Clinical trial NCT02783300
Conditions: Neoplasms
Keywords: GSK3326595 Solid tumor Non-Hodgkin's lymphoma (NHL) Urinary tract cancer Dose escalation Adenoid cystic carcinoma (ACC) Non small-cell lung cancer (NSCLC) Squamous cell carcinoma of the head and neck (HNSCC) Melanoma
Sponsor: GlaxoSmithKline
Start date: 2016-08-30; Completion date: 2023-08-30
Enrollment: 297 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This first time in human (FTIH) open-label, dose escalation study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of GSK3326595 in participants with advanced or recurrent solid tumors, as well as clinical activity in participants with a subset of solid tumors and non-Hodgkin's lymphoma (NHL).

Detailed description:

Arms: arm 1: Participants will receive escalating doses of GSK3326595 until the maximum tolerated dose level is reached. The recommended phase 2 dose (RP2D) will be determined. Participants will be dosed in a fed (high-fat, high-calorie meal) and fasted state to determine the effect of food on bioavailability of GSK3326595, and will be dosed with tablet and capsule to compare two formulations of GSK3326595 (capsule versus tablet). arm 2: Participants with triple-negative breast cancer (TNBC), metastatic transitional cell carcinoma of the urinary system (mTCC), Grade IV anaplastic astrocytoma (glioblastoma multiforme \[GBM\]), non-Hodgkin's lymphoma (NHL), adenoid cystic carcinoma (ACC), hormone receptor-positive adenocarcinoma of the breast (ER+BC), human papillomavirus (HPV)-positive solid tumors of any histology, and p53-wild type non-small cell lung cancer (NSCLC) will be administered GSK3326595 at the recommended phase 2 dose (RP2D) as determined in Part 1. arm 3: Participants with selected solid tumors will be administered GSK3326595 in combination with pembrolizumab as part of this dose determination study.
Interventions: intervention 1: GSK3326595 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: GSK3326595 will be administered with and without food, in tablet and capsule formulation. intervention 2: Pembrolizumab will be administered.

Protocol documents:
Prot_000.pdf: 
Protocol Amendment 8 
Study ID:  204653
Official 
Title 
of 
Study: An open-label, dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK3326595 in 
participants with solid tumors and non-Hodgkin’s lymphoma
NCT ID: NCT02783300
Date of Document: 20 April 2022


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TITLE PAGE 
Division: Worldwide Development 
Information Type: Protocol Amendment 
Title: 
A phase I, open-label, dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamics and clinical 
activity of GSK3326595 in subjects with solid tumors and non 
Hodgkin’s lymphoma 
Compound Number: GSK3326595 
Development Phase: 
I 
Effective Date: 
20 Apr 2022 
Protocol Amendment Number:  08 
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application. 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
Sponsor Signatory 
Timothy Crossman, BM BS MRes   
Group Sr. Medical Director, Clinical Development Lead Oncology R&D 
Approval Date 20 Apr 2022 
 
 
Copyright 2022 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited 


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Regulatory Agency Identifying Number(s):  
Compound Number 
IND Number 
EudraCT Number 
GSK3326595 
IND146168 
2016-000278-39 


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REVISION CHRONOLOGY 
GlaxoSmithKline 
Document Number 
Date 
Version 
2015N237263_00 
2015-NOV-30 
Original 
2015N237263_01 
2015-DEC-16 
Republished 
The original protocol dated 2015-Nov-30 was not submitted outside of GSK and was 
republished to incorporate clarifications in the Time and Events Table prior to 
submission.  The clarifications were made in the timing and acquisition of PD/Metabolite 
sampling in the Time and Event Tables. The protocol was republished as the original 
protocol based on these clarifications but has a different document number to reflect this 
change. 
2015N237263_02 
2016-MAR-17 
Amendment No. 1 
Changes have been made to the definition of dose-limiting toxicities and toxicity 
attribution during dose escalation, in response to FDA comments.  In addition, 
clarification has been provided for the timing and modalities of baseline and disease 
response scans, collection of echocardiograms, and the addition of exploratory objectives 
and endpoints to the PK/PD cohort. 
2015N237263_03 
2017-JUN-16 
Amendment No. 2 
Changes have been made to the highest permitted dose and the investigational product 
formulation in light of emerging pharmacokinetic data demonstrating exposures that are 
approximately 2/3 lower than preclinical modeling predicted.  Changes have been made 
to the endpoints for the glioblastoma multiforme cohort after discussion with area 
experts, substituting 6-month progression free survival as a more meaningful metric than 
overall response rate in this population.  This change prompted additional changes to the 
statistical modeling and total study size.  In addition, clarification has been provided for 
inclusion/exclusion criteria, dose-limiting toxicities, objectives/endpoints, and time & 
events tables. 
2015N237263_04 
2018-SEP-11 
Amendment No. 3 
Changes have been made to include 3 additional cohorts (adenoid cystic carcinoma, 
human papillomavirus positive solid tumors and hormone receptor-positive 
adenocarcinoma of the breast) due to the emergence of new pre-clinical and clinical data. 
Changes have been made to the response criteria for non-Hodgkin’s lymphoma (NHL), 
based on the publishing of new criteria. Details of a new tablet formulation for the 
compound GSK3326595 has been added. A food effect cohort has been added to evaluate 
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GSK3326595. Changes have been made to add in the collection of Patient Reported 
Outcomes to ascertain the impact of cancer and its treatment with GSK3326595 on 
patients’ health related quality of life. In addition, clarification has been provided for 
inclusion/exclusion criteria, collection of unscheduled biological samples, and correction 
of typographical errors. 
2015N237263_05 
2019-OCT-23 
Amendment No. 4 
The following changes have been made.  
• Addition of a new cohort in Part 2 (dose expansion) to test GSK3326595 in non-small 
cell lung cancer.  
• Addition of a new cohort in Part 2 to test a new tablet formulation of GSK3326595 in 
adenoid cystic carcinoma.   
• Addition of Part 3 to test the combination of GSK3326595 with a PD-1 inhibitor in 
solid tumors.   
• Changes to the eligibility criteria regarding renal function and asymptomatic brain 
metastases.   
• Expansion of the food effect cohort to include a relative bioavailability comparison of 
capsules to the new tablet formulation.   
• Changing the starting dose for all new subjects enrolled, including new cohorts to 300 
mg QD. 
• Removal of the 25 mg capsules, as they will no longer be available.  
2015N237263_06 
2020-APR-04 
Amendment No. 5 
The following changes have been made: 
• Duration of study updated to 6 years. 
• Cardiac monitoring reduced: LVEF and valvular toxicity stopping criteria removed; 
echocardiogram and troponin collection removed; cardiac risk and mitigation strategy 
updated; inclusion/exclusion criteria updated, and withdrawal criteria updated. 
• Addition of bone and teeth non-clinical findings and risk mitigation strategy. 
Addition of DEXA scans for bone density assessment and serum sampling to check 
biomarkers of bone metabolism and turnover. 
• Revised information for Table 4, Pre-clinical and Clinical Risks and Mitigation 
Strategies, based on review of safety data as of the IB cut-off date (04 February 
2020). 
• Part 1 FE/rBA cohort: sample size reduced to 12 patients (6 per sequence) and overall 
subject numbers updated. Wording added to allow subjects to move from capsules to 
tablets, depending on the results of the rBA study. 
• Part 2: 
o ACC tablet cohort: eligibility criteria changed to systemic therapy-naïve 


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subjects only and subjects who have progressed per RECIST 1.1 in the 
previous 13 months. Overall survival moved from exploratory to secondary 
endpoint. 
o NHL cohort: eligibility criteria changed to indolent subtypes of NHL; subjects 
75 years of age and subjects who have received 4 prior lines of systemic 
therapy. 
o NSCLC cohort: clarification that subjects whose tumors harbor actionable 
mutations (e.g., EGFR mutations or ALK rearrangements) must have received 
prior therapy with targeted agents prior to enrollment 
• Part 3:  
o Sites in France are ineligible to participate in Part 3.  
o Pembrolizumab PK and immunogenicity sample collection schedule reduced 
and clarified. 
o Clarification of inclusion criteria: subjects with SD as best response to prior 
PD(L)-1 therapy must have documented iRECIST progression on PD(L)-1 
therapy to be eligible for this study. 
o Additional adverse event management guidance added to reflect changes in 
October 2019 pembrolizumab Summary of Product Characteristics. 
• Clarification has been provided for inclusion/exclusion criteria and Time & Events 
tables; new IND number added, and typographical errors corrected. 
2015N237263_07 
2020-OCT-20 
Amendment No. 6 
The following changes have been made: 
• If the GSK3326595 tablet bioavailability is comparable to that of the GSK3326595 
capsules, all new and ongoing subjects may be switched from capsules to tablets for 
the remainder of the study, once they have been notified by the Sponsor. 
• Addition of inhibitors of MATE2-K, OAT3 and OCT2 in prohibited medications in 
Section 7.1.2.1, in alignment with IB version 4.0 data cut off 4th February 2020. 
• Inclusion of Appendix 12 outlining clinical study delivery under circumstances of 
pandemic caused by COVID19 in future. 
• Inclusion of reference to Appendix 12 and COVID 19 in Section 4.8.1 regarding 
clinical risks and mitigations strategies. 
• Addition of language to Section 1 (Type and Number of Subjects), 4.2.1 and 4.5 to 
allow for approximately 12 but no more than 24 patients for the food effect cohort 
and relative bioavailability sub-study. 
•  The following changes have been made to Table 4, Section 4.8.1: 
o Inclusion of statement on conclusions from GLP genotoxicity study and 
embryo fetal development risks  
o Removal of Cardiac Effects risks 


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o Inclusion of statement for the preclinical data for hepatic event risks  
o Addition of statement to the preclinical data for damage to exocrine tissue 
• Section 4.8.2- added additional data for ACC and HPV. 
• Section 5.2 clarification circumstances under which HIV and HepB patients may be 
eligible, as per FDA Guidance 
• Section 5.4. Removal of text as confirmation of disease progression is not required 
for parts 1 and 2 based on RECIST. Part 3 uses iRECIST which requires confirmation 
of progression 
• Section 6.4. Added language to refer reader for further guidance around IP storage 
and temperature excursions 
• In Section 8.4.1 Locally collected ECG may be read centrally 
• Correction of Pregnancy information collection from Investigator to GSK within 24 
hours (Appendix 10 and Section 8.4.4) 
• Inclusion of collection of TSH and free T3 and free T4 for all patients (Section 8.4.2 
and SoA) 
• In Section 8.4.3 Locally collected DEXA Scans may be read centrally 
• Correction of typographical errors 
Part 2:  
• Inclusion of requirements for all NHL subjects in Part 2 to have local p53 mutational 
analysis done and results available prior to dosing in the trial unless the subject’s 
tumor has previously been demonstrated to harbor a p53 mutation. If p53 status was 
not determined, an archival sample or a fresh biopsy must be provided (Section 
8.2.1). 
 
• In case one NHL cohort reaches futility at any Interim Analysis, further enrolment 
into the other NHL cohort will require central confirmation (Section 8.2.1).  
 
Part 3:  
• Inclusion of collection of local and central PD-L1 test results (Section 8.7.2). 
• Clarification of Pembrolizumab contraceptive requirements for females of 
reproductive potential (Section 4.9.1). 
• Inclusion of cervical cancer patients as additional population for enrolment into the 
Dose Escalation cohort and relevant changes in the inclusion criteria (Section 5.1).  
• Inclusion of language to allow for over-recruitment of 1 patient in Part 3 along with 
updates to the safety stopping rules for dose escalation decisions within Part 3 
(Section 4.4.4). Operating characteristics for Part 3 in the event of over-recruitment 
were added in Section 11.10.4.7. 


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• Addition of requirement to replace any subject who fails to receive 80% of planned 
doses in Part 3 due to reasons other than toxicity (Section 4.4.4). 
• Administrative change with regards to change in name of Programme Physician lead 
name. 
TMF-11799334 
17-FEB-21 
Amendment No. 7 
This protocol amendment also serves to include additional safety assessments, reduce the 
total blood volume drawn per subject and to update the HIV/HCV, HBV exclusion 
criteria.  As such, ophthalmic evaluations, Folate/B12 vitamin testing and clarifications 
for thyroid function testing have been added and the updated SoAs are applicable to all 
ongoing subjects. 
The following changes have been made (in addition to the correction of minor 
typographical and formatting errors): 
Study Population 
• An error has been corrected in Exclusion Criterion 9 to specify the exclusion of 
subjects with a CD4 count 350 cells/uL rather than >300 cells/uL. 
• Exclusion Criteria has been updated to specify that subjects with HBV infection may 
participate in the study provided they are on a suppressive antiviral therapy prior to 
initiation of cancer therapy. 
• An exclusion criterion has been added to exclude patients with a history of optic 
nerve neuropathy or neuritis. 
Part 1: 
• There have been two observations of optic neuropathy possibly related to folate 
deficiency in subjects treated with study drug over a prolonged period (>12 months 
exposure) in this study.  Although no causal relationship has been established, in 
order to ensure appropriate ongoing monitoring of subjects, the following items have 
been added to safety testing and are applicable to all ongoing subjects:  
o a requirement for investigators to ask patients about vision symptoms at each 
routine visit and document responses  
o ophthalmology assessments 
o monitoring of folate/B12 levels 
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• No further survival follow-up will be conducted in Part 1 except in subjects with a 
diagnosis of ACC. 
Part 2: 
• 
• A review of vision symptoms, ophthalmology assessments and folate/B12 levels have 
been added to safety testing and are applicable to all ongoing subjects. 
• A discrepancy in the instructions for thyroid function testing has been corrected and 
text made consistent throughout the protocol.  Thyroid function testing is now 
consistently specified as required at screening, Weeks 4 or 6, every 8 weeks starting 
at Week 8 and at EOT. 
• The collection of serum samples for the analysis of circulating biomarkers has been 
removed from the SoA and no further sample should be collected. 
• Instructions for the collection of plasma samples for the analysis of circulating 
biomarkers has been amended in the SoA and no samples should be collected after a 
subject’s Week 24 visit. 
• Collection of plasma samples for circulating biomarkers to be collected as per the 
SoA until Week 24 only. 
• Survival follow-up has been amended to only include subjects in an ACC cohort. 
Part 3: 
• 
• A review of vision symptoms, ophthalmology assessments and folate/B12 levels have 
been added to safety testing and are applicable to all ongoing subjects. 
• The collection of serum samples for the analysis of circulating biomarkers has been 
removed from the SoA and no further sample should be collected. 
• Instructions for the collection of plasma samples for the analysis of circulating 
biomarkers has been amended in the SoA and no samples should be collected after a 
subject’s Week 24 visit. 
• No further survival follow-up will be conducted in Part 3. 
In addition: 
• The list of authors has been removed from the protocol cover page to align with 
current guidance on the use of Personally Identifiable Information (PII). 
• The Sponsor Signature Page has been updated to reflect the current GSK template. 
• The Investigator Signature Page has been removed from the protocol and will be 
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provided as a stand-alone document to the Investigator for signature alongside the 
final protocol. 
• The duration of study has been updated to 8 years. 
• The statement concerning the approximate total blood volume to be taken over the 
course of the study has been removed, as this is information is included in the ICF. 
• The list of concomitant medications to be used with caution in conjunction with 
GSK3326595 have been updated with the most recent nonclinical information. 
• The instructions for the assessment of intensity in Section 14.9.5 Evaluating AEs and 
SAEs have been corrected to provide the NCI-CTCAE terminology. 
TMF-13861543 
09-AUG-2021 
Amendment No. 7/France 
France specific requirements are listed in Appendix 13 inclusive of additional cardiac 
monitoring implemented at the request of Health Authority in France for the remaining 
ongoing patient on treatment, it was approved on 08-Oct-2021.  
TMF-14123404 
20-APR-2022 
Amendment No. 8 
This protocol has been amended to provide updates related to stopping recruitment into 
the Part 2 ACC tablet cohort, and therefore stopping any further recruitment in the study, 
updating the end of study definition with final analysis plan (Section 5.5), and clarifying 
study treatment access for subjects continuing to derive clinical benefit from study drug 
as per Investigator judgement post final analysis, as described in Section 4.1. 
A description of all changes is provided below: 
• Additional content to the overall study has been added in the Section 4.1, Section 
4.3.3 and synopsis, which includes the stop in recruitment into the ACC tablet cohort 
in Part 2. 
• Amendment of primary endpoint for ACC tablet cohort; “ACC tablet formulation will 
score ORR by independent central review (ICR)” for Part 2 will be replaced by 
Investigator assessed RECIST review 
• Change in secondary endpoint for Duration of Response read out of the ACC tablet 
cohort from Independent central review to Investigator assessment 
• Moved the following Secondary endpoints to exploratory for Part 2 
o 
o 
• Revised information for Section 4.8.1 (Risk Assessment) and Section 4.8.3 (Overall 
Benefit: Risk Conclusion), based on review of safety data as of the IB cut-off date (04 
February 2022). 
• Additional content added in below Sections to implement Protocol Amendment 8. 
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o Section 5.4.1 Discontinuation of Study Treatment 
o Section 5.4.3 Withdrawal from the study 
o Section 5.4.4 End of Survival Follow-up 
o Section 6 Study Treatment 
o Section 8.3 Safety 
o Section 8.7 Efficacy; Post Protocol Amendment 8 implementation, no efficacy 
assessments will be performed as part of the study. 
o Section 10 Data Management 
o Section 11.9.7 Final Analysis 
o Section 14.9.4 Recording of AEs and SAEs 
o Section 14.9.6 Reporting of SAEs to GSK 
o Section 14.10 Collection of Pregnancy Information 
• In section 5.5 (End of study definition), inclusion of end of study definition, a 
predefined data cut off, following which database will be closed for new data. 
• In section 6.7 (Treatment after the End of the Study) inclusion of clarification that 
patients who are receiving GSK3326595 may continue to receive GSK3326595, if 
they are continuing to derive clinical benefit as assessed by the Investigator, or can 
choose to discontinue the study drug. 
• Additional content to the time period and frequency for collecting AEs, SAEs, AEs 
leading to treatment discontinuation and AESIs have been added in Section 8 (Study 
Assessments and Procedures) and Section 9.2 (Time period and Frequency for 
collecting AE and SAE Information). 
• New Section 9.1.2 (Adverse Events of Special Interest) added to clarify ocular events 
and bone-related events. 
• Additional details added in Section 11.9.6 (Interim Futility Analysis) to clarify on 
interim analyses. 
• Added table on Algorithm for determining combined imaging response based on 
Lugano criteria in Section 14.4.3 


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TABLE OF CONTENTS 
PAGE 
REVISION CHRONOLOGY ............................................................................................ 3 
TABLE OF CONTENTS ................................................................................................ 11 
1. 
PROTOCOL SYNOPSIS FOR STUDY 204653 ...................................................... 17 
2. 
INTRODUCTION .................................................................................................... 26 
2.1. 
Study Rationale .......................................................................................... 26 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 31 
4. 
STUDY DESIGN .................................................................................................... 35 
4.1. 
Overall Design ............................................................................................ 35 
4.2. 
Part 1: Dose Escalation .............................................................................. 37 
4.2.1. 
Type and Number of Subjects (Part 1) ......................................... 37 
4.2.2. 
Initial Dose Exploration (accelerated titration) .............................. 38 
4.2.3. 
Determining the MTD ................................................................... 38 
4.2.3.1. 
Reverting to Accelerated Dose Titration ..................... 39 
4.2.4. 
Dose Escalation Decisions and Determination of MTD ................ 40 
4.2.4.1. 
Dose-Limiting Toxicity ................................................ 40 
4.2.4.2. 
Non-Limiting Toxicities ............................................... 41 
4.2.4.3. 
Maximum Dose Increment .......................................... 41 
4.2.4.4. 
Planned Dose Levels .................................................. 41 
4.2.4.5. 
Dose Escalation Decisions ......................................... 41 
4.2.4.6. 
Alternative Dosing Schedules ..................................... 42 
4.2.4.7. 
Intra-subject Dose Escalation ..................................... 42 
4.2.4.8. 
Completion of Dose Escalation and 
Determination of MTD/RP2D ...................................... 43 
4.2.5. 
PK/PD, Metabolite, and Biomarker Expansion Cohort(s) ............. 43 
4.2.6. 
Food Effect and Relative Bioavailability Sub-Study ...................... 44 
4.3. 
Part 2: Disease-Specific Expansion Cohort(s) ............................................ 45 
4.3.1. 
Type and Number of Subjects (Part 2) ......................................... 46 
4.3.2. 
R2PD Dose Selection .................................................................. 47 
4.3.3. 
Statistical Design ......................................................................... 48 
4.3.3.1. 
GBM Cohort ............................................................... 48 
4.3.3.2. 
mTCC, TNBC, and NHL Cohorts ................................ 48 
4.3.3.3. 
ACC Cohorts (Capsule and Tablet 
Formulation) ............................................................... 49 
4.3.3.4. 
Hormone Receptor-Positive Breast Cancer 
Cohort ........................................................................ 49 
4.3.3.5. 
HPV-Positive Solid Tumor Cohort ............................... 50 
4.3.3.6. 
NSCLC Cohort ........................................................... 50 
4.4. 
Part 3: GSK3326595 + Pembrolizumab Combination Study [Active 
in all regions, except France] ...................................................................... 50 
4.4.1. 
Type and Number of Subjects (Part 3) ......................................... 51 
4.4.2. 
Treatment Arms and Duration ...................................................... 51 
4.4.3. 
Dose Selection ............................................................................ 51 
4.4.4. 
Cohort Design .............................................................................. 51 


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4.4.4.1. 
Safety Stopping Criteria .............................................. 53 
4.4.5. 
Statistical Design ......................................................................... 54 
4.5. 
Type and Number of Subjects (Overall) ...................................................... 54 
4.6. 
Design Justification ..................................................................................... 55 
4.6.1. 
Part 1 ........................................................................................... 55 
4.6.2. 
Additional Pharmacodynamic, Metabolic & Biomarker 
Profiling ....................................................................................... 55 
4.6.3. 
Food Effect and Relative Bioavailability Profiling.......................... 55 
4.6.4. 
Part 2 ........................................................................................... 56 
4.6.5. 
Part 3 [Active in all regions, except France] ................................. 56 
5. 
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA ............. 73 
5.1. 
Inclusion Criteria ......................................................................................... 73 
5.2. 
Exclusion Criteria ........................................................................................ 77 
5.3. 
Screening/Baseline/Run-in Failures ............................................................ 80 
5.4. 
Withdrawal/Stopping Criteria....................................................................... 80 
5.4.1. 
Discontinuation of Study Treatment ............................................. 80 
5.4.2. 
Lost to Follow-up ......................................................................... 81 
5.4.3. 
Withdrawal from the study ........................................................... 82 
5.4.4. 
End of Survival Follow-up ............................................................ 82 
5.4.5. 
Liver Chemistry Stopping Criteria ................................................ 83 
5.4.5.1. 
Study Treatment Restart or Rechallenge .................... 84 
5.4.6. 
QTc Stopping Criteria .................................................................. 84 
5.4.7. 
Other Stopping Criteria ................................................................ 85 
5.5. 
Subject and Study Completion .................................................................... 85 
6. 
STUDY TREATMENT ............................................................................................ 86 
6.1. 
GSK3326595 and Pembrolizumab .............................................................. 86 
6.2. 
Treatment Assignment ................................................................................ 87 
6.3. 
Packaging and Labeling .............................................................................. 87 
6.4. 
Preparation/Handling/Storage/Accountability .............................................. 88 
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6.5. 
Compliance with Study Treatment Administration ....................................... 88 
6.6. 
Treatment of Study Treatment Overdose .................................................... 89 
6.7. 
Treatment after the End of the Study .......................................................... 89 
7. 
MEDICATION, LIFESTYLE, AND DIETARY RESTRICTIONS ............................... 90 
7.1. 
Concomitant Medications and Non-Drug Therapies .................................... 90 
7.1.1. 
Permitted Medications and Non-Drug Therapies .......................... 90 
7.1.2. 
Prohibited Medications and Non-Drug Therapies ......................... 90 
7.1.2.1. 
Prohibited Medications ............................................... 90 
7.1.2.2. 
Prohibited Non-Drug Therapies .................................. 91 
7.1.3. 
Cautionary Medications ............................................................... 92 
7.2. 
Dietary Restrictions ..................................................................................... 93 
7.3. 
Lifestyle Restrictions ................................................................................... 93 
7.3.1. 
Female Subjects .......................................................................... 93 
7.3.2. 
Male Subjects .............................................................................. 94 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 95 
8.1. 
Time and Events Tables ............................................................................. 97 
8.2. 
Screening and Critical Baseline Assessments .......................................... 113 
8.2.1. 
Critical Baseline Assessments ................................................... 113 
8.2.2. 
Visit Windows ............................................................................ 115 
8.3. 
Safety ....................................................................................................... 116 
8.3.1. 
Physical Exams ......................................................................... 117 
8.3.2. 
Performance Status ................................................................... 117 
8.3.3. 
Vital Signs .................................................................................. 117 
8.3.4. 
Electrocardiogram (ECG) ........................................................... 117 
8.3.5. 
Clinical Safety Laboratory Assessments .................................... 118 
8.3.6. 
Bone Mineral Density ................................................................. 120 
8.3.7. 
Ophthalmic Assessment ............................................................ 121 
8.3.8. 
Pregnancy ................................................................................. 121 
8.4. 
Pharmacokinetics ..................................................................................... 122 
8.4.1. 
Blood Sample Collection ............................................................ 122 
8.4.2. 
Urine Sample Collection ............................................................ 122 
8.5. 
Metabolite Analysis ................................................................................... 122 
8.5.1. 
Blood Sample Collection ............................................................ 122 
8.5.2. 
Urine Sample Collection ............................................................ 123 
8.5.3. 
Sample Analysis ........................................................................ 123 
8.6. 
Pharmacodynamics/Biomarkers ............................................................... 123 
8.6.1. 
Blood Sample Collection ............................................................ 123 
8.6.2. 
Tumor Biopsy Collection ............................................................ 124 
8.6.3. 
Assessments for 18FDG-PET/CT................................................ 124 
8.7. 
Efficacy ..................................................................................................... 124 
8.7.1. 
Subjects with Solid Tumors (Part 1 and Part 2) .......................... 124 
8.7.2. 
Subjects with GBM .................................................................... 125 
8.7.3. 
Subjects with Non-Hodgkin’s Lymphoma ................................... 125 
8.7.4. 
Subjects in Part 3 ....................................................................... 125 
8.8. 
Pharmacogenetic Analysis ........................................................................ 126 
8.9. 
Immunogenicity Analysis (Part 3) .............................................................. 126 
8.10. 
Translational and Exploratory Research ................................................... 127 
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8.10.4. 
Circulating cell free DNA (cfDNA) Analysis ................................ 128 
8.11. 
Patient Reported Outcomes ...................................................................... 129 
9. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: DATA 
COLLECTION, REPORTING, AND FOLLOW-UP ................................................ 131 
9.1. 
Definition of AE/SAE ................................................................................. 131 
9.1.1. 
Cardiovascular/Death events ..................................................... 131 
9.1.2. 
Adverse Events of Special Interest ............................................ 132 
9.1.3. 
Other Sentinel Events ................................................................ 132 
9.2. 
Time period and Frequency for collecting AE and SAE Information .......... 132 
9.2.1. 
Method of Detecting Unsolicited AEs and SAEs ........................ 133 
9.2.2. 
Method of Detecting Solicited AEs and SAEs ............................ 133 
9.2.3. 
Follow-up of AEs and SAEs ....................................................... 133 
9.2.4. 
Regulatory Reporting Requirements for SAEs ........................... 133 
10. DATA MANAGEMENT ......................................................................................... 134 
11. STATISTICAL CONSIDERATIONS AND DATA ANALYSES ............................... 135 
11.1. 
Hypotheses ............................................................................................... 135 
11.2. 
mTPI Method ............................................................................................ 135 
11.3. 
Bayesian Predictive Adaptive Design for GBM Cohort .............................. 136 
11.4. 
Bayesian Hierarchical Modelling ............................................................... 137 
11.5. 
Simon’s Two Stage Design for ACC Cohorts ............................................ 138 
11.6. 
Bayesian Predictive Adaptive Design for ER+BC Cohort .......................... 138 
11.7. 
Bayesian Predictive Adaptive Design for HPV+ Cohort ............................. 140 
11.8. 
Statistical Design for NSCLC cohort ......................................................... 141 
11.9. 
Sample Size Considerations ..................................................................... 141 
11.9.1. 
Sample Size Assumptions ......................................................... 141 
11.9.2. 
Sample Size Sensitivity .............................................................. 142 
11.9.3. 
Sample Size Re-estimation or Adjustment ................................. 142 
11.9.4. 
Data Analysis Considerations .................................................... 142 
11.9.5. 
Analysis Populations .................................................................. 143 
11.9.6. 
Interim Futility Analysis .............................................................. 143 
11.9.7. 
Final Analysis ............................................................................ 144 
11.10. Key Elements of Analysis Plan ................................................................. 144 
11.10.1. Primary Analyses ....................................................................... 145 
11.10.2. Secondary Analyses .................................................................. 145 
11.10.2.1. Safety Analyses ........................................................ 145 
11.10.2.1.1. Extent of Exposure ............................... 145 
11.10.2.1.2. Adverse Events .................................... 145 
11.10.2.1.3. Clinical Laboratory Evaluations ............. 146 
11.10.2.2. Pharmacokinetic Analyses ........................................ 146 
11.10.2.2.1. Pharmacokinetic Parameters ................ 146 
11.10.2.2.2. Statistical analysis of 
pharmacokinetic parameters ................. 147 
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11.10.2.2.3. Food Effect and Relative 
Bioavailability Sub-Study ...................... 147 
11.10.2.3. Efficacy Analysis ...................................................... 148 
11.10.3. Other Analyses .......................................................................... 149 
11.10.3.1. Translational Research Analysis ............................... 149 
11.10.3.2. Pharmacokinetic/Pharmacodynamic Analyses ......... 149 
11.10.3.3. Pharmacodynamic/Biomarker Analysis..................... 149 
11.10.4. Simulations and Design Operating Characteristics .................... 150 
11.10.4.1. Simulation Description .............................................. 150 
11.10.4.2. Software Details ....................................................... 150 
11.10.4.3. Trial Sample Size and Simulation Scenarios ............ 150 
11.10.4.4. Operation Characteristics ......................................... 151 
11.10.4.5. Stopping Early .......................................................... 152 
11.10.4.6. Mean Proportion of Correct Decisions ...................... 152 
11.10.4.7. Operating characteristics of the safety stopping 
rule in Part 3 (GSK3326595 in combination 
with pembrolizumab) ................................................ 152 
12. STUDY GOVERNANCE CONSIDERATIONS ...................................................... 155 
12.1. 
Posting of Information on Publicly Available Clinical Trial Registers .......... 155 
12.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ...................................................................................... 155 
12.3. 
Quality Control (Study Monitoring) ............................................................ 155 
12.4. 
Quality Assurance ..................................................................................... 156 
12.5. 
Study and Site Closure ............................................................................. 156 
12.6. 
Records Retention .................................................................................... 157 
12.7. 
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ............... 157 
13. REFERENCES ..................................................................................................... 159 
14. APPENDICES ...................................................................................................... 165 
14.1. 
Appendix 1: Abbreviations and Trademarks .............................................. 165 
14.2. 
Appendix 2: Guidelines for Management of Toxicity ................................. 171 
14.2.1. 
Management of Selected Toxicities for GSK3326595 ................ 171 
14.2.2. 
Management of Immune-Related Events, Part 3 
pembrolizumab combination ...................................................... 176 
14.2.3. 
Dose Modification and Toxicity Management of Infusion-
Reactions Related to Immunotherapy Treatment, Part 3 ............ 182 
14.3. 
Appendix 3: ECOG Performance Status ................................................... 186 
14.4. 
Appendix 4: Guidelines for Assessment of Disease, Disease 
Progression, and Response Criteria ......................................................... 187 
14.4.1. 
Response Criteria for Solid Tumors (RECIST 1.1 
[Eisenhauer, 2009]) ................................................................... 187 
14.4.1.1. Assessment Guidelines ............................................ 187 
14.4.1.2. Guidelines for Evaluation of Disease ........................ 188 
14.4.1.2.1. Measurable and Non-measurable 
Definitions ............................................. 188 
14.4.1.3. Baseline Documentation of Target and Non-
Target Lesions .......................................................... 188 
14.4.1.4. Response Criteria ..................................................... 189 
14.4.1.4.1. Evaluation of target lesions ................... 189 


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14.4.1.4.2. Evaluation of non-target lesions ............ 190 
14.4.1.4.3. New lesions .......................................... 191 
14.4.1.4.4. Evaluation of overall response .............. 191 
14.4.1.4.5. Evaluation of best overall 
response ............................................... 192 
14.4.1.4.6. Confirmation Criteria ............................. 192 
14.4.2. 
Response Criteria for GBM ........................................................ 192 
14.4.3. 
Evaluation, Staging and Response Assessments for Non-
Hodgkin’s Lymphoma: The Lugano Classification 
(according to Cheson, 2014) ...................................................... 195 
14.4.4. 
iRECIST Guidelines ................................................................... 201 
14.5. 
Appendix 5: Estimated Glomerular Filtration Rate ..................................... 208 
14.6. 
Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments ............................................................................................ 209 
14.7. 
Appendix 7: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines ................................................................................................. 213 
14.8. 
Appendix 8: Genetic Research ................................................................. 216 
14.9. 
Appendix 9: Definition of and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting of Adverse Events ............................................ 219 
14.9.1. 
Definition of Adverse Events ...................................................... 219 
14.9.2. 
Definition of Serious Adverse Events ......................................... 220 
14.9.3. 
Definition of Cardiovascular Events ........................................... 221 
14.9.4. 
Recording of AEs and SAEs ...................................................... 222 
14.9.5. 
Evaluating AEs and SAEs .......................................................... 222 
14.9.6. 
Reporting of SAEs to GSK ......................................................... 224 
14.10. Appendix 10: Collection of Pregnancy Information .................................... 225 
14.11. Appendix 11: Details of Bayesian Hierarchical Model ............................... 226 
14.12. Appendix 12:  COVID-19 APPENDIX: RECOMMENDED 
MEASURES ............................................................................................. 229 
14.13. Appendix 13: Country Specific Amendment (France) ................................ 233 
 
 


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1. 
PROTOCOL SYNOPSIS FOR STUDY 204653 
Rationale 
Protein arginine methyltransferases (PRMTs) are a subset of enzymes that methylate 
arginine residues in various cellular proteins including splicing factors, transcription 
factors, and histone tails.  One of these PRMTs, PRMT5, is aberrantly upregulated in 
malignant cells compared to wild type, and overexpression of PRMT5 in vitro is 
sufficient for fibroblast transformation.  Clinically, upregulation of PRMT5 confers poor 
prognosis in a number of tumor types including breast cancer and glioma.  In preclinical 
models, PRMT5 inhibition has been associated with potential benefit in multiple human 
malignancies. The study drug, GSK3326595, is an inhibitor of PRMT5 that potently 
inhibits tumor growth in vitro and in vivo in animal models.  This first time in human 
(FTIH), open-label, dose escalation study will assess the safety, pharmacokinetics (PK), 
pharmacodynamics (PD), and preliminary clinical activity of GSK3326595 in subjects 
with advanced or recurrent solid tumors, as well as clinical activity in subjects with a 
subset of solid tumors and non-Hodgkin’s lymphoma (NHL).  The study will also assess 
a tablet formulation of GSK3326595, and clinical activity of GSK3326595 in 
combination with pembrolizumab in subjects with a subset of solid tumors. 
Objectives/Endpoints 
Part 1 (Dose Escalation) 
Objectives  
Endpoints  
Primary 
• 
To determine the safety, tolerability, and 
maximally tolerated dose (MTD) of orally-
administered GSK3326595 in subjects with 
solid tumors 
• 
Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicities 
(DLTs), withdrawals due to AEs, dose 
interruptions and reductions, and changes 
in safety assessments (e.g., clinical 
laboratory parameters, vital signs, physical 
examinations, and organ-specific 
parameters) 
Secondary  
• 
To determine the recommended Phase 2 
dose (RP2D) of orally-administered 
GSK3326595 
• 
Safety profile (AEs, SAEs, DLTs), clinical 
response, and pharmacodynamic (PD) data  
• 
To describe the pharmacokinetics of 
GSK3326595 after single- and repeat-dose 
administration 
• 
GSK3326595 PK parameters in plasma 
following single- (Day 1) and repeat-dose 
administration of GSK3326595 
• 
To determine clinical activity of 
GSK3326595 
• 
Overall response rate [ORR: Complete 
Response (CR) + Partial Response (PR)], 
based on Response Evaluation Criteria in 
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Part 1 (Dose Escalation) 
Objectives  
Endpoints  
• 
To evaluate the preliminary effects of fed 
versus fasted administration on the 
pharmacokinetics of GSK3326595 
• 
GSK3326595 PK parameters in plasma 
following single-dose administration of 
GSK3326595 in a fed or fasted state 
• 
To evaluate the relative bioavailability of 
GSK3326595 tablets as compared to 
capsules 
• 
GSK3326595 PK parameters in plasma 
following single-dose administration of 
GSK3326595 in tablet or capsule 
formulation 
Exploratory 
 
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Part 2 (Dose Expansion) 
Objectives  
Endpoints  
Primary  
• 
To determine clinical activity of 
GSK3326595 in disease-specific expansion 
cohorts 
• 
Solid tumor (non-glioblastoma multiforme, 
GBM) cohorts: Overall response rate 
(ORR, defined as % of subjects achieving 
CR and PR) based on RECIST 1.1 criteria 
• 
GBM cohort: Six-month progression free 
survival (PFS) rate, defined as the 
percentage of subjects free from 
radiographic progression per Response 
Assessment in Neuro-Oncology (RANO) 
criteria, or death due to any cause, for six 
months after starting GSK3326595. 
• 
Non-Hodgkin’s lymphoma cohort(s): ORR 
(% of subjects achieving CR and PR) 
based on Lugano criteria 
Secondary 
• 
To further describe the clinical activity of 
GSK3326595 
• 
PFS, defined as time from first dose until 
radiographic progression per standard 
criteria, or death due to any cause, 
whichever is earlier. 
• 
GBM cohort: Overall Response Rate (CR + 
PR) based on RANO Working Group 
criteria  
• 
ACC tablet cohort: Duration of response 
(DOR), defined as time from first evidence 
of response (CR or PR per RECIST 1.1) to 
earlier date of disease progression or death 
due to any cause, as determined by 
Investigator assessment 
• 
ACC tablet cohort: Overall survival (OS), 
defined as time from first dose until death 
from any cause in ACC subjects who are 
systemic-treatment naïve 
• 
To evaluate the safety and tolerability of 
GSK3326595 in subjects treated at the 
RP2D 
• 
AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., clinical 
laboratory parameters, vital signs, physical 
examinations, and organ-specific 
parameters). 
Exploratory 
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Part 2 (Dose Expansion) 
Objectives  
Endpoints  
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Part 3 (Combination with Pembrolizumab) 
Objectives  
Endpoints  
Primary  
• To determine the safety and tolerability 
of orally-administered GSK3326595, 
administered in combination with 
pembrolizumab, in subjects with solid 
tumors 
• 
AEs, SAEs, withdrawals due to AEs, dose 
interruptions and reductions, and changes in safety 
assessments (e.g., clinical laboratory parameters, 
vital signs, physical examinations, and organ-
specific parameters) 
Secondary 
• To determine the RP2D of orally-
administered GSK3326595, when 
administered in combination with 
pembrolizumab 
• 
Safety profile (AEs, SAEs), clinical response, PK, 
and pharmacodynamic (PD) data  
• To describe the clinical activity of 
GSK3326595 in combination with 
pembrolizumab in subjects with solid 
tumors 
• 
Overall response rate (% of subjects achieving CR 
and PR) based on immune-based RECIST 
(iRECIST) criteria  
• To describe the pharmacokinetics of 
GSK3326595 after single and repeat 
dose administration of GSK3326595, 
when administered in combination with 
pembrolizumab  
• 
GSK3326595 PK parameters in plasma following 
single- (Day 1) and repeat-dose administration  
Exploratory 
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Part 3 (Combination with Pembrolizumab) 
Objectives  
Endpoints  
Overall Design 
This is an open-label, repeat-dose, multicenter, three-part study to establish the 
maximally tolerated dose (MTD)/ recommended phase 2 dose (RP2D) (based on safety 
and tolerability) and preliminary clinical efficacy of orally-administered GSK3326595, 
administered as a single agent in subjects with solid tumors and non-Hodgkin’s 
lymphoma, or administered in combination with pembrolizumab in subjects with select 
solid tumors. 
Part 1 is a dose-escalation phase to identify the MTD/RP2D based on the safety, PK, and 
PD profiles observed after oral administration of GSK3326595, and to preliminarily 
identify whether or not there is an effect of fed versus fasted state, and of tablet versus 
capsule formulation, on the PK of GSK3326595.  This Part will be conducted in adult 
subjects with relapsed and/or refractory solid tumors. 
Disease-specific expansion cohorts (Part 2) are planned to further explore clinical 
activity of GSK3326595 in subjects with select solid tumors and non-Hodgkin’s 
lymphomas.  Based on pre-clinical data, as well as clinical data that emerged during Part 
1, enrollment will be limited to subjects with triple-negative breast cancer (TNBC), 
metastatic transitional cell carcinoma of the urinary system (mTCC), Grade IV 
anaplastic astrocytoma (glioblastoma multiforme [GBM]), non-Hodgkin’s lymphoma 
(NHL), adenoid cystic carcinoma (ACC), hormone receptor-positive adenocarcinoma of 
the breast (ER+BC), human papillomavirus (HPV) positive solid tumors of any 
histology (including cervical cancer and squamous cell carcinoma of the head and neck 
[HNSCC]), and p53-wild type non-small cell lung cancer (NSCLC) of any histological 
subtype; additional cohorts may be added based on emerging pre-clinical data and 
clinical responses identified during Part 1 or Part 2 of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
This Protocol Amendment 8 is the follow up of this decision with the primary intent to 
update study language related to stopping recruitment into the Part 2 ACC tablet cohort, 
and therefore stopping any further recruitment in the study, updating the end of study 
definition with final analysis plan (Section 5.5), and clarifying study treatment access for 
subjects continuing to derive clinical benefit from study drug as per Investigator 
judgement post final analysis (Section 4.1). 
Part 3 is a dose determination study to evaluate the safety, PK/PD profile, and clinical 
activity of orally-administered GSK3326595 at daily doses of 100 mg, 200 mg and 
300 mg, in combination with pembrolizumab administered at the approved dose.  
Enrollment in Part 3 will be limited to subjects with NSCLC, mTCC, melanoma, 
HNSCC that have failed to respond to treatment with prior programmed cell death 
protein-1 (PD-1) or programmed death-ligand 1 (PD-L1) directed therapy. In addition 
squamous cell carcinoma of the cervix patients that have progressed on or after PD-1 or 
PD-L1 directed therapy OR are PD-1/PD-L1 treatment naïve will be enrolled in Part 3.  
 
 
. 
Final Last Subject Last visit will be defined as last subject’s treatment discontinuation 
(including 30-day safety follow up). 
The end of this study is defined as the date of the last visit of the last subject undergoing 
the study. 
A final data-cut off (DCO), closure of the study database and final analysis will occur 
when all subjects have either died, discontinued treatment (including 30-day safety 
follow up), withdrawn consent, or have consented to continue with treatment as defined 
in this amendment (Protocol Amendment 8). 
When Protocol Amendment 8 is implemented at a site, the collection of data for all 
enrolled subjects who no longer receive study treatment will stop entirely. Subjects still 
on treatment at the time of the final DCO date may continue to receive study treatment 
for as long as they continue to derive clinical benefit from study treatment as assessed by 
the Investigator and do not meet any protocol-defined study treatment stopping criteria 
(maximum until the end of availability of study drug which is anticipated to be Q3 
2023); subjects may also choose to discontinue study treatment at any time. Subjects in 
survival follow-up at the time of the final DCO date will be considered to have 
completed the study. 
Subjects who continue study treatment following Protocol Amendment 8 will receive 
follow-up care in accordance with standard local clinical practice. Assessments will 
revert to the standard of care at a subject’s particular study site with recommendations 
for local safety laboratory monitoring of GSK3326595. Only SAEs, AEs leading to 
treatment discontinuation, overdoses, pregnancies, and pre-defined ocular and bone AEs 
(AESIs) will be reported directly to the Sponsor via a paper process. In addition, 
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• Ocular assessments will be required and reported via a paper process to the 
Sponsor only if reporting criteria is met for SAEs, AESIs, or AEs leading to 
treatment discontinuation. 
• Bone (DEXA) assessments will be performed at the discretion of the investigator 
and reported via a paper process to the Sponsor only if reporting criteria is met 
for SAEs, AESIs, or AEs leading to treatment discontinuation. 
Treatment Arms and Duration 
All subjects in the study will receive the investigational agent.  Part 1 (including the 
PK/PD expansion, relative bioavailability and food effect cohorts) will have a single 
arm.  Part 2 will incorporate multiple disease-specific arms.  Part 3 will incorporate 
multiple arms comprising a fixed dose of pembrolizumab and three dose levels of 
GSK3326595.  In Part 1 and Part 2, subjects may continue treatment in the study until 
disease progression, unacceptable toxicity, or withdrawal of consent. In Part 3, subjects 
may remain on GSK3326595 until these criteria are met; however, pembrolizumab will 
only be administered for a maximum of 24 months.  The duration of study will depend 
on recruitment rates and the timing of subjects’ duration on study (withdrawal rates due 
to toxicity or progression), with an approximate duration of 8 years. 
Type and Number of Subjects 
Part 1: It is estimated that 66 subjects will be enrolled into the dose escalation cohort of 
the study, including around 42 subjects to identify the MTD, approximately 12 
additional subjects in the PK/PD/metabolite/biomarker expansion cohort(s), and 
approximately 12 subjects but no more than 24 subjects in the food effect and relative 
bioavailability sub-study.  The study population will be adults, with histologically- or 
cytologically-confirmed metastatic or non-resectable solid malignancies.  
Part 2: It is estimated that up to 316 subjects will be enrolled in the disease-specific 
expansion cohorts of the study.  Cohorts will include adult subjects with a diagnosis of 
one of the following diseases: 
• 
Triple-negative breast cancer (TNBC) 
• 
Metastatic transitional cell carcinoma of the urinary system (mTCC) 
• 
Glioblastoma multiforme (GBM) 
• 
Non-Hodgkin’s lymphoma (NHL), all sub-types recruited to Protocol 
Amendments 1-4, and more indolent subtypes recruited to Protocol Amendment 5 
onwards  
• 
Adenoid cystic carcinoma (ACC), dosed with GSK3326595 capsule formulation  
• 
Adenoid cystic carcinoma (ACC), in subjects who have not received any 
systemic therapy for locally advanced or metastatic disease, dosed with 
GSK3326595 tablet formulation.  
• 
Hormone receptor-positive adenocarcinoma of the breast (ER+BC) 
• 
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• 
p53 wild-type non-small cell lung cancer (NSCLC) of any histological subtype  
Part 3: It is estimated that approximately 30 subjects will be enrolled in Part 3, all with 
locally advanced or metastatic NSCLC, melanoma, mTCC, or HNSCC that have failed to 
respond to treatment (e.g., SD, with subsequent documented progression as per iRECIST, 
or PD as best response) with prior PD-1 or PD-L1 directed therapy. In addition, 
squamous cell carcinoma of the cervix patients that have progressed on or after PD-1 or 
PD-L1 directed therapy or are PD-1/PD-L1 treatment naïve will be enrolled in Part 3. 
These subjects will be divided evenly between three cohorts, each receiving a different 
dose of GSK3326595 in combination with a single dose of pembrolizumab.
 
 
 
 
Analysis 
Part 1: A modified toxicity probability interval (mTPI) method will be used to make 
dose escalation decisions.  Dose decisions, including dose increments, will be based on 
the totality of clinical safety assessment including dose-limiting toxicities, clinical, and 
laboratory safety data.  All data will be pooled and descriptive analyses summarized and 
listed by cohort at study conclusion. No formal statistical hypotheses will be tested. 
Analyses will be descriptive and exploratory. 
Part 2: The primary goal of Part 2 is to evaluate disease-specific efficacy in subjects with 
TNBC, mTCC, recurrent GBM, NHL (which will be divided into two cohorts: TP53 
mutated and TP53 wild-type), ACC, ER+BC, HPV-positive solid tumors and NSCLC.  
Except for the ACC cohorts, this portion of the study will employ a Bayesian design that 
allows the trial to be frequently monitored with the constraint of both Type I and Type II 
error rates. The ACC cohorts will use a Simon’s optimal two stage design. For all tumors 
except GBM, the primary endpoint will be defined as overall response rate (ORR), per 
standard evaluation criteria.  Bayesian hierarchical modeling will be used to investigate 
the clinical activity of GSK3326595 in the TNBC, mTCC, and NHL cohorts. 
Hierarchical modeling allows information about the treatment effect in one cohort to be 
‘borrowed’ when estimating the treatment effect in another cohort.  For the GBM cohort, 
the primary endpoint will be defined as the six-month PFS rate. The NSCLC cohort is 
intended to explore the clinical activity in the p53 wild-type NSCLC population using a 
Simon’s optimal two-stage design to define the interim futility analysis.  The results of 
the interim futility analysis (performed after 10 evaluable subjects) will be used to 
inform further development in this population. For all cohorts, clinical activity will be 
monitored through interim analyses. 
A secondary goal of Part 2 is to test the hypothesis that clinical response to 
GSK3326595 in NHL subjects is influenced by tumor p53 status (wild type versus 
mutant). 
Part 3:  No formal statistical hypothesis will be tested in this cohort. Analyses will be 
descriptive and exploratory. 
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2. 
INTRODUCTION 
GSK3326595 is a potent, selective, reversible inhibitor of the protein arginine 
methyltransferase 5 (PRMT5)/Methylosome protein 50 (MEP50) complex that is being 
tested as an oral treatment for human subjects with cancer. 
2.1. 
Study Rationale 
Protein arginine methyltransferases (PRMTs) are a subset of enzymes that methylate 
arginines in proteins that contain regions rich in glycine and arginine residues (GAR 
motifs). PRMT5 methylates arginines in proteins involved in various cellular proteins 
including splicing factors, transcription factors, kinases and others [Karkhanis, 2011].  
PRMT5 also methylates histone arginine residues (Histone 3 Arginine 8 [H3R8], 
Histone 2A arginine 3 [H2AR3] and Histone 4 arginine 3,  [H4R3]), and these histone 
marks are associated with transcriptional silencing of tumor suppressor genes such as 
RB1 and 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, as well as increased 
ubiquitylation (and subsequent degradation) of p53 via differential splicing of MDM4, a 
p53 ubiquitin ligase.  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]. 
Increasing evidence suggests that PRMT5 is involved in tumorigenesis. PRMT5 protein 
is overexpressed in a number of cancer types, including lymphoma, glioma, breast and 
lung cancer and PRMT5 overexpression alone is sufficient to transform normal 
fibroblasts [Pal, 2007; Ibrahim, 2014; Powers, 2011; Yan, 2014].  Knockdown of 
PRMT5 often leads to a decrease in cell growth and survival in cancer cell lines. In 
breast cancer, high PRMT5 expression, together with high programmed cell death 4 
(PDCD4) levels predict overall poor survival [Powers, 2011]. High expression of 
PRMT5 in glioma is associated with high tumor grade and overall poor survival and 
PRMT5 knockdown provides a survival benefit in an orthotopic glioblastoma model 
[Yan, 2014]. Increased PRMT5 expression and activity contribute to silencing of several 
tumor suppressor genes in glioma cell lines. 
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Nevertheless, p53 is not the only mechanism by which PRMT5 has its effect on 
lymphoma cells, as several p53-mutant cell lines were also highly sensitive to treatment 
with GSK3326595.  For instance, cyclin D1, the oncogene that is translocated in the vast 
majority of MCL patients, associates with PRMT5 and through a cdk4-dependent 
mechanism increases PRMT5 activity [Aggarwal, 2010]. PRMT5 mediates the 
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suppression of key genes that negatively regulate deoxyribonucleic acid (DNA) 
replication allowing for cyclin D1-dependent neoplastic growth. PRMT5 knockdown 
inhibits cyclin D1-dependent cell transformation causing death of tumor cells.  Thus, 
because other gene pathways (apart from p53) that are important for lymphomagenesis 
are regulated by PRMT5, subjects with lymphoma will be enrolled in Part 2 irrespective 
of p53 status and the response to therapy with GSK3326595 will be compared between 
cohorts. 
Adenoid cystic carcinoma (ACC) is a tumor arising from salivary glands that is 
clinically distinct from squamous cell tumors of the head and neck.  While typically 
characterized by a long overall survival (OS), it nevertheless portends frequent 
metastatic progression and steadily progressive disease [Wysocki, 2016].  To date, there 
are no approved therapies for metastatic or unresectable ACC, as response rates to 
traditional chemotherapy are typically poor and novel targeted therapies have been 
unable to improve on this [Dillon, 2017; Goncalves, 2017; Locati, 2016] .  Epigenetic 
agents have recently found favour in ACC therapeutic trials, as recurrent mutations in 
transcriptional mediators (including myb and NOTCH) have been identified in a subset 
of ACC tumor samples [Ferrarotto, 2016].  As inactivating p53 mutations are rare in 
ACC samples, any agent (such as GSK3326595) that increases p53 activity may yield 
therapeutic benefit in this population. 
HPV is a DNA virus that has been associated with numerous squamous cell carcinomas 
when mucocutaneous squamous cells are infected with high-risk strains of the virus.  
Tumorigenesis is mediated via viral oncogenes, including E6 and E7, which lead to 
degradation and/or inhibition of endogenous tumor suppressors.  This effect phenocopies 
inactivating mutations in these tumor suppressors.  Critically, viral oncogene expression 
is dependent on host mRNA-processing machinery (i.e., the spliceosome) [Graham, 
2017].  In the absence of viral oncogene expression, the endogenous tumor suppressors 
would be expected to resume expression, potentially leading to reduction in tumor size.  
GSK3326595 may be expected to provide therapeutic benefit in HPV-infected solid 
tumors in multiple ways: either by reducing viral oncogene expression via effects on 
mRNA splicing of viral oncogenes, or else by direct upregulation of p53 via other 
PRMT5-dependent processes as described above.  As HPV induces tumors via a 
common mechanism irrespective of the cell type of origin (e.g., cervical, head/neck, etc), 
PRMT5 inhibition may yield clinical benefit in multiple HPV-infected tumor types. 
Recently, immunotherapy has emerged as a significant field for novel therapies in 
oncology.  These agents act via modulation of the acquired immune system in order to 
drive recognition and destruction of tumors [Gandhi, 2018]. Pembrolizumab, a 
humanized Immunoglobulin G4 (IgG4) against the Programmed Cell Death protein-1 
(PD-1) protein, has been approved as an option for patients with a variety of solid 
tumors and hematological malignancies, including lung, head and neck, melanoma, 
bladder, and cervical cancers [KEYTRUDA, Prescribing Information (PI), 2019; 
KEYTRUDA, Summary of Product Characteristics (SPC), 2019].  Treatment with 
pembrolizumab is characterized by responses that exhibit significant durability 
[KEYTRUDA, PI, 2019; KEYTRUDA, SPC, 2019].  However, not all patients respond 
to pembrolizumab therapy, and wild-type p53 has emerged as a potential biomarker for 
lack of response [Carlisle, 2018].  Given the preclinical activity of GSK3326595 
observed in many pembrolizumab-sensitive tumor types, the unmet medical need of the 


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pembrolizumab-treated patients who fail to respond to their therapy, and the potential 
p53-modulating effects of GSK3326595, PRMT5 inhibition may yield clinical benefit 
when administered in combination with pembrolizumab.  
GSK3326595 in combination with Pembrolizumab will be explored in subjects with 
NSCLC, mTCC, melanoma, squamous cell carcinoma of the head and neck (HNSCC) 
and with squamous cell carcinoma of the cervix. 
Cervical cancer is the fourth leading cause of cancer related mortality in women 
worldwide (Torre, 2015), third in US (Siegel, 2020) and HPV is the driver behind 97% 
of invasive cervical cancer (Walboomers, 1999).  Response rates associated with ﬁrst-
line treatment of recurrent/metastatic cervical cancer ranged from 19% to 36% for 
cisplatin alone or in combination with paclitaxel respectively (Moore, 2004) to 
approximately 50% for bevacizumab containing regimens (Tewari, 2017).  Median OS 
values ranged from 8.8 to 9.7 months for cisplatin alone or in combination with 
paclitaxel respectively (Moore, 2004) to 16.8 months for bevacizumab-containing 
regimens (Tewari, 2017). Responses to second-line treatments for recurrent/metastatic 
cervical cancer are limited. In June 2018, pembrolizumab received accelerated approval 
in the US for the treatment of patients with recurrent/metastatic cervical cancers 
expressing programmed death ligand (PD-L1) post chemotherapy showing ORR of 
14.3% in Combined Percentage Score (CPS)≥1% population (KEYTRUDA 
(pembrolizumab) [package insert]). Whitehouse Station, NJ: Merck & Co; June 2019). 
In addition, Pembrolizumab approval in microsatellite instability-high (MSI-H) or 
mismatch repair deficient solid tumors that have progressed following prior treatment 
and who have no satisfactory alternative treatment options is appropriate for selected 
cervical cancer patients. 
A number of approaches are currently under clinical exploration including a combination 
of immune oncology agents (Checkmate 358, NCT02488759) or a combination of 
immunotherapy and chemotherapy (Keynote 826, NCT03635567). Based on preliminary 
data from HPV positive cohort of study 204653, some tumor shrinkage was seen in 
cervical cancer patients. A proposed inclusion of cervical cancer patients that have 
progressed on or after PD-1 or PD-L1 directed therapy or are PD-1/PD-L1 treatment 
naïve is based on hypothesis that GSK3326595 may augment pembrolizumab activity in 
this population when compared to pembrolizumab alone. It is anticipated that patients 
with CPS<1% and CPS≥1% may obtain benefit from treatment, given this novel 
combination approach and patients will be enrolled irrespective of PD-L1 status. 
In summary, relapsed metastatic solid malignancies (including those under investigation 
in this study), and virtually all relapsed/refractory hematologic malignancies are 
incurable diseases which will ultimately prove fatal.  In particular, recurrent urinary tract 
cancer and GBM portend a particularly grim prognosis with an overall survival typically 
measured in months.  At this time, there is no standard of care for these diseases, and as 
such these patients often consider investigational agents in an attempt to provide some 
clinical benefit.  A wealth of data, including genetics, biochemistry, and cellular biology, 
implicate PRMT5 in a multitude of human malignancies including those investigated in 
this study. This study is the first in humans to investigate inhibition of PRMT5 in an 
attempt to treat and ameliorate malignancy in this population with a high degree of 
unmet medical need. 


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3. 
OBJECTIVES AND ENDPOINTS 
Part 1 (Dose Escalation) 
Objectives  
Endpoints  
Primary 
• To determine the safety, tolerability, 
and maximally tolerated dose (MTD) 
of orally-administered GSK3326595 
in subjects with solid tumors 
• 
Adverse Events (AEs), Serious Adverse Events 
(SAEs), Dose Limiting Toxicities (DLTs), withdrawals 
due to AEs, dose interruptions and reductions, and 
changes in safety assessments (e.g., clinical 
laboratory parameters, vital signs, physical 
examinations, and organ-specific parameters) 
Secondary  
• To determine the recommended 
Phase 2 dose (RP2D) of orally-
administered GSK3326595 
• 
Safety profile (AEs, SAEs, DLTs), clinical response, 
and pharmacodynamic (PD) data  
• To describe the pharmacokinetics of 
GSK3326595 after single- and 
repeat-dose administration 
• 
GSK3326595 PK parameters in plasma following 
single- (Day 1) and repeat-dose administration of 
GSK3326595 
• To determine clinical activity of 
GSK3326595 
• 
Overall response rate (ORR; CR + PR), based on 
Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 criteria 
• To evaluate the preliminary effects of 
fed versus fasted administration on 
the pharmacokinetics of 
GSK3326595 
• 
GSK3326595 PK parameters in plasma following 
single-dose administration of GSK3326595 in a fed 
or fasted state 
• To evaluate the relative bioavailability 
of GSK3326595 tablets as compared 
to capsules  
• 
GSK3326595 PK parameters in plasma following 
single-dose administration of GSK3326595 in tablet 
or capsule formulation 
Exploratory 
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Part 1 (Dose Escalation) 
Objectives  
Endpoints  
Part 2 (Dose Expansion) 
Objectives  
Endpoints  
Primary  
• To determine clinical activity of 
GSK3326595 in disease-specific 
expansion cohorts 
• 
Solid tumor cohorts (non-GBM) cohorts: Overall 
response rate (ORR, defined as % of subjects 
achieving CR and PR) based on RECIST 1.1 
criteria. 
• 
GBM cohort: Six-month progression free survival 
(PFS) rate, defined as the percentage of subjects 
free from radiographic progression per Response 
Assessment in Neuro-Oncology RANO criteria, or 
death due to any cause, for six months after 
starting GSK3326595. 
• 
Non-Hodgkin’s lymphoma cohort(s): ORR (% of 
subjects achieving CR and PR) based on Lugano 
criteria 
Secondary 
• To further describe the clinical activity 
of GSK3326595 
• 
PFS, defined as time from first dose until 
radiographic progression per standard criteria or 
death due to any cause, whichever is earlier. 
• 
GBM cohort: Overall Response Rate (CR + PR) 
based on RANO Working Group criteria 
• 
ACC tablet cohort: Duration of response (DOR), 
defined as time from first evidence of response (CR 
or PR per RECIST 1.1) to earlier date of disease 
progression or death due to any cause, as 
determined by Investigator assessment 
• 
ACC tablet cohort: Overall survival (OS), defined as 
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Part 1 (Dose Escalation) 
Objectives  
Endpoints  
time from first dose until death from any cause in 
ACC subjects who are systemic-treatment naïve 
• To evaluate the safety and tolerability 
of GSK3326595 in subjects treated at 
the RP2D 
• 
AEs, SAEs, dose reductions or delays, withdrawals 
due to toxicities and changes in safety 
assessments (e.g., clinical laboratory parameters, 
vital signs, physical examinations, and organ-
specific parameters). 
Exploratory 
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Part 1 (Dose Escalation) 
Objectives  
Endpoints  
Part 3 (Combination with Pembrolizumab) 
Objectives  
Endpoints  
Primary  
• To determine the safety and tolerability 
of orally-administered GSK3326595, 
administered in combination with 
pembrolizumab, in subjects with solid 
tumors 
• 
AEs, SAEs, withdrawals due to AEs, dose 
interruptions and reductions, and changes in safety 
assessments (e.g., clinical laboratory parameters, 
vital signs, physical examinations, and organ-
specific parameters) 
Secondary 
• To determine the RP2D of orally-
administered GSK3326595, when 
administered in combination with 
pembrolizumab 
• 
Safety profile (AEs, SAEs), clinical response, PK, 
and pharmacodynamic (PD) data  
• To describe the clinical activity of 
GSK3326595 in combination with 
pembrolizumab in subjects with solid 
tumors 
• 
Overall response rate (% of subjects achieving CR 
and PR) based on immune-based RECIST 
(iRECIST) criteria 
 
• To describe the pharmacokinetics of 
GSK3326595 after single and repeat 
dose administration of GSK3326595, 
when administered in combination with 
pembrolizumab  
• 
GSK3326595 PK parameters in plasma following 
single- (Day 1) and repeat-dose administration  
Exploratory 
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Part 1 (Dose Escalation) 
Objectives  
Endpoints  
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is an open-label, repeat-dose, multicenter, three-part study to establish the 
MTD/RP2D (based on the profile of safety and tolerability) and preliminary clinical 
efficacy of orally-administered GSK3326595, administered as a single agent in subjects 
with solid tumors and non-Hodgkin’s lymphoma, or administered in combination with 
pembrolizumab in subjects with select solid tumors. 
Part 1 is a dose-escalation phase to identify the MTD/RP2D based on the safety, PK, and 
PD profiles observed after oral administration of GSK3326595, and to preliminarily 
identify whether or not there is an effect of fed versus fasted state, and of tablet versus 
capsule formulation, on the PK of GSK3326595.  This Part will be conducted in adult 
subjects with relapsed and/or refractory solid tumors. 
Disease-specific expansion cohorts (Part 2) are planned to further explore clinical 
activity of GSK3326595 in subjects with select solid tumors and non-Hodgkin’s 
lymphomas.  Based on pre-clinical data, as well as clinical data from Part 1 of the study, 
enrollment in Part 2 will be limited to subjects with triple-negative breast cancer 
(TNBC), metastatic transitional cell carcinoma of the urinary system (mTCC), Grade IV 
anaplastic astrocytoma (glioblastoma multiforme [GBM]), non-Hodgkin’s lymphoma 
(NHL) (all sub-types recruited to Protocol Amendments 1-4, and indolent subtypes of  
NHL recruited to Protocol Amendment 5 onwards), adenoid cystic carcinoma (ACC), 
hormone receptor-positive adenocarcinoma of the breast (ER+BC), human 
papillomavirus (HPV)-positive solid tumors of any histology, and p53-wild type non-
small cell lung cancer (NSCLC) of any histological subtype. Additional cohorts may be 
added, via future protocol amendment, based on pre-clinical data and clinical responses 
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identified during conduct of the study.  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
This Protocol Amendment 8 is the follow up of this decision with the primary intent to 
update study language related to stopping recruitment into the Part 2 ACC tablet cohort, 
and therefore stopping any further recruitment in the study, updating the end of study 
definition with final analysis plan (Section 5.5), and clarifying study treatment access for 
subjects continuing to derive clinical benefit from study drug as per Investigator 
judgement post final analysis. 
Part 3 is a dose determination study to evaluate the safety, PK/PD profile, and clinical 
activity of orally-administered GSK3326595 at daily doses of 100 mg, 200 mg and 
300 mg, in combination with pembrolizumab administered at the approved dose.  
Enrollment in Part 3 will be limited to subjects with NSCLC, mTCC, melanoma, and 
HNSCC that have failed to respond to treatment with prior PD-1 or PD-L1 directed 
therapy. In addition, squamous cell carcinoma of the cervix patients that have progressed 
on or after PD-1 or PD-L1 directed therapy or are PD-1/PD-L1 treatment naïve will be 
enrolled in Part 3.  
 
