Conditions: Advanced or Metastatic Breast Cancer ER+ve Advanced or Metastatic Breast Cancer
Keywords: advanced breast cancer, metastatic breast cancer, ER+ve breast cancer, Estrogen receptor positive breast cancer, PIK3CA mutated advanced or metastatic breast cancer AKT inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 148
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate the safety and efficacy of different doses and schedules of AZD5363, when in combination with paclitaxel, in treatment of patients with advanced or metastatic breast cancer. Also to investigate a selected dose and schedule of AZD5363 in combination with paclitaxel vs. paclitaxel in combination with placebo in treatment of patients with estrogen receptor-positive advanced or metastatic breast cancer, including a subgroup who have the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) tumour mutation.

Detailed description:
This is a Phase I/II multicentre, study investigating the safety, tolerability and efficacy of a twice-daily oral formulation of AZD5363 when combined with a weekly intravenous paclitaxel infusion in patients with advanced or metastatic breast cancer. Study treatment is given in 28-day cycles, comprising three weeks on-therapy followed by one week off-therapy.

The study will be conducted in two parts:

Part A. Approximately 40 patients will be recruited to this Phase I multiple ascending-dose safety run-in evaluation of each of two intermittent dosing schedules (2 days per week or 4 days per week) of AZD5363 given in combination with weekly paclitaxel. The study population is female patients, 18 years or older, with advanced or metastatic breast cancer.

The purpose of Part A is to assess the comparative safety, tolerability, pharmacokinetics and preliminary efficacy of both schedules to determine one dose and schedule of AZD5363 to take forward to study Part B in combination with weekly paclitaxel.

Part A assessments will be made in dose-escalating cohorts of 3 to 6 patients to determine a recommended dose in each of the schedules. A total of 6 patients must be evaluated at a selected dose level for it to be confirmed as the recommended dose. All dose evaluations and recommendations will be conducted by a Safety Review Committee.

Part A Patients will undergo assessments up to to withdrawal from the study or to discontinuation of study therapy.

Part B. A minimum of 100 patients will be recruited to this Phase II double-blind, placebo-controlled, stratified and randomised evaluation of two treatment regimens: AZD5363 (at a dose selected and schedule from Part A) in combination with weekly paclitaxel vs. weekly paclitaxel plus placebo. The study population is female patients with Estrogen Receptor Positive advanced or metastatic breast cancer; of which approximately 50 will have the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) mutation.

Part B patients will be stratified by PIK3CA tumour mutation status as: tumour mutation positive or tumour mutation not-detected. Under each stratum patients will be randomised to receive either paclitaxel + AZD5363 or paclitaxel + placebo.

The purpose of Part B is to assess relative efficacy of both active and placebo regimens by comparison of: progression-free survival, overall survival, tumour response, safety and tolerability in the overall ER+ve advanced or metastatic breast cancer population, and in a subgroup of these patients with the PIK3CA tumour mutation. Patient safety and therapy tolerability will be monitored by an independent Safety Review Committee throuighout the course of Part B.

Part B patients will be followed for assessment of overall survival, or to withdrawal from the study.

Arms:
arm 1: See intervention description below. arm 2: See intervention description below. arm 3: See intervention description below. arm 4: See intervention description below.

Interventions: intervention 1: AZD5363 when combined with weekly paclitaxel. intervention 2: AZD5363 when combined with weekly paclitaxel. intervention 3: AZD5363when combined with weekly paclitaxel. intervention 4: A placebo in combination with weekly paclitaxel.
Intervention descriptions: intervention 1: AZD5363: oral capsule, twice daily in a weekly 2 days on-treatment, 5 days-off, schedule. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles. intervention 2: AZD5363: oral capsule, twice daily in a weekly 4 days on-treatment, 3 days-off, schedule. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles. intervention 3: Either a 2/5 or 3/4 intermittent dosing schedule of AZD5363 based on the outcome of Part A. Dosage: oral formulation, twice daily. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles. intervention 4: Either a 2/5 or 3/4 intermittent dosing schedule of placebo matched to AZD5363 based on the outcome of Part A. Dosage: oral formulation, twice daily. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. placebo and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.

Protocol document:
Prot_002.pdf: 
 
 
 
Clinical Study Protocol 
 
Drug Substance 
AZD5363 
 
Study Code 
D3610C00002 
 
Edition Number 
1 
 
Date 
24 February 2012 
 
 
 
 
 
 
 
A Phase I/Ib, Multicentre, Study Comprising a Safety Run-In of AZD5363 
when Combined with Paclitaxel in Patients with Advanced or Metastatic 
Breast Cancer; Followed by a Randomised Expansion of AZD5363 when 
Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-
Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA 
Mutation Status (BEECH). 
 
 
Sponsor: 
 
 
The following Amendment(s) and Administrative Changes have been made to this protocol since the date 
of preparation: 
Amendment No. 
 Date of Amendment 
 
Local Amendment 
No: 
 
Date of Local 
Amendment 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
Administrative 
Change No. 
 Date of Administrative 
Change 
 
Local Administrative 
Change No. 
 
Date of Local 
Administrative Change 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
 
 


Clinical Study Protocol Synopsis 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
2(131) 
PROTOCOL SYNOPSIS 
 
A Phase I/Ib, Multicentre, Study Comprising a Safety Run-In of AZD5363 
when Combined with Paclitaxel in Patients with Advanced or Metastatic 
Breast Cancer; Followed by a Randomised Expansion of AZD5363 when 
Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-
Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA 
Mutation Status (BEECH). 
 
 
International Co-ordinating Investigator  
Dr Nicholas Turner 
The Royal Marsden Hospital 
Fulham Road 
London 
SW3 6JJ 
UK 
 
Study centre(s) and number of patients planned 
Number of patients planned (enrolled): 
Safety Run-in. n= 40 
Randomised Expansion. n= 70 
Total number of study centres planned = 12 
Number of patients to be recruited per site: 
Maximum – not defined 
Minimum: n= 2 
Study period 
 
Phase of development 
Estimated date of first patient enrolled 
Q2 2012 
I 
Estimated date of last patient completed 
Q4 2014 
Ib 


Clinical Study Protocol Synopsis 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
3(131) 
Objectives 
Primary objectives. 
Part A. Safety run-in:  
To assess the safety and tolerability of two schedules of AZD5363 (continuous and 
intermittent dosing) when combined with weekly paclitaxel in patients with advanced or 
metastatic breast cancer; and to recommend, by assessment of dose limiting toxicities and 
other safety, tolerability, pharmacokinetic and pharmacodynamic data, a dose and schedule of 
AZD5363 for further study when combined with weekly paclitaxel. 
Part B. Randomised expansion:  
To assess the relative anti-tumour activity of AZD5363 when combined with weekly 
paclitaxel vs. weekly paclitaxel plus placebo by comparison of change in tumour size at 12 
weeks (target lesion assessment using RECIST 1.1) in the overall advanced or metastatic 
Estrogen Receptor positive breast cancer population and in a Phosphoinositide 3-kinase 
(PIK3CA) mutation-positive sub-population. 
Secondary objectives (summarised) 
Part A. Safety run-in: 
To make a preliminary assessment of the anti-tumour activity of AZD5363 when combined 
with paclitaxel.  
Part B. Randomised expansion: 
x
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel 
compared with weekly paclitaxel plus placebo. 
x
To assess the safety and tolerability of AZD5363 when combined with weekly 
paclitaxel compared with weekly paclitaxel plus placebo.  
x
To investigate the effect on patients’ quality of life of AZD5363 when combined 
with weekly paclitaxel, compared with weekly paclitaxel plus placebo. 
Parts A and B: 
x
To assess the pharmacokinetics of AZD5363 when combined with paclitaxel. 
x
To assess the pharmacokinetics of paclitaxel alone and when combined with 
AZD5363. 
x
To assess the pharmacokinetic/pharmacodynamic relationship between AZD5363 
exposure and biomarkers in blood and anti-tumour activity. 


Clinical Study Protocol Synopsis 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
4(131) 
Study design 
This international, multicentre, study of AZD5363 when combined with paclitaxel vs 
paclitaxel plus placebo will be conducted in two parts:   
Part A: Safety Run-in.   
An open-label run-in to assess the comparative safety, tolerability pharmacokinetics and 
pharmacodynamics of ascending doses of AZD5363 in two schedules (continuous and 
intermittent dosing) when combined with weekly paclitaxel; and to make a preliminary 
assessment of the anti-tumour activity of the combination. 
The primary output of Part A will be a recommended dose and schedule of AZD5363 when 
combined with paclitaxel for conduct of the study Part B randomised expansion phase.    
AZD5363 and paclitaxel will be given in the dosing schedules detailed below.  Cohorts of 3 to 
6 patients will be evaluated in escalating doses of AZD5363 to determine a recommended 
dose and, where applicable, a maximum tolerated dose for each schedule. 
Patient assessments will continue up to cessation of both AZD5363 and paclitaxel or 
withdrawal of consent or death.  A 28-day safety follow-up assessment should be conducted 
following cessation of all study therapy (AZD5363 and paclitaxel). 
Part A: Safety run-in - Subsidiary Japanese patient evaluation (optional) 
A subsidiary dose-escalating safety evaluation may optionally be conducted in a 
Japanese patient population at a starting dose, and under one schedule, determined by 
the Safety Review Committee.  This evaluation would be conducted to determine a 
safe and tolerable dose of AZD5363 when combined with weekly paclitaxel in a 
Japanese population. 
This separate Japanese safety run-in evaluation would commence following 
determination of the RD and dosing schedule in the Western population.  It would 
proceed in parallel with the Part B randomised expansion, but would not inform any 
decision regarding the conduct of Part B.  The schedule of assessments in the 
subsidiary Part A would be as detailed in this protocol for Part A.  It is not envisaged 
that a Japanese population would be evaluated under study Part B. 
Part B: Randomised Expansion 
A randomised double-blind assessment of the safety, tolerability, pharmacokinetics, 
pharmacodynamics and anti-tumour activity of the dose and schedule of AZD5363 selected 
from Part A when combined with weekly paclitaxel - versus weekly paclitaxel plus placebo 
matched to AZD5363.  
AZD5363/placebo and paclitaxel will be given in either the continuous or intermittent dosing 
schedule detailed below.   
Patients will be assessed at screening for presence/absence of PIK3CA tumour mutations and 
will be stratified in to PIK3CA mutation-positive and PIK3CA mutation-not detected arms. 
Within each stratum, patients will be randomised to receive either paclitaxel plus AZD5363 or 
paclitaxel plus placebo.   




Clinical Study Protocol Synopsis 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
6(131) 
Target patient population 
Part A. Safety run-in: Female patients, 18 years or older, with advanced or metastatic breast 
cancer. 
Part B. Randomised expansion:  Female patients, 18 years or older, with ER+ve advanced or 
metastatic breast cancer.  For inclusion in Part B, patients must not have received any prior 
chemotherapy in the advanced or metastatic settings.  
Investigational product, dosage and mode of administration 
AZD5363: A twice daily regimen of an oral capsule formulation given on a continuous or 
intermittent weekly dosing schedule.  Administration of AZD5363 will commence in Part A 
as detailed in section 5.5.3: 
x
Continuous dosing: 320 mg bd (640 mg daily) throughout a patient’s participation 
in the study. 
x
Intermittent dosing (4 days of treatment followed by 3 days off-treatment): 360 mg 
bd (720 mg daily) each week that paclitaxel is received, and then each week 
following cessation of paclitaxel throughout a patient’s participation in the study. 
Placebo (Part B only): Oral capsule formulation, matched to AZD5363. 
Comparator, dosage and mode of administration 
Paclitaxel: A weekly single intravenous infusion of 90 mg/m2 given over approximately one 
hour.  A 28-day treatment cycle to comprise three consecutive weeks of treatment, followed 
by one week off-treatment. 
Duration of treatment 
Patients may receive study treatment, AZD5363/placebo and/or paclitaxel, to objective 
disease progression or withdrawal from study participation.  It is anticipated that 
approximately 6 cycles of paclitaxel therapy will be given in the absence of disease 
progression or unacceptable toxicity; but further cycles can be continued at an investigator’s 
discretion based on the patient’s risk/benefit profile.   
Outcome variable(s):  
To meet the objectives for this study, data for the following endpoints will be collected: 
Parts A and B: 
x
Safety and Tolerability. 
x
Tumour response as assessed by RECIST 1.1. 
x
AZD5363 and paclitaxel pharmacokinetics. 






Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
9(131) 
TABLE OF CONTENTS 
PAGE
 
TITLE PAGE...........................................................................................................1 
PROTOCOL SYNOPSIS.........................................................................................2 
TABLE OF CONTENTS.........................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................16 
1. 
INTRODUCTION .................................................................................................20 
1.1 
Background............................................................................................................20 
1.1.1 
Investigational agent ..............................................................................................20 
1.1.2 
Non-clinical information and correlative studies...................................................20 
1.1.3 
Clinical information...............................................................................................21 
1.1.3.1 
Pharmacokinetics ...................................................................................................23 
1.2 
Research hypotheses ..............................................................................................23 
1.3 
Rationale for conducting this study .......................................................................23 
1.3.1 
Breast Cancer.........................................................................................................23 
1.3.2 
Rationale for AZD5363 in breast cancer. ..............................................................24 
1.3.3 
Rationale for evaluation of PIK3CA mutation sub-population. ............................26 
1.3.4 
Rationale for study design. ....................................................................................27 
1.3.5 
Rationale for Paclitaxel as combination therapy. ..................................................27 
1.4 
Benefit/risk and ethical assessment........................................................................28 
1.4.1 
Potential benefits....................................................................................................28 
1.4.2 
Potential risks identified from non-clinical toxicology studies with 
AZD5363 ...............................................................................................................28 
1.4.3 
Potential risks identified from early clinical studies with AZD5363: ...................31 
1.4.4 
Risk minimisation activities for potential risks identified in early clinical 
studies with AZD5363:..........................................................................................31 
1.4.5 
Overall benefit-risk and ethical assessment...........................................................32 
2. 
STUDY OBJECTIVES..........................................................................................32 
2.1 
Primary objective...................................................................................................32 
2.2 
Secondary objectives .............................................................................................33 
2.3 
Exploratory objectives ...........................................................................................33 
3. 
STUDY PLAN AND PROCEDURES ..................................................................34 
3.1 
Overall study design and flow chart ......................................................................34 
3.1.1 
Part A: Safety run-in ..............................................................................................34 
3.1.2 
Part B: Randomised expansion ..............................................................................36 
3.1.3 
Treatment Schedules..............................................................................................39 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
10(131) 
3.1.4 
Assessment Schedule.............................................................................................39 
4. 
PATIENT SELECTION CRITERIA.....................................................................47 
4.1 
Inclusion criteria ....................................................................................................47 
4.2 
Exclusion criteria ...................................................................................................49 
5. 
STUDY CONDUCT..............................................................................................52 
5.1 
Restrictions during the study .................................................................................52 
5.2 
Patient enrolment, randomisation and initiation of investigational product..........53 
5.2.1 
Procedure for identification of tumour PIK3CA mutation status and 
stratification. ..........................................................................................................55 
5.2.2 
Procedures for allocation and randomisation.........................................................56 
5.3 
Procedures for handling patients incorrectly enrolled or initiated on 
investigational product...........................................................................................57 
5.4 
Blinding and procedures for unblinding the study.................................................58 
5.4.1 
Methods for ensuring blinding...............................................................................58 
5.4.2 
Methods for unblinding the study..........................................................................58 
5.5 
Treatments..............................................................................................................58 
5.5.1 
Identity of investigational product(s).....................................................................58 
5.5.2 
Identity of combination product.............................................................................59 
5.5.3 
Doses and treatment regimens ...............................................................................59 
5.5.4 
Dose modifications ................................................................................................61 
5.5.5 
Safety Run-In: Starting dose and dose escalation scheme.....................................63 
5.5.6 
Randomised expansion: Selected Dose..................................................................63 
5.5.7 
Labelling ................................................................................................................63 
5.5.8 
Storage ...................................................................................................................64 
5.6 
Concomitant and post-study treatment(s) ..............................................................64 
5.6.1 
Use of metformin ...................................................................................................65 
5.6.2 
Prohibited medications...........................................................................................65 
5.7 
Treatment compliance............................................................................................65 
5.7.1 
Accountability........................................................................................................65 
5.8 
Discontinuation of investigational product............................................................66 
5.8.1 
Procedures for discontinuation of a patient from investigational product.............67 
5.9 
Withdrawal from study ..........................................................................................67 
5.9.1 
Screening failures...................................................................................................68 
5.10 
Conduct of Part A: Safety Run-in Phase................................................................68 
5.10.1 
Starting dose...........................................................................................................68 
5.10.2 
Safety Review Committee and Dose Escalation Process ......................................68 
5.10.3 
Criteria to conduct dose escalation and reduction .................................................70 
5.10.4 
Definition of maximum tolerated dose ..................................................................72 
5.10.5 
Definition of evaluable patient for Part A..............................................................72 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
11(131) 
5.10.6 
Definition of dose-limiting toxicity .......................................................................72 
6. 
COLLECTION OF STUDY VARIABLES...........................................................75 
6.1 
Recording of data...................................................................................................75 
6.2 
Data collection at enrolment and follow-up...........................................................75 
6.2.1 
Enrolment procedures ............................................................................................75 
6.2.2 
PIK3CA Mutation Status........................................................................................76 
6.2.3 
Follow-up procedures ............................................................................................76 
6.2.3.1 
Study Drug Discontinuation ..................................................................................77 
6.2.3.2 
28-Day Safety follow-up........................................................................................77 
6.2.3.3 
Progression follow-up............................................................................................77 
6.3 
Efficacy..................................................................................................................77 
6.3.1 
Tumour assessments ..............................................................................................77 
6.4 
Safety .....................................................................................................................78 
6.4.1 
Definition of adverse events ..................................................................................79 
6.4.2 
Definitions of serious adverse event......................................................................79 
6.4.3 
Recording of adverse events ..................................................................................79 
6.4.4 
Reporting of serious adverse events (SAEs)..........................................................83 
6.4.5 
Laboratory safety assessment ................................................................................83 
6.4.6 
Physical examination .............................................................................................86 
6.4.7 
Height and weight..................................................................................................86 
6.4.8 
WHO Performance status ......................................................................................87 
6.4.9 
Resting ECG ..........................................................................................................87 
6.4.10 
Muga scan / Echocardiogram.................................................................................88 
6.4.11 
Vital signs: Pulse and blood pressure ....................................................................88 
6.4.12 
Other safety assessments........................................................................................89 
6.4.12.1 Lipids .....................................................................................................................89 
6.4.12.2 Glycosylated haemoglobin.....................................................................................89 
6.4.12.3 Glucose, insulin and insulin c-peptide...................................................................89 
6.4.12.4 Patient meal information........................................................................................90 
6.5 
Patient reported outcomes (PRO) ..........................................................................90 
6.5.1 
Quality of Life: EORTC QLQ C-30 and BR-23 questionnaires (Part B: 
Randomised expansion only).................................................................................90 
6.5.2 
Administration of EORTC QLQ C-30 and BR-23 questionnaires ........................91 
6.6 
Pharmacokinetics ...................................................................................................92 
6.6.1 
Collection of samples.............................................................................................92 
6.6.2 
Pharmacokinetic sampling schedule......................................................................92 
6.6.3 
Determination of drug concentration.....................................................................94 
6.7 
Pharmacodynamics ................................................................................................95 
6.7.1 
Collection of pharmacodynamic markers ..............................................................95 
6.8 
Exploratory research ..............................................................................................95 
6.8.1 
Exploratory biomarker research.............................................................................95 
6.8.1.1 
Collection of circulating tumour cells....................................................................95 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
12(131) 
6.8.1.2 
Collection of archival tumour samples ..................................................................96 
6.8.1.3 
Collection of paired tumour biopsies (optional) ....................................................96 
6.8.1.4 
Collection of eyebrow hairs (optional) ..................................................................96 
6.8.1.5 
Collection of exploratory blood-borne biomarkers (optional)...............................96 
6.8.1.6 
Pharmacodynamic and exploratory biomarker sampling schedule........................97 
6.9 
Pharmacogenetics ..................................................................................................99 
6.9.1 
Collection of pharmacogenetic samples (optional)................................................99 
7. 
BIOLOGICAL SAMPLING PROCEDURES.......................................................99 
7.1 
Volume of blood ....................................................................................................99 
7.2 
Handling, storage and destruction of biological samples ....................................100 
7.2.1 
Pharmacokinetic and/or pharmacodynamic / biomarker samples .......................100 
7.2.2 
Pharmacogenetic samples ....................................................................................101 
7.3 
Labelling and shipment of biohazard samples.....................................................101 
7.4 
Chain of custody of biological samples...............................................................101 
7.5 
Withdrawal of informed consent for donated biological samples .......................102 
8. 
ETHICAL AND REGULATORY REQUIREMENTS.......................................102 
8.1 
Ethical conduct of the study.................................................................................102 
8.2 
Patient data protection..........................................................................................102 
8.3 
Ethics and regulatory review................................................................................103 
8.4 
Informed consent .................................................................................................104 
8.5 
Changes to the protocol and informed consent form...........................................104 
8.6 
Audits and inspections .........................................................................................105 
9. 
STUDY MANAGEMENT BY ASTRAZENECA..............................................105 
9.1 
Pre-study activities...............................................................................................105 
9.2 
Training of study site personnel...........................................................................105 
9.3 
Monitoring of the study .......................................................................................105 
9.3.1 
Source data...........................................................................................................106 
9.4 
Study agreements.................................................................................................106 
9.4.1 
Archiving of study documents.............................................................................106 
9.5 
Study timetable and end of study.........................................................................106 
10. 
DATA MANAGEMENT BY ASTRAZENECA ................................................107 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA.................................................................................................107 
11.1 
Calculation or derivation of efficacy variable(s) .................................................107 
11.1.1 
Change in tumour size at 12 weeks......................................................................108 
Missing Data Imputation Methods.......................................................................109 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
13(131) 
11.1.2 
Objective response rate (ORR) ............................................................................109 
11.1.3 
Duration of response (DoR).................................................................................109 
11.1.4 
Progression-free Survival (PFS) ..........................................................................109 
11.1.5 
Response rate at 12 weeks and best objective tumour response..........................110 
11.1.6 
Proportion of patients without progressive disease at 12 weeks..........................111 
11.2 
Calculation or derivation of safety variable(s).....................................................111 
11.2.1 
Other significant adverse events (OAE) ..............................................................111 
11.3 
Calculation or derivation of pharmacokinetic variables ......................................112 
11.4 
Calculation or derivation of pharmacodynamic variable(s).................................112 
11.4.1 
Population analysis of pharmacokinetic/pharmacodynamic variables ................112 
11.5 
Calculation or derivation of health related quality of life variables (Part B: 
Randomised expansion only)...............................................................................112 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
BY ASTRAZENECA ..........................................................................................116 
12.1 
Description of analysis sets..................................................................................116 
12.1.1 
Efficacy analysis set.............................................................................................116 
12.1.2 
Safety analysis set................................................................................................117 
12.2 
Methods of statistical analyses.............................................................................117 
12.2.1 
Change in tumour size at 12 weeks......................................................................118 
12.2.2 
Progression Free Survival....................................................................................119 
12.2.3 
Response rate at 12 weeks and best objective tumour response..........................120 
12.2.4 
Duration of response (DoR).................................................................................120 
12.2.5 
Safety ...................................................................................................................120 
12.2.6 
Pharmacokinetics .................................................................................................122 
12.2.7 
Pharmacodynamics and PK/PD relationships......................................................123 
12.2.8 
Health related quality of life (HR QoL) data (Part B only) .................................123 
12.2.9 
Exploratory biomarkers and pharmacogenetics...................................................124 
12.3 
Interim analyses ...................................................................................................124 
12.4 
Determination of sample size...............................................................................124 
12.5 
Data monitoring committee .................................................................................126 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................127 
13.1 
Medical emergencies and AstraZeneca contacts .................................................127 
13.2 
Overdose ..............................................................................................................127 
13.3 
Pregnancy.............................................................................................................128 
13.3.1 
Maternal exposure................................................................................................128 
14. 
LIST OF REFERENCES.....................................................................................129 
 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
14(131) 
LIST OF TABLES 
Table 1 
Dosage form and strength of investigational product...............................58 
Table 2:  
PK sampling schedule:  Safety Run-in Phase...........................................92 
Table 3:  
PK sampling schedule:  Randomised Expansion Phase...........................93 
Table 4:  
PD and exploratory biomarker sampling schedule:  Part A Safety 
Run-in Phase.............................................................................................97 
Table 5.  
PD and exploratory biomarker sampling schedule: Part B 
Expansion Phase.......................................................................................98 
Table 6 
Estimated Maximum volume of blood to be drawn per patient .............100 
Table 7 
Scoring the QLQ C30 version 3 .............................................................112 
Table 8 
Scoring BR-23........................................................................................113 
Table 9 
Categorisation of visit scores into visit responses..................................114 
Table 10 
Calculation of best overall response.......................................................115 
 
LIST OF FIGURES 
Figure 1 
AZD5363 sensitises HCC-1187 xengrafts to docetaxel (Taxotere) 
(A).............................................................................................................25 
Figure 2 
AZD5363 sensitises HCC-1187 xengrafts to docetaxel (Taxotere) 
(B).............................................................................................................26 
Figure 3 
Randomised Expansion: Stratification and Randomisation .....................37 
Figure 4 
Study Flow Chart......................................................................................38 
Figure 5 
Schedule 1: AZD5363/placebo – Continuous Dosing..............................40 
Figure 6 
Schedule 2: AZD5363/placebo – Intermittent Dosing. ............................43 
Figure 7 
Safety run-in dose escalation decision tree...............................................71 
 
LIST OF APPENDICES 
Appendix A 
Signatures 
Appendix B 
Additional Safety Information  
Appendix C 
IATA 6.2 Guidance document 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
15(131) 
Appendix D 
Pharmacogenetics Research 
Appendix E 
Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law 
Appendix F 
Guidelines for Evaluation of Objective Tumour Response using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumours) 
Appendix G 
Guidance Regarding Potential Interactions With Concomitant Medications 
Appendix H 
Instructions for study drug dose modifications   
Appendix I 
Quality of Life: EORTC QLQ C-30 and BR-23 questionnaires 
 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
16(131) 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
The following abbreviations and special terms are used in this study Clinical Study 
Protocol. 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event (see definition in Section 6.4.1) 
AGC kinase family 
cAMP dependent, cGMP dependent & protein kinase C 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AZ 
AstraZeneca 
bd 
’bis in die’: twice daily  
BOR 
Best Objective Response 
cAMP 
cyclic adenosine monophophate 
cfDNA 
circulating free plasma DNA 
cGMP 
cyclic guanosine monophophate 
CRF 
Case Report Form (electronic/paper, e/p) 
CR 
Complete Response 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTC 
Common Terminology Criteria 
CTCs 
Circulating Tumour Cells 
CTCAE 
Common Terminology Criteria for Adverse Event 
CV 
Coefficient of variation 
CYP 
cytochrome P450 enzyme 
DBP 
Diastolic Blood Pressure 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic acid  
DoR 
Duration of Response 
ECG 
Electrocardiogram 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
17(131) 
Abbreviation or 
special term 
Explanation 
EORTC 
European Organisation for the Research and Treatment of Cancer 
EORTC-QLQ 
European Organisation for the Research and Treatment of Cancer Quality 
of Life Questionnaire (EORTC QLQ-C30 is a core questionnaire) 
ER  
 
