Clinical trial NCT01531894
Conditions: Cancer
Keywords: solid tumor GSK2110183 hematologic malignancy AKT inhibitor cancer safety
Sponsor: Novartis Pharmaceuticals
Start date: 2012-02-08; Completion date: 2018-06-20
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This multicenter, non-randomized, open-label, treatment continuation or 'rollover' study was designed to provide continued access to eligible subjects who had previously participated in a GSK2110183 study (parent study) sponsored by GlaxoSmithKline (GSK) or another research organization working on behalf of GSK. Eligible subjects had previously received clinical benefit from continued treatment and had to have ad an acceptable safety profile with GSK2110183. Subjects who had participated in a GSK2110183 combination study with an approved anti-cancer agent were also be eligible to enroll in this rollover study. Subjects who participated in combination studies with two investigational compounds (one being GSK2110183) were not eligible for this rollover study. Subjects were enrolled by cohort based on the duration and treatment received while in their parent study. Safety assessments (physical examinations, vital sign measurements, 12-lead electrocardiograms, echocardiograms or multiple-gated acquisition scans, clinical laboratory assessments and monitoring of adverse events) were evaluated during this study. Disease assessment were performed using local standard of care imaging practices and criteria appropriate for disease type and location.

Detailed description:

Arms: arm 1: All patients received the GSK2110183 (afuresertib) treatment
Interventions: intervention 1: GSK2110183 (afuresertib)
Intervention descriptions: intervention 1: Afuresertib is an oral, low nanomolar pan-AKT kinase inhibitor immediate release (IR) 50 mg or 75 mg tablets was to be taken orally with at least 200 mL of water, with or without food, in the morning.

Protocol documents:
Prot_000.pdf: 
Clinical Development
GSK2110183/Afuresertib
Protocol PKB115131 / NCT01531894
An Open Label Continuation Study of the Oral AKT 
Inhibitor GSK2110183 in Subjects with Solid Tumors and 
Hematologic Malignancies
Authors
 
Document type
Amended Protocol Version Clean
EUDRACT number
2014-002041-22
Version number
4.0 (Amendment 3.0)
Development phase
II
Document status
Final
Release date
31-MAR-2016
Novartis internal 
reference number
CASB183X2X01B
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Amendment 03
Amendment rationale 
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GSK2110183, the 
purpose of this protocol Amendment 03 is to:
-
Delete or replace references to GlaxoSmithKline or its staff with that of Novartis 
and its authorized agents to align with the change of sponsorship;
-
Make administrative changes to align with Novartis processes and procedures;
As of 24-March-2016:
11 patients have received study treatment in 5 countries; 
7 patients have completed or discontinued study treatment.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities (HAs).
The changes herein affect the Informed Consent and all sites are required to update and 
submit for approval, a revised Informed Consent that takes into account the change of 
study sponsorship described in the protocol amendment.
Upon approval of this amendment, patients who have already been enrolled in the study 
will sign a new informed consent form indicating Novartis is the new study sponsor and 
continue the appropriate visit schedule.


Novartis
Confidential
Page 3
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2010N109478_00
2011-APR-29
Original
2010N109478_01
2011-JUN-24
Original-Republished
2010N109478_02
2011-NOV-10
Amendment 01
2010N109478_03
2014-SEP-30
Amendment No. 02
2016-MAR-31
Amendment No. 03
Delete or replace references 
to GSK or its staff with that 
of Novartis/Novartis and its 
authorized agents.
Make administrative 
changes to align with 
Novartis processes and 
procedures.


Novartis
Confidential
Page 4
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
SPONSOR SIGNATORY
,MD
 
 
Phone:
 
Email:
Date


Novartis
Confidential
Page 5
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
SPONSOR INFORMATION PAGE
Medical Lead Contact Information:
,MD
 
 
Novartis Pharmaceuticals Corporation 
One Health Plaza,Bldg 337/
 
East Hanover, NJ 07936-1080 USA 
Phone:
 
Mobile:
 
Email:
www.novartis.com
 Contact Information:
Novartis Pharmaceuticals Corporation
One Health Plaza
Bldg. 337/
East Hanover,
NJ 07936-1080
USA
Phone:
Mobile:
Email:
If you have any questions regarding the protocol, please contact your local Novartis 
office
Regulatory Agency Identifying Number US [IND 111439]
Health Canada reference number = 9427-G0838-279C
S. Korea: Receipt number = 20110110591
EudraCT number = 2014-002041-22.


Novartis
Confidential
Page 6
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number PKB115131/CASB183X2X01B
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


Novartis
Confidential
Page 7
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
TABLE OF CONTENTS
PAGE
ABBREVIATIONS .........................................................................................................11
PROTOCOL SYNOPSIS...............................................................................................13
1.
INTRODUCTION....................................................................................................15
1.1.
Background ................................................................................................15
1.1.1.
Afuresertib ...................................................................................15
1.1.2.
Pharmacokinetics of Afuresertib in Humans.................................15
1.1.3.
Clinical Safety of Afuresertib........................................................16
1.1.4.
PKB116611 .................................................................................18
1.1.5.
LCH115397 .................................................................................19
1.1.6.
Clinical Activity of Afuresertib.......................................................19
1.2.
Rationale ....................................................................................................20
1.2.1.
Study Rationale ...........................................................................20
1.2.2.
Dose Rationale ............................................................................20
1.2.3.
Population Rationale....................................................................21
1.2.4.
Endpoint Rationale ......................................................................21
1.3.
Summary of Risk Management...................................................................21
1.3.1.
Risk Assessment for Afuresertib..................................................22
2.
OBJECTIVE(S) ......................................................................................................22
2.1.
Primary.......................................................................................................22
2.2.
Secondary ..................................................................................................22
3.
INVESTIGATIONAL PLAN.....................................................................................23
3.1.
Study Design/Schematic.............................................................................23
3.2.
Study Design ..............................................................................................23
3.2.1.
Cohort A and Cohort B: Afuresertib Monotherapy........................24
3.2.2.
Cohort C: Afuresertib Combination Therapy ................................25
4.
SUBJECT SELECTION AND DISCONTINUATION/ COMPLETION 
CRITERIA ..............................................................................................................26
4.1.
Subject Selection Criteria............................................................................26
4.1.1.
Number of Subjects .....................................................................26
4.1.2.
Inclusion Criteria..........................................................................26
4.1.3.
Exclusion Criteria.........................................................................27
4.1.4.
Other Eligibility Criteria Considerations........................................28
4.2.
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria.....................................................................................28
4.2.1.
Permanent Discontinuation from Study Treatment.......................28
4.2.2.
Subject Completion Criteria .........................................................30
5.
STUDY ASSESSMENTS AND PROCEDURES .....................................................30
5.1.
Transition Visit ............................................................................................30
5.2.
Continuous Dosing Treatment Period .........................................................31
5.2.1.
Cohort A and B............................................................................31
5.2.2.
Cohort C......................................................................................32
5.3.
Final Study Visit..........................................................................................32


Novartis
Confidential
Page 8
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
5.4.
Safety .........................................................................................................33
5.4.1.
Physical Examinations.................................................................33
5.4.2.
Vital Signs....................................................................................33
5.4.3.
Electrocardiograms......................................................................33
5.4.4.
Clinical Laboratory Assessments .................................................34
5.5.
Multiple Myeloma Specific Disease Assessments:......................................35
5.6.
Disease Assessments for Malignancies Other Than MM ............................35
5.7.
Performance Status....................................................................................35
5.8.
Pregnancy ..................................................................................................35
5.8.1.
Time period for collecting pregnancy information.........................35
5.8.2.
Action to be taken if pregnancy occurs ........................................35
5.8.3.
Action to be taken if pregnancy occurs in a female partner 
of a male study subject ................................................................36
5.9.
Adverse Events (AE) and Serious Adverse Events (SAE)...........................36
5.9.1.
Adverse Events............................................................................36
5.9.1.1.
Definition of an AE......................................................36
5.9.1.2.
Definition of a SAE .....................................................37
5.9.1.3.
Laboratory and Other Safety Assessment 
Abnormalities Reported as AEs and SAEs .................38
5.9.1.4.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................39
5.9.1.5.
Time Period and Frequency of Detecting AEs 
and SAEs ...................................................................39
5.9.1.6.
Prompt Reporting of Serious Adverse Events 
and Other Events to Novartis......................................40
5.9.1.7.
Regulatory Reporting Requirements For SAEs...........41
6.
STUDY TREATMENTS..........................................................................................41
6.1.
Afuresertib Investigational Product Dosage/Administration.........................41
6.2.
Other Anti-Cancer Agents (Cohort C) .........................................................43
6.3.
Administration of Study Treatment..............................................................43
6.4.
Handling and Storage of Study Treatment ..................................................43
6.5.
Treatment Assignment................................................................................43
6.6.
Dose Modifications .....................................................................................44
6.6.1.
Afuresertib Dose Modification ......................................................44
6.6.2.
Dose Modification: Other Anti-Cancer Agent(s)............................45
6.7.
Guidelines for Adverse Events of Special Interest.......................................45
6.7.1.
Supportive Measures for Nausea or Vomiting..............................46
6.7.2.
Supportive Measures for Hyperglycemia .....................................46
6.7.3.
Management of Diarrhea .............................................................46
6.7.4.
Management of Rash...................................................................46
6.7.5.
Guidelines for Management of Dyspepsia....................................47
6.7.6.
Guidelines for Management of Mucositis .....................................48
6.7.7.
Liver Chemistry Stopping Criteria ................................................48
6.7.7.1.
Actions if Liver Chemistry Stopping Criteria are 
met.............................................................................49
6.7.7.2.
Liver Event Follow-Up Assessments ..........................50
6.7.7.3.
Liver Chemistry Monitoring Criteria.............................51
6.7.7.4.
Drug Restart/Rechallenge Following Liver 
Events that are Possibly Related to IP........................51
6.7.8.
QTc Withdrawal Criteria...............................................................52
6.8.
Blinding.......................................................................................................52


Novartis
Confidential
Page 9
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
6.9.
Product Accountability ................................................................................52
6.10.
Treatment Compliance................................................................................53
7.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................53
7.1.
Permitted Medication(s) and non-Drug Therapies.......................................53
7.2.
Prohibited Medication(s) and Non-Drug Therapies .....................................54
7.2.1.
Drugs Potentially Affected by Afuresertib (afuresertib
perpetrator interaction potential ...................................................54
7.2.1.1.
Drugs that may potentially affect afuresertib
(perpetrators)..............................................................55
8.
LIFESTYLE AND/OR DIETARY RESTRICTIONS..................................................56
8.1.
Contraception Requirements ......................................................................56
8.1.1.
Female Subjects..........................................................................56
8.1.2.
Male Subjects..............................................................................57
8.2.
Meals and Dietary Restrictions ...................................................................57
8.3.
Activity ........................................................................................................57
9.
DATA MANAGEMENT ...........................................................................................57
10. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................58
10.1.
Hypotheses and Treatment Comparisons...................................................58
10.2.
Sample Size Considerations.......................................................................58
10.2.1.
Sample Size Assumptions ...........................................................58
10.2.2.
Sample Size Re-estimation..........................................................58
10.3.
Data Analysis Considerations .....................................................................58
10.3.1.
Analysis Populations....................................................................58
10.3.2.
Analysis Data Sets.......................................................................58
10.3.3.
Interim Analysis ...........................................................................58
10.3.4.
Key Elements of Analysis Plan ....................................................58
10.3.5.
Safety Analyses...........................................................................59
10.3.5.1.
Extent of Exposure .....................................................59
10.3.5.2.
Adverse Events ..........................................................59
10.3.5.3.
Clinical Laboratory Evaluations ..................................59
10.3.5.4.
Other Safety Measures...............................................59
10.3.5.5.
Clinical Activity Analyses ............................................60
11. STUDY CONDUCT CONSIDERATIONS ...............................................................60
11.1.
Posting of Information on Clinicaltrials.gov..................................................60
11.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
11.3.
Urgent Safety Measures .............................................................................60
11.4.
Quality Control (Study Monitoring) ..............................................................60
11.5.
Quality Assurance.......................................................................................61
11.6.
Study and Site Closure ...............................................................................61
11.7.
Records Retention......................................................................................62
11.8.
Provision of Study Results to Investigators, Posting to the Clinical 
Trials Register and Publication ...................................................................62
12. REFERENCES.......................................................................................................63
APPENDICES...............................................................................................................65
Appendix 1:  Time and Events Table for Cohort A and B........................................65


Novartis
Confidential
Page 10
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 2:  Time and Events Table for Cohort C..................................................67
Appendix 3:  Liver Safety Drug Restart Guidelines.................................................69
Appendix 4:  COCKCROFT-GAULT FORMULA.....................................................73
Appendix 5:  Disease Assessments and Response Criteria ...................................74
Appendix 6:  RECIST Guidelines............................................................................85
Appendix 7:  Hy’s Law............................................................................................90
Appendix 8: Protocol Amendment Changes ...........................................................91
Section: 1.1.1 Afuresertib..........................................................................146


Novartis
Confidential
Page 11
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
ABBREVIATIONS
-HCG
Beta-Human Chorionic Gonadotropin
µg
Microgram
µL
Microliter
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
ANOVA
Analysis of Variance
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
BP
Blood pressure
BPM
Beat Per Minute
BUN
Blood urea nitrogen
CBC
Complete blood count
CDMP
Clinical Document Management and Publishing
CIB
Clinical Investigator’s Brochure
CO2
Carbon dioxide
CPDS
Clinical Pharmacology Data Sciences
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacokinetics Modelling & Simulation
CPSR
Clinical Pharmacology Study Report
CRF
Case Report Form
CRF
Case Report Form
CRO
Contract Research Organization
CRU
Clinical Research Unit
CV
Coefficient of variance
DBP
Diastolic blood pressure
DDS
Drug Development Sciences
DILI
Drug Induced Liver Injury
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic data capture
EISR
Expedited Investigator Safety Report
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
FTIH
First time in humans
GCP
Good Clinical Practice
GCPH
Global Clinical Program Head
GCSP
Global Clinical Safety and Pharmacovigilence
GSK
GlaxoSmithKline
h/hr
Hour(s)


Novartis
Confidential
Page 12
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HIV
Human Immunodeficiency Virus
HR
Heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IND
Investigational New Drug
IP
Investigational Product
IR
Immediate Release Tablet
IRB
Institutional Review Board
IU
International Unit
IV
Intravenous
Kg
Kilogram
L
Liter
LFTs
Liver function tests
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
msec
Milliseconds
MUGA
Multi Gated Acquisition Scan
PD
Pharmacodynamic
PK
Pharmacokinetic
QC
Quality control
QD
Once daily
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAMOS
Registration and Medication Ordering System
RAP
Reporting and Analysis Plan
RBA
Relative Bioavailability
RBC
Red blood cells
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SD
Standard deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
SPM
Study Procedures Manual
SUSAR
Suspected, Unexpected, Serious Adverse drug Reaction
TSH
Thyroid stimulating hormone
UK
United Kingdom
ULN
Upper limit of normal
US
United States
WBC
White blood cells


Novartis
Confidential
Page 13
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
PROTOCOL SYNOPSIS

PRODUCT:  Afuresertib (GSK2110183)

PROTOCOL TITLE:  An Open Label Continuation Study of the Oral AKT 
Inhibitor GSK2110183 in Subjects with Hematologic or Solid Tumor 
Malignancy

PROTOCOL/AMENDMENT NO.:  PKB115131/Amendment 03

U.S. IND NO.:  111439
CLINICAL PHASE:  II

OBJECTIVES:  To provide continued treatment with afuresertib for subjects
who have completed participation in a Novartis-sponsored afuresertib study, or 
an afuresertib study sponsored by another research organization working on 
behalf of Novartis. Additional safety information about afuresertib will also be 
collected.  

HYPOTHESES:  There are no hypotheses being explored in this treatment 
continuation or ‘rollover’ study.

STUDY DESIGN AND DURATION:  Multicenter, non-randomized, open-label, 
rollover study.  Eligible subjects will be enrolled in the appropriate cohort based 
upon the duration and treatment received in their parent study.  Enrollment into 
this study will be dependent upon the site’s agreement to participate in this study.  
Subjects will receive afuresertib and possibly other anti-cancer agents at the 
same dose and regimen most recently taken in their parent study.  The dose will 
not exceed the maximum tolerated dose established in prior studies.  Subjects 
may continue treatment in the rollover study until disease progression, 
unacceptable toxicity, withdrawal of consent, or death.

PATIENT SAMPLE:  Approximately 200 subjects worldwide.

DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN:          
Afuresertib - Up to 150 mg (provided as 100 mg and 25 mg gelatin capsules or 
50 mg and 75 mg Immediate Release (IR) tablets), given orally, once daily in 3 
or 4 week cycles, depending on the schedule and treatment used in the parent 
study.  Dose adjustments are allowed to address tolerability and safety issues.
Other anti-cancer agents will continue to be given at the same dose and regimen 
as in the parent study.  Any dose modifications will follow. parent protocol or 
most recent prescribing information.

PHARMACOKINETIC/PHARMACODYNAMIC MEASUREMENTS:  There 
is no serial pharmacokinetic (PK) sampling for this study.  Single, safety PK 
blood draws may be collected for subjects with liver or rash adverse events.

EFFICACY MEASUREMENTS:  This study will not collect efficacy data.  
However, clinical activity will be assessed using local standard of care practices 
to determine eligibility for continued study participation.  Only subjects who are 
clinically benefitting and tolerating treatment with afuresertib may continue on 
study.


Novartis
Confidential
Page 14
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

SAFETY MEASUREMENTS:  Routine physical examinations, vital sign 
measurements, 12-lead electrocardiograms, echocardiograms or multiple-gated 
acquisition scans, clinical laboratory tests, and monitoring of adverse events.  
Additional safety assessments may be necessary if a combination treatment 
regimen is administered to address specific safety concerns with the other 
agent(s) being administered.

DATA ANALYSIS:  Subject demographic and safety data will be collected on 
eCRFs.  All data will be pooled and descriptive safety analyses summarized and 
listed by cohort at study conclusion.


Novartis
Confidential
Page 15
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
1.
INTRODUCTION
1.1.
Background
AKT is a serine/threonine protein kinase with three isoforms (AKT1, AKT2, and AKT3) 
that participate in multiple pathways regulating several cellular processes, including 
survival, proliferation, tissue invasion, and metabolism [Tanno, 2001; Morgensztern, 
2005].  Aberrant activation of the PI3K/AKT pathway occurs in virtually every type of 
hematologic malignancy, suggesting that dysregulation of these pathways may be 
required for carcinogenesis.  The importance of AKT-mediated pathways in tumor 
proliferation and survival render AKT kinases promising targets for therapeutic 
intervention.  Hyperactivation of the AKT pathway can also correlate with chemotherapy 
resistance and poorer prognosis.  Nonclinical data suggest that blocking AKT1 and 
AKT2 activity can inhibit the proliferation of tumor cells and either induce an apoptotic 
response or sensitize tumors to undergo apoptosis in response to other cytotoxic agents 
[DeFeo-Jones, 2005].  
1.1.1.
Afuresertib
Afuresertib was evaluated in 10 different MM cell lines either alone or in combination 
with a proteasome inhibitor (either bortezomib or carfilzomib).  Six of 10 MM cell lines 
showed <1 µM gIC50 (concentration producing 50% inhibition of growth) for afuresertib 
as a single agent in a 3-day cell proliferation assay.  The combination of afuresertib with 
bortezomib showed strong synergy in all 10 cell lines tested at concentrations that are 
clinically achievable.  Similar synergy was also observed with combination of afuresertib 
and carfilzomib.  The synergistic anti-proliferative effect of AKT inhibitor and 
bortezomib is likely mediated by increased induction of apoptosis, as evidenced by 
increase in caspase 3/7 activity in National Cancer Institute (NCI) H929 cells.
The safety, pharmacokinetic (PK) and pharmacodynamic profiles and activity of 
afuresertib administered as monotherapy was evaluated in the first time in humans 
(FTIH) trial PKB112835.  Among 34 relapsed/refractory MM subjects treated with 
afuresertib three have achieved partial response (PR), and a further 3 achieved minimal 
response (MR) accounting for clinical benefit rate (CBR) of 17.6 in this heavily 
pretreated population.  The combination of afuresertib with bortezomib and 
dexamethasone is being currently evaluated in PKB115125 study.  The preliminary 
results (data cut-off 29-Jun-2014) in relapsed MM population demonstrate overall 
response rate (ORR) of 61% (PR or better) and CBR of 78%.  The investigator should 
refer to the current version of the afuresertib Investigator’s Brochure (IB) for detailed 
information regarding all completed and ongoing clinical studies with afuresertib, PK in 
the target disease populations, as well as observed safety and clinical activity findings.
1.1.2.
Pharmacokinetics of Afuresertib in Humans
In the FTIH monotherapy study in subjects with relapsed or refractory hematologic 
malignancies (PKB112835), afuresertib plasma concentrations following single 
afuresertib doses were measured over the 72-hour sample collection period in all subjects.  
Afuresertib accumulated 1.4- to 5.1-fold with repeat daily dosing.  Single-dose and 


Novartis
Confidential
Page 16
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
repeat-dose mean area under the plasma concentration-time curve (AUC(0-24)) and 
maximum observed plasma concentration (Cmax) values increased with increasing doses; 
however, given the intersubject variability, there was substantial overlap in the 
AUC(0-24) and Cmax values between successive dose groups.  The 100 mg and 125 mg 
multiple-dose exposure data were similar.  Median time to Cmax (tmax) across doses was 
2 hours.  Based on available data from all cohorts, the mean accumulation half life (t1/2) 
is approximately 1.7 days and the median tmax on Day 8 is 2 hours.  For details of the 
PK of afuresertib see the current version of the IB.
Preliminary PK results from the PKB115125 combination study of afuresertib with 
bortezomib and dexamethasone indicate mean afuresertib exposure (n=7) was similar 
alone or in combination with bortezomib and dexamethasone, and mean bortezomib 
exposure (n=7) co-administered with dexamethasone was similar with and without 
afuresertib.  Mean dexamethasone exposure co-administered with bortezomib was 30-
50% higher when dosed with afuresertib than without afuresertib; although sample size 
was small (n=5) and exposure values overlapped.
1.1.3.
Clinical Safety of Afuresertib
As of 29-Jun-2013, 226 subjects had received at least 1 dose of afuresertib either as 
monotherapy or in combination with other agents in the 7 original GSK-sponsored 
studies with afuresertib.  The most common adverse events (AEs) reported in all studies 
were primarily gastrointestinal (GI) disorders including: diarrhea, nausea, and vomiting, 
dyspepsia, and constipation.
More detailed safety characteristics from the two most relevant studies are described in 
greater detail below.  The studies are considered most relevant because they were 
conducted in subjects with hematologic malignancies (PKB112835), and in subjects with 
MM (PKB115125). 
Additional information from all studies where subjects with other diseases are 
administered afuresertib, as monotherapy or in combination, can be found in the current 
afuresertib IB.
PKB112835
This was an open-label, 2-part, FTIH study designed to investigate the safety, tolerability, 
PK, and pharmacodynamics of afuresertib in subjects with hematologic malignancies.  A 
total of 73 subjects were enrolled in this study, 26 in Part 1 (dose escalation), and 47 in 
Part 2 (expansion).  Afuresertib was administered orally once daily at doses of 25 mg, 
75 mg, 100 mg, 125 mg, or 150 mg and the maximum tolerated dose (MTD) was 
established at 125 mg for this dosing based on dose limiting toxicities (DLTs) in 
2/6 subjects at the 150 mg dose.  Both DLTs were elevations in liver function tests 
(LFTs).  No DLT was reported in any subject enrolled in Part 1 at doses below 150 mg.  
Both subjects with DLTs had non-Hodgkin’s lymphoma (NHL): 1 subject had Grade 3 
elevations in alanine aminotransferase (ALT) and alkaline phosphatase (ALP), 
accompanied by elevations in aspartate aminotransferase (AST), total bilirubin, and 
eosinophilia, the other subject had liver involvement from lymphoma and experienced 
Grade 3 elevations in ALT and ALP.


Novartis
Confidential
Page 17
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
The most frequent type of malignancy in the trial was MM (34 subjects; 47%), followed 
by NHL (13 subjects, 18%), Hodgkin’s lymphoma (HD) (8 subjects, 11%), acute myeloid 
leukemia (AML) (9 subjects, 12%), chronic lymphocytic leukemia (CLL) (7 subjects, 
10%), acute lymphoblast leukemia (ALL) (1 subject, 1%), and Langerhans cell 
histiocytosis (LCH) (1 subject, 1%).  The most frequent (10% of subjects) AEs were 
nausea (35.6%), diarrhea (32.9%), dyspepsia (24.7%), fatigue (20.5%), gastroesophageal 
reflux disease (GERD; Grade 1) (19.2%), anorexia (19.2%), vomiting (19.2%), anemia 
(15.1%), upper respiratory tract infection (13.7%), asthenia (13.7%), back pain (12.3%), 
rash (12.3%), insomnia (12.3%), constipation (11.0%), odynophagia (11.0%), and cough 
(11.0%).  Grade 3 or higher AEs (in 2 subjects) included anemia (9.6%), neutropenia 
(9.6%), thrombocytopenia (6.8%), sepsis (4.1%), febrile neutropenia (4.1%), 
odynophagia (4.1%), rash (4.1%), asthenia (2.7 %), diarrhea (2.7%), fatigue (2.7%), 
pneumonia (2.7%), and abnormal LFTs (2.7%).  Grade 5 AEs were observed in 2 
subjects: septic shock, considered not related to afuresertib and concomitant pneumonia 
and sepsis, considered not related to afuresertib in a subject who died from disease 
progression.  There was no obvious relationship between the type of AEs and malignancy 
type.  Three deaths were reported during the study (disease progression, n=2; septic 
shock, n=1).
PKB115125
This is an ongoing open-label, 2-part, repeat- and escalating-dose study designed to 
investigate the safety, tolerability, PK, pharmacodynamics, and clinical activity of 
afuresertib administered once daily in combination with bortezomib and dexamethasone 
(twice weekly schedule) in subjects with relapsed/refractory MM.  In the study’s Part 1 
dose-escalation, 34 subjects were administered doses of afuresertib in combination with 
bortezomib and dexamethasone in the following sequence: 75 mg/day (n=4), 100 mg/day 
(n=6), 125 mg/day (n=6), 150 mg/day (n=12), 175 mg/day (n=6) and plus dexamethasone 
(40 mg) on days of bortezomib administration (n=6).  The MTD for afuresertib was 
established at 150 mg once daily in combination with bortezomib (1.3 mg/m2 on Days 1, 
4, 8, and 11 of a 21-day cycle) and dexamethasone 40 mg (on days of bortezomib dosing 
only).  Four subjects experienced DLTs during Part 1: 100 mg/day, Grade 2 elevations in 
ALT; 125 mg/day, Grade 3 erythema multiforme; 175 mg/day, Grade 3 diarrhea, 
thrombocytopenia, and rash; 175 mg/day, Grade 3 maculo-papular rash.  Part 1 was 
followed by a cohort-expansion phase (Part 2).  As of the data cut-off date of 
18-Oct-2013, Part 2 included 23 subjects who received 150 mg of afuresertib once daily 
in combination with bortezomib and dexamethasone.  An additional 10 subjects were 
enrolled into the PK/pharmacodynamic cohort.  
The most common AEs (>10% of subjects) were primarily GI toxicities.  No new safety 
concerns were identified from the use of afuresertib in combination compared with the 
safety profile observed with afuresertib monotherapy.  The most common AEs (in 10% 
of subjects) were as follows: fatigue (51% [2% Grade 3, no Grade 4]), diarrhea (49% 
[14% Grade 3, no Grade 4]), thrombocytopenia 38%, [16% Grade 3, 11% Grade 4]), 
nausea (37% [1% Grade 3, no Grade 4]), constipation (33% [2% Grade 3, no Grade 4]), 
dyspepsia (32% [1% Grade 3, no Grade 4]), hyperglycemia (28% [6% Grade 3, 1%
Grade 4]), vomiting (27% [2% Grade 3, no Grade 4]), anemia (22% [10% Grade 3, no 
Grade 4), peripheral neuropathy (22% [no Grade 3/4]), insomnia (20% [no Grade 3/4]), 


Novartis
Confidential
Page 18
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
rash (20% [7% Grade 3, no Grade 4]), dizziness (20% [no Grade 3/4]), upper respiratory 
tract infection (17% [no Grade 3/4]), cough (14% [no Grade 3/4]), lymphopenia 
(14%[5% Grade 3, 2% Grade 4]), pyrexia (14% [no Grade 3/4]), blood creatinine 
increased (12% [1% Grade 3, 1% Grade 4]), asthenia (11% [2% Grade 3, no Grade 4]), 
dysgeusia (11% [no Grade 3/4]), headache (11% [no Grade 3/4]), neutropenia (11% [5% 
Grade 3, 2% Grade 4]), abdominal pain (10% [1% Grade 3, no Grade 4]), ALT increased 
(10% [2% Grade 3, no Grade 4]), decreased appetite (10% [1% Grade 3, no Grade 4]), 
exertional dyspnea (10% [no Grade 3/4]), epistaxis (10% [no Grade 3/4]), herpes zoster 
(10% [no Grade 3/4]), hypotension (10% [2% Grade 3, no Grade 4]), and urinary tract 
infection (10%[1% Grade 3, no Grade 4]).  Grade 5 AEs were observed in 2 subjects: 
septic shock, and sepsis.  
1.1.4.
PKB116611
PKB116611 is an ongoing open-label, Phase 1/2 dose-escalation study of afuresertib in 
combination with carboplatin and paclitaxel in subjects with platinum-resistant/refractory 
ovarian cancer.  The primary objective of the Phase 1 part of the study is to determine the 
safety and tolerability of the triplet combination, which will be used to define the dosing 
regimen to be evaluated in Phase 2.  The primary objective of the Phase 2 part of the 
study is to evaluate the clinical efficacy (defined by the overall response rate) of the 
triplet combination, in patients with platinum-resistant or platinum-refractory ovarian 
cancer.
Afuresertib doses of 50 to 150 mg/day were explored in combination with carboplatin 
(IV) AUC 5 and paclitaxel (IV) 175 mg/m2 administered day 1 every 21 days for a 
maximum of 6 doses.  Phase 2 expansion cohorts at the recommended Phase 2 afursertib 
dose of 125 mg are ongoing in platinum resistant and platinum refractory cohorts.
As of the data cut-off date of 29-Jun-2014, 52 subjects have been enrolled in the study; 
29 subjects in Part 1 and 23 subjects in Part 2.  Of these, data are available for 49 subjects, 
including all subjects in Part 1 and 20 subjects in Part 2.  For those subjects with 
available data, 2 subjects who are platinum refractory have been enrolled to Part 2; all 
other subjects are platinum resistant.  Three subjects (6.1%) discontinued study treatment 
because of AEs and 13 subjects (26.5%) discontinued because of progressive disease.
The most common AEs (≥10% of subjects) were primarily gastrointestinal toxicities, 
alopecia, and fatigue.  The event of fatigue was reported at a similar incidence in 
Study PKB115125, where afuresertib was administered with bortezomib/dexamethasone. 
In total, 18 (36.7%) subjects reported Grade 3 AEs and 12 (24.5%) subjects reported 
Grade 4 AEs.  The following Grade 3 AEs were reported: hypomagnesaemia (8.2%), 
neutropenia (8.2%), hyperglycaemia (6.1%), vomiting (6.1%), ascites (4.1%), dyspnoea 
(4.1%), lower respiratory tract infection (4.1%), nausea (4.1%), rash (4.1%), rash 
maculo-papular (4.1%), small intestinal obstruction (4.1%), and abdominal pain, anaemia, 
chills, colonic obstruction, dermatitis acneiform, diarrhoea, drug hypersensitivity, 
escherichia urinary tract infection, fatigue, febrile neutropenia, gastroenteritis viral, 
hypersensitivity, hypertension, hyperthyroidism, hypophosphataemia, lobar pneumonia, 
neutropenic sepsis, oesophagitis, platelet count decreased, pneumonia, pyrexia, renal 


Novartis
Confidential
Page 19
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
failure acute, supraventricular tachycardia, syncope, urinary tract infection, and white 
blood cell count decreased (each reported in 2.0% subjects).  In addition, the following 
Grade 4 AEs were reported: neutropenia (20.4%), thrombocytopenia (4.1%), 
hypomagnesaemia (2.0%), platelet count decreased (2.0%), and white blood cell count 
decreased (2.0%).«There were also 2 uncoded Grade 3 AEs in the eye disorders SOC 
(2.0% each).
Five subjects discontinued treatment with afuresertib due to AEs; these were abdominal 
pain, blood creatinine increased, decreased appetite, dehydration, diarrhea, 
gastroesophageal reflux disease, headache, muscle spasms, nausea, neutropenia, pleural 
effusion, syncope, and vomiting (1 subject each).
As of 29-Jun-2014, 1 subject died while on study.  Two additional patients died while off 
study (>30 days after the last dose of afuresertib).
Overall 56 SAEs have been reported in 34 subjects; of these, 18 SAEs in 10 subjects 
were considered by the investigator to be related to afuresertib.
1.1.5.
LCH115397
LCH115397 was an open label, repeat-dose study designed to investigate the efficacy and 
safety of afuresertib in subjects with LCH.  This study is complete.
In total, 17 subjects were enrolled in the study at doses up to 125 mg administered 
continuously, once daily.  Of these, 16 of the 17 subjects completed the study and 
1 subject voluntarily withdrew from the study.
One subject, receiving 125 mg/day, discontinued treatment because of an AE (Grade 2 
impaired gastric emptying) which was considered to be not related to afuresertib, in the
opinion of the investigator.
Five (29%) subjects had AEs of Grade 3 or higher, these were: ALT increased, diarrhea, 
fatigue, hyponatraemia, impaired gastric emptying, lung infection, esophageal ulcer, pain, 
perineal pain, pseudomonas infection, soft tissue necrosis, and vulvovaginal pain.  None 
of these occurred in more than 1 subject.
No subject died during the study.  Five SAEs have been reported in 3 subjects, only 1 of 
which (soft tissue necrosis) was considered possibly related to afuresertib
1.1.6.
Clinical Activity of Afuresertib
Clinical activity of afuresertib monotherapy was seen in subjects with hematologic 
malignancies in the PKB112835 FTIH study.  Of the 34 subjects with MM, three subjects 
demonstrated confirmed PR and median time on study for those subjects was 319 days 
(range 215-541).  Three additional subjects had MR and their median time on study was 
336 days (range 157-484).  The overall CBR for MM subjects (PR+MR) was therefore, 
17.6% (6/34).  An additional 14 subjects with MM had prolonged stabilization of their 


Novartis
Confidential
Page 20
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
disease for a median 118.5 days (range 48-426).  Clinical activity has also been observed 
in subjects with lymphomas (1 complete response [CR] and 2 partial responses [PRs] in 
13 subjects with NHL) and 4/8 subjects with HD achieving unconfirmed PR.
In the ongoing combination study (PKB115125) of afuresertib with bortezomib and 
dexamethasone, responses have been reported in the dose escalation and expansion 
phases of the study.  In the population of relapsed MM subjects treated at the 
afuresertib’s MTD (150 mg) in Part 2 of the study, the confirmed overall response rate 
was 61% (14/23 subjects; 3 very good partial responses [VGPR] and 11 PR).  Data on 
duration of responses are not available yet from this ongoing study.
Additional information from all studies where subjects with other diseases are 
administered afuresertib, as monotherapy or in combination, can be found in the current 
afuresertib IB.
1.2.
Rationale
1.2.1.
Study Rationale
The purpose of this study is to allow for continued treatment with afuresertib in subjects 
who have participated in a ‘parent’ GSK or Novartis sponsored study of afuresertib, 
either as monotherapy or as part of a combination regimen, and met the protocol 
requirements for transitioning to this rollover study. The parent study will have met it’s 
primary endpoint and transitioning to this rollover study will allow data to be reported for 
the parent study.  In addition, subjects will be monitored for adverse events, as this study 
will continue to collect safety information on afuresertib.
Subject enrollment into Cohorts A and B is based on the duration of treatment on a  
monotherapy parent study with Cohort A enrolling subjects who received less than 24 
weeks of treatment, while Cohort B will enroll subjects who have received 24 weeks or 
greater afuresertib therapy.  Cohort C will enroll subjects who have participated on a 
combination study where afuresertib is given with another anti-cancer agent(s).  The 
purpose of having separate cohorts is to be able to better report and define the safety 
profile for these subject groups. 
1.2.2.
Dose Rationale
The dose of study treatment to be administered to subjects will be individualized based 
upon the dose/regimen received during their participation in the parent study at the time 
of transition to this rollover study.  No dose of afuresertib above the MTD established in 
the parent study will be allowed in this study.
Cohort A and B: 
Subjects who have received <24 weeks ( Cohort A) or 24 weeks (Cohort B) of 
afuresertib as monotherapy in the parent study will receive the same continuous dosing 
regimen of afuresertib at completion of the parent study.  If a subject required a dose 
modification while receiving treatment in the parent study, the subject will enter the 
rollover study and continue treatment on the modified dose unless after consultation with 


Novartis
Confidential
Page 21
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
the Novartis Medical Lead, it is appropriate to escalate the dose.  The dose may be 
escalated up to the MTD established in the parent study.
Cohort C:
Subjects who have received any duration of a combination regimen with afuresertib and 
another anti-cancer agent will continue treatment in the rollover study at the current dose 
level(s) administered in the parent study at the time of transition to the rollover study. If 
the subject discontinued the anticancer drug, which was studied as a part of a parent 
study- the subject will enter and continue on the roll over study while receiving 
monotherapy with afuresertib. Adding additional anticancer drugs is not allowed. If a 
subject required a dose modification while receiving treatment in the parent study, the 
subject will enter the rollover study and continue treatment on the modified dose unless 
after consultation with the Novartis Medical Lead, it is appropriate to escalate the dose.  
Any dose modifications will follow parent protocol or most recent prescribing 
information.
1.2.3.
Population Rationale
Afuresertib is being explored for its anti-cancer activity in subjects with hematologic and 
solid tumor malignancies.  All subjects enrolled into this study will have participated in a 
prior afuresertib study.  Subjects must meet entry criteria at the time of transition to this 
study.
1.2.4.
Endpoint Rationale
This study will collect additional safety data from prolonged exposure to afuresertib, as 
monotherapy or in combination with other therapies. Primary endpoints for the study will 
be: adverse events, changes in laboratory values, and changes in vital signs. 
1.3.
Summary of Risk Management
Summaries of findings from clinical and nonclinical studies conducted with afuresertib 
can be found in the current IB.  The most common AEs seen to date in afuresertib studies 
include; nausea, diarrhea, dyspepsia, fatigue, thrombocytopenia, neutropenia, 
hyperglycemia, upper respiratory infection, anorexia, gastrointestinal reflux and rash.  
The anticipated resks are listed below. 


