MCH) 
% Reticulocytes 
White Blood Cell (WBC) count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Myeloblasts (if present) 
RBC Count 
Hemoglobin 
 
Hematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
Glucose 
(fasting) 
Calcium 
Alkaline 
phosphatase 
Albumin 
Amylase 
Lipase 
Serum bicarbonate 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
120 
 
Laboratory 
Assessments 
Parameters 
Folate and 
selected 
vitamins 
Serum B12 and Folate. For borderline results of B12 and/or folate, the 
following 2 additional tests will be performed within 2 weeks of the borderline 
result: Methylmalonic acid (serum or plasma) and Homocysteine (serum or 
plasma). 
B12: 
• >300 pg/mL (above 221 pmol/L) – Normal 
• 200 to 300 pg/mL (148 to 221 pmol/L) – Borderline 
• <200 pg/mL (below 148 pmol/L) – Low; consistent with deficiency 
Folate: 
• >4 ng/mL (above 9.1 nmol/L) – Normal.  
• From 2 to 4 ng/mL (from 4.5 to 9.1 nmol/L) – Borderline.  
• <2 ng/mL (below 4.5 nmol/L) – Low; consistent with folate 
deficiency. 
Thyroid 
Function 
Thyroid stimulating hormone (TSH), free Tri-iodothyronine (T3), Free 
thyroxine (T4) – Screening, Week 5 Day 1, and Week 9 Day 1 and every 
8 weeks thereafter and EOT. 
Coagulation 
Partial Thromboplastin Time (PTT), Prothromin time/International Normalized 
Ration (PT/INR) 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase, by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Additional Urine 
and serum renal 
biomarkers 
(Only 
participants with 
baseline eGFR 
<60 
ml/min/1.73 m2) 
• 
NGAL, KIM-1, and albumin/creatinine ratio (urine) 
• 
Cystatin C (serum) 
Pregnancy 
testing 
• Human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)2 
Screening Tests 
• Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) 
• Serology: HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus [HCV] antibody.  A positive HCV antibody must be 
confirmed via second study (e.g., HCV RNA or comparable test) 
The results of each test must be entered into the CRF. 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
121 
 
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 and Appendix 6. 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. 
Serum testing is required at screening.  For all other pregnancy tests specified in the SoA, either serum or 
urine testing may be used. 
From the first dose of GSK3326595 until 30 days after the last dose of study treatment, 
all laboratory tests with abnormal values that are considered clinically significant should 
be repeated as clinically indicated until the values return to normal (per institutional 
guidelines) or back to the pre-study baseline. If such values do not return to normal 
within a period judged reasonable by the investigator, the etiology should be identified 
and the sponsor notified. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
122 
 
11.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
11.3.1. 
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. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after 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 drug-drug 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. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
123 
 
• 
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. 
11.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
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. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils 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. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
124 
 
Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 
11.3.3. 
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 
 
11.3.4. 
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 (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 2 5  
 
•  
It is n ot  acce pta bl e f or t h e i n vesti gat or t o se n d p h ot oc o pies of t he partici p a nt’s 
me dical rec or ds t o G S K i n lie u of c o m pleti o n of t he G S K / A E/ S A E C R F pa ge.  
•  
T here ma y b e i nsta nces w he n c o pies of m e dical r ec or ds f or certai n cas es are 
re q ueste d b y G S K. I n t his case, all partici pa nt i de ntifiers, wit h t he e x ce pti o n of t he 
partici pa nt n u m ber, will be re dacte d o n t he c o pies of t he me dical r ec or ds bef ore 
s u b missi o n t o G S K. 
•  
T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s y m pt o ms, a n d/ or ot her cli nical i nf or mati o n. W he ne ver p ossi ble, t he dia g n osis 
( n ot t he i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E. 
 
 
A s s e ss m e nt of C a u s alit y  
•  
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n 
a n d eac h occ urre n ce of eac h A E/ S A E.  
•  
A "reas o na bl e p ossi bilit y" of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g gest a ca us al relati o ns hi p, rat her t ha n a rel ati o ns hi p ca n n ot 
be r ule d o ut.  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
126 
 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
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. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
11.3.5. 
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) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
127 
 
• 
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 medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in SRM.  
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in SRM. 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
128 
 
11.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
11.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with one (or more) of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
• 
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 consistent with the local laboratory’s reference range for 
postmenopausal females is required.  Females on Hormonal Replacement 
Therapy (HRT) and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 
 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
129 
 
11.4.2. 
Contraception Guidance: 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 13.  Female participants of non-childbearing potential have no requirements for 
contraception. 
Table 13 
Highly Effective Contraceptive Methods 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency  
• 
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. 
• 
Highly Effective Methodsb That Are User Dependent 
• 
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 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
130 
 
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 for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction) 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test  
• 
Additional pregnancy testing (either serum or urine) must be performed every four 
weeks during the treatment period and at the EOT visit. 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected  
Male participants 
• 
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 5.1:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent  
• Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 13 when having 
penile-vaginal intercourse with a woman of childbearing potential  
• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame  
• 
In addition male participants must refrain from donating sperm for duration of 
study and for 95 days after the last dose of GSK3326595 or as indicated in 
package insert for 5-Azacitidine. 
11.4.3. 
Collection of Pregnancy Information: 
Male participants with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive GSK3326595. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
131 
 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
• 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
Female Participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.   
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK as described in Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting. While the investigator is not 
obligated to actively seek this information in former study participants, he or she 
may learn of an SAE through spontaneous reporting.  
Any female participant who becomes pregnant while participating will be withdrawn 
from the study 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
132 
 
11.5. 
Appendix 5: Genetics 
USE/ANALYSIS OF DNA 
• 
Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a saliva sample will be collected for DNA analysis 
• 
DNA samples will be used for research related to GSK3326595 or MDS, CMML 
and AML, and related diseases. They may also be used to develop tests/assays 
including diagnostic tests) related to GSK3326595 or study interventions of this drug 
class, and MDS, CMML and AML. Genetic research may consist of the analysis of 
one or more candidate genes or the analysis of genetic markers throughout the 
genome or analysis of the entire genome (as appropriate) 
• 
DNA samples will be analyzed for relationships between genetic variants and 
response after treatment with GSK3326595, e.g. safety/tolerability, and/or efficacy. 
Additional analyses may be conducted if it is hypothesised that this may help further 
understand the clinical data.  
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK3326595 or study interventions of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• 
The samples will be retained while research on GSK3326595 or study interventions 
of this class) or MDS, CMML and AML continues but no longer than 15 years after 
the last participant’s last visit or other period as per local requirements. 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
133 
 
11.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Rechallenge 
Guidelines 
Liver Safety: Required Actions and Follow-up Assessments 
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology (in alignment with 
the FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Phase I/II liver chemistry stopping criteria and required follow up assessments  
Liver Chemistry Stopping Criteria – Liver Stopping Event 
Participant with entry criteria ALT≤ 2.5 x ULN 
ALT-absolute 
ALT  5xULN 
ALT Increase 
ALT  3xULN persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5, if INR measured 
Cannot Monitor 
ALT  3xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
ALT  3xULN 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 
an 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  
• 
Viral hepatitis serology4 
• 
Only in those with underlying chronic hepatitis B 
at study entry (identified by positive hepatitis B 
surface antigen) quantitative hepatitis B DNA and 
hepatitis delta antibody5. 
• 
Blood sample for pharmacokinetic (PK) analysis, 
obtained 2 days after 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 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
134 
 
• 
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 
MONITORING: 
For bilirubin or INR criteria:  
• 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs 
• 
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 perform 
liver event follow up assessments within  
24-72 hrs  
• 
Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• 
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 
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 computerised 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, 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); INR measurement is not required and 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. 
 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
135 
 
Phase I/II Oncology liver chemistry increased monitoring criteria with continued 
therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
Participant with entry criteria ALT≤2.5x 
ULN 
ALT 3xULN but <5xULN and 
 bilirubin <2xULN, without symptoms believed 
to be related to liver injury or hypersensitivity 
and who can be monitored weekly for 4 weeks 
Participant with documented liver 
metastases/tumor infiltration at baseline 
AND entry criteria ALT>2.5 x ULN but ≤5 x 
ULN 
ALT ≥3x ULN and 1.5x baseline value but ALT 
<5x ULN and 2x baseline value and bilirubin 
<2xULN, without symptoms believed to be 
related to liver injury, or hypersensitivity and 
who can be monitored weekly for 4 weeks 
• 
Notify the GSK medical monitor within 24 hours 
of learning of the abnormality to discuss 
participant safety.  
• 
Participant can continue study treatment 
• 
Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline  
• 
If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above 
For participants with entry criteria ALT≤2.5 x ULN 
• 
If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline. 
 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  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;43(5):2363–2369.  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
136 
 
Liver Safety – Study Treatment Restart or Rechallenge Guidelines 
If participant meets liver chemistry stopping criteria do not restart/rechallenge participant 
with study intervention 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/rechallenge participant with study 
intervention is not granted, then participant must permanently discontinue study 
intervention and may continue in the study for protocol-specified follow up assessments. 
1. Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Intervention  
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies.1 Clinical outcomes vary by drug, 
with nearly 50% fatality with halothane readministered within one month of initial injury. 
However, some drugs seldom result in recurrent liver injury or fatality.   
Risk factors for a fatal drug rechallenge outcome include: 
• 
hypersensitivity1 with initial liver injury (e.g. fever, rash, eosinophilia)  
• 
jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total) 
• 
participant currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5 
• 
serious adverse event or fatality has earlier been observed with drug 
rechallenges2,3 
• 
evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment3) 
Rechallenge refers to resuming study intervention following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a participant for whom there is compelling evidence of benefit from a 
critical or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favourable. 
Approval by GSK for rechallenge with study intervention can be considered where: 
• 
Investigator requests consideration of rechallenge with study intervention for a 
participant who is receiving compelling benefit with study intervention that exceeds 
risk, and no effective alternative therapy is available.   


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
137 
 
• 
Ethics Committee or Institutional Review Board approval for rechallenge with study 
intervention must be obtained, as required.    
• 
If the rechallenge 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 intervention administration, including the possibility of recurrent, more 
severe liver injury or death.   
• 
The participant must also provide signed informed consent specifically for the 
rechallenge with study intervention.  Documentation of informed consent must be 
recorded in the study chart.   
• 
Study intervention must be administered at the dose specified by GSK. 
• 
Participants approved by GSK Medical Governance for rechallenge with study 
intervention must return to the clinic twice a week for liver chemistry tests until 
stable liver chemistries have been demonstrated and then standard laboratory 
monitoring may resume as per protocol. 
• 
If after study intervention rechallenge, participant meets protocol-defined liver 
chemistry stopping criteria, study intervention should be permanently discontinued.  
• 
GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study intervention 
rechallenge.  
• 
GSK to be notified of any adverse events, as per Section 8.4.  
2. Restart Following Transient Resolving Liver Stopping Events NOT Related to 
Study Intervention 
Restart refers to resuming study intervention 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, there 
should be no evidence of alcoholic hepatitis or hypersensitivity, and the study 
intervention should not be associated with Human Leukocyte Antigen (HLA) markers of 
liver injury. 
Approval by GSK for study intervention restart can be considered where: 
• 
Investigator requests consideration for study intervention 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 x baseline and ALT 
<3xULN). 
• 
Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study intervention-induced liver injury or study intervention has 
an HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded 
• 
Ethics Committee or Institutional Review Board approval of study intervention 
restart must be obtained, as required. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
138 
 
• 
If restart of study intervention 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 intervention administration, including the possibility of recurrent, more 
severe liver injury or death.   
• 
The participant must also provide signed informed consent specifically for the study 
intervention restart.  Documentation of informed consent must be recorded in the 
study chart.   
• 
Study intervention must be administered at the dose specified by GSK. 
• 
Participants approved by GSK Medical Governance for restarting study intervention 
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 intervention re-start, participant meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions. 
• 
GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study intervention 
restart.  
• 
GSK to be notified of any adverse events, as per Section 8.5. 
References: 
• 
1Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714. 
• 
2Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced 
liver injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90.  
• 
3Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222. 
 
 


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 3 9  
 
1 1. 7.  
A p p e n di x 7: I P S S -R S c ori n g S y st e m f or M D S  
T a bl e 1 4  
I P S S-R pr o g n o sti c s c or e v al u e s  
 
T a bl e 1 5  
I P S S-R pr o g n o sti c ri s k c at e g ori e s/ s c or e s  
 
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al 
O ut c o m e A s s e s s m e nt d at a c oll e cti o n 
q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s 
a n d t h er ef or e h a v e b e e n e x cl u d e d.


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 4 0  
 
1 1. 8.  
A p p e n di x 8: C M M L S c ori n g S y st e m  
1 1. 8. 1.  
C P S S S c ori n g S y st e m ( S u c h , 2 0 1 3) 
T a bl e 1 6  
C P S S: V ari a bl e s a n d s c or e s u s e d f or pr e di cti n g li k eli h o o d of 
s ur vi v al a n d l e u k e mi c e v ol uti o n i n t h e i n di vi d u al p ati e nt  wit h C M M L  
T a bl e 1 7  
C P S S: V ari a bl e s a n d s c or e s u s e d f or pr e di cti n g li k eli h o o d of 
s ur vi v al a n d l e u k e mi c e v ol uti o n i n t h e i n di vi d u al p ati e nt  wit h C M M L  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 4 1  
 
1 1. 8. 2.  
C P S S -m ol S c ori n g S y st e m ( El e n a , 2 0 1 6)  
T a bl e 1 8  
V ari a bl e s a n d pr o g n o sti c  s c or e v al u e s of t h e C M M L g e n eti c s c or e  
•  
—  , N ot a p plica ble. 
•  
↵* C yt o ge n etic ris k gr o u p s are defi ne d acc or di n g t o S uc h1 3: l o w, n or mal, a n d 
is olate d – Y; i nter me diate, ot her a b n or malities; a n d hi g h, tris o m y 8, c o m ple x 
kar y ot y p e ( ≥3 a b n or malities), a n d a b n or malities of c hr o m os o me 7. 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 4 2  
 
T a bl e 1 9  
V ari a bl e s a n d pr o g n o sti c s c or e v al u e s of t h e C P S S -M ol  
•  
—  , N ot a p plica ble. 
•  
↵* Ge netic ris k gr o u ps are defi ne d as re p orte d i n Ta ble 1 8 . 
•  
↵† R B C tra nsf usi o n de pe n de nc y is defi ne d acc or di n g t o Ele na a n d S uc h . 
Refere nces  
Ele na C, Galli A, S uc h E, Me g ge n d orfer M, Ulric h G, Rizz o E . I nte grati n g cli nical 
feat ur es a n d ge n etic lesi o n i n t he ris k assess me nt of patie nts wit h c hr o nic 
m yel o m o n oc ytic le u k e mia. Bl o o d. 2 0 1 6; 1 2 8( 1 0): 1 4 0 8 -1 4 1 7  
S uc h E, Ger mi n g U, Mal c o vati L, C er vera J, K ue n d ge n A, Della P orta M G . De vel o p me nt 
a n d vali dati o n of a p r o g n ostic sc ori n g s yste m f or patie nts wit h c hr o nic m yel o m o n oc ytic 
le u ke mia. Bl o o d, 2 0 1 3 ; 1 2 1( 1 5) : 3 0 0 5-1 5.  
 
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
143 
 
11.9. 
Appendix 9: IWG Criteria for Response for Participants in 
Part 1 and Part 2 
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 
relevant reduction of units of RBC transfusions by an absolute number 
of at least 4 RBC transfusions/8wk compared with the pretreatment 
transfusion number in the previous 8 wk ; 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/uL 
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 
a. 
Dysplastic changes should consider the normal range of dysplastic changes (modification). 
b. Modification to IWG response criteria for MDS [Cheson, 2006]. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
144 
 
References 
Cheson BD, Greenberg PL, Bennett JM, Lowenberg R, Wijermans PW, Nimer SD, Pinto 
A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, 
and Kantarjian H. 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. 
http://www.bloodjournal.org/content/bloodjournal/108/2/419.full.pdf?sso-checked=true 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
145 
 
11.10. 
Appendix 10: ECOG Performance Status  
The performance status assessment is based on the ECOG scale [Oken, 1982] 
0 = Fully active, able to carry on all pre-disease performance without restriction. 
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light house work, office work). 
2 = Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours. 
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 = Dead 
References 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. American Journal of 
Clinical Oncology. 1982 Dec; 5(6):649-55 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
146 
 
11.11. 
Appendix 11: Guidelines for Management of Toxicity  
The following dose modification criteria for GSK3326595 should provide guidance for, 
but not act as a replacement for sound clinical judgment. The investigator should use 
clinical judgment to determine which drug may be contributing to the toxicity 
necessitating dose adjustment, and make the appropriate change for that drug. Dose 
modifications should be made after discussion with the GSK medical monitor. 5-
Azacitidine dose adjustments shall be made in accordance with FDA package insert 
registered label. 
Table 20 
Dose Adjustment/Stopping Safety Criteria for GSK3326595 
Toxicity 
Dose Adjustment/Stopping 
Criteria 
Management Guidelines 
Thrombocytopenia Grade 1 & 2 (platelet count 
above 50,000) 
Continue dosing at same dose level with weekly or 
more frequent monitoring as necessary 
Grade 3 (platelet count 
between 25,000-50,000) 
After discussion with medical monitor and using 
sound clinical judgement, continue at same dose. 
Monitor complete blood count (CBC) at least twice 
weekly, more frequently if clinically indicated. 
Grade 4 (platelet count below 
25,000)  
If platelet count <25,000 but ≥10,000 
• 
Continue at same dose or at a reduced 
dose 
• 
Monitor CBC at least twice weekly 
• 
Transfuse platelets as per institutional 
standards 
If platelet count <10,000 
• 
Continue at same dose or at a reduced 
dose 
• 
Monitor CBC at least twice weekly 
• 
Transfuse platelets as per institutional 
standard with subsequent CBC post-
transfusion to ensure appropriate 
improvement in platelet counts. 
• 
If transfusion is unable to rescue platelet 
counts, then study intervention(s) should 
be interrupted until platelet counts recover 
to > 20,000 (either spontaneously or via 
transfusion).   
Anemia, 
Neutropenia, and 
other Hematologic 
Toxicity 
Grades 1 & 2 
Continue dosing at same dose level with weekly or 
more frequent monitoring as necessary 
Grades 3 & 4 
• Implement supportive measures (e.g., 
transfusion, growth factor support, prophylactic 
antimicrobials) per institutional standard 
• Continue dosing at same dose or consider 
reducing dose 
• Monitor CBC at least twice weekly, more 
frequently as necessary 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
147 
 
Toxicity 
Dose Adjustment/Stopping 
Criteria 
Management Guidelines 
QTcF 
If >30 msec and <60 msec 
change from baseline AND 
manual QTcF <500 (average 
of three ECGs) 
 
• 
Continue current dose of study intervention(s) 
• 
Supplement electrolytes, particularly 
potassium and magnesium, to 
recommended levels: 
(1) Maintain serum potassium > 4 mol/L 
(2) Maintain serum magnesium levels 
>0.85 mmol/L 
• 
Discontinue any concomitant medications 
with potential for QTcF prolongation. 
• 
Consider 24 hour or longer telemetry 
monitoring if clinically indicated. 
If  60 msec change from 
baseline occurs 
 
OR 
 
QTcF 500  
 
(average of three ECGs) 
 
• 
Discontinue study intervention(s) and notify 
the GSK Medical Monitor.  
(1) Supplement electrolytes to recommended 
levels: 
a. Maintain serum potassium > 4 mol/L 
b. Maintain serum magnesium levels 
>0.85 mmol/L 
(2) Rule out other potential etiologies for 
prolonged QTcF such as cardiac ischemia 
(3) Discontinue any concomitant medications 
with potential for QTcF prolongation. 
(4) Consider telemetry monitoring if clinically 
indicated. 
• 
This participant may consider restarting study 
intervention at a previous dose level if the 
following criteria for QTcF rechallenge are met 
: 
 
• 
QTcF Rechallenge Procedures: 
Do not rechallenge with study intervention 
unless under the following conditions:  
(1) QTcF event reduced to <450 msec, 
(2) potassium and magnesium levels are 
within institutional normal range, 
(3) a favorable risk/benefit profile (in the 
medical judgement of the Investigator and 
the GSK Medical Monitor), 
(4) approval within GSK medical governance: 
a. 
agreement with Safety Evaluation 
Medical Director and the Project 
Physician Lead, 
b. 
review with Chair or co-Chair of the 
GSK QT panel, 
c. 
Safety Evaluation Vice President 
(VP) and Clinical VP approval 
d. 
Head Unit Physician approval 
(5) Institutional IRB (or equivalent) approval, 
and 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
148 
 
Toxicity 
Dose Adjustment/Stopping 
Criteria 
Management Guidelines 
(6) The participant is re-consented regarding 
the possible increased risk of QTc 
prolongation.  
• 
If approval for re-challenge is granted, the 
participant must be re-consented (with a 
separate informed consent specific to 
QTc prolongation) 
 
• 
Discontinuation procedures: 
If the participant is withdrawn due to QTcF event, 
the participant should complete the following 
activities post-dose: 
(1) Evaluation by cardiologist. 
(2) Weekly assessments for QTcF should be 
monitored weekly for two weeks, and then next 
assessment at 4 weeks post-dose.  
(3) If QTcF results have not resolved to baseline by 
4 weeks post-dose, then continue every 4-5 weeks 
until resolution 
Liver  
 
• 
Refer to procedures outlined in Section 7.1.2 
Liver Safety Required Actions and Follow up 
Assessments 
Diarrhea 
Grade 1 
• 
Initiate supportive care including loperamide.  
Grade 2 
• 
Initiate supportive care including loperamide. 
• 
Consider temporary discontinuation of study 
drug(s) and discuss with GSK Medical 
Monitor. 
Grade 3 
• 
Above plus consider intravenous (IV) 
hydration, hospital admission and prophylactic 
antibiotics as appropriate. 
• 
Hold study drug(s) and discuss with GSK 
Medical Monitor. 
• 
If diarrhea recovers to Grade 1, discuss with 
medical monitor; consider resuming treatment 
at the same or lower dose based on clinical 
judgement. 
Grade 4 
• 
Above plus consider intravenous (IV) 
hydration, hospital admission and prophylactic 
antibiotics as appropriate. 
• 
Discontinue study drug(s) permanently 
Nausea/Vomiting 
Grade 1 
• 
Initiate supportive care with antiemetics as 
necessary.  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
149 
 
Toxicity 
Dose Adjustment/Stopping 
Criteria 
Management Guidelines 
Grade 2 
• 
Initiate supportive care with antiemetics as 
necessary 
• 
Consider temporary discontinuation of study 
drug(s) and discuss with GSK medical 
monitor.  If drug is held, participant may 
resume therapy at same level once 
nausea/vomiting has resolved to ≤Grade 1. 
Grade 3 
• 
Supportive care as above, plus consider 
intravenous (IV) hydration, hospital admission 
and IV nutrition as appropriate. 
• 
Hold study drug(s) and discuss with GSK 
Medical Monitor. 
• 
If nausea/vomiting recovers to less than Grade 
2, discuss with medical monitor; consider 
resuming treatment at lower dose based on 
clinical judgement. 
Grade 4 
• 
Supportive care as above, plus consider 
intravenous (IV) hydration, hospital admission 
and IV nutrition as appropriate 
• 
Discontinue study intervention(s) permanently 
All Other Non-
Hematologic 
Toxicity* 
Grade 1 
• 
Continue dosing with no change  
Grade 2 
• 
Continue dosing with no change  
 
OR 
 
• 
Hold study drug(s) for up to 1 week for toxicity 
to be < Grade 2, then continue at the same 
dose (dose reduction is required if the grade 2 
toxicity is considered a DLT) 
Grade 3 
• 
1st episode: Hold dose for one week intervals 
until Grade 2, then restart study drug(s) at 
the same or reduced dose.  
• 
2nd episode: Utilize an alternative, less 
frequent schedule or reduce by one dose 
level.  
If no recovery to ≤Grade 1* after a 21 day 
delay, participant should discontinue therapy. 
Grade 4 
• 
Discontinue study drug(s) 
 
OR 
 
• 
In rare situations, based on discussion and 
written agreement between GSK medical 
monitor and investigator, if the participant is 
receiving benefit then the episode may be 
managed as per Grade 3 toxicity. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
150 
 
11.12. 
Appendix 12: Rationale for Response Assumptions  
The statistical design for each Part of the study will test the hypothesis that GSK3326595 
(either as a single agent or in combination with 5-Azacitidine, depending on the Part) will 
achieve a clinically meaningful result, versus the null hypothesis that the combination 
will achieve a response that is no better than historical controls. For each Part, the 
hypotheses were determined based on historical response rates in a comparable patient 
population. When determining appropriate efficacy hurdles, the following factors were 
taken into account: 
Part 1: 
For participants enrolled in Part 1, efficacy is defined as a clinical benefit rate (the 
percentage of participants that have achieved a CR, marrow CR, PR, HI, or SD lasting at 
least 8 weeks, by IWG criteria) of 50% relative to a 30% CBR.  This was based, in part, 
on the study of rigosertib in a similar population of relapsed and refractory MDS (Garcia-
Manero, 2016).  This study demonstrated a CBR of approximately 60% with rigosertib, 
compared to a 30% CBR with best available care. Of note, this publication did not 
specify the duration of stable disease.  Furthermore, a Phase I/II study of risogertib in 
relapsed/refractory MDS and AML that progressed from MDS (a similar population to 
the one in study 208809), demonstrated a 53% CBR (Navada, 2018).  Taken together, 
30% is a reasonable estimate for an ineffective therapy, and a CBR of 50% (which takes 
into account a durable stable disease in addition to complete and partial responses) is the 
threshold for further evaluation of GSK3326595 in this population. 
Part 2: 
In the pivotal AZA001 study in treatment-naïve participants, 5-Azacitidine demonstrated 
a significant improvement in OS compared to conventional care (Fenaux, 2009). In 
addition to the significant improvement in OS, 5-Azacitidine yielded an improved ORR 
(29% versus 12%) including a significant improvement in CR rate (17% versus 8%); on 
the other hand, the stable disease rate was not significantly different between the two 
arms. As treatment with 5-Azacitidine yielded an improved OS, as well as improved 
ORR and CR, CR rate was selected as the surrogate endpoint to evaluate in Part 2 of the 
current study. In a study that was conducted to validate the IWG criteria in higher-risk 
MDS patients using AZA001 study data, patients that achieved CR had a longer OS 
(median OS of 41 months), compared to patients who achieved PR (median OS of 26 
months), marrow CR (median OS of 12 months) or heamatologic improvement (median 
OS of 13 months) (Komrokji, 2015). Based on this data CR was chosen as a surrogate 
endpoint for OS in this population.   
As 5-Azacitidine alone in the AZA001 study yielded a 17% CR rate, this was selected as 
an assumption that any CR rate observed with the combination of 5-Azacitidine plus 
GSK3326595 was due to the effects of 5-Azacitidine alone. 32% was selected as an 
assumption for the combination, in order to demonstrate a benefit for the two agents in 
combination over 5-Azacitidine alone.   