 
. 
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 subject safety. 
Final Last Subject Last visit will be defined as last subject’s treatment discontinuation 
(including 30-day safety follow up). 
The end of this study is defined as the date of the last visit of the last subject undergoing 
the study. 
A final data-cut off (DCO), closure of the study database and final analysis will occur 
when all subjects have either died, discontinued treatment (including 30-day safety 
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follow up), withdrawn consent, or have consented to continue with treatment as defined 
in this amendment (Protocol Amendment 8). 
When Protocol Amendment 8 is implemented at a site, the collection of data for all 
enrolled subjects who no longer receive study treatment will stop entirely. Subjects still 
on treatment at the time of the final DCO date may continue to receive study treatment 
for as long as they continue to derive clinical benefit from study treatment as assessed by 
the Investigator and do not meet any protocol-defined study treatment stopping criteria 
(maximum until the end of availability of study drug which is anticipated to be Q3 
2023); subjects may also choose to discontinue study treatment at any time. Subjects in 
survival follow-up at the time of the final DCO date will be considered to have 
completed the study. 
Subjects who continue study treatment following Protocol Amendment 8 will receive 
follow-up care in accordance with standard local clinical practice. Assessments will 
revert to the standard of care at a subject’s particular study site with recommendations 
for local safety laboratory monitoring of GSK3326595. Only SAEs, AEs leading to 
treatment discontinuation, overdoses, pregnancies, and pre-defined ocular and bone AEs 
(AESIs) will be reported directly to the Sponsor via a paper process. In addition,  
• Ocular assessments will be required and reported via a paper process to the 
Sponsor only if reporting criteria is met for SAEs, AESIs, or AEs leading to 
treatment discontinuation.   
• Bone (DEXA) assessments will be performed at the discretion of the investigator 
and reported via a paper process to the Sponsor only if reporting criteria is met 
for SAEs, AESIs, or AEs leading to treatment discontinuation. 
4.2. 
Part 1: Dose Escalation 
The primary objective of Part 1 is to identify the MTD of GSK3326595 when 
administered orally in subjects with solid tumors. As described in Section 4.7, dosing 
will start at 12.5 mg once daily and escalate until the MTD is reached.  In Part 1, any 
subject who prematurely discontinues therapy during the DLT observation period for 
reasons other than a DLT will be replaced by additional subject(s) assigned to the same 
dose level. 
 
 
. Subjects will also be enrolled at or about the RP2D 
into a food effect and relative bioavailability sub-study (Section 4.2.6) to evaluate the 
effects of food and GSK3326595 formulation on GSK3326595 pharmacokinetics.  
Dose escalation will be conducted in two stages: dose exploration (Section 4.2.2) and 
MTD confirmation (Section 4.2.3). Details common to both stages, including DLT 
definitions and dose increments, are described in Section 4.2.4. 
4.2.1. 
Type and Number of Subjects (Part 1) 
It is estimated that up to 66 subjects will be enrolled into the dose escalation cohort of 
the study, including approximately 42 subjects to identify the MTD, approximately 
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12 subjects in the PK/PD/metabolite/biomarker expansion cohort(s), and approximately 
12 subjects but no more than 24 subjects in the food effect and relative bioavailability 
sub-study. The study population will be adults, with histologically- or cytologically-
confirmed solid malignancies as described in Section 5.1. 
4.2.2. 
Initial Dose Exploration (accelerated titration) 
In order to minimize the number of subjects enrolled at sub-optimal doses, an 
accelerated titration design will be implemented until the first evidence of a non disease-
related ≥ Grade 2 toxicity, with the exception of toxicities listed in Section 4.2.4.2.  One 
subject at each dose level will be enrolled, starting at the dose described in Section 4.7.  
If the subject enrolled at the first dose level experiences a dose-limiting toxicity (DLT), 
then lower doses (i.e., Dose Level -1) will be explored and re-escalation may be 
attempted based on safety and tolerability data.  Accelerated titration will continue until 
a subject experiences a non-disease-related ≥ Grade 2 toxicity, then the implementation 
of the MTD confirmation stage (Section 4.2.3) will be triggered.  Each subject must 
complete the 21-day DLT evaluation period, and the available safety data must be 
reviewed before a decision is made on whether to proceed to the next dose level.  If a 
subject fails to receive more than 80% of the planned doses within the 21-day DLT 
evaluation period for reasons other than toxicity, the subject will be replaced.  
Guidelines for selecting the next dose level are described in Section 4.2.4.2. Additional 
subjects may be enrolled at previously cleared dose levels if safety and PK analysis 
suggest this is warranted for better understanding the safety and PK profile.  Safety 
assessments from these subjects will be included in the MTD determination. 
4.2.3. 
Determining the MTD 
Starting with the first cohort exhibiting a non disease-related ≥ Grade 2 toxicity (except 
for those listed in Section 4.2.4.2), a modified Toxicity Probability Interval (mTPI) 
design will be implemented (Figure 4-1) [Ji, 2010].  Cohorts will be recruited in blocks 
of three subjects.  The maximum number of subjects assigned to any single dose will be 
at the discretion of the Sponsor in consultation with the investigators. 
The design assumes (i) approximately 38 subjects will complete the DLT evaluation 
period and (ii) the true underlying toxicity rate for GSK3326595 falls within the range 
from 25% to 35% and centered at 30%.  The monitoring rules guiding dose escalation 
are provided in Figure 4-1.  Columns provide the numbers of subjects treated at the 
current dose level, and rows provide the corresponding numbers of subjects experiencing 
toxicity.  The entries of the table are dose-finding decisions (i.e., E, S, and D) 
representing escalating the dose, staying at the same dose, and de-escalating the dose.  In 
addition, decision U means that the current dose level is unacceptable because of high 
toxicity and should be excluded from the trial.  For example, when one of three subjects 
experiences toxicity, the decision can be located at row 1 and column 3, which is S – to 
stay at the current dose level.  Consequently, the next cohort of subjects will be treated at 
the same dose level currently being used.  If zero of three subjects experiences toxicity, 
the decision is at row 0 and column 3, which is E – to escalate.  Thus, the next cohort of 
subjects will be treated at the next-higher dose level.  If three of three subjects 
experiences toxicity, the decision is DU – to de-escalate to the next-lower dose level and 
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During dose escalation, when 2 or more subjects are enrolled in a cohort, no two subjects 
may start treatment on the same day. This staggered dosing start is not required for 
subjects enrolling at previously cleared doses or for subjects enrolled in Part 2 of the 
study. 
Figure 4-1 
Dose-finding spreadsheet of the modified toxicity probability 
interval (mTPI) method 
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
2
DU D
S
S
S
S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
3
DU DU D
S
S
S
S
S
S
S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
4
DU DU DU D
D
S
S
S
S
S
S
S
S
S
S
S
S
E
E
E
E
E
E
E
E
E
E
5
DU DU DU DU DU D
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
E
E
E
E
E
6
DU DU DU DU DU DU D
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
E
7
DU DU DU DU DU DU DU D
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
8
DU DU DU DU DU DU DU DU DU D
S
S
S
S
S
S
S
S
S
S
S
S
S
9
DU DU DU DU DU DU DU DU DU DU DU S
S
S
S
S
S
S
S
S
S
S
10
DU DU DU DU DU DU DU DU DU DU DU DU D
S
S
S
S
S
S
S
S
11
DU DU DU DU DU DU DU DU DU DU DU DU DU DU S
S
S
S
S
S
12
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU S
S
S
13
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU S
14
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU
15
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU
16
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU
17
DU DU DU DU DU DU DU DU DU DU DU DU DU DU
18
DU DU DU DU DU DU DU DU DU DU DU DU DU
19
DU DU DU DU DU DU DU DU DU DU DU DU
20
DU DU DU DU DU DU DU DU DU DU DU
21
DU DU DU DU DU DU DU DU DU DU
22
DU DU DU DU DU DU DU DU DU
23
DU DU DU DU DU DU DU DU
24
DU DU DU DU DU DU DU
25
DU DU DU DU DU DU
26
DU DU DU DU DU
27
DU DU DU DU
28
DU DU DU
29
DU DU
30
DU
Number of patients treated at current dose
Number of dose limiting toxicities (DLT's)
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
U = The current dose is unacceptably toxic
MTD = 30%
Sample Size = 30
Epsilon1 = 0.05
Epsilon2 = 0.05
 
The spreadsheet was generated based on a beta/binomial model and precalculated before trial initiation.  The letters in 
different colors are computed based on the decision rules under the mTPI method and represent different dose-finding 
actions.  In addition to actions de-escalate the dose (D), stay at the same dose (S), and escalate the dose (E), the 
table includes action unacceptable toxicity (U), which is defined as the execution of the dose-exclusion rule in mTPI. 
4.2.3.1. 
Reverting to Accelerated Dose Titration 
Subsequent cohorts may revert to one subject per cohort in either of the following 
scenarios:  
• Two additional subjects are added at the dose where the non-disease-related 
≥ Grade 2 toxicity is seen in the initial subject, and no non disease-related 
Grade 2 or higher toxicity is seen in either of the two new subjects. 
• All subjects treated at next higher dose level do not have a non-disease-related 
Grade 2 or higher toxicity. 
However, the dose escalation may continue with multiple subjects per cohort per the 
clinical judgment of the Medical Monitor in consultation with the investigators. The 


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decision on the number of subjects will be documented in writing together with the dose 
escalation decision and the rationale. 
4.2.4. 
Dose Escalation Decisions and Determination of MTD 
4.2.4.1. 
Dose-Limiting Toxicity 
An event is considered to be a dose-limiting toxicity (DLT) if the event occurs within the 
first 21 days of treatment and meets the criteria listed in Table 1, unless it can be clearly 
established that the event is unrelated to treatment. 
Table 1 
Dose-Limiting Toxicity Criteria 
Toxicity 
DLT Definition 
Hematologic 
• 
Grade 3 neutropenia (absolute neutrophil count [ANC] <1000/mm3) for 
5 days or Grade 4 neutropenia of any duration 
• 
Grade 3 or greater febrile neutropenia  
• 
Grade 4 or greater anemia of any duration 
• 
Grade 4 thrombocytopenia (platelets <25,000/mm3), or Grade 3 
thrombocytopenia with bleeding 
Non-hematologic 
• 
Alanine aminotransferase (ALT) >3x upper limit of normal (ULN) + bilirubin 
2xULN (>35% direct) or ALT between 3-5 X ULN with bilirubin < 2xULN 
but with hepatitis symptomsa or rash (See Section 5.4.5 for Liver Stopping 
Criteria) 
• 
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 
• 
Grade 3 hypertensionb (uncontrolled despite addition of up to 
2 antihypertensive medications) 
• 
Grade 4 or greater hypertension 
• 
Grade 3 or greater clinically significant non-hematologic toxicity per National 
Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-
CTCAE), v4 except toxicities listed in Section 4.2.4.2. 
Other 
• 
Inability to receive at least 80% of scheduled doses in the DLT observation 
period due to toxicityc 
• 
Grade 2 or higher toxicity that occurs beyond 21 days which in the judgment 
of the investigator and GlaxoSmithKline (GSK) Medical Monitor is 
considered to be a DLT 
Toxicity Grading based on NCI-CTCAE v4 
a. 
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) 
b. 
Grade 3 hypertension adequately controlled by antihypertensive medication(s) is not considered to be a DLT. 
c. Subjects unable to receive at least 80% of scheduled doses 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 
Table 1 provides a list of protocol-defined DLTs; it does not provide guidelines for 
management of these toxicities.  In appropriate clinical circumstances, resumed dosing 
after a DLT (at a reduced dose level) may be considered after discussion between the 


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investigator, medical monitor, and GSK medical governance (as necessary). For 
management of liver toxicity, please refer to Section 5.4.5.  For management of cardiac 
toxicity, see Section 5.4.6.  For management of all other toxicities, see Appendix 2. 
4.2.4.2. 
Non-Limiting Toxicities 
The following toxicities have been deemed to be non-serious for the purposes of this 
study. These toxicities will not be taken into account for dose escalation decisions 
unless, in the opinion of the investigator and the GSK Medical Monitor, they represent a 
dose-limiting toxicity. For all other toxicities and their management, see Appendix 2. 
• 
Grade 2 or less: 
o Fatigue 
o Rash 
o Alopecia 
• 
Grade 3 or less nausea, vomiting, or diarrhea controlled within 24h 
• 
Electrolyte imbalance or other laboratory abnormalities controlled within 24h 
4.2.4.3. 
Maximum Dose Increment 
Built-in safety constraints are in place to prevent exposing subjects to undue risk of 
toxicity. The maximum allowable dose increment will be determined based on the prior 
dose level data.  The permitted dose increments are a protocol-defined maximum; a 
smaller increment may always be used based on the decision of the investigators and 
medical monitor (Section 4.2.4.5). Planned dose levels are detailed in Section 4.2.4.4. 
For each individual dose escalation step: 
If no grade  2 non-hematologic non disease-related toxicity (except those listed in 
Section 4.2.4.2) is observed at the current dose, the dose increment will be no more than 
100% of the current dose. 
If one or more grade > 2 non-hematologic non disease-related toxicity (except those 
listed in Section 4.2.4.2), grade > 2 anemia or thrombocytopenia, or DLT is observed, the 
dose increment to the immediate next dose level will be no more than 50% of the current 
dose. 
4.2.4.4. 
Planned Dose Levels 
Projected daily dose levels are 12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, 
600 mg, 800 mg, and 1200 mg.  BID dosing may divide this total daily dose into two 
equal doses, administered twice daily.  Additional doses (either lower than 12.5 mg, 
higher than 1200 mg, or intermediate doses between those listed above) and schedules 
may be explored based on emerging safety, PK, and PD data.  
4.2.4.5. 
Dose Escalation Decisions 
The GSK medical monitor, in joint discussion with the participating investigators, will be 
responsible for determining whether dose escalation during Part 1 should continue as 


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recommended by the mTPI approach.  Prior to the dose escalation decision, the medical 
monitor, clinical scientist, safety physician, clinical pharmacologist, 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 PK and 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 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). 
4.2.4.6. 
Alternative Dosing Schedules 
Alterations may be made to the schedule of administration and/or PK/PD sampling 
schedule based on the results of emerging PK and safety data.   
Schedules that incorporate a recovery period may be explored (e.g., 3 weeks on, 1 week 
off). This approach will be considered if the safety and PK data suggest that a therapeutic 
exposure cannot be achieved using the initial schedule without excessive toxicity. The 
starting dose for the alternate schedule will be the highest completed dose level (at or 
below MTD) with the initial schedule. Escalation can then proceed as described in 
Section 4.2.3. 
Schedules that use a different daily regimen (e.g., twice daily [BID] dosing) may also be 
explored. This approach will be considered if the safety, PK, and PD data suggest that a 
sufficient therapeutic exposure cannot be achieved using the initial schedule. If a shorter 
recovery period is used, the initial dose level will be 50% of the highest completed dose 
level (at or below MTD) with the initial schedule. Escalation can then proceed as 
described using in Section 4.2.3. If BID dosing is to be utilized, study events will occur 
as detailed in Table 11 and Table 12. 
The dosing schedule may also be adjusted to expand a prior dose cohort to further 
evaluate safety, pharmacokinetic and/or pharmacodynamic findings at a given dose level, 
or to add cohorts to evaluate additional dose levels. The study procedures for these 
additional subject(s) or cohort(s) will be the same as that described for other study 
subjects. 
Any changes to the dosing schedule may be made only after review of all available data 
and clearance by the GSK medical monitor.  Any planned changes will apply to a cohort 
of subjects and not an individual subject.  Changes will be communicated to the site in 
writing along with justification and data supporting the change.  A modified SRM, 
including updated Time and Events Table, will be provided to the sites prior to initiation 
of the alternative regimen. 
4.2.4.7. 
Intra-subject Dose Escalation 
In Part 1, intra-subject dose escalations may be considered on a case-by-case basis, 
provided that the subject has completed at least the DLT observation period without 


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≥ Grade 2 non disease-related toxicity in the first 21 days of therapy, that all subjects at 
the next highest dose level have completed the DLT observation period, and that prior 
approval has been obtained from the GSK Medical Monitor. Subjects may be dose-
escalated to the highest cleared dose.  Individual subjects may dose-escalate multiple 
times provided that the above criteria are met at each intra-subject dose escalation step.  
Safety assessments from these subjects will be included in the MTD determination. 
Subjects approved for intra-subject dose escalation will initiate daily dosing from Day 1 
of the higher dose (i.e., no dose interruption from Day 2 until Day 4) and will require 
additional PK sampling on Day 15 at the higher dose, as specified in Time and Events 
table (see Section 8.1).  Additional safety assessments may be specified at the time of 
dose escalation or schedule modification based on the safety profile in previous subjects 
at the higher dose level. Intra-subject 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. 
4.2.4.8. 
Completion of Dose Escalation and Determination of MTD/RP2D 
The dose escalation portion of Part 1 is expected to be completed when approximately 42 
subjects enrolled in the dose escalation and dose confirmation stages have completed the 
DLT evaluation period.  The RP2D will be the MTD or a lower dose that provides 
adequate PK exposure and biologic activity with superior tolerability.  The identification 
of MTD may not be necessary if a clear RP2D emerges without reaching the MTD.  The 
final determination of RP2D will be based on the mTPI suggested dose level, or the 
biologically active dose (e.g., clinical response), the safety profile, and available PK and 
PD data generated from all subjects in Part 1.  If necessary, alternate schedules can be 
explored to determine additional biologically active doses even after a RP2D is defined. 
Subjects may be enrolled at previously completed dose levels for the purpose of 
obtaining additional safety, PK, PD, metabolite, or biomarker data.  Paired fresh biopsies 
(pre- and post-dose) may be required in these subjects based on the need to obtain tumor 
PD data.  In addition, a reduced PK schedule may be used in subjects enrolled to obtain 
additional PK/PD data. 
4.2.5. 
PK/PD, Metabolite, and Biomarker Expansion Cohort(s) 
Any dose level at or near the MTD/RP2D in Part 1 may be expanded up to 12 subjects in 
order to collect additional data on safety and pharmacokinetics (PK).  More than one dose 
level may be selected for expansion (e.g., to establish a dose-response curve for PD or 
other biomarkers), based on emerging data.  Clinical samples from this/these cohort(s) 
will also be collected for analysis of pharmacodynamics (PD), metabolite profiling, and 
biomarkers.  Subjects may be enrolled into this cohort even after MTD/RP2D has been 
identified and Part 2 of the study (Section 4.3) has been initiated. 
Refer to Section 8.1, Time and Events Table (Table 10), which highlights the additional 
sampling requirements for this cohort.  In addition to the safety and PK evaluations 
necessary for all subjects in Part 1, blood and urine will be collected at time points 
specified in Section 8.1 (Table 10) for PD, biomarker, and metabolite profiling.  Pre-dose 


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and post-dose tumor biopsies will be required from subjects in this/these cohort(s).  
Subjects consenting to pre- and post-dose biopsies will be prioritized to enrollment in 
these cohorts. 18fluorodeoxyglucose (FDG) positron emission tomography (PET) (FDG-
PET)/computed tomography (CT) scan (PET/CT scan) will be required for all subjects in 
this cohort, as described in Section 8.6.3.  
 
 
 
4.2.6. 
Food Effect and Relative Bioavailability Sub-Study 
Part 1 will include a sub-study that will be an open-label, randomized, single dose, three 
period, cross over study to investigate the effect of a high-fat, high-calorie meal on the 
bioavailability of GSK3326595, and compare two formulations of GSK3326595 (capsule 
versus tablet). The dose of GSK3326595 will be 300 mg once a day (QD) (refer to 
Section 4.3.2).  GSK3326595 dosing will be separated by at least 48 hours between each 
period. Up to 12 subjects in the United States may be enrolled in the sub-study. A subject 
requiring dose reduction or discontinuation from study before completion of the sub-
study will be replaced by a new subject. Depending on the data from the initial 12 
subjects, up to an additional 12 patients may be enrolled in this sub-study. All subjects 
enrolled to the sub-study, on completion of their participation in this segment of the 
study, will continue on a daily dosing schedule until discontinuation criteria are met, as 
described in Section 5.4.  Further details will be provided in the SRM. The sub-study will 
be open to adults, with histologically- or cytologically-confirmed solid malignancies as 
described for Part 1 in Section 5.1. 
The high-fat (approximately 50% of the total caloric content of the meal), high-calorie 
meal (approximately 800 to 1000 calories) will be the representative example given by 
the 2002 US Food and Drug Administration (FDA) guidance [FDA, 2002]. Additional 
details of the required meal will be provided in the SRM. 
Subjects enrolled in the sub-study will be assigned to one of two sequences, as described 
in Table 2; equal numbers will be assigned to each sequence. The schedule of visits for 
subjects enrolled in the sub-study is detailed in Table 13 in Section 8.1.  Upon 
completion of the sub-study, all subjects will continue to undergo scheduled assessments 
as described in Table 9.  Additional details, including the process of sequence 
assignment, will be provided in the SRM. 
Table 2 
Food Effect and Relative Bioavailability Sub-Study 
Food-Effect Sub-Study: Single Dose Administrations 
Sample Size 
Sequence 
Period 1 (D1) 
Period 2 (D4) 
Period 3 (D8) 
6 
1 
Fasted / tablet 
Fed / tablet  
Fasted / capsule 
6 
2 
Fed / tablet 
Fasted / tablet 
Fasted / capsule 
Fasted: Subjects should take nothing by mouth apart from water and other medications 
for at least 8 hours before drug administration and should continue fasting until at least 4 
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hours after administration of the morning dose. Subjects should be administered the drug 
product as a capsule or tablet (as indicated) with 200 mL (8 fluid ounces) of water. Water 
can be allowed, as desired, except for one hour before and after drug administration. All 
subjects will receive standardized meals at approximately 4- and 9- hours post dose. 
Additional details of the meals will be provided in the SRM.  
Fed: Following an overnight fast (at least 8 hours), subjects should start the 
recommended high fat, high calorie breakfast 30 minutes prior to administration of the 
GSK3326595. Study subjects should eat this meal in 30 minutes or less; however, 
GSK3326595 should be administered 30 minutes after start of the meal. The 
GSK3326595 should be administered as a tablet with 200 mL (8 fluid ounces) of water. 
No food should be allowed for at least 2 hours post-dose. Water can be allowed, as 
desired, except for one hour before and after drug administration. All subjects will 
receive standardized meals at approximately 4- and 9- hours post dose.  Further details of 
the meals will be provided in the SRM.  
Any subject who experiences vomiting within 3 hours of dosing will be removed from 
the statistical analysis of PK comparability between tablet/capsule and tablet 
(fasted)/tablet (fed), and additional subjects will be enrolled to ensure 12 subjects 
complete all three periods.   
As described in Section 8.2.2, the Day 4 (Period 2) visit may be performed on Day 4 or 
Day 5.  The Day 8 (Period 3) visit (capsule administered in a fasting state) may be 
performed ± 1 day.  Continuous daily dosing with GSK3326595 will only commence 
once the subject has completed the Period 3 visit, irrespective of whether that visit occurs 
± 1 day. 
If the GSK3326595 tablet bioavailability is comparable to that of the GSK3326595 
capsules, all new and ongoing subjects may be switched from capsules to tablets for the 
remainder of the study, once they have been notified by the Sponsor.  
 
4.3. 
Part 2: Disease-Specific Expansion Cohort(s) 
Once the RP2D has been determined, subjects will be enrolled in disease-specific 
expansion cohorts at the RP2D in order to better characterize the clinical activity and 
safety profile of GSK3326595.  Expansion cohorts will enroll subjects with TNBC, 
mTCC, recurrent GBM, NHL (all subtypes recruited to Protocol Amendments 1-4 and 
indolent subtypes of NHL recruited to Protocol Amendment 5 onwards, which will be 
analyzed based on TP53 status: p53 mutant and p53 wild-type), ACC (which will be 
separated into two separate cohorts: one dosed with GSK3326595 capsules, and a second 
dosed with GSK3326595 tablets [this tablet cohort will enroll subjects who have not 
received any systemic therapy for their locally advanced or metastatic ACC]), ER+BC, 
HPV-positive solid tumors of any histology, and p53 wild-type NSCLC of any 
histological subtype.  Other tumor types may be added via protocol amendment, based 
on additional pre-clinical data and/or clinical responses observed during Part 1 or Part 2 
of the study.  
 
 
 
  
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Subjects in Part 2 will start with a continuous daily dosing schedule unless safety, PK or 
PD data necessitate a different dosing schedule. The final dose and regimen for Part 2 
will be decided upon completion of dose escalation in Part 1.  Dose reduction and/or 
scheduled interruptions will be permitted based on tolerability and toxicity. 
Plasma samples for PK evaluation will be collected, at reduced frequency compared to 
Part 1, in all subjects.  Plasma samples and other clinical samples (e.g. lymph node or 
bone marrow biopsies) will be collected pre- and post- study drug treatment as defined in 
the Time and Events Table in Section 8.1 for the PD evaluations. The timing of samples 
may be altered and/or extra samples may be obtained at additional time points to ensure 
thorough PK and PD monitoring.  For example, the timing of PK and PD monitoring may 
be moved earlier or later in the evaluation schedule based on emerging preclinical or 
clinical data that suggests a more optimal time frame to monitor biologic activity. 
4.3.1. 
Type and Number of Subjects (Part 2) 
It is estimated that up to 316 subjects will be enrolled in the disease-specific expansion 
cohorts of the study.  Cohorts will initially be limited to the following diseases (see 
Section 5.1 for all required disease characteristics); however, additional tumor-specific 
cohort(s) may be added based upon emerging pre-clinical and clinical data from Part 1 or 
Part 2 of the study: 
• 
Triple-negative breast cancer (TNBC) 
• 
Metastatic transitional cell carcinoma of the urinary system (mTCC) 
• 
Glioblastoma multiforme (GBM) 
• 
Non-Hodgkin’s lymphoma (NHL) – all subtypes recruited to Protocol Amendments 
1-4 and indolent subtypes of NHL recruited to Protocol Amendment 5 onwards, 
without mutations in the TP53 gene (p53 wild-type, NHL[-]) 
• 
Non-Hodgkin’s lymphoma all subtypes recruited to Protocol Amendments 1-4 and 
indolent subtypes of NHL recruited to Protocol Amendment 5 onwards, with 
mutations in the TP53 gene (p53 mutant, NHL[+]) 
• 
Adenoid cystic carcinoma (ACC), dosed with GSK3326595 capsule formulation 
• 
Adenoid cystic carcinoma (ACC), dosed with GSK3326595 tablet formulation, in a 
population that is systemic therapy-naïve.  
• 
Hormone receptor-positive adenocarcinoma of the breast (ER+BC) 
• 
Human papillomavirus (HPV)-positive solid tumors of any histology 
• 
p53 wild-type non-small cell lung cancer (NSCLC) of any histological subtype 
In Part 2, subjects will not be replaced if they prematurely discontinue therapy. 
Initially, the NHL cohorts enrolled subjects irrespective of histological subtype.  
However, in December 2019 it was noted that of the subjects enrolled with high-grade 
and other aggressive subtypes of diffuse large B-cell lymphoma (DLBCL), including 
double- and triple-hit lymphomas, there were zero objective responses out of 14 subjects 
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(including complete/partial responses in were observed in subjects with FL and 
transformed follicular lymphoma (tFL), and stable disease for several disease 
assessments was observed in subjects with MCL). Therefore, Protocol Amendment 5 
limited further enrollment to this population to subjects with more indolent disease who 
may receive more benefit from treatment with GSK3326595 monotherapy. 
4.3.2. 
R2PD Dose Selection 
Subjects will start dosing on Day 1 with the dose and schedule selected as the RP2D in 
Part 1 of the study. 
At a 21 March 2018 investigator meeting, 400 mg once daily (QD) was selected as the 
RP2D, based on safety, tolerability, efficacy, PK, and PD.  Dose reductions and 
scheduled interruptions are permitted for toxicity and tolerability as described in Table 3.  
At that meeting, it was also determined that if emerging data demonstrated that 400 mg 
QD proved intolerable for a majority of subjects, that the starting dose for all subjects 
enrolled from that time forward may be reduced (e.g., to Dose level [DL]-1). The final 
dose selection will take into account all available clinical data, as well as a PK/PD model 
to predict the optimal dose with minimal cytopenias. 
Table 3 
RP2D and Planned Dose Reduction 
RP2D 
400 mg QD 
DL-1 
300 mg QD 
DL-2 
200 mg QD 
DL-3 
200 mg QD, administered for 3 weeks, 
followed by a 1-week rest period 
Note: These dose levels may be adjusted on a case-by-case basis after discussion with the 
GSK medical monitor. 
Subsequent evaluation of safety and tolerability data was performed, using data from the 
04 February 2019 data cut included in the IB for GSK3326595 [GlaxoSmithKline 
Document Number 2017N314773_03].  As of that date, 71 subjects had been treated at 
the 400 mg RP2D in the 204653 study.  Of those 71 subjects, 33 (46%) required at least 
one dose reduction.  Of the 33 subjects requiring dose reduction, the majority (23 subjects 
[70%]) remained on 300 mg for their duration on study.  Overall, only 10 subjects (14% 
of the total number treated at 400 mg) required more than one dose reduction (i.e., to 
doses below 300 mg).   
Clinical activity was observed in Part 1, in subjects with ACC who were treated at doses 
of 300 mg and below.  Of the three patients who exhibited confirmed partial responses, 
two were started at a dose of 200 mg QD and remained at that dose throughout their time 
on study.  The third responder began treatment with GSK3326595 at 400 mg QD, but 
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All new subjects enrolled, following approval of Protocol Amendment 4 (food effect and 
relative bioavailability sub-study in Part 1, and all dose expansion cohorts in Part 2), will 
start on 300 mg QD (i.e., at Dose level-1 [DL-1] in Table 3).  In all cohorts, dose 
reduction for toxicity will be permitted, as described in Table 3. 
4.3.3. 
Statistical Design 
Continued recruitment into each disease-specific expansion cohort is determined using 
the rules described in this section.  
 
 
 
 
 
 
 
 
 
4.3.3.1. 
GBM Cohort 
In Part 2, the GBM cohort will employ a Bayesian adaptive design that allows the study 
to be frequently monitored with the constraint of both Type I and Type II error rates. The 
first interim analysis will be conducted after a minimum of 10 evaluable subjects who 
have had at least three post-baseline assessments, have progressed or died, or have 
permanently discontinued from study treatment. Up to 28 subjects may be enrolled in the 
GBM cohort; for details of the design and decision rules, refer to Section 11.3.  
4.3.3.2. 
mTCC, TNBC, and NHL Cohorts 
For mTCC, TNBC and NHL cohorts, a “basket” Bayesian hierarchical modeling 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 ORR, per standard 
evaluation criteria (see Section 14.4 for definitions of response assessments and criteria).  
Bayesian hierarchical modeling will be used to investigate the clinical activity of 
GSK3326595 in the four tumor-specific cohorts of subjects.  Hierarchical modeling 
allows information about the treatment effect in one cohort to be ‘borrowed’ when 
estimating the treatment effect in another cohort [Berry, 2013].   
Clinical activity will be monitored through frequent interim analyses.  The first interim 
analysis will be conducted when about 40 evaluable subjects are enrolled across the four 
tumor-specific cohorts (mTCC, TNBC, p53 WT NHL, and p53 mutant NHL) at a dose 
level based on RP2D or at least 10 evaluable subjects are available in any cohort.  
Subjects treated at the RP2D in Part 1, with disease subtypes under study in Part 2, will 
be incorporated into clinical activity analysis provided that they are evaluable.  Each 
subsequent interim analysis can be conducted after every five additional subjects become 
evaluable.  The timing of subsequent interim analyses will be based on the enrollment 
rate into each of the cohorts with the expected duration of Part 2 of the trial to be 104 
weeks.  A subject is evaluable for the interim futility analysis if they have either 
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progressed or died, withdrawn from the study treatment, or are ongoing and have 
completed at least two post baseline disease assessments. 
Decisions are based on whether the posterior probability that the ORR exceeds its 
corresponding historical control is sufficiently low compared to fixed statistical 
thresholds. If this posterior probability is sufficiently low within a given cohort (0.15), 
then enrollment may be halted early for futility. At the final analysis and after the study 
has been closed, if the posterior probability is sufficiently high (0.87), then the dose will 
be declared efficacious for that cohort. Separate from model estimates, the observed ORR 
will also be reported for each cohort. 
Enrollment into each disease-specific cohort will continue during the conduct of each 
interim analysis subsequent to the decision of whether or not to declare futility.  The total 
number may be increased up to a total of 32 evaluable subjects for the TNBC cohort, up 
to a total of 25 evaluable subjects for each of the two NHL cohorts, and up to 40 
evaluable subjects for the mTCC cohort, depending on the results observed; a separate 
decision will be made for each disease cohort.  Enrollment into each tumor specific 
cohorts can only be terminated for futility (i.e., lack of clinical activity), notwithstanding 
the provisions of Section 5.5; otherwise enrollment will continue to the planned 
maximum sample size in each cohort.  Inference stemming from the Bayesian 
hierarchical model of GSK3326595 efficacy in subjects harboring these four tumor types 
are intended to inform decision making.  Actual decisions will depend on the totality of 
the data. 
Subjects enrolled in Part 1 may be included in the Part 2 efficacy analysis provided that 
they were treated at the RP2D and have a disease under study in Part 2. 
The decision to terminate a disease-specific 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 subjects treated at the time of interim analysis), 
additional subjects in a cohort may be enrolled even if the model suggests a low 
likelihood of activity in that tumor type. 
4.3.3.3. 
ACC Cohorts (Capsule and Tablet Formulation) 
The Simon’s optimal two stage design will be utilized for the ACC cohorts.  Up to 38 
subjects in the capsule cohort will be enrolled, and up to 50 subjects in the tablet cohort 
will be enrolled. One interim analysis will be performed in each cohort after at least the 
first 10 treated subjects for the capsule cohort and the first 17 treated subjects for the 
tablet cohort become evaluable (i.e. who have had at least three post-baseline 
assessments, have progressed or died, or have permanently discontinued from study 
treatment). Please refer to Section 11.5 for details of the design and decision rules. 
4.3.3.4. 
Hormone Receptor-Positive Breast Cancer Cohort 
The ER+BC cohort will employ a Bayesian adaptive design that allows the study to be 
frequently monitored with the constraint of both Type I and Type II error rates. The first 
interim futility analysis will be conducted after a minimum of 10 evaluable subjects who 


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have had at least two post-baseline assessments, have progressed or died, or have 
permanently discontinued from study treatment. If the cohort does not meet the futility 
criteria, then up to 25 additional subjects may be enrolled in this cohort; for details of the 
design and decision rules, refer to Section 11.6. 
4.3.3.5. 
HPV-Positive Solid Tumor Cohort 
The HPV-positive cohort will employ a Bayesian adaptive design that allows the study to 
be frequently monitored with the constraint of both Type I and Type II error rates. The 
first interim futility analysis will be conducted after a minimum of 10 evaluable subjects 
who have had at least two post-baseline assessments, have progressed or died, or have 
permanently discontinued from study treatment. If the cohort does not meet the futility 
criteria, then up to 18 additional subjects may be enrolled in this cohort; for details of the 
design and decision rules, refer to Section 11.7. 
4.3.3.6. 
NSCLC Cohort 
The p53 wild-type NSCLC cohort will be used to estimate the clinical activity for 
GSK3326595 for this population. The analysis will be performed on a minimum of 10 
and maximum of 15 evaluable subjects with confirmed p53 wild-type status. The 
additional 5 subjects are intended to account for any discrepancies between local p53 
testing and central, comprehensive testing to ensure a minimum of 10 evaluable p53 
wild-type subjects. Only those evaluable subjects whose central test results confirm p53 
wild-type status will be included in the analysis. A subject is evaluable for analysis if 
they have either progressed or died, withdrawn from the study treatment, or are ongoing 
and have completed at least two post-baseline disease assessments. A Simon’s optimal 
two stage design will be utilized as a framework for the analysis of this cohort, where one 
interim analysis will be performed after at least the first 10 treated subjects become 
evaluable. Please refer to Section 11.5 for details of the design and decision rules. 
4.4. 
Part 3: GSK3326595 + Pembrolizumab Combination Study 
[Active in all regions, except France] 
The primary objective of Part 3 is to evaluate the safety and tolerability of GSK3326595 
when administered in combination with pembrolizumab in subjects with select solid 
tumors.  As described in Section 4.4.4, three cohorts will be evaluated.  All subjects will 
receive pembrolizumab at the approved dose (200 mg IV every 3 weeks [q3w]), in 
combination with GSK3326595 dosed orally at 100 mg QD, 200 mg QD, or 300 mg QD.  
 
 
 
All available data from Part 3, including safety, tolerability, efficacy, PK, and PD will be 
used to select a dose of GSK3326595 to be administered with pembrolizumab in future 
studies.  In order to collect PD data, pre- and on-study biopsies will be required for all 
subjects.  Subjects will receive GSK3326595 at the assigned dose as monotherapy for 
14 days, at which time the on-study biopsy will be collected.  Subjects will then 
commence therapy with pembrolizumab administered every 3 weeks.  Safety will be 
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assessed continuously.  Cohort(s) may be closed to further enrolment based on toxicity 
emerging at any time on study, as described in Section 4.4.4. 
4.4.1. 
Type and Number of Subjects (Part 3) 
The study population will be adults, with locally advanced or metastatic NSCLC, 
melanoma, mTCC, or HNSCC that have failed to respond to treatment (e.g., SD, with 
subsequent documented progression as per iRECIST, or PD as best response) with prior 
PD-1 or PD-L1 directed therapy.  Subjects who initially responded (e.g., iPR or iCR) to 
these therapies, then subsequently progressed, will not be eligible for participation in 
Part 3.  In addition, squamous cell carcinoma of the cervix patients that have progressed 
on or after PD-1 or PD-L1 directed therapy or are PD-1/PD-L1 treatment naïve will be 
enrolled in Part 3. For full details of eligibility criteria, please refer to Section 5.1. 
Overall, approximately 30 subjects will be enrolled in Part 3.  These subjects will be 
divided evenly between three cohorts, each receiving a different dose of GSK3326595 in 
combination with a single dose of pembrolizumab.  For details of subject enrolment, 
please refer to Section 4.4.4 and to the SRM.  
 
  
 
 
4.4.2. 
Treatment Arms and Duration 
All subjects in Part 3 will receive GSK3326595 in combination with pembrolizumab.  
Subjects may continue therapy with GSK3326595 until progression, unacceptable 
toxicity, or withdrawal of consent.  Subjects may continue therapy with pembrolizumab 
until progression, unacceptable toxicity, or withdrawal of consent, for a maximum of 
24 months. 
4.4.3. 
Dose Selection 
Subjects will be assigned prior to first dose to receive either 100 mg, 200 mg, or 300 mg 
of GSK3326595 administered once daily, based on the dose escalation schema described 
in Section 4.4.4.  All subjects will receive pembrolizumab at the approved dose (200 mg 
IV every 3 weeks).  Subjects may dose-interrupt and/or dose-reduce GSK3326595 and/or 
dose interruption of pembrolizumab for toxicity as described in Section 14.2. There will 
be no intra-subject dose escalation.  Subjects who require dose interruption of 
GSK3326595 and/or pembrolizumab, and/or dose reduction of GSK3326595 for toxicity 
may continue on protocol at the lower dose or delayed schedule. 
4.4.4. 
Cohort Design 
Overall, approximately 10 subjects per dose level may be enrolled.  Allowing for late 
screen failures and early (non-AE related) withdrawals/discontinuations, up to 6 subjects 
may be enrolled to deliver a minimum of 5 evaluable subjects for each dose decision 
meeting.  Each subject must complete the 35-day DLT evaluation period, and the 
available safety data must be reviewed before a decision is made on whether to proceed 
to the next dose level. If a subject fails to receive more than 80% of the planned doses of 
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GSK3326595 or full first cycle of pembrolizumab within the 35-day DLT evaluation 
period for reasons other than toxicity, the subject will be replaced. Refer to Table 15 for 
the schedule of activities for subjects enrolled in Part 3.  Dosing will commence in the 
100 mg cohort.  Safety will be reviewed on an ongoing basis by, at a minimum, the GSK 
medical monitor and GSK Global Safety representative. 
Figure 4-2 
Part 3 Schema 
 
 
 
 
Enrollment into Part 3 will occur in two stages at each dose level. The target sample size 
for each stage is 5 subjects, however, an additional subject may be enrolled at stage 1 and 
stage 2 of each dose level, to deliver a minimum of 5 subjects per stage and at least 10 
subjects per dose level.  Hence, it is possible that six subjects may be dosed in stage 1 or 
stage 2, resulting in 11 total subjects at any one dose level.  At the analysis of each stage, 
the full number of subjects dosed will be included, i.e. if 6 subjects are dosed in stage 1, 
data from all 6 subjects will be used to make the decision to either stop or continue 
enrolment at the current dose level. 
Five (or six) subjects may be enrolled immediately at the 100 mg dose level (stage 1).  
Planned analysis of the cohort safety data will take place in a dose decision meeting (see 
Section 4.4.4.1) after all subjects dosed in stage 1 complete 35 days of study treatment 
(i.e., 5 weeks of GSK3326595, as well as the first cycle of pembrolizumab treatment) or 
discontinue prior to 35 days Figure 4-2; A).  It is recommended that the cohort stop 
enrolling for safety reasons if the following criterion is met: 
• 3 or more subjects out of the first 5 or 6 enrolled experience a toxicity (at any 
time on-study) as described in Section 4.4.4.1 
If the safety stopping criteria (as defined in Section 4.4.4.1) are not triggered by the first 
5 (or 6) subjects, enrollment may continue, with continuous evaluation of safety after 
each subject enrolled. The additional 5 subjects may all be enrolled immediately at the 
same dose level.  The cohort will be recommended to stop for safety and higher dose 
cohorts will not be opened (Figure 4-2; B) if the following criterion is met: 
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• 4 or more subjects in the 100 mg dose level (i.e. 10 or 11 subjects) experience a 
toxicity (at any time on-study) described in Section 4.4.4.1 
Once 10 (or 11) subjects at the 100 mg dose level have completed at least 35 days of 
study treatment (Figure 4-2; B), the safety data from the cohort will be reviewed in a dose 
decision meeting, in accordance with the Dose Escalation Plan.  All safety events from all 
Part 3 subjects on treatment will be reviewed prior to dose escalation.  Upon the 
agreement at the dose decision meeting, the 200 mg cohort may open. 
Five (or six) subjects may be enrolled in the 200 mg cohort immediately (stage 1), and 
evaluation and further enrolment will proceed as described above for the 100 mg cohort 
(Figure 4-2; C).  Once all 10 (or 11) subjects have been enrolled in the 200 mg cohort 
(Figure 4-2; D), then all available safety data will be reviewed in a dose decision meeting 
prior to making a decision about opening the 300 mg cohort. 
Five (or six) subjects may be enrolled in the 300 mg cohort, and evaluation and further 
enrolment will proceed as the 100 mg and 200 mg cohorts (Figure 4-2; E).  
Approximately 10 (or 11) subjects may be enrolled in the 300 mg cohort. 
If, at any time, more than 4 subjects per cohort at a lower dose meet the stopping criteria 
described in Section 4.4.4.1, then further enrolment in higher dose cohort(s) may be 
terminated upon review of all available safety data (Figure 4-2; F).  In the event that a 
dose cohort is closed to further enrolment, subjects already enrolled in Part 3 may 
continue to receive treatment until disease progression, unacceptable toxicity, or 
withdrawal of consent as described in Section 4.4.2. 
4.4.4.1. 
Safety Stopping Criteria 
As described above, all available safety data will be reviewed in dose decision meetings:  
after the first 5 (or 6) subjects in each cohort complete 35 days of study treatment, or 
discontinue prior to 35 days (Figure 4-2; A, C, and E); and after all 10 (or 11) subjects in 
each cohort complete 35 days of study treatment, or discontinue prior to 35 days (Figure 
4-2; B and D).  Dose decision meetings will be attended by the GSK medical monitor, 
GSK clinical scientist, GSK safety physician, GSK clinical pharmacologist, and the 
Investigators.  Agreement to proceed with dosing in the cohort, or to open the next cohort 
to enrolment, will be made in accordance with the Dose Escalation Plan.  Safety data will 
also be reviewed on an ongoing basis (Figure 4-2; F).   
The number of subjects with adverse events meeting one or more of the following 
criteria, emerging at any time during study treatment, will be defined.  In all cases, “drug-
related” may pertain to either GSK3326595 or pembrolizumab alone, or the two 
administered in combination: 
• Any drug-related Grade 4 non-hematological toxicity 
• Any drug-related Grade 4 hematological toxicity, or any drug-related Grade 3 
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• Any drug-related hepatic toxicity that meets liver stopping criteria as defined in 
Section 5.4.5 
• Any drug-related Grade 2 or greater toxicity that, in the opinion of the 
Investigator and Medical Monitor, should limit further enrolment into the study 
• Inability to receive at least 80% of scheduled doses in the DLT observation period 
due to drug-related toxicity. 
If it is clearly established that the event is unrelated to treatment, the event will not meet 
the above criteria.  Grade 4 toxicities that are known to occur with pembrolizumab 
therapy and are controlled within 2 weeks using the recommended supportive measures 
(refer to Section 14.2.2 and Section 14.2.3) do not meet the above criteria (though could 
be considered cause for stopping based on the clinical judgement of the Investigator(s) 
and Medical Monitor).  These known toxicities will be evaluated during dose decision 
meetings, to assess for parameters that include increases in frequency or severity.    
Subjects who are unable to receive at least 80% of scheduled doses during the 35-day 
DLT observation period for reasons other than drug-related toxicity (e.g. acute illness, 
disease progression) will not be evaluable for DLT purposes and will be replaced in the 
cohort. 
The safety stopping criteria were chosen to align with an mTPI-2 [Guo, 2017] design 
with a target toxicity rate of 40%, considering the longer watch period for observing 
adverse events. This will allow for higher accumulation of events and renders the 
traditional design too conservative for the purpose of this study. The safety stopping 
criteria were confirmed via simulation of the operating characteristics of the model 
(provided in Section 11.10.4).  If the decision is made to close enrolment at a particular 
dose, then further enrolment in higher-dose cohorts may also be terminated at that time.   
4.4.5. 
Statistical Design 
No formal statistical hypothesis will be tested in this cohort. Analyses will be descriptive 
and exploratory. 
4.5. 
Type and Number of Subjects (Overall) 
All subjects enrolled in this study will have a diagnosis of relapsed or refractory cancer 
for which no standard therapy is expected to provide a significant response.  It is 
estimated that a maximum of 412 subjects will be enrolled in the study, divided as 
follows:  As planned, approximately 42 subjects will be enrolled in the dose escalation 
phase of Part 1.  In addition, approximately 12 subjects will be enrolled in the 
PK/PD/biomarker/metabolite cohort(s) and approximately 12 subjects but no more than 
24 subjects will be enrolled in the food effect and relative bioavailability cohort.  An 
additional 316 subjects may be enrolled in the disease-specific efficacy cohorts of Part 2.  
Approximately 30 subjects may be enrolled in Part 3.  Further details of the type and 
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4.6. 
Design Justification 
Given the high unmet medical need of relapsed/refractory advanced solid tumors and 
non-Hodgkin’s lymphoma, this three-part Phase I study (204653) is proposed.  The study 
comprises a dose-escalation part, followed by a series of cohorts to determine preliminary 
efficacy in selected tumor types, as well as a dose-finding study of GSK3326595 plus 
pembrolizumab to identify a starting dose of GSK3326595 for future study(s). 
4.6.1. 
Part 1 
Part 1 is a conventional dose-escalation study using the mTPI approach, a well-validated 
method to identify the MTD/RP2D of a given compound.  While preliminary efficacy 
data will be collected as part of the course of this Part, it will not be a primary endpoint.  
In addition to identification of MTD/RP2D, blood and urine collections will be 
performed to characterize the pharmacokinetic parameters of GSK3326595 as well as to 
partially characterize the biomarker profile of GSK3326595 treatment. 
4.6.2. 
Additional Pharmacodynamic, Metabolic & Biomarker Profiling 
All subjects in Part 1 will be evaluated for pharmacodynamic data.  
 
 (
 has been identified and validated as a pharmacodynamic 
biomarker of PRMT5 inhibition in multiple preclinical in vitro and in vivo studies.  
Analysis of 
 will provide valuable information regarding target engagement by 
GSK3326595. 
A cohort of subjects in Part 1, treated at or close to the MTD, will be evaluated more 
extensively for metabolic and biomarker profiling (Section 4.2.5).  This cohort will 
provide samples for biomarker, pharmacodynamic, and metabolite assessment.  Analysis 
of human samples will provide first-hand information on metabolism and disposition of 
GSK3326595 in humans. 
 
 
.   
4.6.3. 
Food Effect and Relative Bioavailability Profiling 
A subset of subjects in Part 1, treated at 300 mg, will be evaluated more extensively to 
preliminarily evaluate the effect of food on the pharmacokinetics of GSK3326595 
(Section 4.2.6).  A relative assessment of bioavailability between capsules and tablets 
will also be conducted in this group.  This cohort will provide data that can be used to 
modify dosing instructions for subjects in this and future studies (e.g., GSK3326595 may 
be taken without respect to food, or GSK3326595 must be taken on an empty stomach).  
It will also be used to support development of GSK3326595 tablet formulation. If the 
GSK3326595 tablet bioavailability is comparable to that of the GSK3326595 capsules, 
then any newly enrolled or ongoing subjects in any of the cohorts may be allowed to 
move over from the capsules to the tablets, once they have been notified by the Sponsor.  
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4.6.4. 
Part 2 
Part 2 is a disease-specific preliminary study of efficacy, examining the effect of 
GSK3326595 on tumor growth (as measured by ORR [mTCC, TNBC, ACC, ER+BC, 
HPV-positive solid tumor, NSCLC and NHL cohorts] or six-month PFS rate [GBM 
cohort]).  Interim analyses and rules for stopping for futility are described in Section 11 
and in the Report and Analysis Plan (RAP). 
4.6.5. 
Part 3 [Active in all regions, except France] 
Part 3 is a dose-escalation study using a continuous assessment approach, a well-
validated method to identify safety and toxicity of a given regimen.  While efficacy, PK, 
and PD will be collected in the course of this part, these will not be primary endpoints.  
However, all available data will be used to identify a recommended dose for further 
evaluation in future clinical studies. 
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5. 
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB/IB supplement(s). 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
5.1. 
Inclusion Criteria 
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply: 
1. Males and females 18 years of age (at the time consent is obtained) 
NOTE: For NHL cohort ONLY, subjects must be 75 years of age at the time 
consent is obtained 
2. Capable of giving signed informed consent 
3. Able to swallow and retain orally-administered medication 
4. Eastern cooperative oncology group (ECOG) performance status (defined in 
Appendix 3) of 0 to 2 
5. Diagnosis of one of the following: 
a. Part 1: Histologically- or cytological-confirmed diagnosis of non-resectable or 
metastatic solid malignancy that has progressed on prior therapy (radiographic 
documentation of progression is adequate for study participation) 
b. Part 2: Histologically- or cytologically-confirmed diagnosis of metastatic or non-
resectable disease that has progressed on or after prior therapy (ACC tablet 
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cohort does not require prior therapy for enrollment; for all tumors, radiographic 
documentation of progression is adequate for study participation):  
• 
TNBC [estrogen receptor negative (ER-), progesterone receptor negative 
(PR-) and human epidermal growth factor receptor 2 negative (Her2-), as 
defined by local laboratory standards];  
• 
ER+BC [estrogen receptor positive (ER+) or progesterone receptor positive 
(PR+), human epidermal growth factor receptor 2 negative (Her2-), as 
defined by local laboratory standards]; 
NOTE: Subjects in this cohort must have previously received therapy with a 
cyclin-dependent kinase (CDK) 4/6 inhibitor or be considered ineligible to 
receive therapy with these agents 
• 
metastatic or non-resectable transitional cell carcinoma of the bladder, 
ureter, or renal pelvis; 
• 
recurrent GBM; 
NOTE: Subjects with prior low-grade glioma with subsequent imaging 
demonstrating progression to GBM may be enrolled without confirmatory 
biopsy on a case-by-case basis after discussion with the medical monitor 
• 
ACC requiring systemic therapy.  In order to be eligible for enrolment, 
ACC subjects must:  
o have shown progression by local evaluation of scans, as per RECIST 
1.1, within the 13 months prior to enrolment, AND 
o have measurable disease, as confirmed by independent central review 
of baseline scans prior to first dose. 
• 
HPV-positive solid tumor of any primary histology  
NOTE: HPV-positive status may be determined locally via any generally 
accepted test [e.g., HPV DNA OR p16 immunohistochemistry].  A 
minimum of 10 subjects must be enrolled with cervical cancer; 
• 
non-Hodgkin’s lymphoma that is NOT one of the following subtypes, as 
determined by local laboratory testing: 
o Burkitt’s lymphoma or other high-grade lymphoma 
o Double- or triple-hit large B-cell lymphoma 
NOTE: Any questions regarding eligibility of subtypes should be 
directed to the medical monitor 
• 
OR NSCLC, of any histologic sub-type; with local mutational analysis 
demonstrating wild-type status of TP53 (i.e., p53 wild-type NSCLC) 
NOTE: Subjects in the cohort must have previously received treatment with 
an anti-PD1 and/or PD-L1 therapy or be considered ineligible to receive 
therapy with these agents 
NOTE: Subjects whose tumors harbor actionable mutations (e.g., EGFR 
mutations or ALK rearrangements) must have received prior therapy with 
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c. Part 3: Histologically- or cytologically-confirmed diagnosis of metastatic or non-
resectable NSCLC (of any histologic sub-type), mTCC, HNSCC, or melanoma 
that failed to respond to prior treatment with PD-1 or PD-L1 targeted therapy and 
recurrent/metastatic cervical squamous cell carcinoma that have progressed on or 
after PD-1 or PD-L1 directed therapy or are PD-1/PD-L1 treatment naïve.  
• 
NOTE: NSCLC, mTCC, HNSCC or Melanoma Subjects must have had SD 
(with subsequent documented progression as per iRECIST) or PD as best 
response to prior PD-1 or PD-L1 targeted therapy to be eligible for enrollment.  
6. Prior therapy 
• ACC tablet cohort: subjects must be systemic therapy-naïve.  Prior surgery 
and/or radiation is permitted 
• NHL cohort: subjects may have received up to 4 prior lines of systemic 
therapy for disease 
• Tumors with actionable mutations (e.g., BRAF V600E in melanoma; EGFR 
mutations or ALK rearrangements in NSCLC) must have received prior 
therapy with targeted agents prior to enrollment 
• Apart from ACC tablet cohort, subjects must have received at least one line 
of prior systemic therapy (or have a disease for which no approved therapy 
exists), AND have no standard-of-care therapy that would be expected to 
achieve a durable clinical response, OR refuse standard therapy, OR are not 
candidates for standard therapy. 
7. Evaluable disease 
a. During Part 1, evaluable disease is required; measurable disease per RECIST v1.1 
is recommended but not required 
b. Subjects enrolled in Part 2 and Part 3 must demonstrate measurable disease per 
the disease-specific criteria described in Appendix 4. 
8. PK/PD/biomarker/metabolite expansion cohort(s) only (Section 4.2.5): Subjects must 
consent to pre- and post-dose tumor biopsies and additional sample collection 
procedures as specified in the Time and Events Table (Section 8.1). 
9. Food effect and relative bioavailability sub-study only (Section 4.2.6): Subjects must 
consent to additional procedures as specified in the Time and Events Table (Table 
13). 
10. Part 3 only: Subjects must consent to additional procedures (including paired 
biopsies) as specified in the Time and Events Table (Table 15) 
11. 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: Subjects with treatment-related toxicities that are unlikely to resolve in the 
opinion of the treating physician may be enrolled on a case-by-case basis after 
discussion with the medical monitor 
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Table 7 
Definitions for Adequate Organ Function 
System 
Laboratory Values 
Hematologic 
 
Absolute neutrophil count (ANC) 
1.5 X 109/L 
Hemoglobina 
Solid malignancy: 9 g/dL 
Non-Hodgkin’s Lymphoma: 8 g/dL 
Plateletsa 
Solid malignancy: 100 X 109/L 
Non-Hodgkin’s Lymphoma: 75 X 109/L,  
PT/INR and PTT 
1.5 X upper limit of normal (ULN), unless subject is 
receiving systemic anticoagulation 
Hepatic 
 
Albumin 
2 g/dL 
Total bilirubin 
1.5 x X ULN 
NOTE: Isolated bilirubin >1.5 X ULN is acceptable if: 
• 
bilirubin is fractionated and direct bilirubin 
<35% OR 
• 
subject has a diagnosis of Gilbert’s 
syndrome 
Alanine aminotransferase (ALT)  
2.5  ULN  
OR 
<5 x ULN is acceptable for subjects with documented 
liver metastases/tumor infiltration 
Renal 
 
Estimated Glomerular filtration rate (eGFR)b 
50 mL/min/1.73 m2 
NOTE: Participants with eGFR of <60 mL/min/1.73m2 
will require additional monitoring as described in 
Section 8.3.5.  
a. 
Subjects with solid tumors that require transfusion or initiation of growth factor support in order to achieve 
necessary platelet and/or haemoglobin must maintain adequate values for at least 7 days without transfusion or 
while on growth factor in order to be eligible for participation 
Subjects with NHL may receive transfusions and/or growth factor support in order to achieve necessary platelet 
and/or haemoglobin values. 
b. 
Estimated GFR should be calculated using the Chronic Kidney Disease Epidemiology Collaborative (CKD-Epi) 
method.  Details are provided in Appendix 5. Glomerular filtration rate (GFR) may also be directly determined via 
24-hour urine creatinine clearance or other equivalent method 
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 subject and the 
subsequent within range screening result may be used to confirm eligibility. 
13. Reproductive criteria: 
a. A male subject with female partner of child bearing potential must agree to use 
one of the methods of contraception specified in Section 7.3.2 for the duration 
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b. A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin [hCG] test), not nursing, and at 
least one of the following conditions applies: 
• 
Reproductive potential: subject must agree to follow one of the options and the 
duration specified in Section 7.3.1. 
• Non-reproductive potential defined as: 
• 
Pre-menopausal females with one of the following: 
• 
Documented tubal ligation 
• 
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion  
• 
Hysterectomy 
• 
Documented Bilateral Oophorectomy 
• 
Postmenopausal defined as 12 months of spontaneous amenorrhea with an 
appropriate clinical profile or females over 60 years of age. Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrollment. 
5.2. 
Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. Malignancy attributed to prior solid organ transplant 
2. Leptomeningeal disease, spinal cord compression, or brain metastases that require 
immediate CNS-specific treatment in the opinion of the Investigator (e.g., for 
symptomatic disease). 
NOTE: Subjects who require local therapy for CNS metastases may be considered 
for eligibility once local therapy is completed and acute treatment-related toxicities 
have resolved 
NOTE: Subjects with untreated lesions should be followed with intracranial imaging 
(e.g., MRI) at each disease assessment, as detailed in Section 8.1. 
NOTE: This criterion does not apply to subjects with GBM. In Part 1, subjects with 
GBM may enroll provided that they are on a stable to decreasing dose of 
corticosteroids for at least 14 days prior to the first dose of GSK3326595.  In Part 2, 
subjects with GBM may enroll irrespective of steroid dose. 
3. 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 GSK3326595. Any nitrosoureas or 
mitomycin C within 42 days prior to the first dose of GSK3326595. Prior therapy 
with biologic agents (including monoclonal antibodies) is permitted so long as 28 
days have elapsed since therapy and all therapy-related AEs have resolved to ≤ 
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with immunotherapy-related endocrinopathies, currently managed with 
replacement therapy, will be allowed on study. 
• Any radiotherapy within 14 days or major surgery within 28 days prior to the first 
dose of GSK3326595. For subjects in the GBM cohort, subjects must have 
completed radiation therapy at least 28 days prior to the first dose of 
GSK3326595. 
• Anti-androgen therapies for prostate cancer, such as bicalutamide, must be 
stopped 4 weeks prior to enrollment. Second-line hormone therapies such as 
enzalutamide or abiraterone should be stopped 2 weeks prior to enrollment. 
Subjects with prostate cancer should remain on luteinizing hormone releasing 
hormone (LHRH) agonists or antagonists. Subjects with prostate cancer may also 
remain on low-dose prednisone or prednisolone (up to 10 mg/day) and still be 
eligible for this study. 
4. Part 3 only: History of any of the following: 
• Recent history (within the past 2 years) of autoimmune disease or syndrome that 
required systemic treatment 
Note: Replacement therapies which include hormone replacement (e.g., thyroid 
hormone) or physiological doses of corticosteroids for treatment of 
endocrinopathies (e.g., adrenal insufficiency) are not considered systemic 
treatments. 
• A diagnosis of immunodeficiency or administration of systemic steroids (≥10 mg 
oral prednisone or equivalent) or other immunosuppressive agents within 7 days 
prior to randomization 
Note: Physiologic doses of corticosteroids for treatment of endocrinopathies or 
steroids with minimal systemic absorption, including topical, inhaled, or 
intranasal corticosteroids may be continued if the participant is on a stable dose.  
Steroids as premedication for hypersensitivity reactions (e.g., computed 
tomography [CT] scan premedication) are permitted. 
• Receipt of any live vaccine within 30 days prior randomization  
• Prior allogeneic/autologous bone marrow or solid organ transplantation 
• Current pneumonitis or history of non-infectious pneumonitis that required 
steroids or other immunosuppressive agents 
Note: post-radiation changes in the lung related to prior radiotherapy and/or 
asymptomatic radiation-induced pneumonitis not requiring treatment (Grade 1) 
may be permitted if agreed upon by the investigator and Medical Monitor. 
• Recent history of allergen desensitization therapy within 4 weeks of 
randomization 
• History of severe hypersensitivity to monoclonal antibodies 
5. History of a second malignancy, excluding non-melanoma skin cell cancer, within 
the last three years.  Subjects with second malignancies that were indolent, in situ or 
definitively treated may be enrolled even if less than three years have elapsed since 


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treatment.  Consult the GSK Medical Monitor if there are questions whether second 
malignancies meet the requirements specified above. 
6. Current use of a prohibited medication or planned use of any forbidden medications 
during treatment with GSK3326595 (see Section 7.1.2 for the list of medications). 
7. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant 
bleeding episodes). Any serious and/or unstable pre-existing medical (aside from 
malignancy), psychiatric disorder, or other conditions that could interfere with 
subject’s safety, obtaining informed consent or compliance to the study procedures, 
in the opinion of the Investigator. 
8. Any clinically significant gastrointestinal (GI) abnormalities that may alter 
absorption such as malabsorption syndrome or major resection of the stomach and/or 
bowels. 
9. 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. 
10. Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test 
result at screening.   
NOTE: Subjects with chronic hepatitis B virus (HBV) infection, who meet the 
criteria for anti HBV therapy may be eligible if subject is on a suppressive antiviral 
therapy prior to initiation of cancer therapy.   
NOTE: Subjects 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 therapy, have a HCV viral load <quantifiable limit. 
11. Any of the following cardiac abnormalities: 
• Recent history (within 6 months of first dose of study drug) of acute coronary 
syndromes (including myocardial infarction and unstable angina), coronary 
angioplasty, or stenting 
• Presence of a cardiac pacemaker 
• Baseline Corrected QT (Fridericia’s formula) interval (QTcF) ≥450 msec  
• Uncontrolled arrhythmias.  Subjects with rate-controlled atrial fibrillation for > 1 
month prior to first dose of study drugs may be eligible. 
• Class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system. 
12. 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. 