Novartis
Confidential
Page 22
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
1.3.1.
Risk Assessment for Afuresertib
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Gastrointestinal toxicity
GI toxicity has been observed both 
afuresertib with most frequent events 
being: diarrhea, nausea, vomiting and 
dyspepsia. 

Exclusion of subjects with significant pre-
existing GI conditions

Close monitoring via continuous 
assessment of AEs, physical examination, 
and clinical laboratory assessments (see 
Section 6.7).

Management guidelines and stopping 
criteria are provided for diarrhea, 
mucositis, and dyspepsia (see Section 
6.7))
Rash
Rash has been frequently observed 
with afuresertib monotherapy and in 
combination therapies

Monitoring rash via assessment of AEs 
and physical examination (see Section
6.7.4.).

Management guidelines and stopping 
criteria are provided (see Section 6.7.4).).
Hepatic toxicity
LFT elevations have been observed 
with afuresertib.  

Exclusion of subjects with impaired liver 
function.

Monitoring and stopping criteria are 
provided (see Section 6.7.7))
Hyperglycaemia
Elevated glucose levels have been 
observed with compounds inhibiting 
PI3/AKT pathway.  Afuresertib can 
potentially cause hyperglycemia.

Only subjects with well-controlled Type 2 
diabetes will be enrolled in the study

Glucose monitoring will be implemented 
as clinically indicated.  

Management guidelines and stopping 
criteria are provided (see Section 6.7.2))
2.
OBJECTIVE(S)
2.1.
Primary
The primary objective of the study is to provide treatment with afuresertib for subjects 
who have previously participated in an afuresertib study sponsored previously by GSK or 
Novartis or another research organization working on behalf of Novartis.
2.2.
Secondary
The secondary objective of the study is to collect safety data on continued treatment with 
afuresertib.


Novartis
Confidential
Page 23
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
3.
INVESTIGATIONAL PLAN
3.1.
Study Design/Schematic
Figure 1
Study design
3.2.
Study Design
This multicenter, non-randomized, open-label, rollover study is designed to provide 
continued access to afuresertib to subjects who have previously participated in an
afuresertib study.  All subjects enrolling in this study must be tolerating and benefitting 
from treatment (ie did not meet any of the study discontinuation criteria from the parent 
study) with afuresertib to be eligible.  Subjects will be enrolled into the appropriate 
cohort (Section 3.2.1) based upon the duration and treatment received in their parent 
study.  Enrollment into this study will be dependent upon the site’s agreement to 
participate in this study.  
Subjects must first provide written informed consent for this rollover study prior to any 
study-related assessment or procedure being performed and before any treatment with 
afuresertib can be administered under this protocol.  After informed consent is obtained, 
subjects will be evaluated for study eligibility in PKB115131/CASB183X2X01B.


Novartis
Confidential
Page 24
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Time and Events Tables for Cohorts 
A, B and C (Appendix 1, and Appendix 2, respectively), are essential.
The study will consist of a transition visit, continuous dosing treatment period, and a final 
study visit.
Safety assessments will be performed throughout the study: including physical 
examinations, vital sign measurements (blood pressure [BP], pulse rate, weight and 
temperature), 12-lead electrocardiograms (ECGs), clinical laboratory assessments, and 
monitoring of AEs.  Additional safety assessments may be necessary if a combination 
treatment regimen is administered to address specific safety concerns with the other 
agent(s).  
Assessment of clinical activity will be performed using local standard of care imaging 
practices and the assessment criteria appropriate for disease type and location to 
determine eligibility for continued study participation and treatment with afuresertib.  
Disease assessments must be performed at least every 12 weeks, or more frequently if the 
investigator decides that it is necessary. Guidelines for solid tumor (RECIST) 
assessments, and assessments of various hematologic malignancies are provided in 
Appendix 5 and Appendix 6. 
Subjects may continue treatment in this rollover study until disease progression, 
unacceptable toxicity or withdrawal of consent occurs, ordeath . Study will be completed 
when the last subject has withdrawn from study treatment.  
Refer to the Time and Events Table for Cohort A and B (Appendix 1) or Time and 
Events Table for Cohort C (Appendix 2) for timing of all assessments. 
Details regarding dose modifications of afuresertib and guidance on additional 
assessments and procedures following events of special interest can be found in 
Section 6.6 and Section 6.7, respectively.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying study procedures manual (SPM).  The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.1.
Cohort A and Cohort B: Afuresertib Monotherapy
Subjects will receive afuresertib as an oral, daily dose up to 150 mg. Protocol specified 
guidelines for dose modifications and treatment discontinuation criteria are provided in 
Section 6.6 and Section 6.7, respectively.  If there are any uncertainties about the dose to 
be administered in this study, the Novartis Medical Lead should be consulted.  


Novartis
Confidential
Page 25
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Cohort A:
Cohort A will consist of subjects who have completed <24 weeks of treatment with 
afuresertib monotherapy during their participation in the parent study.  It is anticipated 
that subjects in this cohort will have participated in a clinical pharmacology or other 
short-term study of afuresertib.  Subjects will complete the Transition Visit; receive 
instruction and study medication, and then return for their next scheduled visit (Study 
Week 4) and then every 4 weeks thereafter.  Subjects who remain on study treatment for 
>52 weeks (including time on parent study) may have the frequency of their interim visits 
decreased to every 8 weeks with approval from the Novartis Medical Lead.  After 
discontinuation of study treatment, the investigator will monitor all AEs/SAEs for 30 
days or until resolution, whichever comes first.
Cohort B:
Cohort B will consist of subjects who have completed 24 weeks of treatment with 
afuresertib monotherapy during their participation in the parent study.  It is expected that 
subjects in this cohort will have participated in a longer term study of afuresertib.  
Subjects will complete the Transition Visit, receive study instruction and study 
medication and then return for their next scheduled visit (Study Week 4), and then every 
4 weeks thereafter.  Subjects who remain on study treatment for >52 weeks (including 
time on parent study) may have the frequency of their interim visits decreased to every 8 
weeks with approval from the Novartis Medical Lead.  After discontinuation of study 
treatment, the investigator will monitor all AEs/SAEs for 30 days or until resolution, 
whichever comes first.
3.2.2.
Cohort C: Afuresertib Combination Therapy
Cohort C:
Cohort C will consist of subjects who have participated in a combination study where 
afuresertib is administered with another anti-cancer agent, regardless of duration on 
study.  Subjects who transition from a combination study may continue to receive 
afuresertib in combination with the anti-cancer agent defined by the parent study, or they 
may receive afuresertib as monotherapy. If the concomitant anticancer drug has been 
terminated according to parent study design, or if, in the opinion of the investigator, the 
subject has received maximum benefit, or is experiencing unacceptable toxicity from the 
anti-cancer agent, then treatment with the anti-cancer agent may be discontinued and the 
subject may remain on study for continued treatment with afuresertib monotherapy. 
Adding any other anticancer drug while on this study, is not allowed. Subjects will 
complete the Transition Visit, receive study instruction and study medication, and then 
return for their next scheduled visit (either Study Week 3 or 4) and then every 3 or 4 
weeks thereafter, depending on the schedule used in the parent study.  Subjects who 
remain on study treatment for >52 weeks (including time on parent study) may have the 
frequency of their interim visits decreased with approval from the Novartis Medical Lead
to every 8 or 9 weeks (whichever is consistent with parent schedule). After 
discontinuation of study treatment, the investigator will monitor all AEs/SAEs for 30 
days or until resolution, whichever comes first.


Novartis
Confidential
Page 26
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
4.
SUBJECT SELECTION AND DISCONTINUATION/ 
COMPLETION CRITERIA
4.1.
Subject Selection Criteria
4.1.1.
Number of Subjects
Approximately 200 subjects from approximately 60 investigative sites worldwide will be 
transitioned to this study from other afuresertib studies.
4.1.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on afuresertib or other agent(s) that may impact subject eligibility is 
provided in the IB for afuresertib or any subsequent IB supplements or in the Prescribing 
Information for any agent(s) administered as part of a combination treatment regimen, as 
applicable.
Deviations from inclusion 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.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Has provided signed informed consent for this study.
2. Is currently participating in an afuresertib study (monotherapy or in combination with 
another anti-cancer agent) sponsored by GSK/Novartis or by another research 
organization working on behalf of Novartis.  
3. Currently tolerating and benefitting from treatment with afuresertib as determined by 
the investigator following previous treatment with afuresertib either as monotherapy 
or as part of a combination treatment regimen.
4. Continued ability to swallow and retain orally administered study treatment(s) and 
does not have any clinically significant GI abnormalities that may alter absorption 
such as malabsorption syndrome or major resection of the stomach or bowels.
5. Male subjects with a female partner of childbearing potential must be willing to 
continue practicing the same acceptable method of contraception as used in the parent 
study during the rollover study and for at least 16 weeks after the last dose of 
afuresertib. 
6. Female subjects of childbearing potential, as defined in the parent study, must be 
willing to continue practicing the same acceptable method of contraception as used in 
the parent study during the rollover study and for at least 4 weeks after the last dose 
of afuresertib.  
7. Female subjects of childbearing potential, as defined in parent study, must have 
negative serum pregnancy tests at the time of transition to this study.


Novartis
Confidential
Page 27
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
8. Maintain a performance status score of 0 to 2 according to the Eastern Cooperative 
Oncology Group (ECOG) scale (Section 5.7) at time of transition into this study.
9. Subjects with Type II diabetes are only allowed if their HbA1C ≤ 8% at study entry.
10. Have adequate organ system function as defined in Table 1.
Table 1
Definitions of Adequate Organ Function
System
Laboratory Value
Hematologic
Absolute neutrophil count (ANC)
Hemoglobin
Platelets
1.0 x 109/L
8.0 g/dL
50 x 109/L 
PT/INR and PTT
1.5x ULN
Hepatic
Total bilirubin
AST and ALT
1.5x ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%)
3xULN. If liver involvement is present and ALT and AST levels 
are>3xUNL and<5xULN, enrollment into PKB115131 can occur 
as long as there is no concurrent bilirubin or INR elevation
Renal (Monotherapy)
Serum creatinine 
OR
Calculated creatinine clearance1
2.5mg/mL
30 mL/min
Renal (in combination with nephtoyoxic anti-cancer agents)
Serum creatinine 
OR
Calculated creatinine clearance1
1.2xULN
50 mL/min
Cardiac
Ejection Fraction (LVEF)
50% by TTE or MUGA
1.
As calculated by Cockcroft-Gault formula (Appendix 4).
4.1.3.
Exclusion Criteria
Deviations from 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.
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Permanent discontinuation of afuresertib in the parent study due to toxicity or 
disease progression.
2.
Concomitant use of any type of anti-cancer treatment other than studied in the parent 
protocol. 
3.
Current use of a prohibitive medication(s) as listed in Section 6.2.
4.
Current use of anticoagulants is only allowed if PTT/INR values fulfil entry criteria. 


Novartis
Confidential
Page 28
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
5.
Any unresolved toxicity > Grade 2 , except for alopecia, (National Cancer Institute-
Common Toxicity Criteria for Adverse Events [NCI-CTCAE], version 4.0) from 
parent study treatment at the time of transition to this study.
6.
History of HIV infection. 
7.
History of hepatitis B or C infection (subjects with evidence of cleared hepatitis B 
are permitted).
8.
Evidence of severe or uncontrolled systemic diseases (e.g., unstable, or 
uncompensated respiratory, hepatic, renal, metabolic or cardiac disease).
9.
QTcF interval > 500 msecs at the time of transition to this study. 
10. Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd 
degree atrioventricular (AV) block.
11. Evidence of current Class III, or IV heart failure as defined by the New York Heart 
Association [NYHA, 1994] functional classification system at the time of transition 
to this study.
12. Symptomatic or untreated leptomeningeal, CNS or brain metastases or spinal cord 
compression at the time of transition to this study.
NOTE: Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs 
(EIAEDs).  Continued stability of brain metastases must be confirmed with imaging.
13. Lactating female or female who becomes pregnant prior to transition to this study.
14. Previously diagnosed diabetes mellitus Type I. Subjects with Type II diabetes are 
allowed if entry criteria are fulfilled (see entry criteria #9).
15. Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions at the time of transition to this study that could interfere with subject’s 
safety, obtaining informed consent or compliance to the study procedures, in the 
opinion of the investigator or Novartis Medical Lead.
4.1.4.
Other Eligibility Criteria Considerations
To assess any potential impact on subject eligibility with regard to safety, the investigator 
must refer to the following document(s) for detailed information regarding warnings, 
precautions, contraindications, adverse events, and other significant data pertaining to the 
Novartis investigational product(s) or other study treatment being used in this study: IB 
for afuresertib, product label(s) for other commercially available co-administered agents.
4.2.
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria
4.2.1.
Permanent Discontinuation from Study Treatment
Subjects may be permanently discontinued from study treatment in the event of 
unacceptable toxicity, which include but are not restricted to: meeting stopping criteria 
for liver chemistry defined in Section 6.7.7 or for hematologic and other non-hematologic 


Novartis
Confidential
Page 29
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
toxicity.  In addition, study treatment will be permanently discontinued for any of the 
following reasons:

Deviation(s) from the protocol

Adverse Event, including but not limited to clinically significant AE leading to 
interruption of treatment for >14 consecutive days1.  

Disease progression (including death due to disease progression)

Request of the subject or proxy (withdrawal of consent by the subject)

Investigator’s discretion

Subject is lost to follow-up

Study is closed or terminated 

Death
The primary reason for permanent study treatment discontinuation must be documented 
in the subject’s medical records and electronic case report form (eCRF).
Once a subject has permanently discontinued from afuresertib, the subject will not be 
allowed to be retreated with afuresertib.
Every attempt will be made to ensure that subjects who discontinue study treatment will 
have safety assessments performed at the Final Study Visit within approximately 21 days 
(7 days) of last dose of study treatment(s) as specified in Appendix 1: Time and Events 
Table for Cohort A and B or Appendix 2: Time and Events Table for Cohort C. 
If the subject withdraws consent for further study treatment, a Final Study Visit should be 
completed.  If the subject withdraws consent for further treatment and data collection, 
then no additional study visits or data collection should occur.
If the subject discontinues from treatment due to toxicity, ‘AE’ will be recorded as the 
primary reason for permanent discontinuation of study treatment in the eCRF.
In the event that a subject permanently discontinues study treatment at any time due to an 
AE (as defined in Section 5.9.1.1, “Definition of an AE”) or serious AE (SAE) (as 
defined in Section 5.9.1.2, “Definition of a SAE”), the procedures stated in Section 5.9
(“Adverse Events”) must be followed.  All subjects who have a Grade 3 or 4 clinical or 
laboratory abnormality at the time of permanently discontinuing study treatment must be 
followed up to 30 days or until resolution, whichever comes first.
If the subject discontinues study treatment from death due to disease progression, 
‘Disease Progression’ will be recorded as the primary reason for permanent study 
treatment discontinuation in the eCRF.  The cause of death should also be documented in 
                                                
1 NOTE:  If the investigator and Novartis Medical Lead agree that continued treatment will benefit the 
subject, then the subject may continue treatment, with or without a dose reduction, with the approval of 
the Novartis Medical Lead.


Novartis
Confidential
Page 30
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
the Death eCRF.  If the subject discontinues study treatment from death due to any other 
cause, then ‘AE’ will be recorded as the primary reason for permanent discontinuation in 
the eCRF.  In both cases the cause of death should be documented in the Death eCRF.
4.2.2.
Subject Completion Criteria
A completed subject is one who took at least one dose of study medication in the rollover
study and discontinued the study for any reason.  For subjects who permanently 
discontinue study treatment, date of discontinuation and reason will be collected.   
5.
STUDY ASSESSMENTS AND PROCEDURES
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments.
Refer to the Time and Events Tables for Cohorts A, B or C for the timing of all 
assessments (Appendix 1 or Appendix 2, respectively).  Further details of study 
procedures and assessments can be found in the SPM.
The study specific assessments and procedures are outlined in the Time and Events 
Schedule for Cohort A, B or C (Appendix 1or Appendix 2, respectively).  Approximately 
3 teaspoons (15 mL) of blood will be collected at each study visit.  The total amount of 
blood collected for the duration of the study is dependent on the length of individual 
subject participation in 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.  The change 
in timing for any planned study assessments must be approved and documented by 
Novartis, but this will not constitute a protocol amendment.  The IRB/IEC will be 
informed of any safety issues that require alteration of the safety monitoring scheme. 
If vital signs, ECGs and blood draws are scheduled for the same nominal time, the ECG 
will be obtained first, followed by the vital signs, and then blood draws.
For all cohorts, disease assessments should be performed at regular intervals per local 
standard practice using criteria appropriate for disease type and location.  Refer to the 
Time and Events Tables for Cohorts A, B or C for the suggested timing of all 
assessments (Appendix 1 or Appendix 2, respectively).  
5.1.
Transition Visit
For this study, the Transition Visit may occur on the same day as the last study visit on 
the parent study.  The most recent disease assessment performed under the parent 
protocol may be used for entry criteria for this rollover protocol, if there are no clinical 
signs of disease progression.  The results of any specified study assessments performed 
on the day of the Transition Visit will serve as the baseline value for said assessment.


Novartis
Confidential
Page 31
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
At the Transition Visit, the following assessments will be performed:

Demographic data, including date of birth, ethnicity, gender, and race.

Subject-related data from parent study, including parent study protocol number, 
previous subject number assigned in parent study, start and stop date, dose of 
afuresertib and other study treatment(s), if applicable, at time of transition to this 
study; and response based on last disease assessment in parent study. At the time 
of transition visit the duration of treatment on parent study will be calculated.

Complete physical examination, including height and weight.

Vital signs (BP, temperature and pulse rate)

Clinical laboratory tests: hematology, TSH and clinical chemistry required for 
study entry, including coagulation tests

Serum beta-human Chorionic Gonadotropin (-hCG) pregnancy test for female 
subjects of childbearing potential only

Single 12-lead ECG

Review of adverse events and concomitant medications

Disease assessments
5.2.
Continuous Dosing Treatment Period
5.2.1.
Cohort A and B
The following assessments must be performed every 4 weeks (3 days) while receiving 
treatment:

Vital signs (BP, temperature and pulse rate)

Complete physical examination

Clinical laboratory tests: hematology and clinical chemistry, including TSH and 
coagulation tests 

Single, 12-lead ECG 
Once the subject has been on study drug for >52 weeks (including the time on parent 
study), and after confirmation with Medical Lead the frequency of those assessments 
can be decreased to every 8 weeks (3 days).
The disease assessments must be performed at least every 12 weeks while receiving 
treatment.
The following assessments must be performed continuously (regardless of the time 
on study) while receiving treatment:

Review of Concomitant Medications

Assessment of study treatment(s) compliance

Assessment of AEs


Novartis
Confidential
Page 32
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
5.2.2.
Cohort C
The following assessments must be performed either every 3 or 4 weeks (3 days)
(depending on schedule used in parent study) while receiving treatment:

Vital signs (BP, temperature and pulse rate)

Complete physical examination

Clinical laboratory tests: hematology and clinical chemistry, including TSH and 
coagulation tests 

Single, 12-lead ECG 

Perform assessments needed for safe administration of other anti cancer agents
used in combination
Once the subject has been on study drug for >52 weeks (including the time on parent 
study), and after confirmation with Medical Lead the frequency of these assessments 
can be decreased to every 8 or 9 weeks (3 days) (whichever is consistent with the 
parent schedule).
The disease assessments must be performed at least every 12 weeks while receiving 
treatment.
The following assessments must be performed continuously (regardless of the time 
on study) while receiving treatment:

Review of Concomitant Medications

Assessment of study treatment(s) compliance

Assessment of AEs
5.3.
Final Study Visit
If a subject is withdrawn from study treatment, the following assessments will be 
performed within one month from the last dose of study treatment(s) and prior to 
initiating any other treatment for cancer:

Complete physical examination

Vital signs (BP, temperature and pulse rate)

Clinical laboratory tests:  hematology, clinical chemistry, and TSH

Single, 12-lead ECG

Review of concomitant medications

Assessment of AEs

Disease assessment 


Novartis
Confidential
Page 33
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
5.4.
Safety
Measurements used to evaluate safety will include weight, physical examinations, vital 
signs (BP, temperature and pulse rate), 12-lead ECGs, ECHO or MUGA scan, clinical 
laboratory tests (hematology and clinical chemistry), and monitoring for AEs.  Planned 
time points for all safety assessments are listed in Appendix 1: Time and Events Table for 
Cohort A and B or Appendix 2: Time and Events Table for Cohort C.
Additional, unplanned safety assessments may be performed during the course of the 
study as clinically indicated in the judgment of the investigator.  Additional time points 
for safety tests may also be added during the course of the study based on newly available 
data to ensure appropriate safety monitoring.
NOTE:  Baseline will refer to the value from the day of the transition visit.  This 
definition of baseline will be applicable to all assessments (i.e., physical examination 
findings, laboratory values) for this study when baseline reference is used. All Adverse 
Events which have been recorded in the parent study eCRFs and are ongoing at the time 
of transition into the rollover study will be reported as “AE continued” at the time of 
transition to the rollover study, i.e., AE status and relationship to the study drug at time of 
transition into the rollover study will become baseline for the rollover study.  
5.4.1.
Physical Examinations
Complete physical examinations will be performed at the time points outlined in 
Section 5.2 and Section 5.3 and in Appendix 1: Time and Events Table for Cohort A and 
B, Appendix 2: Time and Events Table for Cohort C.  Height will also be measured and 
recorded at the initial physical examination only.
5.4.2.
Vital Signs
Vital sign measurements (BP, temperature, and pulse rate) will be taken at the time points 
outlined in Section 5.2 and Section 5.3 and in Appendix 1: Time and Events Table for 
Cohort A and B or Appendix 2: Time and Events Table for Cohort C.  Vital signs will be 
measured more frequently if warranted by clinical condition of the subject.  Refer to the 
SPM for details regarding measurement of vital signs.
5.4.3.
Electrocardiograms
Single 12-lead ECGs will be obtained at each time point during the study according to 
Appendix 1: Time and Events Table for Cohort A and B or Appendix 2: Time and Events 
Table for Cohort C using an ECG machine that automatically calculates the heart rate and 
measures RR, PR, QRS, QT, and QTc intervals.
If there are any clinically significant abnormalities including, but not limited to, QTcF 
>500 msec, confirm with 2 additional ECGs taken at least 5 minutes apart.
Refer to Section 6.7.7.4 for QTc withdrawal criteria and additional readings that may be 
necessary.  Refer to the SPM for details regarding ECG procedures.


Novartis
Confidential
Page 34
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
5.4.4.
Clinical Laboratory Assessments
Clinical laboratory tests (Table 2) will be performed as outlined in Appendix 1: Time and 
Events Table for Cohort A and B or Appendix 2: Time and Events Table for Cohort C.  
To address any immediate safety concerns by the investigator, additional laboratory 
samples may be taken as clinically necessary.
All laboratory tests with values that are significantly abnormal during study participation 
or within 28 days after the last dose of study treatment(s) should be repeated until the 
values return to within normal range or baseline.  All subjects who have a Grade 3 or 4 
laboratory abnormality at time of study withdrawal must be followed until resolution to 
Grade 2 or less, unless it is unlikely to improve due to underlying disease.  If such values 
do not return to within normal range within a period judged reasonable by the 
investigator, the etiology should be identified and the Novartis Medical Lead notified.
Table 2
List of Clinical Laboratory Assessments
Hematology
Automated WBC Differential:
White blood cell (WBC) Count (absolute) 
Neutrophils
Hemoglobin
Lymphocytes
RBC
Monocytes
Platelet Count
Eosinophils
Basophils
Clinical Chemistry
Blood urea nitrogen (BUN)
Potassium
Creatinine
Inorganic phosphorus
Sodium
Magnesium
Albumin
Chloride
Calcium
LDH
Bicarbonate
Glucose
Total protein
AST
ALT
Alkaline Phosphatase
Total bilirubin (bilirubin fractionation 
recommended if total bilirubin >2 times ULN)
Other tests

TSH

Triglycerides and total cholesterol

HbA1c

Coagulation: PT/PTT, INR

Serum -hCG pregnancy (female subjects of childbearing potential only; performed at baseline and 
every 12 weeks while on study)


Novartis
Confidential
Page 35
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
5.5.
Multiple Myeloma Specific Disease Assessments:
The following assessments will be performed to assess disease in subjects with MM only 
every 4 weeks until week 42 and every 8 weeks thereafter: 
Serum M-protein, urine M-protein, serum FLC, urine FLC,  imaging for extramedullary 
MM (only in subjects in whom there is a clinical evidence of extramedullary MM- the 
imaging technique should be the same throughout the study (ie if subject initially had CT-
should be followed by CT, if MRI- follow by MRI, or if PET scan- follow by PET scan.)).
5.6.
Disease Assessments for Malignancies Other Than MM
Disease assessments will be performed at regular intervals, at least every 12 weeks per 
local standard practice using criteria appropriate for the disease type and location. The 
investigator may decide that more frequent disease assessments are needed, and perform 
them according to medical practice. 
5.7.
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.
5.8.
Pregnancy
5.8.1.
Time period for collecting pregnancy information
All pregnancies in female subjects will be collected after the start of dosing and until 
28 days after the last dose of afuresertib.
5.8.2.
Action to be taken if pregnancy occurs
The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  The investigator will record pregnancy 
information on the appropriate form and submit it to Novartis within 24 hours of learning 
of a subject's pregnancy.  The subject will also be followed to determine the outcome of 
the pregnancy.  Information on the status of the mother and child will be forwarded to 


Novartis
Confidential
Page 36
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Novartis.  Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date.  Any premature termination of the pregnancy will be reported.
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.
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to Novartis
as described in Section 5.9.1.6.  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 be withdrawn from 
the study.
5.8.3.
Action to be taken if pregnancy occurs in a female partner of a 
male study subject
The investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  The 
investigator will record pregnancy information on the appropriate form and submit it to 
Novartis within 24 hours of learning of the partner’s pregnancy.  The 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 Novartis.  Generally, follow-up will be no longer 
than 6 to 8 weeks following the estimated delivery date.  Any premature termination of 
the pregnancy will be reported.
5.9.
Adverse Events (AE) and Serious Adverse Events (SAE)
5.9.1.
Adverse Events
AEs and SAEs will be monitored from the time of consent until the final study visit.  All 
AEs and SAEs must be recorded and reported as detailed in the following sections and in 
the SPM.  At the time of consent, all ongoing AEs that began during participation in the 
parent study must be recorded in the eCRF.
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 5.9.1.1 and 
Section 5.9.1.2, respectively.
5.9.1.1.
Definition of an AE
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.


Novartis
Confidential
Page 37
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
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.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse.  Examples of events 
meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or grade 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). 
Events that do not meet the definition of an AE include:

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.

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.
5.9.1.2.
Definition of a SAE
A serious adverse event is 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.


Novartis
Confidential
Page 38
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
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.
Medical or scientific judgement 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.
All events of possible drug-induced liver injury with hyperbilirubinemia defined as 
ALT 3 times ULN and bilirubin 2 times ULN (>35% direct) (or ALT 3 times 
ULN and INR >1.5, if INR is measured) termed ‘Hy’s Law’ events (Appendix 7).  
INR measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants.
NOTE: Bilirubin fractionation is performed if testing is available.  If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury.  If testing is unavailable and a 
subject meets the criterion of total bilirubin 2 times ULN, then the event is still 
reported as an SAE.  If INR is obtained, include values on the SAE form.  INR 
elevations >1.5 suggest severe liver injury.
h.
Additionally, new primary cancers and laboratory abnormalities as referenced in 
Section 5.9.1.3 are considered to be serious events by virtue of being medically 
important.  These should be reported in the same manner as other SAEs.
5.9.1.3.
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs
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 events  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.  


Novartis
Confidential
Page 39
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
All events of possible drug-induced liver injury with hyperbilirubinemia (defined as ALT 
3 times ULN plus bilirubin 2 times ULN and/or INR >1.5) or Hy’s Law events, 
require immediate study treatment cessation and reporting as an SAE. 
NOTE: bilirubin fractionation is performed if testing is available.  If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury.
If testing is unavailable and a subject meets the criterion of total bilirubin 2.0 times 
ULN, then the event is still reported as an SAE.  If INR is obtained, include values on the 
SAE form. INR elevations >1.5 suggest severe liver injury.
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.  
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs.  
5.9.1.4.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
an SAE.  Death due to disease under study is to be recorded on the Death eCRF form.  
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the subject, or if the investigator considers that there was a 
causal relationship between treatment with study treatment(s) or protocol design/ 
procedures and the disease progression, then this must be reported as an SAE.
5.9.1.5.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the time of first dose of study treatment until 30 days after last 
study treatment dose. 
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment must be recorded from the 
time a subject consents to participate in the study up to and including any follow-up 
contact.  All SAEs will be reported to Novartis within 24 hours, as indicated in 
Section 5.9.1.6. 


Novartis
Confidential
Page 40
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
5.9.1.6.
Prompt Reporting of Serious Adverse Events and Other Events to 
Novartis
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to Novartis as described in the following table once 
the investigator determines the event meets the protocol definition for that event.
Table 3
Serious Adverse Events
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE data 
collection tool 
Pregnancy
24 hours
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow 
up Form
Liver chemistry abnormalities Phase II:
ALT 3 times ULN 
and bilirubin 2 times 
ULN (>35% direct) (or 
ALT 3 times ULN 
and INR >1.5
24 hours1
SAE data 
collection tool.
Liver Event eCRF 
and liver imaging 
and/or biopsy 
CRFs if 
applicable2
24 hours
Updated SAE data 
collection tool. 
Updated Liver 
Event eCRF2
ALT 3 times ULN 
with hepatitis or rash
or 5 times ULN 
2 weeks (if no liver 
involvement) or 
ALT8 times ULN if 
liver involvement 
present at enrollment; 
24 hours1
Liver Event 
eCRF2
24 hours
Updated Liver 
Event eCRF2
ALT 3 times ULN 
and <5 times ULN 
and bilirubin <2 times 
ULN 
24 hours1
Liver event eCRF 
does not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
1.
Novartis to be notified at onset of liver chemistry elevations to discuss subject safety.
2.
Liver event documents should be completed as soon as possible
Methods for detecting, recording, evaluating, and following up on AEs and SAEs are 
provided in the SPM.