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
151 
 
References 
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A. Efficacy 
of azacitidine compared with that of conventional care regimens in the treatment of 
higher-risk myelodysplatic syndromes : a randomised, open-label, phase III study.   
Lancet Oncology. 2009 Mar;10(3):223-32 
Garcia-Manero G, Fenaux P, Al-Kali A, Baer MR, Sekeres MA, Roboz GJ. Rigosertib 
versus best supportive care for patients with high-risk myelodysplastic syndromes after 
failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. 
Lancet Oncology 2016; 17: 496–508 
Navada SC, Fruchtman SM, Odchimar-Ressig R, Dermakis EP, Petrone ME, Zbyszewski 
PS. A phase ½ study of rigosertib in patients with myelodysplastic syndromes (MDS) and 
MDS progressed to acute myeloid leukemia. Leukemia Research 2018; 64: 10-16 
Perl A, Altman J, Cortes J, Smith C, Litzow M, Baer M. Selective inhibition of FLT3 by 
gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first in 
human, open label, phase 1-2 study. Lancet Oncology, 2017. 18 (8) p1061–1075  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
152 
 
11.13. 
Appendix 13: Overall Rationale for this Appendix  
COVID-19 pandemic may impact the conduct of clinical studies. Challenges may arise 
from quarantines, site closures, travel limitations, interruptions to the supply chain for the 
investigational product or other considerations if site personnel or study participants 
become infected with COVID-19. These challenges may lead to difficulties in meeting 
protocol-specified procedures, including administering or using the investigational 
product or adhering to protocol-mandated visits and laboratory/diagnostic testing.  
This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. 
These measures will remain in place until the site is able to resume normal working 
activities. 
Study Procedures During COVID-19 Pandemic 
During the special circumstances caused by the current COVID-19 pandemic, the 
following considerations should be taken into account:  specific public health guidance, 
the impact of any travel restrictions implemented by local/regional health authorities and 
local institutions, and individual benefit /risk when making enrollment and treatment 
decisions for trial participants. 
Every effort should be made to adhere to protocol-specified assessments for participants 
on study intervention, including follow up however when not possible, for the duration of 
these special circumstances, the following measures may be implemented for enrolled 
participants where applicable country and local regulations and infrastructure allow. 
• 
Clinical investigators should document in site files and in participant 
notes/Electronic Heath Records as appropriate how restrictions related to COVID-19 
led to the changes in study conduct and duration of those changes and indicate which 
trial participants were impacted and how those trial participants were impacted (as 
per the current local COVID-19 related regulatory guidance).  
• 
Missing protocol required data/visits due to COVID-19 must be noted in participant 
notes and recorded as a COVID-19-related protocol deviation.  
Protocol Defined Procedures/Visits: 
• 
Where applicable country and local regulations and infrastructure for home 
healthcare allow, home healthcare may take place at a location other than the clinical 
trial site to perform study assessments, which may include collection of blood and 
urine samples, measurement of vital signs and weight, and preparation and 
administration of study drug (at the discretion of the Investigator, based on safety 
and tolerability). It is the responsibility of the investigator to inform GSK when this 
occurs and to document in source notes. The participant should be informed of the 
plan and any potential risks associated with this approach and sign a revised 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
153 
 
Informed Consent Form if required. IRB/Ethics committee should be informed 
and/or approve of this change in approach and the process documented in study files. 
• 
Additional unscheduled safety assessments such as routine blood sampling may be 
performed at the discretion of the Investigator including in the participant’s home, if 
deemed necessary. Biological samples may be collected at a different location, other 
than the study site (e.g., at participant’s home) by qualified study personnel or at a 
local medical facility according to standard operating procedures and applicable 
regulations (see note). Biological samples should not be collected if they cannot be 
processed in a timely manner or appropriately stored until the intended use.  
• 
Where applicable country and local regulations allow for telemedicine, and if visits 
to a site/home are not feasible, then the medical evaluation of the participant may 
take place by telemedicine. Telemedicine will use secure video conferences, phone 
calls, and a web portal and/or mobile application as a way of communicating with 
and monitoring the participant’s progress. Details of telemedicine will be included in 
the SRM. The study investigator is responsible for ensuring that the identification, 
management, and reporting of AEs and SAEs are completed in accordance with the 
protocol and applicable regulations. AEs are first reported by participants to the 
investigator/study team or may be identified by the study team during interactions 
with the participants via telemedicine encounters. In addition, mobile nurses may 
identify AEs as well and report them to the investigator for evaluation. Additionally, 
AEs may be identified from lab reports, and other records. As determined by the 
investigator, the appropriate medical intervention, therapeutic intervention, and/or 
support measures are instituted, as necessary. The participant should be informed of 
the plan and any potential risks associated with the virtual medium and sign a revised 
Informed Consent Form if required. IRB/Ethics committee should be informed 
and/or approve of this change in approach and the process documented in study files. 
Note: If the Investigator wishes to conduct a trial visit at a location that has not been 
previously assessed by GSK, it is the investigator’s responsibility to identify an adequate 
alternate location and to notify GSK of the alternate location. The investigator should 
ensure that this alternate location meets ICH GCP requirements, is well-equipped to 
perform study procedures and covered by an adequate insurance. Furthermore, the 
investigator should have sufficient oversight to ensure that the staff at the alternate 
location are trained to perform study procedures.  
Study Intervention(s) 
• 
If despite best efforts it is not possible to administer the dose of study intervention as 
defined in the protocol (see Section 6 Study Interventions and Concomitant 
Therapy), the participant may still continue in the trial at Investigator discretion and 
advice of the Medical Monitor may be sought as appropriate. If allowed by country 
regulation/ethics, then GSK3326595 can be shipped direct-to-participant (DTP) from 
the investigational site to the participant’s home address. The process for this 
shipment must be agreed with GSK who will provide the relevant documentation and 
links to courier sites required to ensure shipments are adequately temperature 
controlled (if required) throughout transportation.  


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
154 
 
• 
Any study participant in Part 2 who cannot attend a clinical site, or local medical 
facility where possible, will not be able to receive 5-Azacitidine at home. The 
participant may continue to receive GSK3326595 at home, if applicable, or withdraw 
from the study, whichever the Investigator and participant decide.  
• 
No special procedures for the safe handling of GSK3326595 are required. Caution 
should be exercised when handling 5-Azacitidine; see package insert for more 
details. 
• 
The Principal Investigator assumes GCP responsibilities for IMP handling and the 
medical control for dispensing to participants. Site Staff should document the 
dispensing in the Dispensing/Accountability Logs adding a comment that this was a 
DTP dispensing.  
• 
Compliance with study intervention administration will be verified through 
observation by study staff or trained home healthcare professionals. 
• 
In some cases, trial participants who no longer have access to investigational product 
or the investigational site may need additional safety monitoring (e.g., on withdrawal 
of an active investigational treatment). 
Data Management/Monitoring: 
• 
Diary cards may be transmitted from and to the investigator by electronic mail and or 
conventional mail. If copies/scans of completed diaries are sent to the investigator by 
electronic mail, the participant should be instructed to maintain the original 
documents and to return them to the site when a visit to the site will be allowed. 
• 
If on-site monitoring is no longer permitted, GSK will consider remote Source Data 
Verification/Source Document Review (SDV/SDR) where permitted by the clinical 
site/institution. Remote SDV/SDR will be proposed to study sites to meet a 
participant and/or critical quality need, e.g., to assess participant safety or to ensure 
data integrity. In case of remote SDV/SDR, GSK will work with the site to ensure 
participant privacy.  
• 
eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) is 
responsible for ensuring that the data within the eCRF casebook and any other data 
sources utilized during the study for each study participant is complete and 
consistent with source documents throughout the study (ICH GCP 4.9.1 4.9.2). The 
PI may sign/re-sign the eCRF from any computer/location by accessing InForm (or 
other electronic data capture [eDC] platform) using his/her unique eCRF log-in 
credentials. The PI may delegate this activity to another medically qualified and 
trained sub-investigator and this must be documented on the Delegation of 
Responsibilities (DoR) Log. It is recommended that the PI identifies a sub-
investigator as a back-up for eCRF signatures. The sub-investigator must be 
appropriately trained on the protocol and eCRF requirements (with training 
documented), and the DoR log updated accordingly.  
• 
Essential Document Sign Off Process: If an investigator is unable to print and sign 
essential documents such as Protocol /Amendment signature page then Email 
approval can be accepted by replying to the relevant email that is sent by GSK. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
155 
 
11.14. 
Appendix 14: Abbreviations and Trademarks 
μL 
Microlitre 
μmol 
Micromole 
ABCG2 
ATP-binding cassette sub-family G member 2 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukaemia 
ANC 
Absolute neutrophil count  
AR 
Accumulation ratio  
AST 
Aspartate aminotransferase 
AUC 
Area under concentration time curve 
AUC(0-t) 
Area under the Concentration-time Curve from time zero (pre-dose) to last 
time of quantifiable concentration within a participant across all treatments 
AUC(0-τ) 
AUC from 0 hours to the time of next dosing. 
AUC(0-) 
Area under the Concentration-time Curve from time zero to infinity 
BAC 
Best available care 
BCRP 
Breast cancer resistance protein  
BID 
Twice a day 
BM 
Bone marrow  
BMD 
Bone mineral density 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count  
CBR 
Clinical benefit rate 
cfDNA 
Circulating cell free deoxyribonucleic acid  
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences  
CKD-Epi 
Chronic Kidney Disease Epidemiology Collaborative 
CL/F 
Oral clearance  
Cmax 
Maximum observed serum concentration 
cm 
Centimeter 
CMML 
Chronic myelomonocytic leukaemia  
CNS 
Central Nervous System  
Caco-2 
heterogeneous human epithelial colorectal adenocarcinoma cell line 
CONSORT 
Consolidated Standards of Reporting Trials  
CPSS (mol) 
CMML-specific prognostic scoring system (molecular) 
CR 
Complete remission  
CRi 
Marrow response as per CR but platelet count <100 x 109/L or neutrophil count 
<1 x 109/L. 
CRp 
Marrow response as per CR but platelet count <100 x 109/L. 
CRF 
Case Report Form 
CV 
Cardiovascular 
D 
Day 
DCIS 
Ductal carcinoma in situ  
del 
Deletion  
DEXA 
Dual-energy X-ray absorptiometry 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
156 
 
DHEA 
Dehydroepiandrosterone  
DILI 
Drug induced liver injury 
DL 
Dose level  
dL 
Decilitres  
DLTs 
Dose limiting toxicities  
DOR 
Duration of response 
DoR 
Delegation of Responsibilities 
DTP 
Direct-to-participant 
ECG 
Electrocardiogram 
ECHOs 
Echocardiogram  
ECOG 
Eastern cooperative oncology group 
eDC 
Electronic data capture 
eCRF 
Electronic case report form 
EGFR 
Epithelial growth factor receptor 
EOT 
End of treatment 
ePRO 
Electronic Patient Reported Outcome 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FDA 
Food and Drug Administration  
FSH 
Follicle stimulating hormone 
g 
Gram 
GALT 
Gut associated lymphoid tissue 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal  
Gi 
Giga 
g/L 
Grams per litre 
GSK 
GlaxoSmithKline 
H0 
Null hypothesis 
HA 
Alternative hypothesis  
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin  
HCV 
Hepatitis C virus  
Hgb 
Hemoglobin  
HI 
Hematologic improvement  
HI-E 
Hematologic improvement Erythroid  
HI-N 
Hematologic improvement Neutrophil 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency virus 
HLA 
Human leukocyte antigen  
HMGCoA 
3-hydroxy-3-methylglutaryl-coenzyme A 
HR 
Hazard Ratio  
HRQL 
Health related quality of life 
HRT 
Hormonal replacement therapy 
h 
Hour 
HPMC  
Hydroxcypropyl methylcellulose  
IB 
Investigator’s Brochure 
ICF 
Informed consent form 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
157 
 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IHC 
Immunohistochemistry  
INDSRs 
Investigational New Drug Safety Reports 
INR 
International normalized ratio 
IP 
Intraperitoneal  
IP 
Investigational product  
IPSS-R 
International Prognostic Scoring System Revised  
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IUD 
Intrauterine devices 
IUS 
Intrauterine hormone release system 
IV 
Intravenous 
IVRS/IWRS 
Interactive voice/web response system 
IWG 
International Working Group  
L 
Liter  
LLN 
Lower limit of normal  
LLS 
Leukemia and Lymphoma Society  
LP 
Lumbar puncture 
LV 
Left ventricle  
LVEF 
Left Ventricular Ejection Fraction 
MATE 
Multidrug and Toxin Extrusion 
mCR 
Complete marrow remission  
MCH 
Mean corpuscular hemoglobin  
MCV 
Mean corpuscular volume  
MDCK 
Madine Darby canine kidney 
MD 
Myelodysplastic  
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities Medical Dictionary for Regulatory 
Activities 
MEP50 
Methylosome protein 50 
mEq/L 
Milliequivalents per Litre  
mg 
Milligram 
mg/m² 
milligrams per meter squared 
min 
Minute 
mIU 
milli international unit 
mL 
milliliter  
mmol 
Millimoles  
MP 
Myeloproliferative  
MPN 
Myeloproliferative neoplasms 
mRNA 
Messenger ribonucleic acid  
MSDS 
Material Safety Data Sheet  
msec 
Millisecond 
MTD 
Maximum tolerated dose 
n 
Number 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
158 
 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse Events  
N-CRM 
Neuenschwander continual reassessment method 
NHL 
Non-Hodgkin’s lymphoma  
Ng 
Nanogram 
nm 
Nanometers  
NYHA 
New York Heart Association  
OAT 
Organic Anionic Transporter 
OCT 
Organic Cationic Transporter 
ORR 
Overall response rate  
OS 
Overall survival 
PCR 
Polymerase chain reaction  
PD 
Pharmacodynamics 
PD 
Progressive disease 
PFS 
Progression free survival  
pg 
Picogram 
Pgp 
P-glycoprotein  
PGx 
Pharmacogenetics  
PI 
Principal Investigator 
PI3K 
phosphoinositol-3 kinase 
PK 
Pharmacokinetic 
pmol 
Picomole 
PP 
Per protocol 
PR 
Partial response 
pre-mRNA 
Precursor messenger ribonucleic acid 
PRMT5 
Protein arginine methyltransferase 5 
PRMT5i 
Protein arginine methyltransferase 5 inhibitor 
PRO 
Patient Reported Outcome 
PT 
Prothromin time  
PTT 
Partial Thromboplastin Time  
Q 
Every 
QD 
Once a day  
QLQ-C30 
Quality of Life Questionnaire Core-30 
QoL 
Quality of life 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate according to Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
RB1 
Retinoblastoma protein 1 
RBC 
Red Blood cells  
R/R 
Relapsed/Refractory 
REML 
Restricted maximum likelihood  
RNA 
Ribonucleic acid  
RT-PCR 
Reverse transcriptase polymerase chain reaction  
SAE 
Serious Adverse Event 
SAS 
Statistical analysis system 
SC 
Subcutaneous  
SD 
Stable disease  


T M F -1 1 7 8 5 9 8 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 5 9  
 
 
 
S D V/ S D R  
S o urc e Dat a V erific ati on/ Sourc e D oc u m ent R evi e w  
S E E R  
S urv eill a nc e,  E pid e mi ol o gy a n d E n d R es ults  
S F 3 B 1  
S plici n g fact or 3 B s u b unit 1  
S G P T  
S er u m gl uta mic pyr uvic tr ans a mi n as e  
S O A  
Sc h e dul e of Activiti es  
S O P  
St a nd ar d o per ati n g pr oc ed ur e  
S R M  
St u dy Ref er enc e M an ual  
S R T  
S af ety R evi e w T e a m  
S R S F 2  
S eri n e a n d ar gi ni ne ric h s plici n g f act or 2 
S S  
St e ady st at e  
S T 7  
S u p press or of T u m orig enicity 7  
S U S A R  
S us p ect e d U n exp ecte d Serio us Adv ers e Ev e nts  
t1/ 2 
H alf lif e  
T 3  
Trii o d ot hyr o nin e  
T 4  
T hyr oxi n e  
TI  
Ti me i nv ari a nc e  
T S H  
T hyr oi d sti m ul ati ng h or mo ne  
T m ax  
Ti me of m axi m u m c o nce ntrati o n o bserv e d 
 
  
U 2 A F 1  
U 2 S m all N ucl e ar R N A A uxili ary F act or 1  
µ L  
Micr olit er  
U L N  
U p p er li mit of nor mal  
U K  
U nit e d Kin g do m  
v 
V ersi o n  
V P  
Vic e Pr esi de nt  
W  
W e ek  
W B C  
W hit e bl oo d c ell  
W H O  
W orl d H e alt h Org a niz ati o n  
W O C B P  
W o m a n of chil d be ari n g p otenti al  
Z R S R 2  
Zi nc Fi n g er C C C H -Ty p e, R N A Bi n di ng M otif a nd S erine/ Ar gi ni ne Ric h 2  
 
Tr a d e m ar k I nf or m ati o n  
Tr a d e m ark s of t h e Gl a x o S mit h Kli n e 
gr o u p of c o m p a ni e s  
 
Tr a d e m ark s n ot o w n e d by t h e 
Gl a x o S mit h Kli n e gr o u p of c o m p a ni es  
N O N E  
 
D ac o g en  
 
 
M e d D R A  
 
 
S A S  
 
 
Vi d az a  
 
 
Wi n N o nli n  
 
C CI
C CI


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
160 
 
11.15. 
Appendix 15: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 1  
Overall Rationale for the Amendment:  
The primary driver for the protocol amendment is to provide a change to the inclusion 
criterion for the renal function. The estimated glomerular filtration rate (eGFR) has been 
lowered to ≥50 mL/min/1.73m2). The risk, rationale for risk and risk mitigation for this 
change has been added to the preclinical and clinical risk assessment table in Section 
2.3.2. 
Other changes are detailed below. 
Further additions to the pre-clinical and clinical risk assessment table following the IB 
update and data cut of 4th February 2019. 
Details of a new tablet formulation (that is still in development) for the compound 
GSK3326595 has been added. 
Revised nomenclature around the classification of inhibitors and inducers of CYP 
isoenzymes and inhibitors of BCRP and PgP has been made. 
Clarification around time windows and visits has been added. 
Clarification around the timings of interim analysis and the definition of evaluable 
participants has been added for each Part of the study. 
Removal of text of AEs of special interest in the statistical analysis section. 
Some additional clarifications in the Schedule of Activities tables. 
Typographical errors have been corrected and minor editorial changes have been made. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 
rationale Section 
and Section 2.1 
study rationale 
Removal of some text about possible 
curative therapy for the diseases MDS 
and AML 
This statement has been 
removed for clarity 
1.3.1 Schedule 
of Activities 
tables 
Addition of a row detailing when study 
drug (GSK3326595) is dispensed and 
when the diary cards are reviewed 
To add clarity 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
161 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
2.3.2 Preclinical 
and clinical risk 
assessment 
The clinical effects listed in the bone 
marrow/hematologic/lymphoid, gastro-
intestinal, heart, liver and renal 
sections of the table have been 
updated. The pre-clinical effects in the 
renal section have also been updated. 
Following the recent IB 
update to version 03, and 
the recent data cut of 4th 
February 2019, these 
sections have been 
updated based on the 
current available clinical 
data on the compound. 
This Section has also been 
updated to provide 
rationale for the change in 
the inclusion criterion 10 
(eGFR has been lowered 
to ≥50 mL/min/1.73m2 
from ≥60 
mL/min/1.73m2). 
4.1.1.5 and 
4.1.3.3.4 
Statistical 
design 
Minor editorial revision around the 
wording of the interim analysis. 
To provide clarity 
5.1 Inclusion 
criteria, number 
10 
Change in the renal function criteria. 
eGFR has been lowered to ≥50 
mL/min/1.73m2 from ≥60 
mL/min/1.73m2). 
Participants with eGFR of <60 
mL/min/1.73m2 will require additional 
monitoring as described in Appendix 
2. 
To aid recruitment on the 
study, the renal function 
has been lowered, the 
rationale for this change 
has been given in Section 
2.3.2. 
6.1 Study 
Intervention 
administered 
Addition of tablet formulation. 
To provide more detail on 
the tablet formulation of 
GSK3326595. 
6.6.1.3 
Prohibited 
medications 
Revised nomenclature around the 
classification of inhibitors and inducers 
of CYP isoenzymes and inhibitors of 
BCRP and PgP has been made. The 
word ‘potent’ has been replaced with 
‘strong and moderate’. 
To provide an update on 
the most current 
terminology. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
162 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
8.1 Visit 
Windows 
Additional text on screening/re-
screening and visit windows has been 
provided. 
To add more clarity and to 
confirm that all visit 
windows on the study 
should refer to the Week 1 
Day 1 (first day of dosing) 
date. 
8.4.6.2 
Additional urine 
and serum safety 
studies 
Additional text placed here to confirm 
that participants with eGFR of <60 
mL/min/1.73m2 will require additional 
monitoring as described in Appendix 2 
of the protocol. Additional urine and 
serum renal biomarkers will be tested 
in these participants. 
The rationale is given in 
Section 2.3.2 of the 
protocol. 
9.3.2.2 Safety 
Analyses, 
Adverse events 
Removal of text referring to AEs of 
special interest. 
There are no AEs of 
special interest at this 
time. 
References, 
Section 10 
Update to the IB reference (to provide 
details of the current version, 03). Also 
to provide a reference to another 
clinical study with GSK3326595 that 
is mentioned in Section 2.3.2 of the 
protocol. 
Updated/additional 
reference added in the text 
of the protocol. 
11.2 Appendix 2 Additional urine and serum renal 
biomarker tests have been added to the 
clinical laboratory tests. 
Rationale for these 
additional tests is given in 
Section 2.3.2 of the 
protocol. 
 