Estrogen Receptor 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GSK3ȕ 
Glycogen synthase kinase 
HDL 
High Density Lipoprotein 
HEOR 
Health Economic Outcomes Research 
HR 
Hazard Ratio 
IATA 
International Air Transport Association 
ICH 
International Conference on Harmonisation 
IP 
Investigational Product  
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LDL 
Low Density Lipoprotein 
LIMS 
Laboratory Information Management System 
LLOQ 
Lower Limit of Quantification 
LVEF 
Left ventricular ejection fraction 
MBC 
Metastatic Breast Cancer 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
mTOR 
mammalian Target Of Rapamycin 
MUGA scan 
Multi Gated Acquisition scan 
NQ 
Non-quantifiable 
NTD 
Non-Tolerated Dose 
NTL 
Non-Target Lesion 
NYHA 
New York Heart Association 
OAE 
Other Significant Adverse Event  
OCT2 
Organic Cation Transporter 2 
ORR 
Objective Response Rate 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
18(131) 
Abbreviation or 
special term 
Explanation 
OS 
Overall Survival 
PD 
Progression of Disease 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PFS 
Progression Free Survival 
PI3K 
Phosphoinositide 3-kinase 
PIK3CA 
Phosphoinositide-3-kinase, catalytic, alpha polypeptide 
PKA 
Protein kinase A 
PKB/AKT 
Protein kinase B 
PR 
Partial Response 
PR 
ECG interval measured from the beginning of the P wave to the beginning 
of the QRS complex 
PRAS40 
Proline-rich AKT substrate of 40 kDaltons 
PTEN 
Phosphatase and Tensin Homolog 
QoL 
Quality of Life 
QRS complex 
A name for the combination of three of the graphical deflections seen on a 
typical electrocardiogram (ECG) 
QT 
ECG interval measured from onset of the QRS complex to the end of the T 
wave 
QTc 
QT interval corrected for heart rate 
QTcB 
interval duration corrected for changes on heart rate using Bazett's formula 
QTcF 
interval duration corrected for changes on heart rate using Friderica’s 
formula 
QTcR 
QT interval duration corrected for changes on heart rate using an individual 
regression method 
QWBA 
Quantitative whole-body autoradiography 
RD 
Recommended Dose 
RECIST 1.1 
Response Evaluation Criteria In Solid Tumours, version 1.1 
ROCK 
Rho associated protein kinase 
RR 
Response rate 
R-R 
the interval between successive Rs, where R is a point corresponding to the 
peak of the QRS complex of the ECG wave 
SAE 
Serious adverse event (see definition in Section 6.4.2). 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
19(131) 
Abbreviation or 
special term 
Explanation 
SD 
Stable Disease 
SD 
Standard Deviation 
SRC 
Safety Review Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T4 
Thyroxine 
TL 
Target Lesion 
TSH 
Thyroid-Stimulating Hormone 
UGT 
Uridine 5’ diphospho-glycosyltransferase 
ULN 
Upper Limit of Normal 
WBDC 
Web Based Data Capture 
WHO 
World Health Organisation 
 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
20(131) 
1. 
INTRODUCTION 
1.1 
Background 
1.1.1 
Investigational agent 
AZD5363 is a potent, selective inhibitor of the kinase activity of the serine/threonine 
AKT/PKB (protein kinase B) that is being developed as a potential treatment for solid and 
haematological malignancies. 
AKT is part of the AGC family of kinases.  Mammalian cells express three closely related 
AKT isoforms: AKT1 (PKBĮ), AKT2 (PKBȕ) and AKT3 (PKBȖ), all encoded by different 
genes.  AKT is a node of multiple signalling pathways promoting tumorigenesis, inhibiting 
apoptosis, impacting on cell cycle and promoting invasion and migration. 
The Phosphoinositide 3-kinase (PI3K)/AKT/Phosphatase and Tension Homolog (PTEN) 
pathway is frequently deregulated in cancer and drives tumour growth and cell survival 
(Lindsley 2010).  All 3 AKT isoforms are activated in different tumour types including breast, 
prostate, ovarian, pancreatic and gastric cancers, and this activation is often associated with 
resistance to established cancer therapies as well as advanced disease and/or poor prognosis 
(Altomere and Testa 2005). AKT activation in tumours is largely due to input from other 
signalling pathways upstream of AKT (eg, mutation of oncogenes such as Ras, Bcr-abl, 
mutation of receptor tyrosine kinases such as EGFR, amplification of Her2, loss of PTEN 
function, mutations of PI3K). 
Inhibitors of AKT are anticipated to have efficacy when dosed when combined with cytotoxic 
chemotherapies or when combined with targeted or antihormonal agents.  AZD5363 inhibits 
all three AKT isoforms (AKT1, AKT2 and AKT3) and therefore has the potential to provide 
clinical benefit over a range of therapeutic indications. 
A significant relationship has been found in pre-clinical studies between the presence of a 
phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) mutation and sensitivity to 
monotherapy AZD5363 in a panel of 182 cancer cell lines (p = 0.0059; T test).  Mutations in 
PIK3CA are common in human breast cancer; 27% of breast cancers harbour PIK3CA 
mutations.  They are most common in Estrogen receptor–positive (ER+) breast tumours (35% 
have PIK3CA mutations).  However, the relationship between PIK3CA mutation and 
sensitivity to AZD5363 is not absolute; some PIK3CA mutation-negative cell lines are also 
sensitive to AZD5363. 
1.1.2 
Non-clinical information and correlative studies 
AZD5363 is a potent inhibitor of AKT 1, 2 and 3 in enzyme assays and inhibits the 
phosphorylation of AKT substrates in cells.  AZD5363 inhibits the proliferation of a range of 
cell lines derived from solid and haematological tumours.  Breast cancer cell lines appear to 
be the tumour types that show the greatest sensitivity to AZD5363.  AZD5363 shows dose 
dependent pharmacodynamic and antitumour activity in xenografts at well-tolerated doses, 




Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
22(131) 
populations with advanced solid malignancies, under two separate AZD5363 monotherapy 
dosing regimens:  
x
continuous dosing at 80 mg bd (n=8), 160 mg bd (n=5), 240 mg bd (n=12), 400 mg 
bd (n=8) and 600 mg (n=2) 
x
intermittent dosing (4 days on and 3 days off) at 480 mg bd (n=5) and 640 mg bd 
(n=6) 
The most commonly reported Adverse Events (AEs), regardless of dose or causality, to date 
are: diarrhoea, hyperglycaemia, fatigue, maculo-papular rash, vomiting, dyspnoea, and 
nausea.  The majority of AEs reported in patients receiving AZD5363 have been Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2 in toxicity. 
Common Terminology Criteria (CTC) Grades 3 and 4 adverse events have been associated 
with the use of AZD5363 in Study D3610C00001 as follows: 
x
diarrhoea: CTCAE grade 3 in the continuous dosing at 240 mg bd (n=1), 400 mg bd 
(n=1), 600 mg bd (n=1) and intermittent dosing (4 days on and 3 days off) at 640 
mg bd (n=2) 
x
hyperglycaemia (post AZD5363 dose), CTCAE grade 3 in the continuous dosing at 
240 mg bd (n=1), 400 mg bd (n=2) and intermittent dosing (4 days on and 3 days 
off) at 480 mg bd (n=1), 640 mg bd (n=4) 
x
maculo-papular rash: CTCAE grade 3 in the continuous dosing at 400 mg bd (n=1) 
and  CTCAE grade 4 in the continuous dosing at 600 mg bd (n=2) 
One dose-limiting toxicity (DLT) of CTCAE grade 3 hypoxia has been reported in a female 
patient with sarcoma with lung metastasis in study D3610C00004 under a continuous dosing 
schedule at a 240 mg bd dose.  
There has been a trend for an increase in plasma glucose levels approximately 2 hours after 
AZD5363 dosing (single and continuous dosing), generally returning to baseline levels within 
4 hours to 8 hours after AZD5363 dosing.  Plasma glucose elevations have been more 
pronounced in the higher dose levels. 
There have been no clinically significant findings identified on review of Electrocardiograms 
(ECGs) or left ventricular ejection fraction (LVEF) decreases attributed to AZD5363. 
One female patient with cervical carcinoma (PIK3CA mutation positive) with metastasis to 
the lymph nodes, receiving 400 mg bd in the continuous dosing regimen, had a confirmed 
partial response for 20 weeks prior to disease progression.  The patient had previously 
received adjuvant and first-line chemotherapy and radiation.  




Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
24(131) 
deaths from breast cancer has continued to rise in Europe (130,000 in 2004 vs 132,000 in 
2006) (Ferlay et al 2007).  In the US, breast cancer is the most common cancer in women with 
an incidence rate of 123.6 per 100,000 from 2001 to 2005.     
The treatment of breast cancer is determined by the extent of the disease and a variety of other 
prognostic factors, including hormone receptor status.  The most important factor determining 
response to hormonal manipulation is the presence of the ER in the target tissue (Fisher et al 
2001).  The choice of treatment sequence is complex and dependent on a number of factors, 
including prior endocrine treatments received.  Irrespective of the treatment sequence received 
a number of patients will experience disease progression, and therefore there remains a need 
to identify further treatment options for those patients who progress on or shortly after 
endocrine therapy. 
1.3.2 
Rationale for AZD5363 in breast cancer. 
AZD5363 has been shown to greatly increase sensitivity to the taxane docetaxel (Taxotere) in 
several breast cancer xenograft models.  For example, both continuous and intermittent 
schedules of AZD5363 enhanced the efficacy of docetaxel in the HCC-1187 xenograft () 
Figure 1).  The sequence of administration appears to be very important; in the HCC-1187 
model, administering docetaxel after an intermittent dosing schedule of AZD5363 (4 days on, 
3 days off) was found to be antagonistic, whilst administering docetaxel before the 
intermittent schedule resulted in enhanced efficacy (Figure 2) 






Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
27(131) 
The frequency of PIK3CA mutations in samples has been studied performing a mutational 
analysis of exons 9 (HD) and 20 (KD) of the PIK3CA gene using tumour deoxyribonucleic 
acid (DNA) obtained from patients with recurrent disease. Mutations in PIK3CA were 
identified in 24.5% of patients (11.3% in HD and 13.2% in KD). PIK3CA mutation was 
significantly correlated with lower tumour grade (47% in grade 1/2 vs 8% in grade 3, 
p=0.004), positive ER (35% in ER+ vs 5% in ER-, p=0.017), and PR (37% in PR+ vs 5% in 
PR-, p=0.011). Overall survival (OS) was 139.5 and 53.7 months for mutation and non-
mutation carriers respectively (p=0.014). (Ma et al 2009). 
Future treatment strategies may be aligned to the presence or absence of PIK3CA mutations. 
The presence of a PIK3CA mutation is correlated with sensitivity to monotherapy AKT 
inhibition (Courtney et al 2010) – and it is therefore considered appropriate to explore 
AZD5363 in this setting for patients in this population.  
1.3.4 
Rationale for study design. 
Pre-clinical data has shown that AZD5363 when given in combination with docetaxel is 
efficacious.  This study will test the hypothesis that this pre-clinical finding is applicable to 
paclitaxel in the clinical setting, utilising the following design: 
Part A. Safety run-in: to identify an appropriate and tolerable dose of AZD5363 and dosing 
schedule (continuous or intermittent), when in combination with weekly paclitaxel, to take 
forward to Part B.  
Part B. Randomised Expansion: to make an assessment of efficacy of the combination 
(paclitaxel plus AZD5363) against an active control (paclitaxel alone) in a specific target 
patient population (ER+ve breast cancer) and to explore whether additional efficacy is likely 
to be present in a PIK3CA mutation-positive sub-group for whom it is hypothesised that there 
will be greater sensitivity to AZD5363.  
1.3.5 
Rationale for Paclitaxel as combination therapy. 
Chemotherapy remains the mainstay of treatment in metastatic breast cancer (MBC) and the 
goals in this setting are to prolong survival, alleviate or prevent tumour-related symptoms and 
improve Quality of Life. 
The taxanes, specifically paclitaxel and docetaxel, are amongst the most active agents in MBC 
(Ghersi et al 2005) and have demonstrated significant activity in MBC in terms of response 
rate (RR) and progression free survival (PFS) (Beslija et al 2009). 
In current clinical practice, paclitaxel is used in doses ranging from 135 to 225 mg/m2 
administered every 3 weeks; however, its weekly administration usually at a dose of 80 mg/m2 
provides superior RR, PFS and overall survival (OS) (Seidman et al 2008). 
The toxicity profile of paclitaxel seems to be both dose and schedule dependent.  Various 
dosages and schedules of paclitaxel have been investigated in patients relapsing or failing after 
previous therapy combinations.  The issue of schedule-dependent activity was addressed in 
several studies.  In a phase I dose-finding study, 90 mg/m2 was found to be the optimal dose in 








Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
31(131) 
All patients should avoid concomitant use of drugs, herbal supplements and/or ingestion of 
foods known to potently modulate CYP3A4 enzyme activity from the time they enter the 
screening period until 2 weeks after the last dose of study treatment.   
All patients should avoid concomitant use of drugs and herbal supplements known to be 
CYP3A4 or CYP2D6 substrates from the time they enter the screening period until 2 weeks 
after the last dose of study treatment wherever possible.  If co-administration is necessary then 
additional monitoring for signs of toxicity related to increased exposure to the substrates is 
required. 
In addition, should AZD5363 pharmacokinetic outlying data be observed in the absence of 
confounding concomitant medications, patient genetic samples will be requested 
 
1.4.3 
Potential risks identified from early clinical studies with AZD5363: 
To date, the most commonly reported AEs, regardless of dose or causality, are: diarrhoea, 
hyperglycaemia, fatigue, maculo-papular rash, vomiting, dyspnoea and nausea. The majority 
of AEs reported in patients receiving AZD5363 have been CTCAE Grade 1 or Grade 2 in 
toxicity.  
Three (DLTs) of maculo-papular rash have been reported in study D3610C00001 under a 
continuous dosing schedule: one in a 400 mg bd cohort (CTCAE grade 3) and two in a 600 
mg bd cohort (CTCAE grade 4). 
Five AEs of diarrhoea: CTCAE grade 3 in the continuous dosing at 240 mg bd (n=1), 400 mg 
bd (n=1), 600 mg bd (n=1) and intermittent dosing (4 days on and 3 days off) at 640 mg bd 
(n=2) 
Seven AEs of  hyperglycaemia (post AZD5363 dose), CTCAE grade 3 in the continuous 
dosing at 400 mg bd (n=2) and intermittent dosing (4 days on and 3 days off) at 480 mg bd 
(n=1), 640 mg bd (n=4) 
1.4.4 
Risk minimisation activities for potential risks identified in early clinical 
studies with AZD5363: 
Glucose homeostasis  
In order to reduce the potential risk of exacerbating abnormal glucose profiles, patients with 
Type I or Type II diabetes mellitus (irrespective of management), fasting glucose 7 mmol/L 
or glycosyated haemoglobin (HbA1c) 8% at screening will be excluded from clinical studies 
with AZD5363.  Glucose, insulin and insulin C-peptide profiles will be performed on the first 
dosing day and at steady state during the first treatment cycle, at the start of each subsequent 
cycle and on discontinuation of AZD5363/placebo.  During the first cycle, urinary glucose 
will be tested twice weekly after patients are discharged from the clinic, with instructions 
regarding clinic contact on finding a high result.  Random blood glucose pre- and post-
AZD5363/placebo dosing will be monitored on planned study visit days and when needed to 
evaluate any episodes of hyperglycaemia.  In addition, because of the pharmacological 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
32(131) 
activity of AZD5363 on glycolysis and insulin signalling, fasting lipid profiles (triglycerides, 
high density lipoprotein (HDL), low density lipoprotein (LDL) and cholesterol) will also be 
monitored at baseline, every 12 weeks and at discontinuation of AZD5363/placebo.  A blood 
glucose intervention algorithm will be provided separately to this protocol to aid investigator 
management of elevated blood glucose. 
Diarrhoea 
There are no standard exclusion criteria for patients with diarrhoea; however, patients with 
previous gastrointestinal surgery that may affect drug absorption are excluded from AZD5363 
clinical studies.  Diarrhoea can be managed with treatment and interruptions to AZD5363 
dosing.  Patient reports of diarrhoea are expected to be evaluated and treated by investigators 
according to local practice (eg, use of medications such as loperamide, need for IV fluid 
replacement).  A toxicity management algorithm will be provided separately to this protocol 
to aid investigator management of diarrhoea. 
Rash 
There are no standard exclusion criteria for patients with rash.  Rash can be managed with 
treatment and interruptions to AZD5363/placebo dosing.  Patient reports of rash are expected 
to be evaluated and treated by investigators according to local practice (eg, use of oral or 
topical steroids, use of oral antihistamine).  A toxicity management algorithm will be provided 
separately to this protocol to aid investigator management of rash. 
1.4.5 
Overall benefit-risk and ethical assessment 
Although there can be no certainty of clinical benefit to patients, non-clinical data with 
AZD5363 support the hypothesis that AKT inhibition may be a valid target for the treatment 
of breast cancers with or without PIK3CA mutation.  The non-clinical safety profile and 
emerging clinical profile from the early clinical studies have not identified risks that would 
preclude investigation in this setting.  The study design aims to minimise potential risks, via 
confirmation of the optimum combination dose prior to the main randomised study.  A dose 
modification strategy for management of toxicity and monitoring is in place for those risks 
deemed to be most likely or serious.  Thus the benefit/risk assessment for this study supports 
the co-administration of AZD5363 with paclitaxel in patients with advanced or metastatic 
breast cancer with or without PIK3CA mutation. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Part A. Safety run-in: To assess the safety and tolerability of two schedules of AZD5363 
(continuous and intermittent dosing) when combined with weekly paclitaxel in patients with 
advanced or metastatic breast cancer; and to recommend, by assessment of dose limiting 
toxicities and other safety, tolerability, pharmacokinetic and pharmacodynamic data, a dose 
and schedule of AZD5363 for further study when combined with weekly paclitaxel. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
33(131) 
Part B. Randomised expansion: To assess the relative anti-tumour activity of AZD5363 when 
combined with weekly paclitaxel vs. weekly paclitaxel plus placebo by comparison of change 
in tumour size at 12 weeks (target lesion assessment using Response Evaluation Criteria In 
Solid Tumours [RECIST 1.1]) in the overall advanced or metastatic ER+ve breast cancer 
population and in the PIK3CA mutation-positive sub-population. 
2.2 
Secondary objectives 
Part A. Safety run-in: 
x
To make a preliminary assessment of the anti-tumour activity of AZD5363 when 
combined with paclitaxel by assessment of objective response rate (ORR), and the 
percentage of patients without progressive disease, at 12 weeks. 
Part B. Randomised expansion: 
x
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel 
compared with weekly paclitaxel plus placebo by assessment of ORR at 12 weeks.  
x
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel 
compared with weekly paclitaxel plus placebo by assessment of PFS, best objective 
response (BOR) and DoR.  
x
To further assess the safety and tolerability of AZD5363 when combined with 
weekly paclitaxel compared with paclitaxel plus placebo.  
x
To investigate the effect on patients’ quality of life (QoL) of AZD5363 when 
combined with weekly paclitaxel, compared with weekly paclitaxel alone by 
changes from baseline, utilising a patient-completed QoL questionnaire. 
Parts A and B: 
x
To assess the PK of AZD5363 when combined with paclitaxel. 
x
To assess the PK of paclitaxel alone and when combined with AZD5363. 
x
To assess the PK/PD relationship between plasma AZD5363 exposure and plasma 
concentrations of biomarkers (including phospo-PRAS40, total PRAS40, pAKT 
and pGSK3ȕ) anti-tumour activity (assessed by RECIST 1.1). 
2.3 
Exploratory objectives 
Parts A and B: 
x
To investigate the relationship between plasma AZD5363 exposure and plasma 
concentrations of exploratory biomarkers and efficacy.  Biomarkers may include, 
but are not restricted to, somatic mutation or amplification of genes on the PI3 
kinase and related pathways in circulating free plasma DNA (cfDNA). 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
34(131) 
x
To obtain a preliminary assessment of AZD5363 treatment effect by quantitative 
change in circulating tumour cells (CTCs). 
x
To investigate the concordance of PIK3CA mutation status between per-patient 
analyses of blood and archival tumour tissue samples.  
x
To collect optional matched pre-and post- treatment tumour biopsy samples to 
conduct assessment of the PD effect of therapy compared to baseline. 
x
To collect and store archival tumour samples and analyse surplus blood or tissue, 
for potential future exploratory research into factors that may influence 
development of cancer and/or response to AZD5363 (where response is defined 
broadly to include efficacy, tolerability or safety). Biomarkers may include, but are 
not restricted to, somatic mutation or amplification of genes on the PI3 kinase and 
related pathways, PTEN protein expression and Akt protein expression. This 
exploratory analysis will be reported separately. 
x
To obtain blood samples for DNA extraction for future exploratory research into 
genes/genetic variation that may influence response (ie, distribution, safety, 
tolerability and efficacy) to AZD5363 treatment and/or susceptibility to cancer. 
This exploratory analysis will be reported separately. 
3. 
STUDY PLAN AND PROCEDURES 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. 
3.1 
Overall study design and flow chart 
This international, multicentre study of AZD5363 when combined with paclitaxel will be 
conducted in two Parts- A and B: 
3.1.1 
Part A: Safety run-in   
A multiple ascending-dose evaluation of AZD5363 in each of two schedules (continuous and 
intermittent dosing) when combined with weekly paclitaxel.  These dose escalation schedules 
may commence at the same time, or one schedule may be inititiated in advance of the other to 
facilitate ease of study initiation.    
This part will assess the comparative safety, tolerability, pharmacokinetics and preliminary 
anti-tumour activity of both schedules of AZD5363 when combined with weekly paclitaxel.  
A recommended dose and schedule of AZD5363 will be determined for conduct of Part B, the 
randomised expansion (see section 3.1.2)    
The patient population will be female, aged 18 years or older, with advanced or metastatic 
breast cancer.  For inclusion in Part A, patients must not have received any more than two 
prior courses of chemotherapy for breast cancer.  Prior endocrine therapy is allowed. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
35(131) 
Patients will be recruited in approximately 8 centres in approximately 4 countries.  The 
number of patients enrolled will be dependent upon the number of dose escalation cohorts 
required, see below, but a total of approximately 40 patients is anticipated.   
Both schedules of AZD5363 will be in combination with 90 mg/m2 paclitaxel (see section 
5.5.3):  
x
Continuous dosing:  AZD5363 capsules taken orally, twice daily, each day.  The 
starting dose for cohort 1 will be 320 mg (640 mg daily). 
x
Intermittent dosing:  AZD5363 capsules taken orally, twice daily, for repeating 
weekly cycles of 4 days on treatment followed by 3 days off treatment during each 
week that paclitaxel is received.  The starting dose for cohort 1 will be 360 mg (720 
mg daily).   
Dose escalating cohorts of 3 to 6 patients will be evaluated under each schedule.  A total of 6 
patients must be evaluated at a selected dose level for it to be confirmed as the RD.  AZD5363 
dose escalations and maximum doses attained will not exceed levels deemed tolerated by the 
Safety Review Committee (SRC) in prior first time in patient study D3610C00001. 
The RD for a schedule may or may not be defined by attainment of non-tolerated dose / 
maximum tolerated dose (NTD / MTD) levels (see section 5.10.2).  If the RD is selected prior 
to attaining MTD, the SRC will determine whether continued dose escalations to NTD/MTD 
are required. 
 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
36(131) 
Safety run-in – Dose escalation: 
 
 
 
Final Cohort (N=6) 
Schedule 1: AZD5363 
continuous dosing 
 
 
AZD5363 
Paclitaxel 
 
Cohort 2 (N=3-6) 
 
 
Cohort 1 (N=3-6) 
AZD5363
Paclitaxel
 
 
AZD5363 
Paclitaxel 
 
 
 
 
 
 
Final Cohort (N=6) 
Schedule 2: AZD5363 
intermittent dosing 
 
 
AZD5363 
Paclitaxel 
 
Cohort 2 (N=3-6) 
 
 
Cohort 1 (N=3-6) 
AZD5363
Paclitaxel
 
 
AZD5363 
Paclitaxel 
 
 
 
 
Subsidiary Japanese patient evaluation (optional) 
A Part A subsidiary dose-escalating safety evaluation may be conducted optionally in a 
Japanese patient population at a starting dose, and under one schedule, determined by the 
Safety Review Committee.  This evaluation would be conducted to determine a safe and 
tolerable dose of AZD5363 when in combination with paclitaxel in a Japanese population. 
This separate Japanese safety run-in evaluation would commence following determination of 
the RD and dosing schedule in the Western population.  It would proceed in parallel with the 
Part B randomised expansion, but would not inform any decision regarding the conduct of 
Part B.  The schedule of assessments in the subsidiary Part A would be as detailed in this 
protocol for Part A.  It is not envisaged that a Japanese population would be evaluated under 
study Part B. 
3.1.2 
Part B: Randomised expansion 
A double-blind, stratified and randomised evaluation of AZD5363 when combined with 
weekly paclitaxel vs. weekly paclitaxel plus placebo.  The dose and schedule of AZD5363 
will be selected as an outcome from Safety run-in Part A. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
37(131) 
The patient population will be female, aged 18 years or older, with ER+ve advanced or 
metastatic breast cancer, and incorporating a subgroup who have PIK3CA mutation-positive 
tumour(s).  For inclusion in Part B, patients must not have received any prior chemotherapy 
for breast cancer in the advanced or metastatic setting.  Prior (neo)adjuvant chemotherapy is 
allowed (if (neo) adjuvant taxane, there must have been a minimum of 12 months from 
completion of therapy to relapse). 
Patients will be recruited in approximately 12 centres in approximately 5 countries.  
Approximately 70 patients will be enrolled in this phase (to ensure that 60 are evaluable at 12 
weeks), of which approximately 35 must have a tumour detectable as carrying a PIK3CA 
mutation.   
To be considered evaluable for the randomised expansion primary efficacy analysis, a 
patient must have baseline and week 12 (r1 week) tumour measurements for 
assessment of the primary endpoint of change in tumour size, or evidence of objective 
progression prior to week 12, or in the absence of week 12 measurements and no 
evidence of objective progression, RECIST measurements available at baseline and 1 
visit before or after week 12 such that a prediction for the week 12 result can be made 
(see section 11.1.1 for details).  An overage of approximately 15% of patients is 
therefore planned to be randomised to allow for potential non-evaluable patients. 
Patients will be stratified to PIK3CA mutation ‘positive’ and ‘not detected’ groups by 
prospective analysis of blood and/or tumour tissue (see sections 5.2 and 6.2.1).  Patients 
within each stratum will be randomised to 28-day cycles (see section 5.5.3) comprising either 
of: 
o Paclitaxel 90 mg/m2 IV once weekly plus AZD5363 capsules taken orally, 
twice daily. 
o Paclitaxel 90 mg/m2 IV once weekly plus AZD5363-matching placebo capsules 
taken orally, twice daily. 
 
Figure 3 
Randomised Expansion: Stratification and Randomisation  
ER+ve BrCa 
(n§70) 
PIK3CA +ve 
(n§35) 
Stratified for 
PIK3CA status 
PIK3CA Not 
detected 
(n§35) 
Randomised
Paclitaxel + AZD5363 
(n§15 evaluable)
Randomised
Paclitaxel + placebo 
(n§15 evaluable)
Paclitaxel + AZD5363 
(n§15 evaluable)
Paclitaxel + placebo 
(n§15 evaluable)
 
 




Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
39(131) 
3.1.3 
Treatment Schedules 
Under both the continuous and intermittent dosing schedules, first receipt of paclitaxel will be 
on Cycle 1, Day 1; first receipt of AZD5363/placebo will be on Day 2.  
Under the intermittent dosing schedule, weekly AZD5363 regimens thereafter will continue to 
start on the day after dosing with paclitaxel. 
 
Cycle 1 
Cycle 2 onwards 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 1 
Week 2 
Week 3 
Week 4 
Paclitaxel. Dose dayĺ 
Day 1 
Day 1 
Day 1 
None 
Day 1 
Day 1 
Day 1 
None 
Continuous. 
Dose days ĺ 
Day 2 to Day 28 
Day 1 to Day 28 
AZD5363  
Intermittent. 
Dose days ĺ 
D2 to D5 D2 to D5
D2 to D5
None 
D2 to D5
D2 to D5 D2 to D5 
None 
 
Please refer to Sections 5.5.3 for further definitions and guidance for conduct of treatment 
cycles. 
Please refer to Section 5.5.4 for guidance for conduct of dose modifications.   
3.1.4 
Assessment Schedule 
Patients will undergo the assessments detailed in the schedules below, presented separately for 
those allocated to either the continuous or intermittent dosing schedule.  Assessments are 
applicable to both the Safety Run-in and Randomised Expansion parts unless otherwise 
indicated.    


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
40(131) 
Figure 5 
Schedule 1: AZD5363/placebo – Continuous Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Paclitaxel 
Discont. 
AZD5363 
Discont. 
28-day 
follow-up 
Details in 
Section: 
Week ĺ 
  
1 
2 
3 
4 
1 
2 
3 
4 
1 
  
  
  
 
Week Day ĺ 
 -28 to 0 1 
2 
3 
1 
2 
1 
1 
1 
1 
1 
1 
1 
  
  
  
 
Paclitaxel dosed (i.v.) 
  