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13. History of optic nerve neuropathy or neuritis. 
5.3. 
Screening/Baseline/Run-in Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently enrolled. In order to ensure transparent reporting of screen failure 
subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, and respond to queries from Regulatory authorities, a minimal set of screen 
failure information is required including Demography, Screen Failure details, Eligibility 
Criteria, and any Serious Adverse Events. 
5.4. 
Withdrawal/Stopping Criteria 
5.4.1. 
Discontinuation of Study Treatment 
Subjects will receive study treatment until disease progression, death or unacceptable 
adverse event, including meeting stopping criteria for liver chemistry, hematologic/non-
hematologic toxicity, or corrected QT interval duration (QTc) prolongation, as defined in 
Section 5.4.5 through Section 5.4.7. 
In addition, study treatment may be permanently discontinued for any of the following 
reasons: 
• deviation(s) from the protocol 
• request of the subject or proxy 
• investigator’s discretion 
• subject is lost to follow-up 
• study is closed or terminated. 
• study drug is no longer available 
Note that discontinuation from study treatment does NOT equal complete withdrawal 
from the study (all efforts should be made to keep subjects with a diagnosis of ACC who 
withdraw from treatment on study for survival follow-up). 
Subjects in Part 3 may be treated past progression as described in Section 14.4.4. 
Subjects in Parts 1 and 2 with equivocal progression or with rising tumor markers in the 
absence of radiographic progression may continue on study therapy provided that safety 
related stopping criteria are not met.  
Subjects in Parts 1 and 2 with progressive disease (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 subject could continue to receive benefit, the subject is not experiencing serious 
toxicity, and there is no alternative treatment that is likely to benefit the subject).  
Discussion between the Investigator and the Medical Monitor must occur in order for a 
subject to continue study treatment once PD has been confirmed.  Subjects who continue 
on study beyond confirmed progression should continue to undergo all assessments 
described in the Time and Events Table. Subjects who demonstrate continued progression 


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at subsequent scheduled scans may be required to discontinue therapy at the discretion of 
the Investigator and the Medical Monitor. 
For subjects in all Parts of the study, the primary reason study treatment was permanently 
discontinued must be documented in the subject’s medical records and electronic case 
report form (eCRF).  
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanent discontinuation on the eCRF.  
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated.  
All subjects who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post study treatment follow-up as specified in Time 
and Events Tables (see Section 8.1).   
Any subject in the ACC tablet cohort who has not yet shown objective radiological 
disease progression at treatment discontinuation should be continued to be followed as 
per RECIST 1.1 for radiological progression. 
All subjects who permanently discontinue study treatment 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 subjects are unable or unwilling to attend 
clinic visits during follow-up, the investigator should inform the subject of modified 
follow-up options (eg, telephone call, email, contact with a relative or treating physician, 
or information from medical records). 
Note: following Protocol Amendment 7, survival follow-up should only be conducted for 
subjects with a diagnosis of ACC.   
Following Protocol Amendment 8 implementation, all recruited subjects who no longer 
receive study treatment will be considered to have completed the study and only subjects 
still deriving benefit from GSK3326595 as assessed by the Investigator may continue to 
receive study treatment. 
5.4.2. 
Lost to Follow-up 
A subject will be considered potentially lost to follow-up if he fails to return for 
scheduled visits and is unable to be contacted by study sites. 
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit: 
• The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible.  
• The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study.  
• In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 


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known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record.  
Efforts to reach the subject should continue until the end of the study. Should the subject 
continue to be unreachable at the end of the study, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”.  
5.4.3. 
Withdrawal from the study 
A subject may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral or 
administrative reasons, as described above.  
If a subject withdraws consent, the investigator/site staff must specifically ask if they are 
withdrawing consent to: 
• Further participation in the study including any further follow-up (eg, survival 
calls, consultation of medical records for vital status) 
• Further participation in study assessments excluding survival follow-up 
[relevant for Part 2 and Part 3 subjects only] (eg, survival calls, consultation 
of medical records for vital status) 
• The use of optional and/or mandatory biological samples that have not already 
been analysed (remaining unanalyzed samples must be destroyed) 
The investigator must document consent withdrawal in the site study records and CRF. 
If the subject has actively withdrawn consent to the processing of their personal data, the 
vital status of the subject can be obtained by site personnel from publicly available 
resources, where it is possible to do so under applicable local laws. 
Following Protocol Amendment 8 implementation, all recruited subjects who no longer 
receive study treatment will stop entirely and only subjects still deriving benefit from 
GSK3326595 as assessed by the Investigator may continue to receive study treatment. At 
the point of discontinuation of study treatment (including 30-day safety follow up), 
subjects will be considered to have completed the study. If a subject withdraws consent, 
the investigator/ site staff must document consent withdrawal in the site study records. 
5.4.4. 
End of Survival Follow-up  
In Part 2 or Part 3 (whichever is latest), unless a disease cohort is closed early, survival 
follow-up will continue in each cohort until approximately 70% of the total number of 
subjects have progressed or died.  At such time, the cohort will be closed and any further 
follow-up on subjects enrolled in that cohort will cease. Subjects with radiologically 
confirmed lack of disease progression who are still receiving GSK3326595 at the time of 
study completion may continue treatment through a separate mechanism (e.g., roll-over 
protocol). 
Note: following Protocol Amendment 7, survival follow-up will only be conducted for 
subjects in Part 1 and Part 2 with a diagnosis of ACC.  Survival follow-up with continue 
until approximately 70% of ACC subjects have died. 


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Following Protocol Amendment 8 implementation, all recruited subjects who no longer 
receive study treatment will stop entirely and only subjects still deriving benefit from 
GSK3326595 as assessed by the Investigator may continue to receive study treatment. 
5.4.5. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance [www.fda.gov, 2009]).  
See Figure 5-1 and Figure 5-2 for liver stopping criteria for subjects without and with 
liver metastases, respectively. 
Figure 5-1 
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm for Subjects WITH entry criteria ALT ≤2.5xULN 
 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6. 


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Figure 5-2 
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm including Subjects 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. 
5.4.5.1. 
Study Treatment Restart or Rechallenge 
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment 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 subject 
Refer to Appendix 7 for full guidance.  
5.4.6. 
QTc Stopping Criteria 
If a subject meets the corrected QT (QTc) interval duration criteria below, study 
treatment(s) will be withheld. 


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• QTcF interval ≥ 500 msec OR interval increase from baseline  60 msec: 
GSK3326595 will be 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 Appendix 2 for rechallenge guidelines). 
NOTE: In order to determine whether QT interval meets stopping criteria, the QT 
interval duration criteria should be based on the average QTc value of triplicate 
electrocardiograms (ECGs), including manual over-read. Routine ECG monitor does not 
require triplicate measurement.  However, 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 10 minutes apart from each 
other), and then use the averaged QTc values of the 3 ECGs to determine whether the 
subjects should have study treatment 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 subjects.  
• For purposes of data analysis, QTcF will be used. 
5.4.7. 
Other Stopping Criteria 
Stopping criteria for hematologic toxicities are detailed in Table 24. To monitor for 
hematologic toxicity, CBCs will be drawn weekly for the first three weeks of study, and 
then every three weeks, as described in the Time and Events table.  Subjects who develop 
Grade 2 or greater anemia or thrombocytopenia may be monitored more frequently, as 
clinically indicated.  Please see Appendix 2 for suggested management of hematologic 
toxicity. 
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 subjects, 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. 
5.5. 
Subject and Study Completion 
In Part 1, a subject who is not treated with the RP2D will be considered to have 
completed the study if: 
• 
they complete screening assessments, at least 21 days of study treatment and the 
post-treatment follow-up visit, or 
• 
they discontinue study treatment for progression or reasons listed in Section 5.4. 
A subject who is treated at RP2D will be considered to have completed the study if: 


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• 
they discontinue study treatment for reasons listed in Section 5.4, or 
• 
they die while receiving study treatment, or 
• 
are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study/perform the final analysis. 
In Part 2 and Part 3, a subject will be considered to have completed the study if: 
• 
they withdraw consent to any further study participation 
• 
they die while on study treatment or during the survival follow-up 
• 
they are ongoing on study at the time of the Sponsor’s decision to close the 
study/perform the final analysis. 
The end of the study is defined as the completion of all cohorts as defined in Section 5.4, 
or termination of the study at any time by the Sponsor.  
Subjects who have not died and are no longer being followed for survival are considered 
to have discontinued the study. The End of Study eCRF should only be completed when a 
subject is no longer being followed. The study may be considered completed for purposes 
of a final analysis when 70% of subjects enrolled in Part 2 or Part 3 (whichever is latest) 
have progressed or died. 
Final Last Subject Last Visit will be defined as patient’s treatment discontinuation 
(including 30-day safety follow up).  
Following Protocol Amendment 8, the end of this study is defined as the date of the last 
visit of the last subject undergoing the study. 
A final DCO, closure of the study database and final analysis will occur when all subjects 
have either died, discontinued treatment (including 30-day safety follow up), withdrawn 
consent, or have consented to continue with treatment as defined in this amendment. 
When the Protocol Amendment 8 is implemented at a site, the collection of data for all 
enrolled subjects who no longer receive study treatment will stop entirely. Those subjects 
still benefiting from GSK3326595 in the opinion of their treating Investigator may 
continue to receive study treatment until the end of availability of study drug which is 
anticipated to be Q3 2023. 
6. 
STUDY TREATMENT 
6.1. 
GSK3326595 and Pembrolizumab 
The term ‘study treatment’ is used throughout the protocol to describe GSK3326595 (or 
GSK3326595 plus pembrolizumab for subjects in Part 3) received by the subject as per 
the protocol design. Post Protocol Amendment 8 implementation, study drug 
GSK3326595 will be provided until the end of availability of study treatment, which is 
anticipated to be Q3 2023. 
Study Treatment 
Product name: 
GSK3326595 
Capsules 
GSK3326595 Tablets 
Pembrolizumab 


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Study Treatment 
Product name: 
GSK3326595 
Capsules 
GSK3326595 Tablets 
Pembrolizumab 
Dosage form: 
Capsules 
Tablet 
Solution for infusion  
Unit dose 
strength(s)/Dosage 
level(s): 
100 mg as free 
base  
100 mg as free base 
100 mg/4 mL  
Route of 
Administration  
Oral 
IV infusion 
Dosing 
instructions: 
The dosing regimen is detailed in Section 8.1 
and is designed to permit collection of detailed 
safety and PK data.  GSK3326595 is to be 
administered orally with water (approximately 
200 mL) at approximately the same time of 
day (± 4 hours) with no food or antacids for 1 h 
before and 2 h after each dose.  If a dose is 
delayed by more than 4 hours, the subject 
should not take that dose and should mark the 
dose as “not taken”.  On serial PK days and for 
two days prior (Days 13 through 16), subjects 
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/tablet should be taken one at a time. 
Administer diluted product 
once Q3W (refer to SRM 
for infusion time) 
Physical 
description: 
Opaque white 
capsules (size 
00) 
White to almost white film 
coated tablets with no 
markings 
Concentrate for solution 
for infusion, clear to 
slightly opalescent, 
colourless to slightly 
yellow solution, pH 5.2 – 
5.8.  
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. 
Treatment Assignment 
Subjects will be assigned to receive GSK3326595, either as monotherapy (Part 1 and 
Part 2), or in combination with pembrolizumab (Part 3), in an open-label fashion.  There 
will be no placebo arm.  Subjects will be identified by a unique subject number that will 
remain consistent for the duration of the study. 
6.3. 
Packaging and Labeling 
GSK3326595 will be provided to the sites by GSK. The contents of the label will be in 
accordance with all applicable regulatory requirements. 


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Pembrolizumab will either be provided to the sites in cartons containing vials by GSK or 
will be sourced locally by the sites themselves.  When provided by GSK, the contents of 
the label will be in accordance with all applicable regulatory requirements.  
6.4. 
Preparation/Handling/Storage/Accountability 
No special preparation of study treatment is required for GSK3326595.  Refer to 
pembrolizumab prescribing information [KEYTRUDA PI, 2019] for relevant 
instructions.  
• Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. Please refer to 
guidance in the Study Reference Manual with regard to storage of IP and 
temperature excursion management. 
• The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (e.g., receipt, reconciliation, and final disposition records).  
• Further guidance and information for final disposition of unused study treatment 
are provided in the SRM.  
Precaution will be taken to avoid direct contact with the study treatment. A Material 
Safety Data Sheet (MSDS) describing occupational hazards and recommended handling 
precautions for GSK3326595 will be provided to the investigator. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor or GSK study 
contact. 
Limited exposure and precautionary action (example: wearing gloves, washing hands 
post exposure) should be taken by site staff dispensing GSK3326595. 
6.5. 
Compliance with Study Treatment Administration 
At each visit, an evaluation of subject compliance with taken medication will be 
performed. The investigator will make every effort to bring non-compliant subjects into 
compliance.  
Compliance with GSK3326595 will be assessed through querying the subject during the 
site visits and documented in the source documents and CRF. A record of the number of 
GSK3326595 capsules/tablets dispensed to and taken by each subject must be maintained 
and reconciled with study treatment and compliance records. Treatment start and stop 
dates, including dates for treatment delays and/or dose reductions will also be recorded in 
the CRF. 
Following Protocol Amendment 8 implementation, refer to SRM for dispensing of study 
treatment and drug accountability. 


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Pembrolizumab will be administered intravenously at site under medical supervision of 
an investigator or designee. The date and time of administration will be documented in 
the source documents and reported in the CRF.  
6.6. 
Treatment of Study Treatment Overdose 
For this study, any dose of GSK3326595 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.  
In the event of an overdose the investigator (or treating physician) should: 
• Contact the Medical Monitor immediately 
• Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK3326595 can no longer be detected systemically (at least 28 days) 
• Obtain a plasma sample for PK analysis within 3 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis) 
• 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 subject. 
Post Protocol Amendment 8 implementation, overdoses are required to be reported to 
GSK via a paper process. 
An overdose of pembrolizumab is defined as 1000 mg (5 times the dose) of 
pembrolizumab. In the event of a suspected overdose, it is recommended that the 
appropriate supportive clinical care be instituted as dictated by the participant’s clinical 
status.  
6.7. 
Treatment after the End of the Study 
Post study treatment will not be provided as part of the protocol. Upon discontinuation 
from assigned study treatment, subjects may receive additional (non protocol) therapy at 
the discretion of the treating physician. New therapy should be documented on the CRF. 
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 8.1 for follow-up assessments and procedures). 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment. 


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Subjects receiving GSK3326595 at the time of DCO date may continue to receive 
GSK3326595 under Protocol Amendment 8; GSK3326595 will be provided until the end 
of availability of study treatment, which is anticipated to be Q3 of 2023. 
After the final DCO subjects may continue to receive GSK3326595 for as long as they 
derive clinical benefit from study treatment as assessed by the Investigator and do not 
meet any protocol-defined study treatment stopping criteria (maximum until the end of 
availability of study drug which is anticipated to be Q3 2023); subjects may choose to 
discontinue study treatment at any time. 
7. 
MEDICATION, LIFESTYLE, AND DIETARY 
RESTRICTIONS 
7.1. 
Concomitant Medications and Non-Drug Therapies 
Subjects 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. 
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. 
7.1.1. 
Permitted Medications and Non-Drug Therapies 
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with erythropoietin, antibiotics, antiemetics, 
antidiarrheals, and analgesics, and other care as deemed appropriate, and in accordance 
with their institutional guidelines.  
Colony-stimulating factors like filgrastim and pegfilgrastim may be used in Month 2 and 
beyond as clinically indicated.  The only caveat is that subjects should not receive those 
medications listed as prohibited in Section 7.1.2.1. 
Bisphosphonates and denosumab will be allowed if subjects have been on a stable dose 
for at least three months prior to receiving the first dose of GSK3326595. 
7.1.2. 
Prohibited Medications and Non-Drug Therapies 
7.1.2.1. 
Prohibited Medications 
Subjects should not receive other anti-cancer therapy [including chemotherapy, 
immunotherapy, biologic therapy, investigational therapy, or hormonal therapy (other 


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than leuprolide, other LHRH agonists/antagonists, or corticosteroids)] while on treatment 
in this study. Other anti-cancer therapy should not be administered unless one of the 
following occurs: documented disease progression; unacceptable or unmanageable 
toxicity; subject is withdrawn from the study at the investigator’s discretion or consent is 
withdrawn; or no further clinical benefit is anticipated which requires permanent 
discontinuation of study drug.  
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 oncology patients 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 
co-administered with GSK3326595.  Any questions regarding co-administration of 
medications should be directed to the GSK medical monitor. 
GSK3326595 was found to be a substrate for P-glycoprotein (P-gp) efflux transporters 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 either P-gp.  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, probenecid, pyrimethamine, metformin and 
benzylpenicillin (penicillin G).  
Any questions regarding co-administration of medications should be directed to the GSK 
medical monitor. 
7.1.2.2. 
Prohibited 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 post-study 
follow-up visit.  
NOTE: Subjects may receive focal palliative treatment (e.g., radiotherapy or 
radiofrequency ablation; limited to non-target lesions only) and/or surgical intervention 
(for example to address pain management) during this study.  Any proposed focal therapy 
must be approved by the investigator and the GSK Medical Monitor prior to intervention. 
Subjects 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. 


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7.1.3. 
Cautionary Medications 
The intrinsic clearance of the GSK3326595 molecule is low in hepatocytes and liver 
microsomes from humans.  Its elimination half-life in plasma ranges from 3 hours to 6 
hours.  Its bioavailability following oral administration notably varies among species, 
from 17% in the mouse to 69% in the rat and to 90% in the dog.   
GSK3326595 is not an in vitro inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6. GSK3326595 inhibited CYP3A4 in vitro at concentrations much 
higher than clinically relevant.   
 risk have 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. As noted in Section 7.1.2.1, GSK3326595 is a substrate 
for P-gp.  Other P-gp substrates include medications such as 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase inhibitors (statins) and digoxin, which may have a 
narrow therapeutic index.  While co-administration of 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, the following medications have the potential to induce a prolonged QT 
and have been associated with torsades de pointes. Co-administration of GSK3326595 
and the following medications is not prohibited, but they should be used with caution and 
with additional monitoring (e.g., more frequent electrocardiograms) as clinically 
appropriate from the time of the first dose of GSK3326595 until discontinuation from the 
study. 
Table 8 
Drugs with a Risk of Torsades de Pointes that Should Be Used With 
Caution 
Amiodarone 
Droperidol 
Ondansetron 
Anagrelide 
Erythromycin 
Papaverine 
Astemizole 
Escitalopram 
Pentamidine (IV) 
Azithromycin 
Flecainide 
Pimozide 
Bepridil 
Fluconazole 
Probucol 
Chloroquine 
Gatifloxacin 
Procainamide 
Chlorpromazine 
Grepafloxacin 
Propofol 
Cilostazol 
Halofantrine 
Quinidine 
Ciprofloxacin 
Haloperidol 
Roxithromycin 
Cisapride 
Hydroquinidine 
Sevoflurane 
Citalopram 
Ibogaine 
Sotalol 
Clarithromycin 
Ibutilide 
Sparfloxacin 
Cocaine 
Levofloxacin 
Sulpiride 
Disopyramide 
Levomepromazine 
Sultopride 
Dofetilide 
Levosulpiride 
Terfenadine 
CCI


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Domperidone 
Mesoridazine 
Terlipressin 
Donepezil 
Methadone 
Terodiline 
Dronedarone  
Moxifloxacin 
Thioridazine 
Data Source: crediblemeds.org revision date 25 June 2019. 
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification. 
7.2. 
Dietary Restrictions 
• 
GSK3326595 will be administered under fasting conditions, with no food or 
antacids for 1 h before and 2 h after each dose.  Requirements for fasting before 
and after dosing may be modified based on available pharmacokinetics (PK), 
pharmacodynamics (PD) and safety data. Fasting will consist of avoiding the 
oral ingestion of calorie-containing products; however, ingestion of water is 
permitted.  Subjects will be instructed to record the time and date of study 
treatments and meals in relation to dosing in the supplied GSK dosing diary. 
Subjects will abstain from ingesting alcohol, tobacco products, caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, chocolate) for 24 hours prior to the start 
of dosing until collection of the final PK and or PD sample on Day 16. In addition, 
subjects should also abstain from ingesting these products prior to clinic visits on days 
scheduled for periodic PK and PD sample collection throughout the study. 
Subjects should abstain from consumption of Seville oranges, grapefruit, grapefruit 
hybrids or grapefruit juice and/or pomelos, exotic citrus fruits, from one day prior to the 
first dose of study treatment until the last dose of study drug. 
• 
On serial PK sampling days, subjects should fast overnight (i.e., nothing by 
mouth apart from water and other medications for at least 8 hours) and should 
continue fasting until at least 2 hours after administration of the morning dose. 
Fasting is required for 1 hour before and 2 hours after administration of the 
evening dose for subjects in BID cohorts. 
If a subject vomits after taking study drug, the subject should be instructed not to retake 
the dose and should take the next scheduled dose. 
For subjects in the food effect sub-study, the administration on the ‘fed’ days will be 
performed as described in Section 4.2.6.  All other days will be administered as described 
above. 
7.3. 
Lifestyle Restrictions 
7.3.1. 
Female Subjects 
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%.  
These allowed methods of contraception are only effective when used consistently, 


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correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.   
The chosen form(s) of contraception must be used consistently and properly from at least 
28 days prior to receiving study drug until at least 5 days plus one menstrual cycle after 
the last dose of GSK3326595 and for at least 4 months after the last dose of 
pembrolizumab or in accordance with local prescribing information if longer. (Part 3 
subjects only). 
Abstinence 
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject and will continue to be abstinent from penile-vaginal intercourse on a long 
term and persistent basis. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception.  
Contraceptive Methods with a Failure Rate of  1% 
• Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure 
rate as stated in the product label. 
• Hormonal means of birth control that meet the standard operating procedure 
(SOP) effectiveness criteria including a <1% rate of failure per year, as stated in 
the product label.  Such methods may include: contraceptive subdermal 
implants, oral combination contraceptives, injectable progestogen, contraceptive 
vaginal ring, or percutaneous contraceptive patches. 
• Male partner sterilization (vasectomy with documentation of azoospermia) prior 
to the female subject's entry into the study, and this male is the sole partner for 
that subject. For this definition, “documented” refers to the outcome of the 
investigator's/designee’s medical examination of the subject or review of the 
subject's medical history for study eligibility, as obtained via a verbal interview 
with the subject or from the subject’s medical records. 
7.3.2. 
Male Subjects 
Male subjects with female partners of childbearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until at least at least 5 half-lives plus 90 days (approximately 95 days) have elapsed after 
the last dose of GSK3326595: 
• Vasectomy with documentation of azoospermia.   
• Male condom plus partner use of one of the contraceptive options below: 
• 
Contraceptive subdermal implant  
• 
Intrauterine device or intrauterine system  
• 
Oral Contraceptive, either combined or progestogen alone [Hatcher, 2011] 
Injectable progestogen [Hatcher, 2011] 
• 
Contraceptive vaginal ring [Hatcher, 2011] 


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• 
Percutaneous contraceptive patches [Hatcher, 2011] 
This is an all-inclusive list of those methods that meet the following GSK definition of 
highly effective: having a failure rate of less than 1% per year when used consistently and 
correctly and, when applicable, in accordance with the product label. For non-product 
methods (e.g., male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH (M3) R2, 
2009]. 
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 8.1.  
The following points must be noted:  
• 
If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order: 
1. 12-lead ECG 
2. vital signs 
3. blood draws.   
• 
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time. 
• 
The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker or other 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.  
• 
The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not require a protocol amendment.  
• 
The IRB/ Independent ethics committee (IEC) will be informed of any safety 
issues that require alteration of the safety monitoring scheme or amendment of 
the Informed Consent Form.  
Subjects who continue to receive study treatment after the DCO date of the final analyses 
will be monitored and receive follow-up care in accordance with standard local clinical 
practice. Assessments will revert to the standard of care at a subject’s particular site with 


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recommendation for local laboratory safety monitoring (refer to SRM). The following 
assessments will be required and reported directly to the Sponsor via a paper process up 
to 30 days after last dose of study treatment (refer to SRM and see Section 6.7): 
• 
SAEs 
• 
AEs leading to treatment discontinuation 
• 
AESIs (Pre-defined Ocular and Bone AEs) 
• 
Overdose 
• 
Pregnancy 
• 
Bone (DEXA) assessments will be performed at the discretion of the investigator and 
reported only if reporting criteria is met for SAEs, AESIs, or AEs leading to 
treatment discontinuation. 
• 
Ophthalmic Assessments, will be required and reported only if reporting criteria is 
met for SAEs, AESIs, or AEs leading to treatment discontinuation; approximately 
every 6 months and at the end of the study treatment (if >8 weeks from previous 
assessment) 
Any SAE or AESI that is ongoing at the time of this data cut-off must be followed up to 
resolution unless the event is considered by the investigator unlikely to resolve, or the 
subject is lost to follow-up. GSK retains the right to request additional information for 
any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 


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8.1. 
Time and Events Tables 
Table 9 
Time and Events for Part 1 
Procedure 
SCR 
DLT Observation Period (Days 1-21) 
Weeks 
4 & 6 
q4w 
(Starting 
Week 8) 
q8w 
(Starting 
Week 8) 
q26w 
(Starting 
Week 26) 
EOT 
Survival 
Follow-up 
D1 
D2 
D3 
D8 
D15 
D16 
D1 
 
 
 
 
 
Screening 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Register Subject 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
Pregnancy test (Females of 
childbearing potential only; must 
be within 7 days of first dose) 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Follicle stimulating hormone 
(FSH)/Estradiol (Only in women 
of non-childbearing potential) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBsAg, HCV Antibody 
Screening1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination2 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Limited Physical Examination2 
 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
ECOG Performance Status3 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
12-lead ECG 
X 
PK4 
 
 
X 
PK4 
 
X 
X 
 
 
 
 
DEXA Bone Densitometry5 
X 
 
 
 
 
 
 
 
 
X 
 
X6 
 
Routine Clinical Laboratory 
Assessments7 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
 


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Procedure 
SCR 
DLT Observation Period (Days 1-21) 
Weeks 
4 & 6 
q4w 
(Starting 
Week 8) 
q8w 
(Starting 
Week 8) 
q26w 
(Starting 
Week 26) 
EOT 
Survival 
Follow-up 
D1 
D2 
D3 
D8 
D15 
D16 
D1 
 
 
 
 
 
Folate and Selected Vitamins7 
X 
 
 
 
 
 
 
X7 
 
X 
 
X 
 
Ophthalmic Assessment8 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Study Treatment 
Administer study drug9 
 
X 
 
================Daily Dosing================→ 
 
Vision Symptom Review10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
AE Review 
 
Continuous from the start of study treatment until the follow-up contact 
 
SAE Review 
Continuous from signing of informed consent until the follow-up contact 
 
Concomitant Medication Review 
Continuous from signing of informed consent 
 
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx) 
PK plasma samples11 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
PD plasma samples (
12 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
Plasma (circulating biomarkers)13 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
Tumor biopsy (archival)14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PD tumor biopsy (fresh)14 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
PGx sample (Blood)15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
Computed tomography (CT) 
chest/abdomen/pelvis (see 
Section 8.2.1 and Section 
8.7.1)16 
X 
 
 
 
 
 
 
 
 
X17 
 
X18 
 
Magnetic resonance imaging 
(MRI) Brain19 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Survival Follow-Up20 
 
 
 
 
 
 
 
 
 
 
 
 
Q6 months 
 
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1. 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 
2. See Section 8.3.1 for components of full and limited physical examinations  
3. See Appendix 3 for definition of ECOG performance status 
4. On serial PK days (Day 1 and Day 15), ECGs will be obtained at or about the time of PK sample collection, as described in the SRM. On other days, ECGs will be obtained pre-
dose. 
5. If possible, DEXA to be performed on same machine for particular subject 
6. Only if EOT is > 8 weeks from prior DEXA 
7. Refer to Section 8.3.5 (Table 16) for complete listing of protocol-required laboratory assessments.  Clinical labs performed during screening within 72 hours of first dose do not 
need to be repeated on Day 1. Folate and selected vitamins to be drawn at Screening, Week 4, Week 8, every 8 weeks thereafter and at EOT. If a subject’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. 
8. Refer to Section 8.3.7 for description of components of ocular assessment.  If a subject’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.  
9. On serial PK days (Day 1 and Day 15), subjects should fast from 8 hours prior to dose until 2 hours after dose.  On all other days, GSK3326595 should be administered on an 
empty stomach at approximately the same time of day (± 4 h), with no food for 1 hour before and 2 hours after each dose. On serial PK days and for two days prior (Days 13 
through 16), subjects should attempt to take GSK3326595 within a 1 hour window (i.e., 23-25 hours after the last dose). 
10. At each visit, the investigator should specifically ask the subject about any changes in vision since their last visit/contact (Section 9.2.2).  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. 
11. PK samples following Day 1 dose will be collected at Pre-dose (within 1 hour prior to dosing), 15m±5m, 30m±5m, 1h±5m, 1.5h±5m, 2h±5m, 3h±5m, 4h±10m, 6h±10m, 8h±15m, 
12h±2h, 24h2h (Day 2), and 48h2h (Day 3; prior to next dose), post-dose. PK samples following Day 15 dose will be collected at Pre-dose, (within 1 hour prior to dosing), 
30m±5m, 1h±5m, 2h±5m, 3h±5m, 4h±10m, 6h±10m, 8h±15m, 12h±2h, 24h2h (Day 16, prior to next dose) post dose. PK samples on days of subsequent visits should be 
collected within 1 hour Pre-dose. 
12. On Day 1, PD plasma samples should be collected within 1 hour Pre-dose. PD plasma samples on Day 8 and Day 15 should be collected 6h post-dose 3 hours. Samples should 
be collected and separated per the SRM. 
13. Plasma for circulating biomarker analysis will be collected pre-dose on Day 1 and 6h post dose 3 hours on Days 8 and 15. 
14. Refer to Section 8.2.1 for discussion of baseline biopsies.  Remaining biopsies are optional unless mandated for individual subject(s) (Section 4.2.5).  If a biopsy is required for PD 
analysis, fresh biopsies must be provided at screening, on Day 15, and at the end-of-study visit. 
15. Informed consent for optional substudies (e.g. genetics research) must be obtained before collecting any samples.  Appendix 8 describes requirements for genetic research. 
16. CT should be performed with oral and IV contrast.  CR or PR should be confirmed as per RECIST 1.1 criteria; see Section 14.4.1. 
17. After week 32, scan frequencies are reduced.  See Section 8.2.2 for details. 
18. Repeat scans required at end of treatment (EOT) visit only if the last radiographic assessment was more than 8 weeks prior to the subject’s withdrawal from study and progressive 
disease has not been documented. 
19. MRI Brain required at screening and then as clinically indicated thereafter; subjects with untreated CNS lesions should have brain MRI performed at each disease assessment.  If 
MRI is contraindicated for an individual subject, then an equivalent study (e.g., contrast-enhanced MRI of the head) may be performed instead. 
20. Survival Follow-Up via telephone, email or other form of communication, every 6 months.  Following Protocol Amendment 7, survival follow-up should only be conducted for 
subjects with a diagnosis of ACC.  Follow-up will continue until approximately 70% of subjects with a diagnosis of ACC have died.  See Section 5.4 for further details.   


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Table 10 
QD Dosing Time and Events: Part 1 PD/Biomarker/Metabolite Cohort[s] 
PK/PD/Biomarker/Metabolite Cohort(s) (Section 4.2.5; samples collected in this section are in addition to any samples, studies, and visits described in Table 9) 
Procedure 
SCR 
DLT Observation Period (Days 1-21) 
 
EOT 
D1 
D2 
D3 
D4 
D8 
D15 
D16 
Week 6 
Plasma (metabolite profiling)1 
 
X 
X 
X 
 
 
X 
X 
 
 
Whole blood (Paxgene [PAX] tube for 
biomarker analysis, e.g., mRNA)2 
 
X 
 
 
X 
X 
X 
 
 
 
Urine – PK sample3 
 
0-12h 
 
 
 
 
0-12h 
 
 
 
Urine – metabolite sample3 
 
0-12h 
 
 
 
 
0-12h 
 
 
 
Tumor biopsy (PD; 1 Formalin fixed paraffin 
embedded (FFPE) and 1 fresh frozen 
core)4 
X 
 
 
 
 
 
X 
 
 
X 
18FDG-PET/CT scan 
X 
 
 
 
 
 
 
 
X 
 
NOTE: Subjects in the expansion cohort are subject to all screening, safety, PK, and efficacy evaluations detailed in Table 9.  Samples collected in this section are in addition to any 
samples collected in Table 9, with the exception of tumor biopsy for PD, in which the time points in Table 10 supersede those in Table 9. 
1. Plasma samples for metabolites will be collected at serial PK timepoints (see Table 9). 
2. Whole blood samples for biomarker analysis will be collected pre-dose on day 1 and 6h post dose  3 hours on days 4, 8 and 15. 
3. Pre-dose urine samples will be collected near the time of dosing on Days 1 and 15 for PK and metabolite profiling. A separate container will be used to collect urine for PK and 
metabolite profiling from the time of dosing until 12h post-dose on days 1 and 15. 
4. Pre- and post-dose biopsies are mandatory for all subjects in this cohort.  End-of-treatment biopsy is preferred but not required.  Refer to Section 8.2.1 for discussion of baseline 
biopsies.  Biopsies should be collected within 14 days prior to Day 1 of dosing (pre-dose) and paired with Day 15 on-therapy 
 


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Table 11 
BID Dosing Time and Events: Part 1 (PK and PD/Biomarker/Metabolites cohorts), Week 11 
 
Day 1 
Day 2 
Days 3-7 
 
Morning Dose 
Evening Dose 
Morning Dose 
Evening Dose3 
Morning Dose3 
Evening Dose3 
 
Pre-
dose2 
0h 
Post-
dose 
Pre-
dose2 
12h± 
0.5h 
Post-
dose 
Pre dose2 
0h± 0.5h 
12h± 1h 
0h± 1h 
12h± 1h 
Dose 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
PK plasma sample4 
X 
 
PK 
PK 
 
PK 
PK 
 
 
 
 
PD plasma sample (
 
X 
 
 
 
 
 
 
 
 
 
 
PK/PD/Biomarker/Metabolite Cohort(s) ONLY (Section 4.2.5) 
Plasma (metabolite profiling)5 
X 
 
X 
X 
 
X 
X 
 
 
 
 
Plasma (circulating biomarkers, e.g., 
cell-free DNA)6 
X 
 
 
 
 
 
 
 
 
 
 
Whole blood (PAX tube for biomarker 
analysis, e.g., mRNA)6 
X 
 
 
 
 
 
 
 
 
 
 
Urine - PK sample7 
X 
0-12h collection 
 
 
 
 
 
 
 
Urine metabolite sample7 
X 
0-12h collection 
 
 
 
 
 
 
 
Tumor biopsy8 
SCR 
 
 
 
 
 
 
 
 
 
 
18FDG-PET/CT scan 
SCR 
 
 
 
 
 
 
 
 
 
 
 
1. 
Events listed in this table are in addition to all Screening, Safety, and Efficacy evaluations listed in Table 9, with the exception those listed for D3 visit.  D3 visit is not required 
for subjects in BID cohorts.  The Dose, PK and PD (
 sampling schedules are in place of the information in Table 9 
2. 
Pre-dose samples should be collected within 1 hour prior to dosing 
3. 
Evening dose on Day 2 and both daily doses on Days 3 through 7 may be administered at home, by subject, at approximately the same time of day 
4. 
Plasma samples for serial PK (“PK” in the table above) should be collected at the following timepoints on Day 1: Pre-dose (within 1 hour prior to dosing), 15m±5m, 30m±5m, 
1h±5m, 1.5h±5m, 2h±5m, 3h±5m, 4h±10m, 6h±10m, 8h±15m, 12h±0.5h (prior to the evening dose), and 24h±0.5h (prior to the Day 2 morning dose).  For sites and 
subjects who are able to accommodate, samples should also be collected at the following timepoints after the Day 1 evening dose: 15m±5m, 1h±0.5h, 2h±0.5h, 3h±0.5h, 
6h±0.5h, and 8h±0.5h (these evening samples are in addition to the pre-dose sample on Day 2 described above). 
5. 
Plasma samples for metabolite profiling will be collected at serial PK timepoints (footnote 4, above) 
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Day 1 
Day 2 
Days 3-7 
 
Morning Dose 
Evening Dose 
Morning Dose 
Evening Dose3 
Morning Dose3 
Evening Dose3 
 
Pre-
dose2 
0h 
Post-
dose 
Pre-
dose2 
12h± 
0.5h 
Post-
dose 
Pre dose2 
0h± 0.5h 
12h± 1h 
0h± 1h 
12h± 1h 
6. 
Plasma and whole blood samples for biomarker analysis will be collected pre-dose on Day 1 
7. 
Pre-dose urine samples will be collected near the time of dosing on Days 1 and 15 for PK and metabolite profiling. A separate container will be used to collect urine for PK 
and metabolite profiling from the time of dosing until 12h post-dose on days 1 and 15. 
8. 
Refer to Section 8.2.1 for discussion of baseline biopsies. Pre-dose tumor biopsy may be collected up to 14 days prior to first dose (“SCR”). Tumor biopsies in the PK/PD 
expansion cohort are mandatory. 
 


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Table 12 
BID Dosing Time and Events: Part 1 (PK and PD/Biomarker/Metabolite cohorts), Weeks 2-3 and Subsequent 
Visits1 
 
Day 8 
Days 9-14 
Day 15 
Day 16 
Days 17-21 
W4D1, W6D1, and 
q4w (starting W8) 
Morning Dose 
 
Even
-ing 
Dose 
Morn
-ing 
Dose 
Even
-ing 
Dose 
Morning Dose 
Evening Dose 
Morning 
Dose 
Even
-ing 
Dose 
Morn
-ing 
Dose 
Even
-ing 
Dose 
Morning 
Dose 
Even
-ing 
Dose 
 
Pre-
dose
2 
0h± 
0.5
h 
Post
-
dose 
12h± 
1h 
0h± 
1h 
12h± 
1h 
Pre-
dose
2 
0h± 
0.5
h 
Post
-
dose 
Pre-
dose
2 
12h
± 
0.5h 
Post
-
dose 
Pre-
dose
2 
0h± 
0.5
h 
12h± 
1h 
0h± 
1h  
12h± 
1h 
Pre-
dose
2 
0h± 
0.5
h 
12h± 
1h 
Dose3 
 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
PK plasma 
sample4 
 
 
 
 
 
 
X 
 
PK 
PK 
 
PK 
PK 
 
 
 
 
X 
 
 
PD plasma 
sample5 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PK/PD/Biomarker/Metabolite Cohort(s) ONLY (Section 4.2.5) 
Plasma 
(metabolite)6 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
Plasma 
(biomarkers)
7 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Whole blood 
(PAX tube)7 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine - PK 
sample8 
 
 
 
 
 
 
X 
0-12h collection 
 
 
 
 
 
 
 
 
 
 
Urine 
metabolite 
sample8 
 
 
 
 
 
 
X 
0-12h collection 
 
 
 
 
 
 
 
 
 
 
Tumor 
biopsy9 
 
 
 
 
 
 
Day 15, Any time 
 
 
 
 
 
 
 
 
18FDG-
PET/CT 
scan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
W6D1, Any time 


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1. 
Events listed in this table are in addition to all Screening, Safety, and Efficacy evaluations listed in Table 9. 
2. 
Pre-dose samples should be collected within 1 hour prior to dosing 
3. 
Evening dose on Day 8, all doses on Days 9-14, all doses on Days 16-21, and all subsequent doses apart from morning doses (on days noted in table, e.g. W4D1, W6D1, and 
q4w starting W8) may be administered at home, by subject, at approximately the same time of day.  Both doses on Day 15 will be administered in clinic. 
4. 
Plasma samples for serial PK (“PK” in the table above) should be collected at the following timepoints on Day 15: Pre-dose (within 1 hour prior to dosing), 30m±5m, 1h±5m, 
2h±5m, 3h±5m, 4h±10m, 6h±10m, 8h±15m, 12h±0.5h (prior to the evening dose), and 24h±0.5h (prior to the Day 16 morning dose).  For sites and subjects who are able to 
accommodate, samples should also be collected at the following timepoints after the Day 15 evening dose: 15m±5m, 1h±0.5h, 2h±0.5h, 3h±0.5h, 6h±0.5h, and 8h±0.5h (these 
evening samples are in addition to the pre-dose sample on Day 16 described above). 
5. 
Plasma samples for PD analysis will be collected 6h post-dose  3 hours on Days 8 and 15 and separated as per the SRM. 
6. 
Plasma samples for metabolite profiling will be collected at serial PK timepoints (footnote 4, above). 
7. 
 
8. 
Pre-dose urine samples will be collected near the time of dosing on Days 1 and 15 for PK and metabolite profiling. A separate container will be used to collect urine for PK and 
metabolite profiling from the time of dosing until 12h post-dose on days 1 and 15. 
9. 
Refer to Section 8.2.1 for discussion of baseline biopsies.  Tumor biopsies in the PK/PD expansion cohort are mandatory 
 
Table 13 
Time and Events for Food Effect and Relative Bioavailability Sub-Study 
Food Effect and Relative Bioavailability Sub-Study (Section 4.2.6; samples collected in this section are in addition to any samples, studies, and visits described in Table 9) 
Procedure 
Screening 
 
 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 and beyond 
Administer study drug1 
 
X 
 
 
X 
 
 
 
X 
============Daily Dosing========→2 
Plasma PK samples3 
 
X 
X 
 
X 
X 
 
 
X 
X 
Refer to Table 9 for subsequent PK 
sample requirements 
Routine Clinical Laboratory 
Assessments (Refer to Table 9) 
X 
X 
 
 
 
 
 
 
X 
 
 
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NOTE: Subjects in the food effect and relative bioavailability sub-study are subject to all screening, safety, PK, and efficacy evaluations detailed in Table 9.  Samples collected in this 
section are in addition to any samples collected in Table 9, with the exception of Day 1-9 PK collections, in which the time points in Table 13 supersede those in Table 9. 
1. Study drug should be administered in fed or fasted state, as capsules or tablets based on assignment as described in Section 4.2.6.  At least 48 hours should separate each 
individual dose; in order to accommodate clinic schedules, the Day 4 visit may be performed up to one day late, and the Day 8 visit may be performed ±1 day (note that it may 
only be performed on Day 8 or Day 9 if the Day 4 visit is performed on Day 5, in order to allow the 48-hour window between doses).  Refer to Section 8.2.2 for full discussion of 
visit windows. 
2. Day 9 dose should be administered in clinic following collection of Day 8 24-hour timepoint PK sample. 
3. PK samples following Day 1, Day 4, and Day 8 doses will be collected at Pre-dose (within 1 hour prior to dosing), 15m±5m, 30m±5m, 1h±5m, 2h±5m, 4h±10m, 6h±10m, 
8h±15m, 12h±2h, 24h2h and 30h2h. 


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Table 14 
Time and Events for Part 2 
Procedure 
Screening 
Days 1-21 
Weeks 4 & 6 
q8w 
(starting 
W8) 
q12w 
(starting 
W12) 
q26w 
(starting 
W26) 
EOT (within 
30 days post-
last dose) 
Survival 
Follow-Up 
D1 
D8 
D15 
D1 
Screening 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Disease Characteristics  
X 
 
 
 
 
 
 
 
 
 
Prior Therapy 
X 
 
 
 
 
 
 
 
 
 
Register Subject 
X 
 
 
 
 
 
 
 
 
 
Safety 
Full Physical Examination1 
X 
 
 
 
 
 
 
 
X 
 
Limited Physical Examination1 
 
X 
X 
X 
X 
X 
 
 
 
 
ECOG Performance Status2 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
 
X 
 
12-lead ECG 
X 
PK3 
 
PK3 
 
X 
 
 
X 
 
DEXA bone Densitometry 
X4 
 
 
 
 
X 
 
 
X5 
 
Pregnancy test (Females of 
childbearing potential only; must 
be within 7 days of first dose) 
X 
 
 
 
X 
X 
 
 
X 
 
FSH/Estradiol (Only in women of 
non-childbearing potential) 
X 
 
 
 
 
 
 
 
 
 
HIV, HBsAg, HCV Antibody 
Screening6 
X 
 
 
 
 
 
 
 
 
 
Routine Clinical Laboratory 
Assessments7 
X 
X 
X 
X 
X 
X 
 
 
X 
 


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Procedure 
Screening 
Days 1-21 
Weeks 4 & 6 
q8w 
(starting 
q12w 
(starting 
q26w 
(starting 
EOT (within 
30 days post-
Survival 
Follow-Up 
TSH, free T3 and free T47  
X 
 
 
 
X 
X 
 
 
X 
 
Folate and Selected Vitamins7 
X 
 
 
 
X7 
X 
 
 
X 
 
Ophthalmic Assessment8 
X 
 
 
 
 
 
 
X 
X 
 
Study Treatment 
Administer study drug9 
 
=====================Daily Dosing================→ 
 
 
Vision Symptom Review10 
X 
X 
X 
X 
X 
X 
 
 
X 
 
AE Review 
 
Continuous from the start of study treatment until the follow-up contact 
 
SAE Review 
Continuous from signing of informed consent until the follow-up contact 
 
Concomitant Medication Review 
Continuous from signing of informed consent 
 
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx) 
PK Plasma11 
 
X 
 
X 
X 
X 
 
 
 
 
Tumor Biopsy (archival) for p53 
status 
X 
 
 
 
 
 
 
 
 
 
Tumor Biopsy (fresh) for p53 and 
PD12 
X 
 
 
X 
 
 
 
 
X 
 
Plasma (circulating biomarkers)13 
 
X 
X 
X 
 
X 
 
 
 
 
Whole blood (PAX tube for 
biomarker analysis, e.g., mRNA)13 
 
X 
X 
X 
 
X 
 
 
 
 
PGx Sample (Blood)14 
X 
 
 
 
 
 
 
 
 
 
Efficacy 
Solid tumor cohorts: CT 
chest/abdomen/pelvis (see 
Section 8.2.1 and Section 8.7.1)15 
X 
 
 
 
 
X16 
 
 
X17 
 
Solid tumor cohorts: MRI Brain18 
X 
 
 
 
 
 
 
 
 
 
GBM cohort: MRI brain (see 
Section 8.2.1 and Section 8.7.2) 
X 
 
 
 
 
X16 
 
 
X17 
 
NHL cohort: Disease assessment 
(see Section 8.2.1 and Section 
8.7.3)19 
X 
 
 
 
 
 
X15 
 
X16 
 
Patient-Reported Outcomes (ACC Tablet Cohort ONLY)
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Procedure 
Screening 
Days 1-21 
Weeks 4 & 6 
q8w 
(starting 
q12w 
(starting 
q26w 
(starting 
EOT (within 
30 days post-
Survival 
Follow-Up 
EQ-5D-3L 
 
X 
 
 
X (Week 4 only) 
X 
 
 
X 
 
Long-Term Follow-Up 
Subsequent cancer treatment 
following discontinuation of study 
treatment20 
 
 
 
 
 
 
 
 
X19 
Q6 months20 
Survival Follow-Up20 
 
 
 
 
 
 
 
 
 
Q6 months20 
 
NOTE: for visit windows, please refer to Section 8.2.2. 
1. 
See Section 8.3.1 for components of full and limited physical examinations 
2. 
See Section 14.3 for definition of ECOG performance status 
3. 
On serial PK days (Day 1 and Day 15), ECGs will be obtained at or about the time of PK sample collection, as described in the SRM. On other days, ECGs will be obtained 
pre-dose 
4. 
If possible, DEXA to be performed on same machine for particular subject. 
5. 
Only if EOT is > 8 weeks from prior DEXA. 
6. 
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. 
7. 
Thyroid function testing including TSH, free T3, and free T4 are to be drawn at Screening, Week 4 or 6, then every 8 weeks starting at Week 8 and EOT. Refer to Section 
8.3.5 (Table 16) for complete listing of protocol-required laboratory assessments. Folate and selected vitamins to be drawn at Screening, Week 4, Week 8, every 8 weeks 
thereafter and at EOT. If a subject’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. 
8. 
Refer to Section 8.3.7 for description of components of ocular assessment.  If a subject’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.  
9. 
On serial PK days (Day 1 and Day 15), subjects should fast from 8 hours prior to dose until 2 hours after dose.  On all other days, GSK3326595 should be administered on 
an empty stomach at approximately the same time of day (± 4 h), with no food for 1 hour before and 2 hours after each dose 
10. At each visit, the investigator should specifically ask the subject about any changes in vision since their last visit/contact (Section 9.2.2).  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. 
11. Plasma PK samples on Day 1 will be collected at Predose (within 1 hour prior to dosing), 30m±5m, 1h±5m, 2h±5m, 4h±10m, 6h±10m, 8h±15m, 12h±2h, 24h2h (Day 2 
prior to next dose) post dose. Additional PK samples will be collected at the following time points: on Day 15 within 1 hr before dosing and between 1 and 3 hrs post dose, on 
Day 15 between 5 and 8 hrs post dose (in the NSCLC and ACC tablet cohorts only), and at subsequent scheduled visits within 1 hr before dosing. 
12. Refer to Section 8.2.1 for discussion of baseline biopsies. Fresh screening biopsy should be taken within 14 days prior to the first dose. Paired biopsy to be taken on Day 15 
after 14 days of GSK3326595 dosing. EOT biopsy to be obtained as able for all subjects.  Subjects in GBM expansion cohort may submit archival tumor sample at screening.  
Day 15 and EOT biopsy not required for GBM cohort. The fresh biopsy will be used to determine p53 status if no archival sample is available  
13. Plasma and whole blood samples for biomarker analysis will be collected predose on day 1 and 6h post-dose (3 h) for all on-treatment samples. Plasma samples for 


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Table 15 
Time and Events for Part 3 (Active in all regions, except France) 
Procedure 
Screening 
Days 1-35 
q3w  
(starting 
W6) 
q8w  
(starting 
W8) 
q26w 
(starting 
W26) 
EOT (within 
30 days post-
last dose) 
Day 1 
Day 8 
Day 15 
Day 22 
Screening 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Disease Characteristics  
X 
 
 
 
 
 
 
 
 
Prior Therapy 
X 
 
 
 
 
 
 
 
 
Register Subject 
X 
 
 
 
 
 
 
 
 
Safety 
Full Physical Examination1 
X 
 
 
 
 
 
 
 
X 
circulating biomarkers to be collected as per the SoA until Week 24 only. 
14. Informed consent for optional sub-studies (e.g. genetics research) must be obtained before collecting any samples.  Appendix 8 describes requirements for genetic research 
15. CT should be performed with oral and IV contrast.  CR or PR should be confirmed not earlier than 28 days from the initial response scan, as per RECIST 1.1 criteria; see 
Section 14.4.1.  Any subject in the ACC tablet cohort who has not yet shown objective radiological disease progression at treatment discontinuation should be continued to 
be followed as per RECIST 1.1 for radiological progression. 
16. After the fourth scheduled scan for disease assessment, scan frequencies are reduced.  See Section 8.2.2 for details. 
17. Repeat scans required at EOT visit only if the last radiographic assessment was more than 8 weeks prior to the subject’s discontinuation of study treatment and progressive 
disease has not been documented. 
18. For subjects in solid tumor cohorts, MRI brain required at screening and then as clinically indicated thereafter; subjects with untreated CNS lesions should have brain MRI 
performed at each disease assessment.  If MRI is contraindicated for an individual subject, then an equivalent study (e.g., contrast-enhanced MRI of the head) may be 
performed instead 
19. CR or PR should be confirmed not earlier than 28 days from the initial response scan, as per international working group criteria; see Section 14.4.3 
20. Survival Follow-Up via telephone, email or other form of communication, every 6 months.  Following Protocol Amendment 7, survival follow-up should only be conducted for 
subjects in an ACC cohort.  Follow-up will continue until approximately 70% of subjects in the ACC cohorts have died.  
 
 
  See Section 5.4 for further details 
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Procedure 
Screening 
Days 1-35 
q3w  
q8w  
q26w 
EOT (within 
Limited Physical Examination1 
 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status2 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
 
X 
12-lead ECG 
X 
PK3 
 
PK3 
 
 
X 
 
X 
DEXA Bone Densitometry 
X4 
 
 
 
 
 
X 
 
X5 
Pregnancy test (Females of childbearing 
potential only; screening test must be 
within 7 days prior to first dose) 
X 
 
 
 
X 
X 
 
 
X 
FSH/Estradiol (Only in women of non-
childbearing potential) 
X 
 
 
 
 
 
 
 
 
HIV, HbsAg, HCV Antibody Screening6 
X 
 
 
 
 
 
 
 
 
Routine Clinical Laboratory Assessments7 
X 
X 
X 
X 
X 
X 
 
 
X 
Folate and selected vitamins7 
X 
 
 
 
X 
 
X 
 
X 
Ophthalmic Assessment8 
X 
 
 
 
 
 
 
X 
X 
Study Treatment 
Administer GSK33265959 
 
=====================Daily Dosing================→ 
 
Administer Pembrolizumab 
 
 
 
X 
 
X 
 
 
 
Vision Symptom Review10 
X 
X 
X 
X 
X 
X 
 
 
X 
AE Review 
 
Continuous from the start of study treatment until the follow-up contact 
SAE Review 
Continuous from signing of informed consent until the follow-up contact 
Concomitant Medication Review 
Continuous from signing of informed consent 
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx) 
PK Plasma11 
 
X 
 
X 
 
 
X 
 
 
Pembrolizumab PK12 
 
 
 
X 
X 
X 
(Q6W 
starting 
W6) 
 
 
X 
Pembrolizumab Immunogenicity13 
 
 
 
X 
 
X 
(Q6W 
starting 
 
 
X 


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Procedure 
Screening 
Days 1-35 
q3w  
q8w  
q26w 
EOT (within 
W6) 
Tumor Biopsy (archival) for p53 status 
X 
 
 
 
 
 
 
 
 
Tumor Biopsy (fresh) for p53 and PD14 
X 
 
 
X 
 
 
 
 
X 
Plasma (circulating biomarkers)15 
 
X 
 
X 
 
 
X 
 
 
Whole blood (PAX tube for biomarker 
analysis, e.g., mRNA)15 
 
X 
 
X 
 
 
X 
 
 
PGx Sample (Blood)16 
X 
 
 
 
 
 
 
 
 
Efficacy 
CT chest/abdomen/pelvis (see Section 
8.2.1 and Section 8.7.1)17 
X 
 
 
 
 
 
X18 
 
X19 
MRI Brain20 
X 
 
 
 
 
 
 
 
 
 
NOTE: for visit windows, please refer to Section 8.2.2. 
1. 
See Section 8.3.1 for components of full and limited physical examinations 
2. 
See Section 14.3 for definition of ECOG performance status 
3. 
On serial PK days (Day 1 and Day 15), ECGs will be obtained at or about the time of PK sample collection, as described in the SRM. On other days, ECGs will be 
obtained pre-dose 
4. 
If possible, DEXA to be performed on same machine for particular subject 
5. 
Only if EOT is > 8 weeks from prior DEXA 
6. 
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. 
7. 
Refer to Section 8.3.5 (Table 16) for complete listing of protocol-required laboratory assessments. Folate and selected vitamins to be drawn at Screening, Day 22, Week 8, 
every 8 weeks thereafter and at EOT. If a subject’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. 
8. 
Refer to Section 8.3.7 for description of components of ocular assessment.  If a subject’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.  
9. 
On serial PK days (Day 1 and Day 15), subjects should fast from 8 hours prior to dose until 2 hours after dose.  On all other days, GSK3326595 should be administered on 
an empty stomach at approximately the same time of day (± 4 h), with no food for 1 hour before and 2 hours after each dose 
10. At each visit, the investigator should specifically ask the subject about any changes in vision since their last visit/contact (Section 9.2.2).  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. 
11. GSK3326595 Plasma PK samples on Day 1 will be collected at Predose (within 1 hour prior to dosing), 30m±5m, 1h±5m, 2h±5m, 4h±10m, 6h±10m, 8h±15m, 12h±2h, 
24h2h (Day 2 prior to next dose) post dose. Additional PK samples will be collected at the following time points: Day 15, within 1 hr before dosing and between 1 and 3 
hrs post dose, and between 5-8 hrs post dose.  At subsequent scheduled visits, PK should be collected within 1 hr before dosing.  
12. Pembrolizumab PK samples on Day 15 will be collected predose (within 1 hour prior to dosing), postdose (30 min after end of infusion) and 24h2 h after the start of 
infusion. For D22, Pembrolizumab PK sample to be collected any time during the visit. At all other visits, predose PK samples will be collected (within 1 hour prior to 


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dosing).  
13. Pembrolizumab samples for immunogenicity will be collected at predose for all visits.  
14. Refer to Section 8.2.1 for discussion of baseline biopsies. A fresh screening biopsy is required, even if there is archival tissue available, and should be taken within 14 
days prior to the first dose. Paired biopsy to be taken on Day 15 prior to pembrolizumab administration, after 14 days of GSK3326595 dosing. EOT biopsy to be obtained 
as able for all subjects. The fresh biopsy will be used to determine p53 status if no archival sample is available. 
15. Plasma and whole blood samples for biomarker analysis will be collected Day 1 (pre-dose) and 6h post-dose (3 h) for all on-treatment samples.  Plasma samples for 
circulating biomarkers to be collected as per the SoA until Week 24 only. 
16. Informed consent for optional sub-studies (e.g. genetics research) must be obtained before collecting any samples.  Appendix 8 describes requirements for genetic 
research 
17. CT should be performed with oral and IV contrast.  CR or PR should be confirmed not earlier than 28 days from the initial response scan, as per RECIST 1.1 criteria; see 
Section 14.4.1 
18. After the fourth scheduled scan for disease assessment, scan frequencies are reduced.  See Section 8.2.2 for details. 
19. Repeat scans required at EOT visit only if the last radiographic assessment was more than 8 weeks prior to the subject’s withdrawal from study and progressive disease 
has not been documented 
20. MRI brain required at screening and then as clinically indicated thereafter; subjects with untreated CNS lesions should have brain MRI performed at each disease 
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8.2. 
Screening and Critical Baseline Assessments 
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening. 
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity. 
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  Medical, surgical, and treatment history including date of first 
diagnosis, best response to prior systemic therapy, histology, and current sites of disease 
will be taken as part of the medical history and disease status. Details concerning 
concomitant medication will be recorded starting from screening through post-study 
follow-up. At a minimum, the drug name, route of administration, dose and frequency of 
dosing, along with start and stop dates should be recorded.  Investigators will be required 
to provide details of prior response assessments, including the dates of evaluation, size of 
target lesions used for determination of response, and changes in management made in 
response to these assessments, for at least two prior lines of therapy (if available) as part 
of the medical history. 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging studies, etc.) and obtained prior to signing of informed consent may be 
utilized for Screening or baseline purposes provided the procedure meets the protocol-
defined criteria and has been performed in the timeframe of the study. 
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring. Appropriate 
local regulatory and ethical approvals should be obtained before any additional testing is 
performed. 
For subjects enrolled in the Part 2 ACC cohort, pre-study baseline scans should be 
provided in order to measure kinetics of tumor growth prior to therapy with 
GSK3326595.  Additional details regarding the number and quality of scans will be 
provided in the SRM. 
8.2.1. 
Critical Baseline Assessments 
The following are required at baseline: 
• 
Imaging/efficacy: 
• 
Part 1: All subjects should undergo contrast-enhanced CT of the chest, 
abdomen, and pelvis (and/or other areas as indicated by the subject’s underlying 
disease) as well as an MRI of the brain. 
NOTE: Although CT scan is preferred, MRI may be used as an alternative 
method of baseline disease assessment for abdomen/pelvis, especially for those 
subjects where a CT scan is contraindicated due to allergy to contrast, provided 
that the method used to document baseline status is used consistently throughout 
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can replace the enhanced CT of the chest, but MRI of the chest is not 
recommended. 
• 
Part 2, solid tumor cohorts, and Part 3: All subjects should undergo contrast-
enhanced CT of the chest, abdomen, and pelvis (and/or other areas as indicated 
by the subject’s underlying disease) as well as an MRI of the brain.  If MRI of 
the brain is contraindicated, then an equivalent scan (e.g., contrast-enhanced CT 
of the brain) may be performed instead. 
• 
Part 2, GBM cohort: All subjects should undergo MRI of the brain.  Refer to the 
Imaging Acquisition Guidelines (IAG) for scanning guidelines 
• 
Part 2, NHL cohorts: All baseline (and subsequent) scanning should be 
performed as clinically indicated based on the NHL subtype and the 
manifestation of the subject’s disease.  For subjects with measurable tumors, 
contrast-enhanced CT of the neck, chest, abdomen, and pelvis should be 
performed.  If PET/CT is used to assess disease, the CT component must be 
performed to diagnostic quality (including the required anatomical coverage and 
use of IV and oral contrast).  Other modalities (e.g., medical photography for 
cutaneous T-cell lymphoma (TCL) or bone marrow biopsy) may be used after 
discussion with the medical monitor. 
• 
Disease characteristics (as available):  
• The results of any mutational analysis of tumor or other associated tissue (e.g., 
cytology, circulating tumor cells, cf-DNA), including p53 status (if available).  
• For Part 2 NHL p53 status and NSCLC p53 WT status is required prior to dosing 
• The size(s) and location(s) of target lesion(s) used for response characterization 
for at least two prior lines of therapy, as well as a description of the dates of 
service and changes made to management 
• 
Tumor biopsies: 
• All subjects in Part 1 (dose escalation and, the PK/PD/biomarker/metabolite 
cohort/s), as well as all subjects in Parts 2 and 3, must submit an archival tumor 
specimen in addition to any fresh biopsies required in individual cohorts (see 
below).  The archival specimen will be used for retrospective testing for 
potential markers of sensitivity and/or resistance (e.g., p53).  If archival 
specimen is not available, a fresh biopsy must be performed. Further details 
regarding processing will be provided in the SRM. 
• NOTE: All NHL subjects in Part 2 must have a local p53 mutational analysis 
result prior to dosing unless the subject’s tumor has previously been 
demonstrated to harbor a p53 mutation. If local p53 status was not determined, 
analysis may be performed on archival tissue, but if archival tissue is not 
available, a fresh biopsy must be performed.  NHL subjects with neither archival 
tumor sample nor accessible tumor for fresh biopsy will not be permitted to 
enroll.  Further details will be provided in the SRM.  The intent is to accrue 10 
subjects each of WT and mutant p53. As the sub-cohorts are filled, it may 
become necessary to delay enrollment until p53 status is formally designated.  In 
case one NHL cohort reaches futility at any Interim Analysis, further enrolment 


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into the other NHL cohort will require central confirmation. NOTE:  All 
NSCLC subjects in Part 2 must have a local genomic p53 mutational analysis 
result prior to dosing.  If local p53 status was not determined, an archival sample 
or a fresh biopsy must be provided. 
• Individual subjects in the dose escalation portion of Part 1 may be required to 
provide paired biopsies for PD evaluation as described in Section 4.2.5 and 
Section 8.6.2.  For these subjects, a fresh baseline tumor biopsy is required and 
should be obtained within 14 days of the first dose of GSK3326595.  Further 
details will be provided in the SRM. 
• In the Part 1 PD/biomarker/metabolite expansion cohort(s), a fresh baseline tumor 
biopsy is required from all subjects and should be obtained within 14 days prior 
to the first dose of GSK3326595.  Further details will be provided in the SRM. 
• In Part 2, in addition to an archival tumor biopsy, a fresh baseline tumor biopsy is 
required from all subjects (except those in the GBM cohort) and should be 
obtained within 14 days prior to the first dose of GSK3326595.  If tumor tissue 
is not accessible, discussion with the GSK medical monitor is required and the 
medical monitor must assent to subject participation; in this circumstance, the 
paired biopsy on Day 15 would not be required.  Further details will be provided 
in the SRM. 
• In Part 3, in addition to an archival tumor biopsy, a mandatory fresh baseline 
tumor biopsy is required from all subjects and should be obtained within 14 days 
prior to the first dose of GSK3326595. The paired on-treatment biopsy should 
be taken on D15 (W3D1) prior to administration of pembrolizumab (see 
Section 8.2.2).  
8.2.2. 
Visit Windows 
Screening (baseline to pre-dose): All assessments including baseline imaging (e.g., CT, 
MRI, or PET/CT) should be performed within 14 days prior to first dose. Note for 
females, pregnancy testing should be performed within 7 days prior to first dose. Also, 
clinical labs performed during screening within 72 hours of first dose do not need to be 
repeated on Day 1. 
Week 1: Visits for Week 1 Days 1, 2, 3, and 4 must be performed on the day indicated. 
For subjects in the food effect/relative bioavailability sub-study, the Day 4 visit may be 
performed on Day 4 or Day 5. 
Week 2 to Week 8: Based on subject and clinic schedule, assessments can be ± 2 days.  
The only exception to this window is the Day 8 visit for subjects in the food 
effect/relative bioavailability sub-study, for whom this assessment must be performed 
± 1 day. 
The Week 3 Day 1 (Day 15) PK and PD sample collections are timed to permit 
evaluation of GSK3326595 PK and PD parameters at steady-state dosing.  If a subject is 
not receiving drug on Week 3 Day 1 (Day 15), either as a consequence of a planned drug 
holiday or due to toxicity, or has not been receiving drug for 14 days such that they are at 


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steady state, then these PK/PD collections should be rescheduled for a later timepoint 
when the subject is again being dosed at steady state, and the alternate collection date 
noted in the eCRF. 
For subjects in Part 3, the preferred order of procedures on Day 15 is: Administration of 
GSK3326595, on-study tumor biopsy, followed by administration of pembrolizumab.  
However, this order may be varied based on clinic schedules and other factors. If 
pembrolizumab is administered prior to the on-study biopsy, the biopsy should be 
collected within 24 hours of pembrolizumab administration. 
The disease assessment at week 8 should be performed ± 2 days. After the fourth 
scheduled scan for disease assessment (i.e., week 32 for solid tumors/GBM and week 48 
for NHL), the frequency of scheduled scans will be reduced to every 16 weeks for 
subjects with solid tumors/GBM and every 24 weeks for subjects with NHL.  For 
subjects enrolled in the PK/PD/Biomarker/Metabolite cohort, the required 18FDG-
PET/CT scan at Week 6 may be performed ± 7 days. 
Every 4-week, 8-week, 12-week and 26-week visits after Week 8 until Week 52: After 
the first disease assessment has been completed, the clinic visits can be scheduled  5 
days. 
In Part 3, all subsequent disease assessments (after the first assessment) may be 
performed  1 week to align with clinic visits for administration of pembrolizumab. 
Every 4-week, 8-week, 12-week and 26-week visits after Week 52: After week 52, the 
every 4-week visits will no longer be required at the discretion of the investigator; any 
procedures or tests originally required every 4 weeks (q4w) should be performed every 8 
weeks (q8w) instead.  For the every 8- and 12-week visits, clinic visits can be scheduled 
 7 days.   
Discontinuation visit: should be within 30 days from last dose of study drug. If a subject 
is unable to return to the clinic due to hospitalization, site staffs are encouraged to 
telephone the subject for assessment of adverse events. 
8.3. 
Safety 
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 8.1).  Additional time points for safety tests may be added during the course of 
the study based on newly available data to ensure appropriate safety monitoring. 
Note that this section details the procedures used to evaluate for safety and toxicity for 
this study. For management of toxicity and management/reporting of any suspected 
Adverse Events, refer to Section 9, Appendix 9, and Appendix 2. 
Post Protocol Amendment 8 implementation, subjects who continue to receive study 
treatment after the DCO date of the final analyses will be monitored and receive 
follow-up care in accordance with standard local clinical practice with recommendations 
provided for local safety laboratory monitoring for GSK3326595 given the absence of a 
label to define standard of care (refer to SRM). Only pre-specified additional safety 
assessments will be required (refer to Section 8). 