Amendment 2: 
Overall Rationale for the Amendment:  
The primary driver for the protocol amendment is the addition of non-clinical bone 
findings and the related risk mitigation strategy, with a DEXA scan procedure being 
added to assess bone density at periodic intervals throughout the study. 
The other main driver for this protocol amendment is the reduction in cardiac monitoring: 
LVEF stopping criteria have been removed; echocardiogram and troponin collection have 
been removed; cardiac risk and mitigation strategy have been updated; and select cardiac 
criteria from the inclusion criterion (number 10) on adequate organ system function have 
been removed. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
163 
 
The non-clinical and clinical risk assessment and mitigation strategies (Section 2.3.2) for 
GSK3326595 have been updated, based on review of safety data as of the IB cut off date 
(04th February 2020).  Also, some of the non-clinical and clinical risk assessment and 
mitigation strategies for 5-Azacitidine have been updated.  Other minor changes are 
detailed below. 
Updates to Section 8.3.1, Section 9.3.1 and Appendix 9 and Appendix 10: to add clarity 
that the IWG disease response criteria (detailed in Appendix 9) will be used for all 
participants enrolled into Part 1 (whether AML, CMML or MDS), Parts 2A and 2B; the 
standard disease response criteria for participants with AML (detailed in Appendix 10) 
will be used for all participants enrolled in Part 2C. 
Removal of 25mg capsule/strength as this is no longer being used going forward. 
Typographical errors have been corrected and minor editorial changes have been made. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
164 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1, Synopsis, 
and Section 2.1, Study 
Rationale 
Correction of “demethylation” to 
“dimethylation” in the text 
“PRMT5 is responsible for the 
majority of symmetric 
dimethylation of arginine in vivo” 
Correction of error. 
Section 1.3, Schedule of 
Activities (SOA) tables 
Removal of Left Ventricle 
Ejection Fraction (LVEF) 
evaluation  
A recent cardiac data review has 
shown no evidence of cardiotoxicity. 
Therefore, specific cardiac monitoring 
of troponin, LVEF and cardiac valves 
are no longer required in this protocol. 
Section 1.3, Schedule of 
Activities (SOA) tables 
Addition of DEXA bone 
densitometry 
Pre-clinical bone findings have been 
observed. Therefore, DEXA scans at 
baseline and periodically during the 
study have been added to this protocol 
as part of the risk/mitigation strategy,  
Section 2.3.2, Preclinical 
and Clinical Risk 
Assessment 
(GSK3326595) 
Addition of a new potential risk of 
bone effects from an ongoing 13 
week rat toxicity study. The 
mitigation strategy for this new 
risk has also been added (DEXA 
scans to be conducted; update to 
the Informed Consent Form). 
 
 
Updated wording on cardiac risk 
and removal of the mitigation 
strategy. 
 
 
 
 
Updated wording to the 
risks/mitigation strategies for 
gastro-intestinal (GI), bone 
marrow/hematologic/lymphoid, 
liver, exocrine tissues and 
reproductive effects 
 
Removal of renal effects from the 
risk assessment table. 
Due to the recent bone findings in the 
13 week rat toxicity study, DEXA 
scans at baseline and periodically 
during the study have been added to 
this protocol as part of the 
risk/mitigation strategy. The Informed 
Consent Form will also be updated 
with this information. 
 
A recent cardiac data review has 
shown no evidence of cardiotoxicity in 
human subjects. Therefore, specific 
cardiac monitoring of troponin, LVEF 
and cardiac valves are no longer 
required. 
 
This wording has been updated, based 
on review of safety data as of the IB 
cut off date (04th February 2020). 
 
 
 
 
A review of AEs and SAEs as of 19 
February 2020 showed no notable 
safety concerns with regard to direct 
nephrotoxicity. Therefore this section 
has been removed from the table. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
165 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3.2 Preclinical 
and Clinical Risk 
Assessment (5-
Azacitidine) 
Addition of a new potential risk, 
differentiation syndrome. Also, 
updated text has been added to 
the mitigation strategy for 
reproductive effects. 
To provide an update regarding the 
latest known information about 5-
Azacitidine. 
Section 5.1, Inclusion 
Criteria, criterion 10, 
Table 10 
Table 10, Definitions of adequate 
organ function, removal of 
cardiac parameters, ejection 
fraction and troponin. 
A recent cardiac data review has 
shown no evidence of cardiotoxicity. 
Therefore, specific cardiac monitoring 
of troponin, LVEF and cardiac valves 
are no longer required. 
Section 6.1, Study 
Intervention(s) 
administered 
Removal of 25 mg strength of 
capsule 
25mg strength will no longer be used 
in this study. 
Section 7.1.1 
Discontinuation of study 
intervention, disease 
progression 
Updated text from “Time and 
Events Table” to “Section 1.3, 
Schedule of Activities (SOA) 
Text corrected. 
Section 7.1.4, LVEF 
Stopping Criteria 
Removal of this section. 
A recent cardiac data review has 
shown no evidence of cardiotoxicity in 
human subjects. Therefore, specific 
cardiac monitoring of troponin, LVEF 
and cardiac valves are no longer 
required. 
Section 8.1, Visit 
Windows 
Removal of text “Baseline Left 
Ventricular function evaluation 
must be performed within 35 
days of first dose”. 
A recent cardiac data review has 
shown no evidence of cardiotoxicity. 
Therefore, specific cardiac monitoring 
of troponin, LVEF and cardiac valves 
are no longer required. 
Section 8.3.1, Efficacy 
assessments, disease 
assessment 
Additional text to state that 
“Participants enrolled in Part 1 
(including those with AML, 
CMML and MDS) will have 
responses graded per IWG 
criteria”. 
To add clarity 
Section 8.4.5, Safety 
Assessments 
New section added “Bone 
Mineral Density” 
Pre-clinical bone findings have been 
observed. Therefore, DEXA scans at 
baseline and periodically during the 
study have been added to this 
protocol. 
Section 8.4.5, Cardiac 
Output Assessments 
 
Section removed. 
A recent cardiac data review has 
shown no evidence of cardiotoxicity. 
Therefore, specific cardiac monitoring 
of troponin, LVEF and cardiac valves 
are no longer required. 


TMF-11785988 
CONFIDENTIAL 
 
 
 
208809 
 
166 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.4.6.1, Clinical 
Safety Laboratory 
Assessments 
Removal of section on troponins. 
A recent cardiac data review has 
shown no evidence of cardiotoxicity. 
Therefore, specific cardiac monitoring 
of troponin, LVEF and cardiac valves 
are no longer required. 
Section 9.3.1.1, 
Statistical Analysis, 
Efficacy Analyses, 
Efficacy Endpoints 
Removal of text “MDS” and 
“AML”, and just referring Parts 1, 
2A and 2B to the IWG criteria (in 
Appendix 9), and referring Part 
2C to the response criteria 
(Appendix 10). 
To add clarity. 
Section 10, References 
Update to the IB reference for 
2020, Version 04 
To add the latest reference for the 
2020 IB, Version 04. 
Section 11.2, Appendix 
2, Clinical lab tests 
 
 
Table 11 
Addition of text stating that the 
additional renal markers will be 
analysed at a central lab. 
 
Removal of cardiac safety 
markers (central and local 
troponin) 
To add clarity 
 
 
 
A recent cardiac data review has 
shown no evidence of cardiotoxicity. 
Therefore, specific cardiac monitoring 
of troponin, LVEF and cardiac valves 
are no longer required. 
Section 11.9, Appendix 
9, IWG Criteria for 
Response for 
Participants with MDS 
Title changed to “IWG Criteria for 
Response for Participants in Part 
1, Part 2A and Part 2B” 
To add clarity 
Section 11.10, Appendix 
10, Response Criteria 
for Participants with 
AML 
Title changed to “Response 
Criteria for Participants in Part 
2C”. 
To add clarity 
 

SAP_001.pdf: 
 
C O N FI D E N TI A L  
 
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 0 8 8 0 9  
1  
 
Di visi o n  
: W orl d wi de  De vel o p me nt  
I nf or m ati o n T y pe 
: Re p orti n g a n d A nal ysis Pla n  ( R A P) 
 
Title  
: Re p orti n g a n d A nal ysis Pla n f or A P hase I/II st u d y t o 
i n vesti gate t he s afet y a n d cli nical acti vit y of G S K 3 3 2 6 5 9 5 a n d 
ot her a ge nts i n s u bjects wit h m yel o d ys plastic s y n dr o me a n d 
ac ute m yel oi d le u kae mia  
C o m p o u n d N u m ber  : G S K 3 3 2 6 5 9 5  
Effecti ve D ate  
: 1 9 -A U G -2 0 2 2  
 
Descri pti o n:  
•  
T his R A P is i nte n de d t o descri be t he detaile d pla n ne d statistical a nal yses a n d o ut p uts 
of Part 1, Part 2 i nteri m a n d fi nal a nal yses of pri mar y, sec o n d ar y a n d ke y e x pl orat or y  
e n d p oi nts  re q uire d f or t he cli nical st u d y re p ort. O n 8 Dece m b er 2 0 2 1 Researc h 
I n v est me nt B oar d c o nfir me d t hat e nr ol me nt i nt o Part 2 of ME T E O R -2 ( pr ot oc ol 
a me n d me nt 3) i n vesti gati n g t he c o m bi nati o n of G S K 3 3 2 6 5 9 5 a n d 5 -Azaciti di ne will 
be cl ose d. As a res ult, o nl y Part 1 a n al ysis will be perf or me d a n d all a n al ys es 
c orres p o n di n g t o Part 2, as well as t he E x pl orat or y O bjecti ves will n ot be. S y n o ptic 
C S R will prese nt baseli ne c haracteristics, e x p os ure, f ull safet y, pri mar y a n d 
sec o n dar y ( hi g h le vel) e n d p oi nts f or Part 1. P K, B M data will be de pri oritize d.  
 
R A P A ut h or(s):  
A p pr o ver  
D ate  
A p pr o v al Met h o d  
 
1 9/ 0 8/ 2 0 2 2   
E mail   
Pri nci pal bi ostatisticia n, P are x el  
1 9/ 0 8/ 2 0 2 2   
E mail   
Pri nci pal Statisticia n , Cli nical Statistics 
C o p yri g ht 2 0 2 2  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d.  
 
 
P P D
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
2  
 
R A P Te a m R e vie w C o nfir m ati o ns : 
A p pr o ver  
D ate  
A p pr o v al 
Met h o d  
1 5/ 0 8/ 2 0 2 2  
E mail  
Pri nci pal Pr o gra m mer , Cli nical Statistics 
0 9/ 0 8/ 2 0 2 2  
E mail  
O nc ol o g y Cli nical D e vel o p me nt  
Safet y a n d Me dic al G o ver na nce Lea d  
1 8/ 0 8/ 2 0 2 2  
E mail  
 
Cli nical P har mac ol o g y  
0 4/ 0 3/ 2 0 2 2  
E mail  
 
Scie ntific Writer  
0 8/ 0 8/ 2 0 2 2  
E mail  
Cli nic al St atistics a n d Cli nic al Pr o gr a m mi n g Li ne A p pr o v als : 
A p pr o ver  
D ate  
A p pr o v al 
Met h o d  
Statistics  Lea der  
1 9/ 0 8/ 2 0 2 2  
P har ma T M F e -
si g nat ur e 
1 9/ 0 8/ 2 0 2 2  
P har ma T M F e -
si g nat ur e 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
CONFIDENTIAL 
 
 
 
208809 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 6 
2.3. 
Study Design .............................................................................................. 11 
2.4. 
Statistical Hypotheses / Statistical Design ................................................... 14 
2.4.1. 
Part 1 ........................................................................................... 14 
2.4.2. 
Part 2 ........................................................................................... 14 
3. 
PLANNED ANALYSES .......................................................................................... 17 
3.1. 
Interim Analyses ......................................................................................... 17 
3.1.1. 
Part 1 Dose Confirmation ............................................................. 17 
3.1.2. 
Part 1 Dose Expansion Interim Futility Analysis............................ 18 
3.1.3. 
Part 2 Dose Escalation ................................................................ 20 
3.1.4. 
Part 2 Dose Expansion Interim Futility Analysis ........................... 21 
3.2. 
Main analyses ............................................................................................. 22 
3.2.1. 
Part 2 Dose Selection .................................................................. 22 
3.2.2. 
Part 2 Dose Expansion ................................................................ 23 
3.3. 
Final Analyses ............................................................................................ 24 
3.3.1. 
Part 1 and Part 2 Final Analysis ................................................... 24 
4. 
ANALYSIS POPULATIONS ................................................................................... 25 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 26 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 26 
5.2. 
Analysis Datasets ....................................................................................... 26 
5.3. 
Reporting Conventions ............................................................................... 27 
5.4. 
Baseline Definitions .................................................................................... 27 
5.4.1. 
Change from baseline .................................................................. 28 
5.5. 
Multiple Assessments ................................................................................. 28 
5.6. 
Multicenter Studies ..................................................................................... 29 
5.7. 
Examination of Covariates, Other Strata and Subgroups ............................ 29 
5.7.1. 
Covariates and Other Strata ........................................................ 29 
5.7.2. 
Examination of Subgroups ........................................................... 29 
A table of summary of investigator assessed clinical benefit response by central 
review spliceosome mutation status across dose levels will be produced 
which will contain CBR and ORR with no CI. .................................................. 29 
5.7.3. 
Multiple Comparisons and Multiplicity .......................................... 29 
5.8. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 29 
6. 
STUDY POPULATION ANALYSES ....................................................................... 30 
6.1. 
Overview of Planned Study Population Analyses ........................................ 30 
6.2. 
Subject’s Disposition ................................................................................... 30 
6.3. 
Protocol Deviations ..................................................................................... 30 
6.4. 
Demographic and Baseline Characteristics ................................................. 31 


 
CONFIDENTIAL 
 
 
 
208809 
 
4 
 
6.5. 
Concomitant Medications ............................................................................ 31 
6.6. 
Exposure and Treatment Compliance ......................................................... 31 
6.7. 
Disease Characteristics .............................................................................. 32 
6.8. 
Prior and Follow-Up Anti-Cancer Therapy................................................... 32 
6.9. 
Duration of Follow-Up ................................................................................. 32 
7. 
EFFICACY ANALYSES .......................................................................................... 33 
7.1. 
Primary Efficacy Analyses .......................................................................... 33 
7.1.1. 
Endpoint / Variables ..................................................................... 33 
7.1.2. 
Summary Measure ...................................................................... 33 
7.1.3. 
Population of Interest ................................................................... 34 
7.1.4. 
Statistical Analyses / Methods ..................................................... 34 
7.2. 
Secondary Efficacy Analyses ...................................................................... 34 
7.2.1. 
Endpoint / Variables ..................................................................... 34 
7.2.2. 
Summary Measure ...................................................................... 37 
7.2.3. 
Population of Interest ................................................................... 37 
7.2.4. 
Statistical Analyses / Methods ..................................................... 38 
7.3. 
Exploratory Efficacy Analyses ..................................................................... 39 
7.3.1. 
Endpoint/Variables ....................................................................... 39 
7.3.2. 
Summary Measure ...................................................................... 39 
7.3.3. 
Population of Interest ................................................................... 39 
7.3.4. 
Statistical Analyses / Methods ..................................................... 40 
8. 
SAFETY ANALYSES ............................................................................................. 41 
8.1. 
Extent of Exposure ..................................................................................... 41 
8.2. 
Adverse Events Analyses ........................................................................... 42 
8.3. 
Deaths and Serious Adverse Events ........................................................... 43 
8.4. 
Adverse Events Leading to Dose Modification of Study Treatment ............. 44 
8.5. 
Clinical Laboratory Analyses ....................................................................... 44 
8.5.1. 
Analyses of Liver Function Tests (LFT) ........................................ 47 
8.6. 
Other Safety Analyses ................................................................................ 47 
8.6.1. 
Performance Status ..................................................................... 47 
8.6.2. 
ECG ............................................................................................. 47 
8.6.3. 
Vital Signs .................................................................................... 48 
8.6.4. 
Cardiovascular Risk Factors ........................................................ 49 
8.6.5. 
LVEF ........................................................................................... 49 
8.6.6. 
Pregnancies ................................................................................. 49 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 50 
9.1. 
Primary Pharmacokinetic Analyses ............................................................. 50 
9.1.2. 
Population of Interest ................................................................... 50 
9.1.3. 
Statistical Analyses / Methods ..................................................... 50 
9.2. 
Secondary Pharmacokinetic Analyses ........................................................ 51 
10. PHARMACODYNAMIC (AND / OR BIOMARKER) ANALYSES ............................. 52 
11. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 53 
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 54 
13. REFERENCES ....................................................................................................... 55 
14. APPENDICES ........................................................................................................ 56 


 
CONFIDENTIAL 
 
 
 
208809 
 
5 
 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 56 
14.1.1. 
Exclusions from Per Protocol Population ..................................... 56 
14.2. 
Appendix 2: Schedule of Activities .............................................................. 57 
14.2.1. 
Protocol Defined Schedule of Events ........................................... 57 
14.3. 
Appendix 3: Assessment Windows ............................................................. 58 
14.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 59 
14.4.1. 
Study Phases .............................................................................. 59 
14.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 59 
14.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 60 
14.5.1. 
Reporting Process ....................................................................... 60 
14.5.2. 
Reporting Standards .................................................................... 60 
14.5.3. 
Reporting Standards for Pharmacokinetic .................................... 61 
14.6. 
Appendix 6: Derived and Transformed Data ............................................... 62 
14.6.1. 
General ........................................................................................ 62 
14.6.2. 
Study Population .......................................................................... 62 
14.6.3. 
Safety .......................................................................................... 63 
14.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 64 
14.7.1. 
Premature Withdrawals ................................................................ 64 
14.7.2. 
Handling of Missing Data ............................................................. 64 
14.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 67 
14.8.1. 
ECG ............................................................................................. 67 
14.8.2. 
Vital Signs .................................................................................... 68 
14.8.3. 
Urinalysis ..................................................................................... 68 
14.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 69 
14.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 70 
14.11. Appendix 11: Abbreviations & Trade Marks ................................................ 71 
14.11.1. Abbreviations ............................................................................... 71 
14.11.2. Trademarks ................................................................................. 72 
14.12. Appendix 12: List of Data Displays.............................................................. 73 
14.12.1. Data Display Numbering .............................................................. 73 
14.12.2. Mock Example Shell Referencing ................................................ 73 
14.12.3. Deliverables ................................................................................. 73 
14.12.4. Study Population Tables .............................................................. 74 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
6 
 
1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe planned statistical 
analyses (interim and final) and outputs of primary, secondary and key exploratory 
endpoints required to be included in the Clinical Study Report (CSR) for study 208809. It 
is based on the protocol amendment 3 dated 15 FEB 2021.  The main CSR will be a 
synoptic report including all primary and secondary endpoints.  
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
For Part 1 and Part 2A, the protocol version 1.0 defined the Clinical Benefit Rate (CBR) 
and Overall response rate (ORR) based on international working group (IWG) criteria for 
myelodysplastic syndrome (MDS). Since the protocol also allows acute myeloid 
leukaemia (AML) participants that have evolved from an antecedent MDS, for which the 
standard AML response criteria will be used, the RAP updated the CBR and ORR 
definition incorporating the AML responses. The same update was made in the 
subsequent protocol amendments. Protocol Amendment 3 discontinued further 
development with monotherapy GSK3326595 based on clinical activity meeting pre-
specified futility criteria as specified in the Protocol (Part 1), while continuing to explore 
GSK3326595 in combination with 5-Azacitidine in the Part 2 Dose Escalation and Dose 
Expansion cohorts.  
The Part 2 Dose Escalation design of GSK3326595 with 5-Azacitidine was amended to 
include intermittent dose schedules of GSK3326595 in relapsed / refractory MDS, 
chronic myelomonocytic leukaemia CMML and AML participants; and Part 2 Dose 
Expansion cohorts were to include treatment naïve MDS and CMML participants.  On 8 
December 2021 Research Investment Board confirmed that enrolment into Part 2 of 
METEOR-2 (protocol amendment 3) investigating the combination of GSK3326595 and 
5-Azacitidine will be closed. As a result, only Part 1 analysis will be performed and all 
analyses corresponding to Part 2, as well as the Exploratory Objectives will not be. 
Synoptic CSR will present baseline characteristics, exposure, full safety, primary and 
secondary (high level) endpoints for Part 1. PK, BM (Pharmacokinetic, Biomarker) data 
will be deprioritized. 
2.2. 
Study Objective(s) and Endpoint(s) 
Part 1 
Objectives 
Endpoints 
Primary 
• 
To determine the clinical activity of 
GSK3326595 in participants with myeloid 
neoplasms 
• 
Clinical Benefit Rate (CBR), as defined as the 
percentage of participants achieving a complete 
remission (CR), complete marrow remission 
(mCR), partial remission (PR), stable disease 
(SD) lasting at least 8 weeks, or hematologic 
improvement (HI), per International Working 
Group (IWG) criteria. 