X 
  
  
X 
  
X 
  
X 
X 
X 
  
Xĺ 
  
  
  
 
AZD5363 dosed (bd) 
  
  
X 
Xĺ X 
Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ 
  
  
  
 
ActivityĻ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Informed consent - PIK3CA 
screen (Part B only) 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
8.4 
PIK3CA mutation testing  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6.2.2 
Informed consent - study 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
8.4 
Demography& baseline 
characteristics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6.2 
Medical/surgical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6.2 
Previous/concomitant therapy 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
5.6 
Previous cancer therapy 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
5.6 
Inclusion / exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
4 
Physical examination 
X 
X 
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
  
6.4.6 
Height and weight 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
6.4.7 
WHO performance status 
X 
X 
  
  
  
  
  
  
 
  
  
  
 
 
 
  
6.4.8 
Vital signs 
X 
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
6.4.11 
12-lead ECG 
X 
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
X 
X 
  
6.4.9 
MUGA / Echocardiogram 
X 
  
  
  
  
  
  
  
X 
  
  
  
X3 
 
X 
  
6.4.10 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
41(131) 
Figure 5 
Schedule 1: AZD5363/placebo – Continuous Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Paclitaxel 
Discont. 
AZD5363 
Discont. 
28-day 
follow-up 
Details in 
Section: 
Week ĺ 
  
1 
2 
3 
4 
1 
2 
3 
4 
1 
  
  
  
 
Week Day ĺ 
 -28 to 0 1 
2 
3 
1 
2 
1 
1 
1 
1 
1 
1 
1 
  
  
  
 
Paclitaxel dosed (i.v.) 
  
X 
  
  
X 
  
X 
  
X 
X 
X 
  
Xĺ 
  
  
  
 
AZD5363 dosed (bd) 
  
  
X 
Xĺ X 
Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ 
  
  
  
 
Haematology, Clinical 
chemistry Urinalysis 
X 
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
6.4.5 
Glycosylated haemoglobin 
X 
  
  
  
  
  
  
  
  
  
  
  
X3 
X 
X 
  
6.4.12.2 
Lipids  
X 
 
  
  
  
  
  
  
 
  
  
  
X3 
  
X 
  
6.4.12.1 
Glucose, insulin, insulin c-
peptide, 
 
X 
X 
  
X 
  
X 
X 
X 
  
  
  
X 
  
X 
  
6.4.12.3 
Pregnancy test 
X 
X 
  
  
  
  
  
  
 
  
  
  
  
X 
X 
  
6.4.5 
Paclitaxel PK blood samples1  
  
X 
X 
  
X2 
X2 
X2 
  
 
  
  
  
 
  
  
  
6.6.2 
AZD5363 PK blood samples1 
  
  
X 
 X 
X 
X  
X 
X 
  
  
  
  
  
  
  
  
6.6.2 
Pharmacodynamic blood 
samples1 
  
X 
X 
X 
X 
X  
X 
X 
X 
  
  
  
X 
  
X 
  
6.7.1 
Exploratory biomarker blood 
samples1 (optional) 
X 
  
X 
  
X 
  
X 
X 
X 
  
  
  
X 
  
X 
  
6.8.1.5 
Exploratory biomarker hair 
samples (optional) 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 
Pharmacogenetics (optional) 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6.9.1 
RECIST Tumour assessments 
X 
  
  
  
  
  
  
  
 
  
  
  
X3 
 
  
  
6.3.1 
Archival tumour sample  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6.8.1.2 
Paired biopsy (optional)  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
6.8.1.3 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
42(131) 
Figure 5 
Schedule 1: AZD5363/placebo – Continuous Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Paclitaxel 
Discont. 
AZD5363 
Discont. 
28-day 
follow-up 
Details in 
Section: 
Week ĺ 
  
1 
2 
3 
4 
1 
2 
3 
4 
1 
  
  
  
 
Week Day ĺ 
 -28 to 0 1 
2 
3 
1 
2 
1 
1 
1 
1 
1 
1 
1 
  
  
  
 
Paclitaxel dosed (i.v.) 
  
X 
  
  
X 
  
X 
  
X 
X 
X 
  
Xĺ 
  
  
  
 
AZD5363 dosed (bd) 
  
  
X 
Xĺ X 
Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ 
  
  
  
 
Circulating tumour cells 
 
X 
  
  
 
  
  
  
X 
  
  
  
X3 
  
  
  
6.8.1.1 
Patient meal information 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
 
 
 
6.4.12.4 
Quality of Life questionnaires  
(Part B only) 
X 
X 
  
  
  
  
  
  
 
  
  
  
X3 
 
X 
  
6.5.1 
Concomitant medication 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5.6 
Subsequent cancer therapy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
5.6 
Adverse events 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
1   
PK, PD and Biomarker samplings are shown as cumulative timepoints. Please refer to individual study segment tables given in sections 6.6.2 (PK) and 
6.8.1.6 (PD/biomarkers) 
2.  
Part A - Safety Run-in phase only: Patients will continue to undergo paclitaxel PK measurements on these occasions. 
3.  
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1). Part 
B - Randomised expansion only: Patients will continue to undergo RECIST assessments after cessation of study therapies up to disease progression or 
withdrawal of consent.   


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
43(131) 
 
Figure 6 
Schedule 2: AZD5363/placebo – Intermittent Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont. 
AZD5363
Discont. 
28-day 
follow-
up 
Details 
in 
Section
: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ      -28 to 
0 
1 
2 
3 
5 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosed 
(i.v.) 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosed 
(bd) 
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 Xĺ
 
Xĺ
 
Xĺ 
 
 
 Xĺ
 
 
 
 
ActivityĻ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent - 
PIK3CA screen (Part 
B only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
PIK3CA mutation 
testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Informed consent - 
study 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Demography& 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Previous/concomitant 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Previous cancer 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Inclusion / exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
44(131) 
Figure 6 
Schedule 2: AZD5363/placebo – Intermittent Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont. 
AZD5363
Discont. 
28-day 
follow-
up 
Details 
in 
Section
: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ      -28 to 
0 
1 
2 
3 
5 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosed 
(i.v.) 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosed 
(bd) 
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 Xĺ
 
Xĺ
 
Xĺ 
 
 
 Xĺ
 
 
 
 
Physical examination X 
X 
 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.6 
Height and weight 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.7 
WHO performance 
status 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.8 
Vital signs 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
6.4.11 
12-lead ECG 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.9 
MUGA / 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X3  
 
X 
 
6.4.10 
Haematology, 
Clinical chemistry 
Urinalysis 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
6.4.5 
Glycosylated 
haemoglobin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3  
X 
X 
 
6.4.12.2
Lipids  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3  
 
X 
 
6.4.12.1
Glucose, insulin, 
insulin c-peptide,  
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
6.4.12.3
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
6.4.5 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
45(131) 
Figure 6 
Schedule 2: AZD5363/placebo – Intermittent Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont. 
AZD5363
Discont. 
28-day 
follow-
up 
Details 
in 
Section
: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ      -28 to 
0 
1 
2 
3 
5 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosed 
(i.v.) 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosed 
(bd) 
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 Xĺ
 
Xĺ
 
Xĺ 
 
 
 Xĺ
 
 
 
 
Paclitaxel PK blood 
samples1 
 
X 
X 
 
 
 
X2  
X2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
AZD5363 PK blood 
samples1 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Pharmacodynamic 
blood samples1 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
6.7.1 
Exploratory 
biomarker blood 
samples1 (optional) 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
6.8.1.5 
Exploratory 
biomarker hair 
samples (optional) 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 
Pharmacogenetics 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.1 
RECIST Tumour 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3  
 
 
 
6.3.1 
Archival tumour 
sample  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.2 
Paired biopsy 
(optional)  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.3 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
46(131) 
Figure 6 
Schedule 2: AZD5363/placebo – Intermittent Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont. 
AZD5363
Discont. 
28-day 
follow-
up 
Details 
in 
Section
: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ      -28 to 
0 
1 
2 
3 
5 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosed 
(i.v.) 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosed 
(bd) 
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 Xĺ
 
Xĺ
 
Xĺ 
 
 
 Xĺ
 
 
 
 
Circulating tumour 
cells 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X3  
 
 
 
6.8.1.1 
Patient meal 
information 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
6.4.12.4
QoL questionnaires 
(Part B only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3  
 
X 
 
6.5.1 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5.6 
Subsequent cancer 
therapy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
5.6 
Adverse events 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
1   
PK, PD and Biomarker samplings are shown as cumulative timepoints. Please refer to individual study segment tables given in sections 6.6.2 (PK) and 
6.8.1.6 (PD/biomarkers) 
2.  
Part A - Safety Run-in phase only: Patients will continue to undergo paclitaxel PK measurements on these occasions.  
3.  
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1). Part 
B Randomised expansion only: Patients will continue to undergo RECIST assessments after cessation of study therapies up to disease progression or 
withdrawal of consent.   


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
47(131) 
4. 
PATIENT SELECTION CRITERIA 
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening. 
4.1 
Inclusion criteria 
For inclusion in the study patients should fulfil the following criteria: 
All patients: 
1. 
Provision of informed consent prior to any study specific procedures.  
2. 
Female patients, aged at least 18 years. 
3. 
Histological or cytological confirmation of breast cancer (see Parts A and B 
inclusion criteria below). 
4. 
World Health Organisation (WHO) performance status 0-1 with no deterioration 
over the previous 2 weeks and minimum life expectancy of 12 weeks. 
5. 
Patients must be able to swallow and retain oral medication.   
6. 
Patients of child-bearing potential should be using adequate contraceptive measures 
(see Restrictions section below), should not be breast feeding and must have a 
negative pregnancy test prior to start of dosing. 
or  
Patients must have evidence of non-child-bearing potential by fulfilling one of the 
following criteria at screening: 

Post-menopausal – defined as aged more than 50 years and amenorrhoeic for at 
least 12 months following cessation of all exogenous hormonal treatments. 

Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy, but not tubal ligation. 
7. 
Patients must not be breast feeding. 
Part A. Safety Run-in: 
1. 
Patients with histological or cytologic diagnosis of breast cancer with evidence of 
advanced or metastatic disease.  Lesions should not be amenable to surgery or 
radiation of curative intent. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
48(131) 
2. 
At least one lesion (measurable and/or non-measurable) that can be accurately 
assessed at baseline by CT or MRI and is suitable for repeated assessment. 
Part B. Randomised Expansion: 
1. 
Patients with histological or cytologic diagnosis of ER+ve breast cancer with 
evidence of relapsed advanced or metastatic disease.  Lesions should not be 
amenable to surgery or radiation of curative intent and must be considered unlikely 
to be rendered eligible for surgery by treatment with paclitaxel in this study. 
2. 
Patients who relapsed more than 12 months after completing adjuvant endocrine 
therapy, or who have not had adjuvant endocrine therapy, must have received prior 
endocrine therapy for advanced or metastatic disease.* 
Patients who relapsed on adjuvant endocrine therapy, or within 12 months of 
completing adjuvant endocrine therapy, may enter the study without prior endocrine 
therapy for advanced or metastatic disease.*  
3. 
Provision of archival tumour sample for PIK3CA mutation testing. 
4. 
Provision of baseline plasma sample for PIK3CA mutation testing. 
5. 
At least one tumour lesion, not previously irradiated, that can be measured 
accurately at baseline as 10 mm in the longest diameter (except lymph nodes 
which must have short axis 15 mm) with computed tomography (CT) or magnetic 
resonance imaging (MRI) which is suitable for accurate repeated measurements. 
* For guidance when evaluating inclusion criteria under item 2 above. 
The following patients would be eligible for inclusion:  
x
Relapsed whilst on adjuvant endocrine therapy 
x
Relapsed <12 months after completing adjuvant endocrine therapy (with or without 
receiving endocrine therapy in the advanced or metastatic setting)  
x
Relapsed >12 months after completing adjuvant endocrine therapy and has received 
endocrine therapy in the advanced or metastatic setting 
The following patients would not be eligible for inclusion:  
x
Adjuvant endocrine therapy- naive 
x
Relapsed >12 months after completing adjuvant endocrine therapy and has not 
received endocrine therapy in the advanced or metastatic setting 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
49(131) 
4.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
All Patients: 
1. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site). 
2. 
Previous enrolment in the present study. 
3. 
Participation in another clinical study with an investigational product (IP) during 
the last 30 days. 
4. 
Receipt of any investigational drug within 30 days or 5 half-lives, whichever is 
longer, of the first dose of AZD5363 or matching placebo. 
5. 
Any prior exposure to agents with primary pharmacological activity of inhibition of 
AKT, any inhibitor with PI3K pharmacology, including prior dosing with AZD5363 
in this, or any other, study (for examples of excluded agents, please refer to 
Appendix H). 
6. 
Any prior exposure to agents with PI3K, or mixed PI3Kand mTOR kinase 
pharmacology or any mTOR kinase inhibitor. Prior exposure to rapalogs and other 
allosteric mTOR/mTORC1 complex inhibitors is allowed. (for examples of 
excluded and allowed agents, please refer to Appendix G). 
7. 
Planned concomitant use of aromatase inhibitors or any cancer therapy, with the 
exception of bisphosphonates and denosumab, during the study. 
8. 
Exposure to potent inhibitors or inducers of CYP3A4 or CYP2D6 or substrates of 
CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St 
John’s Wort). 
9. 
Clinically significant abnormalities of glucose metabolism as defined by any of the 
following: 

Diagnosis of diabetes mellitus type I or II (irrespective of management). 

Glycosylated haemoglobin (HbA1C) 8.0% at screening (64 mmol/mol) 
(conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C 
(%) – 2.15] x 10.929) 

Fasting Plasma Glucose   7.0mmol/L (126 mg/dL) at screening. Fasting is 
defined as no caloric intake for at least 8 hours. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
50(131) 
10. 
Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a 
limited field of radiation for palliation within 2 weeks before the first dose of IP 
(AZD5363/placebo). 
11. 
Last dose of anticancer therapy - other than for advanced or metastatic breast cancer 
(chemotherapy, radiation therapy, surgery, immunotherapy, endocrine therapy, 
targeted therapy, biologic therapy, or tumour embolisation) must be more than 21 
days (more than 6 weeks for nitrosurea or mitomycin C) prior to the first dose of 
study treatment.  If sufficient wash-out time has not occurred due to schedule or PK 
properties, a longer wash-out period will be required as agreed by AZ and the 
investigator. 
12. 
Major surgery (excluding placement of vascular access) within 4 weeks before the 
first dose of study treatment. 
13. 
Spinal cord compression or brain metastases unless asymptomatic, treated and 
stable and not requiring steroids for at least 4 weeks prior to start of study treatment. 
14. 
As judged by the Investigator, any evidence of severe or uncontrolled systemic 
diseases, including uncontrolled hypertension, active bleeding diatheses, or active 
infection including hepatitis B, hepatitis C and human immunodeficiency virus 
(HIV).  Screening for chronic conditions is not required. 
15. 
Any of the following cardiac criteria: 

Mean resting corrected QT interval (QTc) >470 msec obtained from 3 
consecutive ECGs. 

Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG eg, complete left bundle branch block, third degree heart block. 

Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events such as heart failure, hypokalaemia, potential for torsades de pointes, 
congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age or any concomitant medication 
known to prolong the QT interval. 

Experience of any of the following procedures or conditions in the preceding 6 
months: coronary artery bypass graft, angioplasty, vascular stent, myocardial 
infarction, angina pectoris, congestive heart failure NYHA Grade 2. 

Uncontrolled hypotension – SBP <90 mmHg and/or DBP <50 mmHg. 

Cardiac ejection fraction outside institutional range of normal or <50% 
(whichever is higher) as measured by echocardiogram (or MUGA scan if an 
echocardiogram cannot be performed or is inconclusive). 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
51(131) 
16. 
With the exception of alopecia, any unresolved toxicities from prior therapy greater 
than CTCAE grade 1 at the time of starting study treatment. 
17. 
Absolute neutrophil count <1.5 x 109/L. 
18. 
Platelet count <100 x 109/L. 
19. 
Haemoglobin <9 g/dL (<5.59 mmol/L).  [Note: any blood transfusion must be 
>14 days prior to the determination of a haemoglobin 9 g/dL (5.59 mmol/L)]. 
20. 
Alanine aminotransferase (ALT) >2.5 times ULN if no demonstrable liver 
metastases or >5 times ULN in the presence of liver metastases. 
21. 
Aspartate aminotransferase (AST) >2.5 times ULN if no demonstrable liver 
metastases or >5 times ULN in the presence of liver metastases.  Elevated Alkaline 
phosphatase (ALP) is not exclusionary if due to the presence of bone metastasis and 
liver function is otherwise considered adequate in the investigator’s judgement. 
22. 
Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the 
presence of liver metastases. 
23. 
Creatinine >1.5 times ULN concurrent with creatinine clearance <50 ml/min 
(measured or calculated by Cockcroft and Gault equation); confirmation of 
creatinine clearance is only required when creatinine is >1.5 times ULN. 
24. 
Proteinuria >3+ on dipstick analysis or >3.5 g/24 hours or a urine protein/creatinine 
ratio >3.5 . 
25. 
Sodium or potassium outside normal reference range for site. 
26. 
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to 
swallow the formulated product or previous significant bowel resection that would 
preclude adequate absorption of AZD5363 / paclitaxel. 
27. 
History of hypersensitivity to active or inactive excipients of AZD5363 or 
paclitaxel or drugs with a similar chemical structure or class to AZD5363 or 
paclitaxel. 
28. 
Judgment by the Investigator that the patient should not participate in the study if 
the patient is unlikely to comply with study procedures, restrictions and 
requirements. 
29. 
Current disease or condition known to interfere with absorption, distribution, 
metabolism or excretion of drugs. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
52(131) 
30. 
Past medical history of interstitial lung disease, drug-induced interstitial lung 
disease, radiation pneumonitis which required steroid treatment, or any evidence of 
clinically active interstitial lung disease. 
31. 
Evidence of dementia, altered mental status or any psychiatric condition that would 
prohibit understanding or rendering of informed consent. 
32. 
Previous allogeneic bone marrow transplant. 
33. 
Known immunodeficiency syndrome. 
34. 
Non-leukocyte depleted whole blood transfusion within 120 days of the date of the 
genetic sample collection will exclude patient from the optional pharmacogenetic 
evaluation, although the patient may enter the main study. 
Part A. Safety Run-In: 
1. 
More than two prior courses of chemotherapy (including taxanes) for breast cancer 
in the advanced or metastatic setting. 
2. 
If patients have received prior treatment with anthracyclines or mitoxantrone, 
cumulative exposure must be less than 360 mg/m2 for doxorubicin, 720 mg/m2 for 
epirubicin or 72 mg/m2 for mitoxantrone. 
Part B. Randomised Expansion: 
1. 
Any prior chemotherapy for breast cancer in the advanced or metastatic breast 
setting.  Prior adjuvant or (neo)adjuvant chemotherapy is allowed, however, if 
the adjuvant or (neo)adjuvant therapy contained a taxane, at least 12 months should 
have elapsed since completion of the therapy before entry to this study. 
For procedures for withdrawal of incorrectly enrolled patients see Section 5.3. 
5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
1. 
Patients who are blood donors should not donate blood during the study and for 3 
months following their last dose of study treatment. 
2. 
Patients to avoid excessive sun exposure and use adequate screening protection.  
The use of sun-beds and tanning booths should be avoided. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
53(131) 
3. 
On PK sampling days in the clinic, patients must fast (water to drink only) from at 
least 2 hours prior to a dose of study therapy to at least 1 hour post-dose. On all 
other study days patients are requested to keep to these fasting restrictions wherever 
possible. 
4. 
On blood glucose assessment days (incorporating Clinical chemistry and 
glucose/insulin/insulin c-peptide) evaluations it is requested that patients refrain 
from calorific intake for a minimum of 8 hours prior to the morning dose of 
AZD5363 / placebo. 
5. 
Females of child-bearing potential should use two forms of highly reliable methods 
of contraception from the time of screening until 4 weeks after discontinuing study 
treatment.  Acceptable methods of contraception include: 

Established use of oral, injected or implanted hormonal methods of 
contraception. 

Placement of an intrauterine device or intrauterine system. 

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. 

Male partner sterilisation (with the appropriate post-vasectomy documentation 
of the absence of sperm in the ejaculate). 

True abstinence.  
It is not known whether AZD5363 has the capacity to affect the metabolism of 
hormonal contraceptives, so hormonal contraception should also be combined with a 
barrier method of contraception. 
6. 
During Cycle 1, following discharge from the clinic, patients will be required to 
carry out a urine glucose assessment by dipstick prior to breakfast two times per 
week.  If a positive result is observed they must contact the clinic for further 
investigation of this result. 
5.2 
Patient enrolment, randomisation and initiation of investigational 
product 
The Principal Investigator will: 
1. 
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed. 
2. 
Obtain a unique enrolment number, beginning with ‘E#’. The E-code is a 7-digit 
number comprising the centre number, the dosing schedule and the patient number 
within that particular centre.  This number is the patient’s unique identifier and is 






Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
56(131) 
 
 
Sample type - Tissue 
 
PIK3CA mutation 
resultĺĻ 
Positive (+ve) 
Not detected 
(ND) 
Unknown / 
unavailable (U) 
Positive (+ve) 
+ve 
+ve 
+ve 
Not detected (ND) 
+ve 
ND 
ND 
Sample 
type - 
Blood 
Unknown (U) 
+ve 
ND 
U 
 
Note: 
Pre-existing PIK3CA mutation status, where generated from a relevant tumour sample 
as part of local clinical practice, will also be recorded. These data may be utilised, if 
necessary, on study completion to assist in confirmation of mutation status where there 
is a discrepancy between blood and tumour PIK3CA mutation results from the central 
analysis.  
Where an archival tumour sample cannot be provided in sufficient time for analysis by 
Quintiles to support determination of defined PIK3CA mutation status (Part B) or the 
result is ‘unknown’ (Part A or B), mutation status derived from a prior locally-
conducted analysis may be utilised.  This, however, will only be acceptable where the 
analytical methodology/kit has been approved in advance by AstraZeneca. 
Patient stratification by PIK3CA mutation status (Part B) 
Patients will be stratified to PIK3CA mutation positive’ or ‘PIK3CA mutation not detected’ 
arms prior to randomisation.  
Patients assigned a PIK3CA mutation status of ‘Unknown’ will not be eligible to participate in 
Part B. In cases where an archival tumour sample is not received in time to be analysed by the 
central laboratory during screening, defined status may be derived from the blood sample 
alone, or it may be applicable to utilise the status from a prior, locally-conducted tumour 
analysis, see above. 
If a patient is initially stratified to the ‘Not detected’ arm based upon a blood sample alone, or 
blood sample plus locally–conducted tumour analysis, and a subsequent, delayed, tumour 
sample is ‘positive’ – the stratification will not be changed but the discrepancy will be noted.  
Any requirement to assign additional patient places to either stratification arm will be 
determined on an as-needed basis, dependent upon the number of discrepant patients. 
5.2.2 
Procedures for allocation and randomisation 
Part A. Safety Run-In 
A central coordinator at AstraZeneca is responsible for the process of allocation of patients to 
treatment schedules 1 or 2.  


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
57(131) 
Once the eligibility of a patient for the Safety run-in phase has been confirmed, the study site 
should notify the AstraZeneca coordinator by completion and e-mailing of a registration form.  
Patients will be allocated sequentially, in the order of notification, to each open dosing 
schedule and will be assigned the four digit identification code. 
If either schedule completes, is terminated or recruitment to it is temporarily halted due to e.g., 
a full quota of patients being entered to a cohort; new patients will be allocated to the other, 
ongoing schedule to ensure that eligible consented patients are not denied, or have delayed, 
access to participation in this study. 
If a patient is allocated to the wrong schedule no attempt should be made to remedy the error 
once study material has been dispensed.  The patient will continue with the allocation number 
and study material, and AstraZeneca should be notified as soon as the error is discovered.  
Admission of subsequent patients will continue using the first unallocated number in the 
original numbering sequence. 
In the event of replacement patients being needed to maintain cohort size, that cohort will be 
opened for recruitment and patients will be allocated to it under the system described above 
until the cohort is complete. 
Part B. Randomised Expansion: 
The biostatistics group within AstraZeneca or representative is responsible for generating the 
randomisation scheme. The randomisation scheme will be produced by a computer software 
program that incorporates a standard procedure for generating random numbers. 
Once the eligibility of a patient for the Expansion phase has been confirmed and the patient 
has been stratified based upon PIK3CA mutation status, the study site should contact the 
Centralized IVRS/IWRS by telephone or using the web for allocation of a randomised 
identification code, as described above.  
Patient eligibility must be established before drug is dispensed. 
5.3 
Procedures for handling patients incorrectly enrolled or initiated 
on investigational product 
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled or receive study medication.  There can be no exceptions to 
this rule. 
Where patients that do not meet the inclusion criteria are enrolled in error or incorrectly 
started on treatment, or where patients subsequently fail to meet the study criteria post-
initiation, the investigator should inform the AstraZeneca Global Study Delivery Team 
Physician immediately. The AstraZeneca Global Study Delivery Team Physician is to ensure 
all such contacts are appropriately documented. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
58(131) 
5.4 
Blinding and procedures for unblinding the study  
This section is applicable to the Part B Randomised Expansion part only. 
5.4.1 
Methods for ensuring blinding 
Study drug will be labelled using a unique Medication Identification (MedID) number, which 
is linked to the randomisation scheme. AZD5363 and matching placebo capsules will be 
identical and presented in the same packaging to ensure blinding of the study drug. 
5.4.2 
Methods for unblinding the study  
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the investigator(s) or pharmacists from the IVRS/IWRS. Routines 
for this will be described in the IVRS/IWRS user manual that will be provided to each centre. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation. The 
investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Treatment codes will not be broken for the planned analyses of data 
until all decisions on the evaluability of the data from each individual patient have been made 
and documented. 
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
Table 1 
Dosage form and strength of investigational product. 
Investigational product 
Dosage form and strength 
AZD5363 (blinded and unblinded) 
5 mg to 165 mg oral formulation 
Matching placebo (blinded) 
5 mg to 165 mg oral formulation 
 
AstraZeneca R&D Supply Chain (or contract research organisation) will pack, label, and 
supply the IP for this study. 
AZD5363/placebo will be packed into white high-density polythene bottles with child 
resistant, tamper evident closures. Study drug must be kept out of the reach of children.  
Patients will be supplied with sufficient amounts of study drug at each dispensing visit plus 
overage.  


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
59(131) 
During the Randomised Expansion phase, IP will be supplied only following notification to 
IVRS/IWRS, and IVRS/IWRS must be contacted before dispensing a new study drug supply 
to the patient 
5.5.2 
Identity of combination product. 
Paclitaxel will be provided from commercially available supplies.  Normally available stock 
will be used in keeping with the standard local practice.  Generic paclitaxel may be used if 
available.   
5.5.3 
Doses and treatment regimens 
AZD5363 / matching placebo:  
A twice daily regimen of an oral formulation given on a continuous or intermittent weekly 
dosing schedule.   
Where possible all doses of AZD5363/placebo should be taken, at approximately the same 
times each day, in a fasted state (water to drink only) from at least 2 hours prior to the dose to 
at least 1 hour post-dose. Please also refer to Restrictions (section 5.1) for further guidance 
regarding patient fasting status on study assessment days. 
If vomiting occurs within 30 minutes after AZD5363/placebo dosing, or later if the capsule(s) 
can be identified in the vomit content, the patient can re-take new capsule(s) 
Should a patient miss a scheduled dose, the patient will be allowed to take the dose up to a 
maximum of 2 hours after the scheduled dose time.  If greater than 2 hours after the scheduled 
dose time (other than to allow for receipt of Day 1 paclitaxel under the continuous dosing 
schedule, see Paclitaxel section below), the missed dose should not be taken and the patient 
should take their allotted dose at the next scheduled time.  If a patient needs to take the dose 
earlier for whatever reason, the patient can take the dose up to 2 hours earlier than the 
scheduled dose time.  The patient should make every reasonable effort to take the 
AZD5363/placebo capsule(s) on time.  
Paclitaxel:  
A weekly single intravenous (iv) infusion of 90 mg/m2 given over approximately one hour 
(with the actual time recorded in the CRF) via a rate-controlling device.  Patients will receive 
3 consecutive weekly paclitaxel infusions (given on Day 1 of weeks 1, 2 and 3), followed by 
one week off-treatment within each 28-day treatment cycle (see below). Please also refer to 
local paclitaxel label.  
Treatment Schedules: 
Under both the continuous and intermittent dosing schedules, first receipt of paclitaxel will be 
on Cycle 1, Day 1; first receipt of AZD5363/placebo will be on Day 2.  
Thereafter, under the intermittent dosing schedule, weekly AZD5363 regimens will continue 
to start on the day after receipt of paclitaxel. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
60(131) 
 
Cycle 1 
Cycle 2 onwards 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 1 
Week 2 
Week 3 
Week 4 
Paclitaxel. Dose dayĺ 
Day 1 
Day 1 
Day 1 
None 
Day 1 
Day 1 
Day 1 
None 
Continuous. 
Dose days ĺ 
Day 2 to Day 28 
Day 1 to Day 28 
AZD5363  
Intermittent. 
Dose days ĺ 
D2 to D5 D2 to D5
D2 to D5
None 
D2 to D5
D2 to D5 D2 to D5 
None 
 
Note:  
For the continuous dosing schedule; on those days in which both paclitaxel and 
AZD5363/placebo are to be received – the paclitaxel infusion must be completed 
before the first dose of AZD5363/placebo is given. 
For the intermittent dosing schedule; AZD5363/placebo should not be taken on any 
week that the paclitaxel infusion is not administered – either due to a scheduled off-
drug week or unscheduled omission or delay.  Where paclitaxel is ceased entirely, 
AZD5363/placebo may be continued on a weekly schedule at the investigator’s 
discretion.  
For the purposes of planning - a standard treatment cycle is defined as 4 weeks:- comprising 
three weeks of paclitaxel followed by one week off-therapy, regardless of receipt of 
AZD5363/placebo.  Where possible, investigators are strongly urged to maintain patients to 
this schedule.  For Part A dose cohort evaluability it is necessary for Cycle 1 to comprise three 
doses of paclitaxel within a four week period in the absence of a DLT (see Section 5.10.5).  
For study conduct - the start of a cycle will be determined by commencement of paclitaxel 
following a period off-therapy of t1 week.  After Cycle 1, a treatment cycle will be defined as 
receipt of a minimum of one, and a maximum of three, weeks of paclitaxel therapy followed 
by a period of  t1 week off-therapy, regardless of receipt of AZD5363/placebo.    
For example; if a patient completes a standard 4 week cycle (Cycle A), but then 
receipt of paclitaxel is delayed by a further week, the next cycle will not formally 
commence until next first receipt of paclitaxel (Day 1 Cycle B).  Under the 
continuous dosing schedule - during the ‘missed’ week, the patient will continue to 
receive AZD5363/placebo; this period will be taken as an extension to the previous 
cycle (Cycle A). 
Where paclitaxel has ceased, but patients continue to receive AZD5363/placebo:  The start of 
a cycle will be the day of first receipt of AZD5363/placebo (or the day before that if the 
patient is on the intermittent dosing schedule).  Each cycle will be 28 days.   




Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
62(131) 
If receipt of AZD5363/placebo is suspended for >28 continuous days, this study therapy 
should be permanently withdrawn.  Any request to continue therapy after such a suspension 
must be agreed with the AstraZeneca Study Delivery Team Physician.   
During the Part A dose evaluation period (Cycle 1).  If a patient experiences a DLT or an 
unacceptable toxicity occurs, AZD5363 treatment will be stopped and supportive therapy 
administered as required.  If the toxicity resolves, or reverts to CTCAE grade 0 or 1 or 
baseline (pre-study), levels within 28 days of onset, and the patient is showing clinical benefit, 
treatment with AZD5363 may be restarted at a lower dose level at the discretion of the 
investigator.  Dose reductions should be in single or multiple increments of 80 mg bd to a 
minimum dose of 80 mg bd for the continuous dosing schedule and 120 mg bd for the 
intermittent dosing schedule. 
During the Part A post-dose evaluation period (Cycle 2 onwards) and Part B.  Any 
toxicity observed during the course of the study that is suspected of being related to 
AZD5363/matching placebo may be managed at the discretion of the investigator by dose 
interruption or by dose reduction. Repeat dose interruptions are to be allowed as required, for 
a maximum of 4 weeks (28 days) on each occasion.  Dose reductions should be in single or 
multiple increments of 80 mg bd to to a minimum dose of 80 mg bd for the continuous dosing 
schedule and 120 mg bd for the intermittent dosing schedule. 
All dose modifications and interruptions (including any missed doses due to AEs), and the 
reasons for the dose modifications/interruptions are to be recorded in the CRF. 
See Appendix H for instruction regarding AZD5363/placebo dose modifications 
Paclitaxel 
During the Part A dose evaluation period (Cycle 1).  Paclitaxel first dose, Cycle 1, Day 1, 
must be administered at 90 mg/m2.  Dose reductions or dose interruptions/omissions for the 
second and third infusions in Cycle 1 may be implemented at the discretion of the investigator 
to alleviate suspected toxicities. Single reductions should be in steps of no more than 20 
mg/m2.  Patients receiving less than 80% of the intended dose (90 mg/m2 x 3) within the 28 
days, and that do not experience a DLT, will not be evaluable under the dose escalation 
review criteria (see section 5.10.5)  
Cycle 1 will comprise a 28-day evaluation period, regardless dose reductions or dose 
omissions, unless the patient experiences a DLT. 
During the Part A post-dose evaluation period (Cycle 2 onwards) and Part B.  At the 
discretion of the investigator, reduced doses may be administered in subsequent cycles to 
alleviate suspected toxicities according to local clinical practice.  In the event of suspected 
neutropenia, guidance regarding paclitaxel dose modifications is provided in Appendix H. 
If receipt of paclitaxel is suspended for 28 continuous days, this study therapy should be 
permanently withdrawn.  Any request to continue therapy after such a suspension must be 
agreed with the AstraZeneca Study Delivery Team Physician. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
63(131) 
5.5.5 
Safety Run-In: Starting dose and dose escalation scheme 
For Study Part A; administration of AZD5363 will commence, when combined with 
paclitaxel, at cohort 1 of each schedule at doses of: 
x
Continuous dosing: 320 mg bd (640 mg daily). 
x
Intermittent dosing (4 days of treatment followed by 3 days off-treatment: 360 mg 
bd (720 mg daily). 
These starting doses are below the AZD5363 monotherapy doses of: 400 mg bd (continuous 
dosing schedule) and 480 mg bd (intermittent dosing schedule) deemed tolerable in the 
ongoing Phase I multiple-ascending dose study (D3610C00001) in patients with advanced 
solid malignancies at the time of initiating Part A.   
Patients will be enrolled to ensure a minimum of three and a maximum of six evaluable 
patients per dose escalation cohort.  For procedures and definitions associated with dose 
escalation, see Section 5.10. 
5.5.6 
Randomised expansion: Selected Dose 
Study Part B will be conducted at a dose and schedule of AZD5363, when combined with 
paclitaxel, selected from Part A.  
5.5.7 
Labelling 
AZ will provide AZD5363/matching placebo capsules to the study sites in bottles with child-
resistant, tamper-evident closures. Bottle labels will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines.  The labels will fulfil GMP 
Annex 13 requirements for labelling.  Label text will be translated into local language.  
The label will include the following information: 

Name of sponsor (AstraZeneca). 

IP/study drug dosage form, route of administration, and quantity of dosage 
units. 

Storage conditions. 

Study code.  

Study Part (i.e., Safety run-in/randomised). 

Enrolment code. 

Directions for use. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
64(131) 

MedID for Part B Randomised phase of study. 
5.5.8 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the bottle specifies the appropriate storage. 
5.6 
Concomitant and post-study treatment(s) 
Information on any treatment received by the patient, with reasons for its provision, will be 
recorded in the eCRF from 4 weeks prior to starting study treatment up to 28 days after the 
last dose of AZD5363/placebo or until objective progression, whichever is the latest.  If 
medically feasible, patients taking regular medication - with the exception of potent inhibitors 
or inducers or substrates of CYP3A4 or substrates of CYP2D6 - (see Section 4.2 Exclusion 8 
and Appendix G), should be maintained on it throughout the study period. 
Other anticancer agents, investigational agents and radiotherapy should not be given while the 
patient is on study treatment although radiation for palliation at focal sites is permitted. 
Pre-medication will be allowed after, but not before the first dose of study treatment.  This 
includes management of diarrhoea, nausea and vomiting. Pre-medication required for 
paclitaxel therapy is allowed as per local standards and label.  
Blood transfusions are allowed at any time during the study. 
Patients already receiving erythropoietin at the time of screening for the study may continue it 
providing they have been receiving it for more than one month at the time study treatment is 
started.  Prophylactic erythropoietin should not be started during Cycle 1 of the study but may 
be started during or after Cycle 2.  
Granulocyte colony stimulating factors should not be used prophylactically during Cycle 1.  
Use of prophylactic colony stimulating factors may be considered after Cycle 1 following 
discussion with the AstraZeneca Study Delivery Team Physician. 
Patients may receive bisphosphonates for the treatment of bone metastases. 
Patients may take warfarin or a coumarin preparation but it is recommended that they should 
have their anticoagulation monitored carefully and dose adjusted accordingly. 
Patients may take corticosteroids, however, increased vigilance is recommended on electrolyte 
and/or glucose levels due to the potential for corticosteroid-related metabolic disturbance. 
Supportive care and other medications that are considered necessary for the patient’s well-
being, may be given at the discretion of the investigator. 
Other medication, which is considered necessary for the patient’s safety and well being, may 
be given at the discretion of the investigator and recorded in the appropriate sections of the 
eCRF. 




Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
66(131) 
x
Study treatments are handled and stored safely and properly as stated on the label. 
x
AZD5363/matching placebo is only dispensed to study patients in accordance with 
the protocol. 
x
Patients return all unused medication and empty containers to the investigator. 
At the end of the study, it must be possible to reconcile delivery records with records of usage 
and destroyed/returned stock.  Records of usage should include the identification of the person 
to whom the AZD5363/matching placebo was dispensed, the quantity and date of dispensing 
and unused AZD5363/matching placebo returned to the investigator.  This record is in 
addition to any drug accountability information recorded on the CRF.  Any discrepancies must 
be accounted for on the appropriate forms.  Certificates of delivery and return must be signed, 
preferably by the investigator or a pharmacist, and copies retained in the investigator site file. 
All unused or returned medication, after drug accountability, should be destroyed according to 
local AZ procedures, this can be at site or in the marketing company wherever possible.  In the 
event that this is not possible, the medication should be returned to the local distribution 
centre for destruction. 
AZD5363/matching placebo and label accountability records will be maintained by the study 
site personnel.  These will be used in conjunction with the handling and preparation 
worksheets for recording all drug and label use. 
5.8 
Discontinuation of investigational product 
Patients may be discontinued from IP at any time, without prejudice to further treatment. If a 
patient discontinues IP for reasons other than death, then they should still continue in the 
study up to objective disease progression assessed by RECIST 1.1, unless they withdraw 
consent from the study. 
Patients may be discontinued from IP in the following situations: 
x
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment. 
x
Adverse Event. 
x
Severe non-compliance to study protocol in the judgement of the investigator and/or 
AstraZeneca. 
x
Confirmed objective disease progression assessed by RECIST 1.1. 
x
Patients incorrectly initated on IP (see Section 5.3). 
x
Patient becomes pregnant. 


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x
Patient experiences CTC grade 4 hyperglycaemia. 
x
Patient experiences: 

 ALT or AST >8x ULN. 

or, ALT or AST >5x ULN for more than 2 weeks. 

or, ALT or AST >3x ULN and (total bilirubin >2x ULN or INR >1.5). 

or, ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
5.8.1 
Procedures for discontinuation of a patient from investigational product  
A patient that decides to discontinue IP will always be asked about the reason(s) and the 
presence of any adverse events.  If possible, they will be seen and assessed by an 
investigator(s) (See Figure 5 and Figure 6 for assessments to be performed).  Adverse events 
will be followed up (See Sections 6.4.3 and 6.4.4); diary cards, questionnaires and all study 
drugs should be returned by the patient. 
If a patient is withdrawn from study, see Section 5.9. 
It is important to determine the wishes of the patient – to differentiate between discontinuation 
from IP or complete withdrawal from the study when consent is withdrawn. 
5.9 
Withdrawal from study 
Patients are at any time free to withdraw from study (IP and assessments), without prejudice 
to further treatment (withdrawal of consent).  Such patients will always be asked about the 
reason(s) and the presence of any adverse events.  If possible, they will be seen and assessed 
by an investigator.  Adverse events will be followed up (See Sections 6.4.3 and 6.4.4); diary 
cards, questionnaires and all study drugs should be returned by the patient. 
Part A.  Safety Run-in: Patients that are withdrawn from the study but are evaluable per the 
definition in Section 5.10.5 will not be replaced.  Any patient that is withdrawn and is not 
evaluable will be replaced to ensure a minimum number of evaluable patients. 
Part B. Randomised Expansion:  Patients that are withdrawn will not be replaced  
At the point of withdrawal, no further study procedures or follow up assessments will be 
performed and no further data will be collected. A call should be made to the IVRS system to 
discontinue the patient. 
The reason for withdrawal from the study should be recorded on the eCRF. Patients will be 
considered to have withdrawn from the study only due to one of the following reasons: 
x
Patient decision (patients withdraws consent from participating in the study). 


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Edition Number 1 
Date 24 February 2012 
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x
Eligibility criteria not fulfilled. 
x
Adverse Event. 
x
Severe non-compliance to protocol. 
x
Condition under investigation worsened. 
x
Death. 
x
Patient lost to follow up. 
Patients may withdraw from any aspects of the voluntary exploratory research (see Section 
6.8.1) at any time, without prejudice to further treatment and independent of any decision 
concerning participation in other aspects of the main study.  Procedures for withdrawal of 
consent for donated biological samples are outlined in Section 7.5. 
5.9.1 
Screening failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study and are 
therefore not enrolled. These patients should have their reason for study withdrawal recorded 
as ‘Eligibility Criteria not fulfilled’ (ie, patient does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screening failures (not enrolled 
patients). 
5.10 
Conduct of Part A: Safety Run-in Phase. 
5.10.1 
Starting dose 
Dose administration of AZD5363 will commence at cohort 1 of each schedule as detailed in 
section 5.5.5. 
5.10.2 
Safety Review Committee and Dose Escalation Process  
After each dose level during Part A of the study, the SRC will evaluate the safety and 
tolerability and pharmacokinetics of AZD5363 to decide the next dose. 
The SRC will consist of: 
x
Study Delivery Team Physician, who will chair the committee, or delegate. 
x
Principal Investigator or delegate from each investigational site. 
In addition, other physicians from the following may be invited: 
x
Patient Safety Physician or delegate. 
x
Medical Science Director or delegate. 


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x
Senior physician from another project. 
The Study Pharmacokineticist, Study Statistician, Patient Safety Scientist, and Study Delivery 
Team Leader may also be invited as appropriate.  The SRC Remit document for this study will 
define the exact membership and who should be present for decisions to be made. 
Further internal or external experts may be consulted by the SRC as necessary.  The Patient  
Safety Physician or delegate should always be present at the SRC if there are safety issues for 
discussion. 
Once there are at least 3 evaluable patients at a dose level the SRC will review and assess all 
available safety data from the cohort, together with available PK and pharmacodynamic data 
to make a decision on the dose for the next cohort of patients.  Any dose interruptions and 
reductions will be taken into account.   
The decision may be to: 
1. 
Proceed with dose escalation – refer to Section 5.10.3. 
2. 
Expand the cohort to a maximum of 6 evaluable patients. 
3. 
Reduce the dose either to a previous lower dose level (up to a maximum of 6 
evaluable patients) or to an intermediate lower dose level. 
4. 
Revise the dosing schedule for the subsequent cohort (intermittent scheduling arm 
only).  
5. 
Define the RD (and NTD/MTD where applicable).  To define a RD or the MTD, 6 
evaluable patients must be assessed at that dose level.  The SRC may elect to assess 
up to a further 6 evaluable patients at the identified MTD to confirm the dose 
selection.  To determine the NTD 2 patients, of up to 6 patients, must experience 
DLTs at that dose level. 
6. 
Stop the dose escalation part of the study. 
When there are other patients that are ongoing at the time of this review, the SRC may decide 
to defer their decision until these further patients become evaluable. 
Any patient started on treatment in error, as he/she failed to comply with all of the selection 
criteria but meets the criteria of an evaluable patient, will be reviewed on a case by case basis 
by the SRC to determine if the patient should be included or excluded in the decision for dose 
escalation. 
The decisions and decision-making of the SRC on the next dose level will be documented and 
provided to the investigators prior to dosing any new patients. 


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Edition Number 1 
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5.10.3 
Criteria to conduct dose escalation and reduction  
Dose Escalation: Parameters. 
Dose escalation and reduction per cohort will be determined by the SRC with reference to the 
following logic: 
x
If no DLT is observed (for definition see Section 5.10.6) in a cohort of 3-6 
evaluable patients then dose escalation may occur.  Dose increases will be permitted 
after review of data from a minimum of 3 evaluable patients has been performed.   
x
If one patient experiences a DLT in a group of 3 or more evaluable patients then the 
cohort will be expanded to include 6 evaluable patients.  If only one DLT is 
observed in the complete cohort of 6 evaluable patients then dose escalation may 
occur. 
x
If 2 or more patients experience a DLT in a group of up to 6 evaluable patients, 
irrespective of the number of patients enrolled, the dose will be considered not 
tolerated and recruitment to the cohort and dose escalation will cease.  A lower 
intermediary dose (reduction) may be considered in order to better define the MTD. 
The dose may initially be increased up to a level the SRC declare is safe and appropriate based 
on clinical PK and/or safety data. The SRC will determine the dose escalation/reduction based 
on the above criteria at the end of each dose group. 
Based on emerging data, including available PK and/or safety data and/or pre-clinical data, the 
SRC can consider alternative treatment schedules, including once-daily dosing of AZD5363, 
in consultation with AZ.  
When an NTD is defined, dose escalation/ will be stopped. All patients receiving the NTD 
should have their dose reduced to a tolerated dose or discontinue AZD5363 if a tolerated dose 
has not been defined. An interim dose (ie, one between the NTD and the last dose tested 
before NTD) may be assessed to determine the MTD and the SRC will decide this upon 
review of the data. The MTD will be defined as the last dose assessed below the NTD. 
If dose reductions or delays greater than those allowed under this protocol (see section 5.5.4) 
occur during the DLT evaluation period, the patient will be considered either as not evaluable 
or as having attained a DLT (see Section 5.10.6 for definition of DLT).  
The DLT evaluation period ends following the completion of all assessments on the last day 
of the first cycle (Day 28). 
Escalations will not exceed doubling of the dose of the prior cohort.  
Intra-patient dose escalation is not permitted. 




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5.10.4 
Definition of maximum tolerated dose 
A primary objective of the Part A Safety Run-in phase is to determine a RD to take forward to 
the Expansion phase. It may not be necessary to escalate to NTD/MTD to establish the RD. 
Where it is necessary, or where the SRC deems it appropriate to do so, the following criteria 
will apply for determination of NTD/MTD.  
A dose will be considered non-tolerated, and dose escalation will cease, if 2 or more of up to 6 
evaluable patients experience a DLT at that dose level. Once the NTD is defined the MTD 
will be confirmed at the previous dose-level below the NTD or a dose between the NTD and 
the last tolerated dose may be investigated. Six evaluable patients are required to determine 
the MTD. 
5.10.5 
Definition of evaluable patient for Part A 
An evaluable patient is defined as one that, during Cycle 1: Weeks 1 to 4 has:  
x
Completed the minimum safety evaluation requirements and has received: 

At least 80% of the total intended dose of AZD5363 within the 28 day cycle. 

3 doses of paclitaxel, comprising at least 80% of the total specified dose (where 
total dose is 3 x 90 mg/m2 = 270 mg/m2)*, within the 28 day cycle**.    
or  
has experienced a DLT prior to fulfilling the above criteria. 
Note: 
* Cycle 1, Day 1, paclitaxel first dose must be administered at a dose of 90 mg/m2.  
Dose reductions for the second and third infusions in Cycle 1 may be implemented, 
if required under the investigator’s discretion for suspected toxicities. Single 
reductions can be in increments of no more than 20 mg/m2 to a minimum dose of of 
60 mg/m2.   
** A dose delay to the second and/or third paclitaxel infusion during Cycle 1 is 
permissable, providing that the total delay is no more than 7 days.  All three doses 
must be received within the 28 day cycle. 
5.10.6 
Definition of dose-limiting toxicity  
A DLT is defined as: 
x
An AE or laboratory abnormality considered to be related to paclitaxel, that 
commences at any time during the DLT evaluation period (Cycle 1) and meets 
either of the following criteria:  


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1. 
Requires a dose reduction or omission to <60% of the intended Cycle 1 
total paclitaxel dose (90 mg/m2 x 3). 
2. 
Any delay to the administration of weekly paclitaxel chemotherapy on 
D1 of Cycle 2 by 7 days as a consequence of paclitaxel induced toxicity 
x
An AE or laboratory abnormality considered to be related to AZD5363, that 
commences at any time during the DLT evaluation period (Cycle 1) and meets any 
of the following criteria: 
1. 
Haematological toxicity: 

CTCAE grade 4 haematological toxicity of any duration. 

Febrile neutropenia (CTCAE grade 3 with temperature 38.5°C which is 
unresponsive to antipyretics). 

CTCAE grade 3 neutropenia requiring hospitalisation. 

CTCAE grade 3 thrombocytopenia associated with non-traumatic bleeding 
(but not applicable to patients on therapeutic anticoagulation). 
2. 
Clinical chemistry toxicity: 

CTCAE  Grade 3 hyperglycaemia (glucose >13.9 mmol/L) for more than 1 
week, despite optimal intervention which is not attributable to another co-
morbidity. 

Grade 4 hyperglycaemia (glucose >27.8 mmol/L). 

AST or ALT >10x ULN and AZD5363 is considered the most likely cause. 

AST or ALT >8x ULN, when combined with doubling of bilirubin from 
baseline, and AZD5363 is considered the most likely cause. 
3. 
Cardiovascular toxicity: 

QTc (Fridericia’s or Bazett’s correction) interval >500msec or QTc increase 
>60msec from baseline on two ECGs at least 30 minutes apart, that cannot be 
attributed to another cause. 

Symptomatic congestive cardiac failure (NYHA class III/IV) and a drop in 
LVEF which cannot be attributed to another cause.  Note: Concomitant use of 
vasotonic drugs, adrenergic blockers, negative inotropic agents and anti-
hypertensives should be taken into consideration when assigning causality. 


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Edition Number 1 
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
A decrease in LVEF of 20% to a level below the institution’s lower limit of 
normal range. 

CTCAE grade 3 hypotension which cannot be attributed to another cause. 
4. 
Other toxicities: 

Clinically significant rash that despite optimal treatment remains CTCAE grade 
3 for 5 days or longer and that cannot be attributed to another cause.  

CTCAE grade 3 nausea, vomiting or diarrhoea, despite optimal anti-emetic or 
anti-diarrhoeal therapy, and which cannot be attributed to another cause. 

Any other CTCAE grade 3 toxicity which, in the opinion of the investigator, 
is clinically significant and related to AZD5363. 

Any delay to the administration of weekly paclitaxel chemotherapy on Day 1 of 
Cycle 2 by 7 days as a consequence of AZD5363 induced toxicity. 

Any other toxicity that is greater than that at baseline, is clinically significant 
and/or unacceptable, does not respond to supportive care and results in a 
disruption of dosing schedule of more than 14 days. 
Any event, including significant dose reductions or omissions, judged to be a DLT by the 
SRC. 
A DLT excludes:  
1. 
Alopecia of any grade. 
2. 
Isolated laboratory changes of any grade without clinical sequelae or clinical 
significance. 
The National Cancer Institute (NCI) CTCAE version 4.1 will be used whenever applicable to 
characterise DLTs.  However, pre defined stopping criteria will supersede the CTCAE criteria. 
Where a criterion for a DLT is reached, any subsequent delays in dosing or dose reductions of 
paclitaxel or AZD5363 due to toxicity are considered to occur after the DLT evaluation 
period. 
If patients present with a potential DLT, the patient should be promptly investigated to define 
the aetiology of the symptoms.  The use of appropriate (ie, non-restricted) medications in 
prophylactic or therapeutic management of toxicities are permitted.   
The decision to interrupt dosing or to stop a patient from receiving further dosing will be 
taken by the principal or co-investigator, in consultation with the AZ Study Delivery Team 


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Date 24 February 2012 
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Physician, based on the clinical significance of the observed toxicity.  If the toxicity is 
subsequently determined by the SRC to not be a DLT, this patient will be replaced. 
The principal investigator, in consultation with the AZ Study Delivery Team Physician, may 
request replacement of patients who develop DLTs that are attributed to confounding factors 
and concomitant medications started during the DLT assessment period.  Confounding 
medications for the specific DLT may be prohibited for the new patient(s) recruited to that 
dose group 
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The investigator will ensure that data are recorded on the eCRFs as specified 
in the study protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
The investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site. 
6.2 
Data collection at enrolment and follow-up 
6.2.1 
Enrolment procedures 
Written informed consent must be obtained prior to conduct of any study specific assessments. 
Procedures that are part of standard care may occur before informed consent is obtained. 
A list of procedures and assessments described in the Study Plans (Figure 5: Continuous 
dosing; Figure 6: Intermittent dosing) for the screening visit must be completed within 4 
weeks (-28 days) of enrolment. At screening, consenting patients will be assessed to ensure 
that they meet inclusion and exclusion criteria (Sections 4.1 and 4.2). 
Demographic data and other characteristics will be recorded at screening and will include: 
date of birth, gender, race, menstrual status and smoking history. 
Part B. Randomised Expansion: Each patient’s PIK3CA mutation status must be determined at 
screening from a blood and archival tumour sample to enable the patient to be stratified as 
PIK3CA mutation positive or not detected prior to randomisation (see section 5.2.1): 
x
Patients will be stratified to the PIK3CA mutation positive arm where either one of 
the sample-type analyses is positive.  Patients will be stratified to the not-detected 
arm where both sample type analyses are negative. 
x
It is requested that all efforts are made to ensure that archival tumour tissue is 
provided for this stratification analysis.  Where tissue cannot be made available in a 


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Edition Number 1 
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timely manner, PIK3CA mutation stratification may be conducted on the blood 
sample analysis alone.  In this event, tumour tissue must be provided for 
retrospective PIK3CA mutation analysis prior to completion of treatment Cycle 1.   
x
Where a patient has been assigned to the not-detected arm from blood sample 
analysis alone but the retrospective tumour tissue analysis is PIK3CA mutation 
positive - the patient will remain stratified to the not-detected arm.  The discrepancy 
will be noted and an additional patient allocation may be made for this arm.   
x
In the event that one stratification arm (PIK3CA mutation positive or not-detected) 
completes recruitment before the other, new candidate patients will be requested to 
provide separate, initial, informed consent to obtain a blood and/or tumour tissue 
sample to screen for PIK3CA mutation status.  Patients with status appropriate for 
entry to the open stratification arm will be invited to provide informed consent for 
entry to the study. 
6.2.2 
PIK3CA Mutation Status 
Patient response to treatment will be assessed against the tumour PIK3CA mutation status to 
determine whether the mutation confers any increased tumour sensitivity to AZD5363. 
Blood and most recent archival tumour samples will be collected at screening (see Figure 5 
and Figure 6) with reference to the criteria and restrictions detailed in section 5.2.1.  The 
PIK3CA mutation assay(s) will genotype for a set of mutations that will cover the majority of, 
but not all, mutations in the PIK3CA gene that have been thus far identified in breast cancer 
patients.  Therefore, there may be patients carrying either a rare mutation, not included in the 
assay(s) used, or who have a level of mutation in cfDNA or tumour tissue DNA beyond the 
range of sensitivity of the selected assay(s).  In this case, their mutation will not be identified 
under the protocolled testing.  In acknowledgment of this, patients who are shown not to be 
‘mutation positive’ in either cfDNA or tumour tissue DNA will be categorised as ‘mutation 
not detected’, rather than a more definitive ‘mutation negative’. 
During Study Part B, PIK3CA mutation status will be utilised to stratify patients to ‘positive’ 
and ‘not detected’ arms (see section 5.2.1). 
6.2.3 
Follow-up procedures 
Patients will be followed up as detailed below unless prior withdrawal from the study or 
death: 
Part A. Safety Run-in:  Patients will be followed to discontinuation of study drug / completion 
of the 28-day safety follow-up.  
Part B. Randomised Expansion:  Patients will be followed to objective disease progression. 