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8.3.1. 
Physical Exams 
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, neurological system, lungs, cardiovascular system, abdomen (liver 
and spleen), lymph nodes and extremities. Height must be recorded at the screening visit.  
Weight will also be measured and recorded at the screening visit and at each subsequent 
visit. 
A brief physical examination will include assessments of the skin, lungs, cardiovascular 
system, and abdomen (liver and spleen).  Weight will also be measured and recorded at 
the screening visit and at each subsequent visit. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses 
8.3.2. 
Performance Status 
The performance status will be assessed using the ECOG scale (Appendix 3) as specified 
in the Time and Events Table (Section 8.1). 
8.3.3. 
Vital Signs 
• 
Vital sign measurements to be measured, in a consistent fashion, per institutional 
standard (e.g., in a seated or semi-supine position after 5 minutes rest), will include 
temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate.  
• 
In case of an abnormal first reading, three readings of blood pressure and pulse rate 
should be taken and averaged to give the measurement to be recorded in the CRF.  
• 
Vital signs will be measured more frequently if warranted by clinical condition of the 
subject.  On days where vital signs are measured multiple times, temperature does 
not need to be repeated unless clinically indicated.  
Refer to the Study Reference Manual (SRM) for details regarding measurement of vital 
signs. 
8.3.4. 
Electrocardiogram (ECG) 
Section 8.1 indicates the visits at which ECGs must be obtained.  At each time point, a 
single 12-lead ECG will be obtained during the study using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals.  
On serial PK days (Days 1 and 15), ECGs will be obtained at multiple time points as 
described in the SRM.  On all other indicated visits, ECGs will be obtained prior to 
dosing.  Refer to Section 5.4.6 for QTcF calculations, to Appendix 2 for management 
strategies for QTcF prolongation, and to Section 5.4.6 for QTc withdrawal criteria. 
Local ECG may be read centrally at chosen timepoints. 


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8.3.5. 
Clinical Safety Laboratory Assessments 
All protocol required laboratory assessments, as defined in Table 16, must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Schedule. 
Laboratory requisition forms must be completed, and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM. Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.  The results of each test must be 
entered into the CRF. 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF. 
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws. 
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 16.  
Table 16 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
WBC count with 
Differential: 
RBC 
Indices: 
Platelet Count 
Reticulocytes 
Neutrophils 
Hemoglobin  
 
Lymphocytes 
Hematocrit 
 
 
Monocytes 
Red blood 
cells (RBC) 
Count 
 
 
Eosinophils 
Mean 
corpuscular 
volume 
(MCV) 
 
 
Basophils 
Mean 
corpuscular 
hemoglobin 
(MCH) 
 
 
Clinical 
Chemistry 
BUN/Urea 
Potassium 
AST (SGOT) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
ALT (SGPT) 
Total Protein 
Glucose  
Total 
calcium 
Alkaline 
phosphatise 
Albumin 
Amylase 
Lipase 
 
 


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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) 
Coagulation 
PTT, PT/INR 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood and ketones by dipstick 
• Urine hCG pregnancy test (only for women of childbearing potential.  Note 
that initial screening test must be serum hCG and subsequent tests may be 
urine hCG) 
• Microscopic examination (if available at the participating site) 
Additional urine 
and serum 
renal 
biomarkers 
Only for participants with screening eGFR <60 mL/min/1.73 m2:  
• Neutrophil gelatinase-associated lipocalin (NGAL), Kidney injury molecule-1 
(KIM-1) and albumin/creatinine ratio (urine) 
• Cystatin C (serum)  
Additional 
endocrine 
studies  
• Thyroid stimulating hormone (TSH) 
• Free T3 
• Free T4 


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Laboratory 
Assessments 
Parameters 
Other 
Screening 
Tests 
• HIV 
• Hepatitis B (HBsAg) 
• Hepatitis C (Hep C antibody) 
• FSH and estradiol (as needed in women of non-childbearing potential only) 
• Serum hCG Pregnancy test (only for women of childbearing potential.  Note 
that initial screening test must be serum hCG and subsequent tests may be 
urine hCG) 
NOTE: Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.4.5 and Section 14.6 
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. 
8.3.6. 
Bone Mineral Density 
In order to assess the clinical bone safety of GSK3326595, dual energy x-ray 
absorptiometry (DEXA) scans will be performed on all patients at baseline and every 
8 weeks thereafter (Section 8.1). 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. 
For consistency in the assessment, DEXA scans should be performed on the same 
machine for all evaluations on a particular subject when possible.  For more details, 
please refer to the SRM. 
Locally collected DEXA scans may be read centrally. 
Post Protocol Amendment 8 implementation, bone assessments (DEXA) will be 
performed at the discretion of the investigator. The data will be collected via a paper 
process and submitted to the Sponsor only if reporting criteria is met for SAEs, AESIs, or 
AEs leading to treatment discontinuation. Locally collected data will not be read 
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8.3.7. 
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 subject who develops visual symptoms and/or signs potentially associated 
with GSK3326595 exposure. 
Management of subjects 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. 
Subjects 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 subject develops any new or evolving ophthalmic 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. 
Post Protocol Amendment 8, ophthalmic assessments will be continued approximately 
every 6 months and at the end of the study treatment (if >8 weeks from the previous 
assessment). The data will be collected via a paper process and submitted to the Sponsor 
only if reporting criteria is met for SAEs, AESIs, or AEs leading to treatment 
discontinuation. Locally collected data will not be read centrally. 
8.3.8. 
Pregnancy 
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of dosing and until 90 days post-last dose. 


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If a pregnancy is reported then the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 10. 
8.4. 
Pharmacokinetics 
8.4.1. 
Blood Sample Collection 
Blood samples (approximately 2 mL each) for pharmacokinetic (PK) analysis of 
GSK3326595 will be collected at the time points indicated in Table 9, Table 13, Table 14 
and Table 15.  Blood samples (approximately 2 mL each) for PK analysis of 
pembrolizumab will be collected at the time points indicated in Table 15.  
The actual date and time of each blood sample collection will be recorded.  The timing of 
PK samples may be altered and/or PK samples may be obtained at additional time points 
to ensure thorough PK monitoring.  Blood samples for pharmacokinetic analysis should 
be collected at the time of a SAE whenever possible. 
Plasma or serum analysis will be performed as described in the Study Reference Manual 
(SRM).  Concentrations of GSK3326595 or pembrolizumab will be determined using the 
currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site (detailed in the SRM). 
Details of PK blood sample collection, processing, storage and shipping procedures are 
provided in the SRM. 
Once the plasma has been analyzed for GSK3326595 any remaining plasma may be 
analyzed for other compound-related metabolites and the results reported under a 
separate GSK protocol. 
8.4.2. 
Urine Sample Collection 
Urine samples for quantitative analysis of GSK3326595 will be collected after single 
dose and at steady state.  The actual date and time of each urine sample collection will be 
recorded. 
Details of PK urine sample processing, storage and shipping procedures are provided in 
the SRM. 
Once the urine has been analyzed for GSK3326595 any remaining urine may be analyzed 
for other compound-related metabolites and the results reported under a separate GSK 
protocol. 
8.5. 
Metabolite Analysis 
8.5.1. 
Blood Sample Collection 
Subjects enrolled in the PK/PD/Biomarker/Metabolite cohort(s) (Section 4.2.5) will have 
blood drawn for PK evaluation on the same schedule as all other subjects participating in 
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blood will be collected at each timepoint from all subjects in the expansion cohorts. 
Samples will be prepared for shipment according to the SRM and processed/separated at 
the clinical site. 
8.5.2. 
Urine Sample Collection 
Urine samples will be collected from subjects in the PK/PD/Biomarker/Metabolite 
expansion cohort(s) (Section 4.2.5) into plastic bottles over the time period specified in 
the Time and Events Table for analysis of GSK3326595 and any metabolite(s). Details of 
the urine sample processing, storage and shipping procedures are provided in the SRM. 
8.5.3. 
Sample Analysis 
Plasma and/or whole blood analysis for circulating biomarkers and metabolites will be 
performed as described in the SRM. 
Plasma and urine samples will be analyzed for GSK3326595 and its metabolites and the 
results reported under a separate report. 
8.6. 
Pharmacodynamics/Biomarkers 
All subjects in Part 1 (both dose escalation and the PK/PD expansion cohort) will have 
limited PD sampling performed.  
 and other biomarkers may be assessed in blood 
or tumor to determine the effects of GSK3326595. Change from baseline levels will be 
measured. In addition, in the PK/PD expansion cohort only, whole blood samples may be 
utilized for the identification and/or validation of a gene signature panel indicative of 
modulation in response to GSK3326595.  Changes in the gene levels from baseline will 
be assessed.  This signature may serve as a novel PD biomarker of PRMT5 inhibition by 
GSK3326595.  The PD outcome may be correlated to clinical outcome.  
All subjects in Parts 2 and 3 will have PD sampling performed.  
 and other 
biomarkers may be assessed in blood or tumor to determine the effects of GSK3326595. 
Change from baseline levels will be measured. Whole blood samples may be utilized for 
the identification and/or validation of a gene signature panel indicative of modulation in 
response to GSK3326595.  Changes in the gene levels from baseline will be assessed.  
This signature may serve as a novel PD biomarker of PRMT5 inhibition by 
GSK3326595.  PD studies may also help us to better understand the mechanism of action 
for GSK3326595 and inform future rational combinations.  The PD outcome may be 
correlated to clinical outcome.  
8.6.1. 
Blood Sample Collection 
Plasma samples from all subjects in Part 1 will be collected as described in Section 8.4.1.  
An aliquot from the PK sample will be separated and stored for the purpose of assessing 
pharmacodynamic biomarkers according to the SRM. 
Whole blood and plasma samples will be collected during the PK/PD expansion cohorts, 
Part 2, and Part 3 as described in the Time and Events table (Section 8.1) and the SRM.  
Additionally, serum will be collected during Parts 2 and 3.  Plasma or serum that is 
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initially collected for the purpose of PK assessments may be utilized for biomarker 
assessments when there is remaining sample. 
8.6.2. 
Tumor Biopsy Collection 
All subjects will be asked to submit an archival tumor biopsy at baseline in order to 
conduct retrospective tests for the identification and/or validation of known and novel 
biomarkers. If archival specimen is not available, a fresh biopsy may be performed. In 
addition, subjects enrolled in PK/PD expansion cohort(s) must submit fresh tumor 
biopsies collected pre- and post-dose in addition to the archival tumor biopsy as 
described in the Time and Events table (Section 8.1) and the SRM.  Unscheduled tumor 
biopsies may be collected based on emerging data (e.g., to evaluate PD in a subject with 
clinical response). 
 
 
 
 
. 
In addition, patients enrolled in part 3 are requested to provide results from any PD-L1 
test performed, including information on the antibody used and, preferably, the vendor or 
institution that performed the test. Also, PD-L1 testing will be done centrally. 
8.6.3. 
Assessments for 18FDG-PET/CT 
All subjects enrolled in the PK/PD/Biomarker/Metabolite expansion cohort(s) (Section 
4.2.5) will have 18FDG PET/CT assessments performed at baseline and on treatment as 
outlined in the Time and Events table.  Additional scans may be performed at different 
timepoints based on emerging data during the study.  
Additional details will be provided in the SRM. Additional analysis may be conducted by 
an independent central reviewer. Instructions for submission of data are provided in the 
SRM. 
8.7. 
Efficacy 
Post Protocol Amendment 8 implementation, no new efficacy assessments will be 
performed as part of the study. 
8.7.1. 
Subjects with Solid Tumors (Part 1 and Part 2) 
The overall response rate is defined as the percentage of subjects with a confirmed 
complete response (CR) or confirmed partial response (PR), as per RECIST 1.1.   
• Lesion assessment method and timing, evaluation of disease, disease progression 
and response criteria will be conducted according to Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1) [Eisenhauer, 2009] as outlined below 
and in Section 14.4.1.  
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• Disease assessment modalities may include imaging (e.g., computed tomography 
[CT] scan, magnetic resonance imaging [MRI]) and physical examination (as 
indicated for palpable/superficial lesions). Contrast-enhanced CT of the chest, 
abdomen, and pelvis is preferred, but other modalities may be used (e.g., in the 
case of contrast allergy) as described in Section 8.2.1. 
• The baseline disease assessment will be completed within 2 weeks prior to the 
first dose of GSK3326595, then every 8 weeks thereafter and at the final study 
visit.  See the Time and Events Table (Section 8.1) for the schedule of 
assessments of anti-cancer activity.  
• 
Assessments must be performed on a calendar schedule (Day 1 being the day of 
the first study treatment administration) and should not be affected by dose 
interruptions/delays.  
• 
For post-baseline assessments, a window of 7 days is permitted to allow for 
flexible scheduling.  If the last radiographic assessment was more than 8 weeks 
prior to the subject’s withdrawal from study and progressive disease has not 
been documented, a disease assessment should be obtained at the time of 
withdrawal from study treatment. 
• 
Subjects whose disease responds (either complete response [CR] or partial 
response [PR]) should have a confirmatory disease assessment performed at 
least 4 weeks after the date of assessment during which the response was 
demonstrated.  
• 
To ensure comparability between the baseline and subsequent assessments for 
each subject, the same method of assessment and the same technique will be 
used when assessing response. 
• 
Any subject in the ACC tablet cohort who has not yet shown objective 
radiological disease progression at treatment discontinuation should continue to 
be followed as per RECIST 1.1 for radiological progression, unless consent has 
been withdrawn. 
8.7.2. 
Subjects with GBM 
Response will be assessed by the investigator every 8 weeks, as outlined in the Time and 
Events Table (Table 14), using standardized Response Assessment in Neuro-Oncology 
(RANO) Working Group Criteria, as detailed in Section 14.4.2. 
8.7.3. 
Subjects with Non-Hodgkin’s Lymphoma 
Response will be assessed by the investigator every 12 weeks, as outlined in the Time 
and Events Table (Table 14), using standardized Lugano Criteria, as described in Section 
14.4.3. 
8.7.4. 
Subjects in Part 3 
The overall response rate is defined as the percentage of subjects with a confirmed 
complete response (CR) or confirmed partial response (PR), as per iRECIST guidelines, 


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as described in Section 14.4.4 [Seymour, 2017].  These guidelines will be used in the 
assessment of response/progression to account for the unique tumor kinetics observed 
with immunotherapeutic agents, which may manifest as an increase in tumor burden then 
later is followed by regression suggesting the apparent observed neoplastic growth 
representing transient lymphocyte infiltration. Thus, participants with disease progression 
by RECIST version 1.1 guidelines are required to have a confirmatory disease assessment 
no sooner than 4 weeks after the date disease progression was declared in order to 
confirm disease progression by iRECIST guidelines [Seymour, 2017]. The visit level 
responses and treatment-based decisions will incorporate iRECIST guidelines [Seymour, 
2017]. 
8.8. 
Pharmacogenetic Analysis 
An important objective of the clinical study is pharmacogenetic (PGx) research. 
Participation in PGx is optional but all subjects who are eligible for the clinical study will 
be given the opportunity to participate. Subjects may decline participation without effect 
on their medical care or care during the clinical study. A separate consent signature is 
required for PGx research. 
Subjects who provide consent will have a blood sample taken for analysis. The 
presence/absence of genetic variations in host DNA from blood will be analyzed to 
determine their relationship with response (safety, tolerability, pharmacokinetics, and 
efficacy) to treatment with GSK3326595.  
Information regarding pharmacogenetic research is included in Appendix 8. In approving 
the clinical protocol, the independent ethics committee/institutional review board 
(IEC/IRB) (and, where required, the applicable regulatory agency) also approve the PGx 
assessments unless otherwise indicated. Where permitted by regulatory authorities, 
approval of the PGx assessments can occur after approval is obtained for the rest of the 
study. If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated. 
When PGx assessments are not approved, then the approval for the rest of the study will 
clearly indicate this and therefore, PGx assessments will not be conducted. 
8.9. 
Immunogenicity Analysis (Part 3) 
Blood samples (approximately 2 mL) for immunogenicity analysis of pembrolizumab 
will be collected at the time points indicated in Table 15. The timing and number of 
planned immunogenicity samples may be altered during the course of the study, based on 
newly available data to ensure appropriate safety monitoring. Serum will be used to 
assess the presence of anti-drug antibodies (ADA). The analysis for the presence of anti-
pembrolizumab antibodies will be performed contingent on availability of a validated 
assay, and if considered clinically relevant. The actual date and time of each blood 
sample collection will be recorded. Details of blood sample collection (including volume 
to be collected), processing, storage, and shipping procedures are provided in the SRM.   
In the event of a hypersensitivity reaction that is either 1) clinically-significant in the 
opinion of the investigator, or 2) leads to the participant withdrawing from study 


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treatment, blood samples may be taken from the participant for immunogenicity testing at 
the time of the event, and at further timepoints specified in the SRM.  
Results of ADA testing may be reported separately at the end of the study.  
8.10. 
Translational and Exploratory Research 
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8.11. 
Patient Reported Outcomes 
Planned time points for all assessments related to PROs are listed in the Time and Events 
Table (Table 14) and will apply to the ACC tablet cohort in Part 2 of the study only.  
PROs will be available on a rolling basis as they are available and data collection tools 
are implemented, with select PROs not being completed in the study when unavailable in 
specific languages. 
Cancer can have a profound impact on patients’ health related quality of life (HRQoL); 
both the symptoms of the disease as well as the tolerability profile of treatments impact 
HRQoL. The patient-reported outcomes (PRO) in this study (Table 17) aim to measure 
changes in symptoms, physical functioning, and symptomatic side effects, tolerability, 
and HRQoL.  
Completion of PRO Questionnaires 
PRO questionnaires are to be administered at the beginning of the visits specified in 
Section 8.11 in the order presented in the electronic device.  To avoid biasing responses, 
the subjects should not be told the results of diagnostic tests prior to completing the 
questionnaires.  Adequate time must be allowed to complete all items on the 
questionnaires, and if necessary, the subject must be encouraged to complete any missing 
items. 
 
Table 17 
PRO Outcomes Assessed in Study 204653 
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9. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DATA COLLECTION, REPORTING, AND FOLLOW-UP 
9.1. 
Definition of AE/SAE 
The definitions of an AE or SAE can be found in Appendix 9. The severity of adverse 
events will be graded utilizing the NCI-CTCAE v4. Additional details regarding 
management of specific AEs or SAEs are described in Appendix 9. 
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.  
9.1.1. 
Cardiovascular/Death events 
For any cardiovascular events detailed in Appendix 9 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
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The CV eCRFs are presented as queries in response to reporting of certain CV 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 eCRF 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. 
9.1.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) for GSK3326595 are ocular events and bone-
related events. These AESIs are pre-defined and are derived from the Osteopenia/ 
Osteoporosis Standardised MedDRA Query (SMQ) and the Optic Nerve Disorders SMQ 
(see SRM for listing of terms for reporting). Post Protocol Amendment 8 implementation, 
AESIs will be reported directly to the Sponsor via a paper process. The severity of all 
AESIs will be graded utilizing the NCI-CTCAE v4 for Adverse Events. 
9.1.3. 
Other Sentinel Events 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, that are felt to be clinically significant in the 
medical and scientific judgment of the investigator are to be recorded as an AE or SAE, 
in accordance with the definitions provided. 
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay. 
Any new primary cancer must be reported as a SAE. 
9.2. 
Time period and Frequency for collecting AE and SAE 
Information 
• Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact.  
• AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 8.2.2), at the timepoints specified in the Time and Events 
Table (Section 8.1). 
• Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
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• All SAEs will be recorded and reported to GSK within 24 hours of the 
investigator/site staff becoming aware of them, as indicated in Appendix 9. 
• Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any AEs or SAE, including a 
death, at any time after a subject has been discharged from the study, and he/she 
considers the event reasonably related to the study treatment or study 
participation, the investigator must promptly notify GSK. 
• Post Protocol Amendment 8 implementation, for those subjects who continue to 
receive study treatment after DCO date of final analyses, the Sponsor will 
continue to collect safety information including SAEs, AESIs and AEs leading to 
treatment discontinuation via a paper process for up to 30 days after last dose of 
study treatment. 
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 9. 
9.2.1. 
Method of Detecting Unsolicited AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include: 
• 
“How are you feeling?”  
• 
“Have you had any (other) medical problems since your last visit/contact?” 
• 
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”  
9.2.2. 
Method of Detecting Solicited AEs and SAEs 
Vision Symptom Review: 
• 
“Have you had any changes in your vision since your last visit/contact?” 
9.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 9.1) will be followed until resolution, until the condition stabilizes, 
until the event is otherwise explained, or until the subject is lost to follow-up (as defined 
in Section 5.4). Further information on follow-up procedures is given in Appendix 9. 
9.2.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to GSK or designee of SAEs related to study 
treatment is essential so that legal obligations and ethical responsibilities towards the 
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GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
10. 
DATA MANAGEMENT 
For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system. When the Protocol Amendment 8 is implemented at a site, the 
collection of data for all enrolled subjects who no longer receive study treatment will stop 
entirely. Those subjects still benefiting from GSK3326595 in the opinion of their treating 
Investigator may continue to receive study treatment under Protocol Amendment 8. In the 
portion of the study continuing treatment under Protocol Amendment 8, only SAEs, AEs 
leading to treatment discontinuation, overdoses, pregnancies, and pre-defined ocular and 
bone AEs (AESIs) will be reported directly to the Sponsor via paper process. In addition,  
• Ocular assessments will be required and reported via a paper process to the 
Sponsor only if reporting criteria is met for SAEs, AESIs, or AEs leading to 
treatment discontinuation.   
• Bone (DEXA) assessments will be performed at the discretion of the investigator 
and reported via a paper process to the Sponsor only if reporting criteria is met 
for SAEs, AESIs, or AEs leading to treatment discontinuation. 
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. 
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  
CRFs (including queries and audit trails) will be retained by GSK or designee, and copies 
will be sent to the investigator to maintain as the investigator copy. Subject initials will 
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11. 
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES 
11.1. 
Hypotheses 
In Part 1, the primary endpoints of this study are safety and tolerability; the MTD and 
RP2D will also be determined. No formal statistical hypotheses will be tested. The 
primary focus will be on determining the recommended dose for further exploration, the 
safety profile, and the PK of GSK3326595 in subjects with advanced solid malignancies. 
Analyses will be descriptive and exploratory. 
The primary goal of Part 2 is to evaluate disease-specific clinical activity in subjects with 
select solid tumors and NHL.  The cohorts will be terminated for futility based on interim 
analysis described in Section 11.9.6. 
• For TNBC and ER+BC, efficacy is defined as a clinically meaningful 
response rate (defined as the percentage of subjects that have achieved a CR 
or PR) of 25% relative to a 10% historical control response rate. 
• For mTCC, efficacy is defined as a clinically meaningful response rate 
(defined as the percentage of subjects that have achieved a CR or PR) of 30% 
relative to a 15% historical control response rate. 
• For recurrent GBM, efficacy is defined as a clinically meaningful 
improvement in the rate of subjects who remain progression-free at six 
months (defined as a 35% six-month PFS rate relative to a 17% historical six-
month PFS rate). 
• For ACC and HPV-positive solid tumors, efficacy is defined as a clinically 
meaningful response rate (defined as the percentage of subjects that have 
achieved a CR or PR) of 30% relative to a 10% historical control response 
rate. 
• For NHL (both p53 wild-type and p53 mutant cohorts), efficacy is defined as 
a clinically meaningful response rate (defined as the percentage of subjects 
that have achieved a CR or PR) of 30% relative to a 10% historical control 
response rate. 
• For NSCLC, efficacy is defined as a clinically meaningful response rate 
(defined as the percentage of subjects that have achieved a CR or PR) of 30% 
relative to a 10% historical control response rate. An interim futility analysis 
will be used to determine the scope of further development in this cohort. 
The primary goal of Part 3 is to evaluate the safety and tolerability of GSK3326595 in 
combination with pembrolizumab in solid tumors. No formal statistical hypotheses will 
be tested. 
 
 
 
11.2. 
mTPI Method 
The mTPI design [Ji, 2010] is an extension of the toxicity probability interval method [Ji, 
2007] and employs a simple beta-binomial hierarchic model. Decision rules are based on 
CCI


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calculating the unit probability mass (UPM) of three intervals corresponding to under 
dosing, proper dosing, and overdosing in terms of toxicity. Specifically, the under dosing 
interval is defined as (0, pT – ε1), the overdosing interval as (pT + ε2, 1), and the proper 
dosing interval as (pT – ε1, pT + ε2), where ε1 and ε2 are small fractions, such as 0.05, to 
account for the uncertainty around the true target toxicity. A sensitivity analysis reported 
by Ji et al [Ji, 2010] showed that the mTPI design is robust to the specification of ε 
values. In addition, ε1 and ε2 could take different values to reflect physician preference 
and the nature of the disease. For advanced diseases with few treatment options, higher 
toxicity rates might be considered acceptable, implying a specification of ε2 > ε1. For 
less-advanced diseases, the two ε values could be identical or ε1 > ε2. The three dosing 
intervals are associated with three different dose-escalation decisions. The under dosing 
interval corresponds to a dose escalation (E), overdosing corresponds to a dose de-
escalation (D), and proper dosing corresponds to staying at the current dose (S). Given an 
interval and a probability distribution, the UPM of that interval is defined as the 
probability of the interval divided by the length of the interval. The mTPI design 
calculates the UPMs for the three dosing intervals, and the one with the largest UPM 
implies the corresponding dose-finding decision. That decision provides the dose level to 
be used for future subjects. For example, if the under dosing interval has the largest 
UPM, decision E, to escalate, will be executed, and the next cohort of subjects will be 
treated at the next-higher dose level. Ji et al [Ji, 2010] show that the decision based on the 
UPM is optimal in that it minimizes a subsequent expected loss. Under the mTPI design, 
a trial is terminated when either the lowest dose is above the MTD or a prespecified 
maximum sample size is reached. 
11.3. 
Bayesian Predictive Adaptive Design for GBM Cohort  
A Bayesian predictive adaptive design [Lee, 2008] that allows the trial to be monitored 
more frequently at multiple stages will employed for GBM cohort in Part 2 of the study. 
The criteria will be based on a historically unimportant six month PFS rate of 17% versus 
a six month PFS rate of interest of 35%. The six month PFS rate is defined as the 
proportion of the subjects who are progression free and still alive at six months from the 
start of treatment. Bayesian statistics will be employed to calculate the posterior 
probability that the six month PFS rate 35% and 17% at interim assuming a Beta prior 
for the Binomial distributed data.  Predictive probability calculates the probability that 
the six month PFS rate 35% or 17% given the responses have already been observed.  
A weak prior Beta (0.03, 0.07) is used, which is equivalent to the information present in 
0.1 subject. The first interim analysis may be conducted when at least 10 evaluable 
subjects are available for GBM cohort at a given dose. The evaluable subjects for GBM 
cohort is defined as the GBM subjects who have had three post baseline disease 
assessments or have progressed or have died or have withdrawn from study treatment due 
to any reason. Futility interim analysis decision rules for the 10th to 27th evaluable 
subjects, specifying the number of subjects who have not progressed six months after 
receiving the first dose of GSK3326595 needed for continuing enrollment or stopping for 
futility when total sample size is up to 27 is presented in Table 18.  These rules are 
intended as a guideline.  Actual decisions will depend on the totality of the data. 
 


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Table 18 
Decision Making Criteria for GBM Futility 
Number of 
Evaluable 
Subjects  
Number progression-
free at 6 months to 
Stop Early for Futility  
Probability of 
declaring futility 
when 6m PFS 
rate=0.17 
Probability 
declaring futility 
when 6m PFS 
rate=0.35  
10 
0 
0.1552 
0.0135 
11 
0 
0.0000 
0.0000 
12 
0 
0.0000 
0.0000 
13 
1 
0.1817 
0.0199 
14 
1 
0.0000 
0.0000 
15 
1 
0.0000 
0.0000 
16 
1 
0.0000 
0.0000 
17 
2 
0.1325 
0.0144 
18 
2 
0.0000 
0.0000 
19 
2 
0.0000 
0.0000 
20 
2 
0.0000 
0.0000 
21 
3 
0.1004 
0.0108 
22 
3 
0.0000 
0.0000 
23 
4 
0.1125 
0.0194 
24 
4 
0.0000 
0.0000 
25 
4 
0.0000 
0.0000 
26 
5 
0.0799 
0.0174 
27 
6 
0.0869 
0.0390 
The enrollment for GBM cohort may be stopped due to futility if the predictive 
probability that the 6 month PFS rate 17% (historical control) is small (e.g., less than a 
2% chance for a total sample size of 28 subjects).  Enrollment may also be stopped due to 
futility if the equivalent of all the evaluable subjects are progressed or off study treatment 
before 6 months from the first dose in the first 10 enrolled evaluable subjects in GBM 
cohort or less than 1 subject who is not progressed still on treatment at month 6 are 
observed in the first 13 evaluable subjects.  For example, when there are 10 evaluable 
subjects available at the time of interim analysis with all subjects progressed before 
month 6, then the cohort may be stop for futility.  Otherwise, the enrollment of the 
respective cohort will continue to the target sample size.  
When the total sample size in a treatment arm is 28 and at least 8 subjects who are not 
progressed before 6 months from first dose and still on treatment at month 6 out of 28 
subjects are observed, we can claim null hypothesis is rejected.  
11.4. 
Bayesian Hierarchical Modelling 
To further investigate clinical activity across the pre-specified cohorts, an adaptive design 
utilizing a Bayesian hierarchical model will be employed for the mTCC, TNBC, p53 WT 
NHL and p53 mutant NHL cohorts in Part 2. Multiple interim evaluations of the 
accumulating data to determine if one or more cohorts should discontinue enrollment 


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early due to futility will be incorporated. Interim and final evaluations will be based on a 
hierarchical model that borrows information in a limited way from cohorts that 
demonstrate similar treatment effects based on the accumulated trial data. Traditional 
estimates based on independent analyses will also be provided. j is the true response rate 
for cohort j, where j = 1,…, 4 and indexes the four cohorts. Cj is the historical control 
response rate for the jth cohort. The historical controls vary by cohort and are provided in 
Table 21. The study is powered to detect a high clinically meaningful response rate and is 
based on the cohort model assessment of whether there is sufficiently high probability 
that j exceeds Cj. The posterior probability that the ORR for a given cohort is greater 
than Cj will be computed according to the following comparison:  
P (πj > Cj | current data) for the j-th cohort 
If this posterior probability is sufficiently low within a given cohort, then this will 
provide insufficient evidence to suggest that the ORR is greater than its respective 
historical control. Conversely, if a sufficiently high posterior probability is observed, this 
will provide evidence that the ORR is greater than the historical control, and the dose will 
be declared efficacious in that cohort. Thresholds for decision making are defined in 
Section 4.3.3. 
Full details regarding the hierarchical modeling framework are in Appendix 11. 
11.5. 
Simon’s Two Stage Design for ACC Cohorts  
Simon's optimal two-stage design (Simon, 1989) will be used for both ACC cohorts 
(tablet and capsule formulation). For both cohorts, the null hypothesis that the true 
response rate is 10% will be tested against a one-sided alternative of 30%.  
For the capsule cohort, in the first stage, 10 subjects will be accrued. If there are 1 or 
fewer responders in these 10 subjects, the cohort will be stopped early for futility. The 
maximum number of subjects to be enrolled for this cohort is 38. The null hypothesis will 
be rejected if 8 or more responders are observed in 38 patients. This design yields a type I 
error rate of 0.023 and power of 80.8% when the true response rate is 30%. 
For the tablet cohort, in the first stage, 17 subjects will be accrued. If there are 2 or fewer 
responders in these 17 subjects, the cohort will be stopped early for futility. This rule is 
intended as a guideline, development decisions will depend on the totality of the data. 
The maximum number of subjects to be enrolled for this cohort is 50. The null hypothesis 
will be rejected if 10 or more responders are observed in 50 patients. This design yields a 
type I error of 0.02 and power of 89.9% when the true response rate is 30%.  
11.6. 
Bayesian Predictive Adaptive Design for ER+BC Cohort 
The ER+BC cohort will employ the 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 10% overall response rate (ORR) representing best available 
therapy in favour of a 25% ORR. A close to non-informative prior will be used. Let p 
denote the response rate, the prior distribution used is p ~ Beta (0.025, 0.075). The cohort 
will be stopped early due to futility if the predictive probability of success is less than 


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8%. The success is defined as posterior probability of ORR > 10% at the end of the 
cohort is larger than 80%. The first interim analysis will be performed when at least 10 
subjects become evaluable. The max sample size is 35 subjects, and the design will have 
type I error of 0.10 and power of 82%. 
The decision rules, specifying the number of subjects with a clinical response needed for 
continuing enrolment or, stopping for futility, are displayed in Table 19. The 
methodology is based on the predictive probability of success if enrolment continues to 
maximum number of subjects [Lee, 2008].  The interim analysis will be for futility only, 
i.e., the dose expansion cohort will not stop early for efficacy. 
Table 19 
Decision Making Criteria for ER+BC Futility 
Number of 
Evaluable 
Subjects  
  This Number of 
Confirmed 
Responses to 
Stop Early for 
Futility  
 Probability of 
continuing 
enrolling when 
ORR=0.1 
 Probability of 
continuing 
enrolling when 
ORR=0.25  
 10 
0 
0.6513 
0.9437 
 11 
0 
0.6513 
0.9437 
 12 
0 
0.6513 
0.9437 
 13 
0 
0.6513 
0.9437 
 14 
1 
0.3971 
0.8843 
 15 
1 
0.3971 
0.8843 
 16 
1 
0.3971 
0.8843 
 17 
1 
0.3971 
0.8843 
 18 
1 
0.3971 
0.8843 
 19 
1 
0.3971 
0.8843 
 20 
1 
0.3971 
0.8843 
 21 
1 
0.3971 
0.8843 
 22 
2 
0.2938 
0.8674 
 23 
2 
0.2938  
0.8674 
 24 
2 
0.2938 
0.8674 
 25 
2 
0.2938 
0.8674 
 26 
2 
0.2938 
0.8674 
 27 
3 
0.2108 
0.8511 
 28 
3 
0.2108 
0.8511 
 29 
3 
0.2108 
0.8511 
 30 
3 
0.2108 
0.8511 
 31 
3 
0.2108 
0.8511 
 32 
4 
0.1509 
0.8369 
 33 
4 
0.1509 
0.8369 
 34 
4 
0.1509 
0.8369 


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11.7. 
Bayesian Predictive Adaptive Design for HPV+ Cohort 
The HPV+ cohort will employ the 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 10% overall response rate (ORR) representing best available 
therapy in favour of a 30% ORR. A close to non-informative prior will be used. Let p 
denote the response rate, the prior distribution used is p ~ Beta (0.03, 0.07). 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 ORR > 10% at the end of the 
cohort is larger than 87.6%. The first interim analysis will be performed when at least 10 
subjects become evaluable. The max sample size is 28 subjects, and the design will have 
type I error of 0.05 and power of 87%. 
The decision rules, specifying the number of subjects with a clinical response needed for 
continuing enrolment or, stopping for futility, are displayed in Table 20. The 
methodology is based on the predictive probability of success if enrolment continues to 
maximum number of subjects [Lee, 2008].  The interim analysis will be for futility only, 
i.e., the dose expansion cohort will not stop early for efficacy.  
Table 20 
Decision Making Criteria for HPV+ Futility 
Number of 
Evaluable 
Subjects  
  This Number of 
Confirmed 
Responses to 
Stop Early for 
Futility  
 Probability of 
continuing 
enrolling when 
ORR=0.1 
 Probability of 
continuing 
enrolling when 
ORR=0.3  
 10 
0 
0.6513 
0.9718 
 11 
0 
0.6513 
0.9718 
 12 
0 
0.6513 
0.9718 
 13 
0 
0.6513 
0.9718 
 14 
0 
0.6513 
0.9718 
 15 
0 
0.6513 
0.9718 
 16 
0 
0.6513 
0.9718 
 17 
1 
0.4660 
0.9618 
 18 
1 
0.4660 
0.9618 
 19 
1 
0.4660 
0.9618 
 20 
1 
0.4660 
0.9618 
 21 
2 
0.3107 
0.9500 
 22 
2 
0.3107 
0.9500 
 23 
2 
0.3107  
0.9500 
 24 
2 
0.3107 
0.9500 
 25 
3 
0.2019 
0.9383 
 26 
3 
0.2019 
0.9383 
 27 
4 
0.1129 
0.9161 


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11.8. 
Statistical Design for NSCLC cohort 
The Part 2 NSCLC cohort is intended to explore the clinical activity in the p53 wild-type 
NSCLC population. Simon’s optimal two-stage design (Simon, 1989) will be used as a 
basis for analysis of the NSCLC cohort. The null hypothesis that the true response rate is 
10% will be tested against a one-sided alternative. ORR will be assessed for the 10 
subjects that are confirmed with p53 wild-type. 
In the first stage, 10 subjects will be accrued. If there are 1 or fewer responders in the first 
10 subjects, the cohort will be stopped for futility. If 2 or more responses are observed, 
further expansion of the p53 wild-type NSCLC cohort may be triggered via protocol 
amendment or as a part of another study. If the cohort were to expand to 29 subjects, the 
null hypothesis would be rejected if 6 or more responders are observed. This design 
yields a type I error rate of 0.047 and power of 80.5% when the true response rate is 30%. 
11.9. 
Sample Size Considerations 
11.9.1. 
Sample Size Assumptions 
The sample size for each part of the trial was chosen to adequately characterize the 
safety, clinical activity, PK, and pharmacodynamic marker data according to the 
objectives of each part of the study.   
The study will enrol a maximum of approximately 412 subjects with tumor types that 
may include TNBC, mTCC, GBM, ACC, ER+BC, HPV+, NHL and NSCLC.  
In Part 1 approximately 42 subjects will complete the DLT evaluation period.  In 
addition, up to 12 subjects will be enrolled at or near the MTD/RP2D in the 
PK/PD/Biomarker/Metabolite expansion cohort(s) (Section 4.2.5) and approximately 12 
subjects in the food and formulation effect sub-study (Section 4.2.6). 
In Part 2, a maximum of 32 subjects, 40 subjects, 38 subjects, 50 subjects, 35 subjects, 28 
subjects, 28 subjects and 15 subjects will be enrolled in TNBC, mTCC, ACC (capsule), 
ACC (tablet), ER+BC, HPV+ solid tumor, GBM and NSCLC cohorts, respectively. A 
maximum of 25 subject will be enrolled in each of the NHL[+] and NHL[-] cohorts. If all 
cohorts enroll the maximum number of subjects, this will result in no more than 316 
subjects total. 
In Part 3 approximately 10 subjects will be enrolled into each of three cohorts: 
GSK3326595 100mg + pembrolizumab, GSK3326595 200mg + pembrolizumab, and 
GSK3326595 300mg + pembrolizumab. 
To determine the maximum sample size for GBM cohort, Bayesian predictive adaptive 
design will be used for testing hypotheses and sample size determination: 
H0: 6 months PFS rate ≤17% 
HA: 6 months PFS rate ≥35% 


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When maximum sample size is 28, the design will have a Type I error () of 0.086 and 
80% power.   
Enrollment into specific cohorts may be halted early based on results from interim 
analyses incorporating emerging response data. Response data from a minimum of 
10 subjects will be required in a cohort before it may discontinue enrollment for futility. 
In addition, at the final analysis and after the study has been closed, a minimum of 
5 subjects will be required in a cohort in order to meet statistical success at the final 
analysis. See Section 11.9.6 for more details. Data from evaluable subjects treated in the 
dose escalation part may be used for futility analysis if the subject is from the same 
population and treated at RP2D.   
Simulation studies were conducted to evaluate the performance of the Bayesian 
Hierarchical design under various assumptions for the distribution of true ORRs across 
the TNBC, mTCC, and NHL cohorts. Operating characteristics including power, type I 
error, estimation of the ORR, and the probability of halting enrollment at interim analyses 
were assessed. 
When the treatment effects are similar across TNBC, mTCC, and NHL histologies, the 
design maintains power 88% to 97% and type I error rate ≤0.1. Estimation efficiencies 
due to borrowing result in very good operating characteristics in these situations, even in 
histologies with low sample sizes. Table 21 provides similar operating characteristics for 
scenarios where not all histologies align in terms of efficacy performance. 
11.9.2. 
Sample Size Sensitivity 
No sample size sensitivity assessments will be performed. 
11.9.3. 
Sample Size Re-estimation or Adjustment 
No sample size re-estimation will be performed. 
11.9.4. 
Data Analysis Considerations 
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report. 
In the dose escalation cohorts, the dose will be escalated based on all available data, 
including biomarker and PK data and the safety profile of prior cohorts.  The DLT 
information on all subjects enrolled in the trial are used to update the estimated dose-
toxicity relationship and provide supportive information in addition to the mTPI design in 
the next escalation/de-escalation decision; the mTPI approach is expected to be used as 
the primary criteria for dose escalation. 
The expansion phases are designed to evaluate preliminary clinical activity.  A futility 
assessment will be conducted and enrollment into a disease-specific cohort may be 
paused in order to evaluate accumulating data including safety, clinical responses, and 


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pharmacokinetic and pharmacodynamic data. Response may also be stratified by p53 
status and other mutational and gene expression data, as described in the RAP. 
Subjects enrolled in Part 1 will be included in a Part 2 disease specific cohort analyses if 
the subjects were treated at the Part 2 dose and has the same disease as required for the 
cohort. 
11.9.5. 
Analysis Populations 
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK3326595. Safety and anti-cancer activity will be evaluated based on this analysis 
population. 
The All Evaluable Population is defined as subjects who have had two post baseline 
disease assessments, have progressed or died, or permanently discontinued from the 
study treatment for mTCC, TNBC, ER+BC, HPV+, NHL and NSCLC cohorts. It is 
defined as subjects who have had three post baseline disease assessments, have 
progressed or died, or permanently discontinued from the study treatment for ACC (both 
capsule and tablet) and GBM cohorts.  
The PK Population will consist of all subjects from the All Treated Population for whom 
a PK sample is obtained and analyzed. 
Pharmacodynamic Population: The PD Population is defined as subjects in the All 
Treated Subjects Population for whom paired and evaluable tumor biopsies (pre- and on-
treatment time points) or plasma were obtained and analyzed for biomarkers. 
Additional analysis populations may be defined in the RAP. 
11.9.6. 
Interim Futility Analysis 
Interim data will be evaluated to monitor efficacy and safety. For the GBM cohort, a 
planned interim analysis for futility will be performed when at least 10 evaluable subjects 
have been enrolled in this expansion cohort.  Enrollment may be stopped early for 
toxicity or lack of efficacy, should various criteria occur based on accrued data.  The 
design criterion for early stop for futility based on Bayesian Predictive Adaptive Design 
is described in Section 11.3. For TNBC, mTCC, and NHL cohorts, the decision criteria 
for early stop for futility based on Bayesian Hierarchical model are described below. The 
decision will be made for each individual disease-specific cohort. For the ACC capsule 
cohort, one interim futility analysis will be performed when first treated 10 subjects 
become evaluable. If there are 1 or fewer responders in these 10 subjects, the cohort will 
be stopped early for futility. For the ACC tablet cohort, one interim futility analysis will 
be performed when the first 17 treated subjects become evaluable. If there are 2 or fewer 
responders in these 17 subjects, the cohort will be stopped early for futility. This rule is 
intended as a guideline, development decisions will depend on the totality of the data. For 
ER+BC cohort, the first interim analysis will be conducted when at least 10 subjects 
become evaluable. The details about interim decision rules are specified in Section 11.6. 
For HPV+ cohort, the first interim analysis will be conducted when at least 10 subjects 
become evaluable. The details about interim decision rules are specified in Section 11.7. 


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For the NSCLC cohort, one interim futility analysis will be performed when first treated 
10 p53 wild-type subjects become evaluable. If there are 1 or fewer responders in these 
10 subjects, the cohort will be stopped early for futility. 
For TNBC, mTCC, and NHL cohorts, the therapeutic effect will be declared insufficient, 
and termination of enrollment will be recommended, if a minimum of 10 subjects become 
evaluable and the posterior probability that the confirmed ORR is greater than its 
corresponding historical control (Cj) is sufficiently low (<15%) based on the hierarchical 
model. That is, 
P (πj > Cj | current data) < 15%, for the j-th cohort, j=1,..4 
However, as described in Section 4.3.3, the decision to terminate a given cohort will not 
be made based on the statistical model alone and will require review of all available data, 
including safety/tolerability, PK, PD, and biomarker data. Operating characteristics 
associated with declaring early futility are provided for multiple scenarios in Table 21. 
For the Part 3 GSK3326595 + pembrolizumab combination cohorts, planned analyses 
will take place after the first 5 subjects in each cohort complete 35 days of study 
treatment or discontinue prior to 35 days. The details of this design can be found in 
Section 4.4. The operating characteristics of the stopping criteria for the Part 3 
GSK3326595 + pembrolizumab combination cohorts have been examined and can be 
found detailed in Section 11.10.4. 
Additional interim analyses may also be conducted to share key results at medical 
conferences, if deemed appropriate. 
11.9.7. 
Final Analysis 
Following Protocol Amendment 8 implementation, the final analysis of the study will be 
performed following the DCO as defined in Section 5.5. 
11.10. 
Key Elements of Analysis Plan 
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis. 
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment. 
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects. Consequently, there will be no 
imputation for missing data.  
All data will be summarized and listed. 


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11.10.1. 
Primary Analyses 
As the primary endpoints of Part 1 of this study are safety and tolerability, the primary 
analyses will be descriptive in nature. Safety endpoints are described in Section 5.4. 
The primary aim of Part 2 is to demonstrate clinically meaningful response rates in each 
of the disease cohorts. Bayesian predictive adaptive designs will be used to evaluate the 
GBM, ER+BC and HPV+ cohorts, independently, as described in Section 11.3, Section 
11.6, and Section 11.7, respectively. Bayesian-based hierarchical modeling will be used 
for the mTCC, TNBC, p53 WT NHL and p53 mutant NHL cohorts, as described in 
Section 11.4. For the NHL cohort, subgroup analyses may also be performed for specific 
indolent histological subtypes (e.g., follicular lymphoma [FL], transformed FL [tFL], and 
mantle cell lymphoma [MCL] subtypes only). Simon’s Two Stage designs will be used 
for both the capsule and tablet formulation cohorts for ACC, as detailed in Section 11.5.  
The primary aim of the NSCLC p53 wild-type cohort is to evaluate the potential of 
GSK3326595 as a treatment for this population. A Simon’s two-stage design will be used 
as a basis for this cohort, where the results of the interim futility analysis will help 
determine the scope of any further development of this cohort, as detailed in Section 
11.8. 
The primary aim of Part 3 is to evaluate the safety and tolerability of GSK3326595 in 
combination with pembrolizumab in subjects with select solid tumors. The primary 
analyses will be exploratory in nature.   
The All Treated Population will consist of all subjects receiving at least one dose of study 
drug and will be used for the analysis of safety and efficacy data. Complete details of the 
analyses will be provided in the RAP. 
11.10.2. 
Secondary Analyses 
11.10.2.1. Safety Analyses 
Safety endpoints are described in Section 5.4. 
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs, electrocardiogram [ECGs]) 
will be summarized according to the scheduled, nominal visit at which they were 
collected and across all on-treatment time points using a “worst-case” analysis. Complete 
details of the safety analyses will be provided in the RAP. 
11.10.2.1.1. 
Extent of Exposure 
The number of subjects administered study treatment will be summarized according to 
the duration of therapy 
11.10.2.1.2. 
Adverse Events 
AEs will be coded using the standard MedDRA and grouped by system organ class.  AEs 
will be graded by the investigator according to the NCI-CTCAE v4. 


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Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term.  Separate summaries will be given for all AEs, treatment-
related AEs, SAEs, and AEs leading to discontinuation of study treatment and dose 
modification.  AEs, if listed in the NCI-CTCAE v 4, will be summarized by the 
maximum grade.   
Dose-limiting toxicities will be listed for each subject and summarized by dose cohort for 
Part 1 subjects. 
AEs of special interest will be outlined in the RAP. 
The incidence of deaths and the primary cause of death will be summarized. 
11.10.2.1.3. 
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.  Further details will be provided in the RAP. 
11.10.2.2. Pharmacokinetic Analyses 
11.10.2.2.1. 
Pharmacokinetic Parameters 
PK analyses will be the responsibility of GSK. The plasma concentrations for individual 
subjects will be determined using a validated analytical method for GSK3326595. 
Individual plasma concentrations of GSK3326595 will be listed and summarized. 
For subjects 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 apparent clearance following oral dosing (CL/F) 
• time invariance (TI) and accumulation ratio (AR) as calculated by the following 
equations: 
 
 
Sparse plasma concentration-time data from Part 2 may be combined with serial data and 
further analyzed using a population approach. A nonlinear mixed effects model may be 


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used to determine population pharmacokinetic parameters and identify important 
covariates (e.g., age, weight, or disease related covariates). Further details of population 
PK analysis will be described in the RAP; results of such an analysis may be included in 
a report separate from the clinical study report. 
In a subset of subjects, GSK3326595 concentrations may be determined in urine samples 
to determine urinary recovery of unchanged drug and renal clearance. 
11.10.2.2.2. 
Statistical analysis of pharmacokinetic parameters 
Plasma concentration-time data will be listed by dose, age group, and summarized using 
descriptive statistics (n, mean, SD, median, minimum and maximum) by planned relative 
assessment time. Mean and/ or median values will be plotted over time. Individual 
plasma and urinary (if available) pharmacokinetic parameter values as well as a 
descriptive summary (mean, standard deviation, median, minimum, maximum, geometric 
mean, and the standard deviation, coefficient of variance percent (CV%) and 95% 
confidence interval 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% 
confidence interval will be estimated from the power model.  
11.10.2.2.3. 
Food Effect and Relative Bioavailability Sub-Study 
Pharmacokinetic (PK) parameters AUC(0-∞), and Cmax will be log-transformed and 
analyzed separately using a mixed-effects model with fixed-effect term for fed status (fed 
or fasted)/formulation (tablet or capsule), and subject as a random effect. Point estimates 
and their associated 90% CIs will be constructed for the differences between fed and in 
fasted state, between tablet and capsule. For the relative bioavailability analysis, tablets 
are the test formulation and capsules are the reference. The point estimates and their 
associated 90% CIs were then back transformed to provide point estimates and 90% CIs 
for the ratios of fed/fasted and tablet/capsule. Non-parametric methods such as the 
Hodges and Lehmann estimator will be used to estimate the median differences between 


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the fed treatments and the fasted state treatments for tmax and t½. An associated 90% CI 
for the median differences will be constructed. 
Based on the US FDA guidance on food-effect bioavailability studies, the absence of a 
food-effect will be established if the 90% CI of the ratio for Cmax and AUC, based on 
log-transformed data, is within the 80 to 125% equivalence limit. Recommendation on 
the clinical significance of the effect of food will be based on the magnitude of the 
change and our understanding of the exposure-clinical response relationship.  
For the evaluation of food effect, tmax at fed and fasted status will be presented by 
subject and dose cohort in tabular and graphical form. 
11.10.2.3. Efficacy Analysis 
The confirmed overall response rate (ORR) is defined as the percentage of subjects 
with a confirmed complete response (CR) or a partial response (PR) at any time as per 
disease-specific criteria (Section 14.4). 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. Exact methods for calculated confidence intervals will be 
given in the RAP. 
The number and types of responses, as outlined in RECIST 1.1 (for subjects with solid 
tumors), RANO (for subjects with GBM), and Lugano (for subjects with NHL), will be 
listed and summarized separately, as appropriate. 
The observed confirmed ORR will be reported at the interim and final analysis for each 
cohort specified in Part 2 treated at RP2D. The estimates along with 95% confidence 
interval (CI) based on a normal approximation will be provided. Bayesian inference 
based on summary statistics from the posterior distributions of each ORR will be reported 
at interim and final analyses. The posterior mean and posterior 2.5% and 97.5% 
percentiles of the ORR will be calculated for each cohort. In addition, the posterior 
probability that the ORR exceeds its corresponding historical control will be reported for 
each cohort. 
Progression-free survival rate (PFSR) is calculated from the start of treatment until the 
date of progression or death from any cause. The PFSRs at 6 months were estimated by 
the Kaplan-Meier method. These rates estimated the proportion of patients who did not 
progress and were alive at month 6. The 95% confidence intervals for the PFSR at month 
6 will be estimated using Greenwood's estimate of the standard error (SE) and a linear 
transformation of the progression-free survival function. 
Duration of response is defined as the time from first documented evidence of CR or PR 
until the first documented sign of disease progression or death, for the subset of subjects 
with a confirmed CR or PR. Duration of response will be summarized descriptively for 
each cohort, if data warrant, using Kaplan-Meier medians and quartiles. Details on rules 
for censoring will be provided in the RAP. 
For the ACC tablet cohort, duration of response will be analyzed as determined by the 
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For the analysis of Progression-free survival (PFS), if the subject received subsequent 
anti-cancer therapy prior to the date of documented events, PFS will be censored at the 
last adequate assessment (e.g. assessment where visit level response is CR, PR, or stable 
disease [SD]) prior to the initiation of therapy.  Progressive disease (PD) will also be 
defined per standard criteria.  Otherwise, if the subject does not have a documented date 
of events, PFS will be censored at the date of the last adequate assessment. Further details 
on rules for censoring will be provided in the RAP.  PFS will be summarized by cohort 
specified in Part 2, if data warrant, using Kaplan-Meier quantile estimates along with 2-
sided 95% CIs at the time of final analysis. 
For the analysis of overall survival (OS), the last date of known contact will be used for 
those subjects who have not died at the time of analysis; such subjects will be considered 
censored. Further details on rules for censoring will be provided in the RAP. OS will be 
summarized by cohort specified in Part 2, if data warrant, using Kaplan-Meier quantile 
estimates along with 2-sided 95% CIs at the time of final analysis. 
11.10.3. 
Other Analyses 
CCI


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11.10.4. 
Simulations and Design Operating Characteristics 
11.10.4.1. Simulation Description 
Extensive simulations have been conducted to develop and understand the performance 
of the adaptive design; the hierarchical model including clustering mechanism, interim 
monitoring, and decision criteria. 
11.10.4.2. Software Details 
Simulations were conducted by the software provided by Berry Consultants. For each 
assumed scenario, 500 sets of trials were simulated. Posterior distributions were 
estimated via Markov chain Monte Carlo methods using 50,000 iterations for each 
analysis, discarding the first 2,000 iterations for each analysis as burn-in. 
11.10.4.3. Trial Sample Size and Simulation Scenarios 
Sample size requirements for halting enrollment at interim analyses for simulations is 
based on the number of subjects enrolled; while in practice, they will be based on the 
number of subjects with available response data. This discrepancy is due to software 
feasibility but should not have a significant impact on operating characteristics of the 
design. Simulations assumed interim analyses occurred every 4 weeks, with the first 
interim analysis occurring once 40 subjects have been enrolled. The time from subject 
entry until the response assessment was performed is assumed to be 24 weeks. The 
maximum length of time for each study is 120 weeks ±6 weeks (roughly 2.5 years). 
Although actual enrollment may vary, predicted enrollment during a 2-year time period is 
incorporated into the simulations. Cohort, projected enrollment and the historical control 
and clinically meaningful response rates used in simulations are shown in Table 21. 
Table 21 
Simulation Scenarios and Design Characteristics 
 
Cohorts 
 
TNBC 
mTCC 
NHL[+] 
NHL[-] 
Project Enrollment in 
2-year time period; n 
32 
40 
25 
25 
Max Sample size; n 
32 
40 
25 
25 
Scenarios 
 
All Null 
10% 
15% 
10% 
10% 
All Positive 
25% 
30% 
30% 
30% 
All Moderate 
20% 
20% 
20% 
20% 
2 Null, 2 Positive 
25% 
15% 
30% 
10% 
3 Null, 1 Positive 
10% 
15% 
30% 
10% 
Proportion of Trials that Declare each Cohort Efficacious (Measure of Power or Type I Error 
Rate) 
All Null 
0.05 
0.10 
0.06 
0.05 
All Positive 
0.92 
0.88 
0.95 
0.96 
All Moderate 
0.67 
0.39 
0.58 
0.57 


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Cohorts 
 
TNBC 
mTCC 
NHL[+] 
NHL[-] 
2 Null, 2 Positive 
0.82 
0.12 
0.87 
0.13 
3 Null, 1 Positive 
0.09 
0.10 
0.81 
0.11 
Proportion of Trials that Declares Early Futility  
All Null 
0.50 
0.52 
0.47 
0.42 
All Positive 
0.03 
0.05 
0.02 
0.01 
All Moderate 
0.09 
0.22 
0.06 
0.08 
2 Null, 2 Positive 
0.09 
0.41 
0.04 
0.24 
3 Null, 1 Positive 
0.39 
0.45 
0.06 
0.31 
Proportion of Trials that Pick all the Positive Cohorts 
All Null 
N/A 
All Positive 
0.76 
All Moderate 
N/A 
2 Null, 2 Positive 
0.74 
3 Null, 1 Positive 
0.81 
Due to the ‘borrowing’ nature of the model, the design is evaluated across a variety of 
scenarios for the distribution of true ORRs across the four cohorts. These are shown in 
Table 21. 
The “All Positive” scenario assumes all cohorts are responsive at the defined clinically 
meaningful RR levels. The “Null” case assumes all cohorts are nonresponsive at the 
historical control RRs. The “All Moderate” scenario assumes all cohorts show moderate 
RR levels in between the historical control and clinically meaningful RR levels. The 
other three scenarios consider various situations where cohorts are either responsive (at 
the clinically meaningful RR level) or not (at the historical control RR level). 
11.10.4.4. Operation Characteristics 
Power and type I error rate are examined across scenarios for the distribution of assumed 
true ORRs for each cohort. The power is the probability of declaring efficacy within an 
individual cohort when the true underlying ORR is greater than its corresponding 
historical control. Type 1 error rate is the probability of declaring efficacy within an 
individual cohort when the true underlying response rate is equal to the historical control. 
The power and type I error rate are dependent upon the sample sizes and response rates 
across the distribution of cohorts. When the treatment effects are the same across all 
cohorts (either all responsive or all non-responsive), estimation efficiencies, due to 
borrowing, result in very good operating characteristics, even in cohorts with low sample 
sizes. The type I error rate is controlled to ≤0.08 across all cohorts (All Null scenario). 
The design maintains power 90% to 97% for all four cohorts (All Great scenario). Also, 
the design exhibits reasonable power to detect a moderate level of activity (All moderate 
scenario). 
When the treatment effects vary across cohorts, the amount of appropriate borrowing also 
varies, impacting the operating characteristics. However, under all scenarios, the design 


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maintains at least 80% power for the positive cohorts. The ‘2 null, 2 positive’ and ‘3 null, 
1 positive’ cases investigate design performance where at least half of the cohorts are not 
responsive. In this situation, the type I error rate is inflated between 0.1 and 0.13 the 
power is at least 81% for the positive cohorts. Generally, improvement in the overall 
distribution of treatment effects tends to coincide with slight increases in type I error rate 
and moderate increases in power. 
Overall type I error rate, the probability of claiming efficacy in at least one group under 
the null hypothesis is 0.23.  
11.10.4.5. Stopping Early 
Table 21 also presents the proportion of trials that halt enrollment early for futility across 
simulation scenarios. Since the study requires at least ten subjects in a particular cohort 
prior to stopping early for futility, the ability for a cohort to stop early is largely 
dependent upon the projected maximum sample size and enrollment rate per cohort. The 
overall distribution of treatment effects across cohorts also impacts the likelihood of 
halting enrollment early. 
When the expected 2-year enrollment is greater than 20, non-responsive cohorts stop 
early for futility between 26% and 47% of the time. Across simulation scenarios, 
responsive cohorts generally do not stop early for futility. 
11.10.4.6. Mean Proportion of Correct Decisions 
To evaluate the design performance in correctly evaluating all four cohorts, Table 21 
listed the probabilities of making a correct decision on concluding efficacy on all the 
cohorts whose true underlying ORR is greater than historical control (pick all positive 
cohorts). In the scenarios where there are positive cohorts, there are 73% to 83% chance 
that all the positive cohorts will be picked.  
11.10.4.7. Operating characteristics of the safety stopping rule in Part 3 
(GSK3326595 in combination with pembrolizumab) 
Simulations were used to evaluate the design performance of the safety stopping rules 
planned for the Part 3 dose determination. In these simulations, we simulate 50,000 
independent trials and evaluate the performance of the model on average.  
Recall that each higher dose cohort is dependent on the result of the previous cohort(s). 
For example, if cohort 1 is not completed, cohorts 2 and 3 will not begin. Thus, in order 
to complete cohort 3, cohorts 1 and 2 must have also been deemed safe with respect to 
our safety stopping criteria. 
Table 22 details the scenarios we have evaluated as well as the average number of 
subjects dosed in each cohort, and the percentage of simulated trials that completed that 
dose level, assuming that 5 subjects were dosed during each stage resulting in 10 subjects 
total per dose level. Table 23 details the same scenarios under the assumption that we 
over-enroll by 1 subject, e.g. dosing 6 subjects in stage 1 and 5 subjects in stage 2 (or 
vice versa), resulting in 11 subjects total per dose level.  Figure 11-1 graphically 


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represents the operating characteristics of our safety stopping rules for each cohort, 
assuming that we enroll 10 subjects in each dose level. Cohorts 1, 2 and 3 are shown in 
separate plots arranged horizontally. Each line of the plot corresponds to a different 
scenario detailed in Table 22. The scenarios considered range from very low toxicity to 
very high toxicity.  In low toxicity scenarios, the cohorts are likely to fully enroll, and as 
toxicity increases, cohorts are more likely to stop early for safety. For example, scenario 
1 represents a low toxicity scenario and 84.8% of the time, our simulations fully enrolled 
the final cohort (dose level 3). A similar plot is shown for the case where 11 subjects are 
enrolled per dose level (Figure 11-2).  In the case where we have 11 subjects per dose 
level, we see a higher percentage of trials that do not complete dose level 3.  This is 
expected, since these trials are larger, and thus have more chances to stop for safety 
reasons.  
Table 22 
Simulation Scenarios and Results (10 subjects per dose level) 
Scenario 
True 
toxicity 
of dose 
1 
Average 
# of 
subjects 
dosed at 
dose 1 
% of trials 
that 
completed 
dose 1 
True 
toxicity 
of dose 
2 
Average 
# of 
subjects 
dosed at 
dose 2 
% of trials 
that 
completed 
dose 2 
True 
toxicity 
of dose 
3 
Average 
# of 
subjects 
dosed at 
dose 3 
% of trials 
that 
completed 
dose 3 
1 
0 
10 
100 
0.1 
9.9 
98.2 
0.2 
9.5 
84.8 
2 
0.1 
9.9 
98.2 
0.2 
9.5 
84.9 
0.3 
7.6 
53.2 
3 
0.2 
9.6 
86.2 
0.2 
8.3 
74.2 
0.2 
7.2 
64.2 
4 
0.2 
9.6 
86.3 
0.3 
7.7 
54.0 
0.4 
4.3 
19.7 
5 
0.2 
9.6 
86.2 
0.4 
6.9 
31.6 
0.6 
1.9 
1.6 
6 
0.4 
8.0 
36.2 
0.4 
2.9 
13.3 
0.4 
1.1 
4.8 
Table 23 
Simulation Scenarios and Results (11 subjects per dose level) 
Scenario 
True 
toxicity 
of dose 
1 
Average 
# of 
subjects 
dosed at 
dose 1 
% of trials 
that 
completed 
dose 1 
True 
toxicity 
of dose 
2 
Average 
# of 
subjects 
dosed at 
dose 2 
% of trials 
that 
completed 
dose 2 
True 
toxicity 
of dose 
3 
Average 
# of 
subjects 
dosed at 
dose 3 
% of trials 
that 
completed 
dose 3 
1 
0 
11 
100 
0.1 
10.9 
97.1 
0.2 
10.1 
78.8 
2 
0.1 
10.9 
97.3 
0.2 
10.1 
79.3 
0.3 
7.5 
42.8 
3 
0.2 
10.4 
81.1 
0.2 
8.5 
65.7 
0.2 
6.8 
53.1 
4 
0.2 
10.4 
81.4 
0.3 
7.7 
43.8 
0.4 
3.6 
12.0 
5 
0.2 
10.4 
81.1 
0.4 
6.8 
22.3 
0.6 
1.5 
0.6 
6 
0.4 
8.4 
27.7 
0.4 
2.3 
7.5 
0.4 
0.6 
2.1 
 


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Figure 11-1 
Operating Characteristics for Safety Stopping Rules of Part 3 
combination cohort (10 subjects per dose level) 
 
Figure 11-2    Operating Characteristics for Safety Stopping Rules of Part 3 
combination cohort (11 subjects per dose level) 
 


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12. 
STUDY GOVERNANCE CONSIDERATIONS 
12.1. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins. 
12.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy. 
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki. This includes, but is not limited to, the following: 
• IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable 
• Obtaining signed informed consent  
• Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC) 
• GSK will provide full details of the above procedures, either verbally, in writing, 
or both. 
• Signed informed consent must be obtained for each subject prior to participation 
in the study 
• The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  
• Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  
• Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated. 
12.3. 
Quality Control (Study Monitoring) 
• In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with 
the site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  


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• When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF 
will serve as the source document. 
GSK will monitor the study and site activity to verify that the: 
• Data are authentic, accurate, and complete. 
• Safety and rights of subjects are being protected. 
• Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents 
12.4. 
Quality Assurance 
• To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during 
or after completion of the study.  
• In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s), and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to 
discuss the conduct of the study, any findings/relevant issues and to implement 
any corrective and/or preventative actions to address any findings/issues 
identified. 
12.5. 
Study and Site Closure 
• Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, 
in accordance with applicable regulations including GCP and GSK Standard 
Operating Procedures. 
• GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical 
issues or severe non-compliance. For multicenter studies, this can occur at one 
or more or at all sites.  
• If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable). When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action. 
• If the study is suspended or prematurely discontinued for safety reasons, GSK 
will promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  


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• If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide 
the reason for the suspension or premature discontinuation. 
12.6. 
Records Retention 
• Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  
• The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  
• Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., 
microfiche, scanned, electronic); however, caution needs to be exercised before 
such action is taken.  
• The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required. Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions. 
• GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements. The minimum retention 
time will meet the strictest standard applicable to that site for the study, as 
dictated by any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  
• The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated 
with the site. 
12.7. 
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication 
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 subjects, as 


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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. 