 
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
7  
 
P art 1  
O bj e cti ve s  
E n d p oi nt s  
S e c o n d ar y  
•  
T o d et er mi n e t he s afety, tol er ability, a n d 
r ec o m m e n d e d myel oid m o noth er a py dos e of 
or ally -a d mi nister e d G S K 3 3 2 65 9 5 i n partici p a nts 
wit h r el a ps e d an d/ or r efract ory my eloi d 
n e o pl as ms  
•  
Fr e q u e ncy a n d s ev erity of a dvers e eve nts  
•  
Fr e q u e ncy of D L Ts  
•  
T o f urt h er descri b e t he cli nic al activity of 
G S K 3 3 2 6 5 95 i n partici p a nts wit h r el aps e d 
a n d/ or r efr ac t ory my el oi d n e o pl as ms 
•  
Ov er all r es p o ns e r at e ( O R R), d efi n e d as t he 
p erc e nt ag e of partici p a nts ac hi evi ng a C R, 
m C R, or P R, p er I W G crit eri a  
•  
Pr o gr essio n fr e e s urviv al ( P F S), d efi n ed as ti m e 
fr o m first d ose t o dis e as e pr ogr essi on, as 
d efi n e d by I W G crit eri a, or d e at h d u e t o a ny 
c a us e, w hic hev er occ urs e arli er 
•  
Ov er all surviv al ( O S), d efi n e d as ti me fr o m first 
d os e t o d e at h d u e t o a ny c a use  
•  
T o c h ar act eriz e t h e p h ar mac oki n etics ( P K) of 
G S K 3 3 2 6 5 95 i n partici p a nts wit h r el aps e d 
a n d/ or r efr act ory my el oi d n e o pl as ms  
•  
G S K 3 3 2 6 5 95 P K p ar a met ers in pl as m a 
f oll o wi ng sin gl e- ( Day 1) a nd re p e at-d os e 
a d mi nistr ati o n of G S K 3 3 2 65 95  
E x pl orat ory  
 
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
8  
 
P art 2 ( D ose Esc al ati o n)  
O bj e cti ve s  
E n d p oi nt s  
Pri m ary  
•  
To deter mine the safety, tolerability, and 
reco m mended co mbination dose of orally- 
ad ministered G S K3326595 when 
ad ministered in co mbination with 5 -
Azacitidine  in participants wit h myeloid 
neoplas ms  
•  
Frequency and severity of adverse events  
•  
Frequency of DL Ts  
•  
Frequency 
of 
dose interruptions, 
dose 
reductions, and treat ment discontinuation due to 
adverse events 
S e c o n d ary  
•  
T o d eter mi n e th e cli nic al activity of  
G S K3326595 plus 5 -Azacitidine  in 
participants with myeloid neoplas ms  
• 
C o m pl ete R e missio n ( C R) r at e, d efine d as 
p erce nt a ge of p articip a nts achi evin g a C R 
p er I W G crit eria  
•  
T o d escri b e t he p h ar mac okin etics ( P K) of 
G S K 33 2 65 95 a n d 5 -Azacitidi n e  aft er 
si n gl e- a nd r e pe at -d os e a d mi nistr ati o n  
•  
G S K3326595 
and 
5 -Azacitidine  
P K 
para meters in plas ma follo wi ng single - ( Day 
1) 
and repeat -dose 
ad ministration 
of 
G S K3326595 in 
co mbination 
with 
5 -
Az aciti di n e  
•  
To further describe the clinic al activity of 
G S K3326595 plus 5 -Azacitidine  in 
participants with myeloid neoplas ms  
•  
O R R, defin e d as the perc ent a ge of 
participants achievin g a C R, m C R, or P R, 
per I W G crit eri a  
E x pl or at or y  
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
9  
 
P art 2 ( D ose Esc al ati o n)  
 
 
P art 2 ( D ose E x p a nsi o n ) 
O bj e cti ve s  
E n d p oi nt s  
Pri m ary  
•  
T o d eter mi n e th e cli nic al activity of  
G S K 33 2 65 95 pl us 5 -Az acitidi n e  i n 
p artici p a nts wit h hi g h risk ne wly di a g n os ed  
M D S or C M M L  
• 
C o m pl ete R e missio n ( C R) r at e, d efine d as 
p erce nt a ge of p articip a nts achi evin g a C R 
p er I W G crit eria  
S e c o n d ary  
• 
T o d et er min e th e s af ety a n d tol er a bility, of  
or ally -a d minist er e d G S K 3 3 26 5 9 5 w h e n  
a d minist er e d in c o m bi n atio n wit h 5 -
Az aciti di n e  in p articip a nts wit h hig h risk n e wly 
di a g n os e d M D S or C M M L  
• 
Fr e q u e ncy a nd s ev erity of a dv ers e  ev e nts  
• 
Fr e q u e ncy of d os e int err uptions, d os e  
r e d ucti o ns, a nd tr e at m ent disc o nti n u atio n 
d u e t o a dv erse ev ents  
•  
T o d escri b e t he p h ar mac okin etics of 
G S K 33 2 65 95 a n d 5 -Azacitidi n e  aft er 
si n gl e- a nd r e pe at -d os e a d mi nistr ati o n  
•  
G S K3326595 
and 
5 -Azacitidine  
P K 
para meters in plas ma follo wi ng single - ( Day 
1) 
and repeat -dose 
ad ministration 
of 
G S K3326595 in 
co mbination 
with 
5 -
Az aciti di n e  
•  
To further describe the clinic al activity of 
G S K3326595 plus 5 -Azacitidine  in 
participants with hi g h risk  n e wly dia g n os e d 
M D S or C M M L  
•  
O R R, defin ed as the perc ent a ge of 
participants achievin g a C R, m C R, or P R, 
per I W G crit eri a  
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 0  
 
P art 2 ( D ose E x p a nsi o n ) 
E x pl or at or y  
 
C CI


 
CONFIDENTIAL 
 
 
 
208809 
 
11 
 
2.3. 
Study Design 
Overview of Study Design and Key Features 
Figure 1 
Study Schematic 
Design Features 
• 
This is an open-label, multicentre, multi-part study of GSK3326595 as 
monotherapy and in combination with 5-Azacitidine in participants with 
myeloid malignancies. 
• 
A formal data analysis was performed with data cut off 30th June 2020 for 
participants in the Part 1 Dose Expansion cohort who have undergone at least 
two post-baseline disease assessments, have progressed or died, or 
permanently discontinued from study intervention. 
• 
It is estimated that a maximum of 113 participants will be enrolled in the study. 
• 
Participants may continue treatment in the study until disease progression, 
unacceptable toxicity, withdrawal of consent, or termination of the study by the 
sponsor. 
PART 1 
• 
Part 1 is composed of a safety evaluation, followed by a single-arm dose 
expansion in participants with relapsed and/or refractory MDS and 
hypoproliferative AML that has evolved from an antecedent MDS.  
• 
The dose of 300 mg QD was the starting dose for the dose expansion cohort 
due to tolerability issues (primarily fatigue) observed with the 400 mg dose in 
the dose confirmation cohort and in 204653 study. 
• 
The Neuenschwander continual reassessment method (N-CRM) will be 
utilized to guide dose escalation/de-escalation decisions based on the rate of 
dose-limiting toxicities (DLTs) observed in participants.  
• 
Six participants will initially be enrolled at the starting dose and up to 12 
participants will be enrolled into Part 1 Dose Confirmation phase. 
• 
Once the Recommended Myeloid Monotherapy Dose is determined, 
additional participants (for a total of up to 35 participants treated at this dose) 
will be enrolled. Overall, up to 41 participants will be enrolled in Part 1. 
• 
Part 1 Dose Expansion will employ a Bayesian design that allows the trial to 
be monitored with the constraint of both Type I and Type II error rates. Clinical 


 
CONFIDENTIAL 
 
 
 
208809 
 
12 
 
Overview of Study Design and Key Features 
response will be assessed by bone marrow biopsy and defined per IWG 
criteria for MDS/CMML subjects and AML subjects. 
• 
Participants in dose confirmation who were treated at the same dose level as 
those in expansion phase will be included in the analysis as appropriate. 
• 
The evaluation is designed to exclude a 30% clinical benefit rate (CBR) 
representing best available therapy in favour of a 50% CBR. 
PART 2 
• 
Part 2 was to be opened to determine a safe and tolerable combination dose 
and regimen of GSK3326595 in combination with standard-of-care therapy, 5-
Azacitidine, in patients with myeloid neoplasms (Part 2 Dose Escalation 
phase); and was to explore the clinical efficacy of the combination of 
GSK3326595 with 5-Azacitidine, in treatment-naïve patients with MDS or 
CMML (Part 2 Dose Expansion phase) 
• 
Part 2 will consist of two dose escalation cohorts with intermittent dosing to 
select a safe and tolerable GSK3326595 dose and regimen in combination 
with 5-Azacitidine (the Recommended Combination Dose and Regimen). 
Once the Recommended Combination Dose and Regimen was to be 
determined, additional participants were planned to be enrolled to assess the 
clinical activity of GSK3326595 plus 5-Azacitidine in newly-diagnosed MDS 
and CMML participants. 
• 
The N-CRM was to be utilized to guide dose escalation decisions based on 
the rate of DLTs observed in participants. Participants were planned to be 
enrolled in cohorts of approximately 3. 
• 
The Recommended Combination Dose was to be the dose that maximizes the 
posterior probability of target toxicity (16% ≤ DLT rate < 33%) while 
controlling the posterior probability of excessive/unacceptable toxicity (33% < 
DLT rate) no more than 25%, or a lower dose that provides adequate PK 
exposure and biologic/clinical activity with superior tolerability. 
• 
Overall, approximately 83 participants were to be enrolled in Part 2: 
approximately 24 participants in each dose escalation cohort and up to 35 
participants in Dose Expansion cohort. 
• 
Part 2 Dose Expansion was planned to employ a Bayesian design.  
• 
Participants in dose escalation who were treated at the same dose level as 
those in expansion phase could have been included in the analysis as 
appropriate. 
Dosing 
PART 1 
• 
The starting dose of GSK3326595 is 400 mg QD., as determined in study 
204653. No dose escalation is planned beyond this dose, unless emerging 
data (e.g., PK or PD data) indicate that a higher dose is appropriate for 
participants with myeloid malignancies.  
• 
The dose of 300 mg QD was the starting dose for the dose expansion cohort 
due to tolerability issues (primarily fatigue) observed with the 400 mg dose in 
the dose confirmation cohort and in 204653 study. 
• 
If dose modification of GSK3326595 is required, the pre-planned dose levels 
in Table 4 in the protocol will be utilized. 


 
CONFIDENTIAL 
 
 
 
208809 
 
13 
 
Overview of Study Design and Key Features 
PART 2 
• 
Dosing of GSK3326595 was planned to start at 200 mg QD in cohort 1 and 
100 mg BID in cohort 2 and escalate up to the Recommended Myeloid 
Combination Dose 
• 
The dose of GSK3326595 administered in combination with 5-Azacitidine was 
planned not exceed the Recommended Myeloid Monotherapy Dose unless 
emerging data suggest that a therapeutic dose in combination requires a 
higher daily dose of GSK3326595. 
• 
The 5-Azacitidine regimen was planned to be administered subcutaneously or 
intravenously at the 75 mg/m2 dose for 7 days in a 28-day cycle, as detailed in 
the Food and Drug Administration (FDA) package insert. The 5-Azacitidine 
regimen was not to be altered beyond the approved dose and schedule. 
• 
If dose modification of GSK3326595 is required, the pre-planned dose levels 
in Table 7 in the protocol was planned to be utilized. 
Time & Events 
• 
Refer to Table 1 to Table 3: Schedule of Activities (SoA) in protocol 
Treatment 
Assignment 
• 
Part 1: GSK3326595 and the dose level is the only treatment assignment. 
• 
Part 2: GSK3326595 and the dose level and schedule plus 5-Azaciditine are 
the only treatment assignment. 
Interim Analysis 
• 
The interim analyses will be conducted separately for Part 1 and Part 2 
according to the design. 
• 
For both Parts the response evaluable participants are defined as those who 
have had at least two post-baseline assessments, have progressed or died, or 
have permanently discontinued from study intervention. 
• 
For both Parts the interim analyses will be for futility only, i.e. none of these 
Parts will stop early for efficacy. 
• 
For both Parts, statistical rules for interim analyses are intended as a 
guideline. Actual decisions will depend on the totality of the data. 
PART 1 
• 
The first interim futility analysis will be conducted when a minimum of 8 
participants become evaluable. 
• 
The subsequent interim futility analysis will be performed every 2-3 months 
with minimum of 5 additional evaluable participants.  
• 
The decision rules based on the predictive probability are indicated in Table 6 
in protocol. 
PART 2 
• 
The first interim futility analysis was to be conducted when a minimum of 8 
participants become evaluable. 
• 
The subsequent interim futility analysis was to be performed every additional 
9 evaluable participants. 
• 
The decision rules based on the predictive probability are indicated in Table 8 
in protocol. 
Final Analysis 
• 
The study will be considered completed for purposes of a final analysis for 
Part 1 or Part 2 when 70% of the participants enrolled in Part 1 have died and 
70% of the participants enrolled in Part 2 dose expansion have died. 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
14 
 
2.4. 
Statistical Hypotheses / Statistical Design 
2.4.1. 
Part 1 
Dose confirmation 
Hypothesis: No formal statistical hypotheses will be tested.  
Design and sample size considerations: The Part 1 dose confirmation will be guided by 
the N-CRM model. N-CRM is a Bayesian model‐based adaptive dose finding approach. 
The design classifies the posterior distributions of probability DLT into four categories 
and makes dose recommendations: 
• Under-dosing: DLT rate<16% 
• Target toxicity: 16%<=DLT rate<33% 
• Excessive toxicity: 33%<=DLT rate<60% 
• Unacceptable toxicity: DLT rate>=60% 
The thresholds were derived via discussion with the clinical team. It is estimated that at 
least 6 and up to 12 participants will be enrolled to determine the Recommended Myeloid 
Monotherapy Dose. CRM model may not be employed until the first DLT occurs and the 
prior distribution assumptions may use the information from the GSK3326595 first time 
in human study 204653. 
Dose expansion  
Hypothesis: Dose expansion is designed to exclude a 30% CBR representing best 
available therapy in favour of a 50% CBR.  
Design and sample size considerations: The Part 1 dose expansion will employ the 
Bayesian predictive probability method to frequently monitor CBR. A close to non-
informative prior will be used. Let p denote the CBR, the prior distribution used is p ~ 
Beta (0.05, 0.05). The cohort will be stopped early due to futility if the predictive 
probability of success is less than 1%. The success is defined as posterior probability of 
CBR > 30% at the end of the cohort is larger than 89.1%. The maximum sample size is 
35 participants, and the design will have type I error of 0.07 and power of 83%. The 
methodology is based on the predictive probability of success if enrolment continues to 
35 [Lee, 2008]. The calculations were performed using Predictive Probability Design 
Software for Phase II Cancer Clinical Trials Version 1.0.0.  
2.4.2. 
Part 2 
Dose escalation 
Hypothesis: No formal statistical hypotheses will be tested.  
Design and sample size considerations: The Part 2 dose escalation will employ N-CRM 
design, similar to that of Part 1 dose escalation. For each Regimen, simulations were 
conducted to determine the average sample size and percentage of times each dose would 
be selected as an MTD under different scenarios, assuming the N-CRM dose 


 
CONFIDENTIAL 
 
 
 
208809 
 
15 
 
recommendations are followed. The simulations assume 3 dose levels starting at the 
second dose level, recruiting in cohort size of approximately 3 DLT evaluable 
participants, with maximum of 6 participants at each dose level (6 needed to declare an 
MTD) with further 6 for MTD confirmation, resulting in approximately 24 participants 
per dose escalation. The prior distribution assumptions for the combination treatment 
incorporates the information from the GSK3326595 monotherapy first time in human 
study 204653, results from Part 1 of this study and discussions with the clinical and 
statistical team. Prior information was elicited and derived using all quartiles method. 
The minimally informative prior for each parameter (α, β) for the N-CRM two parameter 
logistic model are specified via a bivariate normal distribution with a separate mean and 
standard deviation (SD) for α and ln(β) and a correlation term, ρ, using reference dose 
level 2. The parameters of the model are: 
QD schedule: α = -1.7681 (2.5018), ln(β) = -5.7972 (0.0012), ρ = -0.9975 
BID schedule: α = -1.4373 (2.2972), ln(β) = -0.1725 (0.4273), ρ = -0.9964 
 
The simulation results are shown in Table 1. For each scenario a dose with a true DLT 
rate falling in the target toxicity interval are highlighted. The average sample sizes over 
the 1000 clinical trials simulated under the four simulation scenarios were 10.4, 9.4, 8.0 
and 7.1 for QD and it is 10.1, 8.6, 7.5 and 6.8 for BID schedule. The percent of trials with 
all toxic dose were 6%, 23% 60% and 72% for QD and these were 9%, 38%, 65% and 
75% for BID schedule. The calculations were conducted using FACTS version 6.1 
software.  
Table 1 
Operating Characteristics 
GSK3326595 
Dose and 
Regimen in 
combination 
with 5-
Azacitidine 
Scenario 1:  
Low Toxicity 
Scenario 2:  
Target Toxicity 
Scenario 3:  
Two Target Toxicity 
Scenario 4:  
High Toxicity 
True 
DLT 
Rate 
(%) 
Percent of 
Times 
Selecting 
Dose as 
MTD (%) 
True 
DLT 
Rate 
(%) 
Percent of 
Times 
Selecting 
Dose as 
MTD (%) 
True 
DLT 
Rate 
(%) 
Percent of 
Times 
Selecting 
Dose as 
MTD (%) 
True 
DLT 
Rate 
(%) 
Percent of 
Times 
Selecting 
Dose as 
MTD (%) 
300 mg QD 
20 
81.3 
20 
65.0 
40 
20.7 
45 
12.2 
200 mg QD 
10 
12.0 
15 
10.8 
30 
15.2 
35 
13.0 
100 mg QD 
0 
6.7 
10 
24.2 
20 
64.1 
25 
74.8 
150 mg BID 
20 
78.5 
25 
47.5 
40 
19.7 
45 
11.5 
100 mg BID 
10 
12.3 
20 
14.3 
30 
15.3 
35 
13.5 
75 mg BID 
0 
9.2 
15 
38.2 
20 
65.0 
25 
75.0 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
16 
 
Dose expansion  
Hypothesis: It is designed to exclude a 17% CR rate for 5-Azacitidine in favour of a 32% 
CR rate.   
Design and sample size considerations: The Part 2 dose expansion will employ the 
Bayesian predictive probability method to monitor the CR rate. The decision making 
framework was set up based on the positive and negative guideline. Positive guideline is 
set as at least 90% probability that the true CR rate with combination treatment is > 17%, 
or Pr (true CR rate > 17% | data) > 90%, and the negative guideline is set as at least 90% 
probability that the true CR rate is < 32%, or Pr(true CR rate < 32% | data) > 90%; if 
neither guidelines are met, ORR and safety will be taken in the decision making. A vague 
prior was used to assess the operating characteristics of the design with the prior 
distribution for the CR rate of Beta (0.017, 0.036), centered on 0.32. The minimum 
observed value that meets the criteria for the positive guideline is 10 or more CR out of 
35 participants, the maximum observed value that meets the criteria for the negative 
guidelines is 7 or less CR out of 35 participants. Predictive probability (which is the 
probability of achieving failure at the end of study with 35 participants given the data 
observed) will be used to guide the interim decision-making, starting with 8 evaluable 
participants. The futility threshold is the predictive probability of negative guideline is 
more than 95%. With such decision making framework, taking into account the interim 
analyses the operating characteristics are presented in Table 2. The calculations were 
performed using SAS version 9.4 and R software.  
Table 2 
Operating Characteristics  
True CR Rate (%) 
Probability of 
continuing (%) 
Probability of stopping 
(%) 
Probability of making a 
decision based on other 
endpoints (%) 
17% 
5.9 
78.5 
15.6 
25% 
36.5 
36.1 
27.4 
32% 
71.2 
12.0 
16.8 
 


 
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
1 7  
 
3.  
P L A N N E D A N A L Y S E S  
3. 1.  
I nt eri m A n al y s e s 
Ti mi n g of A n al yses  
 
P art 1 D ose C o nfir m ati o n  
C o h orts will be recr uite d i n bl oc ks of a p pr o xi matel y t hree partici pa nts. A p pr o xi matel y 
si x partici pa nts will i nitiall y be e nr olle d at t he starti n g d ose. T h e ma xi m u m n u m ber of 
partici pa nts assi g ne d t o a n y si n gle  d ose will be at t he discreti o n of t he S p o ns or i n 
c o ns ultati o n wit h t he i n vesti gat ors.   
 
P art 1 D ose E x p a nsi o n  
T he  first i nteri m f utilit y a nal ysis (I F A) will be c o n d ucte d w he n a mi ni m u m of e val ua ble 
8 partici pa nts ha ve c o m plete d at least t w o p ost -baseli ne  efficac y assess me nts, ha ve 
pr o gresse d or die d, or ha ve per ma n e ntl y disc o nti n ue d fr o m  st u d y i nter ve nti o n. T he 
s u bse q ue nt i nteri m f utilit y a n al ysis will be p erf or me d e ver y 2 -3 m o nt hs wit h mi ni m u m of 
5 a d diti o nal e val ua ble partici pa nts.   
P art 2 D ose Esc al ati o n  
It is esti mate d t hat a p pr o xi matel y 4 8  partici pa nts will be e nr olle d  t o deter mi ne t he 
Rec o m me n de d C o m bi nati o n D ose . T he i nteri m a n al yses are pl a n ne d after a p pr o xi matel y 
3 partici pa nts at a d ose l e vel bec o me D L T e val u a ble.  
P art 2 D ose E x p a nsi o n  
T he  first I F A will be c o n d ucte d w he n a mi ni m u m of 8 partici pa nts bec o me e val ua ble. 
T he s u bse q ue nt i nteri m f utilit y a n al ysis will be perf or me d e v er y a d diti o nal 9 e val ua ble 
partici pa nts , i.e. 
a n d 
 
 
F or b ot h Parts e x pa nsi o n c o h orts , t he i nteri m a nal yses will be f or f utilit y o nl y, i.e. n o n e 
of t he parts  will st o p earl y f or efficac y.  
3. 1. 1.  
P art 1 D o s e C o nfir m ati o n  
Decisi o n M a ki n g  
F or t he pri mar y e n d p oi nt, i n t he a bse nce of D L Ts, t he d ose escalati o n r ules are 
deter mi nistic a n d n o p osteri or distri b uti o n s u m maries will be pr o vi de d . If D L Ts are 
o bser ve d, a n N -C R M m o del will be i m ple me nte d t o g ui de d os e escalati o n/ de -escalati o n 
decisi o ns. A t t he e n d of t he D L T o bser vati o n peri o d f or eac h d ose le vel, t he p osteri or 
distri b uti o n of D L T rate will be  s u m marize d b y t h e p osteri or pr o ba bilit y of t he D L T rate 
falli n g i nt o t he i nter val of u n der-d osi n g, tar get t o xicit y, e x cessi ve t o xicit y, a n d 
u nacce pta ble t o xicit y res pecti vel y. If t he pr o ba bilit y of e x cessi ve or u nacce pta ble t o xicit y 
is m ore t ha n 2 5 %, a d ose de-escalati o n will be re q uire d.  Ne xt rec o m me n de d d ose le vel 
will be prese nte d.  T h e st u d y te a m will re vie w critical data defi ne d i n t he D ose Escalati o n 
Pla n pri or t o t he d ose escalati o n/ de -escalati o n decisi o n.  
P P D
P P D


 
CONFIDENTIAL 
 
 
 
208809 
 
18 
 
3.1.1.1. 
Displays to Be Created for Part 1 Dose Confirmation 
Study Data Tabulation Model (SDTM) datasets will be available 6-8 weeks after first 
subject first visit. Before that, DM data dump in spreadsheets containing relevant study 
data will be supplied if needed. 
For dose escalation/de-escalation decisions, data review will be primarily based on 
GSK’s Spotfire system. The following three listings will be created by Statistics and 
Programming group. The analysis will be based on the All Treated Population. 
(1) Listing of All Adverse Events 
(2) Listing of All Laboratory Data for Participants with Grade 2 or Above Lab Tests 
(3) Listing of Study Treatment Exposure 
Details of the planned displays will be presented in Appendix 12: List of Data Displays. 
3.1.2. 
Part 1 Dose Expansion Interim Futility Analysis  
Decision Making  
The primary endpoint is CBR, defined as the percentage of participants with complete 
remission (CR), complete marrow remission (mCR), partial remission (PR), stable 
disease (SD) lasting at least 8 weeks, and hematologic improvement (HI), as per IWG 
criteria for MDS/CMML/AML. SD duration is calculated from the first study treatment 
dose date. The decision rules, specifying the number of participants with a CBR needed 
for continuing enrolment or, stopping for futility, are indicated in Table 3.  


 
CONFIDENTIAL 
 
 
 
208809 
 
19 
 
Table 3 
Part 1 Expansion Cohort Stopping Criteria for Futility 
 Number of Evaluable 
Participants  
  This Number of CR, mCR, 
PR, SD≥8 weeks or HI to 
Stop Early for Futility  
Probability of continuing 
enrolling when Clinical 
Benefit Rate (CBR)=0.3 
 Probability of continuing 
enrolling when CBR=0.5  
8 
0 
0.9424 
0.9961 
9 
1 
0.8040 
0.9805 
10 
1 
0.8040 
0.9805 
 11 
1 
0.8040 
0.9805 
 12 
1 
0.8040 
0.9805 
 13 
2 
0.7399 
0.9761 
 14 
2 
0.7399 
0.9761 
 15 
3 
0.6547 
0.9691 
 16 
3 
0.6547 
0.9691 
 17 
3 
0.6547 
0.9691 
 18 
4 
0.5924 
0.9648 
 19 
4 
0.5924 
0.9648 
 20 
5 
0.5202 
0.9588 
 21 
5 
0.5202 
0.9588 
 22 
5 
0.5202 
0.9588 
 23 
6 
0.4702  
0.9553 
 24 
6 
0.4702 
0.9553 
 25 
7 
0.4134 
0.9505 
 26 
7 
0.4134 
0.9505 
 27 
8 
0.3578 
0.9450 
 28 
8 
0.3578 
0.9450 
 29 
9 
0.3064 
0.9389 
 30 
10 
0.2407 
0.9259 
 31 
10 
0.2407 
0.9259 
 32 
11 
0.1968 
0.9156 
 33 
12 
0.1468 
0.8960 
 34 
13 
0.1035 
0.8677 
 35  
14 
0 
0 
These rules are intended as a guideline. Actual decisions will depend on the totality of the 
data. The decision to terminate the cohort will not depend solely on the results of the 
statistical model but will take all factors into account, including the results of the model, 
safety, tolerability, PK, and PD data. In some cases (e.g., under-representation of a given 
predictive biomarker in the participants treated at the time of interim analysis), additional 
participants may be enrolled even if the model suggests a low likelihood of activity. 
Participants in dose confirmation who were treated at the same dose level as those in 
expansion phase will be included in the analysis as appropriate. 