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6.2.3.1 
Study Drug Discontinuation 
The discontinuation visits for AZD5363/matching placebo and paclitaxel should take place at 
the time of the last dose of the applicable study drug, or as soon as possible following 
confirmation that no further dosing will take place. 
6.2.3.2 
28-Day Safety follow-up     
For safety follow-up as a minimum, telephone contact should be made with the patient 
28 days following the discontinuation of both AZD5363/matching placebo and paclitaxel, to 
follow up on any SAE/AE’s, surgery, concomitant medications, concomitant procedures, 
radiotherapy and subsequent cancer therapy.  Any SAEs will be followed to resolution where 
possible.   
6.2.3.3 
 Progression follow-up 
Part B. Randomised Expansion only.  Patients who discontinue AZD5363/matching placebo 
for reasons other than progression will continue RECIST 1.1 assessments every 12 weeks 
(from Cycle 1 Day 1) r7days up to objective disease progression.  This schedule of RECIST 
1.1 assessments should be maintained even if study treatment cycles have been delayed.  Only 
new SAEs due to study procedures should be collected.     
6.3 
Efficacy  
6.3.1 
Tumour assessments 
RECIST 1.1 criteria will be used to assess patient response to treatment by determining 
change in tumour size at 12 weeks, percentage of patients without progressive disease, at 12 
weeks, overall response rate (ORR), BoR, DoR and PFS. The RECIST 1.1 guidelines for 
measurable, non-measurable, target, and non-target lesions (NTL) and the objective tumour 
response criteria (CR, PR, stable disease [SD], or progressive disease [PD]) are presented in 
Appendix F. 
RECIST assessments will be performed using CT or MRI scans of the chest, abdomen and 
pelvis.  Baseline assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients.  Baseline assessments should be 
performed no more than 28 days before the start of study treatment, and ideally should be 
performed as close as possible to the start of study treatment.   
The methods of assessment of tumour burden used at baseline (CT or MRI scans of the chest, 
abdomen and pelvis) must be used at each subsequent follow-up assessment.  
Follow-up assessments will be performed every 12 weeks (r7 days) after start of treatment 
(Cycle 1 day 1) until objective disease progression as defined by RECIST 1.1.  For the Safety 
Run-in phase (Part A), tumour assessments will stop after cessation of study drug where prior 
to progression.  For the Randomised Expansion phase (Part B), if a patient discontinues 
treatment (and/or receives a subsequent cancer therapy) prior to progression then the patient 


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should still continue to be followed until objective disease progression as defined by RECIST 
1.1. 
Any other sites at which new disease is suspected should also be appropriately imaged.  If an 
unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. 
For Part A, for patients with non-measurable disease only at baseline, categorisation of 
objective tumour response assessment will be based on the RECIST 1.1 criteria of response: 
complete response (CR), PD (progression of disease) and Non CR/Non PD. 
For Part B, categorisation of objective tumour response assessment will be based on the 
RECIST 1.1 criteria of response: CR, PR (partial response), SD (stable disease) and PD 
(progression of disease).  Target lesion (TL) progression will be calculated in comparison to 
when the tumour burden was at a minimum (i.e. smallest sum of diameters previously 
recorded on study).  In the absence of objective progression, tumour response (CR, PR, SD) 
will be calculated in comparison to the baseline tumour measurements obtained before starting 
treatment. 
If the Investigator is in doubt as to whether objective progression has occurred, particularly 
with response to NTL or the appearance of a new lesion, it is advisable to continue treatment 
until the next scheduled assessment, or sooner if clinically indicated, and reassess the patient’s 
status.  If repeat scans confirm progression, then the date of the initial scan should be declared 
as the date of objective progression. 
To achieve ‘unequivocal progression’ on the basis of 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 tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more NTLs is usually 
not sufficient to quality for unequivocal progression status. 
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plan in Figure 5 and Figure 6. 
The primary analysis for this study will be based on the tumour assessments recorded on the 
eCRF. 
Radiological examinations performed in the conduct of this study for RECIST response 
assessments must be retained at site as source data and a copy anonymised for personal 
identifiers, e.g. name, initials, be available for collection by the Sponsor to support any future 
regulatory requests. 
6.4 
Safety 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 


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6.4.1 
Definition of adverse events  
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, ECG). In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. AEs will be graded 
according to CTCAE version 4.1. 
The term AE is used to include both serious and non-serious AEs. 
6.4.2 
Definitions of serious adverse event 
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria: 
x
Results in death. 
x
Is immediately life-threatening. 
x
Requires in-patient hospitalisation or prolongation of existing hospitalisation . 
x
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions. 
x
Is a congenital abnormality or birth defect. 
x
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol. 
6.4.3 
Recording of adverse events 
Time period for collection of adverse events  
Adverse Events will be collected from time of signature of informed consent, throughout the 
treatment period up to, and including, the follow-up period. The follow-up period is defined as 
28 days after study treatment (both AZD5363/placebo and paclitaxel) is discontinued. 
For the Randomised Expansion phase, SAEs occurring after the 28-day follow-up, that are 
considered related to study procedures, should continue to be recorded while patients are 
followed-up for disease progression.  


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If the investigator learns of any SAE(s), including death, at any time after a patient has 
completed the study, and he/she considers there is a reasonable possibility that the event is 
related to AZD5363, the investigator should notify AstraZeneca. 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the patient’s last visit in the study will be followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF. 
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
Variables 
The following variables will be collect for each AE; 
x
AE (verbatim). 
x
The date when the AE started and stopped. 
x
Whether the AE is serious or not. 
x
Investigator causality rating against the IP (yes or no). 
x
Investigator causality rating against paclitaxel (yes or no).  
x
Action taken with regard to IP. 
x
Action taken with regard to paclitaxel. 
x
Outcome. 
In addition, the following variables will be collected for SAEs: 
x
Date AE met criteria for serious AE. 
x
Date Investigator became aware of serious AE. 
x
AE is serious due to (specify reason). 
x
Where applicable: 

Date of hospitalisation. 

Date of discharge. 

Probable cause of death. 

Date of death. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
81(131) 

Autopsy performed. 
x
Causality assessment in relation to Study procedure(s). 
x
Causality assessment in relation to Other medication. 
x
Description of AE. 
The grading scales found in the revised National Cancer Institute CTCAE version 4.1 will be 
utilised for all events with an assigned CTCAE grading.  For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used.  A copy of the CTCAE version 4.1 can be 
downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.4.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
Causality collection 
The Investigator will assess causal relationship between IP and each Adverse Event, and 
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the investigational product?’ 
For SAEs causal relationship will also be assessed for other medication, including paclitaxel 
and study procedures.  Note that for SAEs that could be associated with any study procedure 
the causal relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol. 
Adverse Events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the CRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
Adverse Events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
Clinical Study Report (CSR).  Deterioration as compared to baseline in protocol-mandated 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
82(131) 
laboratory values, vital signs, ECGs and other safety assessments, should therefore only be 
reported as AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of 
treatment with the IP. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
Hy’s Law 
Cases where a patient shows an AST or ALT 3x ULN or total bilirubin  2x ULN may need 
to be reported as SAEs, please refer to Appendix E ‘Actions required in cases of combined 
increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions. 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease.  The development of 
new, or progression of existing metastasis to the primary cancer under study should be 
considered as disease progression and not an AE.  Events, which are unequivocally due to 
disease progression, should not be reported as an AE during the study. 
Deaths 
All deaths (both cancer-related and other) that occur during the study and within 28 days after 
the last dose of AZD5363 must be reported as follows: 
x
Death clearly resulting from unequivocal disease progression should be reported to the 
study monitor at the next monitoring visit and should be documented on the relevant 
eCRF but should not be reported as an AE or SAE. 
x
When death is not due to progression of disease under study, the AE causing death 
must be reported to the study monitor as a SAE within 24 hours. The report should 
contain a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign main and contributory causes of death. 
In the event of death, the patient will be considered as having completed the study. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
83(131) 
New cancers 
The development of a new cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New cancers are those that are not the primary reason for 
administration of study treatment and have been identified after inclusion of the patient into 
the clinical study. They do not include metastases of the original cancer. Symptoms of 
metastasis or the metastasis itself should not be reported as an AE/SAE as they are considered 
to be disease progression. 
6.4.4 
Reporting of serious adverse events (SAEs) 
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the CRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives within one day ie, immediately but no later than the 
end of the next business day of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within one 
calendar day of initial receipt for fatal and life threatening events and within five calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than the end of the next business day 
of when he or she becomes aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 
The reference document for definition of expectedness/listedness is Section 5.4 of the 
Investigators’ Brochure for AZD5363, and the EU Summary of Product Characteristics (SPC) 
for paclitaxel.  
6.4.5 
Laboratory safety assessment 
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the Study Plan (see Figure 5 and Figure 6) at the 
following timepoints: 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
84(131) 
x
Screening 
x
Continuous Dosing schedule: 

Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose; Weeks 2, 3 and 4: Day 1 
pre-dose.  

Cycle 2: Weeks 1, 2, 3 and 4: Day 1 pre-dose. 

Cycle 3+: Week 1, Day 1 pre-dose up to discontinuation of both study 
therapies. 
x
Intermittent dosing schedule:  

Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose; Day 5 pre-dose; Weeks 2, 3 
and 4: Day 2 pre-dose. 

Cycle 2: Week 1: Day 2 pre-dose; Weeks 2, 3 and 4: Day 1 pre-dose. 

Cycles 3+: Week 1: Day 2 pre-dose up to discontinuation of both study 
therapies. 
x
Discontinuation of AZD5363/placebo: at any time of the day.   
x
Discontinuation of paclitaxel: at any time of the day.  
x
Urine pregnancy test to be completed at: Screening, Cycle 1 Week 1 Day 1 and on 
discontinuation of study therapies. 
Serum/Plasma glucose to be additionally measured, for evaluation of potential abnormalities 
of glucose metabolism, from one sample taken between 2 to 4 hours following receipt of 
the morning dose of AZD5363 at the following timepoints:   
x
Continuous dosing schedule: 

Cycle 1: Week1: Day 2; Weeks 2, 3 and 4: Day 1. 

Week 1, Day 1, of every Cycle thereafter up to discontinuation of AZD5363. 
x
Intermittent dosing schedule:   

Cycle 1: Week 1: Day 2; Day 5; Weeks 2, 3 and 4: Day 2. 

Day 2 of every Cycle thereafter up to discontinuation of AZD5363. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
85(131) 
If screening laboratory assessments are performed within 3 days prior to Cycle 1, Week 1, 
Day 1, these do not need to be repeated at Week1, Day 1. Eligibility criteria should be 
reviewed once screening laboratory results are available (refer to Section 4.2). 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator / delegate. The date, time of collection and results will be recorded on the 
appropriate eCRF. 
The clinical chemistry, haematology, and urinalysis will be performed at a local laboratory at 
or near to the Investigator site. Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site. For total blood volumes see 
Section 7.1. 
The following laboratory variables will be measured: 
Clinical chemistry 
Haematology 
Serum (S)/Plasma (P)-Albumin 
Blood (B)-Haemoglobin 
S/P-ALT 
B-Leukocyte 
S/P-AST 
B-Absolute leukocyte differential count: 
S/P-Alkaline phosphatase 
Neutrophils 
S/P-Bilirubin, total 
Lymphocytes 
S/P-Calcium, total 
Eosinophils 
S/P-Creatinine 
B-Platelet count 
S/P-FSH 
 
S/P-Glucose 
 
S/P-Magnesium 
Urinalysis 
S/P-Oestradiol  
U-Glucose 
S/P-Potassium 
U-Protein 
S/P-Total Protein 
U-Blood 
S/P Free T4 
U-Ketones 
S/P TSH 
S/P Troponin I or T 
U-Microscopy (red blood cells and white blood 
cells, bacteria, casts and crystals) only perform if 
urinalysis is abnormal
S/P-Sodium 
 
S/P-Urea nitrogen 
 
 
 
 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
86(131) 
NB. In case a patient shows an AST or ALT 3x ULN or total bilirubin 2x ULN please refer 
to Appendix E ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions. 
Urinalysis – supplementary evaluations: 
x
If 3+ proteinuria is identified by dipstick assessment, a 24-hour urine collection for 
formal quantification of the level of protein excretion should be performed.   
x
During Cycle 1, following discharge from the clinic, patients will be required to 
carry out a urine glucose assessment by dipstick prior to breakfast two times per 
week.  If a positive result is observed the patient must contact the clinic for further 
investigation of this result. 
6.4.6 
Physical examination 
A complete physical examination will include an assessment of the following: general 
appearance, respiratory, cardiovascular, abdomen skin, head and neck (including ears, eyes, 
nose and throat), lymph nodes, thyroid, abdomen, musculo-skeletal (including spine and 
extremities) and neurological systems. 
Physical examinations will be conducted at the times indicated in the Study Plan (see Figure 5 
and Figure 6) at the following timepoints: 
x
Screening. 
x
Cycle 1: Week 1 and 2: Day 1 pre-dose. 
x
Intermittent dosing schedule only.  Cycle 1: Week1: Day 5 pre-dose. 
x
Cycles 2+: Week 1: Day 1 pre-dose. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 
x
Discontinuation of paclitaxel: at any time of the day. 
6.4.7 
Height and weight 
The patient’s height (cm) and weight (kg) will be measured at the times indicated in the Study 
Plan (see Figure 5 and Figure 6) at the following timepoints: 
Height: 
x
Screening. 
Weight: 
x
Screening. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
87(131) 
x
Each Cycle: Week 1: Day 1 at any time of the day. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 
x
Discontinuation of paclitaxel: at any time of the day. 
6.4.8 
WHO Performance status 
Performance status will be assessed at screening and prior to the first dose of study treatment 
according to WHO criteria as follows: 
0 =  
Fully active, able to carry out all pre-disease activities without restrictions. 
1 =  
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature eg, light housework, office work. 
2 =  
Ambulatory and capable of 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 self-care, totally confined to bed or chair. 
6.4.9 
Resting ECG 
ECG measurements will be conducted at the study site or other local institution as applicable.  
At each timepoint, at approximately the same time of day, a standard 12-lead ECG should be 
performed after the patient has been resting in a semi-supine position for at least 5 minutes.  A 
paper speed of 25mm/second, covering at least 6 sequential beats, is recommended. Three 
ECGs per timepoint should be conducted within a 5-minute period. 
ECG measurements should be conducted as indicated in the Study Plan (see Figure 5 and 
Figure 6) at the following timepoints: 
x
Screening. 
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose, 1, 2, 6 and 24 hours post-dose; 
Week 2: Day 1 pre-dose. 
x
Intermittent dosing schedule only.  Cycle 1: Week1: Day 5 post-dose. 
x
Cycle 2: Week 1: Day 1 post-dose. 
x
Cycles 3+: Week 1: Day 1 at any time of the day.   
x
Discontinuation of AZD5363/placebo: at any time of the day.   


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
88(131) 
x
Discontinuation of paclitaxel: at any time of the day.   
ECG parameters: The following parameters will be recorded for each ECG: date and time of 
ECG, heart rate (beats/min), PR, R-R, QRS, QT (ms), QTc (ms), sinus rhythm (yes/no), and 
overall evaluation (normal/abnormal). 
The ECG will be evaluated by suitably qualified personnel and entered as “Normal” or 
“Abnormal” in the eCRF. If the ECG is evaluated as “Abnormal” the abnormality should be 
further specified. Any clinically significant abnormal findings observed and recorded on ECG 
during the treatment period will be reported as AEs (for details on AE recording refer to 
Section 6.4.3). 
For each ECG, one original ECG printout, initialled and dated by the Investigator, will be kept 
in the medical records, ensuring a copy is maintained in the source documents for the study. 
6.4.10 
Muga scan / Echocardiogram 
A MUGA scan or echocardiogram to assess LVEF will be conducted at the times indicated in 
the Study Plan (see Figure 5 and Figure 6) at the following timepoints: 
x
Screening. 
x
Cycle 2: Week 1: Day 1 (±1 week).  
x
Every 12 weeks from baseline thereafter: at any time of the day.  
x
Where clinically indicated.  
x
Discontinuation of AZD5363/placebo: at any time of the day.   
The modality of the cardiac function assessments must be consistent within patient i.e. if 
echocardiogram is used for the screening assessment then echocardiogram should also be used 
for subsequent scans if required.  The patients should also be examined using the same 
machine and operator whenever possible. 
6.4.11 
Vital signs: Pulse and blood pressure 
Supine blood pressure and pulse rate will be measured after 10 minutes rest.   
Assessments  will be conducted at the times indicated in the Study Plan (see Figure 5 and 
Figure 6) at the following timepoints: 
x
Screening 
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose; 1, 2, and 6 hours post-dose; 
Weeks 2, 3 and 4: Day 1 pre-dose. 
x
Intermittent dosing schedule only.  Cycle 1 Week 1: Day 5 post-dose. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
89(131) 
x
Cycle 2: Week 1: Day 1 pre-dose; Weeks 2, 3 and 4: Day 1 post-dose. 
x
Cycles 3+: Week 1: Day 1 at any time of the day. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 
x
Discontinuation of paclitaxel: at any time of the day. 
6.4.12 
Other safety assessments 
6.4.12.1 Lipids 
Blood samples for determination of triglycerides, HDL, LDL and cholesterol will be taken at 
the times indicated in the Study Plan (see Figure 5 and Figure 6) at the following timepoints: 
x
Screening. 
x
Every 12 weeks from baseline: at any time of the day.  Up to cessation of 
AZD5363/placebo.  
x
Discontinuation of AZD5363/placebo: at any time of the day. 
6.4.12.2 Glycosylated haemoglobin 
Blood samples for determination of glycosylated haemoglobin (HbA1c), will be taken taken at 
the times indicated in the Study Plan (see Figure 5 and Figure 6) at the following timepoints: 
x
Screening. 
x
Every 12 weeks from baseline: at any time of the day.  
x
Discontinuation of AZD5363/placebo: at any time of the day.   
x
Discontinuation of paclitaxel: at any time of the day.  
6.4.12.3 Glucose, insulin and insulin c-peptide 
Blood samples for determination of glucose, insulin and insulin c-peptide, will be taken taken 
at the times indicated in the Study Plan (see Figure 5 and Figure 6) at the following 
timepoints: 
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose; 2, 4, 6 and 8 hours post-dose. 
x
Continuous dosing schedule only:  

Cycle 1: Week 2: Day 1 pre-dose, 2, 4, 6 and 8 hours post-dose; Weeks 3 and 
4: Day 1 pre-dose. 

Cycles 2+: Week 1 Day 1 pre-dose and between 2 to 4 hours post-dose. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
90(131) 
x
Intermittent dosing schedule only: 

Cycle 1: Week 1: Day 5 pre-dose, 2, 4, 6 and 8 hours post-dose; Weeks 2, 3 
and 4: Day 2 pre-dose. 

Cycles 2+: Week 1: Day 2 pre-dose and between 2 to 4 hours post-dose. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 
6.4.12.4 Patient meal information. 
The times and types of meals (tickbox) received by patients will be recorded on the days that 
the patient attends the study site and received AZD5363/placebo at the following timepoints: 
x
Cycle 1: Week 1: Day 2.  
x
Continuous dosing schedule only:  

Cycle 1: Weeks 2, 3 and 4: Day 1.  

Cycles 2+: Week 1 Day 1. 
x
Intermittent dosing schedule only: 

Cycle 1: Week 1: Day 5; Weeks 2, 3 and 4: Day 2.  

Cycles 2+: Week 1 Day 2. 
6.5 
Patient reported outcomes (PRO) 
6.5.1 
Quality of Life: EORTC QLQ C-30 and BR-23 questionnaires (Part B: 
Randomised expansion only). 
These questionnaires were developed to assess and monitor changes from baseline in global 
health status / quality of life and disease-related symptoms. Validated translations of the 
questionnaires will be administered as appropriate.   
The European Organisation for the Research and Treatment of Cancer Quality of Life 
Questionnaire, EORTC QLQ-C30, is a 30-item generic instrument designed specifically to 
assess quality of life (QoL) in patients with cancer, and is applicable across a range of cancer 
types, treatments, and cultural settings. The instrument incorporates 5 functional scales 
(physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea/vomiting), a global health scale, 5 single items assessing common physical symptoms 
of cancer (dyspnea, loss of appetite, insomnia, constipation, and diarrhoea), and a single item 
assessing the financial effect of cancer. Per the EORTC scoring manual, all raw scores 
obtained from the QLQ-C30 will be transformed to a scale of 0–100; higher scores in the 
functioning and global QoL scales indicating better functioning, and higher scores in the 
symptom scales indicating more problems with the particular symptom being assessed. A 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
91(131) 
change of  10 points from baseline will indicate a meaningful increase or decrease in the 
specific health related QoL (HEQOL) scale. 
The QLQ-C30 assessment will be supplemented with the BR-23 breast cancer–specific 
questionnaire. This EORTC-developed questionnaire includes 23 questions to assess the 
symptoms and side effects of treatment (surgery, chemotherapy, radiation therapy, and 
hormone), body image, sexuality, and future perspective.  
During the Randomised Expansion phase only; patients will be requested to complete both 
questionnaires at the times indicated in the Study Plan (see Figure 5 and Figure 6) at the 
following timepoints: 
x
Screening. 
x
Cycle 1: Week 1: Day 1: pre-dose. 
x
Every 12 weeks from baseline: at any time of the day and after cessation of study 
therapies up to disease progression or withdrawal of consent.   
x
Discontinuation of AZD5363/placebo: at any time of the day. 
6.5.2 
Administration of EORTC QLQ C-30 and BR-23 questionnaires 
Each centre must allocate the responsibility for the administration of the questionnaires to a 
specific individual (eg, a research nurse, study coordinator) and if possible assign a back-up to 
cover absence.  The AZ Study Delivery Team (or delegate) will provide relevant training in 
administration of the questionnaires.  The paper questionnaire should be administered and 
completed, where possible, at the clinic.  Where this will not be possible, patients will be 
provided with paper copies of the questionnaire to complete at home, and return to the site by 
post. 
It is important that the significance and relevance of the data are explained carefully to 
participating patients so that they are motivated to comply with data collection. 
The instructions for completion of the questionnaires are as follows: 
x
They must be completed prior to any other study procedures (following informed 
consent) and before discussion of disease progress to avoid biasing the patient’s 
responses to the questions. 
x
It must be completed in private by the patient. 
x
The patient should be given sufficient time to complete at their own speed. 
x
The patient should not receive help from relatives, friends or clinic staff to answer 
the questionnaire.  However, if the patient is unable to read the questionnaire the 
questionnaire may be read out by trained clinic staff and responses recorded. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
92(131) 
x
On completion of the questionnaire it should be handed back to the designated 
responsible person who should check for completeness. 
x
Only one answer should be recorded for each question. 
Data from the questionnaires will be transcribed at site onto the eCRF.  Information on 
compliance with completion of the questionnaires will be collected throughout the study. 
6.6 
Pharmacokinetics 
6.6.1 
Collection of samples 
Venous blood samples (4 mL) for each determination of concentrations of AZD5363, its 
metabolites, and paclitaxel in plasma will be taken at the times presented in the Study Plan 
(see Figure 5 and Figure 6) at the timepoints shown below and will be analysed by Covance 
on behalf of Clinical Bioanalysis Alliance, AstraZeneca R&D.  Where AZD5363/placebo or 
paclitaxel are not received to schedule, post-dose PK sampling will not be applicable. 
Samples will be collected, labelled stored and shipped as detailed in Laboratory Manual.  
Samples will be disposed of as detailed in Section 7.2.1.  The exact date and time of each PK 
sample must be recorded in the CRF.   
6.6.2 
Pharmacokinetic sampling schedule 
Code:  
P = Samples for paclitaxel PK.   
A = Samples for AZD5363 PK 
 
Table 2:  
PK sampling schedule:  Safety Run-in Phase. 
Continuous dosing schedule 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Time relative 
to first dose 
in cycle 
Day 1 
Day 2 
Day 3 
Day 1 
Day 2 
Day 1 
Day 1 
Predose 
P 
P 
A 
 
A 
P 
A 
P 
A 
P 
A 
 
A 
2 hours  
P 
 
A 
 
P 
A 
 
 
 
4 hours  
P 
 
A 
 
P 
A 
 
 
 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
93(131) 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Time relative 
to first dose 
in cycle 
Day 1 
Day 2 
Day 3 
Day 1 
Day 2 
Day 1 
Day 1 
8 hours  
P 
 
A 
 
P 
A 
 
 
 
 
Intermittent dosing schedule: 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Time relative 
to first dose 
in cycle 
Day 1 
Day 2 
Day 3 
Day 5 
Day 2 
Day 2 
Day 2 
Predose 
P 
P 
A 
 
A 
 
A 
P 
A 
P 
A 
 
A 
2 hours  
P 
 
A 
 
 
 
 
 
4 hours  
P 
 
A 
 
 
 
 
 
8 hours  
P 
 
A 
 
 
 
 
 
 
Table 3:  
PK sampling schedule:  Randomised Expansion Phase. 
Continuous dosing schedule 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Time 
relative to 
first dose in 
cycle 
Day 1 
Day 2 
Day 3 
Day 1 
Day 2 
Day 1 
Day 1 
Predose 
P 
P 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
2 hours  
P 
 
A 
 
 
 
 
 
4 hours  
P 
 
A 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
94(131) 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Time 
relative to 
first dose in 
cycle 
Day 1 
Day 2 
Day 3 
Day 1 
Day 2 
Day 1 
Day 1 
8 hours  
P 
 
A 
 
 
 
 
 
 
Intermittent dosing schedule 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Time relative 
to first dose 
in cycle 
Day 1 
Day 2 
Day 3 
Day 5 
Day 2 
Day 2 
Day 2 
Predose 
P 
P 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
2 hours  
P 
 
A 
 
 
 
 
 
4 hours  
P 
 
A 
 
 
 
 
 
8 hours  
P 
 
A 
 
 
 
 
 
 
6.6.3 
Determination of drug concentration 
Samples for determination of drug concentration in plasma will be analysed by Covance on 
behalf of Clinical Bioanalysis Alliance, AstraZeneca R&D, using appropriate bioanalytical 
methods.  The lower limits of quantification (LLOQ) for AZD5363 and paclitaxel in plasma 
are 1.0ng/mL and 10ng/mL respectively.  Full details of the analytical methods used will be 
described in separate bioanalytical reports. 
All samples still within the known stability of the analytes of interest (AZD5363 and 
paclitaxel) at the time of receipt by the bioanalytical laboratory will be analysed. 
In addition, the pharmacokinetic samples may be subjected to further analyses in order to 
investigate the presence and/or identity of metabolites of AZD5363.  This may involve 
pooling of samples if required.  Any results from such analyses will be reported separately 
from the CSR. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
95(131) 
6.7 
Pharmacodynamics 
6.7.1 
Collection of pharmacodynamic markers  
Venous blood samples (8.1 mL) to provide platelet-rich plasma will be taken for assessment 
of pharmacodynamic (PD) markers at the times presented in the Study Plan (see Figure 5 and 
Figure 6) at the timepoints shown in Table 4 and Table 5. 
Samples will be collected, labelled stored and shipped as detailed in Laboratory Manual.  The 
exact date and time of each PD sample must be recorded in the CRF.  Samples will be 
disposed of after a maximum of 25 years following the Last Patient’s Last Visit in the study. 
6.8 
Exploratory research  
6.8.1 
Exploratory biomarker research 
Blood and eyebrow hair will be collected and may be analysed for exploratory biomarkers to 
assess correlations with disease activity, effects of study drug and clinical outcomes.  
Archival tumour samples will be collected for identification of patient PIK3CA mutation 
status (see sections  5.2.1 and  6.2.2) and, where a patient consents, optional paired biopsies 
(see section 6.8.1.3) may also be analysed for exploratory biomarker analysis as outlined 
above.  
The results of this exploratory biomarker research will be reported separately and will not 
form part of the CSR. 
The results of this exploratory biomarker research may be pooled with biomarker data from 
other studies with the study drug to generate hypothese to be tested in future studies. 
6.8.1.1 
Collection of circulating tumour cells 
A whole blood sample (10 mL) for analysis of CTCs will be taken at the times presented in 
the Study Plan (see Figure 5 and Figure 6) on each of the following timepoints: 
x
Cycle 1: Week 1: Day 1 pre-dose. 
x
Cycle 2: Week 1: Day 1 pre-dose. 
x
Cycle 3: Week 1: Day 1 pre-dose. 
x
Thereafter: every 12 weeks from baseline: at any time of the day up to cessation of 
study therapies. 
The date and time of collection will be recorded in the CRF. Samples will be utilised within 
days of collection and will not be stored beyond the completion of the study.  


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
96(131) 
Samples of CTCs will be shipped under ambient conditions on the day of acquisition so as to 
be received at an AstraZeneca approved laboratory within 72 hours of blood sampling.  
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
6.8.1.2 
Collection of archival tumour samples 
All patients will be asked to provide consent to supply a sample of their most recently 
obtained archival tumour block (tissue derived from the diagnostic tumour or a metastatic site) 
for transfer to the AstraZeneca biobank. 
The tumour sample preferably will be in the form of a formalin-fixed paraffin embedded 
block.  If this is not possible, 10-20 slides of freshly prepared unstained 5 micron sections 
from the archival tumour block may be provided. 
It is anticipated that, where consent is given, remaining tissue samples or slides collected for 
PIK3CA mutation analysis (see section 6.2.2) will be transferred to the biobank.  Samples will 
be disposed of, or returned to the study site dependent upon local requirements, after a 
maximum of 25 years following the Last Patient’s Last Visit in the study. 
6.8.1.3 
Collection of paired tumour biopsies (optional)  
All patients will be asked to provide consent for collection of tumour biopsies.  Where consent 
is given, these samples should be collected at the times presented in the Study Plan (see Figure 
5 and Figure 6): at screening or at pre-dose on Day 1 of Cycle 1 and on Day 1 of Cycle 2 (± 1 
week).  
The samples will be analysed for biomarkers that may influence development of cancers 
and/or response to AZD5363.  The date and time of collection will be recorded in the CRF. 
Samples will be disposed of after a maximum of 25 years following the Last Patient’s Last 
Visit in the study.   
6.8.1.4 
Collection of eyebrow hairs (optional) 
Four eyebrow hairs will be taken at the times presented in the Study Plan (see see Figure 5 
and Figure 6) on each of the timepoints presented in Table 4 and Table 5 below. 
The samples will be analysed for concentrations of exploratory biomarkers which may 
correlate with drug response. The date and time of collection will be recorded in the CRF. 
Samples will be disposed of after a maximum of 25 years following the Last Patient’s Last 
Visit in the study. 
6.8.1.5 
Collection of exploratory blood-borne biomarkers (optional) 
5mL venous blood will be taken at the times presented in the Study Plan (see Figure 5 and 
Figure 6) on each of the timepoints presented in Table 4 and Table 5 below.  