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14. 
APPENDICES 
14.1. 
Appendix 1: Abbreviations and Trademarks 
ABCG2 (BCRP) 
Breast cancer resistance protein 
ACC 
adenoid cystic carcinoma 
ADA 
Anti-drug antibodies 
AE(s) 
Adverse Event(s) 
Aft 
After 
ALL 
Acute lymphoblastic leukemia 
ALT (SGPT) 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AR 
Accumulation ratio 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time 
curve 
BC 
Breast cancer 
BCRP 
Breast Cancer Resistance Protein 
BCVA 
Best corrected visual acuity  
BID 
Twice daily  
BMD 
Bone mineral density  
Caco-2  
Continuous cell of heterogeneous human 
epithelial colorectal adenocarcinoma cells 
CBC 
Complete blood count 
CDK 
cyclin-dependent kinase 
cf-DNA 
Circulating cell free DNA 
CKD-Epi 
Chronic Kidney Disease Epidemiology Collaborative 
CL/F 
Apparent clearance following oral dosing 
Cmax  
Maximum observed plasma concentration 
CML 
Chronic myeloid leukemia 
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CPS 
Combined Percentage Score 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CV 
Cardiovascular 
CV% 
Coefficient of variance percent 
D 
Day 
DART5 
D. Melanogaster analog of mammalian prmt5 
DCR 
Disease control rate 
DHEA 
Dehydroepiandrosterone 
DEXA 
Dual-energy x-ray absorptiometry 


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DILI 
Drug induced liver injury 
DL-1 
Dose Level 1 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report form 
EGFR 
Epithelial growth factor receptor 
EIAC 
Enzyme-inducing anticonvulsant 
EOT 
End of treatment 
ER- 
Estrogen receptor negative 
ER+ 
Estrogen receptor positive 
ER+BC 
Hormone receptor-positive adenocarcinoma of 
the breast 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FFPE 
Formalin fixed paraffin embedded 
FL 
Follicular lymphoma 
FSH 
Follicle stimulating hormone 
FTIH 
First time in human 
GALT 
Gut-associated lympoid tissue 
GAR 
Glycine and arginine residues 
GBM 
Glioblastoma multiforme 
GCP 
Good clinical practice 
GDI 
Growth-Death Index 
GFR 
Glomerular Filtration Rate 
GI 
Gastrointestinal 
GLP 
Global laboratory practice 
GSEA 
Gene set enrichment analysis 
GSK 
GlaxoSmithKline 
h 
Hour/s 
CCI
CCI
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H3R8, H2AR3 and H4R3 
Histone 3 Arginine 8, Histone 2A arginine 3 
and Histone 4 arginine 3 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotrophin 
HCV 
Hepatitis C Virus 
Hep C 
Hepatitis C 
Her2- 
Human epidermal growth factor receptor 2 
negative 
HIV 
Human immunodeficiency virus 
HL 
Hodgkin’s lymphoma 
HLA 
Human leukocyte antigen 
HMG-CoA 
3-hydroxy-3-methylglutaryl-coenzyme A 
HN 
Head and neck carcinoma 
HNSCC 
squamous cell carcinoma of the head and 
neck 
HNSTD 
Highest non severely toxic dose 
HPLC 
High-performance liquid chromatography 
HPMC 
Hydroxypropyl methylcellulose 
HPV 
human papillomavirus 
HRQoL 
Health related quality of life 
HRT 
Hormone replacement therapy 
IAG 
Imaging acquisition guidelines 
IB 
Investigator’s brochure 
IC50 
Fifty percent inhibitory concentration 
ICF 
Informed consent form 
ICR 
Independent central review 
ICH 
International Conference on Harmonization of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IgG4 
Immunoglobulin G 4 
INDSRs 
Investigational new drug safety reports 
INR 
International normalized ratio 
IRB 
Institutional review board 
iRECIST 
Immune-based RECIST 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IV 
Intravenous 
IVD 
Invitro diagnostic device 
KIM-1 
Kidney injury molecule-1 
KPS 
Karnofsky Performance Status 
LDH 
Lactate dehydrogenase 
LHRH 
Luteinizing hormone releasing hormone 
LLN 
Lower limit of normal 
LV 
Left ventricle 


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LVEF 
Left ventricular ejection fraction 
MABEL 
Minimum anticipated biologically effective level 
MCH 
Mean corpuscular hemoglobin 
MCL 
Mantle cell lymphoma 
MCV 
Mean corpuscular volume 
MDCK-II 
Madine-Darby Canine Kidney-II cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEP50 
Methylosome protein 50 
mg 
milligram 
MM 
Multiple myeloma 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger RNA 
MSDS 
Material safety data sheet 
mTCC 
metastatic transitional cell carcinoma of the 
urinary system 
MTD 
Maximumally tolerated dose 
mTPI 
Modified Toxicity Probability Interval  
n 
Number 
NCI-CTCAE 
National Cancer Institute - Common 
Terminology Criteria for Adverse Events 
NGAL 
Neutrophil gelatinase-associated lipocalin 
NHL 
Non-Hodgkin’s lymphoma 
NOAEL 
No-observed adverse effect level 
NSCLC 
Non small-cell lung cancer 
NYHA 
Newyork heart association 
OCT 
Optical coherence tomography  
ORR 
Overall response rate 
OS 
Overall survival 
PAX 
Paxgene 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PD-1 
Programmed Cell Death Protein 1 
PDCD4 
Programmed cell death 4 
PD-L1 
Programmed Death-Ligand 1 
PDX 
Patient-derived tumor models 
PEL 
Primary effusion lymphoma 
PET 
Positron emission tomography 
PET/CT 
Positron emission tomography/Computed 
tomography 
PFS 
Progression free survival 
PFSR 
Progression free survival rate 
P-gp  
P-glycoprotein 
PGx 
Pharmacogenetic 
PI 
Prescribing Information  
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PI3K 
Phosphoinositol-3 kinase 
PK 
Pharmacokinetic 
PR 
Partial response 
PR- 
Progesterone receptor negative 
PR+ 
Progesterone receptor positive 
PRMT 
Protein arginine methyltransferases 
PRO 
Patient-reported outcomes 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
Q3W 
Every 3 weeks 
q4w 
Every 4 weeks 
q8w 
Every 8 weeks 
QD 
Once a day 
QLQ 
Quality of life questionnaire 
QT  
QT interval duration 
QTc 
Corrected QT interval duration 
QTcF 
QT duration corrected for heart rate by 
Fridericia’s formula 
RANO 
Response Assessment in Neuro-Oncology 
RAP 
Report and Analysis Plan 
RBC 
Red blood cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
REML 
Restricted maximum likelihood 
RNA 
Ribonucleic acid 
RNAseq 
RNA sequencing 
RNFL 
Retinal nerve fiber layer 
RP2D 
Recommended phase 2 dose 
RR 
Response rate 
RT-PCR 
Reverse transcription-polymerase chain 
reaction 
SAE(s) 
Serious Adverse Event(s) 
SAS 
Statistical analysis system 
SCLC 
Small-cell lung cancer 
SCR 
Screening 
SD 
Stable disease 
 
 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics  
SPD 
Sum of products of the diameters 
SRM 
Study reference manual 
SRT 
Safety review team 
STD 
Severely toxic dose 
STD10 
Severely toxic dose to 10% of the animals 
t½ 
Half-life 
CCI
CCI
CCI


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TCL 
T-cell lymphoma 
tFL 
Transformed follicular lymphoma 
TGI 
Tumor growth inhibition 
TI 
Time invariance 
tmax 
Time to Cmax 
TNBC 
Triple-negative breast cancer 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
UPM 
Unit probability mass 
VP 
Vice president 
Vss 
Human volume of distribution 
W1D1 
Week 1 Day 1 
W1D3 
Week 1 Day 3 
W3D1 
Week 3 Day 1 
WBC 
White blood cell 
WHO 
World health organization 
WT 
Wild type 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
Phoenix WinNonlin 
 
 
SAS 
 


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14.2. 
Appendix 2: Guidelines for Management of Toxicity 
The following dose modification criteria 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.  For management of suspected pembrolizumab 
toxicity in Part 3, please refer to Section 14.2.2, Section 14.2.3, or to the pembrolizumab 
prescribing information. 
14.2.1. 
Management of Selected Toxicities for GSK3326595 
Table 24 
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) 
For subjects with solid tumors, temporarily 
interrupt study medication.  For subjects 
with non-Hodgkin’s lymphoma, consider 
interruption of study medication. 
After discussion with medical monitor and 
using sound clinical judgement, continue 
at same dose or adjust dose (e.g. 
consider reduced daily dosing or dosing 
on alternate days). Monitor complete 
blood count (CBC) at least twice a week, 
more frequently if necessary  
Grade 4 (platelet 
count below 25,000)  
Interrupt study medication and monitor 
CBC every 2-3 days.  
1. If platelet counts recover to Grade 2 
and are steady for at least 2 CBC 
measurements at least 3 days apart, 
or rising, discuss with the medical 
monitor. Based on clinical 
judgement, resume treatment at the 
same or previously cleared lower 
dose.  
2. Platelet transfusion is allowed based 
on institutional guidelines.  If platelet 
transfusions are required, hold drug 
until platelet counts recover to 
Grade 2, and are steady for at least 
2 CBC measurements at least 3 
days apart, or rising. Using clinical 
judgement and after consultation 
with the medical monitor, consider 
resuming treatment at same or the 


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Toxicity 
Dose 
Adjustment/Stopping 
Criteria 
Management Guidelines 
previously cleared lower dose.  
3. Discontinue treatment if drug has to be 
held for >14 days. 
Anemia 
Grades 1 & 2 (HgB 
>8.0 g/dL) 
Continue dosing at same dose level with 
weekly or more frequent monitoring as 
necessary 
Grade 3 (HgB <8.0 
g/dL, or transfusion 
required) 
Transfuse and treat as necessary.  
Monitor CBC at least twice a week, more 
frequently if necessary.  After discussion 
with medical monitor and using sound 
clinical judgement, continue at same dose 
or adjust dose (e.g. consider reduced 
daily dosing or dosing on alternate days). 
Grade 4 (Life-
threatening 
consequences; 
urgent intervention 
indicated) 
Transfuse and treat as necessary.  
Temporarily interrupt study medication 
and monitor CBC every 2-3 days. If 
hemoglobin recover to Grade 2 and is 
steady/rising for at least 2 CBC reads at 
least 3 days apart, discuss with medical 
monitor resuming treatment at the same 
or adjusted dose (see Grade 3) based on 
sound clinical judgement. 
QTcF 
If >30msec and < 60 
msec change from 
baseline  AND 
manual QTcF <500 
(average of three 
ECGs over at least 
15 minutes) 
 
• Continue current dose of 
GSK3326595 
• 
Supplement electrolytes, 
particularly potassium and 
magnesium, to recommended 
levels: 
(1) Maintain serum potassium > 
4mol/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  
 
• Discontinue GSK3326595 and notify 
the GSK Medical Monitor.  
(1) Supplement electrolytes to 
recommended levels: 
a. Maintain serum potassium > 
4mol/L 
b. Maintain serum magnesium 


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Toxicity 
Dose 
Adjustment/Stopping 
Criteria 
Management Guidelines 
(average of three 
ECGs over at least 
15 minutes) 
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 subject may consider 
restarting study treatment at a previous 
dose level if the following criteria for QTcF 
rechallenge are met : 
 
• QTcF Rechallenge Procedures: 
Do not rechallenge with study 
treatment 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 VP and 
Clinical VP approval 
d. Head Unit Physician approval 
(5) Institutional IRB (or equivalent) 
approval, and 
(6) The subject is re-consented 
regarding the possible increased 
risk of QTc prolongation.  
• 
If approval for re-challenge is 
granted, the subject must be re-
consented (with a separate 
informed consent specific to QTc 
prolongation) 


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Toxicity 
Dose 
Adjustment/Stopping 
Criteria 
Management Guidelines 
 
• 
Discontinuation procedures: 
If the subject is withdrawn due to QTcF 
event, the subject 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 14.6: 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 
GSK3326595 and discuss with GSK 
Medical Monitor. 
Grade 3 
• 
Above plus consider intravenous (IV) 
hydration, hospital admission and 
prophylactic antibiotics as 
appropriate. 
• 
Hold GSK3326595 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 GSK3326595 
permanently 
Nausea/Vomiting 
Grade 1 
• 
Initiate supportive care with 
antiemetics as necessary.  


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Toxicity 
Dose 
Adjustment/Stopping 
Criteria 
Management Guidelines 
Grade 2 
• 
Initiate supportive care with 
antiemetics as necessary 
• 
Consider temporary discontinuation 
of GSK3326595 and discuss with 
GSK medical monitor.  If drug is held, 
subject 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 GSK3326595 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 GSK3326595 
permanently 
All Other Toxicity 
Grade 1 
• 
Continue dosing with no change  
Grade 2 
• 
Continue dosing with no change  
• 
 
• 
OR 
• 
 
• 
Hold GSK3326595 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 
GSK3326595 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, subject should 
discontinue therapy. 


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Toxicity 
Dose 
Adjustment/Stopping 
Criteria 
Management Guidelines 
Grade 4 
• Discontinue GSK3326595 
 
OR 
 
• In rare situations, based on discussion 
and written agreement between GSK 
medical monitor and investigator, if the 
subject is receiving benefit then the 
episode may be managed as per Grade 3 
toxicity. 
Note*: Exceptions to  the drug-related Grade 1 requirement may be made for certain 
AEs as defined in Section 4.2.4.2. 
14.2.2. 
Management of Immune-Related Events, Part 3 pembrolizumab 
combination  
AEs associated with immunotherapy treatment may be immune-mediated. These 
immune-related AEs (irAEs) may occur shortly after the first dose, several months after 
the last dose of treatment, or during the treatment course and may affect more than one 
body system simultaneously. Therefore, early recognition of and initiation of treatment 
for these events is critical to reduce potential complications. Refer to pembrolizumab 
documents [KEYTRUDA, PI, 2019; KEYTRUDA, SPC, 2019] for additional 
information regarding the background and the management of other AEs or potential 
safety-related issues. The investigator may consult the GSK Medical Monitor on study 
treatment modifications (i.e., holds or discontinuation) or on the management of AEs. 
For suspected irAEs, ensure adequate evaluation to confirm the etiology or exclude other 
causes. Additional procedures or tests such as, but not limited to, bronchoscopy, 
endoscopy, or skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue treatment and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs 
associated with immunotherapies are provided in Section 14.2.3. 
Before administration of study treatment, investigators are to review a participant’s AEs, 
concomitant medications, and clinical evaluation results, e.g., vital signs, laboratory 
results, ECOG PS, physical examination findings, responses, as outlined in the Time and 
Events table (Table 15), to monitor for new or worsening irAEs and ensure that continued 
dosing is appropriate. 
Table 25 
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs 
General instructions: 
• Corticosteroid taper should be initiated upon AE improving to Grade 1 or less 
and continue to taper over at least 4 weeks. 


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• For situations where immunotherapy treatment has been withheld, treatment 
can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Immunotherapy treatment should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤ 10 mg prednisone or equivalent per 
day within 12 weeks.  
• 
For severe and life-threatening irAEs, IV corticosteroid should be initiated 
first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids. 


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Immune-rela
ted AEs 
Severity 
Grade or 
Conditions 
Action 
Taken with 
Pembrolizu
mab  
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies  
Monitor 
and 
Follow-up  
Respiratory 
Pneumonitis  
Grade 2 
Withhold  
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
methylprednisol
one or 
equivalent) 
followed by 
taper 
Monitor 
participants 
for signs 
and 
symptoms 
of 
pneumonitis
. 
Evaluate 
participants 
with 
suspected 
pneumonitis 
with 
radiographic 
imaging and 
initiate 
corticosteroi
d treatment. 
Add 
prophylactic 
antibiotics 
for 
opportunisti
c infections. 
Grade 3 or 
4, or 
recurrent 
Grade 2 
Permanently 
discontinue 
Gastrointestinal 
Diarrhea / 
Colitis  
Grade 2 or 
3 
Withhold 
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
methylprednisol
one or 
equivalent) 
followed by 
taper 
Monitor 
participants 
for signs 
and 
symptoms 
of 
enterocolitis 
(i.e., 
diarrhea, 
abdominal 
pain, blood 
or mucus in 
stool with or 
without 
fever) and 
of bowel 
perforation 
(i.e., 
peritoneal 
signs and 
ileus). 
Participants 
with ≥ 
Grade 2 
Grade 4 
Permanently 
discontinue 


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Immune-rela
ted AEs 
Severity 
Grade or 
Conditions 
Action 
Taken with 
Pembrolizu
mab  
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies  
Monitor 
and 
Follow-up  
diarrhea 
suspecting 
colitis 
should 
consider GI 
consultation 
and 
performing 
endoscopy 
to rule out 
colitis.  
Participants 
with 
diarrhea/coli
tis should be 
advised to 
drink liberal 
quantities of 
clear fluids. 
If sufficient 
oral fluid 
intake is not 
feasible, 
fluid and 
electrolytes 
should be 
substituted 
via IV 
infusion. 
Hepatobiliary 
AST / ALT 
elevation or 
increased 
bilirubin 
Grade 2 
Withhold 
Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
methylprednisol
one or 
equivalent) 
followed by 
taper 
Monitor 
with liver 
function 
tests 
(consider 
weekly or 
more 
frequently 
until liver 
enzyme 
value 
returned to 
baseline or 
is stable. 
Refer to 
Section 14.6 
for liver 
safety 
required 
actions and 
follow-up 
Grade 3 or 
4  
Permanently 
discontinue 
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
methylprednisol
one or 
equivalent) 
followed by 
taper 


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Immune-rela
ted AEs 
Severity 
Grade or 
Conditions 
Action 
Taken with 
Pembrolizu
mab  
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies  
Monitor 
and 
Follow-up  
assessments 
and study 
treatment 
guidelines. 
Endocrine 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglycem
ia 
 
New onset 
T1DM or  
Grade 3 or 
4 
hyperglyce
mia 
associated 
with 
evidence of 
-cell 
failure 
Withhold 
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM  
Administer anti-
hyperglycemic 
in participants 
with 
hyperglycemia  
Monitor 
participants 
for 
hyperglyce
mia or other 
signs and 
symptoms 
of diabetes. 
Adrenal 
insufficiency 
Symptomatic 
hypophysitis 
Grade 1 or 
2 
Withhold 
until adverse 
reactions 
recover to 
Grades 0-1. 
Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated. 
Monitor for 
signs and 
symptoms 
of 
hypophysitis 
(including 
hypopituitar
ism and 
adrenal 
insufficienc
y). 
If treatment-
related 
toxicity does 
not resolve 
to Grades 0-
1 within 12 
weeks after 
last dose of 
pembrolizum
ab, or if 
corticosteroi
d dosing 
cannot be 
reduced to 
≤10 mg 
prednisone 
or equivalent 
per day 
within 12 
weeks, 
pembrolizu
mab should 
be 
Grade 3 or 
4  
For patients 
with Grade 3 
or 
Grade 4 
endocrinopat
hy that 
improved to 
Grade 2 or 
lower and 
is controlled 
with hormone 
replacement, 
if indicated, 
continuation 
of 
pembrolizum
ab 
may be 
considered 
after 
corticosteroid 
taper, if 


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Immune-rela
ted AEs 
Severity 
Grade or 
Conditions 
Action 
Taken with 
Pembrolizu
mab  
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies  
Monitor 
and 
Follow-up  
needed. 
Otherwise 
treatment 
should be 
discontinued 
permanently 
discontinued
. 
Hyperthyroidi
sm  
Grade 2 
Continue 
Treat with non-
selective beta-
blockers (e.g., 
propranolol) or 
thionamides as 
appropriate  
Monitor for 
signs and 
symptoms 
of thyroid 
disorders. 
Grade 3 or 
4  
Withhold or  
Permanently 
discontinue 
Hypothyroidi
sm 
Grade 2-4 
Continue 
Initiate thyroid 
replacement 
hormones (e.g., 
levothyroxine or 
liothyronine) per 
standard of care 
Monitor for 
signs and 
symptoms 
of thyroid 
disorders. 
Renal 
Nephritis and 
renal 
dysfunction 
Grade 2 
Withhold 
Administer 
corticosteroids 
(methylprednisol
one 1-2 mg/kg 
or equivalent) 
followed by 
taper. 
Monitor 
changes of 
renal 
function. 
Grade 3 or 
4  
Permanently 
discontinue 
Cardiovascular 
Myocarditis 
Grade 1 or 
2 
Withhold 
Based on 
severity of AE 
administer 
corticosteroids 
Ensure 
adequate 
evaluation 
to confirm 
etiology 
and/or 
exclude 
other 
causes. 
Grade 3 or 
4 
Permanently 
discontinue 
Other 
All other 
immune-
related AEs 
Grade 3, or 
intolerable/ 
persistent 
Grade 2 
Withhold or 
discontinue 
based on the 
type of event. 
Events that 
require 
discontinuati
on include 
and are not 
limited to: 
Guillain-
Barre 
Based on 
severity of AE 
administer 
corticosteroids  
Ensure 
adequate 
evaluation 
to confirm 
etiology or 
exclude 
other 
causes. 


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Immune-rela
ted AEs 
Severity 
Grade or 
Conditions 
Action 
Taken with 
Pembrolizu
mab  
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies  
Monitor 
and 
Follow-up  
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
NOTES:  
The decision whether to withhold or permanently discontinue immunotherapy treatment is at the discretion 
of the investigator or treating physician. For participants with Grade 3 or 4 immune-related endocrinopathy 
where interruption of immunotherapy treatment is required, treatment may be resumed when the event 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or, for T1DM, metabolic control 
has been achieved.  
Abbreviations: AE=adverse events; ALT=alanine aminotransferase; AST= aspartate aminotransferase; 
CTCAE=common terminology criteria for adverse events; GI=gastrointestinal irAE=immune-related AE; 
IV=intravenous; kg=kilogram; mg=milligram; T1DM=Type 1 diabetes mellitus 
14.2.3. 
Dose Modification and Toxicity Management of Infusion-
Reactions Related to Immunotherapy Treatment, Part 3 
Infusion reactions are a well-documented AE associated with the administration of mAb. 
Infusion reactions typically develop within 30 minutes to 2 hours after initiation of drug 
infusion, although symptoms may be delayed for up to 48 hours. The incidence of 
infusion reactions varies by mAb agent, and there are multiple mechanisms known to 
lead to infusion-related reactions including both IgE-dependent anaphylactic and non-IgE 
dependent anaphylactoid hypersensitivities. Cytokine release syndrome, and when 
severe, cytokine “storm”, has been identified as a sequela of the immune system 
activation associated with infusion reactions. 
Infusion reactions may affect any organ system in the body; most are mild in severity, 
although severe and even fatal reactions occur. As a group, infusion reactions (including 
both cytokine-mediated and allergic) usually occur during or within a few hours of drug 
infusion. Occasionally, a reaction may occur 1 to 2 days after administration. The NCI-
CTCAE for grading adverse reactions during chemotherapy administration has a scale for 
grading the severity of infusion reactions and separate grading scales for allergic 
reactions and anaphylaxis. While use of these separate grading scales may be useful for 
classifying the nature of an infusion reaction for research purposes, they are less useful 
for clinical care, since it may not be obvious if the participant is having an allergic 
infusion reaction or a non-allergic infusion reaction.  
Clinically, an infusion reaction may present with flushing, itching, urticaria, and/or 
angioedema, 
 cough, sudden nasal congestion, shortness of breath, chest 
tightness, wheeze, sensation of throat closure or choking, and/or change in voice quality, 
faintness, tachycardia (or less often bradycardia), hypotension, hypertension and/or loss 
of consciousness, nausea, vomiting, abdominal cramping, and/or diarrhea, sense of 
impending doom, tunnel vision, dizziness, and/or seizure, severe back, chest, and pelvic 
CCI


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pain. Refer to Table 27 for dose modification and treatment guidance for immunotherapy 
infusion reactions. 
To better understand the underlying etiology of these events, serum tryptase, C-reactive 
protein (CRP), ferritin, and a cytokine panel should be drawn during the occurrence of an 
infusion reaction/CRS of any grade as outlined in Table 26. The serum tryptase, CRP and 
ferritin panels should be performed at the investigator’s designated local laboratory. The 
serum cytokine panel will be performed at a GSK designated laboratory. These data will 
aid in the classifying (albeit retrospectively) the etiology of the AE. 
Table 26 
Infusion-Related Reaction Laboratory Panel 
Analyte 
Relationship to Adverse Event 
Serum tryptasea 
IgE-related infusion reaction 
(Allergic/anaphylaxis) [Schwartz, 
2006] 
Serum CRPa 
Elevated in CRS [Lee, 2014] 
Serum ferritina 
Elevated in CRS [Lee, 2014] 
Serum cytokine panelb 
(IFNγ*^, TNFα*^, IL1, IL2*, IL4, I-6*^, 
IL8*, IL10*, IL12p70, and IL13) 
* Reported to be elevated in CRS [Lee, 
2014] 
^ Consistently reported as elevated in 
CRS [Lee, 2014] 
Abbreviations: CRP = C-reactive protein; CRS = Cytokine release syndrome; IFNγ = Interferon 
gamma; TNFα =Tumor necrosis factor alpha; IL = Interleukin.  
a. 
Performed by investigator designated local laboratory if available; otherwise performed by GSK 
designated laboratory 
b. Performed by a GSK designated laboratory 
The guidelines provided in Table 27 are suggestions. Investigators and site staff may also 
follow their site standard operating procedures for the treatment of these events. 
Table 27 
Infusion Reaction Dose Modification and Treatment Guidelines 
NCI CTCAE 
Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated 
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy 
• Stop Infusion 
• Additional appropriate 
Participant may be premedicated 
1.5hr (± 30 minutes) prior to 


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NCI CTCAE 
Grade 
Treatment 
Premedication at Subsequent 
Dosing 
or infusion 
interruption but 
responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for ≤24 
hrs. 
medical therapy may include 
but is not limited to: 
o IV fluids 
o Antihistamines 
o NSAIDs 
o Acetaminophen 
o Narcotics 
• Increase monitoring of vital 
signs as medically indicated 
until the participant is 
deemed medically stable in 
the opinion of the 
investigator 
• If symptoms resolve within 1 
hour of stopping drug 
infusion, the infusion may be 
restarted at 50% of the 
original infusion rate (e.g. 
from 100 mL/hr to 50 
mL/hr). Otherwise dosing 
will be held until symptoms 
resolve and the participant 
should be premedicated for 
the next scheduled dose 
Participants who develop 
Grade 2 toxicity despite 
adequate premedication should 
be permanently discontinued 
from further study treatment 
infusion of study drugs with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., 
not rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following initial 
improvement; 
hospitalization 
indicated for 
other clinical 
• Stop Infusion 
• Additional appropriate 
medical therapy may include 
but is not limited to: 
o 
Epinephrine** 
o 
IV fluids 
o 
Antihistamines 
o 
NSAIDs 
o 
Acetaminophen 
No subsequent dosing 


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NCI CTCAE 
Grade 
Treatment 
Premedication at Subsequent 
Dosing 
sequelae (e.g., 
renal 
impairment, 
pulmonary 
infiltrates) 
Grade 4: Life-
threatening; 
pressor or 
ventilatory 
support indicated 
o 
Narcotics 
o 
Oxygen 
o 
Pressors 
o 
Corticosteroids 
• Increase monitoring of vital 
signs as medically indicated 
until the participant is 
deemed medically stable in 
the opinion of the 
investigator 
• Hospitalization may be 
indicated. 
**In cases of anaphylaxis, 
epinephrine should be used 
immediately. 
Participant is permanently 
discontinued from further 
study treatment. 
Note: Appropriate resuscitation equipment should be available at the bedside and a physician readily 
available during the period of drug administration. For further information, please refer to the 
Common Terminology Criteria for Adverse Events at http://ctep.cancer.gov 
Abbreviations: CTCAE=common terminology criteria for adverse events; hr=hour; IV=intravenous; 
mg=milligram; ml=millilitres; NSAID=nonsteroidal anti-inflammatory drug; po=per os [by mouth] 
 


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14.3. 
Appendix 3: 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 
 


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14.4. 
Appendix 4: Guidelines for Assessment of Disease, Disease 
Progression, and Response Criteria 
14.4.1. 
Response Criteria for Solid Tumors (RECIST 1.1 [Eisenhauer, 
2009]) 
14.4.1.1. 
Assessment Guidelines 
Please note the following: 
• The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion. Contrast agents must be used in 
accordance with the Image Acquisition Guidelines. 
• All measurements should be taken and recorded in millimeters (mm), using a 
ruler or calipers. 
• Ultrasound is not a suitable modality of disease assessment.  If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required. 
• Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing assessments 
of disease.  However FDG-PET can be useful in confirming new sites of disease 
where a positive FDG-PET scans correlates with the new site of disease present 
on CT/MRI or when a baseline FDG-PET was previously negative for the site of 
the new lesion. FDG-PET may also be used in lieu of a standard bone scan 
providing coverage allows interrogation of all likely sites of bone disease and 
FDG-PET is performed at all assessments. 
• If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the 
required anatomical coverage and prescribed use of contrast.  The method of 
assessment should be noted as CT on the CRF. 
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules) [Eisenhauer, 2009].   
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended. 
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences should be optimised for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations.  Whenever possible the same 
scanner should be used [Eisenhauer, 2009]. 
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition.  Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however chest CT is preferred over chest 
X-ray [Eisenhauer, 2009]. 
Brain Scan:  If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT. 


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Bone Scan (typically bone scintigraphy):  If a bone scan is performed and a new 
lesion(s) is equivocal, then correlative imaging (i.e., X-ray, CT, or MRI) is required to 
demonstrate malignant characteristics of the lesion(s).   
Note:  PET [FDG or fluoride] may be used in lieu of a standard bone scan providing 
coverage allows interrogation of all likely sites of bone disease and PET is performed at 
all assessments. 
14.4.1.2. 
Guidelines for Evaluation of Disease 
14.4.1.2.1. Measurable and Non-measurable Definitions 
Measurable lesion 
A non-nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of 
• 
10 mm with MRI or CT when the scan slice thickness is no greater than 5mm.  If 
the slice thickness is greater than 5mm, the minimum size of a measurable lesion 
must be at least double the slice thickness (e.g., if the slice thickness is 10 mm, a 
measurable lesion must be 20 mm). 
• 
10 mm caliper/ruler measurement by clinical exam or medical photography.  
• 
20 mm by chest x-ray. 
Additionally lymph nodes can be considered pathologically enlarged and measurable if 
• 
15mm in the short axis when assessed by CT or MRI (slice thickness recommended 
to be no more than 5mm).  At baseline and follow-up, only the short axis will be 
measured [Eisenhauer, 2009]. 
Non-measurable lesion 
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques [Eisenhauer, 2009]. 
Measurable disease: The presence of at least one measurable lesion.  Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized as 
the only measurable lesion. 
Non-Measurable only disease: The presence of only non-measurable lesions.  
14.4.1.3. 
Baseline Documentation of Target and Non-Target Lesions 
• All baseline lesion assessments must be performed within (28) days of 
randomization.  


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• Lymph nodes that have a short axis of <10mm are considered non-pathological 
and should not be recorded or followed. 
• Pathological lymph nodes with <15mm and but 10mm short axis are considered 
non-measurable. 
• Pathological lymph nodes with 15mm short axis are considered measurable and 
can be selected as target lesions, however lymph nodes should not be selected as 
target lesions when other suitable target lesions are available.   
• Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions, and 
recorded and measured at baseline. These lesions should be selected on the basis 
of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).  
Note: Cystic lesions thought to represent cystic metastases should not be selected as 
target lesions when other suitable target lesions are available. 
Note: Measurable lesions that have been previously irradiated and have not been shown 
to be progressing following irradiation should not be considered as target lesions.  
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered measurable.   
Bone scans, FDG-PET scans or X-rays are not considered adequate imaging 
techniques to measure bone lesions. 
• All other lesions (or sites of disease) should be identified as non-target and should 
also be recorded at baseline. Non-target lesions will be group by organ. 
Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up.  
14.4.1.4. 
Response Criteria 
14.4.1.4.1. Evaluation of target lesions 
Definitions for assessment of response for target lesion(s) are as follows: 
• Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes must be <10mm in the short axis. 
• Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as a reference, the baseline sum of the diameters (e.g. 
percent change from baseline). 
• Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease. 
• Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded 
since the treatment started (e.g. percent change from nadir, where nadir is 
defined as the smallest sum of diameters recorded since treatment start). In 
addition, the sum must have an absolute increase from nadir of 5mm. 


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• Not Applicable (NA): No target lesions at baseline. 
• Not Evaluable (NE): Cannot be classified by one of the five preceding definitions. 
Note: 
• If lymph nodes are documented as target lesions the short axis is added into the 
sum of the diameters (e.g. sum of diameters is the sum of the longest diameters 
for non-nodal lesions and the short axis for nodal lesions).  When lymph nodes 
decrease to non-pathological size (short axis <10mm) they should still have a 
measurement reported in order not to overstate progression. 
• If at a given assessment time point all target lesions identified at baseline are not 
assessed, sum of the diameters cannot be calculated for purposes of assessing 
CR, PR, or SD, or for use as the nadir for future assessments.  However, the sum 
of the diameters of the assessed lesions and the percent change from nadir 
should be calculated to ensure that progression has not been documented.  If an 
assessment of PD cannot be made, the response assessment should be NE. 
• All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g. 2 mm).  If lesions are present but too small to measure, 5 
mm should be recorded and should contribute to the sum of the diameters, 
unless it is likely that the lesion has disappeared in which case 0 mm should be 
reported. 
• If a lesion disappears and reappears at a subsequent time point it should continue 
to be measured.  The response at the time when the lesion reappears will depend 
upon the status of the other lesions.  For example, if the disease had reached a 
CR status then PD would be documented at the time of reappearance.  However, 
if the response status was PR or SD, the diameter of the reappearing lesion 
should be added to the remaining diameters and response determined based on 
percent change from baseline and percent change from nadir. 
14.4.1.4.2. Evaluation of non-target lesions 
Definitions for assessment of response for non-target lesions are as follows: 
• Complete Response (CR):  The disappearance of all non-target lesions. All lymph 
nodes identified as a site of disease at baseline must be non-pathological (e.g. 
<10 mm short axis). 
• Non-CR/Non-PD:  The persistence of 1 or more non-target lesion(s) or lymph 
nodes identified as a site of disease at baseline ≥ 10 mm short axis. 
• Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  
• Not Applicable (NA):  No non-target lesions at baseline. 
• Not Evaluable (NE):  Cannot be classified by one of the four preceding 
definitions. 


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Note: 
• 
In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 
• 
In the presence of non-measurable only disease consideration should be given to 
whether or not the increase in overall disease burden is comparable in magnitude to 
the increase that would be required to declare PD for measurable disease. 
• 
Sites of non-target lesions, which are not assessed at a particular timepoint based on 
the assessment schedule, should be excluded from the response determination (e.g. 
non-target response does not have to be "Not Evaluable").  
14.4.1.4.3. New lesions 
New malignancies denoting disease progression must be unequivocal.  Lesions identified 
in follow-up in an anatomical location not scanned at baseline are considered new 
lesions. 
Any equivocal new lesions should continue to be followed.  Treatment can continue at 
the discretion of the investigator until the next scheduled assessment.  If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented. 
14.4.1.4.4. Evaluation of overall response 
Table 28 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline. 
Table 28 
Evaluation of Overall Response for Subjects with Measurable 
Disease at Baseline 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR or NA 
No 
CR 
CR 
Non-CR/Non-PD or NE 
No 
PR 
PR 
Non-PD or NA or NE 
No 
PR 
SD 
Non-PD or NA or NE 
No 
SD 
NE 
Non-PD or NA or NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, and 
NE=Not Evaluable 
 
Table 29 presents the overall response at an individual time point for all possible 
combinations of tumor responses in non-target lesions with or without the appearance of 
new lesions for subjects with non-measurable only disease at baseline. 


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Table 29 
Evaluation of Overall Response for Subjects with Non-Measurable 
Only Disease at Baseline 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non CR/Non PD 
No 
Non CR/Non PD 
NE 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR=complete response,  PD=progressive disease, and NE=Not Evaluable 
 
Note: Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having "symptomatic deterioration." Objective response status is determined 
by evaluations of disease burden. Every effort should be made to document the objective 
progression even after discontinuation of treatment.   
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of CR depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 
14.4.1.4.5. Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by GSK 
based on the investigators assessment of response at each time point.  
• To be assigned a status of SD, follow-up disease assessment must have met the 
SD criteria at least once after first dose at a minimum interval of 49 days (based 
on the expected 56  7 day window)  
• If the minimum time for SD is not met, best response will depend on the 
subsequent assessments.  For example if an assessment of PD follows the 
assessment of SD and SD does not meet the minimum time requirement the best 
response will be PD.  Alternatively, subjects lost to follow-up after an SD 
assessment not meeting the minimum time criteria will be considered not 
evaluable. 
14.4.1.4.6. Confirmation Criteria 
• To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first 
met. 
14.4.2. 
Response Criteria for GBM 
This study employs response criteria from the Response Assessment in Neuro-Oncology 
(RANO) Working Group [Wen, 2010]. 
All measurable and non-measurable lesions should be assessed using the same techniques 
as at baseline.  Ideally, subjects should be imaged on the same MRI scanner, or at least 


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with the same magnet strength, for the duration of the study to reduce difficulties in 
interpreting changes. 
Measurable disease is defined as bidimensionally contrast enhancing lesions with clearly 
defined margins by CT or MRI scan, with two perpendicular diameters of at least 10 mm, 
visible on two or more axial slices that are preferably, at most, 5 mm apart with 0-mm 
skip. As with RECIST version 1.1, in the event the MRI is performed with thicker slices, 
the size of a measurable lesion at baseline should be two times the slice thickness. In the 
event there are interslice gaps, this also needs to be considered in determining the size of 
measurable lesions at baseline. Measurement of tumor around a cyst or surgical cavity 
represents a particularly difficult challenge. In general, such lesions should be considered 
non-measurable unless there is a nodular component measuring ≥10 mm in diameter. The 
cystic or surgical cavity should not be measured in determining response.  
Non-measurable disease is defined as either unidimensionally measurable lesions, masses 
with margins not clearly defined, or lesions with maximal perpendicular diameters less 
than 10 mm.  
Radiographic response should be determined in comparison to the tumor measurements 
obtained at pretreatment baseline for determination of response, the smallest tumor 
measurements at either pretreatment baseline or after initiation of therapy should be used 
for determination of progression.   
• 
Complete response (CR): Complete disappearance of all enhancing measurable 
and non-measurable disease on contrast enhanced MRI scan sustained for at 
least 4 weeks, no new lesions, and stable or improved nonenhancing 
(T2/FLAIR) lesions. In addition, subject must be off steroids or only on 
physiologic replacement doses.  In the absence of a confirming scan 4 weeks 
later, this response will be considered only stable disease. 
• 
Partial response (PR): Greater than or equal to a 50% reduction, compared to 
baseline, in the sum of products of the perpendicular diameters for all 
measurable lesions for at least 4 weeks, no progression of non-measurable 
disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) 
lesions.  In addition, subject must be on a corticosteroid dose not greater than the 
dose at the time of baseline scan and be stable or improving clinically.  In the 
absence of a confirming scan 4 weeks later, this response will be considered 
only stable disease. 
• 
Progressive Disease (PD): Greater than or equal to a 25% increase in sum of the 
products of perpendicular diameters of enhancing lesions (compared with 
baseline if no decrease) on stable or increasing doses of corticosteroids, OR a 
significant increase in T2/FLAIR nonenhancing lesions on stable or increasing 
doses of corticosteroids compared with baseline scan or best response after 
initiation of therapy, not due to comorbid events, OR the appearance of any new 
lesions, OR clear progression of non-measurable lesions, OR definite clinical 
deterioration not attributable to other causes apart from tumor, or to decrease in 
corticosteroid dose.  Failure to return for evaluation as a result of death or 
deteriorating condition should also be considered as progression.  


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• 
Stable disease (SD): If subject does not qualify for CR, PR, or PD and has stable 
nonenhancing (T2/FLAIR) lesions on same or lower doses of corticosteroids 
compared with baseline scan and clinically stable status.  In the event that the 
corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression on neuroimaging and subsequent follow-up 
imaging shows that this increase in corticosteroid dose was required because of 
disease progression, the last scan considered to show stable disease will be the 
scan obtained when the corticosteroid dose was equivalent to the baseline dose. 
Increase in corticosteroid dose alone, in the absence of clinical deterioration related to 
tumor, will not be used as a determinant of progression. Subjects with stable imaging 
studies whose corticosteroid dose was increased for reasons other than clinical 
deterioration related to tumor do not qualify for stable disease or progression. They 
should be observed closely. If their corticosteroid dose can be reduced back to baseline, 
they will be considered as having stable disease; if further clinical deterioration related to 
tumor becomes apparent, they will be considered to have progression. The date of 
progression should be the first time point at which corticosteroid increase was necessary. 
The definition of clinical deterioration is left to the discretion of the treating physician, 
but it is recommended that a decline in the Karnofsky Performance Status (KPS) from 
100 or 90 to 70 or less, a decline in KPS of at least 20 from 80 or less, or a decline in 
KPS from any baseline to 50 or less, for at least 7 days, be considered neurologic 
deterioration unless attributable to comorbid events or changes in corticosteroid dose. 
Similarly, a decline in the Eastern Cooperative Oncology Group and world health 
organization (WHO) performance scores from 0 or 1 to 2 or 2 to 3 would be considered 
neurologic deterioration.   
Subjects with non-measurable enhancing disease whose lesions have significantly 
increased in size and become measurable (minimal bidirectional diameter of ≥ 10 mm 
and visible on at least two axial slices that are preferably, at most, 5 mm apart with 0-mm 
skip) will also be considered to have experienced progression. The transition from a non-
measurable lesion to a measurable lesion resulting in progression can theoretically occur 
with relatively small increases in tumor size (e.g., a 9 X 9mm lesion [non-measurable] 
increasing to a 10 X 11mm lesion [measurable]). Ideally, the change should be significant 
(>5 mm increase in maximal diameter or ≥ 25% increase in sum of the products of 
perpendicular diameters of enhancing lesions).   
In general, if there is doubt about whether the lesion has progressed, continued treatment 
and close follow-up evaluation will help clarify whether there is true progression.  If 
there is uncertainty regarding whether there is progression, the subject may continue on 
treatment and remain under close observation (e.g., evaluated at 4-week intervals). If 
subsequent evaluations suggest that the subject is in fact experiencing progression, then 
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14.4.3. 
Evaluation, Staging and Response Assessments for Non-
Hodgkin’s Lymphoma: The Lugano Classification (according to 
Cheson, 2014) 
Evaluation, staging, and response criteria are summarized in 3 tables below. 
Criteria for Involvement of Site 
Tissue Site 
Clinical 
FDG Avidity 
Test 
Positive Finding 
Lymph nodes 
Palpable 
FDG-avid 
histologies 
PET-CT 
Increased FDG uptake 
Non-avid disease 
CT 
Unexplained node enlargement 
Spleen 
Palpable 
FDG-avid 
histologies 
PET-CT 
Diffuse uptake, solitary mass, 
miliary lesions, nodules 
Non-avid disease 
CT 
> 13 cm in vertical length, mass, 
nodules  
Liver 
Palpable 
FDG-avid 
histologies 
PET-CT 
Diffuse uptake, mass 
Non-avid disease 
CT 
Nodules 
CNS 
Signs, 
symptoms 
 
CT 
Mass lesion(s) 
MRI 
Leptomeningeal infiltration, 
mass lesions 
CSF assessment 
Cytology, flow cytometry 
Other (e.g., 
skin, lung, GI 
tract, bone, 
bone marrow) 
Site 
dependent 
 
PET-CTa, 
biopsy 
Lymphoma involvement 
Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; FDG, fluorodeoxyglucose; MRI, 
magnetic resonance imaging; PET, positron emission tomography.  
a: PET-CT is adequate for determination of bone marrow involvement and can be considered highly 
suggestive for involvement of other extralymphatic sites. Biopsy confirmation of those sites can be 
considered if necessary.  
 


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Staging System for Primary Nodal Lymphomas 
Stage 
Involvement 
Extranodal (E) Status 
Limited 
I 
One node or a group of adjacent nodes 
Single extranodal lesions without 
nodal involvement 
II 
Two or more nodal groups on the same side 
of the diaphragm 
Stage I or II by nodal extent with 
limited contiguous extranodal 
involvement 
II bulkya 
II as above with “bulky” disease 
Not applicable 
Advanced 
III 
Nodes on both sides of the diaphragm; 
nodes above the diaphragm with spleen 
involvement 
Not applicable 
IV 
Additional noncontiguous extralymphatic 
involvement 
Not applicable 
 
NOTE. Extent of disease is determined by positron emission tomography–computed tomography for avid 
lymphomas and computed tomography for nonavid histologies. Tonsils, Waldeyer's ring, and spleen are 
considered nodal tissue.  
a: Whether stage II bulky disease is treated as limited or advanced disease may be determined by histology 
and a number of prognostic factors. 
Criteria for Response Assessment of Non- Hodgkin’s Lymphoma 
Response 
Site 
PET-CT-Based Response 
CT-Based Response 
Complete 
 
Complete metabolic 
response (all of the 
following) 
Complete radiologic 
response (all of the 
following) 
Lymph nodes 
and 
extralymphatic 
sites 
Score 1, 2, or 3a with or 
without a residual mass on 
5PS2 
 
It is recognized that in 
Waldeyer's ring or 
extranodal sites with high 
physiologic uptake or with 
activation within spleen or 
marrow (e.g., with 
chemotherapy or myeloid 
colony-stimulating factors), 
uptake may be greater than 
Target nodes/nodal 
masses must regress 
to ≤1.5 cm in LDi 
 
No extralymphatic 
sites of disease 


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Response 
Site 
PET-CT-Based Response 
CT-Based Response 
normal mediastinum and/or 
liver. In this circumstance, 
complete metabolic response 
may be inferred if uptake at 
sites of initial involvement is 
no greater than surrounding 
normal tissue even if the 
tissue has high physiologic 
uptake 
Non-measured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid 
disease in marrow 
Normal by 
morphology; if 
determinate, IHC 
negative 
Partial 
 
Partial metabolic response 
(all of the following) 
Partial remission (all 
of the following) 
Lymph nodes 
and 
extralymphatic 
sites 
Score 4 or 5b with reduced 
uptake compared with 
baseline and residual 
mass(es) of any size 
 
At interim, these findings 
suggest responding disease 
 
At end of intervention, these 
findings indicate residual 
disease 
≥ 50% decrease in 
SPD of up to 6 target 
measurable nodes 
and extranodal sites 
 
When a lesion is too 
small to measure on 
CT, assign 5 mm × 5 
mm as the default 
value 
 
When no longer 
visible, 0 × 0 mm 
For a node > 5 mm × 
5 mm, but smaller 
than normal, use 
actual measurement 
for calculation 
Non-measured 
lesion 
Not applicable 
Absent/normal, 
regressed, but no 
increase 


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Response 
Site 
PET-CT-Based Response 
CT-Based Response 
Organ 
enlargement 
Not applicable 
Spleen must have 
regressed by > 50% 
in length beyond 
normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than 
uptake in normal marrow but 
reduced compared with 
baseline (diffuse uptake 
compatible with reactive 
changes from chemotherapy 
allowed). If there are 
persistent focal changes in 
the marrow in the context of 
a nodal response, 
consideration should be 
given to further evaluation 
with MRI or biopsy or an 
interval scan 
Not applicable 
No 
response or 
stable 
disease 
 
No metabolic response 
Stable disease 
Lymph nodes 
and 
extralymphatic 
sites 
Score 4 or 5 with no 
significant change in FDG 
uptake from baseline at 
interim or end of 
intervention 
< 50% decrease from 
baseline in SPD of 
up to 6 dominant, 
measurable nodes 
and extranodal sites; 
no criteria for 
progressive disease 
are met 
Non-measured 
lesion 
Not applicable 
No increase 
consistent with 
progression 
Organ 
enlargement 
Not applicable 
No increase 
consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive 
disease 
 
Progressive metabolic 
disease 
 Progressive disease 
requires at least 1 of 
the following: 
Individual 
target 
nodes/nodal 
masses 
Score 4 or 5 with an increase 
in intensity of uptake from 
baseline and/or 
PPD progression: 


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Response 
Site 
PET-CT-Based Response 
CT-Based Response 
Extranodal 
lesions 
New FDG-avid foci 
consistent with lymphoma at 
interim or end-of-
intervention assessment 
An individual 
node/lesion must be 
abnormal with: 
LDi > 1.5 cm and 
Increase by ≥ 50% 
from PPD nadir and 
An increase in LDi 
or SDi from nadir. 
0.5 cm for lesions ≤ 
2 cm 
1.0 cm for lesions > 
2 cm 
In the setting of 
splenomegaly, the 
splenic length must 
increase by > 50% of 
the extent of its prior 
increase beyond 
baseline (eg, a 15-cm 
spleen must increase 
to > 16 cm). If no 
prior splenomegaly, 
must increase by at 
least 2 cm from 
baseline 
New or recurrent 
splenomegaly 
Non-measured 
lesions 
None 
New or clear 
progression of 
preexisting non-
measured lesions 
New lesions 
New FDG-avid foci 
consistent with lymphoma 
rather than another etiology 
(e.g., infection, 
inflammation). If uncertain 
regarding etiology of new 
lesions, biopsy or interval 
scan may be considered 
Regrowth of 
previously resolved 
lesions 
A new node > 1.5 cm 
in any axis 
A new extranodal 
site > 1.0 cm in any 
axis; if < 1.0 cm in 
any axis, its presence 
must be unequivocal 
and must be 
attributable to 


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Response 
Site 
PET-CT-Based Response 
CT-Based Response 
lymphoma 
Assessable disease of 
any size 
unequivocally 
attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid 
foci 
New or recurrent 
involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance 
imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular 
diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular 
diameters for multiple lesions.  
a: A score of 3 in many patients indicates a good prognosis with standard intervention, especially if at 
the time of an interim scan. However, in trials involving PET where de-escalation is investigated, it 
may be preferable to consider a score of 3 as inadequate response (to avoid underintervention). 
Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal 
lesions selected to be clearly measurable in two diameters. Nodes should preferably be from 
disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal 
areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI 
involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not 
selected as measured, dominant disease and truly assessable disease should be considered not 
measured. These sites include any nodes, nodal masses, and extranodal sites not selected as 
dominant or measurable or that do not meet the requirements for measurability but are still 
considered abnormal, as well as truly assessable disease, which is any site of suspected disease that 
would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, 
bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed 
and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, 
but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as 
a result of chemotherapy or myeloid growth factors).  
b: PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ 
liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new 
areas of uptake unlikely to be related to lymphoma. 
Algorithm for determining combined imaging response based on Lugano criteria 
Anatomic/Radiologic 
Response 
Metabolic Response 
Combined Imaging 
Response 
CR 
CMR, NE, or missing 
CR 
PR 
CMR 
CR 
CR 
PMR 
PR 
CR 
NMR 
PR 


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PR 
PMR 
PR 
PR 
NMR 
PR 
SD 
PMR 
PR 
PD 
PMR 
PD 
SD 
NMR 
SD 
CR, PR, SD or NE 
PMD 
PD 
CR, PR, SD or NE 
NE or missing 
CR, PR, SD or NE 
(Anatomic Response) 
PD 
NMR 
PD 
PD 
PMD 
PD 
 
14.4.4. 
iRECIST Guidelines 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response 
seen with immunotherapeutic drugs.  iRECIST will be used to assess tumor response and 
progression, and make treatment decisions.  When clinically stable, participants should 
not be discontinued until progression is confirmed according to the rules described 
below.  This allowance to continue treatment despite initial radiologic PD takes into 
account the observation that some participants can have a transient tumor flare in the first 
few months after the start of immunotherapy, and then experience subsequent disease 
response.  These data will be captured in the clinical database. 
Clinical stability is defined as meeting all of the following:  
• 
Absence of symptoms and signs indicating clinically significant progression of 
disease 
• 
No decline in ECOG performance status  
• 
No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment 
at site-assessed radiologic evidence of PD.  It is strongly preferred to obtain the repeat 
tumor imaging, when feasible, for confirmation of PD by iRECIST. The tumor 
assessment should be repeated at least 4 weeks and up to 8 weeks later to confirm PD by 
iRECIST.  Images should continue to be sent in to the central imaging vendor for 
potential central review. 
If repeat imaging does not confirm PD per iRECIST and the participant continues to be 
clinically stable, study treatment may continue and follow the regular imaging schedule.  
If PD is confirmed, participants will be discontinued from study treatment. 


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If a participant has confirmed radiographic progression (iCPD) as defined below, study 
treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, as assessed by the Investigator and confirmed by the Medical 
Monitor, continuation of study treatment may be considered upon agreement of all 
parties.  In this case, if study treatment is continued, tumor imaging should continue to be 
performed following the intervals as outlined in Section 8.1 and submitted to the central 
imaging vendor.  
Description of the iRECIST Process for Assessment of Disease Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct 
iRECIST assessment. 
Assessment and Decision at RECIST 1.1 Progression 
For participants who show evidence of radiological PD by RECIST 1.1 the investigator 
will decide whether to continue a participant on study treatment until repeat imaging is 
obtained (using iRECIST for participant management (see Table 30 and Figure 14-1).  
This decision should be based on the participant’s overall clinical condition (See 
discussion of clinical stability above).  
Tumor flare may manifest as any factor causing radiographic progression per RECIST 
1.1, including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% 
and ≥5 mm from nadir 
o Note: the iRECIST publication uses the terminology “sum of 
measurements”, but “sum of diameters” will be used in this protocol, 
consistent with the original RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, the 
first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual. 
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1.  From measurable 
new lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – 
Target.  The sum of diameters of these lesions will be calculated and kept distinct from 
the sum of diameters for target lesions at baseline.  All other new lesions will be followed 
qualitatively as New Lesions – Non-target. 


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Assessment at the Confirmatory Imaging 
At the confirmatory imaging visit assessment, the participant will be classified as 
progression confirmed (with an overall response of iCPD), or as showing persistent 
unconfirmed progression (with an overall response of iUPD), or as showing disease 
stability or response (iSD/iPR/iCR).  Timing of confirmatory imaging is described in 
Section 8.1. 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of 
the following occurs: 
• 
Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
▪ An increase in the new lesion sum of diameters by ≥5 mm from a prior 
iUPD time point  
▪ Visible growth of new non-target lesions  
▪ The appearance of additional new lesions 
• 
Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• 
None of the progression-confirming factors identified above occurs AND 
• 
The target lesion sum of diameters (initial target lesions) remains above the initial 
PD threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging 
on which iUPD is seen.  This may correspond to the next visit in the original visit 
schedule.  The assessment of the subsequent confirmation imaging proceeds in an 
identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, 
if: 
• 
None of the progression-confirming factors identified above occurs, AND 


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• 
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.”  This means that the next visit that shows 
radiographic progression, whenever it occurs, is again classified as iUPD by iRECIST, 
and the confirmation process is repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and 
the participant continues to be clinically stable, study treatment may continue and follow 
the regular imaging schedule.  If PD is confirmed, participants will be discontinued from 
study treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, 
but the participant is achieving a clinically meaningful benefit, continuation of study 
treatment may be considered following consultation with the Sponsor.  In this case, if 
study treatment is continued, tumor imaging should continue to be performed following 
the intervals as outlined in the Time and Events Tables and submitted to the central 
imaging vendor. 
Detection of Progression at Visits after Pseudo-Progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is 
indicated by any of the following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase 
from nadir) either for the first time, or after resolution of previous 
pseudo-progression.  The nadir is always the smallest sum of diameters 
seen during the entire trial, either before or after an instance of pseudo-
progression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, doing so 
for the first-time results in iUPD. 
o If non-target lesions have shown previous unequivocal progression, and 
this progression has not resolved, iUPD results from any significant 
further growth of non-target lesions. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 


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o Previously identified new target lesions show an increase of ≥ 5 mm in the 
new lesion sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the 
iUPD evaluation process (see Assessment at the Confirmatory Imaging above) is 
repeated.  Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, 
with one exception:  if new lesions occurred at a prior instance of iUPD, and at the 
confirmatory imaging the burden of new lesions has increased from its smallest 
value (for new target lesions, the sum of diameters is ≥5 mm increased from its 
nadir), then iUPD cannot resolve to iSD or iPR.  It will remain iUPD until either a 
decrease in the new lesion burden allows resolution to iSD or iPR, or until a 
confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication 
[Seymour, 2017]. 
Table 30 
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First 
radiologic 
evidence of 
PD by 
RECIST 1.1  
Repeat 
imaging at 4 
to 8 weeks to 
confirm PD. 
May continue 
study treatment 
at the 
investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging 
by site by 
iRECIST. 
Repeat 
imaging at 4 
to 8 weeks to 
confirm PD 
per 
investigator’s 
discretion 
only. 
Discontinue 
treatment 


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Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
Repeat tumor 
imaging 
confirms PD 
(iCPD) by 
iRECIST per 
investigator 
assessment 
No additional 
imaging 
required. 
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor). 
No additional 
imaging 
required. 
Not applicable 
Repeat tumor 
imaging 
shows iUPD 
by iRECIST 
per 
investigator 
assessment 
Repeat 
imaging at 4 
to 8 weeks to 
confirm PD.  
May occur at 
next regularly 
scheduled 
imaging visit. 
Continue study 
treatment at the 
investigator’s 
discretion. 
Repeat 
imaging at 4 
to 8 weeks to 
confirm PD 
per 
investigator’s 
discretion 
only. 
Discontinue 
treatment 
Repeat tumor 
imaging 
shows iSD, 
iPR, or iCR 
by iRECIST 
per 
investigator 
assessment. 
Continue 
regularly 
scheduled 
imaging 
assessments. 
Continue study 
treatment at the 
investigator’s 
discretion. 
Continue 
regularly 
scheduled 
imaging 
assessments. 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion.  Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = 
iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria 
in Solid Tumors 1.1. 


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Figure 14-1 
Imaging and Treatment for Clinically Stable Participants after 
First Radiologic Evidence of PD Assessed by the Investigator 
RECIST 1.1 PD identified by Investigator
Subject clinically stable
Does Investigator
confirm PD per
iRECIST?
YES
(confirms PD per 
iRECIST)
NO
(does not confirm PD 
per iRECIST)
1.
Subject discontinues trial 
treatment
2.
Exception possible upon 
sponsor consultation
3.
Tumor imaging done only 
if needed for follow-up
1.
Subject may remain on study drug at 
Investigator discretion
2.
Regular imaging schedule followed; 
unscheduled imaging if clinically indicated
3.
Future imaging and subject management per 
iRECIST. Continue to submit imaging to vendor
Repeat tumor imaging at 4-8 weeks
 


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14.5. 
Appendix 5: Estimated Glomerular Filtration Rate 
CKD-Epi: 
Females, serum creatinine >62 μmol/L: 144  (serum creatinine  0.0113/0.7)−1.209  0.993age 
Females, serum creatinine ≤62 μmol/L: 144  (serum creatinine  0.0113/0.7)−0.329  0.993age 
Males, serum creatinine >80 μmol/L: 141  (serum creatinine  0.0113/0.9)−1.209  0.993age 
Males, serum creatinine ≤80 μmol/L: 141  (serum creatinine  0.0113/0.9)−0.411  0.993age 
[Levey, 2009] 
 
 


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14.6. 
Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments 
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and to evaluate liver event etiology (in alignment with 
the FDA premarketing clinical liver safety guidance) [www.fda.gov, 2009].Phase I/II 
liver chemistry stopping criteria and required follow up assessments  
Liver Chemistry Stopping Criteria – Liver Stopping Event 
Subject 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 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
Including subjects with documented liver metastases/tumor infiltration at baseline AND 
entry criteria ALT>2.5 x ULN but ≤5 x ULN 
ALT-absolute 
Both ALT  5xULN and 2x baseline value 
ALT Increase 
Both ALT  3xULN and ≥ 1.5x baseline value that persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5, if INR measured 
Cannot 
Monitor 
Both ALT  3xULN and ≥ 1.5x baseline value that cannot be monitored for 4 
weeks 
Symptomatic3 
Both ALT  3xULN and ≥ 1.5x baseline value associated with symptoms (new 
or worsening) believed to be related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping Event 
Actions 
Follow Up Assessments 
• Immediately discontinue  study 
• Viral hepatitis serology4 


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Liver Chemistry Stopping Criteria – Liver Stopping Event 
Subject with entry criteria ALT≤ 2.5 x ULN 
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 subject until liver chemistries  
resolve, stabilize, or return to within 
baseline (see MONITORING below) 
• 
Do not restart/rechallenge 
subject with study treatment unless 
allowed per protocol and GSK Medical 
Governance approval is granted (refer 
to Appendix 7)  
• If restart/rechallenge not allowed per 
protocol or not granted, permanently 
discontinue study treatment and may 
continue subject in the study for any 
protocol specified follow up 
assessments  
MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within 24 hrs 
• Monitor subjects 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 subjects weekly until liver 
chemistries resolve, stabilize or return 
• 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 
• 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 (CRF) 
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 high-
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury in 
subjects with definite or likely acetaminophen 
use in the preceding week [James, 2009]). 
• 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. 


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Liver Chemistry Stopping Criteria – Liver Stopping Event 
Subject with entry criteria ALT≤ 2.5 x ULN 
to within baseline 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject 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 subjects 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 subjects 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 
subject’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.   
 
Phase I/II Oncology liver chemistry increased monitoring criteria with continued 
therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
Subject 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 
Subject 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 
• Notify the GSK medical monitor within 24 
hours of learning of the abnormality to discuss 
subject safety.  
• Subject can continue study treatment   
• Subject 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 subject meets the liver chemistry 
stopping criteria, proceed as described above 
For subjects with entry criteria ALT≤2.5 x ULN 
• If, after 4 weeks of monitoring, ALT <3xULN 
and bilirubin <2xULN, monitor subjects twice 
monthly until liver chemistries normalize or 
return to within baseline. 
For subjects with documented liver 


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Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
weekly for 4 weeks 
 
metastases/tumor infiltration at baseline AND 
entry criteria ALT>2.5 x ULN but ≤5 x ULN 
• If, after 4 weeks of monitoring, ALT <3xULN 
and <1.5x baseline value, and bilirubin 
<2xULN, monitor subjects twice monthly until 
liver chemistries normalize or return to within 
baseline 
 


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14.7. 
Appendix 7: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines 
Drug restart may be considered for a subject exhibiting compelling benefit for a critical 
medicine following drug-induced liver injury, if there is favorable benefit: risk ratio and 
no alternative medicine available. 
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless: 
• 
GSK Medical Governance approval is granted (as described below), 
• 
Ethics and/or IRB approval is obtained, if required, and 
• 
Separate consent for treatment restart/rechallenge is signed by the subject 
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments 
Background Information on Drug Restart/Rechallenge 
Rechallenge Following Liver Stopping Events that are Possibly Related to Study 
Treatment 
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane re-administered 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: 
• Hypersensitivity [Andrade, 2009] with initial liver injury (e.g. fever, rash, 
eosinophilia)  
• jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total) 
• subject 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 rechallenges 
[Papay, 2009; Hunt, 2010] 
• evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment) [Hunt, 2010] 
 
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject 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. 