 
CONFIDENTIAL 
 
 
 
208809 
 
20 
 
3.1.2.1. 
Displays to Be Created for Part 1 Dose Expansion Interim Futility 
Analysis  
The All Treated Population (refer to Section 4) will be used for study population and 
safety analyses. The Response Evaluable Population will be used for efficacy analysis at 
interim. 
A summary of the number of subjects in each of the analysis populations will be 
provided. Also, a summary of treatment status and reasons for discontinuation of study 
treatment will be produced.  
The demographic characteristics (e.g., race, age, ethnicity, sex, height, and baseline body 
weight) will be summarized. Disease characteristics will be summarized.  
Summaries of best overall response and subjects who achieved clinical benefit per IWG 
criteria for MDS/CMML/AML will be provided for the study team to examine the 
stopping rules for futility. In the efficacy table, CBR will be summarized along with 95% 
exact confidence interval (CI). Subjects with unknown or missing response will be 
treated as non-responders i.e. these subjects will be included in the denominator when 
calculating the percentage.  
A swimmer plot of the duration of study treatment, including the occurrences of dose 
modification, number of lines of prior anti-cancer therapies, onset of CR/mCR/PR 
/HI/SD, disease progression, SAE and death, will be provided. 
A listing of subject status and best overall response (BOR) per IWG criteria for 
MDS/CMML/AML subjects will be provided. This listing will be sorted by date of first 
dose and will show whether each subject is ongoing with study treatment, whether the 
subject has had at least two post-baseline disease assessments, whether the subject is 
evaluable for the futility analysis, and BOR. 
An overview summary of adverse events (AEs), including counts and percentages of 
subjects with any AE, AEs related to GSK3326595, Grade 3/4 AEs, Grade 3/4 AEs 
related to GSK3326595, AEs leading to dose reductions of GSK3326595, AEs leading to 
dose interruptions of GSK3326595, AEs leading to permanent discontinuation of 
GSK3326595, SAEs, SAEs related to GSK3326595, fatal SAEs, and fatal SAEs related 
to GSK3326595 will be provided. AEs will be summarized by maximum grade and 
preferred term. SAEs and SAEs related to study treatment will be summarized by 
preferred term separately. 
Details of the planned displays will be presented in Appendix 12: List of Data Displays.  
3.1.3. 
Part 2 Dose Escalation 
Decision Making  
For the primary endpoint, the analysis is planned as per Section 3.1.1. 


 
CONFIDENTIAL 
 
 
 
208809 
 
21 
 
3.1.3.1. 
Displays to Be Created for Part 2 Dose Escalation 
For each dose escalation meetings, the following two outputs will be created by Statistics 
and Programming group. The analysis will be based on the All Treated Population. 
SDTM datasets and DM data dump may be supplied if needed as per Section 3.1.1.1. 
(1) Listing of All Adverse Events 
(2) Summary of Dose-Limiting Toxicities  
Details of the planned displays will be presented in Appendix 12: List of Data Displays. 
3.1.4. 
Part 2 Dose Expansion Interim Futility Analysis  
Decision Making  
The primary endpoint is CR rate, defined as the percentage of participants achieving a 
CR as per IWG criteria. The decision rules, specifying the number of participants with a 
complete remissions needed for continuing enrolment or, stopping for futility, are 
displayed in Table 4. For example, if in the first 17 participants there is one or 
fewer complete remissions observed, the study can be stopped for futility. 
Table 4 
Part 2 Expansion Cohort Stopping Criteria for Futility 
 Number of Evaluable 
Participants  
  This Number of 
Confirmed Complete 
Remissions to Stop Early 
for Futility  
Probability of Continuing 
Enrolling When CR 
Rate=0.17 
Probability of Continuing 
Enrolling When CR 
Rate=0.32 
8 
0 
0.7753 
0.9546 
17 
1 
0.7059 
0.9496 
26 
3 
0.5733 
0.9417 
35 
7 
0.2151 
0.8803 
These rules are intended as a guideline. The decision to terminate the cohort will not 
depend solely on the Bayesian predictive probability of study failure but will take into 
account, safety, tolerability, available PK and PD data. 
Participants in dose confirmation who were treated at the same dose level as those in 
expansion phase will be included in the analysis as appropriate. 
3.1.4.1. 
Displays to Be Created for Part 2 Dose Expansion Interim Futility 
Analysis  
The outputs specified in Section 3.1.2.1 will be produced for each interim analysis, 
except the primary endpoint for the Part 2 is CR rate, not CBR. In addition, summary of 
treatment exposure of GSK3326595 and 5-Azacitidine; summary of dose reductions of 
GSK3326595 and 5-Azacitidine will be provided. In addition to safety analyses the 
following information will be added: AEs related to 5-Azacitidine and study treatment, 
Grade 3/4 AEs related to 5-Azacitidine and study treatment, AEs leading to dose 


 
CONFIDENTIAL 
 
 
 
208809 
 
22 
 
reductions of 5-Azacitidine and study treatment, AEs leading to dose interruption/delay 
of 5-Azacitidine and study treatment, AEs leading to dose delay of 5-Azacitidine, AEs 
leading to infusion of 5-Azacitidine interrupted but completed, AEs leading to infusion of 
5-Azacitidine stopped early and not completed, AEs leading to permanent 
discontinuation of 5-Azacitidine, SAEs related to 5-Azacitidine and study treatment, fatal 
SAEs related to 5-Azacitidine, and study treatment.  
Details of the planned displays will be presented in Appendix 12: List of Data Displays. 
3.2. 
Main analyses 
Timing of Analyses 
 
Part 2 Dose Selection  
Dose selection analysis is planned after MTD has been selected with 6 DLT evaluable 
patients and further 6 DLT evaluable patients have been recruited for each dose schedule. 
Part 2 Dose Expansion   
The main analysis will be conducted when 35 participants become evaluable for the 
primary endpoint. 
  
3.2.1. 
Part 2 Dose Selection 
Decision Making  
For the primary endpoint, Recommended Combination Dose will be the dose that 
maximizes the posterior probability of target toxicity interval while controlling the 
posterior probability of excessive or unacceptable toxicity no more than 25%, or a lower 
dose that provides adequate PK exposure and biologic/clinical activity with superior 
tolerability. The Recommended Combination Dose and Regimen selection will be based 
on safety and tolerability and available PK and PD data. For the important secondary 
endpoint ORR, the following guideline is planned to be considered to help with the dose 
and regimen selection for expansion cohort:  
Go:  
Pr (true ORR > 0.30|data) > 55%      
And Stop otherwise.     
 
The simulations were conducted to understand the operating characteristics of the rules 
under different true ORR. A vague prior was used to assess the operating characteristics 
of the design with the prior distribution for the ORR rate of Beta (0.017, 0.036), centered 
on 0.32. The minimum observed value that meets the guideline is 4 or more ORR out of 
12 participants. The analysis is Bayesian conjugate beta binomial. The actual number of 
responders analysed may be different to anticipated 12 patients. With such decision-
making framework, the operating characteristics are presented in Table 5. The 
calculations were performed using R software.  


 
CONFIDENTIAL 
 
 
 
208809 
 
23 
 
Table 5 
Operating characteristics for ORR endpoint  
True ORR 
Go (%) 
Stop (%) 
Consider (%) 
0.20 
20% 
80% 
0% 
0.30 
50% 
50% 
0% 
0.50 
92% 
8% 
0% 
The study team will review critical data defined in the Dose Escalation Plan prior to the 
dose escalation/de-escalation decision. For the primary endpoint, the analysis is planned 
as per Section 3.1.1. 
3.2.1.1. 
Displays to Be Created for Part 2 Dose Escalation  
In addition to displays to be created in the Section 3.1.3.1, the following information is 
planned to be presented: key baseline data: demography, eligibility, regimen, medical 
history, disease characteristics, prior treatment, spliceosome mutation status; exposure to 
study drugs: dosing start and end dates, scheduled and actual dose, dose or schedule 
modifications and reason (as applicable); treatment discontinuation including reasons for 
withdrawal: primary reason and date of discontinuation; all AEs and SAEs, all AEs grade 
3-5, all AEs and SAEs: preferred term, start date, outcome, end date, frequency, max 
grade, grade at onset, causality, actions taken re AE treatment. Grade changes; all AEs 
and SAEs leading to drug interruption, reduction or discontinuation; All related AEs and 
SAEs leading to drug interruption, reduction or discontinuation; Reason for Withdrawal; 
Concomitant Medications: drug name, dose/units, frequency, route, reason for 
medication, start/end dates; Clinical Laboratory Data: Visit date, lab test, result, lab 
ranges, clinical significance; Vital Signs; Electrocardiogram; ECOG; Protocol deviations; 
clinical response (including response by presence or absence of the spliceosome 
mutations).  
 
3.2.2. 
Part 2 Dose Expansion 
Decision Making  
For the primary endpoint, Positive and Negative guidelines are described in Section 2.4.2. 
The minimum observed value that meets the criteria for the positive guideline is 10 or 
more CR out of 35 participants, the maximum observed value that meets the criteria for 
the negative guidelines is 7 or less CR out of 35 participants. If neither guidelines are 
met, ORR and safety will be taken in the decision making. 
 
3.2.2.1. 
Displays to Be Created for Part 2 Dose Escalation  
In addition to displays to be created in the Section 3.1.4.1, the following information is 
planned to be presented: clinical response (including response by presence or absence of 
the spliceosome mutations). 


 
CONFIDENTIAL 
 
 
 
208809 
 
24 
 
3.3. 
Final Analyses 
3.3.1. 
Part 1 and Part 2 Final Analysis 
The Part 1 and Part 2 final analysis for CSR purposes will be performed after the 
completion of the following sequential steps: 
1. When 70% of the participants enrolled in Part 1 and 70% participants enrolled in 
Part 2 Dose Expansion cohort have died or termination of the study by the sponsor. 
Survival follow up for remaining participants may not be needed. 
2. All required database cleaning activities have been completed and final database 
freeze (DBF) has been declared by Data Management. 
Data from the dose confirmation and expansion cohort will be combined as appropriate. 
 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
25 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility with 
signed consent 
• 
Study Population 
Enrolled 
• 
All participants who sign the ICF 
• 
Study Population 
DLT Evaluable 
• 
For DLT assessment (Part 1 dose confirmation and Part 
2 dose escalation): defined as participants who received 
at least 75% of GSK3326595 (and all 7 doses of 5-
Azacitidine for Part 2) of the planned doses within the 
28-day DLT observation period or those who have had a 
DLT. 
• 
DLT 
Response 
Evaluable 
 
 
• 
For interim futility analyses (Part 1 expansion and Part 2 
expansion) and for Part 2 Dose Escalation analysis: 
defined as participants who have had two post baseline 
disease assessments, have progressed or died, or 
permanently discontinued from the study intervention 
• 
Separate 
population flag 
for each interim 
futility analyses 
of Part 1, Part 2 
and Part 2 Dose 
Escalation 
analysis 
All Treated 
• 
Participants who receive at least one dose of 
GSK3326595 as monotherapy or at least one dose of 
both combination drugs as combination treatment. 
• 
Study Population 
• 
Safety 
• 
Efficacy 
Pharmacokinetic 
(PK) 
• 
Participants from the All Treated Population for whom a 
PK sample is obtained and analysed 
• 
Separate PK populations will be defined for each drug, 
i.e. GSK3326595 and 5-Azacitidine 
• 
PK 
Refer to Appendix 12: List of Data Displays which details the population used for each display. 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
26 
 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Part 1 begins with dose confirmation of GSK3326595 followed by a single-arm dose 
expansion cohort to determine the CBR of GSK3326595.  
Part 2 is composed of dose escalation cohorts followed by a single-arm dose expansion 
cohort to determine the CR rate of the combination of GSK3326595 plus 5-Azacitidine.  
In the data displays 5-Azacitidine will be abbreviated as 5-aza. Data will be listed and 
summarized per the GSK reporting standards whenever applicable. In Part 1 and Part 2 
data will be listed and summarized by dose levels where applicable. 
Treatment Group Descriptions 
IVRS Randomization System 
Data Displays for Reporting  
Code 
Description 
Treatment Label 
Order in TLF  
Part 1 
 
GSK3326595 400mg 
GSK3326595 400mg 
1 
 
GSK3326595 300mg 
GSK3326595 300mg 
2 
Part 2 Escalation Cohort 
 
GSK3326595 QD + 5-aza 
GSK3326595 QD + 5-aza 
1 
 
GSK3326595 BID + 5-aza 
GSK3326595 BID + 5-aza 
2 
Part 2 Expansion Cohort 
 
GSK3326595 + 5-aza 
GSK3326595 + 5-aza 
1 
Part 2 codes were not added due to Part 2 closure 
 
5.2. 
Analysis Datasets 
Analysis datasets are “analysis-ready” datasets, i.e., analysis datasets that have a structure 
and content that allows statistical analysis to be performed with minimal programming, 
as sorting of the observations or the selection of the appropriate records from the analysis 
dataset. No complex data manipulations such as transformations or transpositions are 
required to perform the supported analysis.  
Analysis datasets will be created according to CDISC standards using GSK standard 
ADaM specifications (where available), and data will be listed and summarized 
according to GSK Integrated Data Standards Library (IDSL) reporting standards. 
Formatting for dates, times, and decimal places will follow GSK standards except where 
specified. 


 
CONFIDENTIAL 
 
 
 
208809 
 
27 
 
5.3. 
Reporting Conventions 
• 
Unless otherwise specified, the denominator in percentage calculation at each 
scheduled visit will be based on the number of subjects with non-missing value at 
each particular visit. 
• 
All data are reported according to the actual treatment received by the subject.  
• 
Data will be listed by treatment group, center ID, and subject.   
• 
Planned times relative to investigational product dosing will be used in all summary 
tables and figures. 
• 
Actual, rather than planned, sampling times will be used in the derivation of PK 
parameters and in the individual concentration-time plots.  Planned times will be 
used in the descriptive summaries and in mean and median plots. Listings of PK 
concentration-time data will be done by actual sampling times relative to dosing 
time. 
• 
Unless stated otherwise, descriptive summaries will include n, mean, standard 
deviation, median, minimum and maximum for continuous variables and n and 
percent for categorical variables.  Display minimum and maximum in the same 
precision as data was collected, mean and median using 1 additional decimal place, 
and standard deviation using 2 additional decimal places. 
• 
This is a multicenter study.  Data from all study sites will be integrated and no 
controlling for center-effect will be considered in the statistical analyses. 
• 
Analyses are to be performed using the SAS System, Version 9.4 or higher.  
Programs will be imported into HARP and the final output will be produced by 
running drivers in HARP.  Some graphics may be produced using S-Plus (R) 7.0.6 or 
higher. In addition R Software Version 4.0.2 or higher and FACTS version 6.1 or 
higher may be used for the analysis.  
• 
Deviations from the analyses in the RAP will be identified in the final CSR. 
 
5.4. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment within 14 days prior to first dose with a non-missing value, 
including those from unscheduled visits. If time is not collected, Day 1 assessments are 
assumed to be taken prior to first dose and used as baseline. For laboratory data except 
for Troponin, baseline will be the latest non-missing pre-dose value from central lab. If 
no central lab value is available, the latest non-missing pre-dose value from local lab will 
be used. Troponin data is analysed separately for central and local labs, where the latest 
non-missing pre-dose value from each lab, respectively, acts as the baseline. If there are 
multiple assessments on the same day, the mean will be used as the baseline value.  
For ECG analyses, subject level baseline is defined as the mean of triplicate baseline 
assessments. 


 
CONFIDENTIAL 
 
 
 
208809 
 
28 
 
For ECOG analyses baseline is defined as the latest non missing value before the first 
dose. 
For liver function test baseline is defined as the latest non missing value before the first 
dose.  
For subjects who did not receive any study intervention (GSK3326595 or 5-Azacitidine) 
during the study, baseline will be defined as the latest, non-missing collected value. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in 
Data Display 
Screening 
(within 35 
days prior to 
first dose) 
Screening 
(within 14 
days prior to 
first dose) 
Day 1 (Pre-Dose) 
 
Efficacy 
Bone marrow biopsy 
 
X 
 
Screening visit 
Safety 
Laboratory 
 
X 
X 
Latest up to Day 1 
Vital Signs  
 
X 
X 
Latest up to Day 1 
ECG* 
 
X 
X 
Latest up to Day 1 
LVEF 
X 
 
 
Screening visit 
*Average of triplicate assessments to be used. 
5.4.1. 
Change from baseline 
Change from baseline is calculated as: 
• 
For records occurring after baseline: (visit value) – baseline value. 
Percent change from baseline is calculated as: 
• 
For records occurring after baseline: ((change from baseline) / baseline value) * 100 
If either the baseline or visit value is missing, the change from baseline and/or percent 
change from baseline is set to missing as well. 
5.5. 
Multiple Assessments 
All data will be reported according to the nominal visit date for which it was reported 
(that is, no visit windows will be applied during dataset creation). Unscheduled data will 
only be included in the display sections that report worst- case post-baseline (except for 
PK parameters). For summaries that collapse data across multiple planned time intervals, 
select the mean data at each collapsed interval. 
If multiple assessments on different days are reported for the same scheduled assessment, 
then the worst case assessment for that scheduled assessment will be analyzed. 


 
CONFIDENTIAL 
 
 
 
208809 
 
29 
 
If multiple assessments are reported on the same date for the same scheduled planned 
time, then the mean of multiple measurements reported for the same date will be 
analyzed, with the exception of laboratory data reported from both central and local 
laboratories such as Troponin. Troponin T is collected by both central and local lab, and 
Troponin I by central lab only, so these two lab parameters will be analysed separately by 
central and local lab. If laboratory data is reported from both central and local 
laboratories with the same date, then the central laboratory data will be analyzed to 
provide consistency with measurements from other subjects.  
For ECG data where 3 assessments are collected for each scheduled planned time, the 
average of the 3 measures will be used for analysis at each scheduled planned time. 
Data from all assessments (scheduled and unscheduled), including multiple assessments, 
will be included in listings. 
5.6. 
Multicenter Studies 
In this multicenter global study, enrolment will be presented by regions where applicable. 
Summaries of data by center will not be provided. 
5.7. 
Examination of Covariates, Other Strata and Subgroups 
5.7.1. 
Covariates and Other Strata 
All analyses are descriptive or unadjusted. No analyses are planned to adjust for any 
covariate and prognostic factor.  
5.7.2. 
Examination of Subgroups 
A table of summary of investigator assessed clinical benefit response by central review 
spliceosome mutation status across dose levels will be produced which will contain CBR 
and ORR with no CI.  
5.7.3. 
Multiple Comparisons and Multiplicity 
No multiple comparisons or multiplicity adjustments are planned in this study. 
5.8. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
Section 14.3 
Appendix 3: Assessment Windows 
Section 14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
Section 14.5 
Appendix 5: Data Display Standards & Handling Conventions 
Section 14.6 
Appendix 6: Derived and Transformed Data 
Section 14.7 
Appendix 7: Reporting Standards for Missing Data 
Section 14.8 
Appendix 8: Values of Potential Clinical Importance 


 
CONFIDENTIAL 
 
 
 
208809 
 
30 
 
6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the All Treated population, unless 
otherwise specified. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, concomitant medications, exposure 
and treatment compliance, disease characteristics at initial diagnosis and at screening, 
prior and follow-up anti-cancer therapy, and duration of follow up will be based on GSK 
Core and Oncology Data Standards. Details of the planned displays are presented in 
Appendix 12: List of Data Displays.  
6.2. 
Subject’s Disposition 
A summary of subject status and reason for study withdrawal and a summary of treatment 
status and reasons for discontinuation of study treatment will be presented. Reason for 
study withdrawal and reason for study treatment discontinuation will be listed separately. 
A summary and listing of screening status and screen failures will be provided using the 
screened population. 
Number of participants by country and site will be summarized and listed.  
Number of participants in each of the analysis populations described in Section 4 will be 
provided using the screened population. A summary and a listing of enrolled participants 
excluded from the All Treated population will also be provided. 
6.3. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized in All Treated population and all protocol important deviations will be listed. 
Protocol deviations will be classified as ‘important’ and ‘non-important’ based on 
Protocol Deviation Specifications. 
 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Specifications developed by PAREXEL. 
o Data will be reviewed prior to freezing the database to ensure all deviations are 
captured and categorized on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 


 
CONFIDENTIAL 
 
 
 
208809 
 
31 
 
There is no Per-Protocol Population for this study. Protocol deviations will not be used to 
determine membership in any particular study population for this study. 
6.4. 
Demographic and Baseline Characteristics 
All demographic characteristics (e.g. race, age, ethnicity, sex, height, and baseline body 
weight) will be summarized and listed. Age, height, and weight will be summarized using 
the mean, standard deviation, minimum, median and maximum. Age will be also 
categorized as ≤18, 19-64, ≥65. The count and percentage will be computed for race, sex, 
and ethnicity. 
In a separate summary, age will be categorized as 18-64, 65-84 and ≥85 using EudraCT 
standard. Race and racial combinations will be summarized in a separate table. Subject-
level race detail will be listed. 
6.5. 
Concomitant Medications 
All concomitant medications will be summarized and listed. Concomitant medications 
will be coded using GSK Drug coding dictionary and summarized. The summary of 
concomitant medications will show the number and percentage of participants taking 
concomitant medication by Ingredient. Multi-ingredient products will be summarized by 
their separate ingredients rather than as a combination of ingredients. Anatomical 
Therapeutic Chemical (ATC) classification Level 1 (Body System) information will be 
included in the dataset created but will not appear on the listing or summary.  
In the summary of concomitant medications, each participant is counted once within each 
unique ingredient. For example, if a participant takes Amoxycillin on two separate 
occasions, the participant is counted only once under the ingredient ‘Amoxycillin’. In the 
summary of concomitant medications, the ingredients will be summarized by the base 
only. 
Blood products and blood supportive care products will be summarized and listed.Past 
and current medical conditions will be summarized separately in two tables. 
6.6. 
Exposure and Treatment Compliance 
The calculation of overall compliance is based on the entire interval of dosing for 
GSK3326595. The formula is compliance (%) = [total cumulative actual dose / (duration 
of study treatment * prescribed dose)] *100 where duration of study treatment is last 
dose-first dose +1. 
Overall compliance for GSK3326595 and 5-Azacitidine (for Part 2) and based on the 
exposure data will be summarized and listed separately. Percentage overall compliance 
will be summarized using the mean, standard deviation, minimum, median and 
maximum. In addition, percentage overall compliance will be categorized and 
summarized by <80%, 80%-105% and >105%. 
In addition, summaries of study treatment exposure and dose modifications (e.g., number 
of dose reductions, number of dose interruptions) for GSK3326595 and 5-Azacitidine 


 
CONFIDENTIAL 
 
 
 