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
97(131) 
The samples will be analysed for a range of oncology biomarkers which may correlate with 
drug response. The date and time of collection will be recorded in the CRF. Samples will be 
disposed of after a maximum of 25 years following the Last Patient’s Last Visit in the study. 
6.8.1.6 
Pharmacodynamic and exploratory biomarker sampling schedule 
The following samples will be taken on each of the timepoints presented below. 
Code:  
x
PD = venous blood for determination of pharmacodynamic parameters.  
x
B = venous blood for analysis of exploratory biomarkers.  
x
BH  = 4 eyebrow hairs for analysis of exploratory biomarkers. 
 
Table 4:  
PD and exploratory biomarker sampling schedule:  Part A Safety Run-
in Phase. 
Continuous dosing schedule 
Screen 
Cycle 1 
Cycle 2+ 
AZD5363 
Disc 
 
Week 1 
Week 2 
Week 3 Week 4 Week 1
 
Time 
relative to 
first dose 
in cycle 
 
Day 1 
Day 2 
Day 3 
Day 1 
Day 2 
Day 1 
Day 1 
Day 1 
 
Any time 
B 
 
 
 
 
 
 
 
 
B PD 
Predose 
 
PD  
B PD 
BH   
PD  
B PD 
BH    
PD    
B PD    
B PD  
B PD 
 
2 hours  
 
 
PD  
 
   
 
 
 
 
 
4 hours  
 
 
PD BH 
 
   
 
 
 
 
 
8 hours  
 
 
PD  
 
   
 
 
 
 
 
 
Intermittent dosing schedule 
Screen 
Cycle 1 
Cycle 2+ 
AZD5363 
Disc 
 
Week 1 
Week 2 Week 3 Week 4 Week 1
 
Time 
relative to 
first dose 
in cycle 
 
Day 1 
Day 2 
Day 3 
Day 5 
Day 2 
Day 2 
Day 2 
Day1 
 
Any time 
B 
 
 
 
 
 
 
 
 
B PD 
Predose 
 
PD  
B PD 
BH   
PD  
PD BH 
B PD    
B PD    
B PD  
B PD 
 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
98(131) 
Screen 
Cycle 1 
Cycle 2+ 
AZD5363 
Disc 
 
Week 1 
Week 2 Week 3 Week 4 Week 1
 
Time 
relative to 
first dose 
in cycle 
 
Day 1 
Day 2 
Day 3 
Day 5 
Day 2 
Day 2 
Day 2 
Day1 
 
2 hours  
 
 
PD  
 
 
 
 
 
 
 
4 hours  
 
 
PD BH 
 
 
 
 
 
 
 
8 hours  
 
 
PD  
 
 
 
 
 
 
 
 
Table 5.  
PD and exploratory biomarker sampling schedule: Part B Expansion 
Phase 
Continuous dosing schedule  
Screen 
Cycle 1 
Cycle 2+
AZD5363 
Disc 
 
Week 1 
Week 2 
Week 3 Week 4 Week 1
 
Time 
relative to 
first dose 
in cycle 
 
Day 1 
Day 2 
Day 3 
Day 1 
Day 2 
Day 1 
Day 1 
Day 1 
 
Any time 
B 
 
 
 
 
 
 
 
 
B PD 
Predose 
 
PD  
B PD 
BH  
PD  
B PD  
BH  
PD 
B PD  
B PD  
B PD 
 
2 hours  
 
 
PD  
 
 
 
 
 
 
 
4 hours  
 
 
PD BH 
 
 
 
 
 
 
 
8 hours  
 
 
PD  
 
 
 
 
 
 
 
 
Intermittent dosing schedule 
Screen 
Cycle 1 
Cycle 2+ 
AZD5363 
Disc 
 
Week 1 
Week 2 Week 3 Week 4 Week 1
 
Time 
relative to 
first dose 
in cycle 
 
Day 1 
Day 2 
Day 3 
Day 5 
Day 2 
Day 2 
Day 2 
Day 1 
 
Any time 
B 
 
 
 
 
 
 
 
 
B PD 
Predose 
 
PD  
B PD 
BH   
PD  
PD BH 
 B PD  
B PD  
B PD   
B PD 
 
2 hours  
 
 
PD  
 
 
 
 
 
 
 
4 hours  
 
 
PD BH  
 
 
 
 
 
 
 
8 hours  
 
 
PD  
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
99(131) 
 
6.9 
Pharmacogenetics 
6.9.1 
Collection of pharmacogenetic samples (optional) 
All patients will be asked to provide consent for collection of a 5mL blood sample 
immediately prior to dosing on Cycle 1: Week 1: Day 1 for genetic research.  Although 
genotype is a stable parameter, early sample collection is preferred to avoid introducing bias 
through excluding patients who may withdraw due to an adverse event (AE), such patients 
would be important to include in any genetic analysis.  If for any reason the sample is not 
drawn at this visit, it may be taken at any other visit until the last study visit.  Only one sample 
should be collected per patient for genetics during the study.  Samples will be collected, 
labelled, stored and shipped as detailed in the Laboratory Manual. 
The results of this pharmacogenetic research will be reported separately and will not form part 
of the CSR. 
Samples will be disposed of after a maximum of 25 years following the Last Patient’s Last 
Visit in the study.   
7. 
BIOLOGICAL SAMPLING PROCEDURES  
7.1 
Volume of blood 
The volume of blood that will be drawn from each patient will vary, dependent upon the 
dosing schedule and phase of the study: 
x
The volume of blood to be drawn from each patient during screening and Cycle 1 
should  not exceed 35 mL and 360 mL respectively 
x
The total volume of blood to be drawn from each patient in the study, assuming 
they complete screening, 6 cycles of combination treatment and a discontinuation 
visit should not exceed 710 mL.   
Safety laboratory assessments will be performed locally at each centre’s laboratory by means 
of their established methods.  The number of samples/blood volumes is therefore subject to 
site-specific change.  
In both phases of the study, extra blood samples may also be collected if, for example, 
additional samples are required for repeat safety assessments or additional PK assessment.   


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
100(131) 
The maximum volume of blood to be drawn from each patient in this study is as follows: 
Table 6 
Estimated Maximum volume of blood to be drawn per patient  
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Haematology 
5 
15 
75 
 
Clinical chemistry 
10 
15 
150 
 
Additional Glucose 
2 
9 
18 
 
Lipids 
5 
3 
15 
 
Glucose, insulin and 
insulin c-peptide 
5 
24 
120 
CTCs 
10 
4 
40 
PIK3CA mutation 
10 
1 
10 
Pharmacokinetic 
4 
23 
92 
Pharmacodynamic 
8.1 (3 x 2.7) 
16 
129.6 
Pharmacogenetics (optional) 
5 
1 
5 
Exploratory Biomarker (optional) 
5 
11 
55 
Total 
 
 
709.6 
Note:  Maximum is taken to reflect Part A, continuous dosing schedule: 6 Cycles plus a 
discontinuation visit. 
7.2 
Handling, storage and destruction of biological samples 
The samples will be used up or disposed of after analyses or retained for further use as 
described here. 
Biological samples for future research will be retained by AstraZeneca Alderley Park, UK for 
a maximum of 25 years following the Last Patient’s Last Visit in the study.  The results from 
future analysis will not be reported in the CSR but separately in a Scientific Report. 
7.2.1 
Pharmacokinetic and/or pharmacodynamic / biomarker samples 
Samples will be disposed of after the CSR has been finalised, unless retained for future 
analyses, see below. 
Key samples for investigation of exploratory biomarkers, bioanalytical validation and 
metabolite identification will be retained at AstraZeneca, Alderley Park, UK for a maximum 
of 25 years following the Last Patient’s Last Visit in the study.  The results from the 
investigation will not be reported in the CSR but separately in bioanalytical/metabolism 
reports. 


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Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
101(131) 
7.2.2 
Pharmacogenetic samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 15 
years, following the Last Patient’s Last Visit in the study, after which they will be destroyed.  
DNA is a finite resource that may be used up during analyses.  Samples will be stored and 
used until no further analyses are possible or the maximum storage time has been reached. 
For all samples, irrespective of the type of coding used, the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number, replacing the information 
on the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory.  No personal 
details identifying the individual will be available to any person (AstraZeneca employee or 
contract laboratory staff working with the DNA.) 
The samples and data for genetic analysis in this study will be single coded.  The link between 
the patient enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access WITHIN the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent when the patient has requested disposal/destruction of collected 
samples not yet analysed. 
7.3 
Labelling and shipment of biohazard samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document’. 
Any samples identified as Infectious Category A materials must not be shipped and further 
samples must not be taken from the patient unless agreed with AstraZeneca, and appropriate 
labelling, shipment and containment provisions are approved. 
7.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the patients while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival when shipped. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival 
when shipped. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
102(131) 
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle. 
7.5 
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research. 
As collection of the biological samples is not regarded as integral to the primary study 
objectives, then the patient may continue in the study. 
The Principal Investigator: 
x
Ensures AstraZeneca is notified immediately of a patient’s withdrawal of informed 
consent to the use of donated samples  
x
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented. 
x
Ensures any local laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed, the action 
documented and the signed document returned to the study site. 
x
Ensures that the patient and AstraZeneca are informed about the sample disposal. 
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics and Human Biological Samples. 
8.2 
Patient data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
103(131) 
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate. 
8.3 
Ethics and regulatory review 
An Ethics Committee (EC) / Investigational Review Board (IRB) should approve the final 
study protocol, including the final version of the Informed Consent Form and any other 
written information and/or materials to be provided to the patients.  The investigator will 
ensure the distribution of these documents to the applicable EC/IRB, and to the study site 
staff. 
The opinion of the EC/IRB should be given in writing. The investigator should submit the 
written approval to AstraZeneca before enrolment of any patient into the study.  
The EC/IRB should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 
If required by local regulations, the protocol should be re-approved by the EC/IRB annually. 
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, must be approved by the national regulatory authority 
or a notification to the national regulatory authority must be made, according to local 
regulations. 
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities. 
AstraZeneca will provide Regulatory Authorities, ECs/IRBs and Principal Investigators with 
safety updates/reports according to local requirements, including Suspected Unexpected 
Serious Adverse Reactions (SUSARs), where relevant. 
Where relevant under national requirements; each Principal Investigator is responsible for 
providing the EC/IRB with reports of any serious and unexpected adverse drug reactions from 
any other study conducted with the IP.  AstraZeneca will provide this information to the 
Principal Investigator so that he/she can meet these reporting requirements. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
104(131) 
8.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
x
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study. 
x
Ensure each patient is notified that they are free to discontinue from the study at any 
time. 
x
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided. 
x
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study. 
x
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File. 
x
Ensure a copy of the signed Informed Consent Form is given to the patient. 
x
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the Informed Consent Form that is approved by an EC/IRB. 
8.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator, the Principal Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant EC/IRB and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed 
for revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to EC see Section 8.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s EC/IRB are to approve the revised Informed Consent Form before the revised 
form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each EC/IRB. 


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Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
105(131) 
8.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an EC/IRB may perform 
audits or inspections at the centre, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements.  The investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the centre. 
9. 
STUDY MANAGEMENT BY ASTRAZENECA 
9.1 
Pre-study activities 
Before the first patient is entered into the study, it is necessary for a representative of 
AstraZeneca to visit the investigational study site to: 
x
Determine the adequacy of the facilities. 
x
Determine availability of appropriate patients for the study. 
x
Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of 
AstraZeneca or its representatives.  This will be documented in a CSA between 
AstraZeneca and the investigator. 
9.2 
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and systems utilised. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
9.3 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
x
Provide information and support to the investigator(s). 
x
Confirm that facilities remain acceptable. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
106(131) 
x
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed. 
x
Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. This 
will require direct access to all original records for each patient (eg, clinic charts). 
x
Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient. 
The AstraZeneca representative will be available between visits if the investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
9.3.1 
Source data 
Refer to the CSA for location of source data. 
9.4 
Study agreements 
The Principal Investigator at each centre should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this Clinical Study Protocol and the CSA, the terms of Clinical Study Protocol shall 
prevail with respect to the conduct of the study and the treatment of patients; and in all other 
respects, not relating to study conduct or treatment of patients, the terms of the CSA shall 
prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled. 
9.4.1 
Archiving of study documents 
The Investigator follows the principles outlined in the CSA. 
9.5 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study’. 
The study is expected to start in Q2 2012 and to end by Q4 2014. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with AZD5363. 


Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
107(131) 
10. 
DATA MANAGEMENT BY ASTRAZENECA 
Data management will be performed by AstraZeneca Data Management Centre staff. 
The data collected through third party sources will be obtained and reconciled against study 
data. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the AstraZeneca Drug Dictionary.  All coding will be 
performed by the Medical Coding Team at the AstraZeneca Data Management Centre. 
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
When all data have been coded, validated and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked. 
Data associated with biological samples will be transferred from laboratories internal or 
external to AstraZeneca.  Data from external providers (e.g. central laboratories) will be 
validated as appropriate to ensure it is consistent with the clinical data and included in the 
final database. In the case of biomarker (tumour tissue or blood for exploratory analyses) data, 
only the original date of biopsy (historical tumour tissue sample and the actual date the 
sample(s) were collected) will be recorded in the eCRF and database.  
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyse samples.  The results from this genetic research may be 
reported in the CSR for the main study, or in a separate report, as appropriate. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database. 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA 
11.1 
Calculation or derivation of efficacy variable(s) 
Patients will undergo regular tumour assessments until documented objective disease 
progression as defined by RECIST 1.1 (see Appendix F).  






Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
110(131) 
analysis then they will be censored at 0 days for PFS.  Symptomatic deterioration will not be 
regarded as a progression event. 
If a patient discontinues treatment prior to progression and/or receives a subsequent therapy 
prior to progression then these patients will continue to be followed until evidence of 
objective disease progression as defined by RECIST 1.1 and their PFS time will be derived as 
defined above. 
The PFS time will always be derived based on scan/assessment dates not visit dates. 
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied: 
x
Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression. 
x
When censoring a subject for PFS the subject will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
11.1.5 
Response rate at 12 weeks and best objective tumour response 
Response rate at 12 weeks is defined as the percentage of patients who have a week 12 visit 
response of CR or PR (as defined by RECIST 1.1), regardless of whether the responses are 
confirmed or not. 
Best objective tumour response will be based on RECIST measurements taken throughout the 
whole study and will classify patients as confirmed complete and partial responses as well as 
unconfirmed complete and partial responses, stable disease, progressive disease and not 
evaluable.  ORR is defined as the percentage of patients who have at least one visit response 
of CR or PR prior to any evidence of progression (as defined by RECIST 1.1). 
A visit response of CR is defined when all TL and NTL lesions present at baseline have 
disappeared (with the exception of lymph nodes which must be <10mm to be considered non-
pathological) and no new lesions have developed since baseline.  A visit response of PR is 
defined when the sum of diameters of the TLs has decreased by 30 % or more compared to 
baseline (with no evidence of progression) and the NTLs are at least stable with no evidence 
of new lesions.  
The denominator for response rate calculations will be: all patients dosed for study Part A and 
all randomised patients for study Part B, with the exception of the PIK3CA mutation - positive 
subgroup where the denominator will be all patients dosed / randomised whose tumours test 
positive for the PIK3CA mutation.   


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11.1.6 
Proportion of patients without progressive disease at 12 weeks 
The proportion of patients without progressive disease at 12 weeks is defined as the 
percentage of patients with a 12 week visit response of CR, PR or SD (as defined by RECIST 
1.1) with no evidence of previous progression.   
The denominator for patients without progressive disease at 12 weeks will be: all patients 
dosed for study Part A and all randomised patients for study Part B. 
11.2 
Calculation or derivation of safety variable(s) 
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs, 
ECG and LVEF.  These will be collected for all patients.  Appropriate summaries of these 
data will be presented as described in Section 12.2. 
ECG Changes 
QTc will be calculated by the Data Management Centre, on behalf of AstraZeneca, using both 
Bazett’s and Fridericia’s formulae. 
Creatinine Clearance 
Estimated creatinine clearance (mL/min) will be calculated using the Cockcroft and Gault 
formula below, from creatinine: 
For creatinine values in mol/L 
Men: [(140 – age) x weight (kg) x 1.23] / creatinine (μmol/L) 
Women: [(140 – age) x weight (kg) x 1.04] / creatinine (μmol/L) 
Corrected Calcium 
Corrected calcium will be calculated using the formula below, from total calcium and 
albumin:  
Corr.  Calcium (mmol/L) = Total Calcium (mmol/L) + ([40 – Albumin (g/L)] x 0.02) 
11.2.1 
Other significant adverse events (OAE) 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as a SAE and/or a Discontinuation of Investigational 
Product due to Adverse Event.  Based on the expert’s judgement, significant adverse events of 
particular clinical importance may, after consultation with the Global Patient Safety Physician, 
be considered OAEs and reported as such in the CSR.  A similar review of laboratory, vital 
signs and ECG data will be performed for identification of OAEs. 
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 
 


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Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
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11.3 
Calculation or derivation of pharmacokinetic variables 
Pharmacokinetic analysis of the plasma concentration data for AZD5363 and paclitaxel will 
be performed by AstraZeneca.  The actual sampling times will be used in the parameter 
calculations and PK parameters will be derived using population pharmacokinetic modelling. 
Where possible, appropriate PK parameters will be reported 
The PK variables for the patients with sparse PK sampling will be estimated using a 
population PK approach.  Details will be included in a separate PK analysis plan. 
11.4 
Calculation or derivation of pharmacodynamic variable(s) 
11.4.1 
Population analysis of pharmacokinetic/pharmacodynamic variables  
The PK, pharmacodynamic, demographic, safety and tumour response data collected in this 
study may also be combined with similar data from other studies and explored using 
population PK and/or PK/PD methods.  The results of any such analyses may be reported 
separately from the CSR. 
11.5 
Calculation or derivation of health related quality of life variables 
(Part B: Randomised expansion only) 
Health related quality of life (HRQoL) and disease-related symptom data will be collected 
using the EORTC QLQ-C30 and BR-23 patient reported outcome (PRO) instruments. 
The QLQ-C30 instrument is composed of both multi-item scales and single-item measures. 
These include five functional scales, three symptom scales, a global health status / QoL scale, 
and six single items. Each of the multi-item scales includes a different set of items - no item 
occurs in more than one scale.  A high scale score represents a higher response level. Thus a 
high score for a functional scale represents a high / healthy level of functioning, a high score 
for the global health status / QoL represents a high QoL, but a high score for a symptom scale 
/ item represents a high level of symptomatology / problems. 
The principle for scoring these scales is the same in all cases.  
Table 7 
Scoring the QLQ C30 version 3 
 
Scale 
Number of 
items 
Item 
range* 
Version 3.0 item 
numbers 
Function 
scales 
Global health status/QoL 
Global health status/QoL 
(revised) † 
QL2 
2 
6 
29,30 
 
Functional scales: 
Physical functioning 
(revised) † 
PF2 
5 
3 
1-5 
F 


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Edition Number 1 
Date 24 February 2012 
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Role functioning (revised) 
† 
RF2 
2 
3 
6,7 
F 
Emotional functioning 
EF 
4 
3 
21-24 
F 
Cognitive functioning 
CF 
2 
3 
20,25 
F 
Social functioning 
SF 
2 
3 
26,27 
F 
Symptom scales/items 
Fatigue 
FA 
3 
3 
10,12,18 
 
Nausea and vomiting 
NV 
2 
3 
14,15 
 
Pain 
PA 
2 
3 
9,19 
 
Dyspnoea 
DY 
1 
3 
8 
 
Insomnia 
SL 
1 
3 
11 
 
Appetite loss 
AP 
1 
3 
13 
 
Constipation 
CO 
1 
3 
16 
 
Diarrhoea 
DI 
1 
3 
17 
 
Financial difficulties 
FI 
1 
3 
28 
 
* Item range is the difference between the possible maximum and the minimum response to individual items; 
† (revised) scales are those that have been changed since version 1.0, and their short names are indicated by a 
suffix “2” – for example, PF2. 
 
The BR-23 instrument comprises 23 questions assessing disease symptoms, side effects of 
treatment (surgery, chemotherapy, radiotherapy and hormonal treatment), body image, sexual 
functioning and future perspective.  The module incorporates five multi-item scales to assess 
systemic therapy side effects, arm symptoms, breast symptoms, body image and sexual 
functioning. In addition, single items assess sexual enjoyment, hair loss and future 
perspective. The scoring approach for the QLQ-BR23 is identical in principle to that for the 
function and symptom scales / single items of the QLQ-C30. 
Table 8 
Scoring BR-23 
 
Scale 
Number 
of items 
Item 
range* 
QLQ-BR23 
item numbers 
Function 
scales 
Functional scales 
Body image 
BRBI 
4 
3 
9-12 
F 
Sexual functioning † 
BRSEF 
2 
3 
14,15 
† 
Sexual enjoyment † 
BRSEE 
1 
3 
16 
† 
Future perspective 
BRFU 
1 
3 
13 
F 
Symptom scales/items 
Systemic therapy side effects 
BRST 
7 
3 
1-4,6,7,8 
 


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Edition Number 1 
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Breast symptoms 
BRBS 
4 
3 
20-23 
 
Arm symptoms 
BRAS 
3 
3 
17,18,19 
 
Upset by hair loss 
BRHL 
1 
3 
5 
 
* “Item range” is the difference between the possible maximum and the minimum response to individual items. 
† Items for the scales marked † are scored positively (i.e. “very much” is best) and therefore use the same 
algebraic equation as for symptom scales; however, the Body Image scale uses the algebraic equation for 
functioning scales. 
 
The raw score will be calculated based on the average of the items that contribute to the 
subscale.  A linear transformation will then be applied to the raw score so that visit scores 
range from 0 to 100 (as per the standard coding provided in EORTC scoring manual). 
For missing items within a subscale, if there are >50% of the items in the subscale completed 
then the missing items will be assumed to have values that are equal to the average of the 
items completed.  Otherwise the visit score will be set to missing. 
If there are cases in which more than one questionnaire has been completed on the same day, 
and provide different answers, the questionnaire with the highest overall score will be used. 
Method of categorising visit scores into visit response 
Osoba et al 1998 suggested that in patients with breast and small-cell lung cancer, changes 
(from baseline to various study time points) in scores of 5-10 on a 1-100 scale represented a 
small difference, 10-20 represented a moderate difference, and those above 20 represented 
large differences. King 1996 used a variety of clinical classifications as anchors and found 
similar results across various studies and cancer sites. Based on these 2 studies, mean 
differences of 10 points or more are widely viewed as being clinically significant when 
interpreting the results and hence a cut-off of a chance of 10 points has been used in this study 
to define visit responses of improvements and worsenings.  Visit scores will be categorised 
into visit responses as defined in Table 9. 
Table 9 
Categorisation of visit scores into visit responses 
Score 
Change from baseline 
Visit response 
Symptom scales / items 
d-10 
Improved 
 
>-10, <10 
No change 
 
t10, or missing questionnaire 
due to “Subject too sick, other 
than disease under 
investigation” or “Subject too 
affected by symptoms of 
disease under investigation” 
Worsened 


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Edition Number 1 
Date 24 February 2012 
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Table 9 
Categorisation of visit scores into visit responses 
Score 
Change from baseline 
Visit response 
 
Missing for reasons other than 
those above 
Not evaluable 
Functional scales, Global 
health status 
t10 
Improved 
 
>-10, <10 
No change 
 
d-10, or missing questionnaire 
due to “Subject too sick, other 
than disease under 
investigation” or “Subject too 
affected by symptoms of 
disease under investigation” 
Worsened 
 
Missing for reasons other than 
those above 
Not evaluable 
 
Method of calculating best overall response 
Visit scores will be combined to calculate best overall response as defined in table 10. 
Table 10 
Calculation of best overall response 
Score 
Definition 
Best overall response 
Any 
Two visit responses of 
“improved” a minimum of 21 
days apart without an 
intervening visit response of 
“worsened” 
Improved 
 
Does not qualify for overall 
score response of “improved”.  
Two visit responses of either 
“no change”, or “improved” 
and “no change” a minimum 
of 21 days apart without an 
intervening visit response of 
“worsened” 
No change 


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Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
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Does not qualify for overall 
score response of 
“improved” or “no change”.  
Either (1) A visit response 
of “worsened” without a 
response of “improved” or 
“no change” within 21 days; 
or (2) Died within 12 weeks 
of last evaluable PRO 
assessment. 
Worsened 
 
Does not qualify for one of 
the above 
Not evaluable 
 
A deterioration is defined as a visit response of worsened without a visit response of no 
change or improved within 21 days.  If there are no further visit responses available then this 
will still count as deterioration.  Death in the absence of PRO deterioration will also count as 
deterioration if it occurs within 12 weeks of the last evaluable PRO assessment.  Time to 
deterioration is calculated as the time from randomisation to the date of the first assessment at 
which deterioration began.  Subjects that have not deteriorated at the time of data cut off will 
be censored at the time of the last evaluable assessment for that PRO. 
Any subject who cannot possibly worsen compared to baseline will be censored for time to 
worsening at time 0. 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION BY ASTRAZENECA 
12.1 
Description of analysis sets 
12.1.1 
Efficacy analysis set 
All efficacy data in Part B of the study (change in tumour size at 12 weeks, PFS, ORR, DoR 
and percentage of patients without progression at 12 weeks) will be analysed on an intention-
to-treat basis (ITT). This will include all randomised patients, wherever possible, and compare 
treatment groups on the basis of randomised treatment, regardless of the treatment they 
actually received. 
To be considered 'evaluable' for the primary efficacy analysis, a patient must have: 
x
Baseline and week 12 (r1 week) tumour measurements; or 
x
Evidence of progression prior to week 12; or 


Clinical Study Protocol 
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Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
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x
In the absence of the week 12 measurements and no evidence of progression, 
RECIST measurements at baseline and 1 visit after or prior to the week 12 visit 
such that a prediction for the week 12 result can be made (see section 11.1.1 for 
details) 
For the Part A safety run-in, the efficacy analysis set will include all patients who received at 
least one dose of study treatment. 
12.1.2 
Safety analysis set 
All patients who receive at least one dose of AZD5363 in Part A, or randomised treatment in 
Part B, will be included in the assessment of the safety data.  Any patient who only receives 
one or more doses of paclitaxel and does not commence dosing with IP will not be included in 
the assessment of safety data.   
Throughout the safety results sections, erroneously treated patients (e.g., those randomised to 
treatment A but actually given treatment B) will be accounted for in the actual treatment 
group. 
12.2 
Methods of statistical analyses 
A comprehensive statistical analysis plan (SAP) will be prepared prior to enrolment of 
patients in the study. 
The primary outcome variable for Part B of change in tumour size at 12 weeks, and the 
secondary outcome variable of PFS, will be analysed formally.  All Part A data, other Part B 
efficacy and safety data will be summarised descriptively. 
For the primary and secondary analysis the null hypothesis is that there is no treatment effect, 
i.e., there is no difference in terms of change in tumour size at 12 weeks between patients 
treated with AZD5363 + paclitaxel and patients treated with matching placebo + paclitaxel. 
No adjustments for multiplicity will be made. 
Details of sensitivity analyses and imputation methods for missing data will be fully 
documented in the SAP. 
There are potentially a number of different analysis points for the study.  The table below 
details which data will be analysed at each time point. 
Analysis 
Trigger 
Data type included 
End of safety run-in 
All patients in Part A followed 
up for at least 12 weeks  
Safety, efficacy (week 12 response 
rate, best response), PK, PD 
Randomised expansion 
interim analysis 
40 patients randomised and 
completed 12 week follow up 
period (or progressed prior to 12 
Change in tumour size, response 
rate at 12 weeks, best objective 
response (No PIK3CA mutation 