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Approval by GSK for rechallenge with study treatment can be considered where: 
• Investigator requests consideration of rechallenge with study treatment for a 
subject who is receiving compelling benefit with study treatment that exceeds 
risk, and no effective alternative therapy is available.   
• Ethics Committee or Institutional Review Board approval for rechallenge with 
study treatment must be obtained, as required.    
• If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.   
• The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment.  Documentation of informed consent must be 
recorded in the study chart.   
• Study treatment must be administered at the dose specified by GSK. 
• Subjects approved by GSK Medical Governance for rechallenge with study 
treatment 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 treatment rechallenge, subject meets protocol-defined liver 
chemistry stopping criteria, study treatment should be permanently discontinued.  
• GSK Medical Monitor, and the Ethics Committee or Institutional Review Board 
as required, must be informed of the subject’s outcome following study treatment 
rechallenge.  
• GSK to be notified of any adverse events, as per Section 9. 
Restart Following Transient Resolving Liver Stopping Events NOT Related to 
Study Treatment 
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with human leukocyte antigen (HLA) markers of liver injury. 
Approval by GSK for study treatment restart can be considered where: 
• Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN). 
• Restart risk factors (e.g., fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment 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 treatment 
restart must be obtained, as required. 


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• If restart of study treatment is approved by GSK Medical Governance in writing, 
the subject must be provided with a clear description of the possible benefits and 
risks of study treatment administration, including the possibility of recurrent, 
more severe liver injury or death.   
• The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the 
study chart.   
• Study treatment must be administered at the dose specified by GSK. 
• Subjects approved by GSK Medical Governance for restarting study treatment 
must return to the clinic once a week for liver chemistry tests until stable liver 
chemistries have been demonstrated and then laboratory monitoring may resume 
as per protocol.  
• If after study treatment re-start, subject 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 subject’s outcome following study treatment 
restart.  
• GSK to be notified of any adverse events, as per Appendix 9. 


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14.8. 
Appendix 8: Genetic Research 
Genetic Research Objectives and Analyses 
The objectives of the genetic research are to investigate the relationship between genetic 
variants and response to medicine, including GSK3326595 or any concomitant 
medicines. 
US Food and Drug Administration states that an in vitro companion diagnostic device 
(IVD) could be essential for the safe and effective use of a corresponding therapeutic 
product to: 
• 
Identify subjects who are most likely to benefit from a particular therapeutic 
product; 
• 
Identify subjects likely to be at increased risk for serious adverse reactions as a 
result of treatment with a particular therapeutic product; 
• 
Monitor response to treatment for the purpose of adjusting treatment (e.g. 
schedule, dose, discontinuation) to achieve improved safety or effectiveness 
Global regulatory requirements for IVD companion diagnostic tests are evolving.  If a 
DNA-based IVD companion diagnostic device might be needed to identify subjects who 
are appropriate for the GSK medicinal product(s) under investigation in this protocol, 
then GSK should collect and retain DNA samples from subjects who carry the genetic 
variant of interest as well as DNA samples from subjects who do not carry the genetic 
variants of interest to validate the performance of the companion diagnostic.  Any IVD 
companion diagnostic research objectives should be described in subject informed 
consent forms. 
Genetic data may be generated while the study is underway or following completion of 
the study. Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives. 
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in the RAP prior to initiation of 
the analysis. Planned analyses and results of genetic investigations will be reported either 
as part of the clinical RAP and study report, or in a separate genetics RAP and report, as 
appropriate. 
Study Population 
Any subject who is enrolled in the study can participate in genetic research. Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research. 


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Study Assessments and Procedures 
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  
• 
A 6 ml blood sample will be taken for deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a 
duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.  This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number).  
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner. GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form. Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product. 
Subjects can request their sample to be destroyed at any time. 
Informed Consent 
Subjects who do not wish to participate in the genetic research may still participate in the 
study. Genetic informed consent must be obtained prior to any blood being taken. 
Subject Withdrawal from Study 
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected: 
• 
Continue to participate in the genetic research in which case the genetic DNA sample 
is retained 
• 
Discontinue participation in the genetic research and destroy the genetic DNA 
sample  
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 


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destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records.  
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis.  
• 
If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  
• 
Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate.  
Screen and Baseline Failures 
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process. In this instance a sample destruction form will not be available to 
include in the site files. 
Provision of Study Results and Confidentiality of Subject’s Genetic Data 
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals.  
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined. Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care. 


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14.9. 
Appendix 9: Definition of and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting of Adverse Events 
14.9.1. 
Definition of Adverse Events 
Adverse Event Definition: 
• An AE is any untoward medical occurrence in a subject or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
• 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 medicinal product. 
 
Events meeting AE definition include: 
• Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital 
signs measurements), including those that worsen from baseline, and felt to be 
clinically significant in the medical and scientific judgement of the investigator. 
• 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 treatment administration even 
though it may have been present prior to the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as 
an AE/SAE unless this is an intentional overdose taken with possible 
suicidal/self-harming intent. This 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. However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the 
definition of an AE or SAE. 
• The signs and symptoms and/or clinical sequelae resulting from lack of efficacy 
will be reported if they fulfil the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE 
or SAE. 
 
 
Events NOT meeting definition of an AE include: 


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• 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 subject’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
subject’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is an AE. 
• Situations where 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. 
 
14.9.2. 
Definition of Serious Adverse Events 
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, etc). 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence 
that, at any dose: 
a. Results in death 
b. Is life-threatening 
NOTE: 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires hospitalization or prolongation of existing hospitalization 
NOTE: 
• In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 


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d. Results in disability/incapacity 
NOTE: 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
• Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These should also be 
considered serious. 
• Examples of such events are 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 
g. Is associated with liver injury and impaired liver function defined as: 
• ALT  3xULN and total bilirubin*  2xULN (>35% direct), or 
• ALT  3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick. If fractionation is unavailable and 
ALT  3xULN and total bilirubin  2xULN, then the event is still to be reported as 
an SAE. 
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants. If INR measurement is obtained, the value is to be 
recorded on the SAE form. 
Refer to Appendix 3 for the required liver chemistry follow-up instructions 
14.9.3. 
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 


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• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 
14.9.4. 
Recording of AEs and SAEs 
AEs and SAE Recording: 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event. 
• The investigator will then record all relevant information regarding an AE/SAE in 
the CRF  
• Post Protocol Amendment 8 implementation, SAEs, AESIs, AEs leading to 
treatment discontinuation and overdoses (as defined in Section 14.9.1) will be 
recorded via a paper process and provided to GSK (refer to SRM) 
• It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to GSK in lieu of completion of the GSK, AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission to GSK. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms. 
• Subject-completed Value Evidence and Outcomes questionnaires and the 
collection of AE data are independent components of the study. 
• Responses to each question in the Value Evidence and Outcomes questionnaire 
will be treated in accordance with standard scoring and statistical procedures 
detailed by the scale’s developer. 
• The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate. 
14.9.5. 
Evaluating AEs and SAEs 
Assessment of Intensity 


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The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories in accordance 
with the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) Version 4.0:  
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.  
• Grade 2: Moderate; minimal, local or non-invasive intervention indicated; 
limiting age appropriate instrumental Activities of Daily Living (ADL)1  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL2  
• Grade 4: Life-threatening consequences; urgent intervention indicated.  
• Grade 5: Death related to AE. 
1. Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.  
2 Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment 
and the occurrence of each AE/SAE. 
• A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated. 
• The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 prior to the initial transmission of the SAE data to GSK. 
• The investigator may change his/her opinion of causality in light of follow-up 


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information, amending the SAE data collection tool accordingly. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as may be indicated or as 
requested by GSK to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. 
• The investigator is obligated to assist. This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other 
health care professionals. 
• If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem 
findings, including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames. 
14.9.6. 
Reporting of SAEs to GSK 
SAE reporting to GSK via electronic data collection tool 
• Primary mechanism for reporting SAEs to GSK will be the electronic data 
collection tool. Post Protocol Amendment 8 implementation, SAEs will be 
collected via paper process and submitted to GSK (refer to SRM). 
• If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool and e-mail it to the Medical Monitor 
• Site will enter the serious adverse event 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 
(e.g., InForm system) will be taken off-line to prevent the entry of new data or 
changes to existing data 
• If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has 
been taken off-line, the site can report this information on a paper SAE form or 
to the Medical Monitor by telephone. 
• Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page. 
 


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14.10. 
Appendix 10: Collection of Pregnancy Information 
• Investigator will collect pregnancy information on any female subject, 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 subject's pregnancy. 
• Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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 treatment by the investigator, will be reported to 
GSK as described in Appendix 9. 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 subject who becomes pregnant while participating will discontinue study 
medication 
For male study subjects: 
• 
Investigator will attempt to collect pregnancy information on any female partner 
of a male study subject who becomes pregnant while participating in this study.  
• 
After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy 
• 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.  
• Post Protocol Amendment 8, pregnancy information will be collected up to 90 
days after last dose of study treatment via paper process and submitted to GSK 
(refer to SRM). 
 


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14.11. 
Appendix 11: Details of Bayesian Hierarchical Model 
Yi is the response indicator for the ith subject, and j = P(Yi =1 | ji = j) is the true response 
rate for cohort j. In the logic scale, θj  is the mean log odds treatment effect of response: 
)
1
log(
)
1
log(
j
j
j
j
j





−
−
−
=
 
Basic Hierarchical Model 
A basic hierarchical model structure is described here and is incorporated within the 
clustered hierarchical model framework used in this study. Borrowing occurs to the 
extent indicated by the data using a hierarchical normal model on the treatment effects: 
θj  N(,2). 
Were only this basic hierarchical model used for analysis, the prior distributions would 
be: 
 N(0,1.82)  and  2  IG(0.5,0.125), 
where IG(,) is the inverse gamma distribution defined by: 
)
(
)
,
|
(
1
/








=
+
−
x
e
x
f
x
 
This distribution is non-informative in the sense that its parameters are analogous to 
having a single observation. The variance component  is a key parameter that plays a 
role in the degree of borrowing among cohorts. Small values of  result in a greater 
degree of borrowing while large values of  correspond to less borrowing. The 
distribution of  is based on the variability of the observations, and the observed between 
cohort variation is an important component of the model’s performance. The effects of 
any particular prior distribution for  can be assessed via simulations in evaluating a 
design’s operating characteristics, type I error rate and statistical power. 
Clustered Hierarchical Model 
A clustered hierarchical model considers the possibility that “clusters” exist among the 
collection of histologies. A therapy may be effective for some histologies but not for 
others. Histologies within the same cluster have greater influence on each other than they 
do on histologies in other clusters. On the other hand, histologies in different clusters are 
conditionally independent given any particular configuration of clusters. There is 
borrowing at the cluster level and borrowing across histologies within a particular cluster. 
Borrowing across clusters depends only on similarities between clusters and not of 
individual histologies. 


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The number of clusters is unknown in advance but information will be gleaned from the 
data using Dirichlet Process Mixtures (DPM). The full prior is constructed in 2 stages. In 
the first stage, the histologies are assigned to particular clusters, with the number of 
clusters unspecified. Conditional on this particular clustering, the hierarchical model is fit 
within each cluster. A difference from the basic hierarchical model is in the parameter . 
Each cluster has its own. And the prior distribution on  is now different: 
2  IG(3,0.5). 
Without the clustering, an informative prior on  that places high probability on small 
values of  could yield conclusions similar to simple pooling across histologies. This is 
not desirable. Instead its preferred to preserve the integrity of individual histologies to the 
extent that they give dissimilar results. With the clustering, a prior such as the one 
selected above meets this desideratum. When  is small, as evinced by the data, 
histologies will only be placed in the same cluster if the data for those histologies are 
sufficiently similar to other histologies in the cluster. When  is large, the histologies will 
be assigned to separate clusters and response rates estimated separately. This clustering 
approach provides further protection against borrowing between dissimilar histologies 
while enhancing the borrowing between similar histologies. 
The prior distribution in a DPM is governed by the parameter . When  is small, the 
prior favors large clusters. As  tends to zero, the prior tends to place all its mass on a 
single cluster containing all the histologies. As  increases, the prior places more mass on 
clustering with a large number of clusters. As  becomes large, the prior places all of its 
mass on having a separate cluster for each histology (thus, no borrowing across 
histologies). A value of = 0 corresponds to the usual hierarchical model with no 
clustering, while a very large treats all the histologies separately. Common values of  
might be between 0.5 and 5. We have selected = 2 for the final model. This value has 
been used for the final algorithm and the operating characteristics including type I error 
and power. 
The key aspect of the clustering portion of the prior involves which histologies are 
clustered together. This is accomplished by creating a sequence of bins (in theory there 
are infinitely many bins, but the number of bins actually used cannot exceed the number 
of histologies). Thus imagine a sequence of bins C1,C2,C3,… with associated 
probabilities pC1,pC2,pC3 and so forth. In the prior, each histology is placed in a bin 
according to the pCk probabilities. Thus, if one pCk is near 1, then all histologies will be 
likely to randomly fall in the same bin. If all the pCk values are small, it will be likely that 
all the histologies will randomly fall in separate bins. Histologies that fall within the same 
bin are defined as being in the same cluster. More details may be found in Escobar 
[Escobar, 1995] or Neal [Neal, 2000]. 
The pCk probabilities are determined through a stick breaking process [Sethuraman, 
1994]. Let pC1~Beta(1,α). This leaves 1-pC1 probability to be allocated to the remaining 
bins. Let pC2 be a Beta(1,α) proportion of that remaining mass, so pC2Beta(1,α)*[1-
pC1]. There is now 1-pC1-pC2 mass unallocated. Let pC3 be a Beta(1,α) proportion of the 
remaining mass, so pC3Beta(1,α)*[1-pC1-pC2] and so on for pC4, pC5, and so forth. This 


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process generates an infinite sequence of pCk values, but generally the first few contain 
most of the probability. In terms of the posterior distribution, only the bins which contain 
the histologies are of interest, and thus only 9 of the infinite bins will actually be used. 
The role of α can be seen from this construction. If α is very small, then the Beta(1,α) 
proportions will tend to be close to 1. Thus, the first pC1 is quite likely to be near 1, and 
thus all the histologies will tend to lie in the first bin. If α is very large, all the Beta(1,α) 
values will tend to be small, and thus each pCk will tend to be small. This creates a 
situation where each histology is likely to be in a separate bin. Our proposed value of α=2 
avoids these forced extremes and allows the data to drive the posterior distribution. After 
the histologies have been assigned to bins in the prior, histologies within the same bin 
will tend to have more similar data than histologies in separate bins. Thus, in the 
posterior distribution, histologies with similar data are viewed as more likely to be from 
the same bin (and hence the same cluster). Histologies with very different data, in 
contrast, will have high posterior probability of being in separate bins/clusters, and thus 
will be estimated separately. 
The posterior distribution also can be thought of in 2 stages, the first being a posterior 
distribution on the clustering, and then conditional on the clustering the posterior 
distribution from the hierarchical model. Conditional on the clustering, borrowing 
happens within clusters, but not across clusters. In situations where the clustering is 
uncertain (always in practice), one will see a proportional amount of borrowing between 
histologies, proportional on the posterior probability of the histologies within the same 
cluster. The aim of the clustering is to identify situations where the drug generally works 
for some histologies and generally does not work for others, so that these two disparate 
effects are not averaged together through the borrowing. 
 


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14.12. 
Appendix 12:  COVID-19 APPENDIX: RECOMMENDED 
MEASURES 
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, you should 
consider 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 or delegate when this occurs and to 


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document in source notes. The participant should be informed of the plan and any 
potential risks associated with this approach 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. 
 
• Remote visits may be performed at the participant’s home by qualified study 
personnel or at a local medical facility, unless the Investigator deems that a site visit 
is necessary. 
 
• 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. 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 for telemedicine allow: If visits to a 
site/home are not feasible, then the medical evaluation of the subject may take place 
by telemedicine which 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.  
 
• 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/site 
staff or may be identified by the site staff 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, imaging or ECG 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 


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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 subject may still continue in the trial at PI discretion – advice of the 
Medical Monitor may be sought as appropriate. 
 
• If allowed by country regulation/ethics, then for patients on part 1 or part 2 
GSK3326595 can be shipped direct-to-patient (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. 
Any study subjects in part 3 who cannot attend a clinical site will not be able to 
receive Pembrolizumab at home and therefore may continue on GSK3326595 study 
medication sent to their home or withdraw from the study whichever the investigator 
and study subject decides. No special procedures for the safe handling of 
GSK3326595 study drug are required. 
 
• The Principal Investigator assumes Good Clinical Practice (GCP) responsibilities for 
IMP handling and the medical control for dispensing to patients. 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 secure 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.  
 
• PROs may be completed by a telephone interview between site staff and subject if 
the subject cannot attend the site to complete the questionnaires on the electronic 
tablet.  
 
• If on-site monitoring is no longer permitted, GSK will consider remote Source 
Data Verification/Source Document Review (SDV/SDR) where permitted by the 


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clinical site/institution. Remote SDV/SDR will be proposed to study sites to meet 
a patient 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 subject 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 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. 
 


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14.13. 
Appendix 13: Country Specific Amendment (France) 
Rationale for amendment 
As per Health Authority request in France dated 16 June 2021 relating to the inclusion of  
cardiac monitoring (encompassing echocardiogram (ECHO) and troponin levels 
measurements) in the Protocol for Study 204653, the Sponsor has included, via this 
Country Specific Protocol Amendment (CSPA), limited to France, the requested 
measures in order to allow continued access to the study drug, for the remaining active 
study subjects in France, which is one (1) subject. No more subjects will be enrolled in 
France until further notice. 
Serial cardiac troponin levels and echocardiograms were originally included as safety 
assessments from the commencement of Study 204653 (until Protocol Amendment 5) to 
assess potential effects of GSK3326595 on myocardial tissue in response to pre-clinical 
findings observed in 4- and 13- week toxicology studies in rat animal models. For more 
information, see latest Investigator Brochure Version 5.0 data cut off 04 February 2021. 
No clinically significant cardiotoxic events have been observed by the Sponsor with 
270 subjects treated in Study 204653, as of the data cut-off date of 04 February 2021. The 
GSK Safety Review Team reviewed the serial cardiac troponin levels, echocardiograms 
and adverse event (AE) reports, and did not identify any events related to study drug and 
consistent with cardiomyopathy, cardiac valve abnormalities, or associated toxicities. The 
study data were also reviewed by the Sponsor Integrated Cardiac Safety Panel, which 
includes internal and external cardiologists, who endorsed discontinuing from Protocol 
Amendment 5 serial echocardiogram and troponin monitoring, this decision was 
reviewed and confirmed in July 2021.  
Study Assessments and Procedures 
Echocardiogram 
For the ongoing subject on study drug, ECHOs will be performed at the next planned 
visit, and at the end of treatment visit.  Additional ECHO assessments should be 
performed as clinically indicated.  The ECHO assessment should include at a minimum 
evaluation of left ventricular ejection fraction (LVEF) and evaluation of both right and 
left-sided valvular function and morphology.  Blood pressure and weight should be 
measured and recorded at the time (or as close to the time as clinically feasible) of the 
ECHO. 
Refer to the Study Reference Manual (SRM) for details regarding the measurement of 
blood pressure. 
Troponins 
For the ongoing subject on study drug, troponin will be collected at the next planned 
visit, then every 8 weeks (±5 days) thereafter, and at the end of the treatment visit. Either 
troponin T or I may be assessed at a local laboratory. The same local laboratory test 


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(troponin I or troponin T) should be used consistently for an individual subject 
throughout the study.  
Withdrawal and Stopping criteria 
LVEF Stopping Criteria 
Subjects with symptoms of left ventricular dysfunction during treatment with 
GSK3326595 should interrupt the investigational agent and have repeat echocardiogram 
performed.   
Subjects with a >10% decrease (from baseline) in LVEF to below the institutional LLN 
should discontinue treatment with GSK3326595.  Ejection fraction should be monitored 
every 4 weeks for a total of 16 weeks or until resolution.  If recovery occurs 
(LVEF >institutional LLN and symptom resolution) within 4 weeks, treatment with 
GSK3326595 may be restarted at a reduced dose in consultation with the GSK Medical 
Monitor.  
Subjects with symptoms of left ventricle (LV) systolic dysfunction without an 
accompanying decrease in LVEF by echocardiogram should have a full evaluation 
performed as appropriate (e.g., cardiology consult, additional workup for 
swelling/shortness of breath) and symptoms should resolve to <Grade 2 prior to 
discussion of restarting GSK3326595 at the same or reduced dose with the GSK Medical 
Monitor. 
Copies of all echocardiograms may be required by GSK for review.  Any cardiology 
consultations performed on subjects who experience a >10% decrease in LVEF from 
baseline and whose cardiac ejection fraction is <institution’s LLN will be required by 
GSK for review.   
Valvular Toxicity Stopping Criteria 
Subjects who have a new asymptomatic, moderate regurgitation or stenosis by 
echocardiogram (Grade 2 mitral/tricuspid/aortic valvular toxicity per NCI-CTCAE v4) 
should temporarily discontinue GSK3326595 and have a repeat evaluation by ECHO 
within 1 week.  ECHO should be repeated every 1 to 2 weeks for 4 weeks or until valve 
recovery to baseline. 
• If the valve recovers to baseline any time during the next 4 weeks after consultation 
with and approval from the GSK Medical Monitor, the subject may be restarted on 
GSK3326595 at a reduced dose(s).  For such subjects, monitoring of the valve via 
ECHO will then be performed 2 and 4 weeks after rechallenge, and every 4 weeks 
thereafter for 16 weeks and then per protocol. 
• If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then the 
subject should permanently discontinue GSK3326595.  The valve should continue to 
be monitored via ECHO every 4 weeks for 16 weeks or until resolution. 


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Subjects with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by imaging with 
symptoms controlled by medical intervention) valvular toxicity must discontinue 
GSK3326595.  Valvular toxicity should continue to be monitored every 4 weeks for 
16 weeks or until resolution.  If recovery occurs (return to baseline via imaging AND 
symptom resolution) within 4 weeks, the subject may restart GSK3326595 at a reduced 
dose after consultation with and approval from the GSK Medical Monitor. 


Signature Page for  204653 TMF-14123404 v2.0
Signature Page for TMF-14123404 v2.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 20-Apr-2022 07:02:24 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  204653
Official 
Title 
of 
Study: An open-label, dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK3326595 in 
participants with solid tumors and non-Hodgkin’s lymphoma
NCT ID: NCT02783300
Date of Document: 8 December 2022


CONFIDENTIAL 
The GlaxoSmithKline group of companies 
 
204653 
 
 
1 
 
 Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for a Phase I, Open-label, Dose 
Escalation Study to Investigate the Safety, 
Pharmacokinetics, Pharmacodynamics and Clinical Activity 
of GSK3326595 in Subjects with Solid Tumors and Non-
Hodgkin’s Lymphoma 
Compound Number  : GSK3326595 
Effective Date  
: 08 December 2022 
 
Description : 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204653. 
• 
This RAP is intended to describe the interim analyses required for the study.  
• 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
 
RAP Author(s): 
Approver 
Date 
Approval 
Method 
 
Senior Biostatistician II, ICON PLC 
02/12/2022 
Email 
 
Principal Statistician, GSK 
05/12/2022 
Email 
 
Copyright 2022 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


 
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RAP Team Review Confirmations: 
Approver 
Date 
Approval 
Method 
 
02/09/2022 
Email 
Principal Programmer, Clinical Statistics 
 
01/09/2022 
Email 
Oncology Clinical Development 
 
Safety and Medical Governance Lead 
31/08/2022 
Email 
  
Clinical Pharmacology 
28/11/2022 
Email 
  
Scientific Writer 
01/09/2022 
Email 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval 
Method 
 
Statistics Leader 
 
Pharma TMF e-
signature 
 
Pharma TMF e-
signature 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 7 
1.1. 
Revision Chronology: .................................................................................... 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 8 
2.1. 
Changes to the Protocol-Defined Statistical Analysis Plan ............................ 8 
2.2. 
Study Objective(s) and Endpoint(s) Per Protocol .......................................... 9 
2.2.1. 
Part 1 Dose Escalation .................................................................. 9 
2.2.2. 
Part 2: Dose Expansion ............................................................... 10 
2.2.3. 
Part 3: Combination with Pembrolizumab .................................... 12 
2.3. 
Study Design .............................................................................................. 14 
2.3.1. 
Part 1: Dose Escalation ............................................................... 14 
2.3.2. 
Part 2: Disease-Specific Expansion Cohort(s) ............................. 16 
2.3.3. 
Part 3: GSK3326595 + Pembrolizumab Combination 
Study ........................................................................................... 18 
2.4. 
Statistical Hypotheses................................................................................. 19 
3. 
PLANNED ANALYSES .......................................................................................... 20 
3.1. 
Interim Analyses ......................................................................................... 20 
3.1.1. 
Interim Analysis for Part 2:  Bayesian Predictive Adaptive 
Design for GBM Cohort ................................................................ 20 
3.1.2. 
Interim Analysis for Part 2:  Bayesian Hierarchical 
Modeling for mTCC, TNBC, and NHL Cohorts ............................. 21 
3.1.3. 
Interim Analysis for Part 1 Cohorts and for ACC Cohort in 
Part 1 and Part 2 .......................................................................... 22 
3.1.4. 
Interim Analysis for Part 2:  Simon’s Two Stage Design for 
ACC Cohort ................................................................................. 22 
3.1.5. 
Interim Analysis for Part 2:  Bayesian Predictive Adaptive 
Design for ER+BC Cohort ............................................................ 22 
3.1.6. 
Interim Analysis for Part 2:  Bayesian Predictive Adaptive 
Design for HPV+ Cohort .............................................................. 24 
3.1.7. 
Interim Analysis for Part 2:  Statistical Design for NSCLC 
Cohort .......................................................................................... 25 
3.1.8. 
Food Effect and Relative Bioavailability Sub-study ...................... 25 
3.1.9. 
Interim Analysis for Part 2: Statistical Design for All Part 2 
Cohorts ........................................................................................ 25 
.............................................................................. 26 
3.3. 
Final Analyses ............................................................................................ 26 
4. 
ANALYSIS POPULATIONS ................................................................................... 26 
4.1. 
List of Populations ...................................................................................... 26 
4.2. 
Protocol Deviations ..................................................................................... 27 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 27 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 27 
5.1.1. 
Treatment Display ........................................................................ 28 
5.1.2. 
PK Analysis: Handling of excluded data after NCA (Non-
Compartmental Analysis) analysis ............................................... 29 
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5.2. 
Baseline Definitions .................................................................................... 30 
5.3. 
Multicenter Studies ..................................................................................... 30 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 30 
5.4.1. 
Covariates and Other Strata ........................................................ 30 
5.4.2. 
Examination of Subgroups ........................................................... 30 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 30 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 30 
6. 
STUDY POPULATION ANALYSES ....................................................................... 31 
6.1. 
Overview of Planned Analyses ................................................................... 31 
6.2. 
Disposition of Subjects ................................................................................ 31 
6.3. 
Protocol Deviations ..................................................................................... 32 
6.4. 
Demographic and Baseline Characteristics ................................................. 32 
6.5. 
Concomitant Medications and Medical Conditions ...................................... 32 
6.6. 
Anti-Cancer Therapy ................................................................................... 32 
6.7. 
Disease Characteristics .............................................................................. 33 
6.8. 
Treatment Compliance ................................................................................ 33 
7. 
EFFICACY ANALYSES .......................................................................................... 33 
7.1. 
Primary Efficacy Analyses .......................................................................... 33 
7.1.1. 
Confirmed Overall Response Rate (ORR) based on 
RECIST 1.1 for Part 2 (non-GBM, non-NHL) cohorts ................... 33 
7.1.2. 
Overall Response Rate (ORR) based on Lugano for Part 2 
NHL Cohorts ................................................................................ 34 
7.1.3. 
Progression Free Survival (PFS) for Part 2 GBM cohort .............. 35 
7.2. 
Secondary Efficacy Analyses ...................................................................... 36 
7.2.1. 
Confirmed Overall Response Rate (ORR) based on 
RECIST 1.1 for Part 1 Cohorts ..................................................... 36 
7.2.2. 
Confirmed Overall Response Rate (ORR) based on 
RANO Criteria for Part 2 GBM Cohort .......................................... 36 
7.2.3. 
Confirmed Overall Response Rate (iORR) based on 
iRECIST for Part 3 Cohort ........................................................... 36 
7.2.4. 
Progression Free Survival (PFS) for Part 1, Part 2 (non-
GBM), Part 3 ................................................................................ 37 
7.2.5. 
Lesion Analysis – Parts 1, 2, and 3 .............................................. 38 
7.2.6. 
DOR and TTR for Part 2 ACC TN Cohort based on 
RECIST 1.1 Criteria ..................................................................... 38 
7.2.7. 
Overall Survival (OS) ................................................................... 38 
8. 
SAFETY ANALYSES ............................................................................................. 38 
8.1. 
Primary Safety Analyses ............................................................................. 39 
8.1.1. 
Safety Analyses – Part 1 and Part 3 ............................................ 39 
8.2. 
Secondary Safety Analyses ........................................................................ 41 
8.2.1. 
Safety Analyses – Part 2 .............................................................. 41 
8.2.2. 
Safety Analyses – Part 1 and Part 2 ............................................ 41 
8.3. 
Adverse Events of Special Interest Analyses .............................................. 42 
8.4. 
Clinical Laboratory Evaluations ................................................................... 42 
8.4.1. 
Chemistry .................................................................................... 43 
8.4.2. 
Hematology ................................................................................. 43 
8.4.3. 
Coagulation ................................................................................. 43 
8.4.4. 
Urinalysis ..................................................................................... 44 


 
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8.4.5. 
Additional Tests ........................................................................... 44 
8.4.6. 
Analysis of Liver Function Tests .................................................. 44 
8.5. 
Other Safety Measures ............................................................................... 44 
8.5.1. 
Vital Signs .................................................................................... 44 
8.5.2. 
Performance Status ..................................................................... 45 
8.5.3. 
ECG ............................................................................................. 45 
8.5.4. 
LVEF ........................................................................................... 46 
8.5.5. 
Liver Events ................................................................................. 46 
8.5.6. 
DEXA Bone Densitometry ............................................................ 46 
8.5.7. 
Ophthalmic Assessments ............................................................ 46 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 47 
9.1. 
Drug Concentration Measures .................................................................... 47 
9.2. 
Pharmacokinetic Parameters ...................................................................... 47 
9.2.1. 
Deriving Pharmacokinetic Parameters ......................................... 47 
9.2.2. 
Statistical Analysis of Pharmacokinetic Parameters ..................... 49 
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 52 
11. PHARMACODYNAMIC (AND/OR BIOMARKER) ANALYSES ............................... 52 
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 52 
13. ADDITIONAL ANALYSES DUE TO THE COVID-19 PANDEMIC ........................... 53 
14. REFERENCES ....................................................................................................... 54 
15. APPENDICES ........................................................................................................ 56 
15.1. 
Appendix 1: Exclusions from Per Protocol Population ................................. 56 
15.2. 
Appendix 2: Schedule of Activities .............................................................. 57 
15.3. 
Appendix 3: Assessment Windows ............................................................. 58 
15.3.1. 
Definitions of Assessment Windows for Analyses ........................ 58 
15.4. 
Appendix 4: Study Phases .......................................................................... 59 
15.4.1. 
Study Phases for Treatment ........................................................ 59 
15.4.2. 
Study Phases for Concomitant Medication and Blood and 
Blood Supportive Care Products .................................................. 59 
15.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 61 
15.5.1. 
Reporting Process ....................................................................... 61 
15.5.2. 
Reporting Standards .................................................................... 61 
15.5.3. 
Reporting Standards for Pharmacokinetic .................................... 62 
15.6. 
Appendix 6: Derived and Transformed Data ............................................... 63 
15.6.1. 
General ........................................................................................ 63 
15.6.2. 
Study Population .......................................................................... 64 
15.6.3. 
Efficacy ........................................................................................ 65 
15.6.4. 
Safety .......................................................................................... 66 
15.6.5. 
Pharmacokinetic .......................................................................... 66 
15.6.6. 
Pharmacodynamic (and / or Biomarker) ....................................... 66 
15.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 67 
15.7.1. 
Premature Withdrawals ................................................................ 67 
15.7.2. 
Handling of Missing Data ............................................................. 67 
15.7.3. 
Handling of Missing and Partial Dates ......................................... 68 
15.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 72 
15.8.1. 
Laboratory Values ........................................................................ 72 


 
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15.8.2. 
ECG ............................................................................................. 72 
15.8.3. 
Vital Signs .................................................................................... 72 
15.8.4. 
Left Ventricular Ejection Fraction ................................................. 73 
15.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 75 
15.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analysis ..................... 76 
15.11. Appendix 11: Abbreviations & Trade Marks ................................................ 77 
15.11.1. Abbreviations ............................................................................... 77 
15.11.2. Trademarks ................................................................................. 82 
15.12. Appendix 12: List of Data Displays.............................................................. 83 
15.12.1. Data Display Numbering .............................................................. 83 
15.12.2. Mock Example Shell Referencing ................................................ 83 
15.12.3. Deliverables ................................................................................. 83 
15.12.4. Study Population Tables .............................................................. 84 
15.12.5. Efficacy Tables ............................................................................ 86 
15.12.6. Efficacy Figures ........................................................................... 87 
15.12.7. Safety Tables ............................................................................... 89 
15.12.8. Safety Figures ............................................................................. 96 
15.12.9. Pharmacokinetic Tables ............................................................... 96 
15.12.10. Pharmacokinetic/Biomarker Figures ............................................ 97 
15.12.11. ICH Listings ................................................................................. 98 
15.12.12. Non-ICH Listings ........................................................................ 100 


 
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1. 
INTRODUCTION 
This reporting and analysis plan (RAP) details all planned analyses required for a Clinical 
Study Report of study 204653.  
The RAP was written by staff of ICON Clinical Research. The execution of primary and 
secondary analyses of the RAP, with exception to mTPI analysis and Part 2 Bayesian 
hierarchical design analysis, will be undertaken by staff of ICON Clinical Research.  
Additional interim and ad hoc analyses are also described within this document. 
In addition, pharmacodynamic/ biomarker analysis and translational research analysis 
maybe identified and addressed in a separate RAP, if applicable.  Exploratory analyses 
may be conducted at a later time. 
All decisions regarding final analysis, as defined in this RAP document, have been made 
prior to database freeze of the study data. 
1.1. 
Revision Chronology: 
Version Date 
Revision Description 
1.0 
8 Sep 2022 
Original 
1.1 
12 Sep 2022 • Section 4.1: Removed stray bullet in Table 7. 
• Section 6.3: Corrected reference in to Section 4.2 (not 4.1). 
• Section 7.2.6: Updated description of TTR endpoint in Section 7.2.6 from time-to-
event to continuous variable 
• Section 15.12.12: Updated example shell for Listing 55 to “custom per GSK”. 
1.2 
21 Sep 2022 • Section 7.2.4: Added the survival estimates to be presented and the method for 
calculating 95% CI, as it differs from the estimates in Section 7.1.3. 
• Section 7.27: Added the estimates presented and method for calculating 95% CI. 
1.3 
30 Sep 2022 • Figure 4.5 should be linear not log-transformed parameters. 
• Added Section 3.1.3 to account for interim analysis that used evaluable population 
on Part 1 subjects. 
• Added evaluable population definition for Part 1 subjects for interim analysis. 
1.4 
18 Oct 2022 • Added hyperlinks within the text. 
• Added “number of infusions” to Section 8.1.1.1. 
• Added “calcium corrected” to list of chemistry measures in Section 8.4.1. 
• Updated titles for Table 3.21, Table 3.65, Table 4.5, Figures 4.6, Listing 14, Listing 
79, Listing 82, and programming notes for Table 4.5 Table 4.7 and Figure 4.1 
Figure 4.4 in Section 15.12. 
• Added more text to Section 8.4.6, and hepatobiliary injury definition. 
• Removed Figure 4.5 per GSK. 
• Added number category definitions for SBP and DBP in Section 15.8.3. 
1.5 
10 Nov 2022 • Corrected template references for Table 3.48 and Table 3.50 in Section 15.12. 
• Corrected subgroup for Listing 29 which should be ACC only. 
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• Update vital signs and ECG category descriptions in Section 15.8 to be more 
consistent with NCI-CTCAE grade definitions. 
• Add 2 more PK summaries and 2 more PK listings for Pembrolizumab PK 
concentration and immunogenicity.  Add log-linear figures 4.2 and 4.3 per GSK 
request (R. Parasrampuria). 
• Update notes for Listing 80 and 81, as only Part 1 had samples collected. 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol-Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 8 (dated: 20/APR/2022).   
Section 2.2 replicates what is in protocol amendment 8 (dated 20 April 2022).   
In general, the plan will be to report all the primary and secondary outcomes, and none of 
the exploratory outcomes (including pharmacodynamics and genetics outcomes).  The 
following is the exception to this plan: 
• 
Additional secondary analyses, for Part 1 are investigator-assessed percent change 
from baseline, and maximum percent reduction from baseline in sum of diameters, 
and progression-free survival (PFS), defined as time from first dose until 
radiographic progression per standard criteria, or death due to any cause, whichever 
is earlier. 
• 
All Part 2 ACC cohorts will be included in the overall survival analysis. 
• 
Time to response listings will be included with duration of response analyses for 
ACC TN cohort. 
• 
All NHL P53 cohorts are being compared as part of secondary analyses, not 
exploratory analyses. 
• 
PK analyses are considered secondary.   
• 
Progression free survival (PFS) rate at six months after starting GSK3326595 will be 
conducted as a secondary analysis for all Part 2 cohorts not including GBM (for 
which this is the primary analysis). 
• 
Progression free survival (PFS) rate at six months after starting GSK3326595 will be 
estimated using Kaplan-Meier plots (only) as a secondary analysis for Part 1 and Part 
3 cohorts. 
White blood cells will be included with laboratory assessments summarized. (Section 
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2.2. 
Study Objective(s) and Endpoint(s) Per Protocol 
The following tables represents the study objectives and endpoints as described in the 
protocol.  Footnotes indicate changes to the SAP from the protocol which are also listed 
in Section 2.1. 
2.2.1. 
Part 1 Dose Escalation 
Objectives 
Estimands / Endpoints 
Primary  
Primary  
• 
To determine the safety, tolerability, 
and maximally tolerated dose (MTD) 
of orally administered GSK3326595 
in subjects with solid tumors 
• 
Adverse events (AEs), serious adverse events 
(SAEs), dose limiting toxicities (DLTs), 
withdrawals due to AEs, dose interruptions and 
reductions, and changes in safety assessments 
(e.g., clinical laboratory parameters, vital signs, 
physical examinations, and organ-specific 
parameters) 
Secondary  
Secondary  
• 
To determine the recommended Phase 
2 dose (RP2D) of orally-administered 
GSK3326595  
• 
Safety profile (AEs, SAEs, DLTs), clinical response, 
and pharmacodynamic (PD) data [1] 
• 
To describe the pharmacokinetics of 
GSK3326595 after single- and repeat-
dose administration 
• 
GSK3326595 PK parameters in plasma following 
single (Day 1) and repeat-dose administration of 
GSK3326595  
• 
To determine clinical activity of 
GSK3326595 
• 
Overall response rate (ORR; CR + PR), based on 
Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1 criteria) [2] 
• 
To evaluate the preliminary effects 
of fed versus fasted administration 
on the pharmacokinetics of 
GSK3326595 
• 
GSK3326595 PK parameters in plasma following 
single-dose administration of GSK3326595 in a 
fed or fasted state  
• 
To evaluate the relative 
bioavailability of GSK3326595 
tablets as compared to capsules 
• 
GSK3326595 PK parameters in plasma following 
single-dose administration of GSK3326595 in 
tablet or capsule formulation 
Exploratory  
Exploratory  
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Objectives 
Estimands / Endpoints 
2.2.2. 
Part 2: Dose Expansion 
Objectives 
Estimands / Endpoints 
Primary 
Primary  
• To determine clinical activity of 
GSK3326595 in disease-specific 
expansion cohorts 
• Solid tumor cohorts (non-GBM): Overall 
response rate (ORR, defined as % of subjects 
achieving a best response of CR and PR) based 
on RECIST 1.1 criteria;  
• 
GBM cohort: Six-month progression free survival 
(PFS) rate, defined as the percentage of subjects 
free from radiographic progression per Response 
Assessment in Neuro-Oncology (RANO) criteria, or 
death due to any cause, for six months after starting 
GSK3326595. 
• 
Non-Hodgkin’s lymphoma cohort(s): ORR (% of 
subjects achieving CR and PR) based on Lugano  
criteria 
 
 
 
 
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Objectives 
Estimands / Endpoints 
  
Secondary  
Secondary 
• 
To further describe the clinical activity of  
GSK3326595  
• 
PFS, defined as time from first dose until radiographic 
progression per standard criteria, or death due to any 
cause, whichever is earlier. 
• 
GBM cohort: Overall response rate (CR + PR) based 
on RANO Working Group criteria.  
• 
ACC tablet cohort: duration of response (DOR), 
defined as time from first evidence of response (CR or 
PR per RECIST 1.1) to earlier date of disease 
progression or death due to any cause, as determined 
by investigator assessments.[1] 
• 
ACC tablet cohort: Overall survival (OS), defined as 
time from first dose until death from any cause in ACC 
subjects who are systemic-treatment naïve [2] 
• 
To evaluate the safety and tolerability of 
GSK3326595 in subjects treated at the 
RP2D 
• 
AEs, SAEs, dose reductions or delays, withdrawals 
due to toxicities and changes in safety assessments 
(e.g., clinical laboratory parameters, vital signs, 
physical examinations, and organ-specific parameters) 
Exploratory Objectives 
Exploratory Endpoints 
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Objectives 
Estimands / Endpoints 
2.2.3. 
Part 3: Combination with Pembrolizumab 
Objectives 
Estimands / Endpoints 
Primary 
Primary 
• To determine the safety and 
tolerability of orally-administered 
GSK3326595, administered in 
combination with pembrolizumab, in 
subjects with solid tumors 
• AEs, SAEs, withdrawals due to AEs, dose 
interruptions and reductions, and changes in 
safety assessments (e.g., clinical laboratory 
parameters, vital signs, physical examinations, 
and organ-specific parameters) 
Secondary 
Secondary[1] 
• To determine the RP2D of orally-
administered GSK3326595, when 
administered in combination with 
pembrolizumab 
• Safety profile (AEs, SAEs), clinical response, PK, 
and pharmacodynamic (PD) data  
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Objectives 
Estimands / Endpoints 
• To describe the clinical activity of 
GSK3326595 in combination with 
pembrolizumab in subjects with solid 
tumors 
• Overall response rate (% of subjects achieving 
CR and PR) based on iRECIST 1.1 criteria 
• To describe the pharmacokinetics of 
GSK3326595 after single and repeat 
dose administration of 
GSK3326595, when administered in 
combination with pembrolizumab  
• GSK3326595 PK parameters in plasma following 
single- (Day 1) and repeat-dose administration 
Exploratory Objectives 
Exploratory Endpoints 
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2.3. 
Study Design 
This is an open-label, repeat-dose, multicenter, three-part study to establish the 
MTD/RP2D (based on the profile of safety and tolerability) and preliminary clinical 
efficacy of orally-administered GSK3326595, administered as a single agent in subjects 
with solid tumors and non-Hodgkin’s lymphoma, or administered in combination with 
pembrolizumab in subjects with select solid tumors. 
The schedule for study assessments can be found in Protocol Section 8. 
2.3.1. 
Part 1: Dose Escalation 
The primary objective of Part 1 is to identify the MTD of GSK3326595 when 
administered orally in subjects with solid tumors.  Dosing will start at 12.5 mg once daily 
and escalate until the MTD is reached.  In Part 1, any subject who prematurely 
discontinues therapy during the DLT observation period for reasons other than a DLT 
will be replaced by additional subject(s) assigned to the same dose level.  At or about the 
MTD, additional subjects will be enrolled in an exploratory expansion cohort to obtain 
additional PK, PD, and samples for analysis of GSK3326595 and its metabolites.  
Subjects will also be enrolled at or about the RP2D into a food effect and relative 
bioavailability sub-study to evaluate the effects of food and GSK3326595 formulation on 
GSK3326595 pharmacokinetics.  
It is estimated that up to 66 subjects will be enrolled into the dose escalation cohort of the 
study, including approximately 42 subjects to identify the MTD, approximately 12 
subjects in the PK/PD/metabolite/biomarker expansion cohort(s), and approximately 12  
subjects in the food effect and relative bioavailability sub-study.  The study population 
will be adults, with histologically- or cytologically-confirmed solid malignancies. 
Part 1: Dose Escalation Decisions and Determination of MTD 
Dose escalation will be conducted in two stages: dose exploration and MTD 
confirmation. Details are described in Protocol Section 4.2. Section 2.2, Section 4.2.3, 
and Section 4.2.4.  
Projected daily dose levels of GSK3326595 are 12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 
400 mg, 600 mg, 800 mg, and 1200 mg. BID dosing may divide this total daily dose into 
two equal doses, administered twice daily. Additional doses (either lower than 12.5 mg, 
higher than 1200 mg, or intermediate doses between those listed above) and schedules 
may be explored based on emerging safety, PK, and PD data 
The dose-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). 
The dose escalation portion of Part 1 is expected to be completed when approximately 42  
subjects enrolled in the dose escalation and dose confirmation stages have completed the  
DLT evaluation period.  The RP2D will be the MTD or a lower dose that provides 
adequate PK exposure and biologic activity with superior tolerability.  The identification 


 
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of MTD may not be necessary if a clear RP2D emerges without reaching the MTD.  The 
final determination of RP2D will be based on the mTPI suggested dose level, or the 
biologically active dose (e.g., clinical response), the safety profile, and available PK and 
PD data generated from all subjects in Part 1.  If necessary, alternate schedules can be 
explored to determine additional biologically active doses even after a RP2D is defined. 
Subjects may be enrolled at previously completed dose levels for the purpose of 
obtaining additional safety, PK, PD, metabolite, or biomarker data.  Paired fresh biopsies 
(pre- and post-dose) may be required in these subjects based on the need to obtain tumor 
PD data.  In addition, a reduced PK schedule may be used in subjects enrolled to obtain 
additional PK/PD data 
Part 1: PK/PD, Metabolite, and Biomarker Expansion Cohort(s) 
Any dose level at or near the MTD/RP2D in Part 1 may be expanded up to 12 subjects in 
order to collect additional data on safety and pharmacokinetics (PK).  More than one dose 
level may be selected for expansion (e.g., to establish a dose-response curve for PD or 
other biomarkers), based on emerging data.  Clinical samples from this/these cohort(s) 
will also be collected for analysis of pharmacodynamics (PD), metabolite profiling, and 
biomarkers.  Subjects may be enrolled into this cohort even after MTD/RP2D has been 
identified and Part 2 of the study has been initiated. 
Refer to Protocol Section 8.1, Time and Events Table (Table 10), which highlights the 
additional sampling requirements for this cohort.   
Food Effect and Relative Bioavailability Sub-Study 
Part 1 will include a sub-study that will be an open-label, randomized, single dose, three 
period, cross over study to investigate the effect of a high-fat, high-calorie meal on the 
bioavailability of GSK3326595, and compare two formulations of GSK3326595 (capsule 
versus tablet). The dose of GSK3326595 will be 300 mg once a day (QD).  GSK3326595 
dosing will be separated by at least 48 hours between each period. Up to 12 subjects in 
the United States may be enrolled in the sub-study. A subject requiring dose reduction or 
discontinuation from study before completion of the sub-study will be replaced by a new 
subject. Depending on the data from the initial 12 subjects, up to an additional 12 patients 
may be enrolled in this sub-study.  
Subjects enrolled in the sub-study will be assigned to one of two sequences, as described 
in Table 1; equal numbers will be assigned to each sequence.  
Table 1 
Food Effect and Relative Bioavailability Sub-Study 
Sample Size 
Sequence 
Period 1 (D1) 
Period 2 (D4) 
Period 3 (D8) 
6 
1 
Fasted / tablet 
Fed / tablet  
Fasted / capsule 
6 
2 
Fed / tablet 
Fasted / tablet 
Fasted / capsule 
 
Fasted: Subjects should take nothing by mouth apart from water and other medications 
for at least 8 hours before drug administration and should continue fasting until at least 4 
hours after administration of the morning dose. Subjects should be administered the drug 
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can be allowed, as desired, except for one hour before and after drug administration. All 
subjects will receive standardized meals at approximately 4- and 9- hours post dose. 
Additional details of the meals will be provided in the SRM.  
Fed: Following an overnight fast (at least 8 hours), subjects should start the 
recommended high fat, high calorie breakfast 30 minutes prior to administration of the 
GSK3326595. Study subjects should eat this meal in 30 minutes or less; however, 
GSK3326595 should be administered 30 minutes after start of the meal. The 
GSK3326595 should be administered as a tablet with 200 mL (8 fluid ounces) of water. 
No food should be allowed for at least 2 hours post-dose. Water can be allowed, as 
desired, except for one hour before and after drug administration. All subjects will 
receive standardized meals at approximately 4- and 9- hours post dose.  Further details of 
the meals will be provided in the SRM.  
Any subject who experiences vomiting within 3 hours of dosing will be removed from 
the statistical analysis of PK comparability between tablet/capsule and tablet 
(fasted)/tablet (fed), and additional subjects will be enrolled to ensure 12 subjects 
complete all three periods.   
The Day 4 (Period 2) visit may be performed on Day 4 or Day 5.  The Day 8 (Period 3) 
visit (capsule administered in a fasting state) may be performed ± 1 day.  Continuous 
daily dosing with GSK3326595 will only commence once the subject has completed the 
Period 3 visit, irrespective of whether that visit occurs ± 1 day. 
If the GSK3326595 tablet bioavailability is comparable to that of the GSK3326595 
capsules, all new and ongoing subjects may be switched from capsules to tablets for the 
remainder of the study, once they have been notified by the Sponsor.  
Note that per GSK communication, 3Nov2021, tablet and capsule cohorts within the 
same disease/dosage groups will be combined. 
2.3.2. 
Part 2: Disease-Specific Expansion Cohort(s) 
Once the RP2D has been determined, subjects will be enrolled in disease-specific 
expansion cohorts at the RP2D in order to better characterize the clinical activity and 
safety profile of GSK3326595.  Expansion cohorts will enroll subjects with TNBC, 
mTCC, recurrent GBM, NHL (all subtypes recruited to Protocol Amendments 1-4 and 
indolent subtypes of NHL recruited to Protocol Amendment 5 onwards, which will be 
analyzed based on TP53 status: p53 mutant and p53 wild-type), ACC (which will be 
separated into two separate cohorts: one dosed with GSK3326595 capsules, and a second 
dosed with GSK3326595 tablets [this tablet cohort will enroll subjects who have not 
received any systemic therapy for their locally advanced or metastatic ACC]), ER+BC, 
HPV-positive solid tumors of any histology, and p53 wild-type NSCLC of any 
histological subtype.  
 
 
 
 
Subjects in Part 2 will start with a continuous daily dosing schedule unless safety, PK or 
PD data necessitate a different dosing schedule. The final dose and regimen for Part 2 
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will be decided upon completion of dose escalation in Part 1.  Dose reduction and/or 
scheduled interruptions will be permitted based on tolerability and toxicity. 
Plasma samples for PK evaluation will be collected, at reduced frequency compared to 
Part 1, in all subjects.  Plasma samples and other clinical samples (e.g. lymph node or 
bone marrow biopsies) will be collected pre- and post- study drug treatment as defined in 
the Time and Events Table in protocol Section 8.1 for the PD evaluations. The timing of 
samples may be altered and/or extra samples may be obtained at additional time points to 
ensure thorough PK and PD monitoring.  For example, the timing of PK and PD 
monitoring maybe moved earlier or later in the evaluation schedule based on emerging 
preclinical or clinical data that suggests a more optimal time frame to monitor biologic 
activity. 
It is estimated that up to 316 subjects will be enrolled in the disease-specific expansion 
cohorts of the study.  Cohorts will initially be limited to the following diseases in Table 
Table 2. However, additional tumor-specific cohort(s) may be added based upon 
emerging pre-clinical and clinical data from Part 1 or Part 2 of the study: 
In Part 2, subjects will not be replaced if they prematurely discontinue therapy. Initially, 
the NHL cohorts enrolled subjects irrespective of histological subtype.  However, in 
December 2019 it was noted that of the subjects enrolled with high-grade and other 
aggressive subtypes of diffuse large B-cell lymphoma (DLBCL), including double- and 
triple-hit lymphomas, there were zero objective responses out of 14 subjects dosed.  
Conversely, clinical benefit was observed in subjects with more indolent subtypes 
(including complete/partial responses in were observed in subjects with FL and tFL, and 
stable disease for several disease assessments was observed in subjects with MCL). 
Therefore, Protocol Amendment 5 limited further enrollment to this population to 
subjects with more indolent disease who may receive more benefit from treatment with 
GSK3326595 monotherapy. 
Table 2 
Part 2 Cohorts and Number of Subjects 
Cohorts 
Number 
of 
Subjects  
Triple-negative breast cancer (TNBC) 
Up to 32 
Metastatic transitional cell carcinoma of the urinary system (mTCC) 
Up to 40 
Glioblastoma multiforme (GBM) 
Up to 28 
Non-Hodgkin’s lymphoma all subtypes recruited to Protocol Amendments 1-4 and 
indolent subtypes of NHL recruited to Protocol Amendment 5 onwards, without 
mutations in the TP53 gene (p53 wild-type, NHL [-]) 
Up to 25  
Non-Hodgkin’s lymphoma all subtypes recruited to Protocol Amendments 1-4 and 
indolent subtypes of NHL recruited to Protocol Amendment 5 onwards, with 
mutations in the TP53 gene (p53 mutant, NHL [+]) 
Up to 25 
Adenoid cystic carcinoma (ACC), dosed with GSK3326595 capsule formulation 
Up to 38 
Adenoid cystic carcinoma (ACC), dosed with GSK3326595 tablet formulation, in a 
population that is systemic therapy-naïve 
Up to 50 
Hormone receptor-positive adenocarcinoma of the breast (ER+BC) 
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Cohorts 
Number 
of 
Subjects  
Human papillomavirus (HPV) positive solid tumors of any histology 
Up to 28 
p53 wild-type non-small cell lung cancer (NSCLC) of any histological subtype 
Up to 15 
 
Subjects will start dosing on Day 1 with the dose and schedule selected as the RP2D in 
Part 1 of the study. At a 21 March 2018 investigator meeting, 400 mg once daily (QD) 
was selected as the RP2D, based on safety, tolerability, efficacy, PK, and PD.  Dose 
reductions and scheduled interruptions are permitted for toxicity and tolerability as 
described in Table 3. At that meeting, it was also determined that if emerging data 
demonstrated that 400 mg QD proved intolerable for a majority of subjects, that the 
starting dose for all subjects enrolled from that time forward may be reduced (e.g., to 
Dose level [DL]-1). The final dose selection will take into account all available clinical 
data, as well as a PK/PD model to predict the optimal dose with minimal cytopenias. 
All new subjects enrolled, following approval of Protocol Amendment 4 (food effect and 
relative bioavailability sub-study in Part 1, and all dose expansion cohorts in Part 2), will 
start on 300 mg QD (i.e., at Dose level-1 [DL-1] in Table 3).  In all cohorts, dose 
reduction for toxicity will be permitted, as described in Table 3).  . 
Table 3 
RP2D and Planned Dose Reduction 
RP2D 
400 mg QD 
DL-1 
300 mg QD 
DL-2 
200 mg QD 
DL-3 
200 mg QD, administered for 3 weeks, 
followed by a 1-week rest period 
 
Note: These dose levels may be adjusted on a case-by-case basis after discussion with the 
GSK medical monitor. 
2.3.3. 
Part 3: GSK3326595 + Pembrolizumab Combination Study 
The primary objective of Part 3 is to evaluate the safety and tolerability of GSK3326595 
when administered in combination with pembrolizumab in subjects with select solid 
tumors.  Three cohorts will be evaluated.  All subjects will receive pembrolizumab at the 
approved dose (200 mg IV every 3 weeks), in combination with GSK3326595 dosed 
orally at 100 mg QD, 200 mg QD, or 300 mg QD. 
All available data from Part 3, including safety, tolerability, efficacy, PK, and PD will be 
used to select a dose of GSK3326595 to be administered with pembrolizumab in future 
studies.  In order to collect PD data, pre- and on-study biopsies will be required for all 
subjects.  Subjects will receive GSK3326595 at the assigned dose as monotherapy for 
14 days, at which time the on-study biopsy will be collected.  Subjects will then 
commence therapy with pembrolizumab administered every 3 weeks.  Safety will be 
assessed continuously.  Cohort(s) may be closed to further enrolment based on toxicity 
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The study population will be adults, with locally advanced or metastatic NSCLC, 
melanoma, mTCC, or HNSCC that have failed to respond to treatment (e.g., SD, with 
subsequent documented progression as per iRECIST 1.1, or PD as best response) with 
prior PD-1 or PD-L1 directed therapy.  Subjects who initially responded (e.g., iPR or 
iCR) to these therapies, then subsequently progressed, will not be eligible for 
participation in Part 3.   
Overall, approximately 30 subjects will be enrolled in Part 3.  These subjects will be 
divided evenly between three cohorts, each receiving a different dose of GSK3326595 in 
combination with a single dose of pembrolizumab. 
 
 
 
 
2.4. 
Statistical Hypotheses  
In Part 1, the primary endpoints of this study are safety and tolerability; the MTD and 
RP2D will also be determined. No formal statistical hypotheses will be tested. The 
primary focus will be on determining the recommended dose for further exploration, 
the safety profile, and the PK of GSK3326595 in subjects with advanced solid 
malignancies. Analyses will be descriptive and exploratory. 
 
The primary goal of Part 2 is to evaluate disease-specific clinical activity in subjects 
with select solid tumors and NHL.  The cohorts will be terminated for futility based on 
interim analysis described in Section 3.1 
 
• For TNBC and ER+BC, efficacy is defined as a clinically meaningful response 
rate (defined as the percentage of subjects that have achieved a CR or PR) of 
25% relative to a 10% historical control response rate. 
• For mTCC, efficacy is defined as a clinically meaningful response rate 
(defined as the percentage of subjects that have achieved a CR or PR) of 30% 
relative to a 15% historical control response rate. 
• For recurrent GBM, efficacy is defined as a clinically meaningful improvement 
in the rate of subjects who remain progression-free at six months (defined as a 
35% six-month PFS rate relative to a 17% historical six-month PFS rate). 
• For ACC and HPV-positive solid tumors, efficacy is defined as a clinically 
meaningful response rate (defined as the percentage of subjects that have 
achieved a CR or PR) of 30% relative to a 10% historical control response rate. 
• For NHL (p53 wild-type, p53 mutant, and p53 unknown cohorts), efficacy is 
defined as a clinically meaningful response rate (defined as the percentage of 
subjects that have achieved a CR or PR) of 30% relative to a 10% historical 
control response rate. 
• For NSCLC, efficacy is defined as a clinically meaningful response rate 
(defined as the percentage of subjects that have achieved a CR or PR) of 30% 
relative to a 10% historical control response rate. An interim futility analysis 
will be used to determine the scope of further development in this cohort. 
 
The primary goal of Part 3 is to evaluate the safety and tolerability of GSK3326595 in 
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combination with pembrolizumab in solid tumors. No formal statistical hypotheses will 
be tested. 
 