208809 
 
32 
 
(for Part 2) will further characterize compliance. These analyses are described in Section 
8.1‘Extent of Exposure’. 
6.7. 
Disease Characteristics 
Disease characteristics at initial diagnosis including primary neoplasm type and time 
since diagnosis to first dose will be summarized and listed. Also, disease characteristics 
at screening including time since diagnosis to 1st study dose, time since progression to 
first dose, CNS disease, loss of function mutation, gene/protein type and disease 
classification (WHO classification of AML, IPSS-R category, and CPPS/CPPS mol-
specific category where applicable) will be summarized and listed. 
6.8. 
Prior and Follow-Up Anti-Cancer Therapy 
The number and percentage of participants that received any prior anti-cancer therapy, 
radiotherapy, or stem cell transplant will be summarized Prior anti-cancer therapy will be 
coded using GSK Drug coding dictionary, then summarized by ingredient. The number of 
prior anti-cancer therapy regimens will be summarized.  
Participant-level details of the prior anti-cancer therapy, prior radiotherapy and stem cell 
transplant will be provided in a listing.   
The number and percentage of participants that received follow-up anti-cancer therapy, 
radiotherapy, surgical procedure for cancer under study, and stem cell transplant will be 
summarized.  A summary of follow-up surgical procedure for cancer under study will be 
provided. Participant level details of the follow-up anti-cancer therapy will be provided in 
a listing. Also follow-up radiotherapy and follow-up surgeries will be listed. 
6.9. 
Duration of Follow-Up 
Duration of follow-up is defined as the time from study start to last contact or death and 
will be summarized in a table. Duration= Date of Last Study Contact – Date of First 
Exposure to Treatment  +1. 
 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
33 
 
7. 
EFFICACY ANALYSES 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Endpoint / Variables 
7.1.1.1. 
Clinical Benefit Rate in Part 1 
The primary endpoint of Part 1 is Clinical Benefit Rate (CBR). It is defined as the 
percentage of participants with CR, mCR, PR, HI, or SD lasting at least 8 weeks for 
MDS/CMML/AML subjects. 
For MDS/CMML/AML subjects, BOR is defined as the best response (complete 
remission [CR] > complete marrow remission [mCR] > partial remission [PR] > 
hematologic improvement [HI] > stable disease [SD] >  disease progression [PD] > not-
evaluable [NE]) from treatment start date until disease progression or initiation of new 
anti-cancer therapy, whichever is earlier, as assessed by IWG criteria. 
7.1.1.2. 
Complete Remission Rate in Part 2 
Part 2 was closed due to study termination and no analysis will be performed. The 
primary endpoint of Part 2 Expansion Cohort (secondary for Escalation Cohort) is CR 
Rate defined as the percentage of participants with CR as BOR per IWG criteria. 
BOR is defined in Section 7.1.1.1. 
7.1.2. 
Summary Measure 
7.1.2.1. 
Clinical Benefit Rate in Part 1 
For MDS/CMML/AML subjects, the number of participants with the BOR in the 
following response categories will be summarized: CR, mCR, PR, SD ≥ 8 weeks, SD < 8 
weeks, HI, clinical benefit response (CR+mCR+PR+SD ≥ 8 weeks+HI), PD and NE. 
CBR and the corresponding exact 2-sided 95% confidence interval (CI, Clopper-
Pearson confidence limits for the binomial proportion) for CBR will also be provided. 
Participants with unknown or missing responses will be included in the denominator 
when calculating percentages of CBR. 
A listing of response at each assessment by subject, including visit, date of assessment, 
response day, response, and best overall response, will be provided.  
7.1.2.2. 
Complete Remission Rate in Part 2 
Part 2 was closed due to study termination and no analysis will be performed. The 
number and percentage of participants with the BOR in the following response categories 
will be summarized: CR, mCR, PR, overall response (CR+mCR+PR), SD ≥ 8 weeks, SD 
< 8 weeks, HI, PD and NE. The corresponding exact 2-sided 95% CI (Clopper-Pearson 
confidence limits for the binomial proportion) for CR rate will also be provided. 
Participants with unknown or missing responses will be treated as non-responders, i.e., 


 
CONFIDENTIAL 
 
 
 
208809 
 
34 
 
these participants will be included in the denominator when calculating percentages of 
CR rate. 
A listing of response at each assessment by subject, including visit, date of assessment, 
response day, response, and best overall response, will be provided. 
7.1.3. 
Population of Interest  
7.1.3.1. 
Part 1 
The primary efficacy analysis will be based on the All Treated opulation. Participants 
enrolled in Part 1 Dose Confirmation will be included in the Dose Expansion cohort 
analysis given the subject was treated at the same dose as the Dose Expansion cohort. 
7.1.3.2. 
Part 2 
Part 2 was closed due to study termination and no analysis will be performed. The 
primary efficacy analysis will be based on the All Treated population. Participants 
enrolled in Part 2 Dose Escalation will be included in the Dose Expansion cohort analysis 
given the subject was treated at the same dose as the Dose Expansion cohort. 
7.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Endpoint / Variables 
7.2.1.1. 
Overall Response Rate  
ORR is defined as the percentage of participants achieving a CR, mCR, or PR, per IWG 
criteria for MDS/CMML/AML subjects. ORR will be included in Part 1. 
7.2.1.2. 
Progression Free Survival  
Progression free survival (PFS) is defined as time from first dose to disease progression 
or recurrence, as defined by IWG criteria, or death due to any cause, whichever occurs 
earlier. Determination of dates of PFS events and dates for censoring are described in 
Table 6. PFS will be included in Part 1. 


 
CONFIDENTIAL 
 
 
 
208809 
 
35 
 
Table 6 
Assignments of Progression and Censoring Dates for PFS and TTP 
Analysis 
Situation 
PFS 
TTP 
Date of Event 
(Progression/ 
Recurrence/Death) 
or Censored 
Event 
(Progression/ 
Recurrence 
/Death) 
Or Censored 
Date of 
Event 
(Progression/ 
Recurrence) 
or Censored 
Event 
(Progression/ 
Recurrence) 
Or Censored 
No adequate baseline 
assessments and the 
subject has not died (if 
the subject has died 
follow the rules for 
death indicted at the 
bottom of the table) 
First dose 
Censored 
First dose 
Censored 
No post-baseline 
assessments and the 
subject has not died (if 
the subject has died 
follow the rules for 
death indicted at the 
bottom of the table) 
First dose 
Censored 
First dose 
Censored 
Progression/Relapse 
documented between 
scheduled visits 
Date of assessment 
of progression 
/relapse 
Event 
Date of 
assessment 
of 
progression 
/relapse 
Event 
With post-baseline 
assessment but no 
progression/Relapse 
after response (or death)  
Date of last 
‘adequate’ 
assessment of 
response1 
Censored 
Date of last 
‘adequate’ 
assessment 
of response1 
Censored 
No adequate post-
baseline assessment 
before start of new 
anticancer therapy 
First dose 
Censored 
First dose 
Censored 
With adequate post-
baseline assessment and 
new anticancer treatment 
started (prior to 
documented disease 
progression/recurrence).2 
Date of last 
‘adequate’ 
assessment of 
response1 (on or 
prior to starting 
anti-cancer therapy)  
Censored 
Date of last 
‘adequate’ 
assessment 
of response1 
(on or prior 
to starting 
anti-cancer 
therapy) 
Censored 
Death before first 
scheduled assessment 
(or Death at baseline or 
without any adequate 
assessments) or new 
anticancer therapy 
Date of death 
Event 
Date of 
death 
Censored 


 
CONFIDENTIAL 
 
 
 
208809 
 
36 
 
Situation 
PFS 
TTP 
Date of Event 
(Progression/ 
Recurrence/Death) 
or Censored 
Event 
(Progression/ 
Recurrence 
/Death) 
Or Censored 
Date of 
Event 
(Progression/ 
Recurrence) 
or Censored 
Event 
(Progression/ 
Recurrence) 
Or Censored 
Death between adequate 
assessment visits  
Date of death 
Event 
Date of 
death 
Censored 
Death or 
progression/recurrence 
after more than one 
missed scheduled 
assessment 
• If death or PD is 
on or prior to day 
174 (W25D1 + 5-
day window), 
then a participant 
will be identified 
as an extended 
loss to follow up 
if the participant 
did not have an 
adequate 
assessment 
during the time 
period of 89 days 
(4 weeks + 8 
weeks + 5-day 
window) prior to 
death or PD;  
• Else if death or 
PD is after day 
174 (W25D1 + 5-
day window) and 
on or prior to day 
342 (W49D1 + 5-
day window), 
then a participant 
will be identified 
as an extended 
loss to follow up 
if the participant 
did not have an 
adequate 
assessment 
during the time 
period of 173 
days (12 wk + 12 
wk + 5-day 
window) prior to 
death or PD. 
PFS will be 
censored at the date 
Censored 
Same as PFS 
Censored 


 
CONFIDENTIAL 
 
 
 
208809 
 
37 
 
Situation 
PFS 
TTP 
Date of Event 
(Progression/ 
Recurrence/Death) 
or Censored 
Event 
(Progression/ 
Recurrence 
/Death) 
Or Censored 
Date of 
Event 
(Progression/ 
Recurrence) 
or Censored 
Event 
(Progression/ 
Recurrence) 
Or Censored 
of last adequate 
disease assessment 
of response prior to 
PD/death. 
1An adequate assessment is defined as an assessment where the determined response is CR, mCR, PR, HI, 
or SD for MDS/CMML/AML subjects. 
2 If PD and new anti-cancer therapy occur on the same day assume the progression/recurrence was 
documented first e.g., outcome is progression and the date is the date of the assessment of progression. 
7.2.1.3. 
Overall Survival 
OS is defined as time from first dose to death due to any cause. Subjects who are alive 
will be censored at the date of last contact. OS will be included in Part 1. 
7.2.2. 
Summary Measure 
7.2.2.1. 
Overall Response Rate 
For Part 1, the ORR will include both MDS/CMML and AML subjects as one single 
proportion. The corresponding exact 2-sided 95% CI (Clopper-Pearson confidence limits 
for the binomial proportion) for ORR will also be provided. Participants with unknown or 
missing responses will be included in the denominator when calculating percentages of 
ORR.  
7.2.2.2. 
Progression Free Survival 
For Part 1, the distribution of PFS (in months) by the interval of 3 months will be 
estimated using the Kaplan-Meier method. The median, 25th and 75th percentiles of time 
to progression or death will be estimated and corresponding 2-sided 95% CI will be 
estimated using the Brookmeyer-Crowley method (1982) using log log transformation.  
Kaplan-Meier curve (if data warrant) and a listing of PFS data will be provided. 
7.2.2.3. 
Overall Survival 
For Part 1, a table, a figure, and a listing will be produced for OS (in months) using 
methods specified in Section 7.2.2.2 for PFS endpoint. 
7.2.3. 
Population of Interest  
The populations will be the same as in the primary efficacy analyses, detailed in Section 
6.1. 


 
CONFIDENTIAL 
 
 
 
208809 
 
38 
 
7.2.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed. 
 


 
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
3 9  
 
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 8 8 0 9  
 
4 0  
 
 
C CI


 
CONFIDENTIAL 
 
 
 
208809 
 
41 
 
8. 
SAFETY ANALYSES 
All safety analyses will be performed on the All Treated population and will be 
separately conducted for Part 1 and Part 2. 
Unless otherwise specified, safety summaries will be conducted by dose level within Part 
1 Dose Confirmation and Part 2 Dose Escalation cohorts respectively. In Part 1, 
participants in Dose Confirmation treated at Recommended Myeloid Monotherapy Dose 
will be included in the Dose Expansion cohort analysis. Similarly, in Part 2, participants 
in Dose Escalation treated at Recommended Combination Dose will be included in the 
Dose Expansion cohort analysis. 
8.1. 
Extent of Exposure 
The duration of exposure to study treatment in months (from first day to last day of 
treatment) will be summarized. Descriptive statistics including mean, median, standard 
deviation, minimum, and maximum will be calculated for time on study treatment. In 
addition, time on study treatment will be categorized in different time periods: <3 
months, 3 months to 6 months, >6 months to 12 months and >12 months.  
For GSK3326595, the subject’s average daily dose, defined as the cumulative dose 
divided by the duration of exposure for each subject, will be summarized. Within Part 2, 
extent of exposure will be summarized separately for GSK3326595 and 5-Azacitidine. 
For 5-Azacitidine, the number of cycles will be summarized. In addition, the duration of 
study treatment (from the first dose of GSK3326595 or 5-Azacitidine to the last dose of 
GSK3326595 or 5-Azacitidine) will be summarized. 
Subject level details for extent of exposure to study treatment will be listed. The listing 
will be sorted by part, disease cohort, center, and subject ID. It will include start and stop 
dates, scheduled dose, actual dose, cumulative dose, average daily dose and number of 
days on the study treatment.  
Dose reductions will be summarized by number of reductions and reasons for reductions. 
Dose interruptions/delays will be summarized by number of interruptions/delays, reasons 
for the interruptions/delays, and interruption/delay duration (days). The mean, standard 
deviation, median, minimum value, and maximum value will be computed for the 
duration of interruptions. For 5-Azacitidine, the incidences of infusion stopped early and 
not completed, and infusion interrupted but completed will also be summarized. 
Summary of dose escalation will also be provided if applicable.  
All the dose reductions, dose escalations, and dose delays/interruptions will be listed 
separately. For 5-Azacitidine, the cases of infusion stopped early and not completed, and 
infusion interrupted but completed will also be listed. 
A swimmer plot of the duration of study treatment, including the occurrences of dose 
modification, number of lines of prior anti-cancer therapies, onset of CR/mCR/PR/HI/, 
progression, SAE and death, will be provided. 
The details of the planned displays are provided in Appendix 12: List of Data Displays. 


 
CONFIDENTIAL 
 
 
 
208809 
 
42 
 
8.2. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. Details on 
treatment emergent AEs are provided in Appendix 4, Section 14.4.2. 
In Part 1 Dose Confirmation and Part 2 Dose Escalation, Dose limiting toxicity (DLT) 
will also be summarized and listed according to GSK Oncology Data Standards using the 
DLT Evaluable population.   
AEs will be graded by the investigator according to the National Cancer Institute- 
Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v4.03. AEs will be coded 
to the Preferred Term (PT) level using the Medical Dictionary for Regulatory Affairs 
(MedDRA).  
An overview summary of AEs, including counts and percentages of subjects with any 
AE, AEs related to GSK3326595, Grade 3/4 AEs, Grade 3/4 AEs related to 
GSK3326595, AEs leading to dose reductions of GSK3326595, AEs leading to dose 
interruptions of GSK3326595, AE leading to study treatment withdrawn, Treatment-
related AE leading to study treatment withdrawn, SAEs, SAEs related to GSK3326595, 
fatal SAEs, and fatal SAEs related to GSK3326595 will be produced. Within Part 2, AEs 
related to any study treatment, AEs related to 5-Azacitidine, Grade 3/4 AEs related to any 
study treatment, Grade 3/4 AEs related to 5-Azacitidine, AEs leading to dose reductions 
of 5-Azacitidine, AEs leading to dose delays of 5-Azacitidine, AEs leading to infusion of 
5-Azacitidine interrupted but completed, AEs leading to infusion of 5-Azacitidine 
stopped early and not completed, AEs leading to permanent discontinuation of 5-
Azacitidine, SAEs related to any study treatment, SAEs related to 5-Azacitidine, fatal 
SAEs related to any study treatment, and fatal SAEs related to 5-Azacitidine will be 
included as well.  
Comment: in tables we also report all AEs by PT, by PT and SOC and by PT, SOC and 
maximum grade (Table 3.2 to Table 3.4) 
Similarly grade 2-5AEs that occurred in strictly 5% or more subjects will be summarized. 
A summary of non-serious AEs that occurred in strictly 5% or more of the subjects will 
be provided. This summary will contain the number and percentage of subjects with the 
event and the number of occurrences of the events. The summary table will be displayed 
by System Organ Class (SOC) and PT.  
The relationship between MedDRA SOC, PT, and Verbatim Text will be displayed. 
A summary of number and percentage of subjects with any AEs by maximum grade will 
be produced. AEs will be sorted by PT in descending order of total incidence. The 
summary will use the following algorithms for counting the subject: 
• 
Preferred term row: Subjects experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum grade. 


 
CONFIDENTIAL 
 
 
 
208809 
 
43 
 
• 
Any event row: Each subject with at least one AE will be counted only once at the 
maximum grade no matter how many events they have. 
In addition, the frequency and percentage of AEs (all grades) will be summarized and 
displayed in two ways: 1) in descending order of total incidence by PT only and 2) in 
descending order of total incidence by SOC and PT. In the SOC row, the number of 
subjects with multiple events under the same system organ class will be counted once.  
Summary of study treatment-related AEs by SOC and PT will be provided. 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. Within Part 2, separate summaries 
will be provided for study treatment-related AEs, one for GSK3326595-related and one 
for 5-Azacitidine-related, as well as a summary of AEs related to any study treatment.  
All AEs will be listed. Additionally, a listing of subject IDs for each individual AE will 
be produced. 
The details of the planned displays are provided in Appendix 12: List of Data Displays. 
8.3. 
Deaths and Serious Adverse Events 
In the event that a subject has withdrawn consent to data collection, no data after the 
withdrawal of consent date to data collection from this subject including death is 
supposed to appear in the database, which should be part of the data cleaning process. All 
deaths will be summarized based on the number and percentage of subjects. This 
summary will classify subjects by primary cause of death. A supportive listing will be 
generated to provide subject-specific details on subjects who died.  
A summary of the number and percentage of subjects and the number of occurrences of 
serious, drug-related serious, fatal serious, and drug-related fatal serious adverse events 
will be created. 
All SAEs will be tabulated based on the number and percentage of subjects who 
experienced the event. The frequency and percentage of SAEs will be summarized in 
descending order of total incidence by PT only. Separate summaries will also be provided 
for study treatment-related SAEs. A study treatment-related SAE is defined as an SAE 
for which the investigator classifies the relationship to study treatment as “Yes”. A worst 
case scenario approach will be taken to handle missing data, i.e. the summary table will 
include events with the relationship to study treatment as ‘Yes’ or missing. Within Part 2, 
separate summaries will be provided for study treatment-related SAEs, one for 
GSK3326595-related and one for 5-Azacitidine-related as well as a summary of SAEs 
related to any study treatment.  
SAEs are included in the listing of all adverse events. Separate supportive listings with 
subject-level details will be generated for fatal SAEs.Reasons for AE considered as a 
SAE will be listed. 


 
CONFIDENTIAL 
 
 
 
208809 
 
44 
 
8.4. Adverse Events Leading to Dose Modification of Study 
Treatment 
The following categories of AEs will be summarized separately in descending order of 
total incidence by PT only and separate supportive listings will be generated with subject 
level details for those subjects: 
• 
AEs Leading to Permanent Discontinuation of GSK3326595  
• 
AEs Leading to Dose Interruptions of GSK3326595 
• 
AEs Leading to Dose Reductions of GSK3326595 
Within Part 2, the following categories of AEs will be summarized and listed in addition 
to AEs leading to dose modification of GSK3326595. 
• 
AEs Leading to Permanent Discontinuation of 5-Azacitidine  
• 
AEs Leading to Dose Delay of 5-Azacitidine 
• 
AEs Leading to Dose Reductions of 5-Azacitidine 
• 
AEs Leading to Infusion of 5-Azacitidine Interrupted but Completed 
• 
AEs Leading to Infusion of 5-Azacitidine Stopped Early and Not Completed 
8.5. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 12: List of Data Displays. 
Summaries by visit will include data from scheduled assessments only, and all data will 
be reported according to the nominal visit date for which it was recorded (i.e., no visit 
windows will be applied). Unscheduled data will be included in ‘worse case post 
baseline’ summaries which will capture a worst case across all scheduled and 
unscheduled visits after the first dose of study intervention. 
Clinical Laboratory Tests are listed in Table 77. 
Table 7 
List of Clinical Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
RBC Count 
Hemoglobin 
Hematocrit 
RBC Indices: MCV, MCH, %Reticulocytes 
WBC count with Differential: Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils, Myeloblasts (if present) 
Clinical 
Chemistry 
BUN 
Creatinine 
Glucose (nonfasting) 


 
CONFIDENTIAL 
 
 
 
208809 
 
45 
 
Laboratory 
Assessments 
Parameters 
Amylase 
Potassium 
Sodium 
Calcium 
Lipase 
AST/SGOT 
ALT/SGPT 
Alkaline phosphatase 
Serum bicarbonate 
Total and direct bilirubin 
Total protein 
Albumin 
Folate and 
selected 
vitamins 
Serum B12 and Folate. For borderline results of B12 and/or folate, the 
following 2 additional tests will be performed within 2 weeks of the 
borderline result: Methylmalonic acid (serum or plasma) and 
Homocysteine (serum or plasma). 
B12: 
• >300 pg/mL (above 221 pmol/L) – Normal 
• 200 to 300 pg/mL (148 to 221 pmol/L) – Borderline 
• <200 pg/mL (below 148 pmol/L) – Low; consistent with 
deficiency 
Folate: 
• >4 ng/mL (above 9.1 nmol/L) – Normal. 
• From 2 to 4 ng/mL (from 4.5 to 9.1 nmol/L) – Borderline. 
• <2 ng/mL (below 4.5 nmol/L) – Low; consistent with folate 
deficiency. 
Thyroid 
Function 
TSH, T3, T4 – Screening, Week 5 Day 1, and Week 9 Day 1 and 
every 8 weeks thereafter and EOT. 
Coagulation 
PTT, PT/INR 
Cardiac Safety Local Troponin (I or T, based on local standards; note that the 
same test (either I or T) should be performed at each timepoint) 
Central Troponin T (separate tube for central laboratory analysis) 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Additional 
Urine and 
serum renal 
biomarkers 
(Only 
participants 
with baseline 
eGFR <60 
• NGAL, KIM-1, and albumin/creatinine ratio (urine) 
• Cystatin C (serum) 


 
CONFIDENTIAL 
 
 
 
208809 
 
46 
 
Laboratory 
Assessments 
Parameters 
ml/min/1.73 
m2) 
Pregnancy 
Testing 
• Human chorionic gonadotropin (hCG) pregnancy test (as needed 
for women of childbearing potential) 
Screening 
Tests 
• Follicle-stimulating hormone and estradiol (as needed in women 
of nonchildbearing potential only) 
• Serology (HIV antibody, HBsAg, and HCV antibody). A positive 
HCV antibody must be confirmed via second study (e.g., HCV 
RNA or comparable test) 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; HBsAg = Hepatitis B surface antigen; HCV = hepatitis C virus; MCH = mean 
corpuscular haemoglobin; MCV = mean corpuscular volume; RBC = red blood cells; SGOT = 
serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; T3 = 
free Tri-iodothyronine; T4 = free thyroxine; TSH = Thyroid stimulating hormone; WBC = white 
blood cells 
 
Laboratory grades will be reported using the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03. 
Summary of lab values change from baseline by scheduled visits using mean, median, 
standard deviation, minimum, and maximum will be provided. This will be done 
separately by chemistry and hematology tests.  
Summaries of worst case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by CTCAE v4.03. These summaries will display the number 
and percentage of subjects with a maximum post-baseline grade increasing from their 
baseline grade. Any increase in grade from baseline will be summarized along with any 
increase to a maximum grade of 3 and any increase to a maximum grade of 4.   
Missing baseline grade will be assumed as grade 0. For laboratory tests that are graded 
for both low and high values, summaries will be done separately and labeled by direction, 
e.g. sodium will be summarized as hyponatremia and hypernatremia. 
For lab tests that are not gradable by CTCAE v4.03, summaries of worst case changes 
from baseline with respect to normal range will be generated. Decreases to low, changes 
to normal or no changes from baseline, and increases to high will be summarized for the 
worst case post-baseline. If a subject has a decrease to low and an increase to high during 
the same time interval, then the subject is counted in both the “Decrease to Low” 
categories and the “Increase to High” categories.  
A supporting listing of laboratory data for subjects with any value outside normal range 
will be provided. This will be done separately by chemistry and hematology tests. A 
separate listing of laboratory data with character values will also be provided. 
Detailed derivation of baseline assessment is specified in Section 5.4. 