Novartis
Confidential
Page 41
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
5.9.1.7.
Regulatory Reporting Requirements For SAEs
Prompt notification of SAEs by the investigator to Novartis is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
Novartis has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  Novartis
will comply with country specific regulatory requirements relating to safety reporting to 
regulatory authorities, IRBs/IECs and investigators.  
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Novartis policy and are 
forwarded to investigators as necessary.  An investigator who receives an investigator 
safety report describing an SAE(s) or other specific safety information (e.g., summary or 
listing of SAEs) from Novartis will file it with the IB and will notify the IRB/IEC, if 
appropriate according to local requirements.
6.
STUDY TREATMENTS
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design.  Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
6.1.
Afuresertib Investigational Product Dosage/Administration
For early trials in the afuresertib clinical program, study drug was provided in hard 
gelatin capsules (25 mg and 100 mg strengths; see Table 6 below).  The initial patients 
enrolled to this protocol from the FTIH study PKB112825 continued to receive 
afuresertib in hard gelatin capsules.  Subsequently, afuresertib has been re-formulated as 
immediate-release (IR) tablets (50 mg and 75 mg strengths).  A relative bioavailability 
study (201039) performed in healthy volunteers showed similar afuresertib 
pharmacokinetic characteristics between the capsule formulation and the IR tablet 
formulation (for details of study 201039 see the afuresertib clinical IB).  Patients 
currently receiving afuresertib as hard gelatin capsules in this protocol will be switched to 
IR tablets from Day 1 of their next treatment cycle following a scheduled clinic visit.  
Patients newly enrolled to this protocol from a parent afuresertib study in which they 
received drug in hard gelatin capsules will immediately switch to IR tablets.  Patients 
newly enrolled to this protocol from a parent afuresertib study in which they received 
drug as IR tablets will continue to receive IR tablets.  Patients switching from capsule to 
tablets will have the change fully explained by their Investigator or Study Nurse.


Novartis
Confidential
Page 42
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Table 4
AfuresertibDosage/Administration
Product name :
Afuresertib
Formulation 
description:
Gelatin capsules: Each 25 mg capsule contains 25 mg of afuresertib as free 
base
Each 100 mg capsule contains 100 mg of afuresertib as free base
OR:
Immediate release tablets (IR tablets): Each 50 mg tablet contains 50 mg of 
afuresertib as free base
Each 75 mg tablet contains 75 mg of afuresertib as free base
Dosage form :
Geletin capsule or immediate release tablet 
CAPSULES
IR TABLETS
Unit dose 
strength(s)/Dose 
Level(s):
25 mg capsule or 100 mg capsule 
50 mg tablet or 75 mg tablet
Physical Description: 
25mg Capsules: Opaque, white, 
size 4 capsules with no external 
markings, filled with a white 
powder.
OR:
OR: 100mg Capsules: Opaque, 
Swedish orange, size 1 capsule 
with no external markings, filled 
with a white powder.
50mg IR tablets: White, film-coated, 
round, biconvex tablet
75mg IR tablets: White, film-coated, oval 
or capsule shaped tablet
Route/
Administration/ 
Duration:
Oral/ The initial regimen will be once daily dosing continuously.
Dosing instructions:
Dose with at least 200 mL of water, and taken in the morning. (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.)  Afuresertib may be given 
without regard to food.
Afuresertib will be provided to sites by Novartis.  The contents of the label will be in 
accordance with all applicable regulatory requirements.  No special preparation of 
afuresertib is required.
Afuresertib must be dispensed or administered only to subjects enrolled in the study and 
in accordance with the protocol.  Only authorized site staff may supply or administer 
afuresertib.
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff, although adequate precautions are to be taken 
to avoid direct contact with study medication.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 


Novartis
Confidential
Page 43
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
provided to the site staff if required by local laws or will otherwise be available from 
Novartis upon request.
6.2.
Other Anti-Cancer Agents (Cohort C)
When the treatment regimen to be administered includes another anti-cancer agent(s) in 
combination with afuresertib, the sites will be responsible for obtaining the necessary 
drug supply for the anti-cancer agent(s) through commercial means; the drug(s) will not 
be supplied by Novartis.  The use of an anti-cancer agent(s) in combination with 
afuresertib that was not part of the parent study is not permitted.  Refer to the Prescribing 
Information for each anti-cancer agent for information regarding the physical and 
chemical properties, storage, and dosing/administration guidelines.
6.3.
Administration of Study Treatment
Afuresertib will be administered with approximately 200mL of water. If a subject vomits 
after taking afuresertib, the subject should be instructed NOT to retake the dose and 
should take the next scheduled dose of study treatment(s).  If vomiting persists, the 
subject should contact the investigator.
If subject misses a dose of afuresertib, the subject should be instructed to skip the missed 
dose and not make it up, then take the next scheduled dose.  The missed dose should be 
recorded in the eCRF.
6.4.
Handling and Storage of Study Treatment
Afuresertib must be stored in a secure area under the appropriate physical conditions for 
the product.  Access to and administration of the afuresertib will be limited to the 
investigator and authorized site staff.  Afuresertib must be dispensed or administered only 
to subjects enrolled in the study and in accordance with the protocol.
Afuresertib is to be stored at room temperature and should not exceed 30°C in an HDPE 
white opaque container.  Maintenance of a temperature log (manual or automated) is 
required.
Anti-cancer agents should be handled per manufacturer instructions.
6.5.
Treatment Assignment
Subjects will be identified by a new, unique subject number that is assigned upon 
enrollment into this study and that will remain consistent for the duration of the study.
The parent study number and subject/treatment numbers originally assigned to subjects 
during their participation in the parent study will be recorded in the eCRF, but will not be 
used to identify subjects in the rollover study.
Upon completion of all the required screening assessments, eligible subjects will be 
registered into RAMOS (Registration and Medication Ordering System), the Novartis
interactive voice response system (IVRS), by the investigator or authorized site staff.  


Novartis
Confidential
Page 44
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
6.6.
Dose Modifications
At each study visit, subjects should be carefully evaluated for evidence of treatment-
related toxicity.  The investigator should refer to parent study guidelines to determine 
which study treatment may be contributing to the treatment-emergent toxicity and make 
the appropriate dosing adjustments, which may include reducing the dose of one or all 
study treatments.  
Guidelines for afuresertib dose modifications are provided below.  Investigators should 
also consult the Novartis Medical Lead and refer to the afuresertib IB or the prescribing 
information for the appropriate anti-cancer combination agent for detailed information 
regarding warnings, precautions, contraindications, AEs, and recommendations for 
supportive care in the event of drug-related toxicity. 
6.6.1.
Afuresertib Dose Modification
Dose modifications for clinically significant toxicities that are considered related to study 
medication are provided in Table 5.  More detailed guidelines for the clinical 
management of hyperglycemia, diarrhea, rash, dyspepsia, mucositis, and liver function 
abnormalities are provided in Section 6.7.  All dose modifications (delays or reductions) 
will be recorded on the appropriate eCRF.


Novartis
Confidential
Page 45
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Table 5
Dose Modifications for Afuresertib
TOXICITY1
Afuresertib
Grade 1
Continue afuresertib at current dose level.  Consider supportive care 
recommendations provided in Section 6.7
Grade 2
Withhold treatment with afuresertib until toxicity resolves to Grade 1 or 
baseline.  Upon resolution, restart afuresertib at current dose level.  Consider 
supportive care recommendations provided in Section 6.7. Consider dose 
reduction if toxicity is intolerable to the subject.
Grade 3
Withhold afuresertib until toxicity resolves to Grade 1 or baseline.  Upon 
resolution, reduce dose of afuresertib by one dose level2.  Consider 
supportive care recommendations provided in Section 6.7. 
Grade 4
Permanently discontinue treatment with afuresertib.
1.
Considered related to study treatment.
2.
Dose level 1: 150mg, Dose level 2: 125mg, Dose level 3: 100mg, Dose level 4:75mg.  If subject requires dose 
reduction below 75mg, then treatment must be discontinued, and subject withdrawn from the study.
Treatment with afuresertib may be delayed for up to 14 days to allow resolution of 
toxicity or based on investigator discretion.  If the investigator and the Novartis Medical 
Lead conclude that continued treatment will benefit a subject who has experienced a 
treatment delay >14 days, then the subject may continue afuresertib therapy with the 
approval of the Novartis Medical Lead.
A maximum of 2 dose reductions (including reductions from the parent study) of 
afuresertib is permitted and each of them requires consultation with the Novartis Medical 
Lead.  Dose reductions should be to a lower dose level previously studied in an 
afuresertib clinical study.  If a third dose reduction or a dose reduction below 75mg is 
required, treatment with afuresertib should be discontinued and subject should be 
withdrawn from study.
6.6.2.
Dose Modification: Other Anti-Cancer Agent(s)
If an anti-cancer agent(s) is being taken in combination with afuresertib at the time of 
transition to the rollover study, treatment will continue with the current dose administered 
in the parent study.  Any dose modification(s) required while on this study should be
made according to the administration and/or dose modification guidelines presented in 
the protocol of the parent study or in the package insert for the agent, whichever is 
appropriate.  If, in the opinion of the investigator, the subject has received maximum 
benefit from the additional anti-cancer agent(s), then treatment with the anti-cancer 
agent(s) may be discontinued.
6.7.
Guidelines for Adverse Events of Special Interest
The severity of AEs will be graded utilizing the NCI-CTCAE, version 4.0.  Guidelines 
for dose modifications and interruptions for management of common toxicities associated 
with the study treatment are provided in this section. 


Novartis
Confidential
Page 46
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
6.7.1.
Supportive Measures for Nausea or Vomiting
Supportive care management of nausea or vomiting should be undertaken as clinically 
indicated.
6.7.2.
Supportive Measures for Hyperglycemia
Subjects with clinically significant glucose elevation, with or without ketoacidosis, 
should be aggressively managed according to standard medical practice.  Study sites with 
a protocol/guideline for management of hyperglycemia should include a copy in the study 
document file.  Early consultation with a diabetes specialist is also encouraged, especially 
for study participants with a history of diabetes.  If significant hyperglycemia (e.g., 
fasting glucose 200 mg/dL) persists despite treatment and after stopping systemic 
glucocorticoids (where applicable), or in the event of life-threatening complications, dose 
modification of afuresertib should also be considered, after discussion with a Novartis 
Medical Lead.  Dose modification of afuresertib should not be performed for 
asymptomatic hyperglycemia, or hyperglycemia that responds to other interventions.
6.7.3.
Management of Diarrhea
Episodes of diarrhea have been reported in subjects receiving afuresertib and this should 
be actively managed as soon as an episode has occurred.  When starting afuresertib, it is 
advisable to provide subjects with a prescription for loperamide (or equivalent), along 
with detailed guidance on how to manage this potential toxicity.  If an episode of diarrhea 
occurs, other potential causes should be promptly ruled out (e.g., concomitant 
medications like stool softeners, laxatives, antacids, etc., infections, partial bowel 
obstruction, etc.).  Supportive therapy will be provided according to standard medical 
practice.  Supportive measures should include the following as clinically indicated 
[Benson, 2004]:

Dietary modifications (e.g., small, frequent meals, low fiber, and lactose avoidance)

Maintain hydration with clear liquids or IV fluids as needed

Loperamide and/or oral antibiotics
6.7.4.
Management of Rash
Subjects should contact the investigator immediately upon onset of a rash.  Full 
supportive care should be provided to subjects who experience a rash while on study.  
Information contained in this section is a guideline.  The investigator’s best medical 
judgment should determine medical intervention for rash. Details should be entered into 
InForm.  


Novartis
Confidential
Page 47
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Table 6
Guidelines for Dose Modification and Management of Rash
1st occurrence
2nd occurrence
3rd occurrence
Grade 1
Symptomatic carea
Consider oral steroids if multiple recurrencesb
Grade 2
Consider oral steroids
Oral steroids
Hold drug until <Grade 1, 
then resume at full dose
Oral steroids
Hold drug until 
<Grade 1, then resume 
at 25 mg dose reduction
Grade 3
Oral steroids
Hold drug until <Grade 1, 
then resume at full dose
Oral steroids
Hold drug until <Grade 1, 
then resume at 25 mg 
dose reduction
Oral steroids
Hold drug until 
<Grade 1, then resume 
at 50 mg dose reduction 
or discontinue
Grade 4
Oral steroids
Hold drug until <Grade 1, 
then resume at 25 mg 
dose reduction
Oral steroids
Hold drug until <Grade 1, 
then resume 50 mg dose 
reduction or discontinue
Discontinue
a.
Recommended symptomatic measures (for all grades) includes topical steroids (e.g., hydrocortisone 1% or 2.5% 
cream), antihistamines, hypoallergenic moisturizers and emollients for dry skin (e.g., 5-10% urea in cetomacrogel 
cream or soft paraffin).
b.
Recommended course of oral steroids is methylprednisolone (or equivalent).
A dermatology consult should be considered for Grade ≥3 rash or multiple occurrences of 
Grade ≤2 rash.
6.7.5.
Guidelines for Management of Dyspepsia
Based on nonclinical data and current clinical experience, it is possible that afuresertib 
may be a direct GI mucosal irritant such that subjects with GI dysmotility or GERD may 
be predisposed to symptoms of dyspepsia.  Therefore, if a subject experiences symptoms 
supportive therapy will be provided according to standard medical practice.  If Grade 1-2 
dyspepsia, the investigator should consider the following recommendations:

Afuresertib may be taken with or without food, except where specified (see 
Section 6.1 and Table 4).

Capsules should be administered approximately 5 minutes apart with divided 
amounts of fluid (4-8 oz with each capsule for a total of at least 12 oz), except where 
specified (see Section 6.1)

Subjects should remain upright for 30 min after taking afuresertib.
In more severe cases of dyspepsia, consider sucralfate and/or aluminum hydroxide with 
magnesium carbonate as supportive measures.  These should be administered at least 
2 hours after dosing to avoid any potential drug-drug interactions (see Section 6.1).

Histamine H2-receptor antagonists (H2 blockers) or proton pump inhibitors may also 
be considered.


Novartis
Confidential
Page 48
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
If the recommendations above are insufficient to resolve symptoms, or if active 
ulceration is suspected, investigators should consider additional tests such as upper 
endoscopy or barium radiography.
6.7.6.
Guidelines for Management of Mucositis
Ulceration throughout the GI tract was observed in nonclinical studies of afuresertib.  
Mucositis has also been reported as a consequence of treatment with AKT inhibitors.  
Prophylaxis for mucositis is recommended in subjects who are receiving afuresertib.  
This should include good oral hygiene (e.g., soft toothbrushes, rinsing and cleaning the 
oral cavity with water after every meal, and removal of dentures at the first sign of oral 
pain or inflammation) and preventive measures for lower GI symptoms (e.g., maintaining 
adequate hydration, reducing dairy intake in the event of lactose intolerance).  Afuresertib 
should be held for episodes of mucositis Grade 2.  Recommended supportive measures 
include the following:

Institute a soft diet and avoid acidic, salty, or dry foods

Provide topical analgesics (e.g., 2% lidocaine solution), or coating agents.  Parenteral 
analgesia may be required for more severe events. 

Work-up for infection, including oral candidiasis and viral infections.  Empiric 
antibiotic treatment may be required while awaiting culture results, especially if 
high-grade neutropenia is present concurrently. 

Administer H2 blockers or proton-pump inhibitor if epigastric symptoms are also 
present.
Hospitalization may be required for more severe cases, especially if IV hydration, 
parenteral analgesia, or supplemental nutrition is required.  Investigators should discuss 
afuresertib dosing with a Novartis Medical Lead before reinstituting treatment after an 
episode of Grade 3 or 4 mucositis.   
6.7.7.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and follow-up criteria have been designed to assure subject 
safety and evaluate liver event etiology in alignment with the United States (US) Food 
and Drug Administration (FDA) premarketing clinical liver safety guidance.  Liver 
chemistry stopping criteria 1 to 4 are defined as follows:
1. Alanine aminotransferase (ALT) 3 times upper limit of normal (ULN) and bilirubin 
2 times ULN (>35% direct bilirubin), or ALT 3 times ULN and INR >1.5, if INR 
is measured).
o
NOTE: Serum bilirubin fractionation should be performed if testing is 
available.  If serum bilirubin fractionation is not immediately available, 
study treatment(s) should be discontinued if ALT 3 times ULN and
bilirubin 2 times ULN.  If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury.


Novartis
Confidential
Page 49
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
2. ALT 8xULN
3. ALT3xULN if associated with the appearance or worsening of symptoms of
hepatitis or hypersensitivity symptoms (e.g., fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, or eosinophilia); or
4. ALT 3xULN persists for more than 4 weeks or ALT 3xULN and subject can’t be 
monitored weekly for 4 weeks.
6.7.7.1.
Actions if Liver Chemistry Stopping Criteria are met
When any of the liver chemistry stopping criteria are met, do the following:

Immediately discontinue investigational product.

Report the event to Novartis within 24 hours of learning its occurrence.

Complete the liver event CRF and SAE data collection tool if the event also meets the 
criteria for an SAE.

All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 
3xULN and INR>1.5, if INR measured; INR measurement is not required and the 
threshold value stated will not apply to subjects receiving anticoagulants), termed
‘Hy’s Law’, must be reported as an SAE.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed.

Perform liver event follow up assessments, and monitor the subject until liver
chemistries resolve, stabilize, or return to baseline values as described below.

Follow-up for overall survival is required following permanent discontinuation from
investigational product.

Do not re-challenge with investigational product.
In addition, for criterion 1 in Section 6.7.7:

Make every reasonable attempt to have subjects return to clinic within 24 hours for
repeat liver chemistries, liver event follow up assessments (refer to Section 6.7.7.2),
and close monitoring.

A specialist or hepatology consultation is recommended.

Monitor subjects twice weekly until liver chemistries (ALT, aspartate
aminotransferase [AST], alkaline phosphatase [ALP], bilirubin) resolve, stabilize or
return to within baseline values.

Monitor subjects twice weekly until liver chemistries (ALT, aspartate
aminotransferase [AST], alkaline phosphatise [ALP], bilirubin) resolve, stabilize or
return to within baseline values.
In addition, for subjects meeting any of the criteria 2-4 in Section 6.7.7:


Novartis
Confidential
Page 50
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for
repeat liver chemistries and liver event follow up assessments (refer to Section
6.7.7.2).
Monitor subjects weekly until liver chemistries (ALT, AST, ALP, bilirubin) resolve,
stabilize or return to within baseline values.
Also, refer to Appendix 3, Liver Chemistry Testing Procedures, for details of the
assessments required if a subject meets any of the above criteria in the absence of
disease progression.
6.7.7.2.
Liver Event Follow-Up Assessments
For subjects meeting any of the liver chemistry stopping criteria, make every attempt to 
carry out the liver event follow-up assessments described below:

Viral hepatitis serology including:

Hepatitis A Immunoglobulin M (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 

Blood sample for PK analysis, obtained within 10 days of last dose of study 
treatment(s).  Record the date/time of the PK blood sample draw and the date/time of 
the last dose of study treatment(s) prior to blood sample draw on the eCRF.  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 SPM. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2 times ULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia as relevant on the AE report form.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form.


Novartis
Confidential
Page 51
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
The following assessments are required for subjects with ALT 3 times ULN and 
bilirubin 2 times ULN (>35% direct) but are optional for other abnormal liver 
chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct assay (quantifies potential acetaminophen contribution 
to liver injury, detectable by HPLC assay more than 1 week following 
acetaminophen use) (James LP. Drug Metab Disp 2009; 37:1779–1784).

Liver imaging (ultrasound, magnetic resonance imaging [MRI], or computerized 
tomography [CT]) to evaluate liver disease.
6.7.7.3.
Liver Chemistry Monitoring Criteria
For subjects with ALT 3 times ULN but <5 times ULN and bilirubin <2 times ULN, 
without hepatitis symptoms or rash, and who can be monitored weekly for 4 weeks, the 
following actions should be taken:

Notify the Novartis Medical Lead within 24 hours of learning of the abnormality to 
discuss subject safety.

Continue study treatment(s).

Return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline. 

If at any time the subject meets any of the liver chemistry stopping criteria 1 to 5, 
proceed as described above.

If, after 4 weeks of monitoring, ALT <3 times ULN and bilirubin <2 times ULN, 
monitor subjects twice monthly until liver chemistries normalize or return to within 
baseline values. 
Refer to Appendix 3 for algorithm of liver chemistry stopping and follow-up criteria.
6.7.7.4.
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to IP
Approval by Novartis after discussion with Novartis Medical Lead for drug restart can be 
considered where:

The subject is receiving compelling benefit, benefit of drug restart exceeds risk, and 
no effective alternative therapy is available. Ethics Committee or Institutional 
Review Board approval of drug restart/rechallenge must be obtained, as required;   

If the restart/rechallenge is approved by Novartis in writing, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death;  


Novartis
Confidential
Page 52
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

The subject must also provide signed informed consent specifically for the IP 
restart/rechallenge. Documentation of informed consent must be recorded in the 
study chart;  

Study drug must be administered at the dose specified by Novartis; and

Subjects approved by Novartis for restart/rechallenge of IP must return to the clinic 
twice a week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. 
6.7.8.
QTc Withdrawal Criteria
QTc should be assessed at the frequency shown in Appendix 1: Time and Events Table 
for Cohort A and B or Appendix 2: Time and Events Table for Cohort C.
A subject that meets the criteria below will be withdrawn from the study.  The QT 
correction formula used to determine discontinuation should be the same one used 
throughout the study.

QTcF > 500 msec or uncorrected QT >600 msec

If subject has underlying bundle branch block then the QTc withdrawal criteria 
depends on the baseline value:
Baseline QTc value (with 
underlying bundle branch block)
QTc withdrawal criteria
<450 ms
>500 ms
450-470 ms
530 ms
Withdrawal decisions are to be based on an average QTc value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period, and 
then use the averaged QTc values of the 3 ECGs to determine whether the subject should 
be discontinued from the study.
6.8.
Blinding
This is an open-label study.
6.9.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
Novartis investigational product (IP) dispensed and/or administered to study subjects, the 
amount returned by study subjects, and the amount received from and returned to 
Novartis, when applicable.  Product accountability records must be maintained 
throughout the course of the study.  Refer to the SPM for further detailed instructions on 
IP accountability.


Novartis
Confidential
Page 53
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
6.10.
Treatment Compliance
Compliance with afuresertib will be assessed through pill counts, and querying the 
subject during the site visits and documented in the source documents and eCRF.
When dosing occurs outside of the study site, the subject will return all unused 
investigational product in the dispensed container on each return visit to the clinic, and 
study staff will note the number of capsules or tablets returned in the source documents.  
Subjects will maintain a daily dosing diary.  
A record of the number of afuresertib capsules or tablets must be maintained and 
reconciled with study treatment and compliance records.  Treatment start and stop dates, 
including dates for treatment interruptions and/or dose reductions will also be recorded in 
the eCRF.
7.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study treatment until the end of the study (Final 
Study Visit). Any concomitant medication(s), including non-prescription medication(s) 
and herbal product(s), taken during the study will be recorded in the electronic case 
report form (eCRF). 
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by Novartis and stored in the study file. Any such 
changes will be communicated to the investigative sites in the form of a letter.
7.1.
Permitted Medication(s) and non-Drug Therapies
Subjects should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines.
Paracetamol or acetaminophen, at the label-recommended dose, is permitted. 
Medications which contain paracetamol or acetaminophen should be counted in label 
recommended dose. Other concomitant medication may be considered on a case by case 
basis by the Novartis Medical Lead.
Concurrent treatment with bisphosphonates is permitted. Prophylactic use of 
bisphosphonates in subjects without metastatic bone disease is not permitted, except for 
the treatment of osteoporosis.
Current use of warfarin for therapeutic anticoagulation is not allowed (Note: low 
molecular weight heparin is permitted). Their use must be monitored in accordance with 
local institutional practice.


Novartis
Confidential
Page 54
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
7.2.
Prohibited Medication(s) and Non-Drug Therapies
Subjects should not receive anti-cancer therapy (chemotherapy, radiation therapy, 
immunotherapy, biologic therapy, hormone therapy other than for replacement, surgery, 
and/or tumor embolization) directed towards the tumor for which they have been enrolled 
on the trial while on treatment in this study; although palliative radiation to control pain 
may be used following discussion with the Novartis Medical Lead.
Subjects should abstain from taking any herbal and dietary supplements within 5 half 
lives (or 14 days if the drug is a potential enzyme inducer) prior to study drug(s) dosing 
and until completion of the follow-up visit, unless there is little concern for a potential 
drug-drug interaction with the study drug(s). These herbal medications include, but are 
not limited to, St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. The investigator should 
contact a Novartis Medical Lead before initiating study treatment in a subject taking any 
herbal preparation.
Short courses (up to 7 days) of oral corticosteroids intended to treat study treatment 
related rash or diarrhea are allowed.
Erythropoiesis-stimulating agents and colony-stimulating factors like filgrastim and 
pegfilgrastim  may be used as clinically indicated.
7.2.1.
Drugs Potentially Affected by Afuresertib (afuresertib perpetrator 
interaction potential
In vitro data indicate that afuresertib has the potential of being a perpetrator in drug-drug 
interactions through enzyme inhibition (with substrates of CYP3A4 and 2C8, IC50
estimates of 3.7 to 6.0 M and 6.3 M, respectively), through transporter inhibition (with 
substrates of OATP1B1 and BCRP, IC50 estimates of 1.7 M and 2.9 M) (Table 7). Co-
administration of afuresertib and medications which are a sensitive substrate of CYP3A4, 
OATP1B1 and BCRP with a low therapeutic index will be prohibited. Co-administration 
of afuresertib and medications which are a sensitive substrate of CYP2C8 with a low 
therapeutic index will be used with caution. Other drugs affected by these enzymes and 
transporters should be used with caution and please refer to SPM.
Table 7
Drugs potentially affected by afuresertib
AVOID: 
CYP3A Substrate
Therapeutic Area
carbamazepine
Anticonvulsants
ergotamine, dihydroergotamine
Antimigraine
pimozide
Antipsychotics
amiodarone, disopyramide, quinidine, bosentan  
Cardiovascular Agents
cyclosporine, everolimus, sirolimus, tacrolimus
Immunosuppressive Agents
OAT1B1 Substrate
Therapeutic Area
methotrexate
Anti-cancer


Novartis
Confidential
Page 55
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
BCRP Substrate
Therapeutic Area
topotecan
Anti-cancer
Note: Boceprevir and telaprevir (anti-HCV drugs) should be used with caution when combining with 
afuresertib.
Table 8
Drugs Potentially Affected by Afuresertib: 
Use with Caution
Generic Drug Name1
Therapeutic Class
CYP3A Substrate
fentanyl
Analgesics
alfentanil, ropivacaine
Anesthetics
losartan
Angiotensin II inhibitors
ethosuximide, trimethadione
Anticonvulsants
buspirone, roboxetine, sertraline, trazodone, venlafaxine
Antidepressants/Anxiolytics
emadastine, loratadine
Antihistamines
artemether, halofantrine, lumefantrine, quinine
Antimalarial
erythromycin, clindamycin, rifabutin, rifampin
Antimicrobials
eletriptan
Antimigraine
-dihydroergocriptine, bromocriptine
Anti-Parkinsonians
aripiprazole, bromperidol, clozapine, haloperidol, quetiapine
Antipsychotics
oxybutynin, tolterodine
Antispasmodics
osentan, delaviridine, tipranavir, nelfinavir
Antivirals
amlodipine, barnidipine, diltiazem, dofetilide, dronedarone, 
eplerenone, felodipine, nifedipine, pranidipine, propafenone, 
verapamil, vesnarinone
Cardiovascular Agents
sildenafil, tadalafil, vardenafil
Erectile dysfunction treatments
aprepitant, lansoprazole
Gastrointestinal Agents
atrovastatin, lovastatin, simvastatin
HMG CoA reductase inhibitors2
alprazolam, chlordiazepoxide, diazepam, flunitrazepam, midazolam, 
propofol, triazolam, zolipidem, zopiclone
Hypnotics and Sedatives
pioglitazone, repaglinide, rosiglitazone
Hypoglycemic agents
temsirolimus
Immunosuppressive Agents
1.
Please note some drugs may be listed more than once. This is due to the fact that they are substrates for 
both CYP and a transporter (e.g., OATP1B1, BCRP).
2.
If subjects are on a high dose of a HMG CoA reductase inhibitor, dose reduction should be considered. 
Monitoring for toxicities (such as rhabdomyolysis) should be considered.
7.2.1.1.
Drugs that may potentially affect afuresertib (perpetrators)
The metabolism of afuresertib may be mediated by CYP450 isozymes which may include 
CYP3A4 with possible contributions from CYP2D6 and CYP1A2. Afuresretib is a 
substrate of human P-gp and of murine Bcrp1. However, the relative contribution of the 
various pathways to the elimination of afuresertib is presently unknown. Substances that 
potently inhibit or induce these enzymes/transporters could lead to alterations in the 
pharmacologic effects of afuresertib and potentially much higher/lower exposure in 
subjects. Those medications which may alter afuresertib elimination and should be 
administered with caution and please refer to SPM.


Novartis
Confidential
Page 56
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Table 9
Drugs that may Potentially Affect Afuresertib: Use with Caution
Generic Drug Name
Therapeutic Class
quinidine
Antiarrhythmics
fluvoxamine, fluoxetine, nefazodone, paroxetine
Antidepressants
fluconazole, itraconazole, ketoconazole, terbinafine, voriconazole
Antifungals
ciprofloxacin, clarithromycin, erythromycin, isoniazid, telithromycin, 
troleandomycin
Anti-infectives
amprenavir, atazanavir, delaviridine, efavirenz, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir
Antivirals
all rifamycin class agents (e.g., rifampicin, rifabutin, rifapentine)
Antibiotics
phenobarbital, oxandrolone, tizanidine, gemfibrozil
Miscellaneous
8.
LIFESTYLE AND/OR DIETARY RESTRICTIONS
8.1.
Contraception Requirements
8.1.1.
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%.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  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% 
effectiveness criteria as stated in the product label

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.

Double barrier method:  condom and occlusive cap (diaphragm or cervical/vault 
caps)
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring subjects understand how to properly use these methods of 
contraception.


Novartis
Confidential
Page 57
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
8.1.2.
Male Subjects
To prevent pregnancy in a female partner or to prevent exposure of any partner to the 
investigational product from a male subject’s semen, male subjects must use one of the 
following contraceptive methods:

Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Condom (during non-vaginal intercourse with any partner - male or female) OR

Condom and occlusive cap (diaphragm or cervical/vault caps (during sexual 
intercourse with a female)
8.2.
Meals and Dietary Restrictions
Subjects may take afuresertib without regard to food.  For combination medications, 
please use its meal and dietary restrictions. Subject should take afuresertib dose at 
approximately same time each day.
In addition, subjects shall abstain from ingestion of any food or drink containing 
grapefruit and grapefruit juice, Seville oranges, or pommelos within 7 days prior to the 
first dose of afureserib until the end of the study.
8.3.
Activity
Subjects will abstain from strenuous exercise for 48 hr prior to each blood collection for 
clinical laboratory tests. 
9.
DATA MANAGEMENT
For this study, data will be collected using the eCRFs, transmitted electronically to the 
sponsor (or designee) and combined with data provided from other sources in a validated 
data system.
Management of clinical data will be performed in accordance with applicable Novartis
standards and data cleaning procedures to ensure the integrity of the data, e.g., resolving 
errors and inconsistencies in the data.  AEs and concomitant medications terms will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) and custom 
drug dictionary.
All laboratory data (i.e., hematology, clinical chemistry, liver function, coagulation, and 
serum pregnancy tests) will be entered into the eCRF.  


Novartis
Confidential
Page 58
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
10.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
10.1.
Hypotheses and Treatment Comparisons
No statistical hypotheses are being tested.  Only descriptive methods will be used in 
analysis of the data obtained from this study.
10.2.
Sample Size Considerations
10.2.1.
Sample Size Assumptions
As this is a roll-over study, no specific sample size considerations are required.  The 
sample size will be based on the number of subjects completing their parent study of 
afuresertib and are eligible for inclusion in this rollover study.
10.2.2.
Sample Size Re-estimation
Sample size re-estimation is not planned for this study.
10.3.
Data Analysis Considerations
10.3.1.
Analysis Populations
The All Treated Subjects Population will consist of all subjects that receive at least one 
dose of afuresertib in this rollover study.  Safety data will be evaluated based on this 
population.
10.3.2.
Analysis Data Sets
Construction of data sets relating to the reporting and analysis of study data will be 
performed in accordance with all applicable Novartis standards and procedures.
10.3.3.
Interim Analysis
No formal interim analysis is planned for this study.
10.3.4.
Key Elements of Analysis Plan
Data will be listed and summarized according to the Novartis reporting standards, where 
applicable.  Complete details will be documented in the Reporting and Analysis Plan 
(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.
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.  Summaries may be provided grouped by appropriate subject 
populations.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.


Novartis
Confidential
Page 59
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Demographic and baseline characteristics will be summarized by cohort and for total 
subjects.  Complete details of the safety analyses will be provided in the RAP.
10.3.5.
Safety Analyses
10.3.5.1.
Extent of Exposure
The number of subjects administered study treatment(s) will be listed and summarized by 
cohort according to the duration of therapy.
10.3.5.2.
Adverse Events
Adverse events (AEs) will be coded using MedDRA and grouped by system organ class.  
AEs will be graded by the investigator according to the NCI-CTCAE (version 4.0).  
Events will be summarized by frequency, cohort and proportion of total subjects, by 
system organ class and preferred term.  Separate summaries will be given for all AEs, 
drug-related AEs, serious AEs and AEs leading to discontinuation of study treatment(s).
If the AE is listed in the NCI CTCAE (version 4.0) table, the maximum grade will be 
summarized.
Characteristics (e.g., number of occurrences, action taken, grade, etc) of the following 
AEs of special interest, but not restricted to them may be listed or summarized separately: 
elevated liver enzymes hyperglycemia, nausea, fatigue, vomiting, anemia, diarrhea, 
abdominal pain, headache, rash, dyspepsia, mucositis and neutropenia.
If the data warrant, the incidence of deaths and the primary cause of death will be listed.
10.3.5.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be listed for each subject and summarized at 
each scheduled assessment according to NCI-CTCAE grade (version 4.0).  The 
proportion of values lying outside the reference range will also be presented for 
laboratory tests that are not graded because there are no associated NCI-CTCAE criteria.  
Summaries will include data from scheduled assessments only, and all data will be 
reported according to the nominal visit date for which it was recorded (i.e., no visit 
windows will be applied).  Unscheduled data will be included in “overall” and “any post-
screening” summaries which will capture a worst case across all scheduled and 
unscheduled visits post first dose of study treatment(s).  Further details will be provided 
in the RAP.
10.3.5.4.
Other Safety Measures
The results of scheduled assessments of vital signs, 12-lead ECG, and ECHO/MUGA 
scan will be listed for each subject and summarized.  All data will be reported according 
to the nominal visit date for which it was recorded (i.e., no visit windows will be applied).  
Further details will be provided in the RAP.