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group whose 12-week data is imputed, will be presented on the footnote to the table of output 
from this analysis. 
The distribution of the tumour size measurement data will be assessed without knowledge of 
the randomised treatment assignment.  If the week 12 changes in tumour size data follow a 
log-normal distribution, these data will be analysed as described previously.  If, however, it is 
judged the data do not adequately follow a log-normal distribution then the use of 
untransformed percentage changes or a non-parametric approach could replace the log 
transformed analysis as the primary approach. 
The week 12 change in tumour size will also be presented graphically by waterfall plots for 
each treatment group which present each patient’s week 12 change in tumour size as a 
separate bar, with the bars ordered from the largest increase to the largest decrease.  This plot 
will be repeated separately by treatment group for those patients whose tumour was PIK3CA 
mutation-positive at entry, and also for the overall analysis but flagging (by colour or pattern) 
whether patients are PIK3CA mutation-positive or not detected.  Reference lines at the +20% 
and -30% change in tumour levels will be added to the plots, which correspond to the changes 
in sum of TLs that would result in the TL responses of progression and partial response, 
respectively.  In these waterfall plots (and also in the listings) the patients whose week 12 
change in tumour size is based on an imputation due to missing TL data but known to be 
progressors will be clearly identified (by different coloured bars for the waterfall plots and a 
flag in the listings). 
Change in tumour size will be presented descriptively for patients in Part A of the study with 
summary tables and waterfall plots.   
Frequencies of NTL progressions and new lesions at week 12 will be presented together with 
the change in tumour size results in order to put the change in tumour size results into 
perspective. 
12.2.2 
Progression Free Survival 
The secondary endpoint of PFS will be analysed for the patients in Part B when recruitment to 
Part B has completed and approximately 45 PFS events in the overall population have 
occurred.  Waiting until recruitment has completed to this part of the study will ensure that as 
many as possible of the PFS events included in the analysis come from a mixture of PIK3CA 
mutation positive and not detected patients.  This aims to safeguard against the possibility that 
the progression events could be largely from the mutation not detected patients if that stratum 
recruits substantially quicker than the other.  PFS will not be presented for patients in Part A 
of the study.  PFS will be analysed for the overall population and for the subgroup of PIK3CA 
mutation patients, using separate Cox proportional-hazards models allowing for the effect of 
treatment and including a term for PIK3CA mutation status in the overall analysis (mutation 
positive or not detected). 
The hazard ratios in the overall population and in the PIK3CA mutation subgroup (HR; 
AZD5363 + paclitaxel: placebo + paclitaxel) for treatment will be estimated together with 




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Edition Number 1 
Date 24 February 2012 
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and schedule for patients in Part A.  For Part B, the main set of safety tables will consist of the 
overall population in the randomised expansion, but a reduced set of key safety outputs will 
also be repeated on patients with PIK3CA mutation positive tumours (as according to 
stratification levels determined at randomisation) to assess if the safety profile remains 
consistent within these patients. 
Adverse Events 
Data from all cycles of initial treatment will be combined in the presentation of the safety 
data.  AEs will be listed individually by patient and treatment group (dose and schedule group 
for the safety run-in phase).  For patients who undergo a dose modification, all AEs (due to 
drug or otherwise) will be assigned to the initial dose group. 
The number of patients experiencing each AE will be summarised by the Medical Dictionary 
for Regulatory Activities (MedDRA) system organ class, MedDRA preferred term and 
CTCAE grade.  The number and percentage of patients with adverse events in different 
categories (AEs, SAEs, AE with outcome death, CTCAE grade 3, AEs leading to permanent 
discontinuation) will be summarised by treatment group, and events in each category will be 
further summarised by MedDRA system organ class and preferred term, by treatment group.  
An additional table of all preferred terms sorted by decreasing frequency will be produced to 
show most frequent AEs regardless of system order class. 
Any AE occurring before the first dose of IP (i.e., before Cycle 1 Week 1 Day 2) will be 
included in the data listings but will not be included in the summary tables of adverse events. 
Any AE occurring within the defined 28 day follow-up period after discontinuation of study 
therapy (AZD5363/placebo and/or paclitaxel) will be included in the AE listings and 
summaries. AEs occurring after the 28-day follow-up period after discontinuation of IP will 
be listed separately, but not included in the summaries. 
Laboratory parameters, vital signs and physical examination data 
Laboratory parameters will be listed and summarised over time in terms of absolute values 
and change from baseline. 
Corrected calcium will be derived by AstraZeneca. 
CTCAE grades will be calculated for laboratory parameters, where possible.  Where CTCAE 
grading is available, a table of 1-grade shift, 2-grade shifts, 3-grade shifts and 4-grade shifts, 
in maximum CTC grade will be produced for each laboratory parameter, to summarise the 
overall worst CTCAE grade over the course of the study compared to the baseline CTCAE 
grade.  Where possible, the direction of the shift will be reported to put the shift into context 
of an event such as hyper- or hypo- clinical event.  Box and whisker plots of lab parameters 
against time will also be produced.  
Vital signs (SBP, DBP and pulse) will be listed and box plots of change from baseline in SBP, 
DBP and pulse will be presented. 


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Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
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Physical exam data will be listed and summarised by initial dose received. 
ECG parameters and echocardiogram data 
ECG parameters (PR, QRS, RR and QT) will be summarised over time in terms of absolute 
values and change from baseline.  QTcB and QTcF derived from these variables by AZ will 
be presented in the same way. 
Echocardiogram findings will be listed and summarised over time in terms of absolute values 
and change from baseline.  Box and whisker plots of LVEF against time will be presented. 
12.2.6 
Pharmacokinetics  
Part A Safety Run-in AZD5363 and paclitaxel pharmacokinetics 
Plasma concentrations of AZD5363 and paclitaxel will be summarised by nominal sample 
time.  Plasma concentrations and derived PK parameters will be summarised by dose level and 
schedule.  Plasma concentrations at each time point will be summarised according to dose and 
schedule by the following summary statistics: 
x
The geometric mean (gmean, calculated as exp [ȝ], where ȝ is the mean of the data 
on a logarithmic scale) 
x
Coefficient of variation (CV, calculated as 100 ¥ [exp(s2)-1], where s is the standard 
deviation of the data on a log scale) 
x
Gmean ± standard deviation (calculated as exp[ȝ±s]) 
x
Arithmetic mean calculated using untransformed data 
x
Standard Deviation calculated using untransformed data 
x
Minimum 
x
Maximum 
x
Number of observations 
In the calculation of plasma concentration summary statistics, plasma concentrations below 
the lower limit of quantification (LLOQ) will be set to zero at pre-dose. Summary statistics 
will be presented according to the following rules: 
x
If, at a given time point, 50% or less of the plasma concentrations are non-
quantifiable (NQ), the geometric mean (gmean), CV, gmean ± standard deviation 
(SD), arithmetic mean, SD and median will be calculated by substituting the LLOQ 
for values which are NQ.  The minimum at that time point will be reported as NQ. 




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Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
124(131) 
x
Summary statistics of time to deterioration for each score using Kaplan-Meier 
estimates 
If sufficient data is collected to warrant further statistical analyses, analysis of time to 
deterioration of PRO scores will be considered by a log rank test to estimate hazard ratios and 
confidence intervals for the effect of treatment on each of the scores.  Kaplan-Meier plots and 
estimates of median time to deterioration will also be produced.  Likewise, if there is 
sufficient data and initial explorations warrant further exploration with statistical analyses, the 
use of repeated-measure analysis of variance models will be considered treating each of the 
scores as continuous endpoints and estimating the effect of treatment on the changes in scores 
over time. 
12.2.9 
Exploratory biomarkers and pharmacogenetics 
The number of patients that will agree to participate in the exploratory biomarker and genetic 
research is unknown.  Therefore, it is not possible to establish whether sufficient data will be 
collected to allow a formal statistical evaluation, or whether only descriptive statistics will be 
generated. 
12.3 
Interim analyses 
An interim analysis will be performed when 40 patients have been recruited to Part B and 
followed up for 12 weeks (or progressed prior to 12 weeks).  The analysis will be primarily 
based on changes in tumour size at 12 weeks, but additional summaries of response rate at 12 
weeks, proportion progression-free at 12 weeks and best objective response during the study 
will support the change in tumour size data at the interim analysis.  The analysis and data 
presentations will be performed on the overall population, no PIK3CA mutation subgroup 
analysis will be performed as the number of patients expected to be recruited with a PIK3CA 
mutation positive tumour by that stage is likely to be low. 
The purpose of the interim analysis is to provide the opportunity for an early trigger to 
commence setting up a phase IIb study, if the results are strong enough, such that once the 
primary analysis is completed to confirm the interim result, the phase IIb study could 
commence with minimal delay.  Therefore, as safety data will be analysed on the full dataset 
at the primary analysis, it is proposed not to include safety data at the interim analysis.  It is 
not considered necessary to adjust the significance level to account for this additional analysis 
of the data, given that this analysis will not form the basis of any stop or acceleration 
decisions. In addition, the results obtained will be interpreted with caution, bearing in mind 
the increased risk of false positive results that this additional analysis introduces. 
12.4 
Determination of sample size 
Part B - Randomised expansion 
The primary endpoint of change in tumour size at week 12 will be assessed by calculating the 
log of the ratio of the week 12 (r1 week) tumour size measurement over the baseline tumour 




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Date 24 February 2012 
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12.5 
Data monitoring committee  
Not applicable 


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Edition Number 1 
Date 24 February 2012 
127(131) 
13. 
 IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Medical emergencies and AstraZeneca contacts 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes an SAE and is to be reported as such, see Section 6.4.4 
In the case of a medical emergency the investigator may contact the Study Delivery Team 
Leader. If the Study Delivery Team Leader is not available, contact the Study Delivery Team 
Physician at AstraZeneca Alderley Park, UK. 
Name  
Role in the study  
Address & telephone number 
Study Delivery Team 
Leader responsible for the 
protocol at central R&D 
site 
AstraZeneca,  
 
UK 
Study Delivery Team 
Physician responsible for 
the protocol at central R&D 
site 
AstraZeneca,  
 
UK 
 
Patient Safety Physician 
responsible for the protocol 
at central R&D site 
AstraZeneca,  
 
UK 
13.2 
Overdose  
There is no known antidote to AZD5363.  Investigators should be advised that any patient 
who receives a higher dose than intended should be monitored closely, managed with 
appropriate supportive care and followed up expectantly. 
Such overdoses should be recorded as follows: 
x
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module. 
x
An overdose without associated symptoms is only reported on the Overdose CRF 
module. 


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Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
128(131) 
If an overdose of AZD5363/placebo occurs in the course of the study, then investigators or 
other site personnel must inform appropriate AstraZeneca representatives within one day, ie, 
immediately but no later than the end of the next business day of when he or she becomes 
aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses with associated SAE, standard reporting timelines apply, see Section 6.4.4.  For 
other overdoses, reporting should be done within 28 days. 
For treatment of overdose with paclitaxel, please refer to the local prescribing information.  
Overdose of paclitaxel with associated AEs/SAEs should be recorded in the relevant AE/SAE 
module of the eCRF and reported according to the standard timelines.  The overdose does not 
need to be entered in to the overdose eCRF module. 
13.3 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
13.3.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study IP should be discontinued 
immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the IP 
under study may have interfered with the effectiveness of a contraceptive medication.  
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented 
even if the patient was discontinued from the study. 
If any pregnancy occurs in the course of the study, then investigators or other site personnel 
must inform appropriate AstraZeneca representatives within one day ie, immediately but no 
later than the end of the next business day of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
days for SAEs, see Section 6.4.4 and within 28 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy. 


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14. 
LIST OF REFERENCES 
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Altomere DA and Testa JR. Perturbations of the AKT signalling pathway in human cancer. 
Oncogene 2005;24:7455-7464. 
Beslija et al 2009 
Beslija S, Bonneterre J, Burstein HJ, Cocquyt V, Gnant M, Heinemann V et al for the Central 
European Cooperative Oncology Group (CECOG). The taxanes, applied as monotherapy or in 
combination with other agents, are the most commonly used compounds in MBC patients 
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Courtney et al 2010 
Courtney KD, Corcoran RB, Engelman, JA. The PI3K pathway as drug target in human 
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Ghersi D, Wilcken N, Simes J, Donoghue E. Taxane containing regimens for metastatic breast 
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Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
130(131) 
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Mutations May Be Discordant between Primary and Corresponding Metastatic Disease in 
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Mutation Associates with Improved Outcome in Breast Cancer. Clin Cancer Res 
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Ma CX, Lin L, Gao F, Giuntoli T, Chia YH, Guo Z et al. PIK3CA mutation analysis in 
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Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA et al. Paclitaxel plus 
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Clinical Study Protocol 
Drug Substance AZD5363  
Study Code D3610C00002 
Edition Number 1 
Date 24 February 2012 
131(131) 
Seidman et al 2008 
Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom K et al. Randomized phase 
III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with 
trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in 
HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J 
Clin Oncol. 2008;26:1642–1649. 


 
 
Clinical Study Protocol Amendment 
 
Amendment Number 
1 
 
Drug Substance 
AZD5363 
 
Study Code 
D3610C00002 
 
Date 
17 May 2012 
 
Protocol Dated 
24 February 2012 
 
 
 
 
 
 
 
 
 
 
A Phase I/Ib, Multicentre, Study Comprising a Safety Run-In of AZD5363 
when Combined with Paclitaxel in Patients with Advanced or Metastatic 
Breast Cancer; Followed by a Randomised Expansion of AZD5363 when 
Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-
Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA 
Mutation Status (BEECH). 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
Sponsor:  
AstraZeneca AB, 151 85 Södertälje, Sweden.  
Centres affected by the Amendment: 
All centres within the study. 
The protocol for the study is to be amended as detailed below:  
It was identified that standard AstraZeneca protocol text describing reporting times for 
Serious Adverse Events (SAEs) had become non-compliant under European Directive 2011/C 
172/01 (CT-3) ‘Detailed guidance on the collection, verification and presentation of adverse 
event/reaction reports arising from clinical trials on medicinal products for human use’ section 
4.3.1 paragraph 29. 
Protocol Edition 1 stated SAE reporting time from the Investigator to the Sponsor 
as: ‘immediate but no later than the end of the next business day’.  
The European Directive states: ‘Immediate reporting should allow the sponsor to 
take the appropriate measures to address potential new risks in a clinical trial. 
Therefore, the immediate report should be made by the investigator within a very 


Clinical Study Protocol Amendment 1 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 17 May 2012 
2(4) 
short period of time and under no circumstances should this exceed 24 hours 
following knowledge of the serious adverse event.’. 
The Study D3610C00002 protocol will therefore be amended to revise the criterion of ‘no 
later than the end of next business day’ to ‘within 24 hours’.  This criterion will be applied to 
reporting of SAEs, overdose and maternal exposure: 
 
The protocol for the study is to be amended as follows (revised text in bold): 
Section of protocol affected: 
6.4.4. Reporting of serious adverse events.  Paragraph 2. 
Previous text: 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives within one day ie, immediately but no later than 
the end of the next business day of when he or she becomes aware of it. 
Revised text: 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it. 
Reason for Amendment:  
Incorporation of revised SAE reporting timelines. 
Persons who initiated the Amendment: 
 Study Leader 
 
Section of protocol affected: 
6.4.4. Reporting of serious adverse events.  Paragraph 4. 
Previous text: 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than the end of the next business 
day of when he or she becomes aware of it. 


Clinical Study Protocol Amendment 1 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 17 May 2012 
3(4) 
Revised text: 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
Reason for Amendment:  
Incorporation of revised SAE reporting timelines. 
Persons who initiated the Amendment: 
 Study Leader 
 
Section of protocol affected: 
13.2. Overdose. Paragraph 3 
Previous text: 
If an overdose of AZD5363/placebo occurs in the course of the study, then investigators or 
other site personnel must inform appropriate AstraZeneca representatives within one day, ie, 
immediately but no later than the end of the next business day of when he or she becomes 
aware of it. 
Revised text: 
If an overdose occurs in the course of the study, then investigators or other site personnel 
inform appropriate AstraZeneca representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it. 
Reason for Amendment:  
Incorporation of revised SAE reporting timelines. 
Persons who initiated the Amendment: 
 Study Leader 
 
Section of protocol affected: 
13.3.1.  
Maternal exposure. Paragraph 3  


Clinical Study Protocol Amendment 1 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 17 May 2012 
4(4) 
Previous text: 
If any pregnancy occurs in the course of the study, then investigators or other site personnel 
must inform appropriate AstraZeneca representatives within one day ie, immediately but no 
later than the end of the next business day of when he or she becomes aware of it. 
Revised text: 
If any pregnancy occurs in the course of the study, then investigators or other site personnel 
must inform inform appropriate AstraZeneca representatives immediately, or no later than 
24 hours of when he or she becomes aware of it. 
Reason for Amendment:  
Incorporation of revised SAE reporting timelines. 
Persons who initiated the Amendment: 
 Study Leader 
 
 


 
 
Clinical Study Protocol Amendment 
 
Amendment Number 
2 
 
Drug Substance 
AZD5363 
 
Study Code 
D3610C00002 
 
Date 
24 April 2013 
 
Protocol Dated 
18 May 2012 
 
 
 
 
 
 
 
 
 
 
A Phase I/Ib, Multicentre, Study Comprising a Safety Run-In of AZD5363 
when Combined with Paclitaxel in Patients with Advanced or Metastatic 
Breast Cancer; Followed by a Randomised Expansion of AZD5363 when 
Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-
Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA 
Mutation Status (BEECH). 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
Sponsor: 
AstraZeneca AB, 151 85 Södertälje, Sweden.   
Centres affected by the Amendment: 
This amendment affects all centres in the study. 
The protocol for the study is to be amended as follows:  
Changed or additional text is indicated in bold, where applicable. Deleted text is indicated as 
scored through. 
Administrative changes - due to, for example, correction of typographical errors or  
renumbering of subsequent sections following addition of new sections - have been amended 
as applicable and have been included in the revised protocol but will not be listed separately in 
this amendment. 
The protocol amendments defined within this document primarily relate to the following 
areas:   


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
2(85) 
1. 
Study Title and phase of development:  Part B of this study had been re-
categorised from Phase Ib to Phase II in reflection of an increase in the size of the 
study and change to progression-free survival as primary endpoint; as detailed in 
item 3 below. 
2. 
Study Part A.  Replacement of AZD5363 continuous dosing schedule with an 
intermittent dosing schedule:  The original design of Part A of this study 
comprised two dosing schedules of AZD5363 in combination with paclitaxel: 
Schedule 1 -  AZD5363 continuous dosing, and Schedule 2 - AZD5363 intermittent 
dosing [weekly - 4 days on-therapy followed by 3 days off].   
Schedule 1 was not initiated in response to findings from associated clinical trial 
D3610C00001 - that an AZD5363 monotherapy continuous dosing schedule may 
not present a sufficiently favourable tolerability  profile.  It is proposed to now 
replace the Schedule 1 continuous regimen with an AZD5363 intermittent dosing 
regimen [weekly - 2 days on-therapy followed by 5 days off] following a strong 
pre-clinical positive evidence of efficacy of this schedule and an adequate clinical 
safety and tolerability profile as monotherapy in study D3610C00001. 
3. 
Study Part B.  Increase of total patient number enrolled from 60 to 100 and 
change of primary endpoint to progression-free survival:   The original design 
of Part B was to provide statistical power to detect a difference in change of tumour 
size in the overall population and in the PIK3CA tumour mutation-positive 
subgroup.  The study was also powered to detect a difference in progression-free 
survival (PFS) in the overall population, but not in the PIK3CA tumour mutation-
positive subgroup.   
Given the hypothesis that patients with a PIK3CA tumour mutation are the most 
likely to benefit from study therapy, it is proposed to increase the total number of 
patients to ensure sufficient statistical power to detect a potential difference in PFS 
in the PIK3CA tumour mutation-positive subgroup as well as in the overall 
population.  This would provide for a more robust evaluation of AZD5363 
combined with weekly paclitaxel, compared with weekly paclitaxel plus placebo, 
upon which to develop subsequent studies. 
As a result of this change, the primary objective for Part B has been revised from 
assessment of relative anti-tumour activity (endpoint variable - change in tumour 
size at 12 weeks) to assessment of relative efficacy (endpoint variable - progression-
free survival).  Assessment of relative anti-tumour activity has become a secondary 
objective. 
4. 
Study Part B.  Addition of overall survival as a secondary endpoint:  Overall 
survival has been added as a secondary endpoint in this study to provide an initial 
assessment of the survival time after treatment with AZD5363 combined with 
weekly paclitaxel compared with weekly paclitaxel plus placebo.  This will provide 
essential guidance to inform the design of subsequent studies. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
3(85) 
5. 
Study Part B.  Extension of WHO performance status evaluations:  Further 
performance status assessments at visits from first receipt of study drug up to 
progression will be performed.  This has been implemented following guidance 
received from the UK  National Institute for Health and Care Excellence (NICE) for 
studies of similar design. 
6. 
Study Part B.  Introduction of an independent Safety Review Committee:  The 
inclusion of an SRC, with membership that is independent of participation in Study 
D3610C00002, is being implemented to enable periodic review of coded 
randomised trial data outputs.  The SRC will assess safety and tolerability findings 
and will provide recommendations regarding continuation, adjustment or cessation 
of the dose and schedule of AZD5363/placebo. 
7. 
Study Part B.  Provision for a change in AZD5363/placebo formulation:   
Allowance will be made for a potential switch in AZD5363/placebo formulation 
from capsules to tablets prior to the start of, or during, Part B.  The implementation 
of a tablet formulation would allow data to be generated from patients who have 
received a dosage form consistent with that of the likely on-market formulation.  
Such a change would be made only following the generation of data from study 
D3610C00001 demonstrating that PK exposure from the new tablet formulation is 
comparable to that of the original capsule formulation.  Any such change would 
also be subject to the agreement of the SRC. 
8. 
Study Part B.  Revision of statistical analysis plans:  The scheduling and conduct 
of statistical analyses will be revised to reflect the increase in patient numbers, 
change in primary objective and addition of overall survival evaluation under the 
scope of this protocol amendment 
9. 
Study Parts A and B.  Inclusion of a Japanese patient population:  Under the 
original protocol it was not envisaged that Japan would participate in Part B, but 
that an optional dose escalation evaluation in Japanese patients could be conducted 
under Part A if indicated.  It is now anticipated that Japanese patients will 
participate in Part B and be treated with the same doses of AZD5363 and paclitaxel 
as those in the West.  This is based on the observation that Japanese patients are 
known to tolerate the required dose of paclitaxel and that no significant differences 
in PK and tolerability of AZD5363 have been observed between the Western and 
Japanese patients who have participated in AZD5363 Studies D3610C00001 and 
D3610C00004 respectively.  In the event that emerging findings from Part B 
indicate a difference between the two populations in terms of tolerability, the 
Japanese dose escalation subsidiary Part A may be conducted at the request of the 
Safety Review Committee.  In this case, enrolment of Japanese patients to Part B 
would be suspended. 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
4(85) 
Section of protocol affected: 
Multiple. 
General Revisions 
1. 
References to a ‘continuous’ dosing schedule have been replaced by ‘intermittent’ 
or ‘intermittent 2-on 5-off’ throughout the amended protocol (please see 
amendment rationale number 2).  Where these occur as solitary text changes only, 
they are not listed separately in this amendment. 
2. 
References to AZD5363/placebo ‘capsule’ formulation for study Part B have been 
replaced by ‘capsule or tablet’ throughout the amended protocol (please see 
amendment rationale number 7).  Where these occur as solitary text changes only, 
they are not listed separately in this amendment. 
3. 
References to suspension of AZD5363/placebo dosing being permitted for single 
periods of up to 28 days due to suspected toxicities have been replaced by up to 14 
days throughout the amended protocol and Appendix H (Instructions for study drug 
dose modification).  After which time study therapy should be withdrawn.  This 
change aligns with a more stringent approach to management of toxicities 
implemented across the AZD5363 clinical studies.  Where these replacements occur 
as solitary text changes only, they are not listed separately in this amendment.   
4. 
In the original protocol - Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.1 was referenced in error.  This has been corrected to version 
4.0  throughout the amended protocol.  Where these replacements occur as solitary 
text changes only, they are not listed separately in this amendment. 
5. 
References to retention of samples by AstraZeneca for a maximum of 25 years for 
conduct of  bioanalytical research have been revised to a maximum of 15 years 
throughout the amended protocol.  This amendment has been made following a 
change in AstraZeneca’s Maximum Retention Period for Human Biological 
Samples policy.   Where these replacements occur as solitary text changes only, 
they are not listed separately in this amendment.   
 
Section of protocol affected: 
Study Title on protocol front sheet and Synopsis. 
Previous text: 
A Phase I/Ib, Multicentre, Study Comprising a Safety Run-In of AZD5363 when Combined 
with Paclitaxel in Patients with Advanced or Metastatic Breast Cancer; Followed by a 
Randomised Expansion of AZD5363 when Combined with Paclitaxel vs. Paclitaxel plus 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
5(85) 
Placebo in Patients with ER-Positive Advanced or Metastatic Breast Cancer, Stratified by 
PIK3CA Mutation Status (BEECH). 
Revised text: 
A Phase I/II, Multicentre, Study Comprising a Safety Run-In of AZD5363 when Combined 
with Paclitaxel in Patients with Advanced or Metastatic Breast Cancer; Followed by a 
Randomised Expansion of AZD5363 when Combined with Paclitaxel vs. Paclitaxel plus 
Placebo in Patients with ER-Positive Advanced or Metastatic Breast Cancer, Stratified by 
PIK3CA Mutation Status (BEECH). 
Reason for Amendment:  
Please see amendment rationale number 1.   
 
Section of protocol affected: 
Protocol Synopsis: Study centre(s) and number of patients planned 
Previous text: 
Number of patients planned (enrolled): 
Safety Run-in. n= 40 
Randomised Expansion. n= 70 
Total number of study centres planned = 12 
Number of patients to be recruited per site: 
Maximum – not defined 
Minimum: n= 2 
Study period 
 
Phase of development 
Estimated date of first patient enrolled 
Q2 2012 
I 
Estimated date of last patient completed 
Q4 2014 
Ib 
 
Revised text: 
Number of patients planned (enrolled): 
Safety Run-in. n= 40 
Randomised Expansion. n= 100 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
6(85) 
Total number of study centres planned = 25 
Number of patients to be recruited per site: 
Maximum – not defined 
Minimum: n= 2 
Study period 
 
Phase of development 
Estimated date of first patient enrolled 
Q2 2012 
I 
Estimated date of last patient completed 
Q4 2016 
II 
 
Reason for Amendment:  
Change to patient and site numbers – Please see amendment rationale number 3. 
Change to estimated date of last patient completed is related to extension of study timings 
associated with follow-up for overall survival - Please see amendment rationale number 4. 
Change to phase of development - Please see amendment rationale number 1. 
 
Section of protocol affected: 
Protocol Synopsis – Primary objectives  
Previous text: 
Part B. Randomised expansion:  
To assess the relative anti tumour activity of AZD5363 when combined with weekly 
paclitaxel vs. weekly paclitaxel plus placebo by comparison of change in tumour size at 12 
weeks (target lesion assessment using RECIST 1.1) in the overall advanced or metastatic 
Estrogen Receptor positive breast cancer population and in a Phosphoinositide 3 kinase 
(PIK3CA) mutation positive sub population. 
Revised text: 
Part B. Randomised expansion:  
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel 
compared with weekly paclitaxel plus placebo by assessment of progression-free survival 
in the overall advanced or metastatic Estrogen Receptor positive breast cancer 
population and in a Phosphoinositide 3-kinase (PIK3CA) mutation-positive sub-
population. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
7(85) 
Reason for Amendment:  
Please see amendment rationale number 3.   
 
Section of protocol affected: 
Protocol Synopsis – Secondary objectives 
Previous text: 
Part B. Randomised expansion: 
x
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel 
compared with weekly paclitaxel plus placebo. 
x
To assess the safety and tolerability of AZD5363 when combined with weekly 
paclitaxel compared with weekly paclitaxel plus placebo.  
x
To investigate the effect on patients’ quality of life of AZD5363 when combined with 
weekly paclitaxel, compared with weekly paclitaxel plus placebo. 
Revised text: 
Part B. Randomised expansion (objectives applicable to all randomised patients and to the 
PIK3CA tumour mutation-positive sub-population alone): 
x
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel 
compared with weekly paclitaxel plus placebo by assessment of best objective 
response and duration of response. 
x
To assess the relative anti-tumour activity of AZD5363 when combined with 
weekly paclitaxel compared with weekly paclitaxel plus placebo. 
x
To assess the safety and tolerability of AZD5363 when combined with weekly 
paclitaxel compared with weekly paclitaxel plus placebo.  
x
To investigate the effect on patients’ quality of life of AZD5363 when combined with 
weekly paclitaxel, compared with weekly paclitaxel plus placebo. 
x
To compare overall survival in patients treated with AZD5363 in combination 
with weekly paclitaxel compared with weekly paclitaxel plus placebo. 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
8(85) 
Reason for Amendment:  
To clarify that the objectives relate to evaluation of the overall patient population and 
additionally to evaluation of the PIK3CA tumour-mutation positive sub-population alone. 
To define the inclusion of assessment of anti-tumour activity and overall survival as secondary 
objectives; and to clarify the separation of assessment of relative efficacy by outcome 
measures.  Please see amendment rationale numbers 3 and 4. 
 