 
CONFIDENTIAL 
 
 
 
208809 
 
47 
 
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit. 
A summary of worst case urinalysis results post-baseline relative to baseline will be 
generated. Also, a listing of urinalysis data for participants with any value of potential 
clinical importance will be provided. For the listing potential clinical importance is 
defined as if there is ‘any increase’ in protein or occult blood results during the study, or 
if microscopy is performed. 
8.5.1. 
Analyses of Liver Function Tests (LFT) 
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above.  
Possible Hy’s law cases are defined as any elevated ALT≥3×ULN, total 
bilirubin≥2×ULN and ALP<2×ULN/missing. Total bilirubin≥2×ULN can be within 28 
days following the ALT elevation and if direct bilirubin is available on the same day, it 
must be ≥ 35% of total bilirubin. ALP<2xULN/missing means the criteria is satisfied 
unless the ALP is ≥2xULN at any time of bilirubin elevation within the 28 days window.  
Medical conditions and substance use for participants with liver stopping events will be 
listed separately. 
LFT patient profiles plots for subjects experiencing an ALT, AST or total bilirubin of 
toxicity grade 2 or above will be produced. 
A scatter plot of maximum total bilirubin versus maximum ALT will be generated. Also, 
a scatter plot of maximum vs baseline for ALT will be produced.  
8.6. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. LVEF and Performance 
status will be summarized and listed based on GSK Oncology Data Standard. The details 
of the planned displays are presented in Appendix 12: List of Data Displays. 
8.6.1. 
Performance Status 
ECOG performance status will be summarized at baseline and post-baseline scheduled 
visits. Summaries will use frequency and percentage of subjects at each planned 
assessment time.  
A supporting listing will also be provided. 
8.6.2. 
ECG 
Triplicate 12-lead ECGs will be obtained using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT and QTcF intervals. Baseline QTcF 
value is determined by the mean of the triplicate Day1 pre-dose QTcF results. If these 


 
CONFIDENTIAL 
 
 
 
208809 
 
48 
 
results are not available, the mean QTcF of the screening triplicate ECG results should be 
used. 
A summary of the number and percentage of subjects who had normal and abnormal 
(clinically significant and not clinically significant) ECG findings will be displayed by 
scheduled visits as well as for the worst case post-baseline. Also a summary of change 
from baseline in ECG values by visit will be produced. 
The QTc values based on Fridericia formula will be rounded to the integer and the values 
will be categorized into the following ranges: Grade 0 (<450), Grade 1 (450-480), Grade 
2 (481-500), and Grade 3 (≥501). Summaries of grade increase will be provided. These 
summaries will display the number and percentage of subjects with any grade increase, 
increase to grade 2 and increase to grade 3 in the worst case post-baseline. 
The changes in QTcF values will be categorized into the clinical concern ranges which 
are specific to changes in QTcF: 31-60 and >60 msec. A summary of change in QTcF 
value will display the number and percentage of subjects with a change within each range 
in the worst case post-baseline. Subjects with missing baseline values will be excluded 
from this summary. 
Listing of all ECG values for participants with any value of potential clinical importance 
provided. Also, a listing of QTcF values of potential clinical importance will be provided. 
A figure plotting the baseline QTcF and the worst-case post-baseline values will be 
produced. The figure will have reference lines at 450 and 500 msec for both the ordinate 
and the abscissa axes. There will be diagonal reference lines at equality (i.e. a 45-degree 
line), at equality plus 30 msec, and at equality plus 60 msec. 
8.6.3. 
Vital Signs 
Values of vital signs as well as the change from baseline will be summarized by 
scheduled visit using mean, median, standard deviation, minimum and maximum.  
In addition, vital sign values will be categorized as follows: 
• 
Systolic BP (mmHg):  
Grade 0 (<120), Grade 1 (120-139), Grade 2 (140-159) and Grade 3 (≥160) 
• 
Diastolic BP (mmHg):  
Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), and Grade 3 (≥100) 
• 
Heart rate (beats/min): 
<60, 60-100, and >100 
• 
Temperature (°C):  
≤35, 36-37, ≥38 
Summaries of increase in vital signs from the baseline with respect to the categories 
defined above will be performed. 
A listing of vital signs with values of potential clinical importance will be provided. 


 
CONFIDENTIAL 
 
 
 
208809 
 
49 
 
8.6.4. 
Cardiovascular Risk Factors 
Summary of Family History of Cardiovascular Risk Factors Summary of Substance Use 
will be summarised in All Treated population by dose level.  
8.6.5. 
LVEF 
Worst-case post-baseline LVEF change from baseline will be summarized. The change 
from baseline will be categorized as follows: 
• No change or any increase 
• Any decrease: 
• 
>0 - <10% Decrease 
• 
10 - 19% Decrease 
• 
≥20% Decrease 
• ≥10% decrease and ≥ LLN 
• ≥10% decrease and < LLN 
• ≥20% decrease and ≥ LLN 
• ≥20% decrease and < LLN 
LVEF results will also be listed with subject level details including absolute change from 
baseline. 
8.6.6. 
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 recorded 
as an AE or SAE as described in the protocol. If subjects and subjects’ partner become 
pregnant while on the study, the information will be included in the narratives and no 
separate table or listing will be produced. 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
50 
 
9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Primary Pharmacokinetic Analyses 
9.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 14.5.3 
Reporting Standards for Pharmacokinetic) 
9.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic (PK) parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using the currently supported version 
of Phoenix WinNonlin. All calculations of non-compartmental parameters will be based 
on actual sampling times. Pharmacokinetic parameters listed will be determined from the 
plasma concentration-time data, as data permits. 
Parameter 
Parameter Description 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time to Cmax 
AUC0-t 
Area under plasma concentration-time curve from 0 to each time point 
AUC0- ∞ 
Area under plasma concentration-time curve from 0 to end 
AUC0- τ 
Area under plasma concentration-time curve from 0 to half-life 
t1/2 
Half life time 
CL/F 
Oral clearance 
TI 
Time invariance equal to 
𝐴𝑈𝐶(0−𝜏),𝐷𝑎𝑦 15
𝐴𝑈𝐶(0−∞),𝐷𝑎𝑦 1 
AR 
Accumulation ratio equal to 
𝐴𝑈𝐶(0−𝜏),𝐷𝑎𝑦 15
𝐴𝑈𝐶(0−𝜏),𝐷𝑎𝑦 1  
 
9.1.3. 
Population of Interest  
The primary pharmacokinetic analyses will be based on the PK population, unless 
otherwise specified. 
9.1.4. 
Statistical Analyses / Methods 
Individual plasma concentration data will be summarized using descriptive statistics of n, 
mean, standard deviation, median, minimum, maximum, by planned assessment time 
points and by treatment. Individual plasma concentration data and mean value will be 
plotted in both original and logarithm scales by time points and by treatment. PK 
parameters listed in Section 9.1.2 will be summarized using descriptive statistics of mean, 
standard deviation, median, minimum, maximum, geometric mean and standard 
deviation, as well as CV%.  


 
CONFIDENTIAL 
 
 
 
208809 
 
51 
 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 9.1.2 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed. 
9.2. 
Secondary Pharmacokinetic Analyses 
Secondary PK endpoints are not planned to be analysed.  
 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
52 
 
10. 
PHARMACODYNAMIC (AND / OR BIOMARKER) 
ANALYSES 
Biomarker data is being collected, but there will be no biomarker analyses formalized in 
the RAP.   


 
CONFIDENTIAL 
 
 
 
208809 
 
53 
 
11. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
No POPPK analyses will be conducted.  


 
CONFIDENTIAL 
 
 
 
208809 
 
54 
 
12. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
No pharmacokinetic/pharmacodynamic analyses will be conducted.  


 
CONFIDENTIAL 
 
 
 
208809 
 
55 
 
13. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982; 38:29-41. 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials 2008: 5. 93–106.  
J Jack Lee 1, Diane D Liu A predictive probability design for phase II cancer clinical 
trials 2008 Clin Trials . 2008;5(2):93-106 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
56 
 
14. 
APPENDICES 
14.1. Appendix 1: Protocol Deviation Management and Definitions for 
Per Protocol Population 
14.1.1. 
Exclusions from Per Protocol Population 
No Per Protocol population is defined and used for this study. 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
57 
 
14.2. 
Appendix 2: Schedule of Activities 
14.2.1. 
Protocol Defined Schedule of Events 
Refer to Protocol Section 1.3. 


 
CONFIDENTIAL 
 
 
 
208809 
 
58 
 
14.3. 
Appendix 3: Assessment Windows 
No assessment window will be applied. 


 
CONFIDENTIAL 
 
 
 
208809 
 
59 
 
14.4. Appendix 4: Study Phases and Treatment Emergent Adverse 
Events 
14.4.1. 
Study Phases 
14.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
• 
Study Treatment Start Date is missing (i.e., subject did not start study treatment), 
or 
• 
Medication End Date < Study Treatment Start Date 
Concomitant 
• 
Medication End Date is on or after Study Treatment Start Date, or 
• 
Medication End Date is completely missing and Start Date < Study Treatment End 
Date 
Follow-up 
• 
Medication End Date is on or after Study Treatment Start Date, or 
• 
Start date > Study Treatment End Date 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of partially missing dates for 
concomitant medication. 
 
14.4.1.2. 
Medical History 
Study Phase 
Definition 
Past 
Medical condition is not marked as ongoing on eCRF 
Current 
• 
Medication End Date is on or after Study Treatment Start Date, or 
Medical condition is not past 
 
14.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
All AEs satisfied either of conditions are considered treatment emergent: If AE onset 
date is on or after treatment start date or missing and on or before treatment stop 
date plus thirty days. 
o Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date 
+ 30 
o  
o AE Start Date is completely missing 
o Study Treatment Start Date ≤ AE Worsening Date ≤ Study Treatment Stop 
Date + 30 
 
Partially missing AE Start Date will be imputed following rules in Section 14.7.2.1 for 
determining Treatment Emergent AEs. 
NOTES:  
• 
Time of study treatment dosing and start time of AEs should be considered, if collected. 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
60 
 
14.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
14.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software and TSCG will be used. 
Reporting Area 
HARP Server 
: US1SALX00259 
HARP Compound 
: gsk3326595\mid208809 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.1.3 & ADaM IG 
Version 1.1]. 
Generation of RTF Files 
• 
RTF files will be generated upon request. 
14.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
o Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
o The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
o Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
o Unscheduled or unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables, except in cases where worst-case post-
baseline is calculated.  
• 
Unscheduled visits will not be included in figures, unless otherwise specified. 
• 
All unscheduled visits will be included in listings. 


 
CONFIDENTIAL 
 
 
 
208809 
 
61 
 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
14.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
[Insert document name].  
Note: Concentration values will be imputed as per GUI_51487 
Descriptive 
Summary Statistics, 
Graphical Displays 
and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
NONMEM/Pop PK 
File 
Not applicable. 
NONMEM/PK/PD 
File 
Not applicable. 
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by 
Programmer 
The following PK parameters will be derived by the Programmer: Cmax, Tmax, 
AUC0-t, AUC0- ∞, AUC0- τ, t1/2, CL/F, TI, AR] 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
Yes, refer to Standards for Handling NQ Impacted PK Parameters. 
Descriptive 
Summary Statistics, 
Graphical Displays 
and Listings 
Refer to IDSL PK Display Standards. 
 
 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
62 
 
14.6. 
Appendix 6: Derived and Transformed Data 
14.6.1. 
General 
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. 
• 
If multiple assessments on different days are reported for the same scheduled assessment, then the 
worst case assessment for that scheduled assessment will be analyzed. 
• 
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. 
Study Day 
• 
Calculated as the number of days from First Dose Date: 
o Ref Date = Missing              → Study Day = Missing  
o Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
o Ref Date ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
Change from Baseline 
• 
Change from Baseline = Post-Baseline Visit Value – Baseline 
• 
% Change from Baseline= 100 x (Post-Baseline Visit Value – Baseline) / Baseline 
• 
Maximum Increase/Decrease from Baseline = maximum (Increase/Decrease from Baseline) 
• 
If either the Baseline or Post-Baseline Visit Value is missing, Change from Baseline and % Change 
from Baseline is set to missing 
Date of New Anti-Cancer Therapy 
• 
Derived as the earliest date of new anti-cancer therapy, stem cell transplant, radiotherapy or cancer-
related surgical procedure. 
• 
 Missing or partial dates will be imputed for derivation of new anti-cancer therapy following rules 
specified in Section 14.7.2.1. 
 
14.6.2. 
Study Population 
Treatment Compliance 
• 
Treatment compliance of GSK3326595 will be calculated based on the formula:   
Treatment Compliance (%) = Total Cumulative Actual Dose / (Duration of Study Treatment * 
Prescribed Dose) * 100 
where duration of study treatment is last dose - first dose +1 
• 
Treatment compliance could be greater than 100% if there are events of overdose.  
Extent of Exposure 
• 
Missing treatment stop date will be imputed following rules specified in Section 14.7.2.1. 
• 
Daily Oral Drugs   
o Number of days of exposure (duration on study treatment) to study drug will be calculated based 
on the formula: 
Duration of Exposure in Days = Treatment Stop Date – Treatment Start Date + 1 
o Participants who were enrolled but did not report a treatment start date will be categorized as 
having zero days of exposure.  


 
CONFIDENTIAL 
 
 
 
208809 
 
63 
 
Treatment Compliance 
o The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Number of Days x Total Daily Dose) 
o If there are any treatment breaks during the study, exposure data will be adjusted accordingly. 
Time since Initial Diagnosis 
• 
Calculated as the number of days from the Date of Initial Diagnosis: 
o If First Dose Date is missing           → Elapse Time = Missing  
o If Date of Initial Diagnosis is completely/partially missing       → Elapse Time = Missing  
o Otherwise       → Elapse Time = First Dose Date – Date of Initial Diagnosis + 1            
• 
To report in months, divide the number of days by 30.4375; to report in weeks divide the number of 
days by 7; to report in years divide the number of days by 365.25. No imputation is needed for partial 
dates. 
 
14.6.3. 
Safety 
Adverse Events 
Adverse Events of Special Interest 
• 
There are no AESI defined for this study therefore the analysis will not be performed.  
Duration of AE 
• 
Calculated as the number of days from AE Start Date to AE Stop Date: 
o AE Start Date = Missing              → Elapse Time = Missing  
o AE Stop Date = Missing              → Elapse Time = Missing 
o Otherwise                                    → Elapsed Time = AE Stop Date – AE Start Date + 1 
• 
To report in months, divide the number of days by 30.4375; to report in weeks divide the number of 
days by 7; to report in years divide the number of days by 365.25. 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
64 
 
14.7. 
Appendix 7: Reporting Standards for Missing Data 
14.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Subject study completion was defined as if the subject has been followed until death 
or study completion. 
• 
Withdrawn subjects may be replaced in the study as specified in the protocol. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
14.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
14.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject 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 (see Section 14.4.1) or for specific analysis 
purposes as outlined below. 
Adverse Events 
• 
Imputations in the adverse events dataset are used for slotting events to the 
appropriate study time periods and for sorting in data listings. 
• 
The eCRF allows for the possibility of partial dates (e.g., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event: 
o Missing Start Day: 
▪ 
If study treatment start date is missing (i.e. participant did not start study 
treatment), then set AE start date = 1st of month. 
▪ 
Else if study treatment start date is not missing: 
If month and year of AE start date = month and year of study treatment 
start date then 
 If AE stop date contains a full date and is earlier than study 
treatment start date, then set AE start date= 1st of month. 
 Else set AE start date = study treatment start date. 
Else set AE start date = 1st of month. 
o Missing Start Day and Month: 
▪ 
If study treatment start date is missing (i.e. participant did not start study 
treatment), then set AE start date = January 1. 


 
CONFIDENTIAL 
 
 
 
208809 
 
65 
 
Element 
Reporting Detail 
▪ 
Else if study treatment start date is not missing: 
If year of AE start date = year of study treatment start date then 
 If AE stop date contains a full date and is earlier than study 
treatment start date, then set AE start date = January 1. 
 Else set AE start date = study treatment start date. 
Else set AE start date = January 1. 
• 
Completely missing start dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 
• 
Completely or partially missing end dates will remain missing, with no 
imputation applied. Consequently, duration of such events will be missing. 
• 
Start dates later than death date will be imputed as the study treatment start 
date 
• 
End dates later than death date will be imputed as the death date 
Concomitant 
Medications/ 
Blood Supportive 
Products 
• 
Completely missing start dates will not be imputed 
• 
Partial start dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
o If day and month are missing: 
‒ If treatment start date is missing (i.e., subject did not start study 
treatment), a '01' will be used for the day and 'Jan' will be used for the 
month; 
‒ If treatment start date is not missing  
▪ 
If year of start date = year of study treatment start date 
 If stop date contains a full date which is earlier than the 
treatment start date, a '01' will be used for the day and 'Jan' 
will be used for the month; 
 else study treatment start date will be used 
▪ 
else a ‘01’ will be used for the day and ‘Jan’ will be used for the 
month 
o If day is missing: 
‒ If treatment start date is missing (i.e., subject did not start study 
treatment), a '01' will be used for the day; 
‒ If treatment start date is not missing  
▪ 
If year and month of start date = year and month of study 
treatment start date 
 If stop date contains a full date which is earlier than the 
treatment start date, a '01' will be used for the day; 
 else study treatment start date will be used 
▪ 
else a ‘01’ will be used for the day and ‘Jan’ will be used for the 
month 
• 
Completing missing end dates will not be imputed 
• 
Partial end dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
o If day and month are missing 
‒ Earliest of (Dec 31st, date of last contact) will be used  
o If day is missing 
‒ Earliest of (last day of the month, date of last contact) will be used 
New Anti-Cancer 
Therapy/  
Start dates for follow-up anti-cancer therapy, stem cell transplant, radiotherapy, and 
surgical procedures will be imputed in order to define event and censoring rules for 


 
CONFIDENTIAL 
 
 
 
208809 
 
66 
 
Element 
Reporting Detail 
Stem Cell 
Transplant/ 
Radiotherapy/ 
Surgical 
Procedures for 
Efficacy 
Evaluation (e.g., 
response rate, 
time to event) 
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, stem cell transplant, 
radiotherapy, 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: 
• 
If both month and day are missing, no imputation will be applied; 
• 
If only day is missing:  
o If the month of partial date is the same as the month of last dosing 
date, minimum of (last dosing date + 1, last day of the month) will be 
used for the day; 
o If the month of partial date is the same as the month of last disease 
assessment and the last disease assessment is PD, minimum of (last 
date of disease assessment + 1, last day of the month) will be used for 
the day; 
o If both conditions above are met, the later date will be used for the day; 
o Otherwise, a ‘01’ will be used for the day; 
• 
Completely or partial missing end dates will remain missing, with no imputation 
applied; 
Prior Anti-Cancer 
Therapy/ 
Radiotherapy/ 
Surgical 
Procedures 
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 (last day of the 
month from the partial date, first dosing date) will be used 
o Else minimum of (last day of the month from the partial date, first dosing 
date - 1) will be used 
Treatment end 
date 
• 
If there is more than one study treatment, imputation of missing treatment end 
date will be applied to all applicable treatments following rules below and 
treatment end date is the latest treatment end date across all study treatments. 
• 
 In general, completely missing end dates are not imputed, with the following 
exceptions for imputation of missing treatment end date at interim analyses. 
• For imputation of missing exposure end date at an interim analysis when 
subjects are still on treatment, the following conventions will be applied: 
o If the missing end date is in the last exposure record, the earliest of: the 
date of the data cut-off, the date of permanently discontinued from the 
study treatment, the date of withdrawal from the study, or the death date 
will be used  
o If the missing end date is not in the last exposure record, treatment start 
date for the record will be used 
• The imputed treatment end date will be used to calculate cumulative dose and 
duration of treatment as specified in Section 6.6  


 
CONFIDENTIAL 
 
 
 
208809 
 
67 
 
14.8. 
Appendix 8: Values of Potential Clinical Importance 
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03) will be used to 
assign grades for laboratory parameters including clinical chemistry, hematology, liver 
function tests, QTc (Fridericia’s) values, and vital signs (heart rate, blood pressure, 
temperature).  
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. The laboratory 
reference ranges will be provided on the listings of laboratory data. Clinical laboratory 
test results outside of the reference range will be flagged in the listings. 
14.8.1. 
ECG 
The following criteria will be used to flag electrocardiogram (ECG) values that are values 
of potential clinical importance:  
To identify QTc (Fridericia’s) values of potential clinical importance, NCI-CTCAE v4.03 
will be used to assign grades (see adverse event ‘Electrocardiogram QT corrected interval 
prolonged’). The CRF collects either QTcF. Note that there is a slight inconsistency 
between CTCAE v4.03 and ICH E14 (Absolute QTc interval prolongation). It was 
decided to align with CTCAE for the oncology standard categories. 
ECG Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute QTcF interval 
450 to <481 (Grade 1) 
481 to <501 (Grade 2) 
501 (Grade 3) 
msec 
Increase from baseline 
QTcF 
Increase of 31 to 60 
Increase of >60 
msec 
 
The following criteria will be used to flag other ECG values that are values of potential 
clinical importance:  
ECG Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute PR interval 
<110 (L) 
>220 (H) 
Msec 
Absolute QRS interval 
<75 (L) 
>110 (H) 
Msec 
 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
68 
 
14.8.2. 
Vital Signs 
To identify heart rate values of potential clinical importance, NCI-CTCAE v4.03 will be 
used to assign categories that align with the grades for ‘Sinus bradycardia’, ‘Sinus 
tachycardia’, ‘Supraventricular tachycardia’, and ‘Ventricular tachycardia’. 
The following criteria will be used to flag vital sign values that are values of potential 
clinical importance: 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute Heart Rate 
<60 (L) 
>100 (H) 
bpm 
 
To identify blood pressure values of potential clinical importance, NCI-CTCAE v4.03 
will be used to assign categories that align with the grades for ‘Hypertension’. 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute Systolic 
Blood Pressure 
120 to <140 (Grade 1) 
140 to <160 (Grade 2) 
160 (Grade 3) 
mmHg 
Absolute Diastolic 
Blood Pressure 
80 to <90 (Grade 1) 
90 to <100 (Grade 2) 
100 (Grade 3) 
mmHg 
 
To identify temperature values of potential clinical importance, NCI-CTCAE v4.03 will 
be used to assign categories that align with the grades for ‘Hypothermia’ and ‘Fever’. 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute Temperature 
35 (L) 
38 (H) 
Degrees 
C 
 
14.8.3. 
Urinalysis 
Values of potential clinical importance will be defined as per GSK IDSL standards.  


 
CONFIDENTIAL 
 
 
 
208809 
 
69 
 
14.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
No POPPK analyses will be conducted.  


 
CONFIDENTIAL 
 
 
 
208809 
 
70 
 
14.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
Biomarker data is being collected, but there will be no biomarker analyses formalized in 
the RAP.   