Novartis
Confidential
Page 60
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
10.3.5.5.
Clinical Activity Analyses
No efficacy analysis is planned for this study.  
11.
STUDY CONDUCT CONSIDERATIONS
11.1.
Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on clinicaltrials.gov before 
enrollment of subjects begins.
11.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, Novartis will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) and applicable country-specific 
regulatory requirements including a US IND.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

IRB/IEC review and approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
Novartis will provide full details of the above procedures, either verbally, in writing, or 
both.
Written informed consent must be obtained from each subject prior to participation in the 
study.  The consent process will be conducted during the Transition Visit.
11.3.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the IP, 
and this new event is likely to affect the study of subjects, the Sponsor, and the 
investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard.
The Sponsor will work with the investigator to ensure the IEC/IRB is notified.
11.4.
Quality Control (Study Monitoring)
In accordance with applicable regulations, ICH GCP, and Novartis procedures, Novartis 
personnel (or designated Clinical Research Organization [CRO]) will be contacted prior 
to the start of the study to review with the site staff the protocol, study requirements, and 


Novartis
Confidential
Page 61
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
their responsibilities to satisfy regulatory, ethical, and Novartis requirements.  When 
reviewing data collection procedures, the discussion will include identification, 
agreement and documentation of data items for which the eCRF will serve as the source 
document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time of their staff to the monitor to discuss any findings and issues.
Monitoring visits will be conducted in a manner to ensure 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, ICH GCP, and all applicable regulatory requirements.
11.5.
Quality Assurance
To ensure compliance with ICH GCP and all applicable regulatory requirements, 
Novartis may conduct quality assurance audits of the site.  Regulatory agencies may 
conduct a regulatory inspection at any time during or after completion of the study.  In 
the event of an audit or inspection, the investigator (and institution) must agree to grant 
the auditor(s) and inspector(s) direct access to all relevant documents and to allocate their 
time and the time of their staff to discuss any findings/relevant issues.
11.6.
Study and Site Closure
The end of the study will be defined as the date of the final study visit of the last subject 
enrolled.
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and Novartis Standard Operating Procedures.
Novartis reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If Novartis determines that such action is required, Novartis will discuss 
the reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, Novartis will provide advance notice to the 
investigator or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, Novartis will promptly inform 
all investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  Novartis will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action.  Where 
required by applicable regulations, the investigator or head of the medical institution 
must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination.


Novartis
Confidential
Page 62
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
11.7.
Records Retention
Following closure of the study, the investigator or 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 easily accessible when needed (e.g., for a Novartis 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 the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must 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.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
Essential documents (written and electronic) should be retained for a period of not less 
than fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides 
written permission to dispose of them or, requires their retention for an additional period 
of time because of applicable laws, regulations and/or guidelines.
The investigator must notify Novartis of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the investigator is no longer associated with the 
site.
11.8.
Provision of Study Results to Investigators, Posting to the 
Clinical Trials Register 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 
access to statistical tables, figures, and relevant reports and will have the opportunity to 
review the complete study results at a Novartis site or other mutually-agreeable location.
Novartis 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 
appropriate.
Novartis aims to post a results summary to the Novartis Clinical Trial Results website 
(www.novartisclinicaltrials.com) and other publicly available registers no later than 
twelve (12) months after the last subject’s last visit (LSLV).  In addition, upon study 
completion and finalization of study report, Novartis aims to submit results of the study 
for publication.  When publication is not feasible, please refer to the Novartis Clinical 
Trial Results website (www.novartisclinicaltrials.com) for a summary of the trial results. 


Novartis
Confidential
Page 63
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
12.
REFERENCES
Altomare DA, Testa JR.  Pertubations of the AKT signaling pathway in human cancer.  
Oncogene. 2005;24:7455-64.
Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in. the management of 
chronic myeloid leukemia recommendations from an expert panel on behalf of the 
European Leukemia Net. Blood. 2006;108 (6):1809-1920.
Bellacosa A, Testa JR, Moore R, Larue L. A portrait of AKT kinases.  Cancer Biol & 
Ther. 2004;3(3):268-75.
Benson III A, Jaffer A, et all Recommended Guidelines for the Treatment of Cancer 
Treatment-Induced Diarrhea. J Clin Oncol 22:2918-2926. 2004 by American Society of 
Clinical Oncology
Blade J, Samson, D, Reece D, et al. Criteria for evaluating disease response and 
progression in patients with multiple myeloma treated by high-dose therapy and 
haemopoietic stem cell transplantation. Br J Hematol. 1998;102:1115-1123.
Cheson BD, Bennett, JM, Kopecky, KJ, et al. Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia. J Clin Oncol. 2003;21 (24):4642-9.
Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for Malignant 
Lymphoma. J Clin Oncol. 2007;25 (5):579-586.
Cohen MH, Johnson, JR, Pazdur, R. U.S. Food and Drug Administration Drug Approval 
Summary: Conversion of Imatinib mesylate (STI571; Gleevec) Tablets from Accelerated 
Approval to Full Approval. Clin Cancer Res. 2005;12 (11):12-19.
Cortes J, Rousselot, P, Kim, D-W, et al. Dasatinib induces complete hematologic and 
cytogenic responses in patients with imatinib-resistant or -intolerant chronic myeloid 
leukemia in blast crisis. Blood. 2007;109 (8):3207-3213.
DeFeo-Jones D, Barnett SF, Fu S, et al.  Tumor cell sensitization to apoptotic stimuli by 
selective inhibition of specific AKT/PKB family members.  Mol Cancer Ther. 
2005;4(2):271-9.
Durie BGM, Harousseau J-L, Miguel JS, Blade J, Barlogie B, Anderson K, et al. 
International uniform response criteria for multiple myeloma. Leukemia 2006:20(12), 
1467-73.
GlaxoSmithKline Document Number 2011N112051_02. LCH115397 Protocol 
Amendment 2.  A Phase 2a, Open Label, Multicenter Study to Assess the Efficacy and 
Safety of the Oral AKT Inhibitor GSK2110183 in Subjects with Langerhans Cell 
Histiocytosis.  Effective date, 02-Aug-2011.  


Novartis
Confidential
Page 64
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
GlaxoSmithKline Document Number 2011N113491_03.  GSK2110183 Investigator's 
Brochure.  Report Date: SEP-2014.
GlaxoSmithKline Document Number RM2008/00788/05 Amendment 5.  
GlaxoSmithKline protocol PKB112835, A Phase I, Open-Label, Two-Stage Study to 
Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the 
Oral AKT Inhibitor GSK2110183 in Subjects with Any Hematologic Malignancy.  
Effective Date: 16-Feb-2010.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, et al. Guidelines for 
the diagnosis and treatment of chronic lymphocytic leukemia: a report from the 
InternationalWorkshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute–Working Group 1996 guidelines. Blood, 2008;111:5446-56.
James, L.P., Letzig, L., Simpson, P.M., Capparelli, E., Roberts, D.W., Hinson, J.A., 
Davern, T.J., and Lee, W.M. Pharmacokinetics of acetaminophen protein adducts in 
adults with acetaminophen overdose and acute liver failure. Drug Metabolism and 
Disposition 37:1779-1784, 2009.
Morgensztern D, McLEod HL. PI3K/AKT/Mtor pathway as target for cancer therapy.  
Anti-Cancer Drugs. 2005;16:797-803.
NCI Common Terminology Criteria for Adverse Events, Version 4, DCTD, NCI, NIH, 
DHHS, 28 May 2009.
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group.  American Journal of Clinical Oncology. 1982;5:649-655.
Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the 
uniform reporting of clinical trials: Report of the International Myeloma Workshop 
Consensus Panel 1. Blood. 2011;117:4691-4695.
Tanno S, Mitsuuchi Y, et al.  AKT activation up-regulates insulin-like growth factor I 
receptor expression and promotes invasiveness of human pancreatic cancer cells.  Cancer 
Res. 2001;61:589-93.
The Criteria Committee of the New York Heart Association (NYHA).  Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, Mass:  
Little, Brown & Co.;  1994:253-256.


Novartis
Confidential
Page 65
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendices
Appendix 1:  Time and Events Table for Cohort A and B
Assessment/
Procedure
Transition 
Visit1
Continuous Dosing 
Treatment Period
Final Study Visit
Every 4 weeks11
(3 days)
during the first 52 
weeks of study 
treatment 
Every 8 weeks11
(3 days)
After 52 weeks 
on study 
treatment
Within 21 days (7 days) 
of Last Dose of Study 
Treatment(s)
Informed Consent2
X
Demographics and 
Parent Study Data
X
Physical  Exam
X
X
X
X
Pregnancy test3
X
Every 12 weeks
Vital Signs4
X
X
X
X
Body Weight
X
X
X
X
12-Lead ECG5
X
X
X
X
Clinical Chemistry6
X
X
X
X
Hematology
X
X
X
X
Coagulation (PT/PTT, 
INR)
X
X
X
X
HbA1c
X
Every 8 weeks
X
TSH
X
Every 8 weeks
X
Triglycerides and Total 
Cholesterol
X
Every 8 weeks
X
Disease Assessment7
X7
X7
AE Monitoring8, 9
Continuous
Review of Concomitant 
Medications10
Continuous
GSK2110183 Dosing
Continuous
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit completed 
during the parent study.  All Transition Visit assessments/procedures must be completed prior to the first dose of 
study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both the final visit on 
parent study and transition visit on this study.  Results from the final visit on parent study should be recorded in 
the eCRF as transition values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and before 
treatment with afuresertib is to be continued.
3.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential at the time of 
transition from the parent study and every 12 weeks thereafter.
4.
Vital signs (BP, temperature and pulse rate) should be taken in a semi-supine position and after the subject has 
rested for at least 5 minutes prior to the reading.  Vital signs may be measured more frequently as clinically 
indicated.
5.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a 
supine position after resting in that position for at least 10 minutes prior to testing.  
6.
Refer to Section 5.4.4 for complete list of clinical laboratory assessments to be performed.
7.
Disease assessments should be performed per local standard practice using criteria appropriate for disease type 
and location, no less frequent than every 12 weeks (more frequent assessments - as determined by investigator).


Novartis
Confidential
Page 66
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 1:  Time and Events Table for Cohort A and B (Continued)
8.
AEs/SAEs will be monitored and recorded beginning on the time of consent until the last study visit.
9.
All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
10. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
11. Subjects who remain on study treatment >52 weeks (including time on parent study) may have the frequency of 
their interim visits decreased to once every 8 weeks with approval from the Novartis Medical Lead.


Novartis
Confidential
Page 67
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 2:  Time and Events Table for Cohort C
Assessment/
Procedure
Transition 
Visit1
Continuous Dosing 
Treatment Period
Final Study Visit
Every 3 or 4 
weeks12
(3 days)
during the first 52 
weeks of study 
treatment 
Every 8 or 9 
weeks12
(3 days)
After 52 weeks 
on study 
treatment
Within 21 days (7 days) 
of Last Dose of Study 
Treatment(s)
Informed Consent2
X
Demographics and 
Parent Study Data
X
Physical  Exam
X
X
X
X
Pregnancy test3
X
Every 12 weeks
Vital Signs4
X
X
X
X
Body weight
X
X
X
X
12-Lead ECG5
X
X
X
X
X
X
Clinical Chemistry7
X
X
X
X
Hematology
X
X
X
X
Coagulation (PT/PTT, 
INR)
X
X
X
X
HbA1c
X
Every 8 or 9 weeks
X
X
TSH
X
Every 8 or 9 weeks
X
X
Triglycerides and Total 
Cholesterol
X
Every 8 or 9  
weeks
X
X
Disease Assessment8
X8
X8
AE Monitoring9,10
Continuous
Review of Concomitant 
Medications11
Continuous
Afuresertib Dosing
Continuous
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit completed 
during parent study.  All Transition Visit assessments/procedures must be completed prior to the first dose of 
study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both the final study visit on 
parent study and transition visit on this study.  Results from the final study visit on parent study should be 
recorded in the eCRF as transition values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and before 
treatment with afuresertib is to be continued.
3.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential at the time of 
transition from the parent study and every 12 weeks thereafter
4.
Vital signs (BP, temperature and pulse rate) should be taken in a semi-supine position and after the subject has 
rested for at least 5 minutes prior to the reading.  Vital signs may be measured more frequently as clinically 
indicated.
5.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a 
supine position after resting in that position for at least 10 minutes prior to testing.  
6.
ECHO or MUGA scan should be performed at the transition visit (or within 30 days prior to study entry), and the 
study final visit (if required) .
7.
Refer to Section 5.4.4 for complete list of clinical laboratory assessments to be performed.
8.
Disease assessments should be performed per local standard practice using criteria appropriate for disease type 
and location, no less than every 12 weeks.


Novartis
Confidential
Page 68
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 2:  Time and Events Table for Cohort C (Continued)
9.
AEs/SAEs will be monitored and recorded beginning on the time of consent until the last study visit.
10. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
11. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
12.
If the subject was treated on a 3 weeks schedule during parent study- he/she will remain on this schedule for the 
first 52 weeks of treatment (including the time on parent study). After 52 weeks the frequency of the visits may/can 
be reduced to every 8 or 9 weeks. If the subject was on 4-week schedule on the parent study he/she will remain 
on this schedule for the first 52 weeks (including time on parent study). After 52 weeks the frequency of visits can 
be decreased to every 8 weeks with approval of Novartis Medical Lead.


Novartis
Confidential
Page 69
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 3:  Liver Safety Drug Restart 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.
Background Information on Drug Restart/Rechallenge
Following drug-induced liver injury, drug restart or rechallenge is associated with a 
13% mortality across all drugs in prospective studies.1  Clinical outcomes vary by 
drug, with nearly 50% fatality with halothane readministered in one month of initial 
injury. However, some drugs seldom result in recurrent liver injury or fatality.  Risk 
factors for a fatal drug restart/rechallenge outcome include: hypersensitivity1 with initial 
liver injury (e.g. fever, rash, eosinophilia), jaundice or bilirubin2xULN or INR>1.5 
suggesting severe liver injury, prior IP-related severe or fatal drug restart/rechallenge2,3 or 
evidence of drug-related preclinical liability / mitochondrial impairment3.
Drug Restart/Rechallenge Process (also see Figure 2)
1.
Principal Investigator (PI) requests consideration of drug restart for a subject 
receiving compelling benefit from a critical or life-saving drug, who exhibits liver 
chemistry elevation meeting subject stopping criteria, with no alternative treatment.
2.
Novartis Medical Lead & Clinical Safety Physician to review the subject’s 
restart/rechallenge risk factors & complete checklist (Table 10)
Table 10
Checklist for drug restart/rechallenge for critical medicine
(Following drug-induced liver injury, drug rechallenge is associated with 13% mortality 
across all drugs in prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject 
and no alternative therapy.  Provide brief explanation:
Relative benefit-risk favorable for drug restart/rechallenge, after 
considering the following high risk factors:
•
Initial liver injury event included: 
–
fever, rash, eosinophilia, or hypersensitivity
–
or bilirubin2xULN (direct bilirubin >35% of total)
•
Subject currently exhibits ALT 3xULN, bilirubin 2xULN (direct 
bilirubin >35% of total, if available), or INR1.5
•
Severe or fatal restart/rechallenge has earlier been observed 
with IP If yes, please provide brief explanation:
•
IP associated with known preclinical hepatic liability/ injury   


Novartis
Confidential
Page 70
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
3.
If Novartis provides written approval for restart/rechallenge following the above 
review, the Principal Investigator (PI) must ensure the following:

The PI is to obtain Ethics Committee or Institutional Review Board review of 
drug re-initiation, as required. 

PI must discuss the possible benefits and risks of drug re-initiation with the 
subject.

The subject must sign informed consent with a clear description of possible 
benefits and risks of drug administration, including recurrent liver injury or death. 
Consent specifically for the IP restart must be recorded in the study chart.

The drug must be reinitiated at Novartis approved dose(s). 

Subjects approved by Novartis for restart of IP must return to the clinic twice a 
week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. If 
protocol defined stopping criteria for liver chemistry elevations are met, study 
drug must be stopped. 

The Ethics Committee or Institutional Review Board is to be informed of the 
subject’s outcome, as required.

Novartis is to be notified of any adverse events, as per Section 5.9.


Novartis
Confidential
Page 71
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Figure 2
Algorithm for Drug Restart After Possible Drug-induced Liver Injury
References:
1.
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury:the attractive hazard. Expert Opin 
Drug Saf 2009;8:709–714.
2.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al. Drug-induced liver injury following positive drug 
rechallenge. Regul Toxicol Pharmacol 2009;54:84-90.
3.
Hunt CM. Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced
liver injury: a systematic review. Hepatology 2010;52:2216–2222
Novartis process for drug restart after possible drug-induced liver injury
Principal Investigator requests Novartis approve 
drug readmin. with Investigational product (IP)
Novartis Medical Lead & Clinical Safety Physician(s) to discuss benefit:risk and
Novartis does not
allow drug
reinitiation
Principal Investigator promptly informed in writing of 
Novartis decision to restart IP & dosing regimen


Novartis
Confidential
Page 72
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Liver Safety Algorithms
Flow chart for Phase II studies:
ALT?3xULN ?
Plus Bilirubin ? 2xULN
(>35% direct) or INR 
>1.5 (if measured)* ?
No
Yes
Yes
Instruct subject to stop IP 
Notify Novartis + arrange clinical 
followup within 24-72h
Obtain weekly liver chemistries (*if possible) until 
resolved, stabilized or returned to baseline values
Perform liver event follow up assessments (serology, 
PK sample, etc as in protocol) 
Complete liver event CRF & if appropriate liver 
imaging and biopsy CRFs (if these tests performed)
Withdraw subject from study after liver chemistry
monitoring complete + do not rechallenge with 
study medication
Instruct subject to stop investigational product (IP)
Notify Novartis and arrange clinical 
followup within 24 hrs
Perform liver event f/u assessments (serology, PK, etc)
Report as an SAE (exc. hepatic impairment or cirrhosis 
studies); complete SAE & liver event CRF + 
liver imaging and biopsy CRFs (if tests performed).
Obtain twice weekly liver chemistries until resolved, 
stabilized or returned to baseline values 
Consultation with hepatologist/specialist recommended
Withdraw subject from study after liver chemistry 
monitoring complete + do not re -challenge with IP
ALT?5xULN ?
Hepatitis
symptoms
or rash ? 
No
Able to 
monitor weekly 
for 4 wks ?
No
Notify Novartis within 24 hrs
Continue IP
Check liver chem weekly 
for 4 wks
No
No*
Yes
Yes
Yes
Yes
ALT?3xULN or 
bilirubin ? 2xULN 
after 4 weeks?
Continue IP
Monitor liver chemistries 
2X/month until values normalize 
or return to baseline
*INR threshold does not apply to 
subjects receiving anticoagulants.


Novartis
Confidential
Page 73
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 4:  COCKCROFT-GAULT FORMULA
CLcr(mL/min) =  
Q x (140-age[yr]) x ideal body wt [kg]*
72 x serum creatinine [mg/dL]
Q = 0.85 for females
Q = 1.0 for males
OR
CLcr(mL/min) =  
K x (140-age[yr]) x ideal body wt [kg]*
Serum creatinine [umol/L]
K = 1.0 for females  
K = 1.23 for males
*Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974]
Ideal body weight
Males = 
50.0 kg + (2.3 kg x each inch over 5 feet) or 50.0 kg + (0.906 kg x each cm over 
152.4 cm)
Females = 
45.5 kg + (2.3 kg x each inch over 5 feet) or 45.5 kg + (0.906 kg x each cm over 
152.4 cm)
Example 1:
Male, actual body weight = 90.0 kg, height = 68 inches.
Ideal body weight = 50.0 + (2.3) (68-60) = 68.4 kg.
This subject’s actual body weight is > 30% over ideal body weight.  Therefore, in this case, the 
subject’s ideal body weight of 68.4 kg should be used in calculating estimated creatinine clearance.
References
Devine, BJ.  Case Number 25 Gentamicin Therapy:  Clinical Pharmacology Case Studies.  
Drug Intelligence and Clinical Pharmacy. 1974; 8:650-655


Novartis
Confidential
Page 74
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 5:  Disease Assessments and Response Criteria
Chronic Lymphocytic Leukemia (CLL) [Hallek, 2008]
Within 4 weeks of transition visit
every 12 weeks3
Imaging as clinically indicated1 
X
X
Bone marrow aspirate/biopsy2
X
X
1.
Investigator discretion as to type
2.
Bone marrow evaluation for cellular morphology, cytogenetics, flow cytometry, and molecular studies as clinically 
indicated.
3.
The intervals of disease assements may be shorter if investigator feels that it is necessary
Chronic Myelogenous Leukemia (CML) [Baccarani, 2006; Cohen, 2005; Cortes, 2007]
Within 4 weeks of 
Transition visit
every 12 weeks
BCR-ABL by RT-PCR
X
X
Bone marrow aspirate/ biopsy 1
X
X
1.
Bone marrow evaluation for cellular morphology, cytogenetics, flow cytometry, and molecular studies as clinically 
indicated.
Multiple Myeloma (MM) [Rajkumar, 2011, Durie, 2006, Blade, 1998]
Within 4 weeks of Transition 
visit
Every 4 weeks within the first 52 weeks of 
treatment and at least every 12 weeks thereafter  
SPEP and UPEP or M-protein 
quantitation & immunofixation 
X
x
24h urine collection for M-
protein or light chain 
quantitation
X
X2
κ/λ ratio
X
X
Imaging3
X
X
Bone marrow aspirate/biopsy4
X
X5
1.
Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP); UPEP only if subject has 
monoclonal paraprotein in urine at original disease assessment prior to Day 1, Cycle 1 dosing.  
2.
24h urine collection only required for subjects with monoclonal paraprotein found in original disease assessment 
collection prior to Day 1, Cycle 1 dosing.
3.
Investigator discretion as to type.
4.
Bone marrow evaluation for cellular morphology, cytogenetics, flow cytometry, and molecular studies as clinically 
indicated.
5.
Not necessary to repeat bone marrow biopsy if monoclonal protein absence in both serum and urine has been 
sustained for six weeks except for subjects with non-secretory multiple myeloma.
Malignant Lymphoma (ML) [Cheson, 2007]
Within 4 weeks of transition visit
Every 12 weeks
Imaging (Investigator discretion as to type)
X
X
Bone marrow aspirate/biopsy1,2
X
X
1.
Bone marrow evaluation for cellular morphology, cytogenetics, flow cytometry, and molecular studies as clinically 
indicated.
2.
Needed only if subject with lymphomatous involvement of bone marrow


Novartis
Confidential
Page 75
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
AML and ALL [Cheson, 2003]
Within 4 weeks of 
transition visit
D1 of each cycle
Every 12 weeks, or more 
often if needed
CDC with differential1
X
x
Bone marrow 
aspirate/biopsy2
X
X
1.
Flow cytometry per investigator’s discretion.
2.
Bone marrow evaluation for cellular morphology, cytogenetics, flow cytometry, and molecular studies as clinically 
indicated.
Langerhans Cell Histocytosis (LCH) 
Within 4 weeks of transition visit
Every 12 weeks
Imaging (Investigator discretion as to type)
X
X
Bone marrow1
X
X
Pulmonary function tests2
X
X
1.
Bone marrow evaluation only if  clinically indicated
2.
Needed in subjects with pulmonary involvement
Response Criteria for Chronic Lymphocytic Leukemia (CLL)
[Hallek, 2008]
Complete remission (CR): The presence of all of the following for 2months.

Peripheral blood lymphocytes < 4000/μL

Absence of lymphadenopathy, hepatomegaly, and splenomegaly by physical 
exam and appropriate radiographic imaging.

Absence of constitutional symptoms.

Normal CBC defined as polymorphonuclear lymphocytes 1500/μL (without 
growth factors), platelets >100,000/μL (without growth factors), and 
hemoglobin >11.0g/dL (untransfused).

Bone marrow aspirate and biopsy (2 months after all the requirements above are 
met) that is at least normocellular for age with <30% of nucleated cells being 
lymphocytes and has no lymphoid nodules.
Partial remission (PR): The presence of 50% decrease in peripheral blood lymphocyte 
count from pre-treatment baseline value and a 50% reduction in lymphadenopathy, 
and/or 50% reduction in the size of the liver and/or spleen, as well as one or more of the 
following features for 2 months.

Polymorphonuclear lymphocytes 1500/μl without growth factors.

Platelets >100,000/μl or 50% improvement over baseline without growth factors.

Hemoglobin >11.0g/dL or 50% improvement over baseline without transfusions.


Novartis
Confidential
Page 76
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Progressive disease (PD): At least one of the following.

Appearance of any new lesions such as lymph nodes >1.5 cm or increase of 50% in 
the greatest determined diameter

50% increase in the size of the liver and/or spleen as determined by measurement 
below the respective costal margin or appearance of palpable 
hepatomegaly/splenomegaly which was not previously present.

50% increase in the absolute number of circulating lymphocytes to at least 5000/μL 
B lymphocytes.

Transformation to a more aggressive histology (e.g., Richter’s syndrome or PLL 
with >55% prolymphocytes).

Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to 
CLL
Stable disease (SD): Not meeting criteria for complete remission, partial remission or 
progressive disease.
Response Criteria for Chronic Myelogenous Leukemia (CML)
[Baccarani, 2006; Cohen, 2005; Cortes, 2007]
Hematologic response criteria (all responses to be confirmed after ≥ four week):
For blast crisis and accelerated phase:
Complete hematologic response (CHR): <5% blasts in bone marrow, no blasts in 
peripheral blood, ANC 1500/μl and platelets 100,000/μl, no extramedullary 
involvement (e.g., nonpalpable spleen).
No evidence of leukemia (NEL): As for CHR but without complete recovery of 
peripheral blood (i.e., 1000 absolute neutrophil count [ANC] < 1500/L and 20,000 
platelets < 100,000/L).
Partial (minor) hematologic response (PHR): <15% blasts in peripheral blood and 
bone marrow, <30% blasts + promyelocytes in peripheral blood and bone marrow, <20% 
basophils in peripheral blood, no extramedullary involvement other than spleen or liver
Chronic phase:
Complete hematologic response (CHR): Platelet count <450,000/μl, white blood cell 
count <10,000/μl, <5% myelocytes + metamyelocytes in peripheral blood, no blasts + 
promyelocytes in peripheral blood, <20% basophils in peripheral blood, no 
extramedullary involvement.  
Partial (minor) hematologic response (PHR): White blood cell count <10,000/L with 
persistence of immature cells (myelocytes or metamyelocytes) in peripheral blood, 
splenomegaly < 50% of the pre-treatment level, and thrombocytosis > 450,000/L but 
<50% of pre-treatment level.  


Novartis
Confidential
Page 77
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Response categories:
Major hematologic response: CHR + NEL.
Overall hematologic response: CHR + NEL + PHR.
Progressive disease in responding subjects: Subjects with CHR, NEL, or PHR who 
lose response over 6 weeks.
Progressive disease in non-responders: Subjects with no change in baseline levels of % 
blasts in peripheral blood or bone marrow on all assessments over 6 week period.
Cytogenetic response:
Complete cytogenetic response: 0% Ph positive cells detectable on metaphase 
cytogenetic evaluation of bone marrow aspirate with 20 to 25 cells analyzed.  Values 
maintained over 3 week period.
Partial cytogenetic response: 1 to 35% Ph positive cells detectable on metaphase 
cytogenetic evaluation of bone marrow aspirate with 20 to 25 cells analyzed.  Values 
maintained over 3 week period.
Minor cytogenetic response: 36 to 65% Ph positive cells detectable on metaphase 
cytogenetic evaluation of bone marrow aspirate with 20 to 25 cells analyzed.  Values 
maintained over 3 week period.
Minimal cytogenetic response: 66 to 95% Ph positive cells detectable on metaphase 
cytogenetic evaluation of bone marrow aspirate with 20 to 25 cells analyzed.  Values 
maintained over 3 week period.  
No cytogenetic response: >95% Ph positive cells detectable on metaphase cytogenetic 
evaluation of bone marrow aspirate with 20 to 25 cells analyzed.  Values maintained over 
3 week period.
Molecular response:
Complete molecular response: No evidence of BCR-ABL mRNA by RT-PCR in 
peripheral blood. Values maintained over 3 week period.
Major molecular response: 3 log reduction in detectable BCR-ABL mRNA in 
peripheral blood.  Values maintained over 3 week period.
Response Criteria for Multiple Myeloma (MM)
[Rajkumar, 2011]
sCR (stringent complete response): 
Complete response as defined below plus: 


Novartis
Confidential
Page 78
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

normal free light chain (FLC) ratio and

absence of clonal cells in bone marrow by immunohistochemistry or 2-4 color 
flow cytometry 
CR (complete response):

Negative serum and urine immunofixation, and

Disappearance of any soft tissue plasmacytomas, and

<5% plasma cells in bone marrow
VGPR (very good partial response):

Serum and urine M-component detectable by immunofixation but not on 
electrophoresis OR

90% or greater reduction in serum M- component plus urine M- component 
< 100mg/24h
PR (partial response):

50% reduction of serum M-protein and reduction in 24 hour urinary M-protein 
by 90% or to < 200 mg/24h, and

If the serum and urine M-protein are not measurable, a 50% decrease in the 
difference between involved and uninvolved free light chain levels is required in 
place of the M-protein criteria.  If serum and urine M-protein are not measurable, 
and serum free light chain assay is also not measurable, 50% reduction in bone 
marrow plasma cells is required in place of M-protein, provided baseline bone 
marrow plasma cell percentage was 30%, and

In addition to the above listed criteria, if present at baseline, a 50% reduction in 
the size of the soft tissue plasmacytomas is also required.
SD (stable disease):

Not meeting criteria for CR, VGPR, PR or PD
PD (progressive disease)a
Requires any one or more of the following:

Increase of 25% from lowest response value in any one or more of the 
following: 

serum M-component (absolute increase must be 0.5 g/dl), or

urine M-component (absolute increase must be 200 mg/24h), or 

the difference between involved and uninvolved free light chain levels 
(absolute increase must by > 10mg/dl): only for patients without 
measurable serum and urine M-protein levels, or


Novartis
Confidential
Page 79
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

bone marrow plasma cell percentage (the absolute % must be 10%) –
only for patients without measurable serum and urine M-protein levels 
and without measurable disease by FLC level

definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue plasmacytomas

development of hypercalcemia (corrected calcium > 11.5 mg/dl or 2.65 mmol/l) 
that can be attributed solely to the plasma cell proliferative disorder

All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive 
assessments made at any time before the institution of any new therapy; CR, sCR, 
VGPR, PR, and SD categories also require no known evidence of progressive or new 
bone lesions if radiographic studies were performed. VGPR and CR categories 
require serum and urine studies regardless of whether disease at baseline was 
measurable on serum, urine, both, or neither. Radiographic studies are not required 
to satisfy these response requirements. Bone marrow assessments need not be 
confirmed. For PD, serum M-component increases of more than or equal to 1 g/dL 
are sufficient to define relapse if starting M-component is ≥ 5 g/dL.

Clarifications to IMWG criteria for coding CR and VGPR in patients in whom the 
only measurable disease is by serum FLC levels: CR in such patients indicates a 
normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in 
such patients requires a > 90% decrease in the difference between involved and 
uninvolved FLC levels. 

Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to 
be used only in patients without measurable disease by M protein and by FLC levels; 
“25% increase” refers to M protein, FLC, and bone marrow results, and does not 
refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest 
response value” does not need to be a confirmed value
References
Durie BGM, Harousseau J-L, Miguel JS, et. al. International uniform response criteria for 
multiple myeloma. Leukemia, 2006:20: 1467-73.
Rajkumar SV, Harousseau JL, Durie B, et al.  Consensus recommendations for the 
uniform reporting of clinical trials: Report of the International Myeloma Workshop 
Consensus Panel 1.  Blood.  2011;117:4691-4695.
Response Criteria for Malignant Lymphoma
[Cheson, 2003; Cheson, 2007]
General Comments:

Lymph nodes should be considered abnormal if the long axis is more than 1.5 
cm regardless of the short axis.  If a lymph node has a long axis of 1.1 to 1.5 cm, 
it should only be considered abnormal if its short axis is more than 1.0 cm.  
Lymph nodes 1.0 X 1.0 cm will not be considered as abnormal for relapse or 
progressive disease.


Novartis
Confidential
Page 80
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

Measurable extranodal disease should be assessed in a manner similar to that for 
nodal disease.  For these recommendations, the spleen is considered nodal 
disease.  Disease that is assessable but not quantifiable (e.g. pleural effusions, 
bone lesions) will be recorded as present or absent only, unless, while an 
abnormality is still noted on imaging studies or physical examination, it is found 
to be histologically negative.

Where PET is unavailable, unnecessary, or inappropriate for use, response 
should be assessed as below, but only using CT scans.
Complete Response: Requires the following:

Complete disappearance of all detectable clinical evidence of disease and 
disease-related symptoms if present before therapy.

Typically FDG-avid lymphoma: in subjects with no pre-treatment PET scan or 
when the PET scan was positive before therapy, a post-treatment residual mass 
of any size is permitted as long as it is PET negative.

Variably FDG-avid lymphomas/FDG avidity unknown: in subjects without pre-
treatment PET scan, or if a pre-treatment PET scan was negative, all lymph 
nodes and nodal masses must have regressed on CT to normal size (1.5 cm in 
their greatest transverse diameter for nodes >1.5 cm before therapy).  Previously 
involved nodes that were 1.1 to 1.5 cm in their long axis and more than 1.0 cm 
in their short axis before treatment must have decreased to 1.0 cm in their short 
axis after treatment.

The spleen and/or liver, if considered enlarged before therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical 
examination and should be considered normal size by imaging studies.  Nodules 
related to lymphoma should disappear.

If the bone marrow was involved by lymphoma before treatment, the infiltrate 
must have cleared on repeat bone marrow biopsy.  The biopsy sample on which 
this determination is made must be adequate (with a goal of >20 mm unilateral 
core).  If the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry (IHC).  A sample that is negative by IHC but that 
demonstrates a small population of clonal lymphocytes by flow cytometry will 
be considered a CR until data become available demonstrating a clear difference 
in subject outcome.
Partial Response: Requires all of the following
1. At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of 
the largest dominant nodes or nodal masses.  These nodes or masses should be 
selected according to all of the following: they should be clearly measurable in at 
least 2 perpendicular dimensions; if possible they should be from disparate regions of 
the body; and they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved.