 
 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
3.1.1. 
Interim Analysis for Part 2:  Bayesian Predictive Adaptive Design 
for GBM Cohort 
A Bayesian predictive adaptive design that allows the trial to be monitored more 
frequently at multiple stages [Lee, 2008] will employed for GBM cohort in Part 2 of the 
study. The criteria will be based on a historically unimportant six-month PFS rate of 17% 
versus a six-month PFS rate of interest of 35%. The six-month PFS rate is defined as the 
proportion of the subjects who are progression free and still alive at six months from the 
start of treatment. Bayesian statistics will be employed to calculate the posterior 
probability that the six-month PFS rate 35% and 17% at interim assuming a Beta prior 
for the Binomial distributed data.  Predictive probability calculates the probability that 
the six-month PFS rate 35% or 17% given the responses have already been observed.  
A weak prior Beta (0.03, 0.07) is used, which is equivalent to the information present in 
0.1 subject. The first interim analysis may be conducted when at least 10 evaluable 
subjects are available for GBM cohort at a given dose. The evaluable subjects for GBM 
cohort are defined as the GBM subjects who have had three post baseline disease 
assessments or have progressed or have died or have withdrawn from study treatment due 
to any reason. Futility interim analysis decision rules for the 10th to 27th evaluable 
subjects, specifying the number of subjects who have not progressed six months after 
receiving the first dose of GSK3326595 needed for continuing enrollment or stopping for 
futility when total sample size is up to 27 is presented in Table 4.  These rules are 
intended as a guideline.  Actual decisions will depend on the totality of the data. 
Table 4 
Decision Making Criteria for GBM Futility 
Number of 
Evaluable 
Subjects  
Number progression-free at 
6 months to Stop Early for 
Futility  
Probability of declaring 
futility when 6m PFS 
rate=0.17 
Probability declaring 
futility when 6m PFS 
rate=0.35  
10 
0 
0.1552 
0.0135 
11 
0 
0.0000 
0.0000 
12 
0 
0.0000 
0.0000 
13 
1 
0.1817 
0.0199 
14 
1 
0.0000 
0.0000 
15 
1 
0.0000 
0.0000 
16 
1 
0.0000 
0.0000 
17 
2 
0.1325 
0.0144 
18 
2 
0.0000 
0.0000 
19 
2 
0.0000 
0.0000 
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Number of 
Evaluable 
Subjects  
Number progression-free at 
6 months to Stop Early for 
Futility  
Probability of declaring 
futility when 6m PFS 
rate=0.17 
Probability declaring 
futility when 6m PFS 
rate=0.35  
20 
2 
0.0000 
0.0000 
21 
3 
0.1004 
0.0108 
22 
3 
0.0000 
0.0000 
23 
4 
0.1125 
0.0194 
24 
4 
0.0000 
0.0000 
25 
4 
0.0000 
0.0000 
26 
5 
0.0799 
0.0174 
27 
6 
0.0869 
0.0390 
The enrollment for GBM cohort may be stopped due to futility if the predictive 
probability that the 6 month PFS rate 17% (historical control) is small (e.g., less than a 
2% chance for a total sample size of 28 subjects).  Enrollment may also be stopped due to 
futility if the equivalent of all the evaluable subjects are progressed or off study treatment 
before 6 months from the first dose in the first 10 enrolled evaluable subjects in GBM 
cohort or less than 1 subject who is not progressed still on treatment at month 6 are 
observed in the first 13 evaluable subjects.  For example, when there are 10 evaluable 
subjects available at the time of interim analysis with all subjects progressed before 
month 6, then the cohort may be stop for futility.  Otherwise, the enrollment of the 
respective cohort will continue to the target sample size.  
When the total sample size in a treatment arm is 28 and at least 8 subjects who are not 
progressed before 6 months from first dose and still on treatment at month 6 out of 28 
subjects are observed, we can claim null hypothesis is rejected.  
3.1.2. 
Interim Analysis for Part 2:  Bayesian Hierarchical Modeling for 
mTCC, TNBC, and NHL Cohorts 
To further investigate clinical activity across the pre-specified cohorts, an adaptive design 
utilizing a Bayesian hierarchical model will be employed for the mTCC, TNBC, p53 WT 
NHL and p53 mutant NHL cohorts in Part 2. [Berry, 2013; Escobar, 1995; Neal, 2000; 
Sethuraman, 1994] Multiple interim evaluations of the accumulating data to determine if 
one or more cohorts should discontinue enrollment early due to futility will be 
incorporated. Interim and final evaluations will be based on a hierarchical model that 
borrows information in a limited way from cohorts that demonstrate similar treatment 
effects based on the accumulated trial data. Traditional estimates based on independent 
analyses will also be provided. j is the true response rate for cohort j, where j = 1,…, 4 
and indexes the four cohorts. Cj is the historical control response rate for the jth cohort. 
The historical controls vary by cohort and are provided in Section 2.4. The study is 
powered to detect a high clinically meaningful response rate and is based on the cohort 
model assessment of whether there is sufficiently high probability that j exceeds Cj. The 
posterior probability that the ORR for a given cohort is greater than Cj will be computed 
according to the following comparison:  
P (πj > Cj | current data) for the j-th cohort 


 
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If this posterior probability is sufficiently low within a given cohort, then this will 
provide insufficient evidence to suggest that the ORR is greater than its respective 
historical control. Conversely, if a sufficiently high posterior probability is observed, this 
will provide evidence that the ORR is greater than the historical control, and the dose will 
be declared efficacious in that cohort. Thresholds for decision making are defined in the 
protocol. 
Full details regarding the hierarchical modeling framework are described in the protocol 
at Appendix 11. 
3.1.3. 
Interim Analysis for Part 1 Cohorts and for ACC Cohort in Part 1 
and Part 2 
The purpose of this interim analysis is to summarize safety and efficacy endpoints within 
all Part 1 cohorts and the Part 1 and Part 2 ACC cohort for the purpose of publication.  
For Part 1 dosing cohorts, demographics, disease history, safety, treatment duration, 
percent change from baseline, best overall response, and PK will be summarized on the 
all-treated population. For ACC cohorts, best overall response, duration of follow-up, 
percent change from baseline, duration of treatment, and disease history will be 
summarized on the all-treated population, while progression-free survival will be 
summarized and plotted using the evaluable population. 
3.1.4. 
Interim Analysis for Part 2:  Simon’s Two Stage Design for ACC 
Cohort 
Simon's optimal two-stage design (Simon, 1989) will be used for both ACC cohorts 
(tablet and capsule formulation). For both cohorts, the null hypothesis that the true 
response rate is 10% will be tested against a one-sided alternative of 30%.  
For the capsule cohort, in the first stage, 10 subjects will be accrued. If there are 1 or 
fewer responders in these 10 subjects, the cohort will be stopped early for futility. The 
maximum number of subjects to be enrolled for this cohort is 38. The null hypothesis will 
be rejected if 8 or more responders are observed in 38 patients. This design yields a type I 
error rate of 0.023 and power of 80.8% when the true response rate is 30%. 
For the tablet cohort, in the first stage, 17 subjects will be accrued. If there are 2 or fewer 
responders in these 17 subjects, the cohort will be stopped early for futility. This rule is 
intended as a guideline, development decisions will depend on the totality of the data. 
The maximum number of subjects to be enrolled for this cohort is 50. The null hypothesis 
will be rejected if 10 or more responders are observed in 50 patients. This design yields a 
type I error of 0.02 and power of 89.9% when the true response rate is 30%.  
3.1.5. 
Interim Analysis for Part 2:  Bayesian Predictive Adaptive Design 
for ER+BC Cohort 
The ER+BC cohort will employ the 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 10% overall response rate (ORR) representing best available 
therapy in favour of a 25% ORR. A close to non-informative prior will be used. Let p 


 
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denote the response rate, the prior distribution used is p ~ Beta (0.025, 0.075). The cohort 
will be stopped early due to futility if the predictive probability of success is less than 
8%. The success is defined as posterior probability of ORR > 10% at the end of the 
cohort is larger than 80%. The first interim analysis will be performed when at least 10 
subjects become evaluable. The max sample size is 35 subjects, and the design will have 
type I error of 0.10 and power of 82%. 
The decision rules, specifying the number of subjects with a clinical response needed for 
continuing enrolment or, stopping for futility, are displayed in Table 5. The methodology 
is based on the predictive probability of success if enrolment continues to maximum 
number of subjects (Lee, 2008). The interim analysis will be for futility only, i.e., the 
dose expansion cohort will not stop early for efficacy. 
Table 5 
Decision Making Criteria for ER+BC Futility 
Number of Evaluable 
Subjects  
  This Number of 
Confirmed Responses to 
Stop Early for Futility  
Probability of 
continuing enrolling 
when ORR=0.1 
 Probability of 
continuing enrolling 
when ORR=0.25  
 10 
0 
0.6513 
0.9437 
 11 
0 
0.6513 
0.9437 
 12 
0 
0.6513 
0.9437 
 13 
0 
0.6513 
0.9437 
 14 
1 
0.3971 
0.8843 
 15 
1 
0.3971 
0.8843 
 16 
1 
0.3971 
0.8843 
 17 
1 
0.3971 
0.8843 
 18 
1 
0.3971 
0.8843 
 19 
1 
0.3971 
0.8843 
 20 
1 
0.3971 
0.8843 
 21 
1 
0.3971 
0.8843 
 22 
2 
0.2938 
0.8674 
 23 
2 
0.2938  
0.8674 
 24 
2 
0.2938 
0.8674 
 25 
2 
0.2938 
0.8674 
 26 
2 
0.2938 
0.8674 
 27 
3 
0.2108 
0.8511 
 28 
3 
0.2108 
0.8511 
 29 
3 
0.2108 
0.8511 
 30 
3 
0.2108 
0.8511 
 31 
3 
0.2108 
0.8511 
 32 
4 
0.1509 
0.8369 
 33 
4 
0.1509 
0.8369 
 34 
4 
0.1509 
0.8369 


 
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3.1.6. 
Interim Analysis for Part 2:  Bayesian Predictive Adaptive Design 
for HPV+ Cohort 
The HPV+ cohort will employ the 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 10% overall response rate (ORR) representing best available 
therapy in favour of a 30% ORR. A close to non-informative prior will be used. Let p 
denote the response rate, the prior distribution used is p ~ Beta (0.03, 0.07). 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 ORR > 10% at the end of the 
cohort is larger than 87.6%. The first interim analysis will be performed when at least 10 
subjects become evaluable. The max sample size is 28 subjects, and the design will have 
type I error of 0.05 and power of 87%. 
The decision rules, specifying the number of subjects with a clinical response needed for 
continuing enrolment or, stopping for futility, are displayed in Table 6. The methodology 
is based on the predictive probability of success if enrolment continues to maximum 
number of subjects (Lee, 2008).  The interim analysis will be for futility only, i.e., the 
dose expansion cohort will not stop early for efficacy.  
Table 6 
Decision Making Criteria for HPV+ Futility 
Number of Evaluable 
Subjects  
  This Number of 
Confirmed Responses to 
Stop Early for Futility  
Probability of 
continuing enrolling 
when ORR=0.1 
 Probability of 
continuing enrolling 
when ORR=0.3  
 10 
0 
0.6513 
0.9718 
 11 
0 
0.6513 
0.9718 
 12 
0 
0.6513 
0.9718 
 13 
0 
0.6513 
0.9718 
 14 
0 
0.6513 
0.9718 
 15 
0 
0.6513 
0.9718 
 16 
0 
0.6513 
0.9718 
 17 
1 
0.4660 
0.9618 
 18 
1 
0.4660 
0.9618 
 19 
1 
0.4660 
0.9618 
 20 
1 
0.4660 
0.9618 
 21 
2 
0.3107 
0.9500 
 22 
2 
0.3107 
0.9500 
 23 
2 
0.3107  
0.9500 
 24 
2 
0.3107 
0.9500 
 25 
3 
0.2019 
0.9383 
 26 
3 
0.2019 
0.9383 
 27 
4 
0.1129 
0.9161 


 
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3.1.7. 
Interim Analysis for Part 2:  Statistical Design for NSCLC Cohort 
The Part 2 NSCLC cohort is intended to explore the clinical activity in the p53 wild-type 
NSCLC population. Simon’s optimal two-stage design will be used as a basis for analysis 
of the NSCLC cohort. The null hypothesis that the true response rate is 10% will be 
tested against a one-sided alternative. ORR will be assessed for the 10 subjects that are 
confirmed with p53 wild-type. 
In the first stage, 10 subjects will be accrued. If there are 1 or fewer responders in the first 
10 subjects, the cohort will be stopped for futility. If 2 or more responses are observed, 
further expansion of the p53 wild-type NSCLC cohort may be triggered via protocol 
amendment or as a part of another study. If the cohort were to expand to 29 subjects, the 
null hypothesis would be rejected if 6 or more responders are observed. This design 
yields a type I error rate of 0.047 and power of 80.5% when the true response rate is 30%. 
Note that at the time GSK made a decision to cease enrollment in the study, this cohort 
did not have 10 subjects.  Therefore, the interim analysis was not conducted.  
3.1.8. 
Food Effect and Relative Bioavailability Sub-study 
This analysis is described in Section 9.2.2.2. 
3.1.9. 
Interim Analysis for Part 2: Statistical Design for All Part 2 
Cohorts 
The purpose of this interim analysis is to summarize safety and efficacy endpoints within 
all Part 2 cohorts for purposes of publication.  Efficacy endpoints for TNBC, mTCC, 
ER+BC, HPV+, ACC, and NSCLC cohorts will be investigator-assessed confirmed, best 
response based on RECIST 1.1 criteria.  For NHL cohorts, investigator-assessed best 
response based on Lugano criteria will be reported. See Section 7.1for further details on 
criteria. For these groups, overall response rate (ORR) defined as the proportion of 
subjects with complete response (CR) or partial response (PR) with 95% confidence 
interval based on the Clopper-Pearson (1934) exact methods will be reported.  In 
addition, frequency of best responses will also be reported by histology subtype for the 
NHL cohorts.  For GBM, progression-free survival rate at 6 months will be reported, with 
a 95% confidence interval estimated using Greenwood’s estimate of standard error. 
Additional endpoints examined will be duration of treatment with best response for all 
cohorts. maximum percent reduction from baseline in sum of diameters as well as change 
from baseline for TNBC, mTCC, ER+BC, HPV+, ACC, and NSCLC cohorts, and 
maximum percent reduction from baseline in sum of areas for the GBM cohort. 
In addition, safety parameters will be reported by dosage type (300 mg, 400 mg).  
Included will be a summary of adverse events, adverse events related to GSK3326595 by 
preferred term and by maximum grade, as well as adverse events leading to dose 
reduction, interruptions/delays, discontinuation and serious adverse events by preferred 
term, and summary of deaths. 


 
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3.3. 
Final Analyses 
The final analysis of the study will be performed after the completion of the following 
sequential steps: As per Protocol Amendment 8 implementation, final analysis will be 
performed following the data cut off (DCO). This will occur when all subjects have either 
died, discontinued treatment (including 30-day safety follow up), withdrawn consent, or 
have consented to continue with treatment as defined in Protocol Amendment 8.  
All required database cleaning activities have been completed and final database release 
(DBR), source data lock (SDL) and database freeze (DBF) have been declared by Data 
Management. 
Data from the three parts may be combined for some analyses at the end of the trial, as 
appropriate. All primary and secondary analyses will be conducted for the final analysis. 
4. 
ANALYSIS POPULATIONS 
4.1. 
List of Populations 
Table 7 
Analysis Populations 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
All participants who were screened for eligibility 
Study Population 
Enrolled 
All participants who signed the ICF 
Study Population 
All Treated 
Defined as all subjects who receive at least one 
dose of GSK3326595.  
Safety 
Anti-cancer activity 
Efficacy (final 
analysis) 
All Evaluable  
For Part 1: Defined as subjects who have had 
any post-baseline response data, or who 
discontinued without any response data 
collected. 
 
For Part 2: Defined as subjects who have had 
two post baseline disease assessments, have 
progressed or died, or permanently discontinued 
from the study treatment for mTCC, TNBC, 
ER+BC, HPV+,  NHL and NSCLC cohorts. It is 
defined as subjects who have had three post 
baseline disease assessments, have progressed 
or died, or permanently discontinued from the 
study treatment for ACC and GBM cohorts.  
Interim Analysis 
CCI


 
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Population 
Definition / Criteria 
Analyses Evaluated 
Pharmacokinetic 
(PK)  
Consist of all subjects from the All Treated 
Population for whom a PK sample is obtained 
and analyzed. 
Note: PK samples that may be affected by 
protocol deviations will be reviewed by the study 
team to determine whether or not the sample will 
be excluded. 
PK 
 
Pharmacodynamic 
(PD) 
Defined as subjects in the All Treated Subjects 
Population for whom paired and evaluable tumor 
biopsies (pre- and on- treatment time points) or 
plasma or urine were obtained and analyzed for 
biomarkers. 
PD 
 
 
 
Refer to Appendix 12: List of Data Displays which details the population used for each 
display.  Note that for the interim analyses, the All Evaluable population will be used for 
efficacy analyses, and the All-Treated Population will be used for safety analyses.  
However, for the final analysis, the All Treated Population will be used for all displays. 
4.2. 
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 and listed. 
Separately, important deviations which result in exclusion from analysis populations and 
events that result in exclusion from analysis populations will be summarized and listed, if 
there are any.  
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan. 
• 
Data will be reviewed prior to freezing the database to ensure all important deviations 
are captured and categorized on the protocol deviations dataset.  
• 
This dataset will be the basis for the summaries and listings of protocol deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF.  
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
All data within scheduled visits up to the time of study completion/withdrawal from 
study will be included in the analysis summaries, regardless of duration of treatment.  
Unscheduled visits will be considered for most extreme result reporting (e.g., worst grade 
post-baseline, response assessments for ORR), and included in data listings. 


 
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5.1.1. 
Treatment Display 
The actual treatment of a subject will be derived from exposure data. The first dose the 
subject received will be used as actual treatment. Scheduled (planned) treatment is 
collected on dosing regimen eCRF page. Efficacy, safety and PK analysis will be based 
on the All Treated Population.    
Per Protocol Amendment 7, if the GSK3326595 tablet bioavailability is comparable to 
that of the GSK3326595 capsules from Part 1 Food Effect and Relative Bioavailability 
Sub-study, all new and ongoing subjects may be switched from capsules to tablets for the 
remainder of the study, once they have been notified by the Sponsor. As of 3 Nov 2021, 
per GSK communication, tablet and capsule cohorts within the same disease/dosage 
groups will be combined. 
The leading dose formulation (tablet or capsule) and the leading dose level are specified 
in treatment.   
• 
For Part 1 dose escalation cohorts, all data will be pooled and descriptive analyses 
summarized and listed by investigated GSK3326595 dose under QD dose escalation 
cohort or BID dose escalation cohort. PK/PD expansion cohorts will be summarized 
together with dose escalation cohorts dose level. If applicable, Part 1 Food Effect 
Relative Bioavailability Sub-study data will also be included in Part 1 summary 
tables as a separate column.  The treatment groups for Part 1 are: 
⎯ Part 1 QD Dose GSK3326595 12.5 mg Capsule 
⎯ Part 1 QD Dose GSK3326595 25 mg Capsule 
⎯ Part 1 QD Dose GSK3326595 50 mg Capsule 
⎯ Part 1 QD Dose GSK3326595 100 mg Capsule 
⎯ Part 1 QD Dose GSK3326595 200 mg Capsule 
⎯ Part 1 QD Dose GSK3326595 300 mg Capsule 
⎯ Part 1 QD Dose GSK3326595 400 mg Capsule 
⎯ Part 1 QD Dose GSK3326595 600 mg Capsule 
⎯ Part 1 BID Dose GSK3326595 50 mg Capsule 
⎯ Part 1 BID Dose GSK3326595 100 mg Capsule 
⎯ Part 1 BID Dose GSK3326595 150 mg Capsule 
⎯ Part 1 BID Dose GSK3326595 200 mg Capsule 
⎯ Food Effect and Relative Bioavailability Sub-study 300mg QD (apply to 
table/figures) 
⎯ Part 1 Food Effect 300mg Sequence 1 (Tablet Fasted - Tablet Fed - Capsule 
Fasted) (apply to listings) 
⎯ Part 1 Food Effect 300mg Sequence 2 (Tablet Fed - Tablet Fasted - Capsule 
Fasted) (apply to listings) 
 
• 
For Part 2 dose expansion cohorts, data will be summarized and listed by cohorts. 
The treatment groups for Part 2 are: 
⎯ Part 2 TNBC 400mg QD Capsule Cohort 


 
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⎯ Part 2 mTCC 400mg QD Capsule Cohort 
⎯ Part 2 GBM 400mg QD Capsule Cohort 
⎯ Part 2 ER+BC 400mg QD Capsule Cohort 
⎯ Part 2 HPV+ 400mg QD Capsule Cohort 
⎯ Part 2 ACC 400mg QD Capsule Cohort 
⎯ Part 2 ACC 300mg QD Tablet Cohort 
⎯ Part 2 NHL P53 Mutant 400 mg QD Capsule  
⎯ Part 2 NHL P53 Mutant 300 mg QD Capsule  
⎯ Part 2 NHL P53 Mutant 300 mg QD Tablet (if applicable) 
⎯ Part 2 NHL P53 Wild Type 400 mg QD Capsule  
⎯ Part 2 NHL P53 Wild Type 300 mg QD Capsule  
⎯ Part 2 NHL P53 Wild Type 300 mg QD Tablet (if applicable) 
⎯ Part 2 NHL P53 Unknown 400 mg QD Capsule  
⎯ Part 2 NHL P53 Unknown 300 mg QD Capsule  
⎯ Part 2 NHL P53 Unknown 300 mg QD Tablet (if applicable) 
⎯ Part 2 NSCLC 300 mg QD Capsule 
⎯ Part 2 NSCLC 300 mg QD Tablet (if applicable) 
⎯ Part 2 ACC TN 300mg Tablet Cohort 
 
NB 1: NHL P53 status is based on central lab data. If the central lab data is missing then 
the status will be considered Unknown.  
 
NB 2: As per GSK communication, as of 3Nov2021 tablet and capsule cohorts within the 
same disease/dosage groups will be combined. 
 
For Part 3 combination dose escalation, some AE and exposure tables and listings will be 
displayed for GSK3326595 and pembrolizumab separately. All others will be 
summarized and listed by dose levels of both GSK3326595 plus pembrolizumab. (e.g., 
GSK3326595 100mg + pembrolizumab). 
 
Subjects enrolled in Part 1, may be included in a Part 2 disease-specific cohort analyses 
(tables and figures) if the subjects were treated at the Part 2 dose expansion and have the 
same disease type as required for the cohort. These subjects will be provided in a separate 
listing as well. Additional safety tables, may be provided for all subjects treated at the 
RP2D, regardless of the Part of the study to which they were enrolled. 
Unless otherwise noted, the denominator for the percentage is the number of subjects in 
the analysis population used for that summary. 
5.1.2. 
PK Analysis: Handling of excluded data after NCA (Non-
Compartmental Analysis) analysis 
When Clinical Pharmacology perform the NCA analysis they may, in some 
circumstances, elect to exclude certain data points from the analysis. These data points 
should also be excluded from summary statistics. A separate analysis dataset ADPCWNL 
will be generated by adding a flag for those records to be excluded. PK listings and 


 
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individual PK figures will keep all the data, with listings indicated the records excluded 
from summary.  
5.2. 
Baseline Definitions 
Baseline will be defined as the most recent, non-missing value prior to or on the first 
study treatment dose date for GSK3326595, including those from unscheduled visits.  
For laboratory data, baseline will be defined as the most recent, non-missing value from a 
central laboratory prior to or on the first study treatment dose date. If there are no central 
labs collected for a subject and lab test prior to or on the first dose of study treatment, the 
most recent, non-missing value from a local laboratory prior to or on the first dose of 
study treatment will be defined as the baseline value.  
If the latest pre-dose value is collected on the day of treatment, the time of treatment will 
be used to identify the baseline value. If time is not collected, Day 1 assessments are 
assumed to be taken prior to first dose and used as baseline. 
Unless otherwise stated, if baseline data are missing, no derivation will be performed and 
baseline will be set to missing.  
5.3. 
Multicenter Studies 
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis. 
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
There are no formal plans for any stratification. There are no formal plans for 
investigating any covariates. 
5.4.2. 
Examination of Subgroups 
There are no formal plans for examining subgroups. 
5.5. 
Multiple Comparisons and Multiplicity 
There is no adjustment for multiplicity in primary or secondary analyses. 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
following appendices: 
Section Component 
15.3 
Appendix 3: Assessment Windows 


 
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Section Component 
15.4 
Appendix 4Study Phases 
15.5 
Appendix 5: Data Display Standards & Handling Conventions 
15.6 
Appendix 6: Derived and Transformed Data 
15.7 
Appendix 7Reporting Standards for Missing Data 
15.8 
Appendix 8Values of Potential Clinical Importance 
6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
The study population analyses will be based on the All Treated population, unless 
otherwise specified. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
exposure and treatment compliance, disease characteristics at initial diagnosis and at 
screening, prior and follow-up anti-cancer therapy, and substance use will be based on 
GSK Core Data Standards.  Details of the planned displays are presented in Appendix 
12Only primary and secondary endpoints will be described in this analysis plan and 
necessarily conducted for the final clinical and statistical report. 
6.2. 
Disposition of Subjects 
A summary of the number of subjects in each of the analysis populations described in 
Section 4 will be provided. In addition, the number of subjects enrolled will be 
summarized by country and by center.  In addition, a listing of subjects excluded from 
any analysis population will also be provided. 
A summary and listing of screening status and reasons for screen failure will be provided 
using the Screened population. 
A summary of subject status and reason for study withdrawal will be provided. This 
display will show the number and percentage of subjects who completed the study, are 
ongoing as of the analysis cutoff date, or withdrew from the study, including primary 
reasons for study withdrawal. Reasons for study withdrawal will be presented in the order 
they are displayed in the eCRF. A listing will also be provided. 
A summary of study treatment status will be provided. This display will show the number 
and percentage of subjects who are ongoing or have discontinued study treatment and a 
summary of the primary reasons for discontinuation of study treatment. Reasons for study 
treatment discontinuation will be presented in the order they are displayed in the eCRF. A 
listing of study treatment discontinuation will be generated. The listing will include last 
dose date, and reasons for study treatment discontinuation.  
6.3. 
Protocol Deviations 
Refer to Section 4.2 for the details.  


 
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6.4. 
Demographic and Baseline Characteristics 
The demographic characteristics (e.g., age, race, ethnicity, sex, baseline height, and 
baseline body weight, BMI) will be summarized and listed. Age, height and weight will 
be summarized using the mean, standard deviation, minimum, median, and maximum.  In 
addition, age will also be categorized and summarized by 18-64, 65-74, and >74. In a 
separate summary, age will be categorized as 12-17, 18-64, 65-84, >=85 using EudraCT 
standard. The count and percentage will be computed for sex and ethnicity. Race and 
racial combinations will be summarized and subject-level race detail will be listed.  
6.5. 
Concomitant Medications and Medical Conditions 
Concomitant medications will be coded using GSK drug coding dictionary and listed.  
Note: To be considered concomitant, the medication must have been taken at some point 
during the on-therapy window. Please refer to Appendix 4for the details of concomitant 
medications classification.   
Past and current medical conditions will be summarized in separate tables. 
6.6. 
Anti-Cancer Therapy 
Prior anticancer therapy will be coded using GSK Drug coding dictionary and will be 
classified by type (chemotherapy, immunotherapy, hormonal therapy, biologic therapy, 
small molecule targeted therapy, and vaccine, etc.). Some prior anticancer therapy may 
not have type available and will be summarized under “Other”. A summary for only 
those marked “Advanced or Metastatic” will also be produced. Prior anticancer therapy 
will also be listed. 
The number and percentage of subjects that received chemotherapy, immunotherapy, 
hormonal therapy, biologic therapy, radioactive therapy, small molecule targeted therapy, 
as post study treatment anti-cancer therapy will be summarized. Time from study 
treatment discontinuation to the first post study treatment anti-cancer therapy will also be 
included in this summary table.  Surgeries and radiotherapies will be added to this 
follow-up table.  A listing of the type of follow-up anti-cancer therapy received 
(chemotherapy, immunotherapy, hormonal therapy, biologic therapy, radioactive therapy, 
small molecule targeted therapy) for each subject will be provided for ACC patients only.  
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. Prior and on-treatment cancer and non-cancer related surgeries will be listed. 
6.7. 
Disease Characteristics 
Disease history and characteristics (time since initial diagnosis in months, stage at initial 
diagnosis, etc.) at screening will be listed. Separate summaries of disease characteristics 
at initial diagnosis and screening will be provided. 


 
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6.8. 
Treatment Compliance 
Compliance will not be reported. However, summaries of study treatment exposure and 
dose modifications (e.g., duration of treatment in months, number of dose reductions, 
number of dose interruptions, number of dose escalations) will characterize exposure. 
These analyses are described in Section 8.1‘Extent of Exposure’. 
7. 
EFFICACY ANALYSES 
All efficacy analyses will be based on the All Treated Population unless otherwise 
specified. Details of data displays are presented in Appendix 12: List of Data Displays. 
Lesion assessment method and timing, evaluation of disease, disease progression and 
response criteria will be conducted according to RECIST 1.1 for subjects with solid 
tumors [Eisenhauer, 2009], standardized Response Assessment in Neuro-Oncology 
(RANO) [Wen, 2010] for subjects with GBM, and Lugano criteria for subjects with NHL 
[Cheson, 2007; Cheson, 2014]. In addition, Part 3 subjects will be assessed according to 
immune-based RECIST (iRECIST) [Seymour, 2017]. The timepoint overall response is 
accessed by the investigator and recorded on the eCRF.   
The following table outlines the response criteria by cohorts or treatment group.  
Table 8 
Response Criteria by Cohort/Treatment Group 
Cohort/Treatment Group   
Response Criteria 
Primary Assessments by 
Part 1 and Part 2, Subjects with solid tumors  
RECIST 1.1 
Investigator 
Part 2, GBM Cohort 
RANO 
Investigator 
Part 2, NHL Cohort 
Lugano  
Investigator 
Part 3 Subjects 
iRECIST 
Investigator 
Abbreviation: RANO = Response Assessment for Neuro-Oncology; RECIST = Response Evaluation Criteria in Solid 
Tumors; GBM= Glioblastoma multiforme; NHL = Non-Hodgkin’s lymphoma. 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Confirmed Overall Response Rate (ORR) based on RECIST 1.1 
for Part 2 (non-GBM, non-NHL) cohorts 
The primary endpoint for all Part 2 cohorts, except GBM, will be overall response rate 
(ORR). The timepoint overall response is assessed by the investigator and recorded on 
the eCRF. The ORR endpoint is defined as % of subjects achieving a best response of CR 
and PR recorded from the start of treatment until disease progression or start of new anti-
cancer therapy, whichever is earlier.  
Best response will be determined programmatically based on investigator assessment at 
each time point.  If there are two assessments, separated by not evaluable (NE) 
assessment(s), the best response shall be assessed applying the algorithm below, 
collapsing data by ignoring NE assessments.  The first assessment may occur before the 
first planned assessment.   


 
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Confirmed responses, as outlined in RECIST 1.1 [Eisenhauer, 2009] will be summarized, 
as appropriate. Confirmation of response may be based on planned and/or unscheduled 
assessments. 
The confirmed overall response rate (ORR) is defined as the ORR as per disease-specific 
criteria (more details in protocol Section 14.4). 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. The best overall response is a subject’s 
best response over the time period referenced. In addition, with respect to best response: 
• 
To be assigned a status of SD, follow-up disease assessment must have met the SD 
criteria at least once after the first dose for a minimum of 49 days.  
• 
If the minimum time for SD is not met, best response will depend on the subsequent 
assessments. For example, if an assessment of PD follows the assessment of SD and 
SD does not meet the minimum time requirement the best response will be PD. 
Alternatively, subjects lost to follow-up after an SD assessment, not meeting the 
minimum time criteria, will be considered not evaluable. 
• 
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.  
The ORR will be summarized with a 2-sided 95% exact confidence interval based on 
the Clopper-Pearson method. The observed confirmed ORR will be reported at the 
interim and final analysis and will be summarized by cohort. 
7.1.2. 
Overall Response Rate (ORR) based on Lugano for Part 2 NHL 
Cohorts 
Overall response confirmation is not needed for assessment according to Lugano criteria 
[Cheson, 2007; Cheson, 2014]. The NHL cohort will only have ORR summarized.  
Timepoint response will be the combined imaging response based on both anatomic and 
metabolic responses according to the following table:  
Table 9 
Overall Response Rate 
Anatomic/Radiologic 
Response  
Metabolic Response  
Combined Imaging 
Response  
CR 
CMR, NE, missing 
CR 
PR 
CMR 
CR 
CR 
PMR 
PR 
CR 
NMR, SMD 
PR 
PR 
PMR 
PR 
PR 
NMR, SMD 
PR 
SD 
PMR 
PR 
PD 
PMR 
PD 
SD 
NMR, SMD 
SD 
CR, PR, SD or NE 
PMD 
PD 


 
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Anatomic/Radiologic 
Response  
Metabolic Response  
Combined Imaging 
Response  
CR, PR, SD or NE 
NE, missing 
CR, PR, SD or NE 
(Anatomic Response) 
PD 
NMR, SMD 
PD 
PD 
PMD 
PD 
PD 
NE, missing 
PD 
CR = complete response; NE = not evaluable; PR = partial response; PD = unconfirmed progressive 
disease; SD = stable disease; SMD = No Metabolic Response.  
7.1.3. 
Progression Free Survival (PFS) for Part 2 GBM cohort 
Progression-free survival (PFS) is defined as the time (in months, interval in months is 
calculated by duration in days/30.4375) from date of first dose date of study drug until 
date of documented disease progression or death due to any cause, whichever comes first.  
The PFS rate at 6 months for Part 2 GBM cohort will be estimated by the Kaplan-Meier 
method. These rates, estimate the proportion of patients who did not progress and were 
alive at month 6. The 95% confidence intervals for the PFS rate at month 6 will be 
estimated using Greenwood's estimate of the standard error (SE) and a log-log 
transformation of the progression-free survival function (Greenwood, 1926). 
A summary of the assignments for progression and censoring dates for PFS is specified in 
the following table:   
Table 10 
Assignments for Progression and Censoring Dates for PFS Analysis 
1. Situation 
1. Date of Event (Progression/ 
Death) or Censoring  
1. Outcome Event 
(Progression/ Death) or 
Censored 
1. No (or inadequate) baseline tumor 
assessments and the subject has not 
died (if the subject has died follow the 
rules for death indicted at the bottom of 
the table) 
2. Start Date of Treatment  
2. Censored 
1. 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) 
3. Start Date of Treatment 
3. Censored 
1. Progression documented between 
scheduled visits 
4. Date of assessment of 
progression1 
4. Event 
1. No progression (or death) or initiation of 
new anti-cancer therapy 
5. Date of last ‘adequate’ 
assessment of response2 
5. Censored 
1. Received subsequent anti-cancer 
therapy prior to the date of documented 
events 
6. Date of last ‘adequate’ 
assessment of respnose2,3 
(prior to initiation of anti-cancer 
therapy) 
6. Censored 
1. Death before first PD assessment (or 
Death at baseline or prior to any 
adequate assessments) 
7. Date of death 
7. Event 


 
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1. Situation 
1. Date of Event (Progression/ 
Death) or Censoring  
1. Outcome Event 
(Progression/ Death) or 
Censored 
1. Death or progression after more than 
one missed visit 
8. Date of last ‘adequate’ 
assessment of response2 (prior 
to missed assessments) 
9. Refer to Section 15.7.2 
8. Censored 
1. 
The earliest of (i) Date of radiological assessment showing new lesion (if progression is based on new lesion); or 
(ii) Date of radiological assessment showing unequivocal progression in non-target lesions, or (iii) Date of last 
radiological assessment of measured lesions (if progression is based on increase in sum of measured lesions) 
2. 
An adequate assessment is defined as an assessment where the Investigator determined response is CR, PR, 
SD, or Non-CR/Non-PD.   
3. 
If PD and new anti-cancer therapy occur on the same day, assume the progression was documented first e.g., 
outcome is ‘progression’ and the date is the date of the assessment of progression). If anti-cancer therapy has 
started prior to any adequate assessments, censoring date should be the start date of treatment. 
7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Confirmed Overall Response Rate (ORR) based on RECIST 1.1 
for Part 1 Cohorts 
Best response will be estimated as described in Section 7.1.1and will be summarized by 
dose levels for Part 1. 
7.2.2. 
Confirmed Overall Response Rate (ORR) based on RANO Criteria 
for Part 2 GBM Cohort 
Best response will be estimated as described in Section 7.1.1 and will be summarized by 
dose levels for Part 1. The RANO criteria will be used to ascertain response (Wen, 2010). 
In comparison to RECIST 1.1 criteria, RANO criteria does not require a minimum of 49 
days to assign as response stable disease (SD). 
7.2.3. 
Confirmed Overall Response Rate (iORR) based on iRECIST for 
Part 3 Cohort 
Overall response rate based on iRECIST (iORR) is defined as the percentage of 
participants with a best overall response (iBOR) of “immune” complete response iCR or 
immune partial response iPR (Seymour, 2017). “Immune” best overall response (iBOR) 
will be summarized by dose levels for Part 3.  The derivation of iBOR per iRECIST will 
be as follows:   
• Progressive disease is “confirmed (iCPD) in the new lesion category, if the next 
imaging assessment, done at 4–8 weeks after iUPD, confirms additional PD, i.e., 
new lesions or a further increase in new lesion size from iUPD (sum of measures 
increase in new lesion target ≥5 mm, any increase for new lesion non-
target)”(Seymour, 2017). 
• iSD, iPR, or iCR can still be assigned if one or more instances of iUPD occurred 
at a previous visit.  However, iCR, iPR, and iSD cannot be assigned if iCPD 
occurred at a previous visit.  


 
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• To be assigned a status of iSD, follow-up disease assessment must have met the 
iSD criteria at least once after the first dose for a minimum of 49 days. 
iBOR takes into account the requirement for confirmation of iCR, iPR, and iPD. If 
iBOR is iUPD and is confirmed consecutively, iBOR will be termed as iCPD.  If 
iBOR is iUPD but not confirmed, there is no subsequent iSD, iPR, or iCR (e.g., NE or 
lost follow-up), the iBOR will be termed as iUPD. If iBOR is iUPD but not 
confirmed and the subject died or discontinued treatment or has initiated new anti-
cancer therapy after this PD assessment, the iBOR will be termed as iCPD. 
Examples of scenarios of assignments of confirmed/unconfirmed iBOR (assuming the 
adjacent timepoints are 28 days apart at least) are provided in the following table: 
 
Table 11 
Examples of iBOR Assignments 
Casea 
Time point 
Response 1 
Time point 
Response 2 
Time point 
Response 3 
Time point 
Response 4 
Time point 
Response 5 
Confirmed 
iBoR 
Unconfirmed 
iBoR 
1 
iCR 
iCR 
iCR,iPR, 
iUPD, or NE 
iUPD 
iCPD 
iCR 
iCR 
2 
iUPD 
iPR, iSD, or 
NE 
iCR 
iCR 
iCR, iPR, iSD, iUPD, 
iCPD, or NE 
iCR 
iCR 
3 
iUPD 
iPR 
iPR, iCR 
iPR, iSD, 
iUPD, NE, or 
iCPD 
iPR, iSD, iUPD, NE, 
or iCPD 
iPR 
iCR 
4 
iUPD 
iSD or NE 
iPR 
iSD 
iSD,iUPD, iCPD, or 
NE 
iSD 
iPR 
5 
iUPD 
iSD 
iSD, iUPD, or 
NE 
iSD, iUPD, 
iCPD, or NE 
iSD, iUPD, iCPD, or 
NE 
iSD 
iSD 
6 
iUPD 
iCPD 
Any 
Any 
Any 
iCPD 
iCPD 
7 
iUPD 
iUPD  
(no iCPD) 
iCPD 
Any 
Any 
iCPD 
iCPD 
8 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
iUPD 
9 
iUPDb 
 
 
 
 
iCPD 
iCPD 
BOR = best overall response; CPD = confirmed progressive disease; CR = complete response; iRECIST = immune Response 
Evaluation Criteria in Solid Tumors; NE = not evaluable; PR = partial response; RECIST = Response Evaluation Criteria in Solid 
Tumors; SD = stable disease; UPD = unconfirmed progressive disease. NOTE: “i” indicates immune responses assigned using the 
iRECIST evaluation criteria 
a   Assume any two adjacent assessments are at least 28 days apart 
b   Last assessment before the subject died/discontinued from treatment  
 
7.2.4. 
Progression Free Survival (PFS) for Part 1, Part 2 (non-GBM), 
Part 3 
Progression-free survival (PFS) will be estimated by cohorts for Part 2 as described in 
Section 7.1.3. RECIST 1.1 criteria will be used for non-NHL cohorts, and Lugano criteria 
for NHL cohorts.  Estimates of 1st quartile survival, median survival, and 3rd quartile 
survival will be presented with 95% confidence intervals based on the Brookmeyer-
Crowley method (Brookmeyer, 1982).D 


 
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7.2.5. 
Lesion Analysis – Parts 1, 2, and 3 
Change/percent change from baseline based on the sum of target lesion diameters will be 
calculated by timepoint for all cohorts except NHL and GBM. Change/percent change from 
baseline based on the sum of target lesion areas will be calculated by timepoint for the 
GBM cohort. The following figures will be produced: 
• Percent change from baseline in target lesions over time (spider plot) – all cohorts 
except NHL. 
• Best change from baseline in target lesions (waterfall plot) – all cohorts except 
NHL. 
• Treatment duration along with the overall response, the best change from baseline 
in target lesions, etc. (swimmer plot). 
7.2.6. 
DOR and TTR for Part 2 ACC TN Cohort based on RECIST 1.1 
Criteria 
Duration of response (DOR) based on RECIST 1.1 for the Part 2 ACC TN cohort will be 
listed and summarized for subjects with a confirmed CR or PR and is defined as the time 
(in months) from first documented evidence of CR or PR until the first documented sign 
of disease progression or death, for the subset of subjects with a confirmed CR or PR.  
Censoring rules will follow those of the PFS analysis. 
If there are a sufficient number of responders who subsequently progress or die due to 
PD, median DoR, first and third quartiles and 95% CI, will be estimated using the 
Brookmeyer-Crowley method (Brookmeyer, 1982).   
Time to response (TTR) is defined as the time from date of first dose to date of first 
documented evidence of PR or CR among participants who achieve a response (i.e. PR or 
CR).  A listing of TTR will be provided for the ACC TN cohort only. 
7.2.7. 
Overall Survival (OS) 
Overall survival (OS) is defined as the interval of time (in months) between the start date 
of treatment and the date of death due to any cause. This will be summarized for the Part 
2 ACC TN cohort and all ACC subjects across Part 1 and Part 2.   
For subjects who are alive, time of death will be censored at the date of last contact. The 
date of death should be taken from the Record of Death eCRF page. Death on study due 
to any cause will be included. Survival will be summarized using the Kaplan-Meier 
method. Estimates of 1st quartile survival, median survival, and 3rd quartile survival will 
be presented with 95% confidence intervals based on the Brookmeyer-Crowley method 
(Brookmeyer, 1982). 
8. 
SAFETY ANALYSES 
Safety analyses will be based on the All Treated Population, unless otherwise specified. 
Details of data displays are presented in Appendix 12: List of Data Displays.  


 
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8.1. 
Primary Safety Analyses 
8.1.1. 
Safety Analyses – Part 1 and Part 3 
8.1.1.1. 
Extent of Exposure 
Extent of exposure to GSK3326595 and pembrolizumab (applies to Part 3 subjects only) 
will be summarized separately. 
The duration of exposure to study treatment in month (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.  
The subject’s average daily dose, defined as the cumulative dose divided by the duration 
of exposure for each subject, will be summarized. Subject’s average daily dose will only 
be calculated for GSK3326595. Number of infusions will be provided for 
pembrolizumab. 
Dose reductions will be summarized by number of reductions and reasons for reductions, 
for GSK3326595 and/or pembrolizumab, where applicable. If there are no reductions, a 
summary will not be provided. Dose interruptions of GSK3326595 will be summarized 
by number of interruptions, reasons for the interruptions, and interruption duration (days). 
The mean, standard deviation, median, minimum value, and maximum value will be 
computed for the duration of interruptions as well as the number and percentage of the 
interruptions 1-5, 6-7, >7 days.   
Dose delays of pembrolizumab will be summarized by number of delays, reasons for 
delay and duration of delay (days). The mean, standard deviation, median, minimum 
value, and maximum value will be computed for the duration of delay as well as the 
number and percentage of the delays 1-5, 6-7, >7 days.  
Dose reductions and interruptions of GSK3326595will be listed separately.   
8.1.1.2. 
Adverse Events 
An overview summary of AEs, including counts and percentages of subjects with any 
AE, AEs related to study treatment, AEs leading to permanent discontinuation of study 
treatment, AEs leading to dose reductions, AEs leading to dose delays/interruptions, 
SAEs, SAEs related to study treatment, fatal SAEs, and fatal SAEs related to study 
treatment will be produced. 
The relationship between MedDRA system organ class (SOC), preferred term (PT), and 
verbatim text will be listed. 
Adverse events (AEs) will be graded according to the CTCAE, Version 4.03, [Basch, 
2014]. Adverse events will be coded to the preferred term (PT) level using the Medical 
Dictionary for Regulatory Affairs (MedDRA dictionary).  


 
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A summary of number and percentage of subjects with any adverse events by maximum 
grade will be produced. AEs will be sorted by preferred term 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. 
• 
Any event row: Each subject with at least one adverse event 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.  
A separate summary will be provided for study treatment-related AEs. 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. The summary table will be displayed in descending order 
of total incidence by PT and by maximum grade sorted by PT in descending order of total 
incidence. 
For Part 3 treatment-related AE, the below 3 sets of tables will be generated by system 
organ class, preferred term, and maximum grade: 
• AEs related to GSK3326595 
• AEs related or pembrolizumab  
• AEs related to GSK3326595 and pembrolizumab 
 
All COVID-19 assessments and symptom assessments for subjects with COVID-19 
adverse events will be summarized based on all recorded AEs.  There will be no separate 
definition of “treatment-emergent” AEs. 
All AEs will be listed. A listing of subject numbers for individual adverse events will be 
provided. 
A listing of adverse events recorded as dose-limiting toxicities for Part 1 subjects will be 
provided. Additionally, a summary of the number of patients experiencing DLTs for Part 
1 subjects will be provided. 
8.1.1.3. 
Deaths and Serious Adverse Events 
In the event that a subject has withdrawn consent, no data after the withdrawal of consent 
date 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 profiles on 
subjects who died.  


 
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All SAEs will be tabulated based on the number and percentage of subjects who 
experienced the event. Separate summaries will also be provided for study treatment-
related SAEs for both GSK3326595 and pembrolizumab where applicable. The 
frequency and percentage of SAEs will be summarized in descending order of total 
incidence by PT only.  
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.  
SAEs are included in the listing of all adverse events. Separate supportive listings with 
subject-level details will be generated for non-fatal SAEs. 
8.1.1.4. 
Adverse Events Leading to Discontinuation of Study Treatment and 
Other Significant Adverse Events 
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 Discontinuation of Study Treatment (note: Part 3 subjects will be 
summarized separately as follows: AEs leading to GSK3326595 discontinuation; 
AEs leading to pembrolizumab discontinuation. Supportive listings will only be 
for GSK3326595). 
• AEs Leading to Dose Interruptions of GSK3326595. 
• AEs Leadings to Dose Reductions of GSK3326595 
8.1.1.5. 
Pregnancies  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE as described in the protocol. If female subjects or female partners of 
male subjects become pregnant while on the study, the information will be included in 
the narratives. 
8.2. 
Secondary Safety Analyses 
8.2.1. 
Safety Analyses – Part 2 
Safety measures described in Section 8.1will comprise a secondary analysis for the Part 2 
cohort and will be summarized and grouped by disease cohort.   
8.2.2. 
Safety Analyses – Part 1 and Part 2 
Safety tables will also be produced as a secondary analysis for all Part 1 and Part 2 
patients combined as follows: 300 mg dose group (combining capsule and tablet cohorts), 
400mg dose group, total RP2P dose group (combining those with 300 and 400 mg), and 
overall group (combining all Part 1 and Part 2 subjects of all dose levels).  Food effect 
sub-study patients will be included with this summary. 


 
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8.3. 
Adverse Events of Special Interest Analyses 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event.  
• 
Selected adverse events include anemia, neutropenia, thrombocytopenia (platelet 
count decrease and thrombocytopenia), and fatigue.  
Summaries of the number and percentage of subjects with these events will be provided 
for each type of events separately. The summary of event characteristics will also be 
provided, including number of subjects with any event, number of events, number of 
subjects with any event that is serious, number of subjects with any event that is related 
to study treatment, the outcome of the event, maximum grade and the action taken for the 
event. The percentage will be calculated in two ways, one with number of subjects with 
event as the denominator and the other with total number of subjects as the denominator. 
The worst-case approach will be applied at subject level for the event outcome and 
maximum grade, i.e., a subject will only be counted once as the worst case from all the 
events experienced by the subject. For action taken to an event, subject will be counted 
once under each action, e.g., if a subject has an event leading to both study treatment 
discontinuation and dose reduction, the subject will be counted once under both actions. 
The onset and duration of the first occurrence of the selected adverse events will be 
summarized. This will include the number of subjects experiencing the event, the time of 
onset of the first occurrence of the event in days from first dose of study treatment, as 
well as the duration of the event in days. 
In addition, summaries of adverse events and serious adverse events by preferred term 
will be provided specifically for bone-related events and ocular events.  
8.4. 
Clinical Laboratory Evaluations 
Laboratory grades will be reported, where applicable, using the Common Terminology 
Criteria for Adverse Events (CTCAE v4.0), [Basch, 2014]. 
Summary of lab values and change from baseline by scheduled visits using mean, 
median, standard deviation, minimum and maximum will be provided. 
Summaries of lab data by maximum toxicity grade will be provided for all the lab tests 
that are gradable by CTCAE v4.0. 
Summaries of worst-case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by CTCAE v4.0. 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. 


 
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For lab tests that are not gradable by CTCAE v4.0, 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 at each 
scheduled visit as well as 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. In addition, 
the summary will include changes from baseline with respect to normal range by 
scheduled visits. 
Separate summary tables for hematology, chemistry, urinalysis, troponin, and coagulation 
laboratory tests will be produced. A supporting listing of laboratory data for participants 
with any value outside the normal range will be provided. Troponin values outside the 
normal range, with value, normal range, abnormal/clinical importance flag will also be 
provided.  
Detailed derivation of baseline assessment is specified in Section 5.2. 
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 specified 
timepoint.  
8.4.1. 
Chemistry 
The laboratory assessment will include the following tests:  
total protein, albumin, sodium, potassium, total calcium, calcium corrected, blood urea 
nitrogen (BUN), creatinine, creatinine clearance, glucose, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin (total), and 
direct bilirubin, amylase, lipase. 
8.4.2. 
Hematology 
The laboratory assessment will include the following tests:  
Hemoglobin (HGB), hematocrit, platelet count, red blood cell (RBC) count, mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), reticulocytes 
(absolute), reticulocytes (%), white blood cell (WBC) count, neutrophils (absolute), 
lymphocytes (absolute), monocytes (absolute), eosinophils (absolute), basophils 
(absolute), neutrophils (%), lymphocytes (%), monocytes (%), eosinophils (%) and 
basophils (%). 
8.4.3. 
Coagulation 
The laboratory assessment will include the following tests:  
Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized 
ratio (INR). Both INR and PTT will be graded. 


 
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8.4.4. 
Urinalysis 
The laboratory assessment will include the following tests:  
pH, microscopic examination, specific gravity, ketones, protein, glucose, blood 
8.4.5. 
Additional Tests 
The laboratory assessments will include the following tests:  
Serum: Troponin I, and troponin T.  There will be a summary for local labs only. 
8.4.6. 
Analysis of Liver Function Tests 
A summary of Hepatobiliary Laboratory Abnormalities will be displayed. The general 
rules are: 
• Categories are for subject counts and percentages, not events. 
• To be counted in the denominator, the subject must have at least one post-baseline 
lab chemistry measurement for the specified lab tests (e.g. in the ‘ALT >3xULN 
and BIL >2xULN’ category, the denominator should include subjects who had 
both a post-baseline ALT value AND a post-baseline BIL value that was up to 28 
days after ALT).  This denominator is the most conservative for reporting 
percentages.  
• Categories are not mutually exclusive.  For example, a subject with ALT 20xULN 
will be included in each of the 3x, 5x, 8x, 10x, and 20x categories. 
• If direct bilirubin is available, on the same day, the direct bilirubin as a portion of 
the total bilirubin must be >35% when total bilirubin is >2xULN. If all criteria for 
Hy’s Law are satisfied except direct bilirubin exists and is <35% then the record 
will not be considered a Hy’s Law event. If total bilirubin value is not provided 
within 28 days on or after ALT value, direct bilirubin cannot be used in place of 
total bilirubin in the Hy’s law criteria. 
• Hepatocellular injury is defined as ((ALT/ALT ULN)/ (ALP/ALP ULN)) >5 and 
ALT >3xULN. ALT and ALP values must occur on the same day. The 
denominator should include subjects who had both a post-baseline ALT and ALP 
on the same day.  In addition, the denominator for Hepatocellular injury and BIL 
>2xULN should include subjects who had both a post-baseline ALT and ALP on 
the same day as well as BIL on or up to 28 days of that day.  
8.5. 
Other Safety Measures 
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. 
8.5.1. 
Vital Signs 
Change from baseline in vital signs will be summarized by scheduled visit using mean, 
median, standard deviation, minimum and maximum.  


 
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Summaries of increase in systolic blood pressure and diastolic blood pressure from the 
baseline with respect to the categories defined in Section 15.8.3will be performed. These 
summaries will display the number and percentage of subjects with any grade increase, 
increase to grade 2 and increase to grade 3 at each scheduled assessment time and in the 
worst-case post-baseline. Subjects with missing baseline value are to be assumed to have 
grade 0. 
Summaries of changes in heart rate and temperature from the baseline value with respect  
to the categories defined in Section 15.8.3 will be performed.  For heart rate and  
temperature, both an increase and decrease in value are of clinical concern. Subjects with 
missing baseline value are to be assumed to have normal baseline. 
The determination of the worst-case post baseline takes into account both planned and 
unscheduled assessments.  The percentages are based on the number of subjects in the 
treatment group with data for the vital sign parameter at the specified planned time.   
 
A supporting listing will also be provided. 
8.5.2. 
Performance Status 
ECOG performance status [Oken, 1982] will be summarized at baseline and each post-
baseline scheduled visit. Summaries will use frequency and percentage of subjects at 
each planned assessment time. A summary of change from baseline by scheduled visits 
will be performed.  
8.5.3. 
ECG 
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 (including unscheduled 
assessments). When more than one ECG is performed during a ‘Time Period’ or when 
there are multiple values used to determine ‘Worst Case Post-Baseline’, the following 
rules will be used to determine the worst case finding based on the interpretation and the 
clinical significance: 
• Count the subject as ‘ABNORMAL’ and ‘CLINICALLY SIGNIFICANT’, if any 
of the findings are ‘ABNORMAL’ and ‘CLINICALLY SIGNIFICANT’ during 
the time period/Post-Baseline.   
• Else count the subject as ‘ABNORMAL’ and ‘NOT CLINICALLY 
SIGNIFICANT’, if any of the findings are ‘ABNORMAL’ and ‘NOT 
CLINICALLY SIGNIFICANT’ and none of the findings are ‘ABNORMAL’ and 
‘CLINICALLY SIGNIFICANT’ during the time period/Post-Baseline.  
• Else count the subject as ‘NORMAL’ if there is a finding of ‘NORMAL’ and 
none of the findings are ‘ABNORMAL during the time period/Post-Baseline.  
• Otherwise, do not count the subject during the time period/Post-Baseline, i.e. little 
n will reflect that the subject is not counted in the time period/Post-Baseline. 
The QTc values based on Fridericia formula will be rounded to the integer and the values 
will be categorized into the ranges identified in Section 15.8.2. Summaries of grade 


 
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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 at each 
scheduled assessment time and in the worst-case post-baseline (including unscheduled 
assessments). For grade increase summaries, missing baseline values will be assumed to 
be grade 0. For triplicate values, grades associated with the highest value will be 
reported. 
The changes in QTc values will be categorized into the clinical concern ranges which are 
specific to changes in QTc: 31-60 and >60 msec. A summary of change in QTc value will 
display the number and percentage of subjects with the worst-case post-baseline 
(including unscheduled assessments). For numerical values measured in triplicate, 
averages at each visit will be used for this analysis.  
Listings of all ECG values will be provided. 
8.5.4. 
LVEF 
Absolute change from baseline in LVEF will be summarized at each scheduled 
assessment time and in the worst-case post-baseline. Only the post-baseline assessments 
that used the same method (ECHO or MUGA) as the baseline assessments will be used to 
derive the change from baseline. The change from baseline will be categorized as 
identified in Section 15.8.4.  
8.5.5. 
Liver Events 
For any liver events that occur during the study, the liver event information for Roussel 
Uclaf Causality Assessment Method (RUCAM) score will be summarized, including 
whether the subject was age 55 or over, whether the subject became pregnant, liver 
imaging normal or not, a biopsy was taken or not, whether there was fasting or significant 
dietary change, whether the subject took any unconventional medications, timing when 
the event occurs (while on treatment or after stopping treatment) and listings will be 
provided for time from first dose to start of liver event and time from last dose to start of 
liver event.  
For subjects with multiple events, the first event will be used for the summary tables. All 
events with subject level details will be displayed in a supporting listing. 
8.5.6. 
DEXA Bone Densitometry 
A listing of DEXA bone densitometry data from local labs will be provided for all 
subjects. These will include scan region and assessment, site, planned time, date, study 
day, BMD in g/cm2, Z-scores, T-scores, and institution assessment.  A summary of bone 
mineral density shifts from baseline relative to normal range will also be provided. 
8.5.7. 
Ophthalmic Assessments 
Listings of optical coherence tomography from local lab results with age/sex/race, date, 
study day, machine type, and left and right eye results in microns will be provided.  In 


 
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addition, a listing of best corrected visual acuity (Snellen Acuity Equivalent) results will 
also be provided. 
9. 
PHARMACOKINETIC ANALYSES 
The pharmacokinetic (PK) analyses will be based on the Pharmacokinetic Population, 
unless otherwise specified. 
Table 12 
 provides an overview of the planned analyses, with full details being 
presented in Appendix 12: List of Data Displays. 
Table 12 
Overview of Planned Pharmacokinetic Analyses 
Endpoint / 
Parameter/ Display 
Type 
Untransformed 
Log-Transformed 
Stats 
Analysis 
Summar
y 
Individu
al 
Stats 
Analysis 
Summar
y 
Individu
al 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Drug Concentration  
Plasma or Urine 
Pharmacokinetic 
Concentration 
 
 
 
  Y 
Y 
Y 
Y 
 
 
 
 
 
 
 
Pharmacokinetic Parameters 
Plasma or Urine 
Pharmacokinetic 
Parameters 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Dose proportionality analysis 
Food effect study 
Relative Bio-availability study 
1. NOTES : 
• 
T = Table, F = Figure, L = Listings, Y = Display generated 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.     
9.1. 
Drug Concentration Measures 
PK analysis of GSK3326595 and pembrolizumab (apply to Part 3 subjects only) drug 
concentration-time data will be conducted by non-compartmental methods under the 
direction of GSK CPMS.  
Drug concentration-time data will be listed for each subject and summarized by 
descriptive statistics at each time point. Summary tables/figures will use planned relative 
time on x-axis; while individual figures will use actual time after dose on x-axis.  
9.2. 
Pharmacokinetic Parameters 
9.2.1. 
Deriving Pharmacokinetic Parameters 
• Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 
15.5.2 Reporting Process & Standards for Pharmacokinetic). 


 
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• The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices [SOP_314000 and GUI_51487] and 
using Phoenix winnonlin. 
• All calculations of non-compartmental parameters will be based on actual sampling 
times. 
• Pharmacokinetic parameters described in Table 13 will be determined from the 
plasma concentration-time data, as data permits. 
Table 13 
Derived Pharmacokinetic Parameters 
Parameter Parameter Description 
AUC(0-t) 
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) will be calculated using the linear trapezoidal rule 
for each incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid. 
AUC(0-∞) Area under the concentration-time curve extrapolated to infinity will be calculated 
as:  
AUC = AUC(0-t) + C(t) / lambda_z 
AUC(0-τ) 
Area under the concentration-time curve from time zero to the predose of the next 
dose. For BID administration, AUC (0-12) will be computed 
Cmax 
Maximum observed plasma concentration, determined directly from the 
concentration-time data. 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
t½ 
Apparent terminal half-life will be calculated as:  
t½ = ln2 / lambda_z 
CL/F 
Oral clearance 
TI 
time invariance will be calculated as: 
• 
𝑇𝐼=
𝐴𝑈𝐶(0−𝜏),𝐷𝑎𝑦 15
𝐴𝑈𝐶(0−∞),𝐷𝑎𝑦 1 
AR 
accumulation ratio will be calculated as: 
• 
AR =
𝐴𝑈𝐶(0−𝜏),𝐷𝑎𝑦 15
𝐴𝑈𝐶(0−𝜏),𝐷𝑎𝑦 1  
1. NOTES: 
• 
Additional parameters may be included as required. 
• 
Lambda_z is the terminal phase rate constant. 
 
GSK3326595 concentrations will be determined in urine samples to determine urinary 
recovery of unchanged drug and renal clearance.  
 
Urinary Recovery: The urinary recovery of unchanged drug in a complete collection up 
to a fixed time point (Ae(0-x)), over a dosing interval (Ae(0- τ)), or up to the time of the 
last measurable urinary concentration when concentrations in subsequent collections are 
non-quantifiable (Ae(0-∞)), will be calculated as the sum of the products of  
concentration and urine volume over the appropriate collection intervals. 
 
Urinary Excretion Rate: The urinary (renal) excretion rate of unchanged drug may be 
calculated based on urine collection over a specified time interval. In situations when 


 
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plasma drug concentrations are non-quantifiable, the estimation of elimination rate 
constant and elimination half-life of a drug can be made by analyzing urinary excretion 
rate data. 
 
Renal Clearance: Renal clearance will be calculated from the ratio of the appropriate 
values for urinary recovery and area under the concentration-time curve e.g., 
𝐶𝐿𝑟= 𝐴𝑒(0 −𝑥)
𝐴𝑈𝐶(0 −𝑥) 
9.2.2. 
Statistical Analysis of Pharmacokinetic Parameters 
Plasma concentration-time data will be listed by dose, age group, and summarized using 
descriptive statistics (median, minimum, maximum, arithmetic mean, 95% confidence 
interval for the arithmetic mean, standard deviation, coefficient of variation (CV = √ 
(exp(SD2) - 1) * 100 [NOTE: SD = SD of log transformed data]), geometric mean, 95% 
confidence interval for the geometric mean and standard deviation of logarithmically 
transformed data) by planned relative assessment time. Mean and/ or median values will 
be plotted over time. For tmax the following summary statistics will be calculated for 
each dose level, median, maximum, minimum, arithmetic mean, 95% confidence interval, 
and standard deviation will be calculated.  
Individual plasma pharmacokinetic parameters values as well as a descriptive summary 
(median, minimum, maximum, arithmetic mean, 95% confidence interval for the 
arithmetic mean, standard deviation, coefficient of variation (CV = √ (exp(SD2) - 1) * 
100 [NOTE: SD = SD of log transformed data]), geometric mean, 95% confidence 
interval for the geometric mean and standard deviation of logarithmically transformed 
data) by dose cohort and age group will be reported. All PK parameters will be reported 
to at least 3 significant digits, but to no more significant digits than the precision of the 
original data. 
All PK parameters and concentration summaries will be reported to at least 3 significant 
digits, but to no more significant digits than the precision of the original data. 
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles).  
9.2.2.1. 
Dose-Proportionality Analysis for Part 1 Dose Escalation Subjects 
Dose proportionality analysis will be done for QD doses and BID doses separately. A 
minimum of 3 values per dose must be available for a given parameter to estimate dose 
proportionality with the power model. 
Dose proportionality of log-transformed parameters AUC(0-∞) (or if not available 
AUC(0-t)) and Cmax will be assessed using the power model for, as described below: 
 
y = α * dose 
 
where y denotes the PK parameter being analysed and α depends on subject and error.  
 


 
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Dose proportionality implies that β=1 and will be assessed by estimating β along with its 
confidence interval. The exponent, β, in the power model will be estimated by regressing 
the loge-transformed parameter on loge-transformed dose: 
 
ln(y) = ln(α) + β ∗ ln(dose) 
 
The power model will be fitted by restricted maximum likelihood (REML), for every 
dose level (treatment) with minimum 3 values. Both the intercept and slope will be fitted 
as random effects. The following SAS code will be used: 
 
proc mixed data = DSETIN; 
 
class subject; 
 
model LNVAR=LNdose / solution alpha=0.1 outp=pred ddfm=kr; 
 
random intercept / type=UN subject=subject; 
ods output solutionf=solutionf; 
run; 
 
Point estimates for the slopes of PK parameters with associated CIs will be presented.  
 
If this model fails to converge, the model will be refitted with slope as a fixed effect.  
 
If the log transformed models are not proportional and sufficient data are available, loge- 
transformed dose-normalised AUC(0-∞) (or if not available AUC(0-t)) and Cmax will be 
analysed using a suitable mixed effects model, fitting treatment as a fixed effect and 
subject as a random effect. Point estimates and corresponding 90% confidence intervals 
for the ratios of each dose level to the reference dose level 1 will be determined using 
code similar to that outlined above. 
 
proc mixed data = DSETIN; 
 
class subject treatment; 
 
model LN(VAR/dose) = dose / ddfm=KR outp=pred_cmax;  
      id dose usubjid; 
      random usubjid; 
      lsmeans dose; 
 
      estimate “DL2 vs DL1” treatment 1 0 0 0 0 0 0 -1 /cl alpha=0.1 e; 
estimate “DL3 vs DL1” treatment 0 1 0 0 0 0 0 -1 /cl alpha=0.1 e; 
estimate “DL4 vs DL1” treatment 0 0 1 0 0 0 0 -1 /cl alpha=0.1 e; 
estimate “DL5 vs DL1” treatment 0 0 0 1 0 0 0 -1 /cl alpha=0.1 e; 
estimate “DL6 vs DL1” treatment 0 0 0 0 1 0 0 -1 /cl alpha=0.1 e; 
estimate “DL7 vs DL1” treatment 0 0 0 0 0 1 0 -1 /cl alpha=0.1 e; 
estimate “DL8 vs DL1” treatment 0 0 0 0 0 0 1 -1 /cl alpha=0.1 e; 
lsmeans treatment; 
ods output estimates=estimates lsmeans=lsmeans; 
run; 
 
The back-transformed estimate and 90% CI will be presented. 
9.2.2.2. 
Food Effect and Relative Bioavailability Sub-Study 
Estimates of LS mean, LS mean difference and 95% CI are based on log transformed 
AUC(0-INF) and Cmax using a mixed-effect model with fixed-effect terms of fed status 
(fed or fasted), sequence and period and subject within sequence as a random effect. The 


 
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point estimates and their associated 90% CIs were then backtransformed to provide point 
estimates of the geometric LS mean, and 90% CIs and ratios of fed (test) vs. fasted 
(reference). 
Programming note: Only use period 1 and period 2 data 
 
ods output LSMeans=lsmean;  
ods output estimates=estg; 
ods output CovParms=Covsparms; 
 
 proc mixed data=pkparm1;  
       class sequence period  treat subjid; 
       model Lcmax=sequence period treat/ DDFM=SATTERTH;  
       random subjid(sequence);  
       lsmeans treat/pdiff cl alpha=0.1;  
      estimate 'Tablet Fed vs Tablet Fasted' treat 1 -1 / cl alpha=0.1;  
 run;  
 
Where TREAT: FET = Tablet Fed; FFT = Tablet Fasted.  
  
 * Anti-log transformation to obtain the Geometric Means; 
 data glsmean;  
       set lsmean;  
       gmean=exp(estimate); *Geometric means;  
 run;  
 
 * Anti-log transformation to obtain the ratio of Geometric Means (point estimate) and its 
90% confidence interval (lower and upper bounds);  
 data diffs;  
      set EST;  
      gratio=exp(estimate); ** Ratio of geometric mean;  
      glower=exp(lower); ** 90% CI lower bound;  
      gupper=exp(upper); ** 90% CI upper bound;  
 run;  
 
 
**Calculate inter-subject CV and intra-subject CV; 
DATA CV; 
 set Covsparms; 
 if covparm="subjid(sequence)" then intermse=estimate; 
 else if covparm="Residual" then intramse=estimate; 
 intercv = sqrt(exp(intermse) -1) *100; 
 intracv = sqrt(exp(intramse) -1) *100; 
run; 
 “ 
 


 
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Non-parametric methods such as the Hodges and Lehmann estimator (Hodges, 1963) will 
be used to estimate the median differences between the fed treatments and the fasted state 
treatments for tmax and t½. An associated 90% CI for the median differences will be 
constructed. The analysis will exclude data for a given period if the subject did not 
receive the correct dose or formulation during that period or the protocol-defined diet was 
not adhered to.  
Based on the US FDA guidance on food-effect bioavailability studies, the absence of a 
food-effect will be established if the 90% CI of the ratio for Cmax and AUC, based on 
log-transformed data, is within the 80 to 125% equivalence limit. Recommendation on 
the clinical significance of the effect of food will be based on the magnitude of the 
change and our understanding of the exposure-clinical response relationship.  
For the evaluation of food effect, tmax at fed and fasted status will be presented by 
subject and dose cohort in tabular and graphical form. 
Relative Bioavailability of Tablet 
Pharmacokinetic (PK) parameters AUC0-∞ (or if not available AUC(0-t)) and Cmax will 
be log-transformed and analyzed using a mixed-effects model with formulation (tablet or 
capsule)sequence and period as fixed effects, and subject as a random effect. Point 
estimates and their associated 90% CIs will be constructed for the differences between 
between tablet and capsule. The point estimates and their associated 90% CIs will then be 
back transformed to provide point estimates and 90% CIs for the ratios of tablet (test) vs. 
capsule (reference) under fasted condition.  
Code will be consistent with the above for food effect analysis. The analysis will exclude 
data for a given period if the subject did not receive the correct dose or formulation 
during that period.  
10. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
Population pharmacokinetic analyses will be conducted under the direction of CPMS, 
Quantitative Sciences, GSK.  The data from this study may be combined with the data 
from other studies for a population PK analysis, which will be reported separately. 
11. 
PHARMACODYNAMIC (AND/OR BIOMARKER) 
ANALYSES 
Pharmacodynamic and biomarker analyses are not within the scope of this reporting and 
analysis plan.  Any planned analyses will be described in a separate document. 
12. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
Further exploratory pharmacokinetic/pharmacodynamic analyses are not within the scope 
of this SAP.  Any planned analyses will be described in a separate document. 


 
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13. 
ADDITIONAL ANALYSES DUE TO THE COVID-19 
PANDEMIC 
A summary of the frequency and percent of subjects with Covid-19 case diagnosis will be 
provided, along with number of case diagnosis events, and subjects with multiple events.  
Also provided will be the following: the frequency and percent of subjects with worst 
case diagnosis of confirmed, probably, or suspected case diagnosis, as well as frequency 
and percent of those tested, and the results of the testing, based on number of tests 
performed.  