 
CONFIDENTIAL 
 
 
 
208809 
 
71 
 
14.11. 
Appendix 11: Abbreviations & Trade Marks 
14.11.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
BAC 
Best Available Care 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Fridericia’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
SAC 
Statistical Analysis Complete 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
SRT 
Safety Review Team 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  


 
CONFIDENTIAL 
 
 
 
208809 
 
72 
 
14.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
WinNonlin 
 
 
SAS 
 
 
NONMEM 
 
 


 
CONFIDENTIAL 
 
 
 
208809 
 
73 
 
14.12. 
Appendix 12: List of Data Displays 
14.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.n 
1.1 to 1.n 
Efficacy 
2.1 to 2.n 
2.1 to 2.n 
Safety 
3.1 to 3.n 
3.1 to 3.n 
Pharmacokinetic 
4.1 to 4.n 
4.1 to 4.n 
Population Pharmacokinetic (PopPK) 
5.1 to 5.n 
5.1 to 5.n 
Pharmacodynamic and / or Biomarker 
6.1 to 6.n 
6.1 to 6.n 
Pharmacokinetic / Pharmacodynamic 
7.1 to 7.n 
7.1 to 7.n 
Section 
Listings 
ICH Listings 
1 to x 
Other Listings 
(x+1) to z 
 
14.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Population Pharmacokinetic (PopPK) 
POPPK_Fn 
POPPK_Tn 
POPPK_Ln 
Pharmacodynamic and / or Biomarker 
PD_Fn 
PD_Tn 
PD_Ln 
Pharmacokinetic / Pharmacodynamic 
PKPD_Fn 
PKPD_Tn 
PK/PD_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
14.12.3. 
Deliverables 
Delivery 
Description 
P1DC 
Part 1 Dose Confirmation 
P1IFA 
Part 1 Dose Expansion Interim Futility Analysis 
P2ESC 
Part 2 Escalation Cohort Final Meeting (Dose Selection) 
P2IFA 
Part 2 Dose Expansion Interim Futility Analysis 
SAC 
Final Statistical Analysis Complete 
 


CONFIDENTIAL 
 
 
208809 
 
74 
 
14.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.1. 
All Treated 
ES8 
Summary of Subject Status and Subject Disposition for the 
Study Conclusion Record 
ICH E3, FDAAA, EudraCT 
 
 SAC 
1.2. 
All Treated 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
ICH E3 
P1IFA, SAC 
1.3. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
SAC 
1.4. 
Enrolled 
NS1 
Summary of Number of Participant by Country and Site ID 
EudraCT/Clinical Operations 
SAC 
Protocol Deviation 
1.5. 
All Treated 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC 
Population Analysed 
1.6. 
Screened 
SP1A 
Summary of Study Populations  
IDSL 
To include Enrolled, DLT Evaluable, 
Response Evaluable, All Treated, PK 
P1IFA, SAC 
1.7. 
All Treated 
SP2A 
Summary of Exclusions from the Safety Population   
IDSL  
If none, to remove 
SAC 
Demographic and Baseline Characteristics 
1.8. 
All Treated 
DM1 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
P1IFA, SAC 
1.9. 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
SAC 
Disease Characteristics 
1.10. 
All Treated 
DC1 
Summary of Disease Characteristics at Initial Diagnosis 
ICH E3 
P1IFA, SAC 
1.11. 
All Treated 
DC2 
Summary of Disease Characteristics at Screening 
ICH E3 
SAC 
1.12. 
 
 
 
 
SAC 


CONFIDENTIAL 
 
 
208809 
 
75 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Prior and Concomitant Medications 
1.13. 
All Treated 
MH1 
Summary of Past Medical Conditions 
ICH E3  
SAC 
1.14. 
All Treated 
MH1 
Summary of Current Medical Conditions 
ICH E3  
SAC 
1.15. 
All Treated 
CM8 
Summary of Concomitant Medications 
ICH E3 
SAC 
Blood and Blood Supportive Care Products 
1.16. 
All Treated 
BP1A 
Summary of Blood Products 
Only produced if sufficient data (i.e. >5 
events), otherwise only list 
SAC 
1.17. 
All Treated 
BP1B 
Summary of Blood Supportive Care Products after the Start of 
Study Medication 
Only produced if sufficient data (i.e. >5 
events), otherwise only list 
SAC 
Anti-Cancer Therapy 
1.18. 
All Treated 
AC1 
Summary of Prior Anti-Cancer Therapy 
IDSL 
Include stem cell transplant 
SAC 
1.19. 
All Treated 
CM1 
Summary of Prior Dictionary Coded Anti-Cancer Therapy 
IDSL 
SAC 
1.20. 
All Treated 
AC3 
Summary of Number of Prior Anti-Cancer Therapy Regimens 
IDSL 
Include stem cell transplant 
SAC 
1.21. 
All Treated 
AC1 
Summary of Follow-Up Anti-Cancer Therapy 
IDSL 
Include stem cell transplant 
SAC 
Surgical/Medical Procedures 
1.22. 
All Treated 
MH1 
Summary of Prior Cancer Related Surgical Procedures 
IDSL 
SAC 
1.23. 
All Treated 
MH1 
Summary of On-Study Cancer Related Surgical Procedures 
IDSL 
SAC 
1.24. 
All Treated 
MH1 
Summary of Follow-Up Cancer Related Surgical Procedures 
IDSL 
SAC 
Follow-up 
1.25. 
All Treated 
FAC2 
Summary of Duration of Follow-up 
 
SAC 


CONFIDENTIAL 
 
 
208809 
 
76 
 
14.12.5. Efficacy Tables 
14.12.6. Efficacy Figures 
Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Responses 
2.1.  
All Treated 
RE1c 
Summary of Investigator Assessed Clinical Benefit Response 
(International Working Group Criteria) 
By dose level. For Part 1, include both 
AML and MDS/CMML subjects in the 
same table. Report CBR and ORR in 
one table (Part 1). 95% CI is based on 
Clopper-Pearson exact CI.  
P1IFA, SAC 
2.2.  
All Treated 
RE1c 
Summary of Investigator Assessed Clinical Benefit Response 
(International Working Group Criteria) by Central Review 
Spliceosome Mutation Status 
Across dose levels. Report CBR and 
ORR in one table (Part 1). No CI.  
SAC 
Time-to-Event Endpoints 
2.3.  
All Treated 
TTE1 
Summary of Progression Free Survival Based on Investigator 
Assessments (International Working Group Criteria) 
By dose level. 
SAC 
2.4.  
All Treated 
TTE1 
Summary of Overall Survival 
By dose level. 
SAC 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
Time-to-Event Endpoints 
2.5.  
All Treated 
TTE10 
Graph of Kaplan Meier Survival Curves of Progression Free 
Survival with 95% Confidence Bands (Investigator Assessment 
using International Working Group Criteria) 
If data warrant. By dose level. 
SAC 
2.6.  
All Treated 
TTE10 
Graph of Kaplan Meier Survival Curves of Overall Survival with 
95% Confidence Bands (Investigator Assessment using 
International Working Group Criteria) 
If data warrant. By dose level. 
SAC 


CONFIDENTIAL 
 
 
208809 
 
77 
 
14.12.7. Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Adverse Events (AEs) 
3.1.  
All Treated 
AE13 
Adverse Event Overview 
Including subjects with any AE, AEs 
related to GSK3326595, Grade 3/4 
AEs, Grade 3/4 AEs related to 
GSK3326595, AEs leading to dose 
reductions of GSK3326595, AEs 
leading to dose interruptions of 
GSK3326595, AEs leading to 
permanent discontinuation of 
GSK3326595, SAEs, SAEs related to 
GSK3326595, fatal SAEs, and fatal 
SAEs related to GSK3326595 
P1IFA, SAC 
3.2.  
All Treated 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term 
ICH E3 
SAC 
3.3.  
All Treated 
AE5B 
Summary of All Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade 
ICH E3 
SAC 
3.4.  
All Treated 
AE1 
Summary of All Adverse Events by Preferred Term 
ICH E3 
SAC 
3.5.  
All Treated 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency 
ICH E3 
SAC 
3.6.  
All Treated 
AE3 
Summary of Common (>=5%) Grade 2-5 Adverse Events by 
Overall Frequency 
ICH E3 
SAC 
3.7.  
All Treated 
AE1 
Summary of All GSK3326595-Related Adverse Events by 
System Organ Class and Preferred Term 
ICH E3 
SAC 
3.8.  
All Treated 
AE5B 
Summary GSK3326595-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Grade 
ICH E3 
SAC 


CONFIDENTIAL 
 
 
208809 
 
78 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.9.  
All Treated 
AE3 
Summary of Common (>=5%) Drug-Related Adverse Events by 
Overall Frequency 
ICH E3 
SAC 
3.10. 
All Treated 
AE3 
Summary of Common (>=5%) Drug-Related Grade 2-5 
Adverse Events by Overall Frequency 
ICH E3 
SAC 
3.11. 
All Treated 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participant and Occurrences) 
FDAAA, EudraCT 
SAC 
3.12. 
All Treated 
AE3 
Summary of Non-Serious GSK3326595-Related Adverse 
Events by Overall Frequency 
Plain Language Summaries (PLS) 
SAC 
3.13. 
All Treated 
AE1 
Summary of Adverse Events Leading to Dose Reductions of 
GSK3326595 by Preferred Term 
ICH E3 
SAC 
3.14. 
All Treated 
AE1 
Summary of Adverse Events Leading to Dose Interruptions / 
Delay of GSK3326595 by Preferred Term 
ICH E3 
SAC 
Serious and Other Significant Adverse Events 
3.15. 
All Treated 
AE5B 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term and Maximum Grade 
ICH E3 
SAC 
3.16. 
All Treated 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
FDAAA, EudraCT 
SAC 
3.17. 
All Treated 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study 
by System Organ Class and Preferred Term 
IDSL 
SAC 
3.18. 
All Treated 
AE20 
Summary of Serious Fatal and Non-Fatal GSK3326595-related 
Adverse Events by Overall Frequency 
Plain Language Summary (PLS) 
SAC 
3.19. 
All Treated 
AE3 
Summary of Serious Adverse Events Related to Study 
Treatment by Preferred Term 
 
P1IFA, SAC 


CONFIDENTIAL 
 
 
208809 
 
79 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.20. 
All Treated 
ESI2A 
Summary of Onset and Duration of First Occurrence of 
Selected Adverse Events 
Anemia, neutropenia, 
thrombocytopenia (platelet count 
decrease and thrombocytopenia), 
fatigue, asthenia, febrile neutropenia 
SAC 
3.21. 
All Treated 
ESI1 
Summary of Event Characteristics of Selected Adverse Events  
Anemia, Thrombocytopenia, Fatigue 
P2ESC, P2IFA, 
SAC 
3.22. 
All Treated 
AE1 
Summary of Adverse Events (Ocular Events) by System Organ 
Class and Preferred Term 
 
SAC 
3.23. 
All Treated 
AE1 
Summary of Serious Adverse Events (Ocular Events) by 
System Organ Class and Preferred Term 
 
SAC 
Deaths 
3.24. 
All Treated 
DD1 
Summary of Deaths 
ICH E3  
Report time to death from last dose (in 
days) as in the mock 
SAC 
Laboratory: Chemistry  
3.25. 
All Treated 
LB1 
Summary of Chemistry Changes from Baseline 
ICH E3 
To include grade increase from 
Baseline Grade Creatinine 
SAC 
3.26. 
All Treated 
LB16 
Summary Worst Case Chemistry Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline 
ICH E3 
Report only worst-case post-baseline. 
Don’t report by-visit summary rows. 
For CTCAE graded tests.  
SAC 
3.27. 
All Treated 
LB15 
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline 
ICH E3 
Report only worst-case post-baseline. 
Don’t report by-visit summary rows. 
For non-graded tests. 
SAC 


CONFIDENTIAL 
 
 
208809 
 
80 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Laboratory: Haematology 
3.28. 
All Treated 
LB1 
Summary of Haematology Changes from Baseline 
ICH E3 
SAC 
3.29. 
All Treated 
LB15 
Summary of Worst Case Haematology Results by Maximum 
Grade Increase Post-Baseline Relative to Baseline 
ICH E3 
Report only worst-case post-baseline. 
Don’t report by-visit summary rows. 
For CTCAE graded tests. 
SAC 
3.30. 
All Treated 
LB16 
Summary of Worst Case Hematology Results Relative to 
Normal Range Post-Baseline Relative to Baseline 
ICH E3 
Report only worst-case post-baseline. 
Don’t report by-visit summary rows. 
For non-graded tests. 
SAC 
Laboratory: Urinalysis 
3.31. 
All Treated 
LB1 
Summary of Urine Concentration Changes from Baseline 
ICH E3 
SAC 
3.32. 
All Treated 
UR1 
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline 
ICH E3 
Define change categories according to 
actual values expected from lab 
dataset 
Report only worst-case post-baseline. 
Don’t report by-visit summary rows. 
SAC 
Laboratory: Hepatobiliary (Liver) 
3.33. 
All Treated 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
IDSL 
SAC 
3.34. 
All Treated 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
IDSL 
SAC 
3.35. 
All Treated 
LIVER11 
Summary of Liver Restart/Re-Challenges 
IDSL 
SAC 
ECG 
3.36. 
All Treated 
EG1 
Summary of ECG Findings  
IDSL 
SAC 


CONFIDENTIAL 
 
 
208809 
 
81 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.37. 
All Treated 
ECG10 
Summary of Maximum QTcF Values Post-Baseline Relative to 
Baseline by Category 
ICHE14 
Report only worst-case post-baseline. 
Don’t report by-visit summary rows. 
SAC 
3.38. 
All Treated 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IDSL 
SAC 
3.39. 
All Treated 
ECG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category 
ICHE14 
Report only worst-case post-baseline. 
Don’t report by-visit summary rows. 
SAC 
Vital Signs 
3.40. 
All Treated 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
SAC 
3.41. 
All Treated 
VS6 
Summary of Worst Case Vital Signs Results by Maximum 
Grade Increase Post-Baseline Relative to Baseline 
ICH E3 
Include blood pressure 
Report only worst-case post-baseline. 
Don’t report by-visit summary rows. 
SAC 
3.42. 
All Treated 
VS3 
Summary of Worst Case Vital Signs Results Relative to Normal 
Range Post-Baseline Relative to Baseline 
ICH E3 Include heart rate and 
temperature 
Report only worst-case post-baseline. 
Don’t report by-visit summary rows. 
SAC 
LVEF 
3.43. 
All Treated 
OLVEF1A 
Summary of Left Ventricular Ejection Fraction Change from 
Baseline 
IDSL 
SAC 
Dose Modifications 
3.44. 
All Treated 
EX1 
Summary of Exposure to Study Treatment 
ICH E3 
Include duration of treatment (months) 
SAC 
3.45. 
All Treated 
ODMOD1 
Summary of Dose Reductions of GSK3326595 
ICH E3 
SAC 


CONFIDENTIAL 
 
 
208809 
 
82 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.46. 
All Treated 
ODMOD2 
Summary of Dose Interruptions of GSK3326595 
ICH E3 
SAC 
Dose Limiting Toxicity (DLT) 
3.47. 
All Treated 
DL1 
Summary of Dose-Limiting Toxicities during the Determinative 
Period 
ICH E3 
SAC 
Performance Status 
3.48. 
All Treated 
PS1A 
Summary of ECOG Performance Status 
ICH E3 
SAC 
Cardiovascular Risk Factors 
3.49. 
All Treated 
FH1 
Summary of Family History of Cardiovascular Risk Factors 
IDSL 
SAC 
Troponin 
3.50. 
All Treated 
LB15 
Summary of Worst-Case Troponin Results Relative to Normal 
Range Post-Baseline Relative to Baseline-Local Lab 
Assessment 
IDSL 
SAC 
3.51. 
All Treated 
LB15 
Summary of Worst-Case Troponin Results Relative to 
Normal Range Post-Baseline Relative to Baseline-Central 
Lab Assessment 
IDSL 
SAC 
Laboratory: Coagulation 
3.52. 
All Treated 
LB1 
Summary of Coagulation Changes from Baseline 
IDSL 
SAC 
3.53. 
All Treated 
LB16 
Summary of Worst-Case Coagulation Results by Maximum 
Grade Increase Post-Baseline Relative to Baseline 
IDSL 
SAC 
3.54. 
All Treated 
LB15 
Summary of Worst-Case Coagulation Results Relative to 
Normal Range Post-Baseline Relative to Baseline 
IDSL 
SAC 


CONFIDENTIAL 
 
208809 
 
83 
 
14.12.8. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Exposure 
3.1.  
All Treated 
OEX12 
Swimmer Plot of Duration of Study Treatment 
IDSL 
P1IFA, SAC 
Laboratory 
3.2.  
All Treated 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT 
IDSL 
SAC 
3.3.  
All Treated 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin 
IDSL 
SAC 
ECG 
3.4.  
All Treated 
EG12 
QTcF Shifts from Baseline to Worst-case Post Baseline   
IDSL 
SAC 


CONFIDENTIAL 
 
 
208809 
 
84 
 
14.12.9. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK 
4.1.  
PK 
PK01 
Summary of GSK3326595 Pharmacokinetic Concentration-
Time Data by Treatment and Study Day 
Use descriptive statistics (n, mean, 
SD, median, min and max) by 
planned relative assessment time; 
concentrations in ng/mL. All 
planned time points. Part 1: A foot 
note to describe ID 600 and 
reference to PK Non-ICH: Listing 1: 
Listing of Pharmacokinetic 
Concentration-Time Data by 
Treatment. 
SAC 
4.2.  
PK 
PK06 
Summary of Derived GSK3326595 Pharmacokinetic 
Parameters by Treatment and Study Day 
PK parameters: Cmax, Tmax, 
Ctrough, AUC0-t, AUC0-tau, 
AUCinf, t½, λz , TI and AR 
determined from the concentration-
time data in ng/ml; descriptive 
summaries: mean, SD, median, 
min, max, geometric mean & SD, 
CV%, and 95%CI of log-
transformed parameters, if 
applicable. Part 1: A foot note to 
describe ID 600 and reference to 
PK Non-ICH: Listing 2 Listing of 
Derived Pharmacokinetic 
Parameters by Treatment. 
SAC 


CONFIDENTIAL 
 
 
208809 
 
85 
 
14.12.10. Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK 
4.1.  
PK 
PK16A 
Individual GSK3326595 Concentration-Time Plots (Linear and 
Semi-Log) by Treatment and Study Day 
IDSL 
ng/mL 
Day 1 and Day 15 only. Part 1: ID 
600 is excluded. 
SAC 
4.2.  
PK 
PK17 
Mean Concentration-Time Plots (Linear and Semi-Log) by 
Treatment and Study Day 
IDSL 
ng/mL 
Day 1 and Day 15 only. Part 1: ID 
600 is excluded. 
SAC 
4.3.  
PK 
PK18 
Median Concentration-Time Plots (Linear and Semi-Log) by 
Treatment and Study Day 
IDSL 
ng/mL 
Day 1 and Day 15 only. Part 1: ID 
600 is excluded. 
SAC 
 
 
 


CONFIDENTIAL 
 
 
208809 
 
86 
 
14.12.11. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
Participant Disposition 
1.  
All Treated 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
SAC 
2.  
All Treated 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
P1DC, SAC 
Protocol Deviations 
3.  
All Treated 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
Report all important PDs 
SAC 
4.  
All Treated 
IE3 
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
SAC 
Populations Analysed 
5.  
Enrolled 
SP3 
Listing of Participants Excluded from All Treated Population 
ICH E3 
Report participants enrolled but not 
treated 
SAC 
Demographic and Baseline Characteristics 
6.  
All Treated 
DM2 
Listing of Demographic Characteristics 
ICH E3 
P1DC, SAC 
7.  
All Treated 
DM9 
Listing of Race 
ICH E3 
SAC 
Exposure and Treatment Compliance 
8.  
All Treated 
EX3 
Listing of Exposure to GSK3326595 
ICH E3 
SAC 
Adverse Events 
9.  
All Treated 
AE8 
Listing of All Adverse Events 
ICH E3 
P1DC, SAC 
10.  
All Treated 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
SAC 
Serious and Other Significant Adverse Events 
11.  
All Treated 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
SAC 


CONFIDENTIAL 
 
 
208809 
 
87 
 
ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
12.  
All Treated 
AE14 
Listing of Reasons for Considering as a Serious Adverse 
Event 
ICH E3 
SAC 
13.  
All Treated 
AE8 
Listing of Adverse Events Leading to Permanent 
Discontinuation of GSK3326595 or Withdrawal from Study 
ICH E3 
To include Permanent 
Discontinuation or Withdrawal in the 
action taken 
P1DC, SAC 
14.  
All Treated 
AE8 
Listing of Adverse Events Leading to Dose Interruptions/Delay 
of GSK3326595 
ICH E3 
SAC 
15.  
All Treated 
AE8 
Listing of Adverse Events Leading to Dose Reductions of 
GSK3326595 
ICH E3 
SAC 
All Laboratory 
16.  
All Treated 
LB5 
Listing of All Laboratory Data for Participants with Any Value of 
Outside Normal Range 
ICH E3 
To include chemistry, hematology,  
SAC 
17.  
All Treated 
UR2 
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance 
ICH E3 
SAC 
 


CONFIDENTIAL 
 
 
208809 
 
88 
 
14.12.12. Non-ICH Listing 
 
Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
Participant Disposition 
18.  
Screened 
ES7 
Listing of Reasons for Screen Failure  
required for submission studies 
only 
SAC 
19.  
All Treated 
TA1 
Listing of Planned and Actual Treatments 
IDSL 
Report only subjects whose actual 
starting dose is different from the 
assigned dose group. 
SAC 
Disease Characteristics 
20.  
All Treated 
DC3 
Listing of Disease Characteristics at Initial Diagnosis 
 
SAC 
21.  
All Treated 
DC4 
Listing of Disease Characteristics at Screening 
 
SAC 
Anti-Cancer Therapy 
22.  
All Treated 
AC6 
Listing of Prior Anti-Cancer Therapy 
List all prior anti-cancer therapy and 
prior stem cell transplant (but not 
radiotherapy or surgery) 
SAC 
23.  
All Treated 
AC6 
Listing of Follow-Up Anti-Cancer Therapy 
 
SAC 
Surgical Procedures 
24.  
All Treated 
PR2 
Listing of Prior Cancer Related Surgical Procedures 
 
SAC 
25.  
All Treated 
PR2 
Listing of On-Study Cancer Related Surgical Procedures 
 
SAC 
26.  
All Treated 
PR2 
Listing of Follow-Up Surgical Procedures 
 
SAC 
Prior and Concomitant Medications / Blood and Blood Supportive Care Products 
27.  
All Treated 
BP4 
Listing of Blood Products 
 
SAC 


CONFIDENTIAL 
 
 
208809 
 
89 
 
Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
28.  
All Treated 
BP5 
Listing of Blood Supportive Care Products 
 
SAC 
Dose Modifications 
29.  
All Treated 
ODMOD10A 
Listing of Dose Reductions of GSK3326595 
 
SAC 
30.  
All Treated 
ODMOD11A 
Listing of Dose Interruptions of GSK3326595 
 
SAC 
Dose-Limiting Toxicities 
31.  
All Treated 
DL3 
Listing of Dose-Limiting Toxicities (DLT) During the 
Determinative Period 
If applicable 
SAC 
Response 
32.  
All Treated 
RE5 
Listing of Best Overall Response (Investigator Assessment 
using International Working Group Criteria) 
Include Response assessment and 
Best Overall Response 
SAC 
Time to Event 
33.  
All Treated 
TTE9 
Listing of Progression Free Survival Based on Investigator 
Assessment (International Working Group Criteria) 
 
SAC 
34.  
All Treated 
TTE9 
Listing of Overall Survival 
 
SAC 
Hepatobiliary (Liver) 
35.  
All Treated 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting  
 
SAC 
36.  
All Treated 
LIVER15 
Liver Stopping Event Profile 
 
SAC 
37.  
All Treated 
MH2 
Listing of Medical Conditions for Participants with Liver 
Stopping Events 
 
SAC 
All Laboratory 
38.  
All Treated 
LB5 
Listing of All Laboratory Data 
 
SAC 
40.  
All Treated 
OLB7 
Listing of Central Troponin Data 
 
SAC 


CONFIDENTIAL 
 
 
208809 
 
90 
 
Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
41.  
All Treated 
OLB7 
Listing of Local Troponin Data 
 
SAC 
ECG 
42.  
All Treated 
EG3 
Listing of All ECG Values 
 
SAC 
43.  
All Treated 
EG5 
Listing of All ECG Findings 
 
SAC 
Other Safety 
44.  
All Treated 
PREG1 
Listing of Subjects or Partners of Subjects Who Became 
Pregnant During the Study  
 
SAC 
45.  
All Treated 
DD3 
Subject Profile for Death 
ICH E3 
SAC 
46.  
All Treated 
PS5A 
Listing of ECOG Performance Status 
 
SAC 
PK 
47.  
PK 
PK07 
Listing of Pharmacokinetic Concentration-Time Data by 
Treatment   
IDSL 
Part 1: to add a dose column. 
SAC 
48.  
PK 
PK13 
Listing of Derived Pharmacokinetic Parameters by Treatment   
IDSL   
Part 1: to add a dose column. 
SAC 
Concomitant medications 
49.  
All Treated 
CM10 
Listing of Concomitant Medications 
 
SAC 
Subject Disposition 
50.  
Enrolled 
 
Listing of Number of Participant by Country and Site ID 
 
SAC