Novartis
Confidential
Page 81
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
2. No increase should be observed in the size of other nodes, liver, or spleen.
3. Splenic and hepatic nodules must regress by 50% in their SPD or, for single nodules, 
in the great transverse diameter.
4. With the exception of splenic or hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present.
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment.  However, if positive, the cell type should be specified (e.g., 
large cell lymphoma or small neoplastic B cells).  Subjects who achieve a CR by the 
above criteria, but who have persistent morphologic bone marrow involvement will 
be considered partial responders.  When the bone marrow was involved before 
therapy and a clinical CR was achieved, but with no bone marrow assessment after 
treatment, subjects should be considered partial responders.
6. No new sites of disease should be observed.
7. Typically FDG-avid lymphoma: for subjects with no pre-treatment PET scan or if the 
PET scan was positive before therapy, the post-treatment PET should be positive in at 
least one previously involved site.
8. Variably FDG-avid lymphomas/FDG avidity unknown: for subjects without a pre-
treatment PET scan, or if a pre-treatment PET scan was negative, CT criteria should 
be used.
9. In subjects with follicular lymphoma or mantle-cell lymphoma, a PET scan is only 
indicated with one or at most two residual masses that have regressed by more than 
50% on CT; those with more than two residual lesions are unlikely to be PET 
negative and should be considered partial responders.
Stable disease: Defined as the following

A subject is considered to have SD when he or she fails to attain the criteria 
needed for a CR or PR, but does not fulfill those for progressive disease.

Typically FDG-avid lymphomas: the PET should be positive at prior sites of 
disease with no new areas of involvement on the post-treatment CT or PET.

Variably FDG-avid lymphoma/FDG-avidity unknown: for subjects without a 
pre-treatment PET scan or if the pre-treatment PET was negative, there must be 
no change in the size of the previous lesions on the post-treatment CT scan.


Novartis
Confidential
Page 82
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Relapsed Disease (after CR)/Progressive Disease (after PR or SD):

Appearance of any new lesion more than 1.5 cm in size in any axis during or at 
the end of therapy, even if other lesions are decreasing in size.  Increased FDG 
uptake in a previously unaffected site should only be considered relapse or 
progressive disease after confirmation with other modalities.  In subjects with no 
prior history of pulmonary lymphoma, new lung nodules identified by CT are 
mostly benign.  Thus a therapeutic decision should not be made solely on the 
basis of the PET without histological confirmation.

At least a 50% increase from nadir in the SPD of any previously involved nodes, 
or in a single involved node, or the size of other lesions (e.g. splenic or hepatic 
nodules).  To be considered progressive disease, a lymph node with a diameter 
of the short axis of less than 1.0 cm must increase by 50% and to a size of 1.5 
X 1.5 cm or more than 1.5 cm in the long axis. 

At least a 50% increase in the longest diameter of any single previously 
identified node more than 1 cm in its short axis.

Lesions should be PET positive if observed in a typical FDG-avid lymphoma or 
the lesion was PET positive before therapy unless the lesion is too small to be 
detected with current PET systems (<1.5 cm in its long axis by CT)
Response Criteria for Acute Myeloid Leukemia (AML) and Acute 
Lymphoblastic Leukemia (ALL)
[Cheson, 2003]
Morphologic leukemia-free state*: <5% blasts in a bone marrow aspirate sample with 
marrow spicules, a count of at least 200 nucleated cells, and no visible Auer rods.
Morphologic complete remission*: absence of peripheral blasts; <5% blasts in a bone 
marrow aspirate sample with marrow spicules, a count of at least 200 nucleated cells, and 
no visible Auer rods; ANC 1000/L; platelets 100,000/L; and transfusion 
independent. 
Morphologic complete remission with incomplete blood count recovery*: absence of 
peripheral blasts, <5% blasts in a bone marrow aspirate sample with marrow spicules and 
a count of at least 200 nucleated cells and no visible Auer rods, residual neutropenia 
(ANC <1000/L) and/or thrombocytopenia (platelets <100,000/L).
Cytogenetic complete remission*: Subject in morphologic complete remission and 
normal karotype on bone marrow aspirate with 20 to 25 metaphase cells analyzed.
Molecular complete remission*: Subject in morphologic and cytogenetic complete 
remission and no evidence of leukemia by flow cytometry or PCR.
Partial remission: ANC 1000 /L; platelets 100,000 /L; decrease of at least 50% in 
the percentage of blasts to 5% to 25% in the bone marrow aspirate.


Novartis
Confidential
Page 83
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Treatment Failure:

Residual disease: Subject survives 7 days post treatment; persistent AML/ALL in 
blood or bone marrow.

Aplasia:  Subject survives 7 days post treatment; death while cytopenic with 
aplastic bone marrow.

Indeterminate cause: Subject who dies <7 days post treatment; subject who dies >7 
days post treatment with no peripheral blasts, but no bone marrow examination; 
subject who doesn’t complete the first course of therapy.
*NOTE: Extramedullary leukemia such as CNS or soft tissue involvement must be absent.
Definition of Disease State, Response Criteria and Response Definition for 
Langerhans Cell Histocytosis (LCH)
Definition of Disease State
NON ACTIVE DISEASE
(NAD)
no evidence of
disease
resolution of all signs or 
symptoms
regressive disease
regression of signs or 
symptoms, no new
lesions*
ACTIVE DISEASE (AD)
stable disease
persistence of signs or 
symptoms, no new
lesions
progressive disease
progression of signs or 
symptoms and/or
appearance of new lesions**
*Plus partial or complete response by RECIST [Eisenhauer, 2009]; and/or pulmonary criteria if applicable
*/** Isolated pulmonary LCH: improvement in lung function is >10% increase in baseline FEV1 or DLCO at time of 
disease assessment. Disease progression is >15% decline from baseline FEV1 or DLCO or FVC OR progression of 
symptoms (dyspnea, cough, constitutional symptoms) that cannot be explained by diagnoses other than pulmonary 
LCH (infection, heart disease, and/or other clinical issues excluded by careful clinical evaluation and testing)
** Isolated bone disease: progression is defined as appearance of new bone lesions or lesions in
other organs


Novartis
Confidential
Page 84
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Response Criteria
BETTER
Complete Resolution
NAD
Regression
AD Better
INTERMEDIATE
Mixed
New lesions in one site, 
regression in another site
Stable
Unchanged
WORSE
Progression
Response Definition for Efficacy
3 Month Assessment
6 Month Assessment
(performance relative to 3 
month assessment)
Response
NAD or AD Better
Mixed
Stable
NAD or AD Better or Stable
NAD or AD Better
NAD or AD Better
Failure
NAD or AD Better
NAD or AD Better
Mixed or Stable1
Progression
Mixed
Progression
Mixed or Stable1 or 
Progression
N/A
NAD = Non Active Disease
AD = Active Disease
Stable = Unchanged
Mixed = New lesions in one site, regression in another site
1. Subjects who are assessed only as stable at the 3 and 6 month assessment are not
considered a treatment response; however, they may be considered for continued treatment


Novartis
Confidential
Page 85
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 6:  RECIST Guidelines
[Eisenhauer, 2009]
Baseline Disease Assessment
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than four weeks before the beginning of the treatment.
Measurable lesions
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm; when CT scans 
have slice thickness >5 mm, the minimum size should be twice the slice thickness).

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as nonmeasurable).

20 mm by chest X-ray.
Malignant lymph nodes
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm 
in short axis when assessed by CT scan (CT scan slice thickness is recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.

‘Lytic bone lesions or mixed lytic-blastic lesions’ with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered measurable if the soft tissue component meets the
definition of measurability described above.

‘Cystic lesions’ thought to represent cystic metastases can be considered measurable 
if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target 
lesions.
Non-measurable lesions
Non-measurable lesions are all other lesions, including small lesions (longest diameter 
<10 mm or pathological lymph nodes with 10 to <15 mm short axis), as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques.

Blastic bone lesions are non-measurable.


Novartis
Confidential
Page 86
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

Lesions with prior local treatment, such as those situated in a previously irradiated 
area or in an area subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion. Study 
protocols should detail the conditions under which such lesions would be considered 
measurable.
Target Lesions

All measurable lesions up to a maximum of two lesions per organ and five lesions in 
total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.

Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, as well as their suitability for 
reproducible repeated measurements.

All measurements should be recorded in metric notation using calipers if clinically 
assessed. A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters, which will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. If lymph nodes are to 
be included in the sum, only the short axis will contribute.
Non-target Lesions
All lesions (or sites of disease) not identified as target lesions, including pathological 
lymph nodes and all non-measurable lesions, should be identified as non-target lesions 
and be recorded at baseline.  Measurements of these lesions are not required and they 
should be followed as ‘present’, ‘absent’ or in rare cases, ‘unequivocal progression’.
Response Criteria
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this may include the baseline sum). 
The sum must also demonstrate an absolute increase of at least 5 mm.
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD.


Novartis
Confidential
Page 87
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Response Criteria
Special notes on the assessment of target lesions

Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study. When 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even 
if complete response criteria are met since a normal lymph node is defined as having 
a short axis of <10 mm.

Target lesions that become ‘too small to measure’. While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small.  However, sometimes 
lesions or lymph nodes become so faint on a CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being ‘too small 
to measure’, in which case a default value of 5 mm should be assigned.

Lesions that split or coalesce on treatment.  When non-nodal lesions ‘fragment’, 
the longest diameters of the fragmented portions should be added together to 
calculate the target lesion sum.  Similarly, as lesions coalesce, a plane between them 
may be maintained that would aid in obtaining maximal diameter measurements of
each individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’.
Evaluation of non-target lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker levels. All lymph nodes must be non-pathological in size (<10 mm short 
axis).
Non-CR / Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker levels above normal limits.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.

When patient has measurable disease. To achieve ‘unequivocal progression’ on the 
basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy. A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status.

When patient has only non-measurable disease. There is no measurable disease
assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified, a useful 
test that can be applied is to consider if the increase in overall disease burden based 
on change in nonmeasurable disease is comparable in magnitude to the increase that 
would be required to declare PD for measurable disease. Examples include an


Novartis
Confidential
Page 88
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
increase in a pleural effusion from ‘trace’ to ‘large’ or an increase in lymphangitic 
disease from localized to widespread.
New lesions
The appearance of new malignant lesions denotes disease progression:

The finding of a new lesion should be unequivocal (i.e., not attributable to 
differences in scanning technique, change in imaging modality or findings thought to 
represent something other than tumor, especially when the patient’s baseline lesions 
show partial or complete response).

If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using 
the date of the initial scan.

A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and disease progression.
It is sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT in assessment of progression (particularly possible ‘new’ disease).  New lesions on 
the basis of FDG-PET imaging can be identified according to the following algorithm:
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is PD based 
on a new lesion.
No FDG-PET at baseline and a positive FDG-PET at follow-up:

If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD.
Time Point Response
Table 1 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline.


Novartis
Confidential
Page 89
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Overall Responses for all Possible Combinations of Tumor Responses in Target 
and Non-target Lesions With or Without the Appearance of New Lesions
Target lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Incomplete response/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
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; and PD = progressive disease.
Confirmation
In non-randomized trials where response is the primary endpoint, confirmation of PR and 
CR is required to ensure responses identified are not the result of measurement error. 
This will also permit appropriate interpretation of results in the context of historical data 
where response has traditionally required confirmation in such trials.  However, in all 
other circumstances, (i.e., in randomized Phase II or III trials or studies where stable 
disease or progression are the primary endpoints), confirmation of response is not 
required since it will not add value to the interpretation of trial results. However, 
elimination of the requirement for response confirmation may increase the importance of 
central review to protect against bias, in particular in studies which are not blinded. In the 
case of SD, measurements must have met the SD criteria at least once after study entry at 
a minimum interval (in general not less than six to eight weeks) that is defined in the 
study protocol.
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would most likely happen in the case of 
PD.
References
Eisenhauer, E. A., P. Therasse, et al. (2009). "New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1)." Eur J Cancer 45(2): 228-247.


Novartis
Confidential
Page 90
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 7:  Hy’s Law
Hy’s law is a prognostic indicator of drug-induced liver injury defined as ALT 3 times 
ULN and bilirubin 2 times ULN (>35% direct) (or ALT 3 times ULN and INR >1.5, if 
INR is measured).


Novartis
Confidential
Page 91
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 8: Protocol Amendment Changes
AMENDMENT 1
Where the Amendment Applies
This amendment applies to all investigator sites participating in this study.
Summary of Amendment Changes with Rationale
Updated regulatory agency identifying numbers
Updated Investigator’s Brochure information with the most recent IB document number 
2011N113491
Added disease assessments to 6.1 Transition Visit
Removed central lab wording from Section 6.4.5 Clinical Laboratory Assessments 
because we are not using central labs
Incorporated liver function tests into the clinical chemistries table (Table 4, Section 6.4.5) 
to insure that liver function tests would be administered whenever clinical chemistries 
were due
Updated AE monitoring language
Updated IP storage wording
Updated Table 7 Dose Modifications for GSK2110183
Added standard Acetaminophen protein adduct testing to Liver Event Follow-up
Assessments (Section 7.7.7.1).  These had been inadvertently left out.  
Updated Section 8.2 Prohibited and Cautionary Meds
Updated Section 8.3 Non Drug Therapies
Updated Time & Events Table
Added LCH and Acetaminophen protein adduct testing reference to Sec 13 References
Added Definition of Disease State, Response Criteria and Response Definition for 
Langerhans Cell Histocytosis (LCH).  These had been inadvertently left out.  


Novartis
Confidential
Page 92
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
List of Specific Changes
Page 3, Regulatory Agency Identifying Numbers 
PREVIOUS TEXT
Regulatory Agency Identifying Number [IND 111439]
OCTAGON: Health Canada reference number = 9427-O1624-21C
Australian CTN number = 2009/272.
S. Korea: Receipt number = 20090399355
REVISED TEXT
Regulatory Agency Identifying Number [IND 111439]
Health Canada reference number = 9427-G0838-279C
S. Korea: Receipt number = 20110110591
Section 6.4.5 Clinical Laboratory Assessments
PREVIOUS TEXT
Whenever possible, every effort should be made to ensure that laboratory results 
submitted to GSK are from the designated central laboratory.  If laboratory assessments 
are performed at the institution’s local laboratory, please refer to the SPM for appropriate 
handling of samples to avoid duplicate and/or additional blood draws.
Table 4 List of Clinical Laboratory Assessments, Section 6.4.5 Clinical 
Laboratory Assessments
PREVIOUS TEXT
Clinical Chemistry
Blood urea nitrogen (BUN)
Potassium
Creatinine
Inorganic phosphorus
Sodium
Magnesium
Albumin
Chloride
Calcium
LDH
Bicarbonate
Glucose
Total protein
M-protein1
1.
For Multiple Myeloma subjects only 


Novartis
Confidential
Page 93
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Liver Function Tests
AST
ALT
Alkaline Phosphatase
Total bilirubin (bilirubin fractionation recommended if total bilirubin >2 times ULN)
REVISED TEXT
Clinical Chemistry
Blood urea nitrogen (BUN)
Potassium
Creatinine
Inorganic phosphorus
Sodium
Magnesium
Albumin
Chloride
Calcium
LDH
Bicarbonate
Glucose
Total protein
M-protein1
AST
ALT
Alkaline Phosphatase
Total bilirubin (bilirubin fractionation 
recommended if total bilirubin >2 times ULN)
3.
For Multiple Myeloma subjects only 
Section 6.8.1 Adverse Events
PREVIOUS TEXT
AEs and SAEs will be monitored from the time of consent until 30 days after the last 
dose of study drug(s).  All AEs and SAEs must be recorded and reported as detailed in 
the following sections and in the SPM.  At the time of consent, all ongoing AEs that 
began during participation in the parent study must be recorded in the eCRF.
REVISED TEXT
AEs and SAEs will be monitored from the time of consent until 
 
 the final study visit.  All AEs and SAEs must be recorded and 
reported as detailed in the following sections and in the SPM.  At the time of consent, all 
ongoing AEs that began during participation in the parent study must be recorded in the 
eCRF.
Section 6.8.1.5 Time Period and Frequency of Detecting AEs and SAEs
PREVIOUS TEXT
AEs will be collected from the time the first dose of study treatment is administered until 
30 days following discontinuation of study treatment regardless of initiation of a new 
cancer therapy or transfer to hospice. 


Novartis
Confidential
Page 94
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
REVISED TEXT
AEs will be collected from the time the first dose of study treatment is administered until 
the final study visit regardless of 
initiation of a new cancer therapy or transfer to hospice. 
Section 7.4 Handling And Storage of Study Treatment
PREVIOUS TEXT
GSK2110183 is to be stored at room temperature and should not exceed 30°C in an 
opaque bottle.  
REVISED TEXT
GSK2110183 is to be stored at room temperature and should not exceed 30°C in an 
HDPE white opaque bottle.  
Section 7.6.1 Dose Modifications
PREVIOUS TEXT
Dose Modifications for GSK2110183
TOXICITY1
GSK2110183
Grade 1
Continue GSK2110183 at current dose level.  Consider supportive care 
recommendations provided in Section 7.7
Grade 2
Withhold treatment with GSK2110183 until toxicity resolves to Grade 1 or 
baseline.  Upon resolution, restart GSK2110183 at current dose level.  
Consider supportive care recommendations provided in Section 7.7. 
Consider dose reduction if toxicity is intolerable to the subject.
Grade 3
Withhold GSK2110183 until toxicity resolves to Grade 1 or baseline.  Upon 
resolution, reduce dose of GSK2110183 to a previously studied lower dose of 
GSK21101832).  Consider supportive care recommendations provided in 
Section 7.7. 
Grade 4
Permanently discontinue treatment with GSK2110183.
1.
Considered related to study treatment.
2.
Dose level 1: 150mg, Dose level 2: 125mg, Dose level 3: 100mg, Dose level 4:75mg.  If subject requires dose 
reduction below 75mg, then treatment must be discontinued, and subject withdrawn from the study.
Treatment with GSK2110183 may be delayed for up to 14 days to allow resolution of 
toxicity or based on investigator discretion.  If the investigator and the GSK Medical 
Monitor conclude that continued treatment will benefit a subject who has experienced a 
treatment delay >14 days, then the subject may continue GSK2110183 therapy with the 
approval of the GSK Medical Monitor.
A maximum of 2 dose reductions (including reductions from the parent study) of 
GSK2110183 is permitted and each of them requires consultation with the GSK medical 
monitor.  Dose reductions should be to a lower dose level previously studied in a 


Novartis
Confidential
Page 95
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
GSK2110183 clinical study.  If a third dose reduction is required, treatment with 
GSK2110183 should be discontinued.
REVISED TEXT
Dose Modifications for GSK2110183
TOXICITY1
GSK2110183
Grade 1
Continue GSK2110183 at current dose level.  Consider supportive care 
recommendations provided in Section 7.7
Grade 2
Withhold treatment with GSK2110183 until toxicity resolves to Grade 1 or 
baseline.  Upon resolution, restart GSK2110183 at current dose level.  
Consider supportive care recommendations provided in Section 7.7. 
Consider dose reduction if toxicity is intolerable to the subject.
Grade 3
Withhold GSK2110183 until toxicity resolves to Grade 1 or baseline.  Upon 
resolution, reduce dose of GSK2110183 by one dose level
 
).  Consider supportive care 
recommendations provided in Section 7.7. 
Grade 4
Permanently discontinue treatment with GSK2110183.
3.
Considered related to study treatment.
4.
Dose level 1: 150mg, Dose level 2: 125mg, Dose level 3: 100mg, Dose level 4:75mg.  If subject requires dose 
reduction below 75mg, then treatment must be discontinued, and subject withdrawn from the study.
Treatment with GSK2110183 may be delayed for up to 14 days to allow resolution of 
toxicity or based on investigator discretion.  If the investigator and the GSK Medical 
Monitor conclude that continued treatment will benefit a subject who has experienced a 
treatment delay >14 days, then the subject may continue GSK2110183 therapy with the 
approval of the GSK Medical Monitor.
A maximum of 2 dose reductions (including reductions from the parent study) of 
GSK2110183 is permitted and each of them requires consultation with the GSK medical 
monitor.  Dose reductions should be to a lower dose level previously studied in a 
GSK2110183 clinical study.  If a third dose reduction or a dose reduction below 
75mg is required, treatment with GSK2110183 should be discontinued and subject 
should be withdrawn from study.
 
Section 7.7.7.1 Liver Event Follow-up Assessments
PREVIOUS TEXT
The following assessments are required for subjects with ALT 3 times ULN and 
bilirubin 2 times ULN (>35% direct) but are optional for other abnormal liver 
chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Liver imaging (ultrasound, magnetic resonance imaging [MRI], or computerized 
tomography [CT]) to evaluate liver disease.


Novartis
Confidential
Page 96
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
REVISED TEXT
The following assessments are required for subjects with ALT 3 times ULN and 
bilirubin 2 times ULN (>35% direct) but are optional for other abnormal liver 
chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct assay (quantifies potential acetaminophen 
contribution to liver injury, detectable by HPLC assay more than 1 week 
following acetaminophen use) (James LP. Drug Metab Disp 2009; 37:1779–
1784).

Liver imaging (ultrasound, magnetic resonance imaging [MRI], or computerized 
tomography [CT]) to evaluate liver disease.
Section 8.2 Prohibited and Cautionary Medications
PREVIOUS TEXT
The use of certain medications, and illicit drugs within 5 half-lives or 28 days (if the drug 
is a potential enzyme inducer) prior to the first dose of study treatment(s) and for the 
duration of the study will not be allowed.  If a prohibited medication is required for single 
use (such as for a procedure) while study treatment(s) is held, the GSK Medical Monitor 
can approve such use.
Anticoagulants at therapeutic doses (e.g., warfarin, low molecular weight heparin, direct 
thrombin inhibitors, etc) are PROHIBITED from seven days prior to the first dose of 
study drug through completion of the Final Study Visit.  Low dose (prophylactic) 
anticoagulants are permitted provided that subject’s PT/PTT meet entry criteria.
The use of certain medications will not be allowed for the duration of the study.  If a 
prohibited medication is required for single use (such as for a procedure) while 
study treatment(s) is held, the GSK Medical Monitor can approve such use.
Anticoagulants are permitted only if the subject meets PTT and INR entry criteria.  
Their use must be monitored in accordance with local institutional practice.


Novartis
Confidential
Page 97
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 8.3 Non-Drug Therapies
PREVIOUS TEXT
The investigator should contact a GSK Medical Monitor before initiating treatment with 
any herbal preparation.
REVISED TEXT
The investigator should contact a GSK Medical Monitor before initiating treatment with 
any herbal preparation. While herbal preparations/medications are prohibited, if one 
is administered to a subject during the study then that herbal medication will be 
recorded in the eCRF.
Section 13  References
PREVIOUS TEXT
GlaxoSmithKline Document Number WM2008/00093/02 Version 2.  GSK2110183 
Investigator's Brochure.  Report Date: 31-AUG-2010.
REVISED TEXT
GlaxoSmithKline Document Number
2011N113491.  
GSK2110183 Investigator's Brochure. Report Date: 
25APR2011.
James, L.P., Letzig, L., Simpson, P.M., Capparelli, E., Roberts, D.W., Hinson, J.A., 
Davern, T.J., and Lee, W.M. Pharmacokinetics of acetaminophen protein adducts in 
adults with acetaminophen overdose and acute liver failure. Drug Metabolism and 
Disposition 37:1779-1784, 2009.
Appendix 1 Time and Events Table
8.Disease assessments should be performed per local standard practice using criteria appropriate for disease 
type and location, no less frequent than every 12 weeks 
9.AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last 
dose of GSK2110183
8.Disease assessments should be performed per local standard practice using criteria appropriate for disease 
type and location, no less frequent than every 12 weeks (more frequent assessments - as determined by 
investigator).
9.AEs/SAEs will be monitored and recorded beginning on the time of consent until 
 
he last study visit.


Novartis
Confidential
Page 98
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Appendix 5 Disease Assessments and Response Criteria
REVISED TEXT
Langerhans Cell Histocytosis (LCH) [Portnoy, 2011]
Within 4 weeks of transition 
visit
Every 12 weeks
Imaging (Investigator discretion as to 
type)
X
X
Bone marrow1
X
X
Pulmonary function tests2
X
X
3.
Bone marrow evaluation only if  clinically indicated
4.
Needed in subjects with pulmonary involvement
Response Criteria for Multiple Myeloma (MM)
[Rajkumar, 2011, Durie, 2006
sCR (stringent complete response): 
Complete response as defined below plus: 

normal free light chain (FLC) ratio and

absence of clonal cells in bone marrow by immunohistochemistry or 2-4 
color flow cytometry 
CR (complete response):

Negative serum and urine immunofixation, and

Disappearance of any soft tissue plasmacytomas, and

<5% plasma cells in bone marrow
VGPR (very good partial response):

Serum and urine M-component detectable by immunofixation but not on 
electrophoresis OR

90% or greater reduction in serum M- component plus urine M-
component < 100mg/24h
PR (partial response):

50% reduction of serum M-protein and reduction in 24 hour urinary M-
protein by 90% or to < 200 mg/24h, and

If the serum and urine M-protein are not measurable, a 50% decrease in 
the difference between involved and uninvolved free light chain levels is 
required in place of the M-protein criteria.  If serum and urine M-protein 
are not measurable, and serum free light chain assay is also not measurable, 
50% reduction in bone marrow plasma cells is required in place of M-


Novartis
Confidential
Page 99
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
protein, provided baseline bone marrow plasma cell percentage was 30%, 
and

In addition to the above listed criteria, if present at baseline, a 50% 
reduction in the size of the soft tissue plasmacytomas is also required.
SD (stable disease):

Not meeting criteria for CR, VGPR, PR or PD
PD (progressive disease)a
Requires any one or more of the following:

Increase of 25% from lowest response value in any one or more of the 
following: 

serum M-component (absolute increase must be 0.5 g/dl), or

urine M-component (absolute increase must be 200 mg/24h), or 

the difference between involved and uninvolved free light chain 
levels (absolute increase must by > 10mg/dl): only for patients 
without measurable serum and urine M-protein levels, or

bone marrow plasma cell percentage (the absolute % must be 
10%) – only for patients without measurable serum and urine M-
protein levels and without measurable disease by FLC level

definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas

development of hypercalcemia (corrected calcium > 11.5 mg/dl or 
2.65 mmol/l) that can be attributed solely to the plasma cell proliferative 
disorder

All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive 
assessments made at any time before the institution of any new therapy; CR, 
sCR, VGPR, PR, and SD categories also require no known evidence of 
progressive or new bone lesions if radiographic studies were performed. VGPR 
and CR categories require serum and urine studies regardless of whether 
disease at baseline was measurable on serum, urine, both, or neither. 
Radiographic studies are not required to satisfy these response requirements. 
Bone marrow assessments need not be confirmed. For PD, serum M-component 
increases of more than or equal to 1 g/dL are sufficient to define relapse if 
starting M-component is ≥ 5 g/dL.

Clarifications to IMWG criteria for coding CR and VGPR in patients in whom 
the only measurable disease is by serum FLC levels: CR in such patients 
indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed 
above. VGPR in such patients requires a > 90% decrease in the difference 
between involved and uninvolved FLC levels. 


Novartis
Confidential
Page 100
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD 
are to be used only in patients without measurable disease by M protein and by 
FLC levels; “25% increase” refers to M protein, FLC, and bone marrow results, 
and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia 
and the “lowest response value” does not need to be a confirmed value
References
Durie BGM, Harousseau J-L, Miguel JS, et. al. International uniform response 
criteria for multiple myeloma. Leukemia, 2006:20: 1467-73.
Rajkumar SV, Harousseau JL, Durie B, et al.  Consensus recommendations for the 
uniform reporting of clinical trials: Report of the International Myeloma Workshop 
Consensus Panel 1.  Blood.  2011;117:4691-4695.
Appendix 5 Disease Assessments and Response Criteria
REVISED TEXT
Definition of Disease State, Response Criteria and Response Definition for 
Langerhans Cell Histocytosis (LCH)
Definition of Disease State
NON ACTIVE DISEASE
(NAD)
no evidence of
disease
resolution of all signs or 
symptoms
regressive disease
regression of signs or 
symptoms, no new
lesions*
ACTIVE DISEASE (AD)
stable disease
persistence of signs or 
symptoms, no new
lesions
progressive disease
progression of signs or 
symptoms and/or
appearance of new lesions**
*Plus partial or complete response by RECIST [Eisenhauer, 2009]; and/or pulmonary criteria if 
applicable
*/** Isolated pulmonary LCH: improvement in lung function is >10% increase in baseline FEV1 or 
DLCO at time of disease assessment. Disease progression is >15% decline from baseline FEV1 or 
DLCO or FVC OR progression of symptoms (dyspnea, cough, constitutional symptoms) that cannot 
be explained by diagnoses other than pulmonary LCH (infection, heart disease, and/or other clinical 
issues excluded by careful clinical evaluation and testing)
** Isolated bone disease: progression is defined as appearance of new bone lesions or lesions in
other organs
Response Criteria


Novartis
Confidential
Page 101
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
BETTER
Complete Resolution
NAD
Regression
AD Better
INTERMEDIATE
Mixed
New lesions in one site, 
regression in another site
Stable
Unchanged
WORSE
Progression
Response Definition for Efficacy
3 Month Assessment
6 Month Assessment
(performance relative to 3 
month assessment)
Response
NAD or AD Better
Mixed
Stable
NAD or AD Better or Stable
NAD or AD Better
NAD or AD Better
Failure
NAD or AD Better
NAD or AD Better
Mixed or Stable1
Progression
Mixed
Progression
Mixed or Stable1 or 
Progression
N/A
NAD = Non Active Disease
AD = Active Disease
Stable = Unchanged
Mixed = New lesions in one site, regression in another site
1. Subjects who are assessed only as stable at the 3 and 6 month assessment are not
considered a treatment response; however, they may be considered for continued treatment


Novartis
Confidential
Page 102
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
AMENDMENT 2
Where the Amendment Applies
This amendment applies to all investigator sites participating in this study.
Summary of Amendment Changes with Rationale
Addition of Immediate Release (IR) tablet description. This description was added 
because it is now the formulation of Aburesertib that is being used.  The protocol 
description, synopsis, study treatments and dosage/administration sections have all been 
updated to reflect this change. 
Since this was an older protocol, GSK2110183 has now been replaced with Afuresertib 
throughout the protocol. 
Due to the fact that this is an older protocol, the following updates and changes have been 
made to bring it up to date:
The introduction, summary of risk management, supportive measures for hyperglycemia, 
management of diarrhea, rash, dyspepsia, mucositis, liver chemistry stopping criteria, 
drug restart/rechallenge, con meds and non-drug therapies, meals and dietary restrictions 
and liver safety drug restart guidelines sections have all been updated with the latest 
information. 
MM specific disease assessments have been added along with the new investigator 
brochure reference. 
AE follow up shortened to 30 days,  ECHO/MUGA scans,  fasting requirements and 
combination studies with two investigational compounds ineligibility wording have been 
removed.
EudraCT number was added.
List of Specific Changes
TITLE PAGE
REVISED TEXT
Description: 
Afuresertib (GSK2110183) is an orally administered, pan-AKT kinase inhibitor that has 
demonstrated encouraging clinical activity in hematologic malignancies (especially in 
multiple myeloma MM), and is currently also being evaluated in clinical trials in solid 
tumors. This multicenter, non-randomized, open-label, treatment continuation or 
‘rollover’ study is designed to provide continued access to afuresertib treatment for
eligible subjects who have previously participated in an afuresertib ‘parent study’
sponsored by GlaxoSmithKline (GSK) or another research organization working on 
behalf of GSK.  Eligible subjects must be receiving clinical benefit 
 


Novartis
Confidential
Page 103
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
tolerating treatment with Afuresertib.
Subjects who have participated in an afuresertib combination study with another anti-
cancer agent will also be eligible to enroll in this rollover study.  
 
 
  Subjects will be enrolled by cohort based on the 
duration and treatment received while in their parent study.  Safety assessments (physical 
examinations, vital sign measurements, 12-lead electrocardiograms, echocardiograms or 
multiple-gated acquisition scans, clinical laboratory assessments and monitoring of 
adverse events) will be evaluated during this study.  Disease assessment will be 
performed using local standard of care imaging practices and criteria appropriate for 
disease type and location.
Subject: Afuresertib,GSK2110183, AKT inhibitor, hematologic malignancy, solid tumor, 
, safety
Author (s): 
 US
, 
, US
, US
 
, US
, US
, US
SPONSOR/MEDICAL MONITOR INFORMATION PAGE 
REVISED TEXT
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
GSK Address
Primary 
Medical 
Monitor
 
 
MD, PhD 
GlaxoSmithKline
1250 South Collegeville Road,
Mailstop 
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
 
 
MD/MPH
GlaxoSmithKline
1250 S Collegeville Road
Mailstop 
Collegeville, PA USA


Novartis
Confidential
Page 104
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
REVISED TEXT
Regulatory Agency Identifying Number US [IND 111439]
Health Canada reference number = 9427-G0838-279C
S. Korea: Receipt number = 20110110591
EudraCT number =.2014-002041-22
Section ABBREVIATIONS
Added the abbreviation IR (Immediate  Release Tablet).
Section PROTOCOL SYNOPSIS
REVISED TEXT

PRODUCT:  Afuresertib (GSK2110183)

PROTOCOL/AMENDMENT NO.:  PKB115131/Amendment 02

OBJECTIVES:  To provide continued treatment with afuresertib for subjects 
who have completed participation in a GSK-sponsored afuresertib study, or  an 
afuresertib study sponsored by another research organization working on behalf 
of GSK. Additional safety information about afuresertib will also be collected.  

HYPOTHESES:  There are no hypotheses being explored in this treatment 
continuation or ‘rollover’ study.

STUDY DESIGN AND DURATION:  Multicenter, non-randomized, open-label, 
rollover study.  Eligible subjects will be enrolled in the appropriate cohort based 
upon the duration and treatment received in their parent study.  Enrollment into 
this study will be dependent upon the site’s agreement to participate in this study.  
Subjects will receive afuresertib and possibly or other anti-cancer agents at the 
same dose and regimen most recently taken in their parent study.  The dose will 
not exceed the maximum tolerated dose established in prior studies.  Subjects 
may continue treatment in the rollover study until disease progression, 
unacceptable toxicity, withdrawal of consent, or death.

DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN:          
Afuresertib - Up to 150 mg (provided as 100 mg and 25 mg gelatin capsules or 
50 mg and 75 mg Immediate Release (IR) tablets), given orally, once daily in 3 
or 4 week cycles, depending on the schedule and treatment used in the parent 
study.  Dose adjustments are allowed to address tolerability and safety issues.
Other anti-cancer agents will continue to be given at the same dose and regimen 
as in the parent study.  Any dose modifications will follow
parent protocol or most recent prescribing information.