 
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14. 
REFERENCES 
Basch E, Reeve BB, Mitchell SA, Clauser SB, Minasian LM, Dueck AC, et al. 
Development of the National Cancer Institute's patient-reported outcomes version of the 
common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst. 
2014;106(9):1-11.  
Berry SM, Broglioa KR, Groshenb S, Berry DA. Bayesian hierarchical modeling of 
patient subpopulations: Efficient designs of Phase II oncology clinical trials Clinical 
Trials. 2013; 10: 720–734.  
Brookmeyer, R., Crowley, JA. Confidence Interval for the Median Survival Time. 
Biometrics 1982; 38(1): 29–41. 
 
Cheson B, Pfister B, Juweid M, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol. 2007; 25:579-586.  
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin 
and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-
68.  
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New 
response evaluation criteria in solid tumours:  Revised RECIST guidelines (Version 1.1).  
Euro J Cancer. 2009;45:228-247. 
Escobar MD, West M. Bayesian Density Estimation and Inference Using Mixtures. J of 
American Statistical Association. 1995; 90 (430): 577-588.  
Greenwood M. A report on the natural duration of cancer. In: Reports on public health 
and medical subjects, vol. 33. His Majesty’s Stationery Office: London; 1926. p. 1–26. 
Hodges, J. L.; Lehmann, E. L. (1963). "Estimation of location based on ranks". Annals of 
Mathematical Statistics. 34 (2): 598–611. 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials 2008: 5. 93–106.  
Neal RM. Markov Chain Sampling Methods for Dirichlet Process Mixture Models. J of 
Computational and Graphical Statistics. 2000; 9 (2): 249-265.  
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982; 5: 649-655.  
Sethuraman J. A Constructive Definition of Dirichlet Priors. Statistica Sinica. 1994; 4: 
639-650. 


 
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Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 
2017; 18: e143-52.   
Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical 
Trials. 1989; 10:1-10.  
The EuroQol Group. EuroQol-a new facility for the measurement of health-related 
quality of life. Health Policy 1990, 16(3):199-208  
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E,  et-al. 
Updated response assessment criteria for high-grade gliomas: response assessment in 
neuro-oncology working group. J. Clin. Oncol. 2010; 28 (11): 1963-72.  
 
 


 
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15. 
APPENDICES 
15.1. 
Appendix 1: Exclusions from Per Protocol Population 
A per-protocol population for this study is not defined and not planned.  


 
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15.2. 
Appendix 2: Schedule of Activities 
Refer to protocol for schedule of events. 


 
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15.3. 
Appendix 3: Assessment Windows 
15.3.1. 
Definitions of Assessment Windows for Analyses 
Visit collected in the data will be used for the analysis and no visit window assigned for 
the study. Tumor response measurements from unscheduled visits will be included as 
well as most extreme result reporting (e.g. worst grade post-baseline). 
 
 


 
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15.4. 
Appendix 4: Study Phases 
15.4.1. 
Study Phases for Treatment 
Assessments and events will be classified according to the time of occurrence relative to 
first dose of study treatment. 
Treatment 
Phase 
Definition 
Pre-therapy 
Time prior to the subject’s first dose of study treatment. 
On-therapy 
Time from first dose of study treatment to the last dose date of study treatment + 
30 days. 
Post-therapy 
Time beyond the on-therapy period 
 
15.4.2. 
Study Phases for Concomitant Medication and Blood and Blood 
Supportive Care Products 
Concomitant medication and blood and blood supportive product start and end dates will 
be assigned to study time periods in relation to first dose of study treatment as defined 
below. The start date references time flag variables and end date reference time flag 
variables will be added to the concomitant medications and blood and blood supportive 
products datasets, respectively. 
15.4.2.1. 
Start Date Relative to Treatment: 
Treatment 
State 
Definition 
Before  
 Start Date < Study Treatment Start Date  
OR 
Study Treatment Start Date is missing (i.e., subject has not taken any study 
treatment) 
OR 
Start Date is missing and Stop Date < Study Treatment Start Date 
During  
Study Treatment Start Date <=Start Date < Study Treatment Stop Date + 30 
days 
OR 
Study Treatment Stop Date is missing 
OR 
 Start Date is missing and Stop Date >= Study Treatment Start Date 
After  
Start Date > Study Treatment Stop Date + 30 days 


 
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15.4.2.2. 
Stop Date Relative to Treatment: 
Treatment State Definition 
Before  
 Stop Date < Study Treatment Start Date  
OR 
Study Treatment Start Date is missing (i.e., subject has not taken any study 
treatment) 
During  
Study Treatment Start Date <=Stop Date < Study Treatment Stop Date + 30 
days 
OR 
Study Treatment Stop Date is missing 
OR 
 End Date is missing and Start Date relative to treatment is not “After” 
After  
Start Date > Study Treatment Stop Date + 30 days 
OR 
End Date is missing and Start Date relative to treatment='AFTER' 
15.4.2.3. 
Blood and Blood Supportive Care Products 
Only on-therapy blood and blood supportive care products that start after the start of 
study treatment are included in the Blood Products and Blood Supportive Care Product 
summaries. Therefore, for summary tables, include blood and blood supportive care 
product records where start relative to treatment in ('DURING') and end relative to 
treatment in ('DURING','AFTER'). All data will be reported in listings.  
15.4.2.4. 
Summary of Concomitant Medication 
Concomitant medication start relative to treatment and end relative to treatment flags are 
used to select data to include in the concomitant medication summaries as follows: 
o Summary of Concomitant Medications: This summary will contain 
medications including those with start date prior to study treatment start and 
continue (missing end date or end date after study treatment start date) on 
therapy. Note that any medications with start date and end date prior to study 
treatment start date will be excluded. In addition, any medication that was 
started during post-therapy will be excluded. Include concomitant medication 
records where start relative to treatment in ('BEFORE','DURING') and end 
relative to treatment in ('DURING','AFTER'). 
 
 


 
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15.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
15.5.1. 
Reporting Process 
Software 
• The currently supported versions of SAS software 9.3 or higher version will be used. 
Reporting Area 
HARP Server 
: [Insert Server] 
HARP Area 
: [Insert Area & Reporting Effort] 
QC Spreadsheet 
: [Insert Location] 
Analysis Datasets  
• Analysis datasets will be created according to CDISC/ADaM standards. 
• For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets 
will be implemented for conversion from SI to SDTM. 
Generation of RTF Files 
• RTF files will be generated for all analyses. 
15.5.2. 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, 
unless otherwise stated: 
• 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 
• All data will be reported according with the All Treated Population, according to the 
actual treatment the subject received unless otherwise stated. 
• 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. 
• 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. 
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses : 
• Planned time relative to dosing will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated. 
• 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:  
• Planned and actual time relative to study drug dosing will be shown in listings 
(Refer to IDSL Statistical Principle 5.05.1). 
Unscheduled Visits 
• Unscheduled visits will not be included in summary tables except for most extreme 
result reporting (e.g. worst grade post-baseline), as well as tumor assessments. 


 
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• Unscheduled visits will not be included in figures except for tumor assessments. 
• All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
1. Continuous Data 1. Refer to IDSL Statistical Principle 6.06.1 
1. Categorical Data 2. N, n, frequency, % 
15.5.3. 
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 VQD-SOP-005939. 
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, Ctrough, AUC0-t, AUC0-tau, AUCinf, t½, λz , TI, AR, C12 or C24, 
Ae(0-x) or Ae(0-∞), CLr 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
 
No.  
 
Descriptive 
Summary 
Statistics, 
Graphical Displays 
and Listings 
Refer to IDSL PK Display Standards. 
Refer to GSK Data Standards and statistical principles 
 
 
 


 
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15.6. 
Appendix 6: Derived and Transformed Data 
15.6.1. 
General 
Multiple Measurements at One Time Point 
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 most extreme result (e.g. worst grade post-baseline). 
If multiple assessments on different days are reported for the same scheduled assessment, then the 
latest assessment for that scheduled assessment will be analyzed. 
If multiple assessments are reported on the same date for the same scheduled planned time, then the 
worst-case result will be analyzed, with the exception of laboratory data reported from both central and 
local laboratories.  
ECG values will be measured in triplicate: 3 assessments are collected for each scheduled planned time, 
the first 3 measures will be used to compute the mean values for ECG intervals at each scheduled 
planned time. For qualitative ECG measures (Normal, Abnormal, Not Clinically Significant, Abnormal, 
Clinically Significant) and QTcF grade, the most clinically significant value (highest grade) will be 
summarized. 
Subjects having both High and Low values for Normal Ranges at any post-baseline visits for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables.  
Data from all assessments (scheduled and unscheduled), including multiple assessments, will be 
included in listings.  
Study Day 
Reference Dates 
Unless otherwise stated, the safety reference (start) date will be the start of treatment of GSK3326595.  
This will also be the efficacy reference date for this study.  The reference date for baseline 
characteristics (e.g. age) will be the date of screening. 
Study Day for Safety Measures/Efficacy 
If the date of interest occurs on or after the safety/efficacy reference date then the safety/efficacy study 
day will be calculated as (date of interest – safety/efficacy reference date) + 1.  If the date of interest 
occurs before the safety/efficacy reference date then the safety study day will be calculated as (date of 
interest-safety/efficacy reference date). There is no safety/efficacy study day 0.  
Duration of Elapsed Time 
Durations (e.g., the duration of an AE, duration of exposure, etc.) are calculated as the stop date minus 
the start date plus one. 
For elapsed time (e.g., the time since initial diagnosis): 
If the reference date is on or after the event date, then the elapsed time is the reference date minus the 
event date + 1. 
If the reference date is before the event date then the elapsed time is the reference date minus the event 
date. 


 
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When reporting time to event (TTE) durations 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. These 
algorithms for time to event return decimal numbers, and ignore the actual numbers of days in the 
months or years between start date and stop date. The "year" used in these algorithms is 365.25 days 
long, and the "month" is one twelfth of that year. 
For converting all other durations (e.g., duration of adverse events, duration of exposure, age) to weeks, 
months or years use the following: 
To report the duration in weeks, divide the number of days by 7. 
To report the duration in months, use: 
(YEAR(stopdate + 1) - YEAR(startdate)) * 12 + (MONTH(stopdate + 1) - MONTH(startdate) - 1) + 
(DAY(stopdate + 1) > = DAY(startdate)) 
To report the duration in years use: 
INTCK('year', startdate, stopdate + 1) - (MONTH(stopdate + 1) < MONTH(startdate) or 
(MONTH(stopdate + 1) = MONTH(startdate) and DAY(stopdate + 1) < DAY(startdate))) 
The algorithms above for age and duration return whole numbers for months and years, accurately 
accounting for the actual numbers of days in the months or years between the start date and the stop 
date. 
15.6.2. 
Study Population 
Demographics 
Age 
• GSK standard IDSL algorithms will be used for calculating age where birth date will be 
imputed as follows: 
• Any subject with a missing day will have this imputed as day ‘15’.  
• Any subject with a missing date and month will have this imputed as ‘30th June’. 
• Birth date will be presented in listings as ‘YYYY’. 
Body Mass Index (BMI) 
• Calculated as Weight (kg) / [Height (m)2 
Extent of Exposure 
GSK3326595 
• 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 
• Participants who were randomized but did not report a treatment start date will be 
categorised as having zero days of exposure.  
• The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Number of Days x Total Daily Dose) 
If there are any treatment breaks during the study, exposure data will be adjusted accordingly. 
• Pembrolizumab 
o Extent of exposure will be calculated based on treatment cycles derived based 
on cycle start dates in the exposure dataset 
o Duration on study treatment will be calculated based on the formula: 


 
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Duration on study treatment = Last Treatment Stop Date – First Treatment Start Date + [lag 
time, e.g., Duration of Cycle] 
Take into account of death date if a lag time>1, e.g., Duration of Cycle is used. 
• Participants who were randomized but did not report a treatment start date will be 
categorised as having zero days of exposure.  
• Combination Treatments (Part 3) 
• Extent of exposure will be calculated for each treatment component 
• Duration of treatment will be calculated based on the formula: 
Duration on study treatment = Maximum of ([IV Treatment Stop Date + lag time], [Oral 
Treatment Stop Date]) – (Minimum of Treatment Start Date) + 1 
Take into account of death date if a lag time>1, e.g., Duration of Cycle is used. 
• Participants who were randomized but did not report a treatment start date will be 
categorized as having zero days of exposure 
Actual Treatment 
• Subject’s actual treatment will be derived from [exposure data] [study treatment data 
provided by Clinical Operations]. If a subject’s actual treatment is the same as assigned 
treatment, actual treatment is the assigned treatment; if a subject received treatment 
different from assigned treatment for the entire duration of treatment, actual treatment is 
different from assigned treatment. 
15.6.3. 
Efficacy 
Change from Baseline 
Change from Baseline = Post-Baseline Visit Value – Baseline 
% Change from Baseline= 100 x (Post-Baseline Visit Value – Baseline) / Baseline 
Maximum Decrease from Baseline = maximum (Decrease from Baseline) prior to disease progression 
If either the Baseline or Post-Baseline Visit Value is missing, Change from Baseline and % Change from Baseline 
is set to missing 
Date of Response 
For post-baseline disease assessments, the date of response (PR or better) is assigned to the latest date of 
disease assessments; for other response categories ([MR,] SD [or Non-CR/Non-PD], NE, PD), the date of 
response is assigned to the earliest date of disease assessments. 
For the BOR, if BOR is SD, the latest date of SD is assigned to the date of BOR.  If for other BOR responses, the 
earliest date of that response will be assigned as the date of BOR.  
Date of New Anti-Cancer Therapy 
Derived as the earliest date of new anti-cancer therapy, radiotherapy (where applicable) or cancer-
related surgical procedure (where applicable) 
Missing or partial dates will be imputed for derivation of new anti-cancer therapy following rules specified 
in Section 15.7.3.3. 


 
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15.6.4. 
Safety 
ECG Parameters 
Corrected QT Intervals 
• The QTc is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF; defined as [QT/(RR1/3)]).  
15.6.5. 
Pharmacokinetic 
See Section 9.2.1for descriptions of derived PK parameters. 
15.6.6. 
Pharmacodynamic (and / or Biomarker) 
Pharmacodynamic analyses are not within the scope of this analysis plan. 
 


 
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15.7. 
Appendix 7: Reporting Standards for Missing Data 
15.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
A subject who is not treated with the RP2D will be considered to have completed the 
study if: 
o they complete screening assessments, at least 21 days of study treatment and the 
post-treatment follow-up visit, or 
o they discontinue study treatment for progression or reasons listed in Protocol 
Section 5.4 
• 
A subject who is treated at RP2D will be considered to have completed the study if: 
o they discontinue study treatment for reasons listed in Protocol Section 5.4, or 
o they die while receiving study treatment, or 
o are receiving ongoing study treatment at the time of the Sponsor’s decision to close 
the study. 
• 
The end of the study is defined as the completion of all cohorts as defined in Protocol 
Section 5.4, or termination of the study at any time by the Sponsor. 
• 
Subjects who have not died and are no longer being followed for survival are 
considered to have discontinued the study.  The End of Study eCRF should only be 
completed when a subject is no longer being followed.  The study may be considered 
completed for purposes of a final analysis when 70% of subjects enrolled in Part 2 or 
Part 3 (whichever is latest) have progressed or died.  If available, subjects continuing on 
treatment at the time of final analysis may be offered the option to continue in a rollover 
trial.  
15.7.2. 
 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. 
• Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument Subjects with the designation of treatment relationship for 
adverse events (AE)s and serious adverse events (SAEs) missing will have the worst 
case assumed to impute the relationship: if relationship to study treatment is missing it 
will be assumed to be “Yes”. There will be no other imputation for missing data other 
than what’s described in Section 15.4.2. for partial dates and for missing exposure end 
dates. 
Outliers 
• Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
Responder 
Analysis  
• For endpoints which determine the percentage of responders, subjects with 
unknown/not evaluable or missing best overall response will be assumed to be 


 
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Element 
Reporting Detail 
non-responders, and will be included in the denominator when calculating the 
percentages. 
15.7.3. 
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 or for specific 
analysis purposes as outlined below. 
• Imputed partial dates will not be used to derive study day, duration (e.g., 
duration of adverse events), or elapsed time variables (e.g., time since 
diagnosis). In addition, imputed dates are not used for deriving the last 
contact date in overall survival analysis dataset. 
• With the exception of new anti-cancer therapy start date in the time to 
event analysis dataset and exposure end date in the exposure analysis 
dataset, imputed dates will not be stored on datasets. 
 
Details on imputing partial dates for specific datasets are outlined below. 
15.7.3.1. 
Adverse Events (AE): 
Imputations in the adverse events dataset are used for slotting events to the appropriate 
study time periods and for sorting in data listings. 
Dataset Date Missing 
Element 
Rule 
Adverse 
Events 
(AE) 
Start 
Date 
day, 
month, 
and year 
No Imputation for completely missing dates 
 
 
day, 
month 
If study treatment start date is missing (i.e. subject did not start 
study treatment), then set start date = January 1. 
Else if study treatment start date is not missing:  
If year of start date = year of study treatment start date then  
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date = January 1.  
Else set start date = study treatment start date.  
Else set start date = January 1. 
 
 
day 
If study treatment start date is missing (i.e. subject did not start 
study treatment), then set start date = 1st of month.  
Else if study treatment start date is not missing:  
If month and year of start date = month and year of study treatment 
start date then  
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date= 1st of month.  
Else set start date = study treatment start date. 


 
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Dataset Date Missing 
Element 
Rule 
Else set start date = 1st of month. 
 
End 
Date 
 
No imputation for partial end dates will be performed 
15.7.3.2. 
Concomitant Medication and Blood and Blood Supportive Care 
Products 
Impute start and end dates for use in derivation of the reference variables concomitant 
medication start and end relative to treatment and blood and blood supportive care start 
and end relative to treatment, but do not permanently store the imputed start and end 
dates in the analysis datasets. The reference variables will be used to differentiate before, 
during and after for the concomitant medication or blood or blood supportive care start 
and end dates. The derived time in relation to treatment variables are not needed for 
reporting of these data. 
Dataset 
Date 
Missing 
Element 
Rule 
Concomitant 
Medication 
 
Blood and 
Blood 
Supportive 
Care Products  
Start 
Date 
day, 
month, 
and year 
No imputation for completely missing dates 
 
 
day, 
month 
If study treatment start date is missing (i.e. subject did not 
start study treatment), then set start date = January 1.  
Else if study treatment start date is not missing:  
If year of start date = year of study treatment start date 
then  
If stop date contains a full date and stop date is earlier 
than study treatment start date then set start date = 
January 1.  
Else set start date = study treatment start date.  
Else set start date = January 1. 
 
 
day 
If study treatment start date is missing (i.e. subject did not 
start study treatment), then set start date = 1st of month.  
Else if study treatment start date is not missing:  
If month and year of start date = month and year of study 
treatment start date then  
If stop date contains a full date and stop date is earlier 
than study treatment start date then set start date= 1st of 
month.  
Else set start date = study treatment start date. 
Else set start date = 1st of month. 


 
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Dataset 
Date 
Missing 
Element 
Rule 
 
End 
Date 
day, 
month, 
and year 
No imputation for completely missing dates 
 
 
day, 
month 
If partial end date contains year only, set end date = 
earliest of December 31 or date of last contact.  
 
 
day 
If partial end date contains month and year, set end date 
= earliest of last day of the month or date of last contact 
(MSTONE.LCONTDT). 
15.7.3.3. 
New Anti-Cancer Therapy/ Radiotherapy/Surgical Procedures for 
Efficacy Evaluation (e.g., response rate, time to event) 
Start dates for follow-up anticancer therapy, radiotherapy (where applicable), and 
surgical procedures (where applicable) will be temporarily imputed in order to define 
event and censoring rules for progression-free survival, response rate, or duration of 
response (i.e. start date for new anticancer therapy). Dates will only be imputed when a 
month and year are available but the day is missing. The imputed date(s) will not be 
stored on the anticancer therapy, radiotherapy, or surgical procedure datasets. The 
following rules will be used to impute the date when partial start dates are present on 
anticancer therapy radiotherapy, and/or surgical procedures dataset[s]: 
 
Dataset 
Date 
Missing 
Element 
Rule 
Anticancer 
Therapy  
 
Where 
applicable:  
- Radiotherapy  
- Surgical 
Procedures 
Start 
Date 
day, month, 
and year 
• 
No imputation for completely missing dates 
 
 
day, month 
• 
No imputation for missing day and month  
 
 
day 
• 
If partial date falls in the same year, same 
month as the last dose of study treatment, then 
assign to earlier of (date of last dose of study 
treatment + 1, last day of month).  
• 
If partial date falls in the same year and month 
as the subject’s last assessment and the 
subject’s last assessment is PD, then assign to 
earlier of (date of last assessment + 1, last day 
of month).  
• 
If both rules above apply, then assign to latest 
of the 2 dates  


 
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Dataset 
Date 
Missing 
Element 
Rule 
• 
Otherwise, impute missing day to the first of the 
month. 
 
End 
Date 
 
• 
No imputation for partial end dates will be 
performed 
15.7.3.4. 
Extended Loss to Follow-up or Extended Time without an Adequate 
Assessment 
If two or more scheduled disease assessments are missed and are then followed by an 
assessment of PD or death (using the earliest date of PD or death), PFS will be censored 
at the last adequate assessment prior to PD or death.  
 
For NHL cohort, as the scheduled disease assessment is every 12 weeks, a window of 
175 days (24 weeks + 7 day window) will be used to determine whether there was an 
extended time without adequate assessment. That is, if the time difference between 
PD/death and last adequate assessment is more than 175 days, then PFS will be censored 
at the last adequate assessment prior to PD/death. 
 
For other cohorts: as the scheduled disease assessment is every 8 weeks, a window of 119 
days (16 weeks + 7 day window) will be used. 
15.7.3.5. 
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: 
• 
If the missing end date is in the last exposure record, the earliest of: the date of the 
data cut-off, the date of withdrawal from the study, or the death date will be used  
• 
If the missing end date is not in the last exposure record, treatment start date for the 
record will be used 
15.7.3.6. 
Death Date 
If death date is missing, the last contact date will be used. 


 
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15.8. 
Appendix 8: Values of Potential Clinical Importance 
15.8.1. 
Laboratory Values 
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.  
Laboratory grades will be reported, where applicable, using the Common Terminology 
Criteria for Adverse Events (CTCAE v4.0).[Basch, 2014] 
For laboratory data which are not listed in the NCI-CTCAE v4.0, a summary of values 
outside the normal range will be provided. 
15.8.2. 
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’). 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.  Note that <=450 is considered to be Grade 0. 
ECG Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute QTcF interval 
>450 to <=480 (Grade 1) 
>480 to <=500 (Grade 2) 
>500 (Grade 3) 
msec 
Increase from baseline 
QTcF  
Increase of 31 to 60 
Increase of >60 
msec 
15.8.3. 
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 
Decrease from baseline Heart Rate 
Decrease to <60 
bpm 
Increase from baseline Heart Rate 
Increase to >100 
bpm 
 


 
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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 
Increase from baseline 
Systolic Blood Pressure 
120 to <140 (Grade 1) 
140 to <160 (Grade 2) 
160 (Grade 3) 
mmHg 
Increase from baseline 
Diastolic Blood Pressure 
80 to <90 (Grade 1) 
90 to <100 (Grade 2) 
100 (Grade 3) 
mmHg 
 
Systolic blood pressure below 120 and diastolic blood pressure below 80 are considered 
as normal range and will receive Grade 0 designations. 
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 
Increase from baseline 
temperature 
Increase to 38 
Degrees C 
Decrease from baseline 
temperature 
Decrease to 35 
Degrees C 
 
Additionally, vital signs will be further categorized for reporting based on the following: 
• 
Heart rate (beats/min): <60, >=60 to =<100, and >100; and  
• 
Temperature (°C): <=35, >35 to <38, ≥38. 
• 
Systolic blood pressure:<90, >=90 to <120, >=120 
• 
Diastolic blood pressure: <60, >=60 to <80, >=80 
15.8.4. 
Left Ventricular Ejection Fraction 
• 
The following criteria will be used to flag left ventricular ejection fraction (LVEF) 
values that are values of potential clinical importance: 
• 
To identify LVEF values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign categories that align with the grades for ‘Ejection fraction decreased’. 


 
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LVEF Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute change from 
baseline LVEF 
No change or any increase 
Any decrease 
>0-<10 decrease 
10-19 decrease 
20 decrease 
10 decrease and  LLN 
10 decrease and below LLN 
20 decrease and  LLN 
20 decrease and below LLN 
% 


 
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15.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses  
Population-based PK analyses are not within the scope of this analysis plan. 


 
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15.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic Analysis 
Pharmacokinetic/Pharmacodynamic analyses are not within the scope of this analysis 
plan.  


 
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15.11. 
Appendix 11: Abbreviations & Trade Marks 
15.11.1. 
Abbreviations 
Abbreviation 
Description 
ABCG2 (BCRP) 
Breast cancer resistance protein 
ACC 
adenoid cystic carcinoma 
ADA 
Anti-drug antibodies 
AE(s) 
Adverse Event(s) 
Aft 
After 
ALL 
Acute lymphoblastic leukemia 
ALT (SGPT) 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AR 
Accumulation ratio 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BC 
Breast cancer 
BCRP 
Breast Cancer Resistance Protein 
BID 
Twice daily  
BMD 
Bone mineral density  
Caco-2  
Continuous cell of heterogeneous human 
epithelial colorectal adenocarcinoma cells 
CBC 
Complete blood count 
CDK 
cyclin-dependent kinase 
cf-DNA 
Circulating cell free DNA 
CKD-Epi 
Chronic Kidney Disease Epidemiology 
Collaborative 
CL/F 
Apparent clearance following oral dosing 
Cmax  
Maximum observed plasma concentration 
CML 
Chronic myeloid leukemia 
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CPS 
Combined Percentage Score 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CV 
Cardiovascular 
CV% 
Coefficient of variance percent 
D 
Day 
DART5 
D. Melanogaster analog of mammalian prmt5 
DCR 
Disease control rate 
DHEA 
Dehydroepiandrosterone 
DEXA 
Dual-energy x-ray absorptiometry 
DILI 
Drug induced liver injury 
DL-1 
Dose Level 1 


 
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Abbreviation 
Description 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report form 
EGFR 
Epithelial growth factor receptor 
EIAC 
Enzyme-inducing anticonvulsant 
EOT 
End of treatment 
ER- 
Estrogen receptor negative 
ER+ 
Estrogen receptor positive 
ER+BC 
Hormone receptor-positive adenocarcinoma of the 
breast 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FFPE 
Formalin fixed paraffin embedded 
FL 
Follicular lymphoma 
FSH 
Follicle stimulating hormone 
FTIH 
First time in human 
GALT 
Gut-associated lympoid tissue 
GAR 
Glycine and arginine residues 
GBM 
Glioblastoma multiforme 
GCP 
Good clinical practice 
GDI 
Growth-Death Index 
GFR 
Glomerular Filtration Rate 
GI 
Gastrointestinal 
GLP 
Global laboratory practice 
GSEA 
Gene set enrichment analysis 
GSK 
GlaxoSmithKline 
h 
Hour/s 
H3R8, H2AR3 and H4R3 
Histone 3 Arginine 8, Histone 2A arginine 3 and 
Histone 4 arginine 3 
CCI
CCI
CCI


 
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Abbreviation 
Description 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotrophin 
HCV 
Hepatitis C Virus 
Hep C 
Hepatitis C 
Her2- 
Human epidermal growth factor receptor 2 
negative 
HIV 
Human immunodeficiency virus 
HL 
Hodgkin’s lymphoma 
HLA 
Human leukocyte antigen 
HMG-CoA 
3-hydroxy-3-methylglutaryl-coenzyme A 
HN 
Head and neck carcinoma 
HNSCC 
squamous cell carcinoma of the head and neck 
HNSTD 
Highest non severely toxic dose 
HPLC 
High-performance liquid chromatography 
HPMC 
Hydroxypropyl methylcellulose 
HPV 
human papillomavirus 
HRQoL 
Health related quality of life 
HRT 
Hormone replacement therapy 
IAG 
Imaging acquisition guidelines 
IB 
Investigator’s brochure 
IC50 
Fifty percent inhibitory concentration 
ICF 
Informed consent form 
ICR 
Independent central review 
ICH 
International Conference on Harmonization of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IgG4 
Immunoglobulin G 4 
INDSRs 
Investigational new drug safety reports 
INR 
International normalized ratio 
IRB 
Institutional review board 
iRECIST 
Immune-based RECIST 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IV 
Intravenous 
IVD 
Invitro diagnostic device 
KIM-1 
Kidney injury molecule-1 
KPS 
Karnofsky Performance Status 
LDH 
Lactate dehydrogenase 
LHRH 
Luteinizing hormone releasing hormone 
LLN 
Lower limit of normal 
LV 
Left ventricle 
LVEF 
Left ventricular ejection fraction 
MABEL 
Minimum anticipated biologically effective level 


 
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Abbreviation 
Description 
MCH 
Mean corpuscular hemoglobin 
MCL 
Mantle cell lymphoma 
MCV 
Mean corpuscular volume 
MDCK-II 
Madine-Darby Canine Kidney-II cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEP50 
Methylosome protein 50 
mg 
milligram 
MM 
Multiple myeloma 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger RNA 
MSDS 
Material safety data sheet 
mTCC 
metastatic transitional cell carcinoma of the 
urinary system 
MTD 
Maximumally tolerated dose 
mTPI 
Modified Toxicity Probability Interval  
n 
Number 
NCI-CTCAE 
National Cancer Institute - Common Terminology 
Criteria for Adverse Events 
NGAL 
Neutrophil gelatinase-associated lipocalin 
NHL 
Non-Hodgkin’s lymphoma 
NOAEL 
No-observed adverse effect level 
NSCLC 
Non small-cell lung cancer 
NYHA 
Newyork heart association 
ORR 
Overall response rate 
OS 
Overall survival 
PAX 
Paxgene 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PD-1 
Programmed Cell Death Protein 1 
PDCD4 
Programmed cell death 4 
PD-L1 
Programmed Death-Ligand 1 
PDX 
Patient-derived tumor models 
PEL 
Primary effusion lymphoma 
PET 
Positron emission tomography 
PET/CT 
Positron emission tomography/Computed 
tomography 
PFS 
Progression free survival 
PFSR 
Progression free survival rate 
P-gp  
P-glycoprotein 
PGx 
Pharmacogenetic 
PI 
Prescribing Information  
PI3K 
Phosphoinositol-3 kinase 
PK 
Pharmacokinetic 
CCI


 
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Abbreviation 
Description 
PR 
Partial response 
PR- 
Progesterone receptor negative 
PR+ 
Progesterone receptor positive 
PRMT 
Protein arginine methyltransferases 
PRO 
Patient-reported outcomes 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
Q3W 
Every 3 weeks 
q4w 
Every 4 weeks 
q8w 
Every 8 weeks 
QD 
Once a day 
QLQ 
Quality of life questionnaire 
QT  
QT interval duration 
QTc 
Corrected QT interval duration 
QTcF 
QT duration corrected for heart rate by Fridericia’s 
formula 
RANO 
Response Assessment in Neuro-Oncology 
RAP 
Report and Analysis Plan 
RBC 
Red blood cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
REML 
Restricted maximum likelihood 
RNA 
Ribonucleic acid 
RNAseq 
RNA sequencing 
RP2D 
Recommended phase 2 dose 
RR 
Response rate 
RT-PCR 
Reverse transcription-polymerase chain reaction 
SAE(s) 
Serious Adverse Event(s) 
SAS 
Statistical analysis system 
SCLC 
Small-cell lung cancer 
SCR 
Screening 
SD 
Stable disease 
SMD 
No metabolic activity 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics  
SPD 
Sum of products of the diameters 
SRM 
Study reference manual 
SRT 
Safety review team 
STD 
Severely toxic dose 
STD10 
Severely toxic dose to 10% of the animals 
t½ 
Half-life 
TCL 
T-cell lymphoma 
tFL 
Transformed follicular lymphoma 
CCI
CCI


 
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Abbreviation 
Description 
TGI 
Tumor growth inhibition 
TI 
Time invariance 
tmax 
Time to Cmax 
TNBC 
Triple-negative breast cancer 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
UPM 
Unit probability mass 
VP 
Vice president 
Vss 
Human volume of distribution 
W1D1 
Week 1 Day 1 
W1D3 
Week 1 Day 3 
W3D1 
Week 3 Day 1 
WBC 
White blood cell 
WHO 
World health organization 
WT 
Wild type 
 
15.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
Phoenix WinNolin 
 
 
SAS 
 
 
 
 
 
 


 
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15.12. 
Appendix 12: List of Data Displays 
15.12.1. 
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 
2.11 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 
y to z 
15.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays. 
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.’ 
15.12.3. 
Deliverables 
Delivery [Priority] [1] 
Description 
DS [X] 
During Study 
DE [X] 
Dose Escalation 
IA SAC [X] 
Interim Analysis Statistical Analysis Complete 
SAC [X] 
Final Statistical Analysis Complete 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 


 
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15.12.4. 
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 To use the following from ES1 shell : 
“Outcome of Adverse Events Which Led to Study Withdrawal” 
with “NON-FATAL” and “FATAL” options.  Add overall column. 
Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
 SAC  
1.2 
All Treated 
SD1 
Summary of Treatment Status and 
Reasons for Discontinuation of Study 
Treatment  (GSK3326595) 
ICH E3 include footnote [1] and [2] from standard, but remove 
footnote [3] use same mock as created for ACC IA, Part 1 by 
dose level, Part 2 by cohort, Part 3 by dose 
IA, SAC 
1.3 
All Treated 
SD1 
Summary of Treatment Status and 
Reasons for Discontinuation of Study 
Treatment  (Pembrolizumab) 
ICH E3 include footnote [1] and [2] from standard, but remove 
footnote [3] use same mock as created for ACC IA, Part 3 
IA, SAC 
1.4 
Screened 
ES6 
Summary of Screening Status and 
Reasons for Screen Failure  
Journal Requirements 
SAC 
1.5 
Enrolled 
NS1 
Summary of Number of Participants by 
Country and Site ID  (Enrolled 
Population) 
EudraCT/Clinical Operations, Part 1 by dose level, Part 2 by 
cohort, Part 3 by dose 
SAC 
Protocol Deviation 
1.7 
All Treated 
DV1 
Summary of Important Protocol 
Deviations  
ICH E3, Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
SAC 
Analysis Populations 
1.8 
Screened 
SP1A 
Summary of Study Populations   
IDSL To include Enrolled, All Treated, PK, Evaluable (if diff 
from enrolled), PD, Part 1 by dose level, Part 2 by cohort, Part 
3 by dose 
IA, SAC 
1.9 
All Treated 
SP2A 
Summary of Exclusions from the Safety 
Population 
IDSL Only if we have exclusions (i.e. food effect subjects?), 
Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
SAC 
Demographic and Baseline Characteristics 
1.10 
All Treated 
DM1 
Summary of Demographic 
Characteristics 
ICH E3, FDAAA, EudraCT, Part 1 by dose level, Part 2 by 
cohort, Part 3 by dose 
IA, SAC 
1.11 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
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No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
Disease Characteristics 
1.12 
All Treated 
DC1 
Summary of Disease Characteristics at 
Initial Diagnosis  
ICH E3 Make note of separate CRF page for NHL subjects, 
Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
IA, SAC 
1.13 
All Treated 
DC2 
Summary   of Disease Characteristics at 
Screening  
ICH E3 Make note of separate CRF page for NHL subjects, 
Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
IA, SAC 
1.14 
All Treated 
MD1 
Summary of Metastatic Disease at 
Screening 
IDSL, Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
SAC 
1.15 
All Treated 
LA1 
Summary of Disease Burden at 
Baseline  
ICH E3, Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
SAC 
1.16 
All Treated 
MH1 
Summary of Past Medical Conditions  
ICH E3 , Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
SAC 
1.17 
All Treated 
MH1 
Summary of Current Medical 
Conditions   
ICH E3, Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
SAC 
Prior and Concomitant Medications and Prior and Follow-up Therapies 
1.21 
All Treated 
AC1 
Summary of Prior Anti-Cancer Therapy 
IDSL 
SAC 
1.23 
All Treated 
AC1 
Summary of Prior Anti-Cancer Therapy 
(Advanced/Metastatic) 
Include only therapies that have been marked “Advanced or 
Metastatic” as intent on eCRF, Part 1 by dose level, Part 2 by 
cohort, Part 3 by dose 
SAC 
1.24 
All Treated 
AC3 
Summary of Number of Prior Anti-
Cancer Therapies 
IDSL, Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
SAC 
1.26 
All Treated 
FAC1 
Summary of Follow-Up Anti-Cancer 
Therapy, Radiotherapy, and Surgery 
IDSL, Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
SAC 
Follow-Up 
1.30 
All Treated 
FAC2 
Summary of Duration of Follow-up  
Part 1 by dose level, Part 2 by cohort, Part 3 by dose 
SAC 


 
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15.12.5. 
Efficacy Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
Tumor Response 
2.1 
All Treated 
RE1a 
Summary of Investigator Assessed Best 
Response with Confirmation (RECIST 
1.1 Criteria)  
By dose level for Part 1, by cohort for Part 2 (all but NHL/GBM) 
95% CI is based on Clopper-Pearson exact CI 
IA, SAC 
2.2 
All Treated 
RE1a 
Summary of Investigator Assessed Best 
Response with Confirmation (RANO 
Criteria)  
Part 2 GBM cohort 95% CI is based on Clopper-Pearson exact 
CI 
SAC 
2.3 
All Treated 
RE1a 
Summary of Investigator Assessed Best 
Response (Lugano Criteria)  
Part 2 NHL cohort 95% CI is based on Clopper-Pearson exact 
CI 
IA, SAC 
2.4 
All Treated 
RE1a 
Summary of Investigator Assessed Best 
Response with Confirmation (iRECIST 
Criteria)  
Part 3 by dose level 95% CI is based on Clopper-Pearson exact 
CI 
SAC 
Time-to-Event 
2.5 
All Treated 
TTE6 
Summary of Kaplan-Meier Estimates of 
Progression-Free Survival at 6 Months 
(RANO Criteria) 
GBM cohort 
IA, SAC 
2.6 
All Treated 
TTE1 
Summary of Progression-Free Survival 
Based on Investigator Assessments 
(RECIST 1.1 Criteria) 
By cohort for Part 2 (excluding GBM, NHL) 
SAC 
2.7 
All Treated 
TTE1 
Summary of Progression-Free Survival 
Based on Investigator Assessments 
(RANO Criteria) 
GBM cohort 
SAC 
2.8 
All Treated 
TTE1 
Summary of Progression-Free Survival 
Based on Investigator Assessments 
(Lugano Criteria) 
NHL cohorts 
SAC 
2.9 
All Treated 
TTE1a 
Summary of Duration of Response 
Based on Investigator Assessments 
(RECIST 1.1 Criteria) 
Part 2 ACC TN cohort 
SAC 


 
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No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
2.10 
All Treated 
TTE1 
Summary of Overall Survival 
Part 2 ACC TN cohort and all ACC subjects across parts 1/2  
SAC 
 
15.12.6. 
Efficacy Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
Change in Sum of Diameters/Areas 
2.11 
All Treated 
RE8a 
Investigator-Assessed Maximum Percent Reduction 
from Baseline in Sum of Diameters (RECIST 1.1 
Criteria) 
Part 1 one plot for QD, one for BID 
color/shade by dose level and indication 
within each 
SAC 
2.12 
All Treated 
RE8a 
Investigator-Assessed Maximum Percent Reduction 
from Baseline in Sum of Diameters (RECIST 1.1 
Criteria) 
part 2 by cohort (excluding NHL , GBM) 
IA, SAC 
2.13 
All Treated 
RE8a 
Investigator-Assessed Maximum Percent Reduction 
from Baseline in Sum of Areas (RANO Criteria) 
Part 2 GBM cohort 
SAC 
2.14 
All Treated 
RE8a 
Investigator-Assessed Maximum Percent Reduction 
from Baseline in Sum of Diameters (iRECIST 
Criteria) 
Part 3 
SAC 
2.15 
All Treated 
custom 
Spider Plot of Percent Change from Baseline in 
Sum of Diameters (Investigator Assessment Using 
RECIST 1.1 Criteria) 
Part 1 one plot for QD, one for BID 
color/shade by dose level and indication 
within each 
SAC 
2.16 
All Treated 
custom 
Spider Plot of Percent Change from Baseline in 
Sum of Diameters (Investigator Assessment Using 
RECIST 1.1 Criteria) 
part 2 by cohort (excluding NHL, GBM) 
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2.17 
All Treated 
custom 
Spider Plot of Percent Change from Baseline in 
Sum of Areas (Investigator Assessment Using 
RANO Criteria) 
Part 2 GBM cohort 
SAC 
2.18 
All Treated 
custom 
Spider Plot of Percent Change from Baseline in 
Sum of Diameters (Investigator Assessment Using 
iRECIST Criteria) 
Part 3 
SAC 
Time-to-Event 
2.19 
All Treated 
TTE10 
Graph of Kaplan-Meier Survival Curves of 
Progression-Free Survival with 95% Confidence 
Bands (Investigator Assessment using RECIST 1.1 
Criteria) 
by dose level for part 1, by cohort for part 2 
(excluding GBM/NHL) 
SAC 
2.20 
All Treated 
TTE10 
Graph of Kaplan-Meier Survival Curves of 
Progression-Free Survival with 95% Confidence 
Bands (Investigator Assessment using RANO 
Criteria) 
GBM cohort 
SAC 
2.21 
All Treated 
TTE10 
Graph of Kaplan-Meier Survival Curves of 
Progression-Free Survival with 95% Confidence 
Bands (Investigator Assessment using Lugano 
Criteria) 
NHL cohorts 
SAC 
2.22 
All Treated 
TTE10 
Graph of Kaplan-Meier Survival Curves of 
Progression-Free Survival with 95% Confidence 
Bands (Investigator Assessment using iRECIST 
Criteria) 
Part 3 
SAC 
2.23 
All Treated 
TTE10 
Graph of Kaplan-Meier Survival Curves of Overall 
Survival with 95% Confidence Bands 
Part 2 ACC TN cohort and All ACC subjects 
(across parts 1/2) 
SAC 
 


 
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15.12.7. 
Safety Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
Adverse Events 
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   
Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
IA, SAC 
3.2 
All Treated 
AE1 
Summary of All Adverse Events by 
System Organ Class and Preferred 
Term  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.3 
All Treated 
AE5B 
Summary of All Adverse Events by 
System Organ Class and Preferred 
Term and Maximum Grade    
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.4 
All Treated 
AE1 
Summary of All Adverse Events by 
Preferred Term  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.5 
All Treated 
AE3 
Summary of Common (>=10%) Adverse 
Events by Overall Frequency  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 
1/Part 2 300mg/400mg/Total/Overall, Part 3 (by 
dose) 
SAC 
3.6 
All Treated 
AE3 
Summary of Common (>=10%) Grade 2-
5 Adverse Events by Overall Frequency  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.7 
All Treated 
AE1 
Summary of All GSK3326595-Related 
Adverse Events by System Organ Class 
and Preferred Term  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) Please include a 
footnote describing how these events are selected (i.e. this 
SAC 


 
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No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
table includes events for which the investigator selected as 
related to GSK only) 
3.8 
All Treated 
AE5B 
Summary of All GSK3326595-Related 
Adverse Events by System Organ Class 
and Preferred Term and Maximum 
Grade  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) Please include a 
footnote describing how these events are selected (i.e. this 
table includes events for which the investigator selected as 
related to GSK only) 
SAC 
3.10 
All Treated 
AE5B 
Summary of All Pembrolizumab-Related 
Adverse Events by System Organ Class 
and Preferred Term and Maximum 
Grade  
Part 3 only Please include a footnote describing how these 
events are selected (i.e. this table includes events for which the 
investigator selected as related to Pembro only) 
SAC 
3.12 
All Treated 
AE5B 
Summary of All GSK3326595 and 
Pembrolizumab-Related Adverse Events 
by System Organ Class and Preferred 
Term and Maximum Grade  
Part 3 only Please include a footnote describing how these 
events are selected (i.e. this table includes events for which the 
investigator selected as related to both GSK and Pembro) 
SAC   
3.13 
All Treated 
AE3 
Summary of Common (>=10%) 
GSK3326595-Related Adverse Events 
by Overall Frequency  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) Please include a 
footnote describing how these events are selected (i.e. this 
table includes events for which the investigator selected as 
related to GSK only) 
SAC 
3.14 
All Treated 
AE3 
Summary of Common (>=10%) 
GSK3326595-Related Grade 2-5 
Adverse Events by Overall Frequency  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) Please include a 
footnote describing how these events are selected (i.e. this 
table includes events for which the investigator selected as 
related to GSK only) 
SAC 
3.15 
All Treated 
AE15 
Summary of Common (>=10%) Non-
serious Adverse Events by System 
Organ Class and Preferred Term 
(Number of Participants and 
Occurrences)  
FDAAA, EudraCT Part 1 (by dose), Part 2 (by cohort), Part 
1/Part 2 300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 


 
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No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
3.17 
All Treated 
AE3 
Summary of Adverse Events Leading to 
Dose Reductions of GSK3326595 by 
Preferred Term  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.18  
All Treated 
AE3 
Summary of Adverse Events Leading to 
Dose Interruptions / Delay of 
GSK3326595 by Preferred Term  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
Serious and Selected Adverse Events 
3.19 
All Treated 
AE5B   
Summary of Serious Adverse Events by 
System Organ Class and Preferred 
Term and Maximum Grade  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.20 
All Treated 
AE16 
Summary of Serious Adverse Events by 
System Organ Class and Preferred 
Term (Number of Participants and 
Occurrences)  
FDAAA, EudraCT Part 1 (by dose), Part 2 (by cohort), Part 
1/Part 2 300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.21 
All Treated 
AE1 
Summary of Adverse Events Leading to 
Permanent Discontinuation of Study 
Treatment by System Organ Class and 
Preferred Term  
IDSL Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.23 
All Treated 
AE3 
Summary of Serious Adverse Events 
Related to GSK3326595 by Preferred 
Term    
Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) Please include a 
footnote describing how these events are selected (i.e. this 
table includes events for which the investigator selected as 
related to GSK only) 
IA, SAC   
3.24 
All Treated 
ESI2A 
Summary of Onset and Duration of First 
Occurrence of Selected Adverse Events  
Anemia, neutropenia, thrombocytopenia (platelet count 
decrease and thrombocytopenia), fatigue, Part 1 (by dose), Part 
2 (by cohort), Part 3 (by dose) 
SAC 
3.25 
All Treated 
ESI1 
Summary of Event Characteristics of 
Selected Adverse Events    
Anemia, neutropenia, thrombocytopenia (platelet count 
decrease and thrombocytopenia), fatigue, Part 1 (by dose), Part 
2 (by cohort), Part 3 (by dose) 
IA, SAC 
3.30 
All Treated 
DD1 
Summary of Deaths  
ICH E3  Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) Report time to 
death from last dose (in days) as in the mock 
SAC 


 
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No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
Laboratory Results 
3.31 
All Treated 
LB1 
Summary of Chemistry Changes from 
Baseline  
ICH E3 To include grade increase from Baseline Grade 
Creatinine 
SAC 
3.32 
All Treated 
LB15 
Summary of 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 Part 1 (by dose), 
Part 2 (by cohort), Part 1/Part 2 300mg/400mg/Total/Overall, 
Part 3 (by dose) 
SAC 
3.33 
All Treated 
LB16 
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 Part 1 (by dose), Part 
2 (by cohort), Part 1/Part 2 300mg/400mg/Total/Overall, Part 3 
(by dose) 
SAC 
3.34 
All Treated 
LB1 
Summary of Haematology Changes 
from Baseline  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.35 
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 Part 1 (by dose), 
Part 2 (by cohort), Part 1/Part 2 300mg/400mg/Total/Overall, 
Part 3 (by dose) 
SAC 
3.36 
All Treated 
LB16 
Summary of Worst Case Haematology 
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 Part 1 (by dose), Part 
2 (by cohort), Part 1/Part 2 300mg/400mg/Total/Overall, Part 3 
(by dose) 
SAC 
3.37 
All Treated 
LB1 
Summary of Coagulation Changes from 
Baseline  
ICH E3,  Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.38 
All Treated 
LB15 
Summary of Worst-Case Coagulation 
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 Part 1 (by dose), 
Part 2 (by cohort), Part 1/Part 2 300mg/400mg/Total/Overall, 
Part 3 (by dose) 
SAC 
3.39 
All Treated 
LB16 
Summary of Worst Case Coagulation 
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 Part 1 (by dose), Part 
2 (by cohort), Part 1/Part 2 300mg/400mg/Total/Overall, Part 3 
(by dose) 
SAC 


 
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No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
3.40 
All Treated 
LB1 
Summary of Urine Concentration 
Changes from Baseline  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.41 
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. Part 1 (by dose), 
Part 2 (by cohort), Part 1/Part 2 300mg/400mg/Total/Overall, 
Part 3 (by dose) 
SAC 
3.42 
All Treated 
LIVER1 
Summary of Liver Monitoring/Stopping 
Event Reporting  
IDSL Part 1 (by dose), Part 2 (by cohort), Part 3 (by dose) 
SAC 
3.43 
All Treated 
LIVER10 
Summary of Hepatobiliary Laboratory 
Abnormalities  
IDSL Part 1 (by dose), Part 2 (by cohort), Part 3 (by dose) 
SAC 
3.45 
All Treated 
LB15 
Summary of Worst Case Troponin 
Results Relative to Normal Range Post-
Baseline Relative to Baseline  
Part 1 (by dose), Part 2 (by cohort), Part 3 (by dose) 
SAC 
ECG, Vital Signs, and LVEF 
3.47 
All Treated 
EG1 
Summary of ECG Findings   
IDSL Part 1 (by dose), Part 2 (by cohort), Part 3 (by dose) 
SAC 
3.48 
All Treated 
EG10 
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. Part 1 (by dose), Part 2 (by cohort), Part 
1/Part 2 300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.50 
All Treated 
EG11 
Summary of Maximum Increase in QTcF 
Values Post-Baseline Relative to 
Baseline by Category  
ICHE14 Report only worst-case post-baseline. Don’t report by-
visit summary rows. Part 1 (by dose), Part 2 (by cohort), Part 
1/Part 2 300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.51 
All Treated 
VS1 
Summary of Change from Baseline in 
Vital Signs  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.52 
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. Part 1 (by dose), 
Part 2 (by cohort), Part 1/Part 2 300mg/400mg/Total/Overall, 
Part 3 (by dose) 
SAC 
3.53 
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. Part 1 
SAC 


 
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No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
(by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
3.54 
All Treated 
OLVEF1A 
Summary of Left Ventricular Ejection 
Fraction Change from Baseline  
IDSL Part 1 (by dose), Part 2 (by cohort), Part 3 (by dose) 
SAC 
Exposure, Dose Modifications, DLT 
3.55 
All Treated 
EX1 
Summary of Exposure to Study 
Treatment  (GSK3326595) 
ICH E3 Include duration of treatment (months) Part 1 (by dose), 
Part 2 (by cohort), Part 1/Part 2 300mg/400mg/Total/Overall, 
Part 3 by dose 
SAC 
3.56 
All Treated 
OEX5 
Summary of Exposure to Study 
Treatment (Pembrolizumab) 
Part 3 
SAC 
3.57 
All Treated 
ODMOD1 
Summary of Dose Reductions of 
GSK3326595  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.58 
All Treated 
ODMOD1 
Summary of Dose Reductions of 
Pembrolizumab 
Part 3 
SAC 
3.59 
All Treated 
ODMOD2 
Summary of Dose Interruptions of 
GSK3326595  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
3.60 
All Treated 
ODMOD3 
Summary of Dose Delays of 
Pembrolizumab 
Part 3 
SAC 
3.65 
All Treated 
AE1 
Summary of Adverse Events Recorded 
as Dose-Limiting Toxicities by Preferred 
Term– Part 1 
ICH E3 Part 1 
SAC 
ECOG Performance 
3.66 
All Treated 
PS1A 
Summary of ECOG Performance Status  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 1/Part 2 
300mg/400mg/Total/Overall, Part 3 (by dose) 
SAC 
Ocular Adverse Events 
3.70 
All Treated 
from IB 2022 Summary of Adverse Events (Ocular 
Events) by Preferred Term 
Part 1, Part 2, Part 3, Part 1+2 
SAC   
3.72 
All Treated 
from IB 2022 Summary of Adverse Events (Bone-
Related Events) by Preferred Term 
Part 1, Part 2, Part 3, Part 1+2 
SAC   
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No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
3.75 
All Treated 
from IB 2022 
Summary of Bone Mineral Density Shifts 
from Baseline Relative to Normal 
Range, Among Patients with Pre-
Treatment Baseline DEXA Scan – Local 
Labs 
Part 1, Part 2, Part 3, Part 1+2 
SAC   
3.77 
All Treated 
from IB 2022 
Summary of Bone Mineral Density Shifts 
from Baseline Relative to Normal 
Range, Among Patients with First DEXA 
Scan Performed on Treatment – Local 
Labs 
Part 1, Part 2, Part 3, Part 1+2 
SAC   
 


 
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15.12.8. 
Safety Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
3.1.    
All Treated 
OEX12 
Swimmer Plot of Duration of Study 
Treatment  (RECIST 1.1 Criteria) 
IDSL Part 2   (by cohort excluding 
GBM/NHL) 
IA, SAC 
3.2.    
All Treated 
OEX12 
Swimmer Plot of Duration of Study 
Treatment  (RANO Criteria) 
IDSL GBM cohort 
IA, SAC 
3.3.    
All Treated 
OEX12 
Swimmer Plot of Duration of Study 
Treatment  (Lugano Criteria) 
IDSL  NHL cohorts 
IA, SAC 
3.4.    
All Treated 
OEX12 
Swimmer Plot of Duration of Study 
Treatment  (iRECIST Criteria) 
IDSL Part 3 
IA, SAC 
 
15.12.9. 
Pharmacokinetic Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
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.  by dose 
for Part 1, by cohort for parts 2 and 3 also by 300mg, 400mg 
QD across all parts,  
For Part 3, include Pembrolizumab 
SAC 
4.2 
PK 
GSK-
provided 
Summary of Pembrolizumab 
Immunogenicity Data by Treatment 
and Study Day 
Part 3 only 
SAC 
4.3 
PK 
PK06 
Summary of Derived GSK3326595 
Pharmacokinetic Parameters by 
Treatment and Study Day 
PK parameters: Cmax, Tmax, Ctrough, AUC0-t, tlast, 
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 
SAC 


 
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No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
parameters, if applicable.  by dose for Part 1, by cohort for 
parts 2 and 3 also by 300mg, 400mg QD across all parts 
4.5 
PK 
 custom 
Dose Proportionality Comparison 
(Power Model) for AUC(0-inf:=) and 
Cmax of GSK3326595 
Provide separately for QD regimens and BID regimens of 
Part 1 only 
SAC  
4.6 
PK 
NA 
Food Effect Sub-Study 
<previously done> 
IA 
4.7 
PK 
NA 
Relative Bio-Availability Sub-Study 
 <previously done> 
IA 
 
15.12.10. Pharmacokinetic/Biomarker Figures 
No. 
Populatio
n 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
4.1.    
PK 
PK16A 
Individual GSK3326595 Concentration-Time 
Plots (Linear) by Treatment and Study Day 
IDSL ng/mL Day 1 and Day 15 only for Part 1 Day 1 
only for Part 2 Part 1 by dose level, Part 2 by cohort 
(and by dose if applicable), Part 3 by dose level by 
time point per page, plasma only 
SAC 
4.2.    
PK 
PK17 
Mean Concentration-Time Plots by Treatment 
and Study Day 
IDSL ng/mL Day 1 and Day 15 only for Part 1 Day 1 
only for Part 2 Part 1 by dose level, Part 2 by cohort 
(and by dose if applicable), Part 3 by dose level 
300mg and 400mg (across all parts), different color 
for dose level, both time points on one plot by time 
point per page, plasma only 
SAC 
4.3.    
PK 
PK18 
Median Concentration-Time Plots  
by Treatment and Study Day 
IDSL ng/mL Day 1 and Day 15 only for Part 1 Day 1 
only for Part 2  Part 1 by dose level, Part 2 by cohort 
(and by dose if applicable), Part 3 by dose level by 
time point per page, plasma only 
SAC 
4.4.    
 PK 
Custom 
Dose proportionality figures 
1.  Provide separately for GD regimens and BID 
regimens of Part 1 only 
 SAC 
4.6 
Biomarker 
Custom 
Change in cf
 level between Baseline and 
Day 15 
By tumor type: ACC, ERBC, GBM, HPV, mTCC, 
NHL, TNBC, NSCLC 
Publication 
CCI


 
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98 
 
15.12.11. 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 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
2 
All Treated 
SD2 
Listing of Reasons for Study Treatment 
Discontinuation  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
84 
Enrolled 
TBD 
Listing of Participants by Country and Site 
ICH E3 IDSL Part 1 (by dose), Part 2 (by cohort), 
Part 3 (by dose) 
SAC 
Protocol Deviations 
3 
Enrolled 
DV2 
Listing of Important Protocol Deviations   
ICH E3 Report all important PDs Part 1 (by dose), 
Part 2 (by cohort), Part 3 (by dose) 
SAC 
4 
All Treated 
IE3 
Listing of Participants with 
Inclusion/Exclusion Criteria Deviations  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
Analysis Populations 
5 
Enrolled 
SP3 
Listing of Participants Excluded from All 
Treated Population  
ICH E3 Report participants enrolled but not treated 
Part 1 (by dose), Part 2 (by cohort), Part 3 (by dose) 
SAC 
Demographic and Baseline Characteristics 
6 
All Treated 
DM2 
Listing of Demographic Characteristics  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
7 
All Treated 
DM9 
Listing of Race  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
Exposure 
8 
All Treated 
EX3 
Listing of Exposure Data 
ICH E3 should be able to include both GSK3326595 
and pembrolizumab in the same listing.  Add column 
for treatment. Note: only part 3 subjects will have 
pembro.  Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
Adverse Events, and Serious Adverse Events 
10 
All Treated 
AE8 
Listing of All Adverse Events  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 


 
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No. 
Population 
IDSL / Example 
Shell 
Title 
Programming notes 
Deliverable 
11 
All Treated 
AE7 
Listing of Subject Numbers for Individual 
Adverse Events  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
12 
All Treated 
AE8 
Listing of Non-Fatal Serious Adverse 
Events  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
13 
All Treated 
AE14 
Listing of Reasons for Considering as a 
Serious Adverse Event  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
14 
All Treated 
AE8 
Listing of Adverse Events Leading to 
Permanent Discontinuation of 
GSK3326595 
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) To include Permanent Discontinuation or 
Withdrawal in action taken 
 SAC 
16 
All Treated 
AE8 
Listing of Adverse Events Leading to 
Dose Interruptions of GSK3326595  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
18 
All Treated 
AE8 
Listing of Adverse Events Leading to 
Dose Reductions of GSK3326595  
ICH E3 Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
All Laboratory 
20 
All Treated 
LB5 
Listing of All Laboratory Data for 
Participants with Any Value of Outside 
Normal Range   
ICH E3 To include chemistry, hematology, 
coagulation  
SAC 
21 
All Treated 
UR2 
Listing of Urinalysis Data for Participants 
with Any Value of Potential Clinical 
Importance   
ICH E3 Display all data for a subject who 
experienced a value of PCI 
SAC 


 
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15.12.12. Non-ICH Listings 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
Participant Disposition 
22 
All Treated 
custom 
Listing of Part 1 Subjects Summarized 
in Part 2 
  
SAC 
23 
Screened 
ES7 
Listing of Reasons for Screen Failure   
required for submission studies only Part 1 
(by dose), Part 2 (by cohort), Part 3 (by 
dose) 
SAC 
24 
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 
26 
All Treated 
DC4 
Listing of Disease Characteristics at 
Screening  
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
27 
All Treated 
MD2 
Listing of Metastatic Disease at 
Screening  
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
Anti-Cancer Therapy 
28 
All Treated 
AC6 
Listing of Prior Anti-Cancer Therapy  
List all prior anti-cancer therapy (but not 
radiotherapy or surgery) Part 1 (by dose), 
Part 2 (by cohort), Part 3 (by dose) 
SAC 
29 
All Treated 
FAC3  
Listing of Follow-Up Anti-Cancer 
Therapy 
ACC Cohorts only 
SAC 
31 
All Treated 
PR2 
Listing of On-Study Cancer Related 
Surgical Procedures  
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
Investigator-Assessed Responses 
43 
All Treated 
RE5 
Listing of Investigator-Assessed 
Response at Each Assessment with 
Confirmation (RECIST 1.1 Criteria) 
Part 1 (by dose) and Part 2 (by cohort, 
excluding GBM/NHL) 
SAC 


 
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No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
44 
All Treated 
RE5A instead 
Listing of Investigator-Assessed 
Response at Each Assessment with 
Confirmation (RANO Criteria) 
Part 2 GBM cohort 
SAC 
45 
All Treated 
RE5 
Listing of Investigator-Assessed 
Response at Each Assessment 
(Lugano Criteria) 
Part 2 NHL cohorts 
SAC 
46 
All Treated 
RE5 
Listing of Investigator-Assessed 
Response at Each Assessment with 
Confirmation (iRECIST Criteria) 
Part 3 
SAC 
Time-To-Event Analyses 
51 
All Treated 
TTE9 
Listing of Duration of Response Based 
on Investigator Assessment (RECIST 
1.1 Criteria)  
Part 2 ACC TN cohort  
SAC 
52 
All Treated 
TTE9 
Listing of Progression Free Survival 
Based on Investigator Assessment 
(RECIST 1.1 Criteria) 
Part 2 by cohort (excluding GBM, NHL) 
SAC 
53 
All Treated 
TTE9 
Listing of Progression-Free Survival 
Based on Investigator Assessment 
(RANO Criteria) 
Part 2 GBM cohort 
SAC 
54 
All Treated 
TTE9 
Listing of Progression-Free Survival 
Based on Investigator Assessment 
(Lugano Criteria) 
Part 2 NHL cohorts 
SAC 
55 
All Treated 
custom per 
GSK 
Listing of Time to Response Based on 
Investigator Assessment (RECIST 1.1 
Criteria) 
Part 2 ACC TN only 
SAC 
56 
All Treated 
TTE9 
Listing of Overall Survival  
Parts 2 and 3 by cohort  
SAC 


 
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102 
 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
Adverse Events/Dose-Limiting Toxicity 
61 
All Treated 
AE8 
Listing of Adverse Events Recorded as 
Dose-Limiting Toxicities 
Part 1 (by dose) 
SAC 
Hepatobiliary 
62 
All Treated 
LIVER5 
Listing of Liver Monitoring/Stopping 
Event Reporting   
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
63 
All Treated 
LIVER15 
Liver Stopping Event Profile  
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
Troponin, ECG, and Vital Signs 
69 
All Treated 
OLB7 
Listing of Local Troponin Data  
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
70 
All Treated 
EG3 
Listing of All ECG Values from Local 
Labs  
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
72 
All Treated 
VS5 
Listing of All Vital Signs for Subjects 
with any Value of Potential Clinical 
Importance    
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) List all VS data for any subject 
with at least one PCI 
SAC 
Other Safety 
74 
All Treated 
DD3 
Subject Profile for Death    
ICH E3 
SAC 
76 
All Treated 
Custom 
Listing of DEXA Bone Densitometry 
Data from Local Labs  
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
77 
All Treated 
Custom 
Listing of Optical Coherence 
Tomography Results  
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
78 
All Treated 
Custom 
Listing of Best Corrected Visual Acuity 
(Snellen Acuity Equivalent) Results 
Part 1 (by dose), Part 2 (by cohort), Part 3 
(by dose) 
SAC 
PK 
79 
PK 
PK07 
Listing of GSK3326595 Plasma 
Pharmacokinetic Concentration-Time 
Data   
IDSL List all data Part 1 (by dose), Part 2 
(by cohort), Part 3 (by dose).  Create 
another listing for Part 3 for Pembrolizumab 
SAC 


 
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103 
 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
80 
PK 
PK09 
Listing of GSK3326595 Urine Sample 
Collections 
IDSL List all data Part 1 (by dose) 
SAC 
81 
PK 
PK11 
Listing of GSK3326595 Urine 
Excretion Rate Data 
IDSL List all data Part 1 (by dose) 
SAC 
82 
PK 
PK13 
Listing of Derived GSK3326595 
Plasma Pharmacokinetic Parameters 
by Treatment   
IDSL List only D1, D15 Part 1 (by dose), 
Part 2 (by cohort), Part 3 (by dose) 
SAC 
86 
PK 
GSK-provided 
Listing of Pembrolizumab 
Immunogenicity Data 
Part 3 
SAC 
Family History 
83 
All Treated 
FH4 
Listing of Family History of 
Cardiovascular Risk Factors  
IDSL Part 1 (by dose), Part 2 (by cohort), 
Part 3 (by dose) 
SAC 
Concomitant Medications 
85 
All Treated 
CM3 
Listing of Concomitant Medications by 
Ingredient  
IDSL Part 1 (by dose), Part 2 (by cohort), 
Part 3 (by dose) 
SAC 
 


Signature Page for  204653 TMF-15191581 v1.0
Signature Page for TMF-15191581 v1.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 08-Dec-2022 09:00:12 GMT+0000
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 08-Dec-2022 12:05:51 GMT+0000
PPD
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