EFFICACY MEASUREMENTS:  This study will not collect efficacy data.  
However, clinical activity will be assessed using local standard of care practices 
to determine eligibility for continued study participation.  Only subjects who are 
clinically benefitting 
and tolerating
treatment 
 
with afuresertib may continue on study


Novartis
Confidential
Page 105
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 1.1.  Background
REVISED TEXT
AKT is a serine/threonine protein kinase with three isoforms (AKT1, AKT2, and AKT3) 
that participate in multiple pathways regulating several cellular processes, including 
survival, proliferation, tissue invasion, and metabolism [Tanno, 2001; Morgensztern, 
2005].  Aberrant activation of the PI3K/AKT pathway occurs in virtually every type of 
hematologic malignancy, suggesting that dysregulation of these pathways may be 
required for carcinogenesis.  The importance of AKT-mediated pathways in tumor 
proliferation and survival render AKT kinases promising targets for therapeutic 
intervention.  Hyperactivation of the AKT pathway can also correlate with chemotherapy 
resistance and poorer prognosis.  Nonclinical data suggest that blocking AKT1 and 
AKT2 activity can inhibit the proliferation of tumor cells and either induce an apoptotic 
response or sensitize tumors to undergo apoptosis in response to other cytotoxic agents 
[DeFeo-Jones, 2005].  
1.1.1  Afuresertib
Afuresertib was evaluated in 10 different MM cell lines either alone or in combination 
with a proteasome inhibitor (either bortezomib or carfilzomib).  Six of 10 MM cell lines 
showed <1 µM gIC50 (concentration producing 50% inhibition of growth) for afuresertib 
as a single agent in a 3-day cell proliferation assay.  The combination of afuresertib with 
bortezomib showed strong synergy in all 10 cell lines tested at concentrations that are 
clinically achievable.  Similar synergy was also observed with combination of afuresertib 
and carfilzomib.  The synergistic anti-proliferative effect of AKT inhibitor and 
bortezomib is likely mediated by increased induction of apoptosis, as evidenced by 
increase in caspase 3/7 activity in National Cancer Institute (NCI) H929 cells.
The safety, pharmacokinetic (PK) and pharmacodynamic profiles and activity of 
afuresertib administered as monotherapy was evaluated in the first time in humans 
(FTIH) trial PKB112835.  Among 34 relapsed/refractory MM subjects treated with 
afuresertib three have achieved partial response (PR), and a further 3 achieved minimal 
response (MR) accounting for clinical benefit rate (CBR) of 17.6 in this heavily 
pretreated population.  The combination of afuresertib with bortezomib and 
dexamethasone is being currently evaluated in PKB115125 study.  The preliminary 
results (data cut-off 29-Jun-2014) in relapsed MM population demonstrate overall 
response rate (ORR) of 61% (PR or better) and CBR of 78%.  The investigator should 
refer to the current version of the afuresertib Investigator’s Brochure (IB) 
[GlaxoSmithKline Document Number 2011N113491_02] for detailed information 
regarding all completed and ongoing clinical studies with afuresertib, PK in the target 
disease populations, as well as observed safety and clinical activity findings.
1.1.2.  Pharmacokinetics of Afuresertib in Humans
In the FTIH monotherapy study in subjects with relapsed or refractory hematologic 
malignancies (PKB112835), afuresertib plasma concentrations following single 
afuresertib doses were measured over the 72-hour sample collection period in all subjects.  
Afuresertib accumulated 1.4- to 5.1-fold with repeat daily dosing.  Single-dose and 
repeat-dose mean area under the plasma concentration-time curve (AUC(0-24)) and 


Novartis
Confidential
Page 106
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
maximum observed plasma concentration (Cmax) values increased with increasing doses; 
however, given the intersubject variability, there was substantial overlap in the 
AUC(0-24) and Cmax values between successive dose groups.  The 100 mg and 125 mg 
multiple-dose exposure data were similar.  Median time to Cmax (tmax) across doses was 
2 hours.  Based on available data from all cohorts, the mean accumulation half life (t1/2) 
is approximately 1.7 days and the median tmax on Day 8 is 2 hours.  For details of the 
PK of afuresertib see the current version of the IB [GlaxoSmithKline Document Number
2011N113491_02].
Preliminary PK results from the PKB115125 combination study of afuresertib with 
bortezomib and dexamethasone indicate mean afuresertib exposure (n=7) was similar 
alone or in combination with bortezomib and dexamethasone, and mean bortezomib 
exposure (n=7) co-administered with dexamethasone was similar with and without 
afuresertib.  Mean dexamethasone exposure co-administered with bortezomib was 30-
50% higher when dosed with afuresertib than without afuresertib; although sample size 
was small (n=5) and exposure values overlapped [GlaxoSmithKline Document Number
2011N113491_02].
1.1.3.  Clinical Safety of Afuresertib
As of 29-Jun-2013, 226 subjects had received at least 1 dose of afuresertib either as 
monotherapy or in combination with other agents in the 7 GSK-sponsored studies with 
afuresertib.  The most common adverse events (AEs) reported in all studies were 
primarily gastrointestinal (GI) disorders including: diarrhea, nausea, and vomiting, 
dyspepsia, and constipation.
More detailed safety characteristics from the two most relevant studies are described in 
greater detail below.  The studies are considered most relevant because they were 
conducted in subjects with hematologic malignancies (PKB112835), and in subjects with 
MM (PKB115125). 
Additional information from all studies where subjects with other diseases are 
administered afuresertib, as monotherapy or in combination, can be found in the current 
afuresertib IB [GlaxoSmithKline Document Number 2011N113491_03].
PKB112835
This was an open-label, 2-part, FTIH study designed to investigate the safety, tolerability, 
PK, and pharmacodynamics of afuresertib in subjects with hematologic malignancies.  A 
total of 73 subjects were enrolled in this study, 26 in Part 1 (dose escalation), and 47 in 
Part 2 (expansion).  Afuresertib was administered orally once daily at doses of 25 mg, 
75 mg, 100 mg, 125 mg, or 150 mg and the maximum tolerated dose (MTD) was 
established at 125 mg for this dosing based on dose limiting toxicities (DLTs) in 
2/6 subjects at the 150 mg dose.  Both DLTs were elevations in liver function tests 
(LFTs).  No DLT was reported in any subject enrolled in Part 1 at doses below 150 mg.  
Both subjects with DLTs had non-Hodgkin’s lymphoma (NHL): 1 subject had Grade 3 
elevations in alanine aminotransferase (ALT) and alkaline phosphatase (ALP), 
accompanied by elevations in aspartate aminotransferase (AST), total bilirubin, and 


Novartis
Confidential
Page 107
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
eosinophilia, the other subject had liver involvement from lymphoma and experienced 
Grade 3 elevations in ALT and ALP.
The most frequent type of malignancy in the trial was MM (34 subjects; 47%), followed 
by NHL (13 subjects, 18%), Hodgkin’s lymphoma (HD) (8 subjects, 11%), acute myeloid 
leukemia (AML) (9 subjects, 12%), chronic lymphocytic leukemia (CLL) (7 subjects, 
10%), acute lymphoblast leukemia (ALL) (1 subject, 1%), and Langerhans cell 
histiocytosis (LCH) (1 subject, 1%).  The most frequent (10% of subjects) AEs were 
nausea (35.6%), diarrhea (32.9%), dyspepsia (24.7%), fatigue (20.5%), gastroesophageal 
reflux disease (GERD; Grade 1) (19.2%), anorexia (19.2%), vomiting (19.2%), anemia 
(15.1%), upper respiratory tract infection (13.7%), asthenia (13.7%), back pain (12.3%), 
rash (12.3%), insomnia (12.3%), constipation (11.0%), odynophagia (11.0%), and cough 
(11.0%).  Grade 3 or higher AEs (in 2 subjects) included anemia (9.6%), neutropenia 
(9.6%), thrombocytopenia (6.8%), sepsis (4.1%), febrile neutropenia (4.1%), 
odynophagia (4.1%), rash (4.1%), asthenia (2.7 %), diarrhea (2.7%), fatigue (2.7%), 
pneumonia (2.7%), and abnormal LFTs (2.7%).  Grade 5 AEs were observed in 2 
subjects: septic shock, considered not related to afuresertib and concomitant pneumonia 
and sepsis, considered not related to afuresertib in a subject who died from disease 
progression.  There was no obvious relationship between the type of AEs and malignancy 
type.  Three deaths were reported during the study (disease progression, n=2; septic 
shock, n=1).
PKB115125
This is an ongoing open-label, 2-part, repeat- and escalating-dose study designed to 
investigate the safety, tolerability, PK, pharmacodynamics, and clinical activity of 
afuresertib administered once daily in combination with bortezomib and dexamethasone 
(twice weekly schedule) in subjects with relapsed/refractory MM.  In the study’s Part 1 
dose-escalation, 34 subjects were administered doses of afuresertib in combination with 
bortezomib and dexamethasone in the following sequence: 75 mg/day (n=4), 100 mg/day 
(n=6), 125 mg/day (n=6), 150 mg/day (n=12), 175 mg/day (n=6) and plus dexamethasone 
(40 mg) on days of bortezomib administration (n=6).  The MTD for afuresertib was 
established at 150 mg once daily in combination with bortezomib (1.3 mg/m2 on Days 1, 
4, 8, and 11 of a 21-day cycle) and dexamethasone 40 mg (on days of bortezomib dosing 
only).  Four subjects experienced DLTs during Part 1: 100 mg/day, Grade 2 elevations in 
ALT; 125 mg/day, Grade 3 erythema multiforme; 175 mg/day, Grade 3 diarrhea, 
thrombocytopenia, and rash; 175 mg/day, Grade 3 maculo-papular rash.  Part 1 was 
followed by a cohort-expansion phase (Part 2).  As of the data cut-off date of 
18-Oct-2013, Part 2 included 23 subjects who received 150 mg of afuresertib once daily 
in combination with bortezomib and dexamethasone.  An additional 10 subjects were 
enrolled into the PK/pharmacodynamic cohort.  
The most common AEs (>10% of subjects) were primarily GI toxicities.  No new safety 
concerns were identified from the use of afuresertib in combination compared with the 
safety profile observed with afuresertib monotherapy.  The most common AEs (in 10% 
of subjects) were as follows: fatigue (51% [2% Grade 3, no Grade 4]), diarrhea (49% 
[14% Grade 3, no Grade 4]), thrombocytopenia 38%, [16% Grade 3, 11% Grade 4]), 
nausea (37% [1% Grade 3, no Grade 4]), constipation (33% [2% Grade 3, no Grade 4]), 


Novartis
Confidential
Page 108
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
dyspepsia (32% [1% Grade 3, no Grade 4]), hyperglycemia (28% [6% Grade 3, 1%
Grade 4]), vomiting (27% [2% Grade 3, no Grade 4]), anemia (22% [10% Grade 3, no 
Grade 4), peripheral neuropathy (22% [no Grade 3/4]), insomnia (20% [no Grade 3/4]), 
rash (20% [7% Grade 3, no Grade 4]), dizziness (20% [no Grade 3/4]), upper respiratory 
tract infection (17% [no Grade 3/4]), cough (14% [no Grade 3/4]), lymphopenia 
(14%[5% Grade 3, 2% Grade 4]), pyrexia (14% [no Grade 3/4]), blood creatinine 
increased (12% [1% Grade 3, 1% Grade 4]), asthenia (11% [2% Grade 3, no Grade 4]), 
dysgeusia (11% [no Grade 3/4]), headache (11% [no Grade 3/4]), neutropenia (11% [5% 
Grade 3, 2% Grade 4]), abdominal pain (10% [1% Grade 3, no Grade 4]), ALT increased 
(10% [2% Grade 3, no Grade 4]), decreased appetite (10% [1% Grade 3, no Grade 4]), 
exertional dyspnea (10% [no Grade 3/4]), epistaxis (10% [no Grade 3/4]), herpes zoster 
(10% [no Grade 3/4]), hypotension (10% [2% Grade 3, no Grade 4]), and urinary tract 
infection (10%[1% Grade 3, no Grade 4]).  Grade 5 AEs were observed in 2 subjects: 
septic shock, and sepsis.  
1.1.4.  PKB116611
PKB116611 is an ongoing open-label, Phase 1/2 dose-escalation study of afuresertib in 
combination with carboplatin and paclitaxel in subjects with platinum-resistant/refractory 
ovarian cancer.  The primary objective of the Phase 1 part of the study is to determine the 
safety and tolerability of the triplet combination, which will be used to define the dosing 
regimen to be evaluated in Phase 2.  The primary objective of the Phase 2 part of the 
study is to evaluate the clinical efficacy (defined by the overall response rate) of the 
triplet combination, in patients with platinum-resistant or platinum-refractory ovarian 
cancer.
Afuresertib doses of 50 to 150 mg/day were explored in combination with carboplatin 
(IV) AUC 5 and paclitaxel (IV) 175 mg/m2 administered day 1 every 21 days for a 
maximum of 6 doses.  Phase 2 expansion cohorts at the recommended Phase 2 afursertib 
dose of 125 mg are ongoing in platinum resistant and platinum refractory cohorts.
As of the data cut-off date of 29-Jun-2014, 52 subjects have been enrolled in the study; 
29 subjects in Part 1 and 23 subjects in Part 2.  Of these, data are available for 49 subjects, 
including all subjects in Part 1 and 20 subjects in Part 2.  For those subjects with 
available data, 2 subjects who are platinum refractory have been enrolled to Part 2; all 
other subjects are platinum resistant.  Three subjects (6.1%) discontinued study treatment 
because of AEs and 13 subjects (26.5%) discontinued because of progressive disease.
The most common AEs (≥10% of subjects) were primarily gastrointestinal toxicities, 
alopecia, and fatigue.  The event of fatigue was reported at a similar incidence in 
Study PKB115125, where afuresertib was administered with bortezomib/dexamethasone. 
In total, 18 (36.7%) subjects reported Grade 3 AEs and 12 (24.5%) subjects reported 
Grade 4 AEs.  The following Grade 3 AEs were reported: hypomagnesaemia (8.2%), 
neutropenia (8.2%), hyperglycaemia (6.1%), vomiting (6.1%), ascites (4.1%), dyspnoea 
(4.1%), lower respiratory tract infection (4.1%), nausea (4.1%), rash (4.1%), rash 
maculo-papular (4.1%), small intestinal obstruction (4.1%), and abdominal pain, anaemia, 
chills, colonic obstruction, dermatitis acneiform, diarrhoea, drug hypersensitivity, 


Novartis
Confidential
Page 109
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
escherichia urinary tract infection, fatigue, febrile neutropenia, gastroenteritis viral, 
hypersensitivity, hypertension, hyperthyroidism, hypophosphataemia, lobar pneumonia, 
neutropenic sepsis, oesophagitis, platelet count decreased, pneumonia, pyrexia, renal 
failure acute, supraventricular tachycardia, syncope, urinary tract infection, and white 
blood cell count decreased (each reported in 2.0% subjects).  In addition, the following 
Grade 4 AEs were reported: neutropenia (20.4%), thrombocytopenia (4.1%), 
hypomagnesaemia (2.0%), platelet count decreased (2.0%), and white blood cell count 
decreased (2.0%).«There were also 2 uncoded Grade 3 AEs in the eye disorders SOC 
(2.0% each).
Five subjects discontinued treatment with afuresertib due to AEs; these were abdominal 
pain, blood creatinine increased, decreased appetite, dehydration, diarrhea, 
gastroesophageal reflux disease, headache, muscle spasms, nausea, neutropenia, pleural 
effusion, syncope, and vomiting (1 subject each).
As of 29-Jun-2014, 1 subject died while on study.  Two additional patients died while off 
study (>30 days after the last dose of afuresertib).
Overall 56 SAEs have been reported in 34 subjects; of these, 18 SAEs in 10 subjects 
were considered by the investigator to be related to afuresertib.
1.1.5.  LCH115397
LCH115397 was an open label, repeat-dose study designed to investigate the efficacy and 
safety of afuresertib in subjects with LCH.  This study is complete.
In total, 17 subjects were enrolled in the study at doses up to 125 mg administered 
continuously, once daily.  Of these, 16 of the 17 subjects completed the study and 
1 subject voluntarily withdrew from the study.
One subject, receiving 125 mg/day, discontinued treatment because of an AE (Grade 2 
impaired gastric emptying) which was considered to be not related to afuresertib, in the 
opinion of the investigator.
Five (29%) subjects had AEs of Grade 3 or higher, these were: ALT increased, diarrhea, 
fatigue, hyponatraemia, impaired gastric emptying, lung infection, esophageal ulcer, pain, 
perineal pain, pseudomonas infection, soft tissue necrosis, and vulvovaginal pain.  None 
of these occurred in more than 1 subject.
No subject died during the study.  Five SAEs have been reported in 3 subjects, only 1 of 
which (soft tissue necrosis) was considered possibly related to afuresertib
1.1.6.  Clinical Activity of Afuresertib
Clinical activity of afuresertib monotherapy was seen in subjects with hematologic 
malignancies in the PKB112835 FTIH study.  Of the 34 subjects with MM, three subjects 
demonstrated confirmed PR and median time on study for those subjects was 319 days 
(range 215-541).  Three additional subjects had MR and their median time on study was 
336 days (range 157-484).  The overall CBR for MM subjects (PR+MR) was therefore, 


Novartis
Confidential
Page 110
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
17.6% (6/34).  An additional 14 subjects with MM had prolonged stabilization of their 
disease for a median 118.5 days (range 48-426).  Clinical activity has also been observed 
in subjects with lymphomas (1 complete response [CR] and 2 partial responses [PRs] in 
13 subjects with NHL) and 4/8 subjects with HD achieving unconfirmed PR.
In the ongoing combination study (PKB115125) of afuresertib with bortezomib and 
dexamethasone, responses have been reported in the dose escalation and expansion 
phases of the study.  In the population of relapsed MM subjects treated at the 
afuresertib’s MTD (150 mg) in Part 2 of the study, the confirmed overall response rate 
was 61% (14/23 subjects; 3 very good partial responses [VGPR] and 11 PR).  Data on 
duration of responses are not available yet from this ongoing study.
Additional information from all studies where subjects with other diseases are 
administered afuresertib, as monotherapy or in combination, can be found in the current 
afuresertib IB [GlaxoSmithKline Document Number 2011N113491_03].
Section 1.2.  Rationale
REVISED TEXT
1.2.1  Study Rationale
The purpose of this study is to allow for continued treatment with afuresertib in subjects 
who have participated in a ‘parent’ GSK sponsored study of afuresertib, either as 
monotherapy or as part of a combination regimen, and met the protocol requirements for 
transitioning to this rollover study. The parent study will have met it’s primary endpoints
and transitioning to this rollover study will allow data to be reported for the parent study.  
In addition, subjects will be 
monitored for adverse events, as this study will 
continue to collect safety information on afuresertib.
Subject enrollment into Cohorts A and B is based on the duration of treatment on a  
monotherapy parent study with Cohort A enrolling subjects who received less than 24 
weeks of treatment, while Cohort B will enroll subjects who have received 24 weeks or 
greater afuresertib therapy.  Cohort C will enroll subjects who have participated on a 
combination study where afuresertib is given with another anti-cancer agent(s).  The 
purpose of having separate cohorts is to be able to better report and define the safety 
profile for these subject groups. 
1.2.2  Dose Rationale
The dose of study treatment to be administered to subjects will be individualized based 
upon the dose/regimen received during their participation in the parent study at the time 
of transition to this rollover study.  No dose of afuresertib above the MTD established in 
the parent study will be allowed in this study.
Cohort A and B: 
Subjects who have received <24 weeks ( Cohort A) or 24 weeks (Cohort B) of 
afuresertib as monotherapy in the parent study will receive the same continuous dosing 


Novartis
Confidential
Page 111
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
regimen of afuresertib at completion of the parent study.  If a subject required a dose 
modification while receiving treatment in the parent study, the subject will enter the 
rollover study and continue treatment on the modified dose unless after consultation with 
the GSK Medical Monitor, it is appropriate to escalate the dose.  The dose may be 
escalated up to the MTD established in the parent study.
Cohort C:
Subjects who have received any duration of a combination regimen with afuresertib and 
another anti-cancer agent will continue treatment in the rollover study at the current dose 
level(s) administered in the parent study at the time of transition to the rollover study. If 
the subject discontinued the
anticancer drug, which was studied as a part of a 
parent study- the subject will enter and continue on the roll over study while receiving 
monotherapy with afuresertib. Adding additional anticancer drugs is not allowed. If a 
subject required a dose modification while receiving treatment in the parent study, the 
subject will enter the rollover study and continue treatment on the modified dose unless 
after consultation with the GSK Medical Monitor, it is appropriate to escalate the dose.  
Any dose modifications will follow parent protocol or most recent prescribing 
information
1.2.4  Endpoint Rationale
This study will collect additional safety data from prolonged exposure to afuresertib, as 
monotherapy or in combination with other 
therapies. Primary endpoints for the 
study will be: adverse events, changes in laboratory values, and changes in vital signs.
Section 1.3 Summary of Risk Management
REVISED TEXT
Summaries of findings from clinical and nonclinical studies conducted with afuresertib 
can be found in the current IB [GlaxoSmithKline Document Number 2011N113491_02].  
The most common AEs seen to date in afuresertib studies include; nausea, diarrhea, 
dyspepsia, fatigue, thrombocytopenia, neutropenia, hyperglycemia, upper respiratory 
infection, anorexia, gastrointestinal reflux and rash.  The anticipated resks are listed 
below. 
 
 
 


Novartis
Confidential
Page 112
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
1.3.1 Risk Assessment for Afuresertib 
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Gastrointestinal toxicity
GI toxicity has been observed both 
afuresertib with most frequent events 
being: diarrhea, nausea, vomiting and 
dyspepsia. 

Exclusion of subjects with significant pre-
existing GI conditions

Close monitoring via continuous 
assessment of AEs, physical examination, 
and clinical laboratory assessments (see 
Appendix 1.).

Management guidelines and stopping 
criteria are provided for diarrhea, 
mucositis, and dyspepsia (see Section
6.7)
Rash
Rash has been frequently observed 
with afuresertib monotherapy and in 
combination therapies

Monitoring rash via assessment of AEs 
and physical examination (see Section 
5.8.1)

Management guidelines and stopping 
criteria are provided (see Section 6.7.4)
Hepatic toxicity
LFT elevations have been observed 
with afuresertib.  

Exclusion of subjects with impaired liver 
function.

Monitoring and stopping criteria are 
provided (see Section 6.7.7 )
Hyperglycaemia
Elevated glucose levels have been 
observed with compounds inhibiting 
PI3/AKT pathway.  Afuresertib can 
potentially cause hyperglycemia.

Only subjects with well-controlled Type 2 
diabetes will be enrolled in the study

Glucose monitoring will be implemented 
as clinically indicated.  

Management guidelines and stopping 
criteria are provided (see Section 6.7.2)


Novartis
Confidential
Page 113
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 3. INVESTIGATIONAL PLAN
3.2  Study Design
Paragraph 1 and 2:
This multicenter, non-randomized, open-label, rollover study is designed to provide 
continued access to afuresertib to subjects who have previously participated in an a
afuresertib study.  All subjects enrolling in this study must be tolerating and benefitting 
from treatment (ie did not meet any of the study discontinuation criteria from the parent 
study) with afuresertib to be eligible.  Subjects will be enrolled into the appropriate 
cohort (Section 4.2.1) based upon the duration and treatment received in their parent 
study.  Enrollment into this study will be dependent upon the site’s agreement to 
participate in this study.  
Subjects must first provide written informed consent for this rollover study prior to any 
study-related assessment or procedure being performed and before any treatment with 
afuresertib can be administered under this protocol.  After informed consent is obtained, 
subjects will be evaluated for study eligibility in PKB115131.
Paragraph 7:
Subjects may continue treatment in this rollover study until disease progression, 
unacceptable toxicity or withdrawal of consent occurs, or death . Study will be completed 
when the last subject has withdrawn from study treatment.
3.2.1  Cohort A and Cohort B: Afuresertib Monotherapy
Subjects will receive afuresertib as an oral, daily dose up to 150 mg. Protocol specified 
guidelines for dose modifications and treatment discontinuation criteria are provided in
Section 7.6 and Section 7.7, respectively.  If there are any uncertainties about the dose to 
be administered in this study, the GSK Medical Monitor should be consulted.  
Cohort A:
Cohort A will consist of subjects who have completed <24 weeks of treatment with 
afuresertib monotherapy during their participation in the parent study.  It is anticipated 
that subjects in this cohort will have participated in a clinical pharmacology or other 
short-term study of afuresertib.  Subjects will complete the Transition Visit; receive 
instruction and study medication, and then return for their next scheduled visit (Study 
Week 4) and then every 4 weeks thereafter.  Subjects who remain on study treatment for 
>52 weeks (including time on parent study) may have the frequency of their interim visits 
decreased to every 8 weeks with approval from the GSK Medical Monitor.  After 
discontinuation of study treatment, the investigator will monitor all AEs/SAEs 
 
 for 30 days or until resolution,
 
whichever comes first..


Novartis
Confidential
Page 114
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Cohort B:
Cohort B will consist of subjects who have completed 24 weeks of treatment with 
afuresertib monotherapy during their participation in the parent study.  It is expected that 
subjects in this cohort will have participated in a longer term study of afuresertib.  
Subjects will complete the Transition Visit, receive study instruction and study 
medication and then return for their next scheduled visit (Study Week 4), and then every 
4 weeks thereafter.  Subjects who remain on study treatment for >52 weeks (including 
time on parent study) may have the frequency of their interim visits decreased to every 8 
weeks with approval from the GSK Medical Monitor.  After discontinuation of study 
treatment, the investigator will monitor all AEs/SAEs for 30 days or until resolution, 
whichever comes first
 
.
3.2.2  Cohort C: Afuresertib Combination Therapy
Cohort C:
Cohort C will consist of subjects who have participated in a combination study where 
afuresertib is administered with another anti-cancer agent, regardless of duration on 
study.  Subjects who transition from a combination study may continue to receive 
afuresertib in combination with the anti-cancer agent defined by the parent study, or they 
may receive afuresertib as monotherapy. If the concomitant anticancer drug has been 
terminated according to parent study design, or if, in the opinion of the investigator, the 
subject has received maximum benefit, or is experiencing unacceptable toxicity from the 
anti-cancer agent, then treatment with the anti-cancer agent may be discontinued and the 
subject may remain on study for continued treatment with afuresertib monotherapy. 
Adding any other anticancer drug while on this study, is not allowed. Subjects will 
complete the Transition Visit, receive study instruction and study medication, and then 
return for their next scheduled visit (either Study Week 3 or 4) and then every 3 or 4 
weeks thereafter, depending on the schedule used in the parent study.  Subjects who 
remain on study treatment for >52 weeks (including time on parent study) may have the 
frequency of their interim visits decreased with approval from the GSK Medical Monitor 
to every 8 or 9 weeks (whichever is consistent with parent schedule). After 
discontinuation of study treatment, the investigator will monitor all AEs/SAEs for 30 
days or until resolution, whichever comes first.
 
 
Section 4.1.2. Inclusion Criteria
REVISED TEXT
Paragraph 1:
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on afuresertib or other agent(s) that may impact subject eligibility is 
provided in the IB for afuresertib [GlaxoSmithKline Document 2011N113491_03] or any 


Novartis
Confidential
Page 115
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
subsequent IB supplements or in the Prescribing Information for any agent(s) 
administered as part of a combination treatment regimen, as applicable.
Inclusion criteria no 2:
Is currently participating in an
afuresertib study (monotherapy or in combination with 
another anti-cancer agent) sponsored by GSK or by another research organization 
working on behalf of GSK.  
Inclusion criteria no 3:
Currently tolerating and benefitting from treatment with afuresertib as determined by the 
investigator following previous treatment with afuresertib either as monotherapy or as 
part of a combination treatment regimen.


Novartis
Confidential
Page 116
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Inclusion criteria no 10:
Have adequate organ system function as defined in Table 1.
Table 1 Definitions of Adequate Organ Function
System
Laboratory Value
Hematologic
Absolute neutrophil count (ANC)
Hemoglobin
Platelets
1.0 x 109/L
8.0 g/dL
50 x 109/L 
PT/INR and PTT
1.5x ULN
Hepatic
Total bilirubin
AST and ALT
1.5x ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%)
3xULN. If liver involvement is present and ALT and AST levels 
are>3xUNL and<5xULN, enrollment into PKB115131 can occur 
as long as there is no concurrent bilirubin or INR elevation
Renal (Monotherapy)
Serum creatinine 
OR
Calculated creatinine clearance1
2.5mg/mL
30 mL/min
Renal (in combination with nephtoyoxic anti-cancer agents)
Serum creatinine 
OR
Calculated creatinine clearance1
<1.2xULN
50 mL/min
Cardiac
Ejection Fraction (LVEF)
50% by TTE or MUGA
1.
As calculated by Cockcroft-Gault formula (Appendix 4).
Section 4.1.4. Other Eligibility Criteria Considerations
REVISED TEXT
To assess any potential impact on subject eligibility with regard to safety, the investigator 
must refer to the following document(s) for detailed information regarding warnings, 
precautions, contraindications, adverse events, and other significant data pertaining to the 
GSK investigational product(s) or other study treatment being used in this study: IB for 
afuresertib [GlaxoSmithKline Document 2011N113491_03], product label(s) for other 
commercially available co-administered agents.


Novartis
Confidential
Page 117
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 4.2.1. Permanent Discontinuation from Study Treatment
REVISED TEXT
Subjects may be permanently discontinued from study treatment in the event of 
unacceptable toxicity, which include but are not restricted to: meeting stopping criteria 
for liver chemistry defined in Section 6.7.7 or for hematologic and other non-hematologic 
toxicity.  In addition, study treatment will be permanently discontinued for any of the 
following reasons:

Deviation(s) from the protocol

Adverse Event, including but not limited to clinically significant AE leading to 
interruption of treatment for >14 consecutive days2.  

Disease progression (including death due to disease progression)

Request of the subject or proxy (withdrawal of consent by the subject)

Investigator’s discretion

Subject is lost to follow-up

Study is closed or terminated (such as when afuresertib becomes locally 
available as commercial product to the subject for continued treatment)

Death
Paragraph 7:
In the event that a subject permanently discontinues study treatment at any time due to an 
AE (as defined in Section 6.8.1.1, “Definition of an AE”) or serious AE (SAE) (as 
defined in Section 6.8.1.2, “Definition of a SAE”), the procedures stated in Section 6.8
(“Adverse Events”) must be followed.  All subjects who have a Grade 3 or 4 clinical or 
laboratory abnormality at the time of permanently discontinuing study treatment must be 
followed 
up to 30 days or until resolution, whichever comes first
 
                                                
2 NOTE:  If the investigator and GSK Medical Monitor agree that continued treatment will benefit the 
subject, then the subject may continue treatment, with or without a dose reduction, with the approval of 
the GSK Medical Monitor.


Novartis
Confidential
Page 118
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 5.1 Transition Visit
REVISED TEXT
For this study, the Transition Visit may occur on the same day as the last study visit on 
the parent study.  The most recent disease assessment performed under the parent 
protocol may be used for entry criteria for this rollover protocol, if there are no clinical 
signs of disease progression.  The results of any specified study assessments performed 
on the day of the Transition Visit will serve as the baseline value for said assessment.
At the Transition Visit, the following assessments will be performed:

Demographic data, including date of birth, ethnicity, gender, and race.

Subject-related data from parent study, including parent study protocol number, 
previous subject number assigned in parent study, start and stop date, dose of 
afuresertib and other study treatment(s), if applicable, at time of transition to this 
study; and response based on last disease assessment in parent study. At the time 
of transition visit the duration of treatment on parent study will be calculated.

Complete physical examination, including height and weight.

Vital signs (BP, temperature and pulse rate)

Clinical laboratory tests: hematology, TSH and clinical chemistry required for 
study entry, including coagulation tests

Serum beta-human Chorionic Gonadotropin (-hCG) pregnancy test for female 
subjects of childbearing potential only

Single 12-lead ECG

Review of adverse events and concomitant medications

Disease assessments
Section 5.2.2 Cohort C
REVISED TEXT
The following assessments must be performed either every 3 or 4 weeks (3 days)
(depending on schedule used in parent study) while receiving treatment:

Vital signs (BP, temperature and pulse rate)

Complete physical examination

Clinical laboratory tests: hematology and clinical chemistry, including TSH and 
coagulation tests 


Novartis
Confidential
Page 119
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

Single, 12-lead ECG

Perform assessments needed for safe administration of other anti cancer agents 
used in combination
Section 5.3 Final Study Visit
REVISED TEXT
If a subject is withdrawn from study treatment, the following assessments will be 
performed within
one month from the last dose of study treatment(s) 
and prior to initiating any other treatment for cancer:

Complete physical examination

Vital signs (BP, temperature and pulse rate)

Clinical laboratory tests:  hematology, clinical chemistry, and TSH

Single, 12-lead ECG

Review of concomitant medications

Assessment of AEs

Disease assessment
Table 2   List of Clinical Laboratory Assessments
REVISED TEXT
Clinical Chemistry
Blood urea nitrogen (BUN)
Potassium
Creatinine
Inorganic phosphorus
Sodium
Magnesium
Albumin
Chloride
Calcium
LDH
Bicarbonate
Glucose
Total protein
AST
ALT
Alkaline Phosphatase
Total bilirubin (bilirubin fractionation 
recommended if total bilirubin >2 times ULN)
 


Novartis
Confidential
Page 120
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 5.5 and Section 5.6
REVISED TEXT
Section 5.5 Multiple Myeloma specific disease assessments:
The following assessments will be performed to assess disease in subjects with MM only 
every 4 weeks until week 42 and every 8 weeks thereafter: 
Serum M-protein, urine M-protein, serum FLC, urine FLC,  imaging for extramedullary 
MM (only in subjects in whom there is a clinical evidence of extramedullary MM- the 
imaging technique should be the same throughout the study (ie if subject initially had CT-
should be followed by CT, if MRI- follow by MRI, or if PET scan- follow by PET scan.)).
Section 5.6  Disease assessments for malignancies other than MM
Disease assessments will be performed at regular intervals, at least every 12 weeks per 
local standard practice using criteria appropriate for the disease type and location. The 
investigator may decide that more frequent disease assessments are needed, and perform 
them according to medical practice. 
Section 5.9.1.5. Time Period and Frequency of Detecting AEs and SAEs
REVISED TEXT
AEs will be collected from the time of
first dose of study treatment until 
 
30 days 
after last study treatment dose. 


Novartis
Confidential
Page 121
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 6.1
REVISED TEXT
6.1 Afuresertib Investigational Product Dosage/Administration
For early trials in the afuresertib clinical program, study drug was provided in hard 
gelatin capsules (25 mg and 100 mg strengths; see Table 6 below).  The initial patients 
enrolled to this protocol from the FTIH study PKB112825 continued to receive 
afuresertib in hard gelatin capsules.  Subsequently, afuresertib has been re-formulated as 
immediate-release (IR) tablets (50 mg and 75 mg strengths).  A relative bioavailability 
study (201039) performed in healthy volunteers showed similar afuresertib 
pharmacokinetic characteristics between the capsule formulation and the IR tablet 
formulation (for details of study 201039 see the afuresertib clinical IB).  Patients 
currently receiving afuresertib as hard gelatin capsules in this protocol will be switched to 
IR tablets from Day 1 of their next treatment cycle following a scheduled clinic visit.  
Patients newly enrolled to this protocol from a parent afuresertib study in which they 
received drug in hard gelatin capsules will immediately switch to IR tablets.  Patients 
newly enrolled to this protocol from a parent afuresertib study in which they received 
drug as IR tablets will continue to receive IR tablets.  Patients switching from capsule to 
tablets will have the change fully explained by their Investigator or Study Nurse.


Novartis
Confidential
Page 122
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Table 4
Afuresertib Dosage/Administration
Product name :
Afuresertib
Formulation 
description:
Gelatin capsules: Each 25 mg capsule contains 25 mg of afuresertib as free 
base
Each 100 mg capsule contains 100 mg of afuresertib as free base
OR:
Immediate release tablets (IR tablets): Each 50 mg tablet contains 50 mg of 
afuresertib as free base
Each 75 mg tablet contains 75 mg of afuresertib as free base
Dosage form :
Geletin capsule or immediate release tablet 
CAPSULES
IR TABLETS
Unit dose 
strength(s)/Dose 
Level(s):
25 mg capsule or 100 mg capsule 
50 mg tablet or 75 mg tablet
Physical Description: 
25mg Capsules: Opaque, white, 
size 4 capsules with no external 
markings, filled with a white 
powder.
OR:
OR: 100mg Capsules: Opaque, 
Swedish orange, size 1 capsule 
with no external markings, filled 
with a white powder.
50mg IR tablets: White, film-coated, 
round, biconvex tablet
75mg IR tablets: White, film-coated, oval 
or capsule shaped tablet
Route/
Administration/ 
Duration:
Oral/ The initial regimen will be once daily dosing continuously.
Dosing instructions:
Dose with
at least 200 mL of water, and taken in the morning. (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.)  Afuresertib may be 
given without regard to food.
Section 6.2  Other Anti-Cancer Agents (Cohort C)
REVISED TEXT
When the treatment regimen to be administered includes another anti-cancer agent(s) in 
combination with afuresertib, the sites will be responsible for obtaining the necessary 
drug supply for the anti-cancer agent(s) through commercial means; the drug(s) will not 
be supplied by GSK.  The use of an anti-cancer agent(s) in combination with afuresertib
that was not part of the parent study is not permitted.  Refer to the Prescribing 
Information for each anti-cancer agent for information regarding the physical and 
chemical properties, storage, and dosing/administration guidelines.


Novartis
Confidential
Page 123
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 6.3  Administration of Study Treatment
REVISED TEXT
Paragraph 1:
Afuresertib will be administered with approximately 200mL of water. 
 
Section 6.4  Handling and Storage of Study Treatment
REVISED TEXT
Paragraph 3:
Anti-cancer agents should be handled per manufacturer instructions.
Section 6.6  Dose Modifications
REVISED TEXT
Paragraph 2:
Guidelines for afuresertib dose modifications are provided below.  Investigators should 
also consult the GSK Medical Monitor and refer to the afuresertib IB [GlaxoSmithKline 
Document Number 2011N113491_03] or the prescribing information for the appropriate 
anti-cancer combination agent for detailed information regarding warnings, precautions, 
contraindications, AEs, and recommendations for supportive care in the event of drug-
related toxicity. 
Section 6.6.2 Dose Modification: Other Anti-Cancer Agent(s)
REVISED TEXT
If an 
 anti-cancer agent(s) is being taken in combination with afuresertib at the 
time of transition to the rollover study, treatment will continue with the current dose 
administered in the parent study.  
Section 6.7.2 Supportive Measures for Hyperglycemia
REVISED TEXT
Subjects with clinically significant glucose elevation, with or without ketoacidosis, 
should be aggressively managed according to standard medical practice.  Study sites with 
a protocol/guideline for management of hyperglycemia should include a copy in the study 
document file.  Early consultation with a diabetes specialist is also encouraged, especially 
for study participants with a history of diabetes.  If significant hyperglycemia (e.g., 
fasting glucose 200 mg/dL) persists despite treatment and after stopping systemic 
glucocorticoids (where applicable), or in the event of life-threatening complications, dose 
modification of afuresertib should also be considered, after discussion with a GSK 


Novartis
Confidential
Page 124
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
medical monitor.  Dose modification of afuresertib should not be performed for 
asymptomatic hyperglycemia, or hyperglycemia that responds to other interventions.
Section 6.7.3 Management of Diarrhea
REVISED TEXT
Episodes of diarrhea have been reported in subjects receiving afuresertib and this should 
be actively managed as soon as an episode has occurred.  When starting afuresertib, it is 
advisable to provide subjects with a prescription for loperamide (or equivalent), along 
with detailed guidance on how to manage this potential toxicity.  If an episode of diarrhea 
occurs, other potential causes should be promptly ruled out (e.g., concomitant 
medications like stool softeners, laxatives, antacids, etc., infections, partial bowel 
obstruction, etc.).  Supportive therapy will be provided according to standard medical 
practice.  Supportive measures should include the following as clinically indicated 
[Benson, 2004]:

Dietary modifications (e.g., small, frequent meals, low fiber, and lactose avoidance)

Maintain hydration with clear liquids or IV fluids as needed

Loperamide and/or oral antibiotics


Novartis
Confidential
Page 125
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
  


Novartis
Confidential
Page 126
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 6.7.4 Management of Rash
REVISED TEXT
Subjects should contact the investigator immediately upon onset of a rash.  Full 
supportive care should be provided to subjects who experience a rash while on study.  
Information contained in this section is a guideline.  The investigator’s best medical 
judgment should determine medical intervention for rash. Details should be entered into 
InForm.  
Table 6
Guidelines for Dose Modification and Management of Rash
1st occurrence
2nd occurrence
3rd occurrence
Grade 1
Symptomatic carea
Consider oral steroids if multiple recurrencesb
Grade 2
Consider oral steroids
Oral steroids
Hold drug until <Grade 1, 
then resume at full dose
Oral steroids
Hold drug until 
<Grade 1, then resume 
at 25 mg dose reduction
Grade 3
Oral steroids
Hold drug until <Grade 1, 
then resume at full dose
Oral steroids
Hold drug until <Grade 1,
then resume at 25 mg 
dose reduction
Oral steroids
Hold drug until 
<Grade 1, then resume 
at 50 mg dose reduction 
or discontinue
Grade 4
Oral steroids
Hold drug until <Grade 1, 
then resume at 25 mg 
dose reduction
Oral steroids
Hold drug until <Grade 1, 
then resume 50 mg dose 
reduction or discontinue
Discontinue
a.
Recommended symptomatic measures (for all grades) includes topical steroids (e.g., hydrocortisone 1% or 2.5% 
cream), antihistamines, hypoallergenic moisturizers and emollients for dry skin (e.g., 5-10% urea in cetomacrogel 
cream or soft paraffin).
b.
Recommended course of oral steroids is methylprednisolone (or equivalent).
A dermatology consult should be considered for Grade ≥3 rash or multiple occurrences of 
Grade ≤2 rash.
 


Novartis
Confidential
Page 127
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 6.7.5 Guidelines for Management of Dyspepsia
REVISED TEXT
Based on nonclinical data and current clinical experience, it is possible that afuresertib 
may be a direct GI mucosal irritant such that subjects with GI dysmotility or GERD may 
be predisposed to symptoms of dyspepsia.  Therefore, if a subject experiences symptoms 
supportive therapy will be provided according to standard medical practice.  If Grade 1-2 
dyspepsia, the investigator should consider the following recommendations:

Afuresertib may be taken with or without food, except where specified (see Section 
3.8.1 and Table 12).

Capsules should be administered approximately 5 minutes apart with divided 
amounts of fluid (4-8 oz with each capsule for a total of at least 12 oz), except where 
specified (see Section 3.8.1).

Subjects should remain upright for 30 min after taking afuresertib.


Novartis
Confidential
Page 128
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
In more severe cases of dyspepsia, consider sucralfate and/or aluminum hydroxide with 
magnesium carbonate as supportive measures.  These should be administered at least 
2 hours after dosing to avoid any potential drug-drug interactions (see Section 7.2).

Histamine H2-receptor antagonists (H2 blockers) or proton pump inhibitors may also 
be considered.
If the recommendations above are insufficient to resolve symptoms, or if active 
ulceration is suspected, investigators should consider additional tests such as upper 
endoscopy or barium radiography.
Section 6.7.6 Guidelines for Management of Mucositis
REVISED TEXT
Ulceration throughout the GI tract was observed in nonclinical studies of afuresertib.  
Mucositis has also been reported as a consequence of treatment with AKT inhibitors.  
Prophylaxis for mucositis is recommended in subjects who are receiving afuresertib.  
This should include good oral hygiene (e.g., soft toothbrushes, rinsing and cleaning the 
oral cavity with water after every meal, and removal of dentures at the first sign of oral 
pain or inflammation) and preventive measures for lower GI symptoms (e.g., maintaining 
adequate hydration, reducing dairy intake in the event of lactose intolerance).  Afuresertib 
should be held for episodes of mucositis Grade 2.  Recommended supportive measures 
include the following:

Institute a soft diet and avoid acidic, salty, or dry foods


Novartis
Confidential
Page 129
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

Provide topical analgesics (e.g., 2% lidocaine solution), or coating agents.  Parenteral 
analgesia may be required for more severe events. 

Work-up for infection, including oral candidiasis and viral infections.  Empiric 
antibiotic treatment may be required while awaiting culture results, especially if 
high-grade neutropenia is present concurrently. 

Administer H2 blockers or proton-pump inhibitor if epigastric symptoms are also 
present.
Hospitalization may be required for more severe cases, especially if IV hydration, 
parenteral analgesia, or supplemental nutrition is required.  Investigators should discuss 
afuresertib dosing with a GSK medical monitor before reinstituting treatment after an 
episode of Grade 3 or 4 mucositis.


Novartis
Confidential
Page 130
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131


Novartis
Confidential
Page 131
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 6.7.7 Liver Chemistry Stopping Criteria
ADDED SECTION
Section 6.7.7.1 Actions if Liver Chemistry Stopping Criteria are met
When any of the liver chemistry stopping criteria are met, do the following:

Immediately discontinue investigational product.

Report the event to GSK within 24 hours of learning its occurrence.

Complete the liver event CRF and SAE data collection tool if the event also meets the 
criteria for an SAE.

All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 
3xULN and INR>1.5, if INR measured; INR measurement is not required and the 
threshold value stated will not apply to subjects receiving anticoagulants), termed
‘Hy’s Law’, must be reported as an SAE.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed.

Perform liver event follow up assessments, and monitor the subject until liver
chemistries resolve, stabilize, or return to baseline values as described below.

Follow-up for overall survival is required following permanent discontinuation from
investigational product.

Do not re-challenge with investigational product.
In addition, for criterion 1 in Section 6.7.7:

Make every reasonable attempt to have subjects return to clinic within 24 hours for
repeat liver chemistries, liver event follow up assessments (refer to Section 6.7.7.2),
and close monitoring.

A specialist or hepatology consultation is recommended.

Monitor subjects twice weekly until liver chemistries (ALT, aspartate
aminotransferase [AST], alkaline phosphatase [ALP], bilirubin) resolve, stabilize or
return to within baseline values.

Monitor subjects twice weekly until liver chemistries (ALT, aspartate
aminotransferase [AST], alkaline phosphatise [ALP], bilirubin) resolve, stabilize or
return to within baseline values.
In addition, for subjects meeting any of the criteria 2-4 in Section 6.7.7:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for
repeat liver chemistries and liver event follow up assessments (refer to Section
6.7.7.2).
Monitor subjects weekly until liver chemistries (ALT, AST, ALP, bilirubin) resolve,
stabilize or return to within baseline values.


Novartis
Confidential
Page 132
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Also, refer to Appendix 3, Liver Chemistry Testing Procedures, for details of the
assessments required if a subject meets any of the above criteria in the absence of
disease progression.
 


Novartis
Confidential
Page 133
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 6.7.7.2 Liver Event Follow-Up Assessments
For subjects meeting any of the liver chemistry stopping criteria 
 make every 
attempt to carry out the liver event follow-up assessments described below:

Viral hepatitis serology including:

Hepatitis A Immunoglobulin M (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 

Blood sample for PK analysis, obtained within 
10 days of last dose of study 
treatment(s).  Record the date/time of the PK blood sample draw and the date/time of 
the last dose of study treatment(s) prior to blood sample draw on the eCRF.  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 SPM. 


Novartis
Confidential
Page 134
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
ADDED SECTION
Section 6.7.7.4
Drug Restart/Rechallenge Following Liver Events that are 
Possibly Related to IP
Approval by GSK after discussion with GSK medical monitor for drug restart can be 
considered where:

The subject is receiving compelling benefit, benefit of drug restart exceeds risk, and 
no effective alternative therapy is available. Ethics Committee or Institutional 
Review Board approval of drug restart/rechallenge must be obtained, as required;   

If the restart/rechallenge is approved by GSK in writing, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death;  

The subject must also provide signed informed consent specifically for the IP 
restart/rechallenge. Documentation of informed consent must be recorded in the 
study chart;  

Study drug must be administered at the dose specified by GSK; and

Subjects approved by GSK for restart/rechallenge of IP must return to the clinic 
twice a week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. 
Section 6.10  Treatment Compliance
REVISED TEXT
Paragraphs 2 and 3:
When dosing occurs outside of the study site, the subject will return all unused 
investigational product in the dispensed container on each return visit to the clinic, and 
study staff will note the number of capsules or tablets returned in the source documents.  
Subjects will maintain a daily dosing diary.  
A record of the number of afuresertib capsules or tablets must be maintained and 
reconciled with study treatment and compliance records.  Treatment start and stop dates, 
including dates for treatment interruptions and/or dose reductions will also be recorded in 
the eCRF.


Novartis
Confidential
Page 135
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 7  Concomitant Medications and Non-Drug Therapies
REVISED TEXT
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study treatment until the end of the study (Final 
Study Visit). Any concomitant medication(s), including non-prescription medication(s) 
and herbal product(s), taken during the study will be recorded in the electronic case 
report form (eCRF). 
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
Permitted Medication(s) and non-Drug Therapies
Subjects should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines.
Paracetamol or acetaminophen, at the label-recommended dose, is permitted. 
Medications which contain paracetamol or acetaminophen should be counted in label 
recommended dose. Other concomitant medication may be considered on a case by case 
basis by the GSK Medical Monitor.
Concurrent treatment with bisphosphonates is permitted. Prophylactic use of 
bisphosphonates in subjects without metastatic bone disease is not permitted, except for 
the treatment of osteoporosis.
Current use of warfarin for therapeutic anticoagulation is not allowed (Note: low 
molecular weight heparin is permitted). Their use must be monitored in accordance with 
local institutional practice.
7.2
Prohibited Medication(s) and Non-Drug Therapies
Subjects should not receive anti-cancer therapy (chemotherapy, radiation therapy, 
immunotherapy, biologic therapy, hormone therapy other than for replacement, surgery, 
and/or tumor embolization) directed towards the tumor for which they have been enrolled 
on the trial while on treatment in this study; although palliative radiation to control pain 
may be used following discussion with the GSK Medical Monitor.
Subjects should abstain from taking any herbal and dietary supplements within 5 half 
lives (or 14 days if the drug is a potential enzyme inducer) prior to study drug(s) dosing 
and until completion of the follow-up visit, unless there is little concern for a potential 
drug-drug interaction with the study drug(s). These herbal medications include, but are 
not limited to, St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. The investigator should 


Novartis
Confidential
Page 136
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
contact a GSK Medical Monitor before initiating study treatment in a subject taking any 
herbal preparation.
Short courses (up to 7 days) of oral corticosteroids intended to treat study treatment 
related rash or diarrhea are allowed.
Erythropoiesis-stimulating agents and colony-stimulating factors like filgrastim and 
pegfilgrastim  may be used as clinically indicated.
7.2.1
Drugs Potentially Affected by Afuresertib (afuresertib perpetrator 
interaction potential
In vitro data indicate that afuresertib has the potential of being a perpetrator in drug-drug 
interactions through enzyme inhibition (with substrates of CYP3A4 and 2C8, IC50
estimates of 3.7 to 6.0 M and 6.3 M, respectively), through transporter inhibition (with 
substrates of OATP1B1 and BCRP, IC50 estimates of 1.7 M and 2.9 M) (Table 14). 
Co-administration of afuresertib and medications which are a sensitive substrate of 
CYP3A4, OATP1B1 and BCRP with a low therapeutic index will be prohibited. Co-
administration of afuresertib and medications which are a sensitive substrate of CYP2C8 
with a low therapeutic index will be used with caution. Other drugs affected by these 
enzymes and transporters should be used with caution and please refer to SPM.
Table 7
Drugs potentially affected by afuresertib 
AVOID: 
CYP3A Substrate
Therapeutic Area
carbamazepine
Anticonvulsants
ergotamine, dihydroergotamine
Antimigraine
pimozide
Antipsychotics
amiodarone, disopyramide, quinidine, bosentan  
Cardiovascular Agents
cyclosporine, everolimus, sirolimus, tacrolimus
Immunosuppressive Agents
OAT1B1 Substrate
Therapeutic Area
methotrexate
Anti-cancer
BCRP Substrate
Therapeutic Area
topotecan
Anti-cancer
Note: Boceprevir and telaprevir (anti-HCV drugs) should be used with caution when combining with 
afuresertib.


Novartis
Confidential
Page 137
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Table 8
Drugs Potentially Affected by Afuresertib: 
Use with Caution
Generic Drug Name1
Therapeutic Class
CYP3A Substrate
fentanyl
Analgesics
alfentanil, ropivacaine
Anesthetics
losartan
Angiotensin II inhibitors
ethosuximide, trimethadione
Anticonvulsants
buspirone, roboxetine, sertraline, trazodone, venlafaxine
Antidepressants/Anxiolytics
emadastine, loratadine
Antihistamines
artemether, halofantrine, lumefantrine, quinine
Antimalarial
erythromycin, clindamycin, rifabutin, rifampin
Antimicrobials
eletriptan
Antimigraine
-dihydroergocriptine, bromocriptine
Anti-Parkinsonians
aripiprazole, bromperidol, clozapine, haloperidol, quetiapine
Antipsychotics
oxybutynin, tolterodine
Antispasmodics
osentan, delaviridine, tipranavir, nelfinavir
Antivirals
amlodipine, barnidipine, diltiazem, dofetilide, dronedarone, 
eplerenone, felodipine, nifedipine, pranidipine, propafenone, 
verapamil, vesnarinone
Cardiovascular Agents
sildenafil, tadalafil, vardenafil
Erectile dysfunction treatments
aprepitant, lansoprazole
Gastrointestinal Agents
atrovastatin, lovastatin, simvastatin
HMG CoA reductase inhibitors2
alprazolam, chlordiazepoxide, diazepam, flunitrazepam, midazolam, 
propofol, triazolam, zolipidem, zopiclone
Hypnotics and Sedatives
pioglitazone, repaglinide, rosiglitazone
Hypoglycemic agents
temsirolimus
Immunosuppressive Agents
1.
Please note some drugs may be listed more than once. This is due to the fact that they are substrates for 
both CYP and a transporter (e.g., OATP1B1, BCRP).
2.
If subjects are on a high dose of a HMG CoA reductase inhibitor, dose reduction should be considered. 
Monitoring for toxicities (such as rhabdomyolysis) should be considered.
7.2.1.1
Drugs that may potentially affect afuresertib (perpetrators)
The metabolism of afuresertib may be mediated by CYP450 isozymes which may include 
CYP3A4 with possible contributions from CYP2D6 and CYP1A2. Afuresretib is a 
substrate of human P-gp and of murine Bcrp1. However, the relative contribution of the 
various pathways to the elimination of afuresertib is presently unknown. Substances that 
potently inhibit or induce these enzymes/transporters could lead to alterations in the 
pharmacologic effects of afuresertib and potentially much higher/lower exposure in 
subjects. Those medications which may alter afuresertib elimination and should be 
administered with caution and please refer to SPM.


Novartis
Confidential
Page 138
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Table 9
Drugs that may Potentially Affect Afuresertib: Use with Caution
Generic Drug Name
Therapeutic Class
quinidine
Antiarrhythmics
fluvoxamine, fluoxetine, nefazodone, paroxetine
Antidepressants
fluconazole, itraconazole, ketoconazole, terbinafine, voriconazole
Antifungals
ciprofloxacin, clarithromycin, erythromycin, isoniazid, telithromycin, 
troleandomycin
Anti-infectives
amprenavir, atazanavir, delaviridine, efavirenz, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir
Antivirals
all rifamycin class agents (e.g., rifampicin, rifabutin, rifapentine)
Antibiotics
phenobarbital, oxandrolone, tizanidine, gemfibrozil
Miscellaneous


Novartis
Confidential
Page 139
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131


Novartis
Confidential
Page 140
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section 8.3  Meals and Dietary Restrictions
REVISED TEXT
 
 Subjects may take afuresertib 
without regard to food.  For combination medications, please use its meal and dietary 
restrictions.  Subject should take afuresertib dose at approximately same time each day.


Novartis
Confidential
Page 141
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
In addition, subjects shall abstain from ingestion of any food or drink containing 
grapefruit and grapefruit juice, Seville oranges, or pommelos within 7 days prior to the 
first dose of afureserib until the end of the study.
Section 12  References
REVISED REFERENCE
GlaxoSmithKline Document Number 2011N113491_03.  GSK2110183 Investigator's 
Brochure.  Report Date: SEP-2014.
Appendix 2 Time and Events Table for Cohort C
ECHO/MUGA scan assessments were deleted from the table.
Appendix 3:  Liver Safety Drug Restart Guidelines
REVISED TEXT
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.
Background Information on Drug Restart/Rechallenge
Following drug-induced liver injury, drug restart or rechallenge is associated with a 
13% mortality across all drugs in prospective studies.1  Clinical outcomes vary by 
drug, with nearly 50% fatality with halothane readministered in one month of initial 
injury. However, some drugs seldom result in recurrent liver injury or fatality.  Risk 
factors for a fatal drug restart/rechallenge outcome include: hypersensitivity1 with initial 
liver injury (e.g. fever, rash, eosinophilia), jaundice or bilirubin2xULN or INR>1.5 
suggesting severe liver injury, prior IP-related severe or fatal drug restart/rechallenge2,3 or 
evidence of drug-related preclinical liability / mitochondrial impairment3.
Drug Restart/Rechallenge Process (also see Figure 2)
1.
Principal Investigator (PI) requests consideration of drug restart for a subject 
receiving compelling benefit from a critical or life-saving drug, who exhibits liver 
chemistry elevation meeting subject stopping criteria, with no alternative treatment.
2.
GSK Medical Monitor & Clinical Safety Physician.to review the subject’s 
restart/rechallenge risk factors & complete checklist (Table 10).


Novartis
Confidential
Page 142
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Table 10
Checklist for drug restart/rechallenge for critical medicine
(Following drug-induced liver injury, drug rechallenge is associated with 13% mortality 
across all drugs in prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject 
and no alternative therapy.  Provide brief explanation:
Relative benefit-risk favorable for drug restart/rechallenge, after 
considering the following high risk factors:
•
Initial liver injury event included: 
–
fever, rash, eosinophilia, or hypersensitivity
–
or bilirubin2xULN (direct bilirubin >35% of total)
•
Subject currently exhibits ALT 3xULN, bilirubin 2xULN (direct 
bilirubin >35% of total, if available), or INR1.5
•
Severe or fatal restart/rechallenge has earlier been observed 
with IP If yes, please provide brief explanation:
•
IP associated with known preclinical hepatic liability/ injury   
3.
If GSK provides written approval for restart/rechallenge following the above review, 
the Principal Investigator (PI) must ensure the following:

The PI is to obtain Ethics Committee or Institutional Review Board review of 
drug re-initiation, as required. 

PI must discuss the possible benefits and risks of drug re-initiation with the 
subject.

The subject must sign informed consent with a clear description of possible 
benefits and risks of drug administration, including recurrent liver injury or death. 
Consent specifically for the IP restart must be recorded in the study chart.

The drug must be reinitiated at GSK approved dose(s). 

Subjects approved by GSK for restart of IP must return to the clinic twice a week 
for liver chemistry tests until stable, liver chemistries have been demonstrated and 
then laboratory monitoring may resume as per protocol. If protocol defined 
stopping criteria for liver chemistry elevations are met, study drug must be 
stopped. 

The Ethics Committee or Institutional Review Board is to be informed of the 
subject’s outcome, as required.


Novartis
Confidential
Page 143
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131

GSK is to be notified of any adverse events, as per Section 8.5.2.
Figure 2
Algorithm for Drug Restart After Possible Drug-induced Liver Injury
References:
1.
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury:the attractive hazard. Expert Opin 
Drug Saf 2009;8:709–714.
2.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al. Drug-induced liver injury following positive drug 
rechallenge. Regul Toxicol Pharmacol 2009;54:84-90.
3.
Hunt CM. Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced 
liver injury: a systematic review. Hepatology 2010;52:2216–2222


Novartis
Confidential
Page 144
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
AMENDMENT 3
Where the Amendment Applies
This amendment applies to all investigator sites participating in this study.
Summary of Amendment Changes with Rationale
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GSK2110183, the 
purpose of this protocol Amendment 03 is to:
-
Delete or replace references to GlaxoSmithKline or its staff with that of Novartis 
and its authorized agents to align with the change of sponsorship;
-
Make administrative changes to align with Novartis processes and procedures;
List of Specific Changes
Title Page: 
REVISED TEXT
The title page replaced as per Novartis requirements. 
Section: Sponsor Signatory
REVISED TEXT
Date
OGD OCD INC/PKC
Phone:
Email:
Section: Sponsor Information Page
REVISED TEXT
Medical Lead Contact Information:


Novartis
Confidential
Page 145
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
 
.
,MD
 
 
Novartis Pharmaceuticals Corporation 
One Health Plaza,Bldg 337/
 
East Hanover, NJ 07936-1080 USA 
Phone:
 
Mobile:
 
Email:
www.novartis.com
 Contact Information:
Novartis Pharmaceuticals Corporation
One Health Plaza
Bldg. 337/
East Hanover,
NJ 07936-1080
USA
Phone:
Mobile:
Email:
If you have any questions regarding the protocol, please contact your local Novartis 
office


Novartis
Confidential
Page 146
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section: Abbreviations
TEXT ADDED:
GCPH
Global Clinical Program Head
Section: PROTOCOL SYNOPSIS
REVISED TEXT

PROTOCOL/AMENDMENT NO.:  PKB115131/Amendment 0 3

OBJECTIVES:  To provide continued treatment with afuresertib for subjects 
who have completed participation in a
Novartis sponsored afuresertib
study, or an afuresertib study sponsored by another research organization 
working on behalf of
Novartis. Additional safety information about 
afuresertib will also be collected.  
Section: 1.1.1 Afuresertib
REVISED TEXT
The investigator should refer to the current version of the afuresertib 
Investigator’s Brochure (IB) 
 
for detailed information regarding all completed and ongoing 
clinical studies with afuresertib, PK in the target disease populations, as well as 
observed safety and clinical activity findings.
Section: 1.1.2 Pharmacokinetics of Afuresertib in Humans
For details of the PK of afuresertib see the current version of the IB 
Mean dexamethasone exposure co-administered with bortezomib was 30-50% 
higher when dosed with afuresertib than without afuresertib; although sample 
size was small (n=5) and exposure values overlapped 
 
Section: 1.1.3 Clinical Safety of Afuresertib
REVISED TEXT
As of 29-Jun-2013, 226 subjects had received at least 1 dose of afuresertib either as 
monotherapy or in combination with other agents in the 7 original GSK-sponsored 
studies with afuresertib. 


Novartis
Confidential
Page 147
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Additional information from all studies where subjects with other diseases are 
administered afuresertib, as monotherapy or in combination, can be found in the current 
afuresertib IB 
Section 1.1.6 Clinical Activity of Afuresertib
REVISED TEXT
Additional information from all studies where subjects with other diseases are 
administered afuresertib, as monotherapy or in combination, can be found in the current 
afuresertib IB
Section 1.2.1 Study Rationale
REVISED TEXT
The purpose of this study is to allow for continued treatment with afuresertib in subjects 
who have participated in a ‘parent’ GSK or Novartis sponsored study of afuresertib, 
either as monotherapy or as part of a combination regimen, and met the protocol 
requirements for transitioning to this rollover study. 
Section 1.2.2 Dose Rationale
REVISED TEXT
If a subject required a dose modification while receiving treatment in the parent study, 
the subject will enter the rollover study and continue treatment on the modified dose 
unless after consultation with the 
Novartis Medical 
Lead, it is appropriate 
to escalate the dose.
If a subject required a dose modification while receiving treatment in the parent study, 
the subject will enter the rollover study and continue treatment on the modified dose 
unless after consultation with the 
Novartis Medical 
Lead, it is appropriate 
to escalate the dose.  Any dose modifications will follow parent protocol or most recent 
prescribing information.
Section: 1.3 Summary of Risk Management
REVISED TEXT
Summaries of findings from clinical and nonclinical studies conducted with afuresertib 
can be found in the current IB
  
Section: 2.1 Primary
REVISED TEXT
The primary objective of the study is to provide treatment with afuresertib for subjects 
who have previously participated in an afuresertib study sponsored previously by GSK
or Novartis or another research organization working on behalf of 
Novartis.


Novartis
Confidential
Page 148
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section: 3.2. Study Design
REVISED TEXT
After informed consent is obtained, subjects will be evaluated for study eligibility in 
PKB115131/CASB183X2X01B.
Section: 3.2.1 Cohort A and Cohort B: Afuresertib Monotherapy
REVISED TEXT
Subjects will receive afuresertib as an oral, daily dose up to 150 mg. Protocol specified 
guidelines for dose modifications and treatment discontinuation criteria are provided in 
Section 6.6 and Section 6.7, respectively.  If there are any uncertainties about the dose to 
be administered in this study, the 
Novartis Medical 
Lead should be 
consulted.  
Subjects will complete the Transition Visit; receive instruction and study medication, and 
then return for their next scheduled visit (Study Week 4) and then every 4 weeks 
thereafter.  Subjects who remain on study treatment for >52 weeks (including time on 
parent study) may have the frequency of their interim visits decreased to every 8 weeks 
with approval from the 
Novartis Medical 
Lead.  After discontinuation of 
study treatment, the investigator will monitor all AEs/SAEs for 30 days or until 
resolution, whichever comes first.
Subjects will complete the Transition Visit, receive study instruction and study 
medication and then return for their next scheduled visit (Study Week 4), and then every 
4 weeks thereafter.  Subjects who remain on study treatment for >52 weeks (including 
time on parent study) may have the frequency of their interim visits decreased to every 8 
weeks with approval from the 
Novartis Medical 
Lead.  After 
discontinuation of study treatment, the investigator will monitor all AEs/SAEs for 30 
days or until resolution, whichever comes first.
Section: 3.2.2 Cohort C: Afuresertib Combination Therapy
REVISED TEXT
Subjects who remain on study treatment for >52 weeks (including time on parent study) 
may have the frequency of their interim visits decreased with approval from the 
Novartis Medical 
Lead to every 8 or 9 weeks (whichever is consistent with 
parent schedule). After discontinuation of study treatment, the investigator will monitor 
all AEs/SAEs for 30 days or until resolution, whichever comes first. 


Novartis
Confidential
Page 149
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section: 4.1.2 Inclusion Criteria
REVISED TEXT
2
Is currently participating in an afuresertib study (monotherapy or in combination with 
another anti-cancer agent) sponsored by GSK/Novartis or by another research 
organization working on behalf of 
Novartis.  
Section: 4.1.3 Exclusion Criteria
REVISED TEXT
15 Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions at the time of transition to this study that could interfere with subject’s 
safety, obtaining informed consent or compliance to the study procedures, in the 
opinion of the investigator or 
Novartis Medical 
Lead.
Section: 4.1.4 Other Eligibility Criteria Considerations
REVISED TEXT
To assess any potential impact on subject eligibility with regard to safety, the investigator 
must refer to the following document(s) for detailed information regarding warnings, 
precautions, contraindications, adverse events, and other significant data pertaining to the 
Novartis investigational product(s) or other study treatment being used in this study: 
IB for afuresertib 
, product label(s) for 
other commercially available co-administered agents.
Section: 5 Study Assessments and Procedures
REVISED TEXT
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.  The change 
in timing for any planned study assessments must be approved and documented by 
Novartis, but this will not constitute a protocol amendment.  The IRB/IEC will be 
informed of any safety issues that require alteration of the safety monitoring scheme. 
Section: 5.2.1 Cohort A and B
REVISED TEXT
Once the subject has been on study drug for >52 weeks (including the time on parent 
study), and after confirmation with Medical 
Lead the frequency of those 
assessments can be decreased to every 8 weeks (3 days).
Section: 5.2.2 Cohort C


Novartis
Confidential
Page 150
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
REVISED TEXT
Once the subject has been on study drug for >52 weeks (including the time on parent 
study), and after confirmation with Medical 
Lead the frequency of these 
assessments can be decreased to every 8 or 9 weeks (3 days) (whichever is consistent 
with the parent schedule).
Section: 5.4.4 Clinical Laboratory Assessments
REVISED TEXT
All laboratory tests with values that are significantly abnormal during study participation 
or within 28 days after the last dose of study treatment(s) should be repeated until the 
values return to within normal range or baseline.  All subjects who have a Grade 3 or 4 
laboratory abnormality at time of study withdrawal must be followed until resolution to 
Grade 2 or less, unless it is unlikely to improve due to underlying disease.  If such values 
do not return to within normal range within a period judged reasonable by the 
investigator, the etiology should be identified and the 
Novartis Medical 
Lead notified.
Section: 5.8.2 Action to be taken if pregnancy occurs
REVISED TEXT
The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  The investigator will record pregnancy 
information on the appropriate form and submit it to 
Novartis within  
24 hours of learning of a subject's pregnancy.  The subject will also be followed to 
determine the outcome of the pregnancy.  Information on the status of the mother and 
child will be forwarded to 
Novartis.  Generally, follow-up will be no longer than 6
to 8 weeks following the estimated delivery date.  Any premature termination of the 
pregnancy will be reported.
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to 
Novartis as described in Section 5.9.1.6.  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.
Section: 5.8.3 Action to be taken if pregnancy occurs in a female partner of 
a male study subject
REVISED TEXT
The investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  The 
investigator will record pregnancy information on the appropriate form and submit it to 
Novartis within
24 hours of learning of the partner’s pregnancy.  The 


Novartis
Confidential
Page 151
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
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 
Novartis.  Generally, follow-
up will be no longer than 6 to 8 weeks following the estimated delivery date.  Any 
premature termination of the pregnancy will be reported.
Section: 5.9.1.5 Time Period and Frequency of Detecting AEs and SAEs
REVISED TEXT
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment 
 
 must be recorded from the time a subject consents to participate in the study 
up to and including any follow-up contact.  All SAEs will be reported to 
Novartis
within 24 hours, as indicated in Section 5.9.1.6. 
Section: 5.9.1.6 Prompt Reporting of Serious Adverse Events and Other 
Events to GSK
REVISED TEXT
5.9.1.6 Prompt Reporting of Serious Adverse Events and Other Events to 
Novartis
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to 
Novartis as described in the following table 
once the investigator determines the event meets the protocol definition for that event.


Novartis
Confidential
Page 152
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Table 11
Serious Adverse Events
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE data 
collection tool 
Pregnancy
 
24 hou
rs
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow 
up Form
Liver chemistry abnormalities Phase II:
ALT 3 times ULN 
and bilirubin 2 times 
ULN (>35% direct) (or 
ALT 3 times ULN 
and INR >1.5
24 hours1
SAE data 
collection tool.
Liver Event eCRF 
and liver imaging 
and/or biopsy 
CRFs if 
applicable2
24 hours
Updated SAE data 
collection tool. 
Updated Liver 
Event eCRF2
ALT 3 times ULN 
with hepatitis or rash
or 5 times ULN 
2 weeks (if no liver 
involvement) or 
ALT8 times ULN if 
liver involvement 
present at enrollment; 
24 hours1
Liver Event 
eCRF2
24 hours
Updated Liver 
Event eCRF2
ALT 3 times ULN 
and <5 times ULN 
and bilirubin <2 times 
ULN 
24 hours1
Liver event eCRF 
does not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
1
Novartis to be notified at onset of liver chemistry elevations to discuss subject safety.
2
Liver event documents should be completed as soon as possible
Section: 5.9.1.7 Regulatory Reporting Requirements For SAEs
REVISED TEXT
Prompt notification of SAEs by the investigator to 
Novartis is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
Novartis has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation.  


Novartis
Confidential
Page 153
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Novartis will comply with country specific regulatory requirements relating to 
safety reporting to regulatory authorities, IRBs/IECs and investigators.  
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and 
Novartis policy and are 
forwarded to investigators as necessary.  An investigator who receives an investigator 
safety report describing an SAE(s) or other specific safety information (e.g., summary or 
listing of SAEs) from 
Novartis will file it with the IB and will notify the IRB/IEC, 
if appropriate according to local requirements.
Section: 6.1 Afuresertib Investigational Product Dosage/Administration
REVISED TEXT
Afuresertib will be provided to sites by 
Novartis.  The contents of the label will be 
in accordance with all applicable regulatory requirements.  No special preparation of 
afuresertib is required.
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff, although adequate precautions are to be taken 
to avoid direct contact with study medication.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be
provided to the site staff if required by local laws or will otherwise be available from 
Novartis upon request.
Section: 6.2 Other Anti-Cancer Agents (Cohort C)
REVISED TEXT
When the treatment regimen to be administered includes another anti-cancer agent(s) in 
combination with afuresertib, the sites will be responsible for obtaining the necessary 
drug supply for the anti-cancer agent(s) through commercial means; the drug(s) will not 
be supplied by 
Novartis.  The use of an anti-cancer agent(s) in combination with 
afuresertib that was not part of the parent study is not permitted.  Refer to the Prescribing 
Information for each anti-cancer agent for information regarding the physical and 
chemical properties, storage, and dosing/administration guidelines.
Section: 6.5 Treatment Assignment
REVISED TEXT
Upon completion of all the required screening assessments, eligible subjects will be 
registered into RAMOS (Registration and Medication Ordering System), the 
Novartis interactive voice response system (IVRS), by the investigator or 
authorized site staff.  


Novartis
Confidential
Page 154
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section: 6.6 Dose Modifications
REVISED TEXT
Guidelines for afuresertib dose modifications are provided below.  Investigators should 
also consult the 
Novartis Medical
Lead and refer to the afuresertib IB 
or the prescribing information 
for the appropriate anti-cancer combination agent for detailed information regarding 
warnings, precautions, contraindications, AEs, and recommendations for supportive care 
in the event of drug-related toxicity. 
Section: 6.6.1 Afuresertib Dose Modification
REVISED TEXT
Treatment with afuresertib may be delayed for up to 14 days to allow resolution of 
toxicity or based on investigator discretion.  If the investigator and the 
Novartis
Medical 
Lead conclude that continued treatment will benefit a subject who has 
experienced a treatment delay >14 days, then the subject may continue afuresertib 
therapy with the approval of the 
Novartis Medical 
Lead.
A maximum of 2 dose reductions (including reductions from the parent study) of 
afuresertib is permitted and each of them requires consultation with the 
 
.Novartis Medical Lead.  Dose reductions should be to a lower dose level 
previously studied in an afuresertib clinical study.  If a third dose reduction or a dose 
reduction below 75mg is required, treatment with afuresertib should be discontinued and 
subject should be withdrawn from study.
Section: 6.7.2 Supportive Measures for Hyperglycemia
REVISED TEXT
If significant hyperglycemia (e.g., fasting glucose 200 mg/dL) persists despite treatment 
and after stopping systemic glucocorticoids (where applicable), or in the event of life-
threatening complications, dose modification of afuresertib should also be considered, 
after discussion with a 
.Novartis Medical Lead.  Dose 
modification of afuresertib should not be performed for asymptomatic hyperglycemia, or 
hyperglycemia that responds to other interventions.
Section: 6.7.6 Guidelines for Management of Mucositis
REVISED TEXT
Hospitalization may be required for more severe cases, especially if IV hydration, 
parenteral analgesia, or supplemental nutrition is required.  Investigators should discuss 
afuresertib dosing with a 
Novartis Medical Lead before 
reinstituting treatment after an episode of Grade 3 or 4 mucositis.   


Novartis
Confidential
Page 155
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section: 6.7.6 Guidelines for Management of Mucositis
REVISED TEXT
Hospitalization may be required for more severe cases, especially if IV hydration, 
parenteral analgesia, or supplemental nutrition is required.  Investigators should discuss 
afuresertib dosing with a 
Novartis Medical Lead before 
reinstituting treatment after an episode of Grade 3 or 4 mucositis.   
Section: 6.7.7.1 Actions if Liver Chemistry Stopping Criteria are met
REVISED TEXT

Report the event to 
Novartis within 24 hours of learning its occurrence.
Section: 6.7.7.3 Liver Chemistry Monitoring Criteria
REVISED TEXT

Notify the 
Novartis Medical 
Lead within 24 hours of learning of the 
abnormality to discuss subject safety.
Section: 6.7.7.4 Drug Restart/Rechallenge Following Liver Events that are 
Possibly Related to IP
REVISED TEXT
Approval by 
Novartis after discussion with 
Novartis Medical 
Lead for drug restart can be considered where:

If the restart/rechallenge is approved by 
Novartis in writing, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death;  

Study drug must be administered at the dose specified by 
Novartis; and

Subjects approved by 
Novartis for restart/rechallenge of IP must return to the 
clinic twice a week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. 
Section: 6.9 Product Accountability
REVISED TEXT
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
Novartis investigational product (IP) dispensed and/or administered to study 
subjects, the amount returned by study subjects, and the amount received from and 
returned to 
Novartis, when applicable.  Product accountability records must be 


Novartis
Confidential
Page 156
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
maintained throughout the course of the study.  Refer to the SPM for further detailed 
instructions on IP accountability.
Section: 7 Concomitant Medications and Non-Drug Therapies
REVISED TEXT
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by 
Novartis and stored in the study file. Any such 
changes will be communicated to the investigative sites in the form of a letter.
Section: 7.1 Permitted Medication(s) and non-Drug Therapies
REVISED TEXT
Medications which contain paracetamol or acetaminophen should be counted in label 
recommended dose. Other concomitant medication may be considered on a case by case 
basis by the 
Novartis Medical 
Lead.
Section: 7.2 Prohibited Medication(s) and Non-Drug Therapies
REVISED TEXT
Subjects should not receive anti-cancer therapy (chemotherapy, radiation therapy, 
immunotherapy, biologic therapy, hormone therapy other than for replacement, surgery, 
and/or tumor embolization) directed towards the tumor for which they have been enrolled 
on the trial while on treatment in this study; although palliative radiation to control pain 
may be used following discussion with the 
Novartis Medical 
Lead.
Subjects should abstain from taking any herbal and dietary supplements within 5 half 
lives (or 14 days if the drug is a potential enzyme inducer) prior to study drug(s) dosing 
and until completion of the follow-up visit, unless there is little concern for a potential 
drug-drug interaction with the study drug(s). These herbal medications include, but are 
not limited to, St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. The investigator should 
contact a 
Novartis Medical 
Lead before initiating study treatment in a 
subject taking any herbal preparation.
Section: 9 Data Management
REVISED TEXT
For this study, data will be collected using
the eCRFs, transmitted electronically 
to 
the sponsor (or designee) and combined with data provided from other sources 
in a validated data system.
Management of clinical data will be performed in accordance with applicable 
Novartis standards and data cleaning procedures to ensure the integrity of the data, 
e.g., resolving errors and inconsistencies in the data.  AEs and concomitant medications 


Novartis
Confidential
Page 157
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and 
custom drug dictionary,
All laboratory data (i.e., hematology, clinical chemistry, liver function, coagulation, and 
serum pregnancy tests) will be entered into the eCRF.  
 
Section: 10.3.2 Analysis Data Sets
REVISED TEXT
Construction of data sets relating to the reporting and analysis of study data will be 
performed in accordance with all applicable 
 
Novartis standards and procedures.
Section: 10.4 Analysis Data Sets
REVISED TEXT
Data will be listed and summarized according to the 
Novartis reporting standards, 
where applicable.  Complete details will be documented in the Reporting and Analysis 
Plan (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.
Section: 11.2 Regulatory and Ethical Considerations, Including the 
Informed Consent Process
REVISED TEXT
Prior to initiation of a study site, 
Novartis will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) and applicable country-specific 
regulatory requirements including a US IND.
Novartis will provide full details of the above procedures, either verbally, in writing, 
or both.
Section: 11.4 Quality Control (Study Monitoring)
REVISED TEXT
In accordance with applicable regulations, ICH GCP, and 
Novartis procedures, 
 
Novartis personnel (or designated Clinical Research Organization [CRO]) will be 
contacted 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 
Novartis
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the eCRF will serve 
as the source document.


Novartis
Confidential
Page 158
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section: 11.5 Quality Assurance
REVISED TEXT
To ensure compliance with ICH GCP and all applicable regulatory requirements, 
Novartis may conduct quality assurance audits of the site.  Regulatory agencies may 
conduct a regulatory inspection at any time during or after completion of the study.  In 
the event of an audit or inspection, the investigator (and institution) must agree to grant 
the auditor(s) and inspector(s) direct access to all relevant documents and to allocate their 
time and the time of their staff to discuss any findings/relevant issues.
Section: 11.6 Study and Site Closure
REVISED TEXT
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and 
Novartis Standard Operating Procedures.
GSKNovartis reserves the right to temporarily suspend or terminate the study at any 
time for reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If 
Novartis determines that such action is required, 
Novartis
will discuss the reasons for taking such action with the investigator or head of the 
medical institution (where applicable).  When feasible, 
Novartis will provide 
advance notice to the investigator or head of the medical institution of the impending 
action.
If a study is suspended or terminated for safety reasons, 
Novartis will promptly 
inform all investigators, heads of the medical institutions (where applicable),and/or 
institutions conducting the study.  
Novartis will also promptly inform the relevant 
regulatory authorities of the suspension/termination along with the reasons for such 
action.  Where required by applicable regulations, the investigator or head of the medical 
institution must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination.
Section: 11.7 Records Retention.
REVISED TEXT
Following closure of the study, the investigator or 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 easily accessible when needed (e.g., for a 
Novartis audit or regulatory 
inspection) and must be available for review in conjunction with assessment of the 
facility, supporting systems, and relevant site staff.
 
 


Novartis
Confidential
Page 159
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
 
Essential documents (written and electronic) should be retained for a period of not 
less than fifteen (15) years from the completion of the Clinical Trial unless Sponsor 
provides written permission to dispose of them or, requires their retention for an 
additional period of time because of applicable laws, regulations and/or guidelines.
The investigator must notify 
Novartis of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the investigator is no longer associated with the 
site.
Section: 11.8 Provision of Study Results to Investigators, Posting to the 
Clinical Trials Register and Publication
REVISED TEXT
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 
access to statistical tables, figures, and relevant reports and will have the opportunity to 
review the complete study results at a 
Novartis site or other mutually-agreeable 
location.
GSKNovartis 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 appropriate.
 Novartis aims to post a results summary 
 to the Novartis Clinical 
Trial Results website (www.novartisclinicaltrials.com
 
 and other publicly available registers no later 
than twelve (12) months 
after the last 
subject’s last visit (LSLV).  In addition, 
upon study completion and finalization of study report, Novartis 
aims to submit results of the study for publication
 
  When 
 publication 
 is not feasible, 
 
please refer to the 
Novartis Clinical Trial Results 
website (www.novartisclinicaltrials.com
 for a 
summary of the trial results. 
Section: Appendix 1:  Time and Events Table for Cohort A and B
REVISED TEXT
11 Subjects who remain on study treatment >52 weeks (including time on parent study) 
may have the frequency of their interim visits decreased to once every 8 weeks with 
approval from the 
Novartis Medical 
Lead


Novartis
Confidential
Page 160
Amended Protocol Version 4.0 (Amendment 3.0)
Protocol No. PKB115131
Section: Appendix 2:  Time and Events Table for Cohort C
REVISED TEXT
12 If the subject was treated on a 3 weeks schedule during parent study- he/she will 
remain on this schedule for the first 52 weeks of treatment (including the time on 
parent study). After 52 weeks the frequency of the visits may/can be reduced to every 
8 or 9 weeks. If the subject was on 4-week schedule on the parent study he/she will 
remain on this schedule for the first 52 weeks (including time on parent study). After 
52 weeks the frequency of visits can be decreased to every 8 weeks with approval of 
Novartis Medical 
Lead.
Section: Appendix 3:  Liver Safety Drug Restart Guidelines
REVISED TEXT
2
Novartis Medical 
Lead & Clinical Safety Physician. to review the 
subject’s restart/rechallenge risk factors & complete checklist (Table 10)
3
If 
Novartis provides written approval for restart/rechallenge following the above 
review, the Principal Investigator (PI) must ensure the following:

The drug must be reinitiated at 
Novartis approved dose(s). 

Subjects approved by 
Novartis for restart of IP must return to the clinic 
twice a week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. If 
protocol defined stopping criteria for liver chemistry elevations are met, study 
drug must be stopped. 

Novartis is to be notified of any adverse events, as per Section 5.9.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
2010N109478_03 
GSK PKB115131 / NCT01531894
1
Division: Worldwide Development
Retention Category: GRS019
Information Type:  Clinical Pharmacology Reporting and Analysis Plan
Title:
Clinical Pharmacology Reporting and Analysis Plan for 
PKB115131: An Open Label Continuation Study of the Oral 
AKT Inhibitor GSK2110183 in Subjects with Solid Tumors and 
Hematologic Malignancies
Compound Number:
GSK2110183
Effective Date:
[27-NOV-2017]
Description: 
The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses 
and output to be included in the Clinical Pharmacology Study Report for Protocol 
PKB115131 (CASB183X2X01B).  This RAP is intended to describe the safety analyses 
required for the study.  This document will be provided to the study team members to 
convey the content of the Statistical Analysis Complete (SAC) deliverable.
Identifier/Version Number: 2010N109478_03
Subject:  Afuresertib, GSK2110183, AKT inhibitor, hematologic malignancy, solid 
tumor, safety
Author’s Name and Functional Area: 
Novartis
Approved by:
DD-MMM-YY
 
DD-MMM-YY
Copyright 2013 the GlaxoSmithKline group of companies.  All rights reserved. 
Unauthorised copying or use of this information is prohibited.


CONFIDENTIAL 
2010N109478_03
GSK PKB115131
2
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION ......................................................................................................6
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S)..............................................................6
2.1.
Study Objectives.............................................................................................6
2.1.1.
Primary Objective ............................................................................6
2.1.2.
Secondary objective..........................................................................6
2.2.
Study Endpoints..............................................................................................6
2.2.1.
Primary Endpoints............................................................................6
3.
STUDY DESIGN .......................................................................................................7
4.
PLANNED ANALYSES.............................................................................................8
4.1.
Interim Analyses.............................................................................................8
4.2.
Final Analyses ................................................................................................8
5.
ANALYSIS POPULATIONS ......................................................................................8
6.
HYPOTHESES AND TREATMENT COMPARISONS..................................................8
7.
TREATMENT DESCRIPTIONS FOR DATA DISPLAYS..............................................8
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING ...............8
8.1.
Reporting Conventions ....................................................................................9
8.2.
Premature Withdrawal and Missing Data ...........................................................9
8.3.
Baseline Definition..........................................................................................9
8.4.
Derived and Transformed Data .......................................................................10
8.4.1.
Change from Baseline.....................................................................10
8.4.2.
Study Day .....................................................................................10
9.
STUDY POPULATION............................................................................................10
9.1.
Disposition of Subjects ..................................................................................10
9.2.
Eligibility and Protocol Violation....................................................................10
9.3.
Demography and Baseline Disease Assessment ................................................10
9.4.
Concomitant Medications...............................................................................10
9.5.
Medical History and Family History................................................................11
9.6.
Information from Parent Study........................................................................11
10. SAFETY ANALYSES ..............................................................................................11
10.1.
Study Compliance and Extent of Exposure.......................................................11
10.2.
Adverse Event ..............................................................................................11
10.3.
Death...........................................................................................................12
10.4.
Clinical Laboratory Assessments.....................................................................12
10.5.
Electrocardiograms........................................................................................12
10.6.
Vital Signs ...................................................................................................12
10.7.
Disease Assessments .....................................................................................12
10.8.
Other Safety Data..........................................................................................12


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
3
10.8.1.
ECHO/MUGA Scans......................................................................12
10.8.2.
Performance Status.........................................................................13
10.8.3.
Pregnancy .....................................................................................13
11. REFERENCES.........................................................................................................14
12. ATTACHMENTS.....................................................................................................15
Table of Contents for Data Display Specifications ........................................................15
12.1.1.
Study Population............................................................................15
12.1.2.
Safety Tables.................................................................................16
12.1.3.
ICH Listings..................................................................................17
12.1.4.
In-text Tables.................................................................................18
LIST OF FIGURES
Figure 1 - Study Design....................................................................................................................7


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
4
LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
BP
Blood pressure
BPM
Beat Per Minute
BUN
Blood urea nitrogen
CRF
Case Report Form
CBC
Complete blood count
CPSR
Clinical Pharmacology Study Report
DBP
Diastolic blood pressure
DDS
Drug Development Sciences
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
GBMD
Global Brand Medical Director
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HR
Heart rate
IB
Investigator’s Brochure
ICH
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
Kg
Kilogram
L
Liter
LVEF
Left Ventricular Ejection Fraction
μg
Microgram
μL
Microliter
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
msec
Milliseconds
MTD
Maximum Tolerated Dose
MUGA
Multi Gated Acquisition Scan
NCI-CTCAE
National Cancer Institute-Common Toxicity Criteria for Adverse Events
PCI
Potential Clinical Importance Range
PD
Pharmacodynamic
PK
Pharmacokinetic
PT
Preferred Term
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
5
RAP
Reporting and Analysis Plan
RBC
Red blood cells
SAE
Serious adverse event(s)
SD
Standard deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
SOC
System Organ Class
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
WBC
White blood cells
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of 
companies
NONE
SAS


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
6
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Pharmacology Study Report for Protocol PKB115131:
Revision Chronology:
Document Number
Date
Version
2010N109478_00
2011-APR-29
Original
2010N109478_01
2011-JUN-24
Original-Republished
2010N109478_02
2011-NOV-10
Amendment 01
2010N109478_03
2014-SEP-30
Amendment 02
2014-002041-22
2016-MAR-31
Amendment 03 (Version 4.0)
All decisions regarding final analysis, as defined in this RAP document, will be made 
prior to Database Freeze of the study data.
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S)
2.1.
Study Objectives
2.1.1.
Primary Objective

To provide treatment with afuresertib for subjects who have previously participated 
in an afuresertib study sponsored by GSK or another research organization working 
on behalf of GSK.
2.1.2.
Secondary objective

To collect safety data on continued treatment with afuresertib.
2.2.
Study Endpoints
2.2.1.
Primary Endpoints

Adverse Events


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
7
3.
STUDY DESIGN
This multicenter, non-randomized, open-label, rollover study is designed to provide 
continued access to afuresertib to subjects who have previously participated in an 
afuresertib study.  Approximately 200 subjects from approximately 60 investigative 
sites worldwide will be transitioned to this study from other afuresertib studies. 
Subjects may enroll into Cohorts A and B based on the duration of treatment on a 
monotherapy in their parent study. Cohort C will enroll subjects who have participated in 
a combination study where afuresertib is given with an approved anti-cancer agent(s). 
The purpose of having separate cohorts is to be able to better report and define the safety 
profile for these treatment groups.
The dose of study treatment to be administered to subjects will be individualized based 
upon the dose/regimen received during their participation in the parent study at the time 
of transition to this rollover study.  No dose of afuresertib above the maximumn 
tolerated dose (MTD) established in the parent study will be allowed in this study. In 
Cohorts A and B, subjects will receive afuresertib as an oral, daily dose up to 150 mg. In 
Cohort C, subjects who transition from a combination study may continue to receive 
afuresertib in combination with the approved anti-cancer agent defined by the parent 
study, or they may receive afuresertib as monotherapy.
The study will consist of a transition visit, continuous dosing treatment period and a final 
study visit, see the following figure for study design.
Figure 1 - Study Design
Safety assessments will be performed throughout the study: including physical 
examinations, vital sign measurements (blood pressure (BP), pulse rate, weight and 


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
8
temperature), 12-lead electrocardiograms (ECGs), echocardiograms (ECHOs) or 
multiple-gated acquisition (MUGA) scans, clinical laboratory assessments and 
monitoring of adverse events (AEs).  Disease assessments must be performed at least 
every 12 weeks or more frequently if the investigator decides that it is necessary.
Subjects may continue treatment in this rollover study until disease progression, 
unacceptable toxicity or withdrawal of consent occurs, or death. Study will be completed 
when the last subject has withdrawn from study treatment.
4.
PLANNED ANALYSES
4.1.
Interim Analyses
No formal interim analyses are planned.
4.2.
Final Analyses
The final planned analyses will be performed after all subjects have completed the study. 
See Sections 9 and 10 for all final planned analyses for this study. Given the low priority 
of this study and low enrolment of subjects, a short close-out CSR will be produced for 
the final analyses.
5.
ANALYSIS POPULATIONS
All Treated Subjects Population:
The All Treated Subjects Population will consist of all subjects who receive at least one 
dose of afuresertib in this rollover study.  Safety data will be evaluated based on this 
population if not otherwise stated.
6.
HYPOTHESES AND TREATMENT COMPARISONS
No statistical hypotheses are being tested. Only descriptive methods will be used in 
analysis and summary of the data obtained from this study.
7.
TREATMENT DESCRIPTIONS FOR DATA DISPLAYS
Given the low enrolment of subjects, summary of data will not be displayed by cohorts. 
All subjects will be used for summary of data.
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
AND HANDLING
Unless otherwise stated, continuous variables will be summarized with the statistics mean, 
median, standard deviation (SD), minimum and maximum.  The mean and median will 
be presented to one decimal place beyond the precision with which the data were 
captured.  The SD will be presented to two decimal places beyond the precision with 


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
9
which the data were captured.  The minimum and maximum will be presented to the 
precision with which the data were captured.
Categorical variables will be summarized with frequency counts and percentages.  A 
percentage will not be presented when the corresponding count is zero in order to draw 
attention to the non-zero counts.
8.1.
Reporting Conventions

All data, including unscheduled assessments, will be listed by subject.

Summaries will include data from scheduled assessments only.  Unscheduled 
data will be included in “overall” and “any post-screening” summaries which will 
capture a worst  case across all scheduled and unscheduled visits post first dose 
of study treatment(s)

Clinical laboratory, Vital signs, will be reported according to the nominal visit 
date for which it was recorded (i.e., no visit windows will be applied).

If multiple assessments at any given time point (baseline or any post-baseline) 
exist, the most recent assessment within the assessment window for that time 
point will be used.

AEs and concomitant medications terms will be coded using the Medical 
dictionary for Regulatory Activities (MedDRA) dictionary version 19.0 or later 
and an internal validated medication dictionary, GSK Drug.

Missing data will not be imputed.

Reporting and analyses are performed using the SAS/STAT® module of the SAS 
System, Version 9.2 or higher.

 standard reporting template will be used.
8.2.
Premature Withdrawal and Missing Data
All subjects who withdraw prematurely from the study/study drug will be documented 
and the reason for their withdrawal recorded in the final Clinical Pharmacology Study 
Report (CPSR).  All available data from subjects who withdraw will be listed and all 
available planned data will be included in the summaries according to the populations 
defined in Section 5.
8.3.
Baseline Definition
Baseline is defined as the last non-missing observed value before the first dose, which is 
generally the assessment performed on the day of transition visit.


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
10
8.4.
Derived and Transformed Data
8.4.1.
Change from Baseline
The results of any specified study assessments performed on the day of the Transition 
Visit will serve as the baseline value for said assessment.  The change from baseline will 
be calculated by subtracting the baseline values from the individual post-Transition Visit 
values.  If either the baseline or post-Transition Visit value is missing, the change from 
baseline is set to missing as well. 
8.4.2.
Study Day
Actual study day will be calculated using the first dose date (in continuous dosing 
treatment period after transition visit) as the reference date. In relevant datasets, if the 
date of assessment is not missing and the reference date is not missing then study day will 
be calculated as (date of assessment – reference date + 1) if the date of assessment is 
greater than or equal to the reference date, otherwise it is equal to (date of assessment –
reference date).
9.
STUDY POPULATION
All tables will use the “All Treated Subjects Population” unless otherwise specified.
9.1.
Disposition of Subjects
The subject disposition, reasons for study treatment discontinuation and reasons for end 
of study will be listed and summarized.
9.2.
Eligibility and Protocol Violation
As a short close-out CSR will be produced, data will not be listed or summarized.
9.3.
Demography and Baseline Disease Assessment
Demographic characteristics consisting of age, sex, race, ethnicity, weight, height and 
body mass index (BMI) will be listed and summarized descriptively for total subjects.
As a short close-out CSR will be produced, baseline disease characteristics will not be 
summarized or listed.
9.4.
Concomitant Medications
A listing of prior and concomitant medications will be presented. Prior medications are 
defined as medications with a stop date occurring before the first dose date (in continuous 
dosing treatment period after transition visit). Concomitant medications are defined as 


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
11
medications with a stop date occurring on or after the first dose date.   Medications with 
start and stop dates which bracket the first dose date will be classified as both prior and 
concomitant medications.
9.5.
Medical History and Family History
All relevant medical histories will be presented in listing. Family histories will not be 
listed or summarized. 
9.6.
Information from Parent Study
A listing presenting subject-related data from parent study, including parent study 
protocol number, previous subject number assigned in parent study, treatment start and 
stop date of the parent study at time of transition to this study will be provided.
10.
SAFETY ANALYSES
10.1.
Study Compliance and Extent of Exposure
Duration of therapy, total amount of study drug taken and average daily dose (afuresertib) 
will be summarized. Details of dosing diary, including dosage volume, treatment start 
and stop date, treatment interruptions or dose reductions or dose escalations, for both 
afuresertib and other anti-cancer agents (in case of Cohort C) will be presented in listing. 
Duration of therapy (day) = date of last study medication dose – date of first study 
medication dose + 1.
As a short close-out CSR will be produced, drug accountability data will not be listed or 
summarized.
10.2.
Adverse Event
Adverse events (AEs) will be coded using MedDRA and grouped by system organ class 
and will be graded by the investigator according to the NCI-CTCAE (version 4.0 or later).
On treatment AEs is defined as any AEs collected from the time of first dose of study 
treatment until 30 days after last study treatment dose. AE summaries will include all on-
treatment AEs.
Listing of all AEs, along with SAEs and AEs leading to permanent discontinuation of 
study treatment will be provided. AEs with start date outside of on-treatment period will 
be flagged in the listings.
Events will be summarized by maximum NCI-CTCAE grade and proportion of total 
subjects, by SOC and preferred term.  At each level of summarization, a subject will be 
counted only once for each AE he/she experiences within that level.  Only the maximum
grade at each level will be summarized when summarizing by grade. 


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
12
Separate summaries will be given for all AEs, drug-related AEs, serious AEs, non-serious 
AEs and AEs leading to study treatment discontinuation.
AEs leading to death and on-treatment Drug Related SAEs leading to death will be 
summarized by proportion of total subjects, by SOC and preferred term.
The complete list of outputs for AE is available in section 12.
10.3.
Death
On-treatment death is defined as deaths occurred from the time of first dose of study 
treatment until 30 days after last study treatment dose. On-treatment death will be 
summarized by preferred term. Summary for all deaths will be produced by SOC and 
preferred term. All death will be listed. 
Summary for on-treatment deaths and SAEs by SOC and preferred term will be produced 
in a separate table.
10.4.
Clinical Laboratory Assessments
All haematology and clinical chemistry laboratory data will be listed for each subject and 
flagged high (H) or low (L) relative to their normal ranges where applicable. 
10.5.
Electrocardiograms
Results for all ECG parameters (PR, QRS, QT, and QTc intervals, RR and Heart Rate 
(HR)) and overall interpretation will not be summarized but listed.
10.6.
Vital Signs
As a short close-out CSR will be produced, data will not be listed or summarized.
10.7.
Disease Assessments
Disease assessments will be performed at regular intervals, at least every 12 weeks per 
local standard practice using criteria appropriate for the disease type and location. Results 
and disease response evaluation will not be summarized but listed. 
10.8.
Other Safety Data
10.8.1.
ECHO/MUGA Scans
As a short close-out CSR will be produced, data will not be listed or summarized. 


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
13
10.8.2.
Performance Status
The performance status (0-5) assessment is based on the Eastern Cooperative Oncology 
Group (ECOG) scale. Data will not be summarized but listed.
10.8.3.
Pregnancy
As a short close-out CSR will be produced, data will not be listed or summarized.


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
14
11.
REFERENCES
Blade J, Samson, D, Reece D, et al. Criteria for evaluating disease response and 
progression in patients with multiple myeloma treated by high-dose therapy and 
haemopoietic stem cell transplantation. Br J Hematol. 1998;102:1115-1123.
Cheson BD, Bennett, JM, Kopecky, KJ, et al. Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia. J Clin Oncol. 2003;21 (24):4642-9.
Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for Malignant 
Lymphoma. J Clin Oncol. 2007;25 (5):579-586. 
Durie BGM, Harousseau J-L, Miguel JS, Blade J, Barlogie B, Anderson K, et al. 
International uniform response criteria for multiple myeloma. Leukemia 2006:20(12), 
1467-73.
GlaxoSmithKline Document Number RM2008/00788/05 Amendment 5. 
GlaxoSmithKline protocol PKB112835, A Phase I, Open-Label, Two-Stage Study to 
Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the 
Oral AKT Inhibitor  GSK2110183 in Subjects with Any Hematologic Malignancy. 
Effective Date: 16-Feb-2010.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, et al. Guidelines for 
the diagnosis and treatment of chronic lymphocytic leukemia: a report from the 
InternationalWorkshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute–Working Group 1996 guidelines. Blood, 2008;111:5446-56.
NCI Common Terminology Criteria for Adverse Events, Version 4, DCTD, NCI, NIH, 
DHHS, 28 May 2009.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. American Journal of Clinical Oncology. 1982;5:649-655.
Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the 
uniform reporting of clinical trials: Report of the International Myeloma Workshop 
Consensus Panel 1. Blood. 2011;117:4691-4695.


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
15
12.
ATTACHMENTS
TABLE OF CONTENTS FOR DATA DISPLAY SPECIFICATIONS
12.1.1.
Study Population
Table No.
Population
Title
14.1-1.1
All Treated
Disposition
14.1-3.1
All Treated
Demographics


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
16
12.1.2.
Safety Tables
Table No.
Population
Title
14.3-1.1
All Treated
Drug Exposure - Afuresertib
14.3.1-1.1
All Treated
Summary of Adverse Events by System Organ Class, Preferred Term and 
Maximum Grade
14.3.1-1.2
All Treated
Summary of Drug Related Adverse Events by Preferred Term and 
Maximum Grade
14.3.1-1.3
All Treated 
Summary of Serious Adverse Events by System Organ Class, Preferred 
Term and Maximum Grade
14.3.1-1.4
All Treated
Summary of Adverse Events Leading to Study Treatment Discontinuation 
by Preferred Term and Maximum Grade
14.3.1-1.5
All Treated
Summary of non-Serious Adverse Events by System Organ Class and  
Preferred Term 
14.3.1-1.6
All Treated
On-Treatment Deaths and Serious Adverse Events by System Organ Class 
and  Preferred Term 
14.3.1-1.7
All Treated
On-Treatment Deaths by Preferred Term
14.3.1-1.8
All Treated
All Deaths by System Organ Class and Preferred Term


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
17
12.1.3.
ICH Listings
Listing No.
Population
Title
L14.3.2-1.1
All Treated
Listing of Death
L14.3.2-1.2
All Treated
All Adverse Events
L14.3.2-1.3
All Treated
All Serious Adverse Events
L14.3.2-1.4
All Treated
Adverse Events Leading to Permanent Discontinuation of Study Treatment
L14.3.4-1.1
All Treated
Haematology
L14.3.4-1.2
All Treated
Chemistry
L16.2.1-1.1
All Treated
Disposition
L16.2.4-1.1
All Treated
Demographics
L16.2.4-1.2
All Treated
Medical Conditions
L16.2.4-1.3
All Treated
Subject Related Information from Parent Study
L16.2.4-1.4
All Treated
Prior and Concomitant Medications
L16.2.5-1.1
All Treated
Study Treatment Administration – Afuresertib
L16.2.5-1.2
All Treated
Study Treatment Administration – Non-Afuresertib
L16.2.6-1.1
All Treated
Disease Response Evaluation
L16.2.9-1.1
All Treated
ECG Values
L16.2.9-1.2
All Treated
ECOG Performance Status


CONFIDENTIAL                                     2010N109478_03
GSK PKB115131
18
12.1.4.
In-text Tables
Table No.
Population
Title
10.1
All Treated
Disposition
11.1
All Treated
Demographics
12.1
All Treated
Drug Exposure - Afuresertib
12.2
All Treated
Summary of Adverse Events by Preferred Term and Maximum Grade
12.3
All Treated
Summary of Adverse Events by System Organ Class and Maximum Grade
12.4
All Treated
Summary of Drug Related Adverse Events by Preferred Term and 
Maximum Grade
12.5
All Treated
Summary of Serious Adverse Events by Preferred Term and Maximum 
Grade
12.6
All Treated
Summary of Adverse Events Leading to Study Treatment Discontinuation 
by Preferred Term and Maximum Grade
12.7
All Treated
On-Treatment Deaths by Preferred Term