Section of protocol affected: 
Protocol Synopsis – Part A: Safety run-in - Subsidiary Japanese patient evaluation (optional). 
Previous text: 
A subsidiary dose-escalating safety evaluation may optionally be conducted in a Japanese 
patient population at a starting dose, and under one schedule, determined by the Safety 
Review Committee.  This evaluation would be conducted to determine a safe and tolerable 
dose of AZD5363 when combined with weekly paclitaxel in a Japanese population. 
This separate Japanese safety run-in evaluation would commence following determination of 
the RD and dosing schedule in the Western population.  It would proceed in parallel with the 
Part B randomised expansion, but would not inform any decision regarding the conduct of 
Part B.  The schedule of assessments in the subsidiary Part A would be as detailed in this 
protocol for Part A.  It is not envisaged that a Japanese population would be evaluated under 
study Part B. 
Revised text: 
A subsidiary dose-escalating safety evaluation may optionally be conducted in a Japanese 
patient population at a starting dose, and under one schedule, determined by the Safety 
Review Committee.  This evaluation would be conducted to determine a safe and tolerable 
dose of AZD5363 when combined with weekly paclitaxel in a Japanese population. 
At the time of preparation of amended protocol 3, it is not anticipated that this 
subsidiary safety run-in will be required, however it may be commenced if emerging 
findings from Japanese patients enrolled in the Part B randomised expansion prompt 
the need for supplementary assessment of the dose of AZD5363 in combination with 
paclitaxel in Japanese patients.  In this case, further enrolment of Japanese patients to 
Part B would then be suspended.  The schedule of assessments in the subsidiary Part A 
would be as detailed in this protocol for Part A.   
Reason for Amendment:  
Please see amendment rationale number 9. 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
9(85) 
Section of protocol affected: 
Protocol Synopsis – Study design;  Part B: Randomised Expansion.  Last paragraph. 
Previous text: 
Patient assessments will continue up to objective disease progression as defined by RECIST 
1.1, death or withdrawal of consent.  A 28-day safety follow-up assessment should be 
conducted following cessation of all study therapy (AZD5363/placebo and paclitaxel). 
Revised text: 
Patient assessments will continue up to death or withdrawal of consent.  A 28-day safety 
follow-up assessment should be conducted following cessation of all study therapy 
(AZD5363/placebo and paclitaxel).  Patients who discontinue treatment for reasons other 
than progression, death or withdrawal of consent will continue to be followed for 
objective disease progression status as defined by RECIST 1.1. 
Reason for Amendment:  
Please see amendment rationale number 4. 
 
Section of protocol affected: 
Protocol Synopsis – Investigational product, dosage and mode of administration. 
Previous text: 
AZD5363: A twice daily regimen of an oral capsule formulation given on a continuous or 
intermittent weekly dosing schedule.  Administration of AZD5363 will commence in Part A 
as detailed in section 5.5.3: 
x
Continuous dosing: 320 mg bd (640 mg daily) throughout a patient’s participation in 
the study. 
x
Intermittent dosing (4 days of treatment followed by 3 days off-treatment): 360 mg bd 
(720 mg daily) each week that paclitaxel is received, and then each week following 
cessation of paclitaxel throughout a patient’s participation in the study. 
Placebo (Part B only): Oral capsule formulation, matched to AZD5363. 
Revised text: 
AZD5363: A twice daily regimen of an oral formulation given on one of two intermittent 
weekly dosing schedules.  Administration of AZD5363 will commence in Part A as detailed in 
section 5.5.3: 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
10(85) 
x
An intermittent dosing schedule of 2 days on-treatment followed by 5 days off-
treatment: 560 mg bd (1120 mg daily) each week that paclitaxel is received, and 
then each week following cessation of paclitaxel throughout a patient’s participation 
in the study. 
x
An intermittent dosing schedule of 4 days of treatment followed by 3 days off-
treatment: 360 mg bd (720 mg daily) each week that paclitaxel is received, and then 
each week following cessation of paclitaxel throughout a patient’s participation in the 
study. 
Placebo (Part B only): Oral formulation, matched to AZD5363. 
Reason for Amendment:  
Change to dosing schedule - please see amendment rationale number 2. 
AZD5363/placebo matched formulation - please see amendment rationale number 7. 
 
Section of protocol affected: 
Protocol Synopsis – Outcome variables;  
Previous text: 
Part B. Randomised expansion:   
x
Treatment efficacy as assessed by progression-free survival.  
x
Tumour size as assessed by RECIST 1.1. 
x
Quality of life. 
Revised text: 
Part B. Randomised expansion:   
x
Treatment efficacy as assessed by progression-free survival.  
x
Tumour size as assessed by RECIST 1.1. 
x
Quality of life. 
x
Overall survival. 
Reason for Amendment:  
Please see amendment rationale number 4. 
 


















Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
19(85) 
been added with reference to conduct of AZD5363 dosing as a 2 days-on, 5 days-off schedule 
(please see amendment rationale number 2). 
The structure of this section has been revised to align with a new common reporting format 
across AZD5363 clinical studies; allowing for more effective, standardised, updates to be 
provided where required in future documents. 
 
Section of protocol affected: 
Section 1.2.  Research hypothesis 
Previous text: 
Part B. Randomised expansion:  
x
The addition of AZD5363 to weekly paclitaxel will be more efficacious than paclitaxel 
alone - as demonstrated by a reduction in tumour size in patients with Estrogen-
Receptor positive (ER+ve) advanced or metastatic breast cancer.  
x
Tumour types that have mutations in PIK3CA (PIK3CA mutation-positive) will have  
increased sensitivity to AZD5363 and may therefore demonstrate greater tumour size 
reduction and clinical response to AZD5363 when combined with paclitaxel than the 
overall population. 
Revised text: 
Part B. Randomised expansion:  
x
The addition of AZD5363 to weekly paclitaxel will be more efficacious than 
paclitaxel alone - as demonstrated by an increase in duration of progression-free 
survival (PFS) in patients with Estrogen-Receptor positive (ER+ve) advanced or 
metastatic breast cancer.  
x
Tumour types that have mutations in PIK3CA (PIK3CA mutation-positive) will 
have  increased sensitivity to AZD5363 and may therefore demonstrate greater 
tumour size reduction and clinical response to AZD5363 when combined with 
paclitaxel than the overall population. 
Reason for Amendment: 
Please see amendment rationale number 3. 
 
Section of protocol affected: 
Section 1.3.2.  Rationale for AZD5363 in breast cancer 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
20(85) 
Previous text: 
AZD5363 has been shown to greatly increase sensitivity to the taxane docetaxel (Taxotere) in 
several breast cancer xenograft models.  For example, both continuous and intermittent 
schedules of AZD5363 enhanced the efficacy of docetaxel in the HCC-1187 xenograft (Figure 
1).  The sequence of administration appears to be very important; in the HCC-1187 model, 
administering docetaxel after an intermittent dosing schedule of AZD5363 (4 days on, 3 days 
off) was found to be antagonistic, whilst administering docetaxel before the intermittent 
schedule resulted in enhanced efficacy  (Figure 2).  
Revised text: 
AZD5363 has been shown to greatly increase sensitivity to the taxane docetaxel (Taxotere) in 
several breast cancer xenograft models.  For example, both continuous and intermittent 
schedules of AZD5363 enhanced the efficacy of docetaxel in the HCC-1187 xenograft (Figure 
1).  The sequence of administration appears to be very important; in the HCC-1187 model, 
administering docetaxel after an intermittent dosing schedule of AZD5363 (4 days on, 3 days 
off) was found to be antagonistic, whilst administering docetaxel before the intermittent 
schedule resulted in enhanced efficacy  (Figure 2).  
Efficacy equivalence has been shown for AZD5363 combined with Taxotere under 
continuous, 4 days-on, 3 days-off and 2 days-on 5 days-off schedules at adjusted dose 
levels (Figure 3). 
 
Additional Figure: 
Figure 3 
Different dosing schedules of AZD5363 deliver equivalent efficacy, as 
monotherapy or in combination with taxotere, in the BT474c xenograft 
model. 
In this model, a dose of 255 mg/kg bd of AZD5363 combined with Taxotere given in a 2 
days on 5 days off intermittent schedule delivers equivalent efficacy to that obtained 
from a combination of Taxotere with either 150mg/kg bd of AZD5363 given in a 
continuous schedule and 210mg /kg bd of AZD5363 given in a 4 days on, 3 days off 
schedule. 






Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
23(85) 
Reason for Amendment:  
Please see amendment rationale number 3. 
 
Section of protocol affected: 
Section 2.2.  Secondary objectives 
Previous text: 
Part B. Randomised expansion: 
x
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel 
compared with weekly paclitaxel plus placebo by assessment of ORR at 12 weeks.  
x
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel 
compared with weekly paclitaxel plus placebo by assessment of PFS, best objective 
response (BOR) and DoR.  
x
To further assess the safety and tolerability of AZD5363 when combined with weekly 
paclitaxel compared with paclitaxel plus placebo.  
x
To investigate the effect on patients’ quality of life (QoL) of AZD5363 when 
combined with weekly paclitaxel, compared with weekly paclitaxel alone by changes 
from baseline, utilising a patient-completed QoL questionnaire. 
Revised text: 
Part B. Randomised expansion (objectives applicable to all randomised patients and to the 
PIK3CA tumour mutation-positive sub-population alone): 
x
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel 
compared with weekly paclitaxel plus placebo by assessment of ORR at 12 weeks, 
best objective response (BOR) and DoR. 
x
To assess the relative anti-tumour activity of AZD5363 when combined with 
weekly paclitaxel vs. weekly paclitaxel plus placebo by comparison of change in 
tumour size at 12 weeks (target lesion assessment using Response Evaluation 
Criteria In Solid Tumours [RECIST 1.1]).   
x
To compare overall survival (OS) in patients treated with AZD5363 in 
combination with weekly paclitaxel compared with weekly paclitaxel plus placebo 
by assessment of time to death. 
x
To further assess the safety and tolerability of AZD5363 when combined with weekly 
paclitaxel compared with paclitaxel plus placebo.  


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
24(85) 
x
To investigate the effect on patients’ quality of life (QoL) of AZD5363 when 
combined with weekly paclitaxel, compared with weekly paclitaxel alone by changes 
from baseline, utilising a patient-completed QoL questionnaire. 
Reason for Amendment:  
Please see amendment rationale numbers 3 and 4. 
 
Section of protocol affected: 
Section 2.3.  Exploratory objectives 
Additional text (new bullet point in position 4): 
x
To explore changes in WHO performance status in patients treated with 
AZD5363 in combination with weekly paclitaxel compared with weekly paclitaxel 
plus placebo. 
Reason for Amendment:  
Please see amendment rationale number 5. 
 
Section of protocol affected: 
Section 3.1.1.  Part A: Safety run-in 
Previous text: 
A multiple ascending-dose evaluation of AZD5363 in each of two schedules (continuous and 
intermittent dosing) when combined with weekly paclitaxel.  These dose escalation schedules 
may commence at the same time, or one schedule may be inititiated in advance of the other to 
facilitate ease of study initiation.    
This part will assess the comparative safety, tolerability, pharmacokinetics and preliminary 
anti-tumour activity of both schedules of AZD5363 when combined with weekly paclitaxel.  
A recommended dose and schedule of AZD5363 will be determined for conduct of Part B, the 
randomised expansion (see section 3.1.2).   
The patient population will be female, aged 18 years or older, with advanced or metastatic 
breast cancer.  For inclusion in Part A, patients must not have received any more than two 
prior courses of chemotherapy for breast cancer.  Prior endocrine therapy is allowed. 
Patients will be recruited in approximately 8 centres in approximately 4 countries.  The 
number of patients enrolled will be dependent upon the number of dose escalation cohorts 
required, see below, but a total of approximately 40 patients is anticipated.   


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
25(85) 
Both schedules of AZD5363 will be in combination with 90 mg/m2 paclitaxel (see section 
5.5.3):  
x
Continuous dosing:  AZD5363 capsules taken orally, twice daily, each day.  The 
starting dose for cohort 1 will be 320 mg (640 mg daily). 
x
Intermittent dosing:  AZD5363 capsules taken orally, twice daily, for repeating weekly 
cycles of 4 days on treatment followed by 3 days off treatment during each week that 
paclitaxel is received.  The starting dose for cohort 1 will be 360 mg (720 mg daily).   
Dose escalating cohorts of 3 to 6 patients will be evaluated under each schedule.  A total of 6 
patients must be evaluated at a selected dose level for it to be confirmed as the RD.  AZD5363 
dose escalations and maximum doses attained will not exceed levels deemed tolerated by the 
Safety Review Committee (SRC) in prior first time in patient study D3610C00001. 
The RD for a schedule may or may not be defined by attainment of non-tolerated dose / 
maximum tolerated dose (NTD / MTD) levels (see section 5.10.2).  If the RD is selected prior 
to attaining MTD, the SRC will determine whether continued dose escalations to NTD/MTD 
are required. 
Revised text: 
A multiple ascending-dose evaluation of AZD5363 in each of two intermittent dosing 
schedules when combined with weekly paclitaxel.    
This part will assess the comparative safety, tolerability, pharmacokinetics and preliminary 
anti-tumour activity of both schedules of AZD5363 when combined with weekly paclitaxel.  
A recommended dose and schedule of AZD5363 will be determined for conduct of Part B, the 
randomised expansion (see section 3.1.2).  Determination of the Part B dose and schedule 
may not require completion of both Part A schedules; a decision to progress to Part B 
may be made on findings from one schedule in advance of completion of the other where 
this is deemed appropriate by the Safety Review Committee (SRC).  
The patient population will be female, aged 18 years or older, with advanced or metastatic 
breast cancer.  For inclusion in Part A, patients must not have received any more than two 
prior courses of chemotherapy for breast cancer.  Prior endocrine therapy is allowed. 
Patients will be recruited in approximately 8 centres in approximately 4 countries.  The 
number of patients enrolled will be dependent upon the number of dose escalation cohorts 
required, see below, but a total of approximately 40 patients is anticipated.   
Both schedules of AZD5363 will be in combination with 90 mg/m2 paclitaxel (see section 
5.5.3).   AZD5363 will be taken orally, twice daily, as detailed below, on each week that 
paclitaxel is received.  AZD5363 will not be taken on any week that paclitaxel is not 
scheduled.  AZD5363 may be taken each week following withdrawal of paclitaxel, at the  
discretion of the investigator, throughout a patient’s participation in the study: 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
26(85) 
x
Schedule 1: A weekly intermittent AZD5363 dosing schedule of 2 days on-
treatment followed by 5 days off-treatment. The starting dose for cohort 1 will be 
560 mg bd (1120 mg daily). 
x
Schedule 2: A weekly intermittent AZD5363 dosing schedule of 4 days on-
treatment followed by 3 days off-treatment.  The starting dose for cohort 1 will be 360 
mg (720 mg daily).   
Dose escalating cohorts of 3 to 6 patients will be evaluated under each schedule.  A total of 6 
patients must be evaluated at a selected dose level for it to be confirmed as the RD.  AZD5363 
dose escalations and maximum doses attained will not exceed levels deemed tolerated by the 
SRC in prior first time in patient study D3610C00001. 
The RD for a schedule may or may not be defined by attainment of non-tolerated dose / 
maximum tolerated dose (NTD / MTD) levels (see section 5.10.2).  If the RD is selected prior 
to attaining MTD, the SRC will determine whether continued dose escalations to NTD/MTD 
are required. 
Reason for Amendment:  
Please see amendment rationale number 2. 
 
Section of protocol affected: 
Section 3.1.1.  Part A: Safety run-in.  Subsidiary Japanese patient evaluation (optional)   
Previous text: 
A Part A subsidiary dose-escalating safety evaluation may be conducted optionally in a 
Japanese patient population at a starting dose, and under one schedule, determined by the 
Safety Review Committee.  This evaluation would be conducted to determine a safe and 
tolerable dose of AZD5363 when in combination with paclitaxel in a Japanese population. 
This separate Japanese safety run in evaluation would commence following determination of 
the RD and dosing schedule in the Western population.  It would proceed in parallel with the 
Part B randomised expansion, but would not inform any decision regarding the conduct of 
Part B.  The schedule of assessments in the subsidiary Part A would be as detailed in this 
protocol for Part A.  It is not envisaged that a Japanese population would be evaluated under 
study Part B. 
Revised text: 
A Part A subsidiary dose-escalating safety evaluation may be conducted optionally in a 
Japanese patient population at a starting dose, and under one schedule, determined by the 
Safety Review Committee.  This evaluation would be conducted to determine a safe and 
tolerable dose of AZD5363 when in combination with paclitaxel in a Japanese population. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
27(85) 
At the time of preparation of amended protocol 3, it is not anticipated that this 
subsidiary safety run-in will be required, however it may be commenced if emerging 
findings from Japanese patients enrolled in the Part B randomised expansion prompt 
the need for supplementary assessment of the dose of AZD5363 in combination with 
paclitaxel in Japanese patients.  In this case, further enrolment of Japanese patients to 
Part B would then be suspended.  The schedule of assessments in the subsidiary Part A 
would be as detailed in this protocol for Part A. 
Reason for Amendment:  
Please see amendment rationale number 9. 
 
Section of protocol affected: 
Section 3.1.2.  Part B Randomised expansion.  3rd paragraph. 
Previous text: 
Patients will be recruited in approximately 12 centres in approximately 5 countries.  
Approximately 70 patients will be enrolled in this phase (to ensure that 60 are evaluable at 12 
weeks), of which approximately 35 must have a tumour detectable as carrying a PIK3CA 
mutation.   
Revised text: 
Patients will be recruited in approximately 25 centres in approximately 10 countries.  
Approximately 100 patients will be enrolled in this phase, of which approximately 50 must 
have a tumour detectable as carrying a PIK3CA mutation. 
Reason for Amendment:  
Increased country and site numbers reflect updated estimates following feasibility reviews, 
and in reference to increased patient number in Part B (please see amendment rationale 
number 3). 
 
Section of protocol affected: 
3.1.3.  Treatment schedules 
Previous text: 
Under both the continuous and intermittent dosing schedules, first receipt of paclitaxel will be 
on Cycle 1, Day 1; first receipt of AZD5363/placebo will be on Day 2.  
Under the intermittent dosing schedule, weekly AZD5363 regimens thereafter will continue to 
start on the day after dosing with paclitaxel. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
28(85) 
 
Cycle 1 
Cycle 2 onwards 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 1 
Week 2 
Week 3 
Week 4 
Paclitaxel. Dose dayĺ 
Day 1 
Day 1 
Day 1 
None 
Day 1 
Day 1 
Day 1 
None 
Continuous. 
Dose days ĺ 
Day 2 to Day 28 
Day 1 to Day 28 
AZD5363  
Intermittent. 
Dose days ĺ 
D2 to D5 D2 to D5
D2 to D5
None 
D2 to D5
D2 to D5 D2 to D5 
None 
 
Revised text: 
Both dosing schedules will be conducted in 4-weekly cycles; comprising 3 weeks on-
treatment and 1 week off-treatment.  During each week on-treatment, paclitaxel will be 
given on Day 1 and AZD5363 will commence on Day 2: 
 
Cycle 1 
Cycle 2 onwards 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 1 
Week 2 
Week 3 
Week 4 
Paclitaxel. Dose dayĺ 
Day 1 
Day 1 
Day 1 
None 
Day 1 
Day 1 
Day 1 
None 
2-on 5-off 
dose days ĺ D2 & D3 D2 & D3 D2 & D3
None 
D2 & D3 D2 & D3 D2 & D3 
None 
AZD5363  
4-on 3-off 
dose days ĺ 
D2 to D5 D2 to D5
D2 to D5
None 
D2 to D5
D2 to D5 D2 to D5 
None 
 
Reason for Amendment:  
Please see amendment rationale number 2. 
 
Section of protocol affected: 
3.1.4.  Assessment Schedule 
Previous text: 
Patients will undergo the assessments detailed in the schedules below, presented separately for 
those allocated to either the continuous or intermittent dosing schedule.  Assessments are 
applicable to both the Safety Run-in and Randomised Expansion parts unless otherwise 
indicated 
Revised text: 
Patients will undergo the assessments detailed in the schedules below, presented separately for 
those allocated to either of the intermittent dosing schedules.  Assessments are applicable to 
both the Safety Run-in and Randomised Expansion parts unless otherwise indicated.    


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
29(85) 
Assessment timing key:  
x
Pre: Pre-dosing;   
x
Post: Post –dosing (or the number of hours post-dosing are specified);  
x
X: At any time of the day.   
Note: For days on which study drug is not received - ‘Pre’ and ‘Post’ indicate that 
assessments/samplings should be conducted at equivalent times to those carried out on 
dosing days, where possible 
Reason for Amendment:  
Following feedback from study sites, daily assessment and sample timepoints (pre-, post- 
dosing and number of hours post-dosing where applicable) have been specified in the 
schedules of assessments (see items below) for clarity.  This additional text describes the key 
used to define these timepoints in the schedule diagrams. 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
30(85) 
Section of protocol affected: 
Figure 5.  Schedule of assessments - Schedule 1  
Previous text: 
Figure 5 
Schedule 1: AZD5363/placebo – Continuous Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Paclitaxel 
Discont. 
AZD5363 
Discont. 
28-day 
follow-up 
Details in 
Section: 
Week ĺ 
  
1 
2 
3 
4 
1 
2 
3 
4 
1 
  
  
  
 
Week Day ĺ 
 -28 to 0 1 
2 
3 
1 
2 
1 
1 
1 
1 
1 
1 
1 
  
  
  
 
Paclitaxel dosed (i.v.) 
  
X 
  
  
X 
  
X 
  
X 
X 
X 
  
Xĺ 
  
  
  
 
AZD5363 dosed (bd) 
  
  
X 
Xĺ X 
Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ 
  
  
  
 
ActivityĻ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Informed consent - PIK3CA 
screen (Part B only) 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
8.4 
PIK3CA mutation testing  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6.2.2 
Informed consent - study 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
8.4 
Demography& baseline 
characteristics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6.2 
Medical/surgical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6.2 
Previous/concomitant therapy 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
5.6 
Previous cancer therapy 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
5.6 
Inclusion / exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
4 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
31(85) 
Figure 5 
Schedule 1: AZD5363/placebo – Continuous Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Paclitaxel 
Discont. 
AZD5363 
Discont. 
28-day 
follow-up 
Details in 
Section: 
Week ĺ 
  
1 
2 
3 
4 
1 
2 
3 
4 
1 
  
  
  
 
Week Day ĺ 
 -28 to 0 1 
2 
3 
1 
2 
1 
1 
1 
1 
1 
1 
1 
  
  
  
 
Paclitaxel dosed (i.v.) 
  
X 
  
  
X 
  
X 
  
X 
X 
X 
  
Xĺ 
  
  
  
 
AZD5363 dosed (bd) 
  
  
X 
Xĺ X 
Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ 
  
  
  
 
Physical examination 
X 
X 
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
  
6.4.6 
Height and weight 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
6.4.7 
WHO performance status 
X 
X 
  
  
  
  
  
  
 
  
  
  
 
 
 
  
6.4.8 
Vital signs 
X 
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
6.4.11 
12-lead ECG 
X 
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
X 
X 
  
6.4.9 
MUGA / Echocardiogram 
X 
  
  
  
  
  
  
  
X 
  
  
  
X3 
 
X 
  
6.4.10 
Haematology, Clinical 
chemistry Urinalysis 
X 
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
6.4.5 
Glycosylated haemoglobin 
X 
  
  
  
  
  
  
  
  
  
  
  
X3 
X 
X 
  
6.4.12.2 
Lipids  
X 
 
  
  
  
  
  
  
 
  
  
  
X3 
  
X 
  
6.4.12.1 
Glucose, insulin, insulin c-
peptide, 
 
X 
X 
  
X 
  
X 
X 
X 
  
  
  
X 
  
X 
  
6.4.12.3 
Pregnancy test 
X 
X 
  
  
  
  
  
  
 
  
  
  
  
X 
X 
  
6.4.5 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
32(85) 
Figure 5 
Schedule 1: AZD5363/placebo – Continuous Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Paclitaxel 
Discont. 
AZD5363 
Discont. 
28-day 
follow-up 
Details in 
Section: 
Week ĺ 
  
1 
2 
3 
4 
1 
2 
3 
4 
1 
  
  
  
 
Week Day ĺ 
 -28 to 0 1 
2 
3 
1 
2 
1 
1 
1 
1 
1 
1 
1 
  
  
  
 
Paclitaxel dosed (i.v.) 
  
X 
  
  
X 
  
X 
  
X 
X 
X 
  
Xĺ 
  
  
  
 
AZD5363 dosed (bd) 
  
  
X 
Xĺ X 
Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ 
  
  
  
 
Paclitaxel PK blood samples1  
  
X 
X 
  
X2 
X2 
X2 
  
 
  
  
  
 
  
  
  
6.6.2 
AZD5363 PK blood samples1 
  
  
X 
 X 
X 
X  
X 
X 
  
  
  
  
  
  
  
  
6.6.2 
Pharmacodynamic blood 
samples1 
  
X 
X 
X 
X 
X  
X 
X 
X 
  
  
  
X 
  
X 
  
6.7.1 
Exploratory biomarker blood 
samples1 (optional) 
X 
  
X 
  
X 
  
X 
X 
X 
  
  
  
X 
  
X 
  
6.8.1.5 
Exploratory biomarker hair 
samples (optional) 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 
Pharmacogenetics (optional) 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6.9.1 
RECIST Tumour assessments 
X 
  
  
  
  
  
  
  
 
  
  
  
X3 
 
  
  
6.3.1 
Archival tumour sample  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6.8.1.2 
Paired biopsy (optional)  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
6.8.1.3 
Circulating tumour cells 
 
X 
  
  
 
  
  
  
X 
  
  
  
X3 
  
  
  
6.8.1.1 
Patient meal information 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
 
 
 
6.4.12.4 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
33(85) 
Figure 5 
Schedule 1: AZD5363/placebo – Continuous Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Paclitaxel 
Discont. 
AZD5363 
Discont. 
28-day 
follow-up 
Details in 
Section: 
Week ĺ 
  
1 
2 
3 
4 
1 
2 
3 
4 
1 
  
  
  
 
Week Day ĺ 
 -28 to 0 1 
2 
3 
1 
2 
1 
1 
1 
1 
1 
1 
1 
  
  
  
 
Paclitaxel dosed (i.v.) 
  
X 
  
  
X 
  
X 
  
X 
X 
X 
  
Xĺ 
  
  
  
 
AZD5363 dosed (bd) 
  
  
X 
Xĺ X 
Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ Xĺ 
  
  
  
 
Quality of Life questionnaires  
(Part B only) 
X 
X 
  
  
  
  
  
  
 
  
  
  
X3 
 
X 
  
6.5.1 
Concomitant medication 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5.6 
Subsequent cancer therapy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
5.6 
Adverse events 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
1.  
PK, PD and Biomarker samplings are shown as cumulative timepoints. Please refer to individual study segment tables given in sections 6.6.2 (PK) and 
6.8.1.6 (PD/biomarkers) 
2   
Part A - Safety Run-in phase only: Patients will continue to undergo paclitaxel PK measurements on these occasions. 
3.  
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1). Part 
B - Randomised expansion only: Patients will continue to undergo RECIST assessments after cessation of study therapies up to disease progression or 
withdrawal of consent.   


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
34(85) 
 
Revised text: 
Figure 6 
Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
ActivityĻ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
- PIK3CA screen 
(Part B only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
PIK3CA mutation 
testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Informed consent 
- study 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Demography& 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Previous/concomi
tant therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Previous cancer 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Inclusion / 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
35(85) 
Figure 6 
Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
Physical 
examination 
X 
Pre  
Pre Pre  
 
 
 
 
Pre  
 
 
 
 
 
 
Pre  
X 
X 
 
6.4.6 
Height and weight X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.7 
WHO 
performance 
status3 
X 
Pre X3 X3 X3  
X3  
 
X3 X3  
X3  
X3  
X3  
X3 
 
X3 
X3 
 
6.4.8 
Vital signs 
X 
Pre Pre 
1h 
2h 
6h 
Post Pre  
Pre  
 
Pre Pre  
Post  
Post  
Post  
X 
 
X 
X 
 
6.4.11 
12-lead ECG 
X 
Pre Pre 
1h 
2h 
6h 
Pre Pre  
 
 
 
 
Post  
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.9 
MUGA / 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
X 
 
6.4.10 
Haematology, 
Clinical chemistry 
Urinalysis 
X 
Pre Pre Pre  
Pre  
Pre  
Pre  
Pre Pre  
Pre  
Pre  
 
Pre X 
X 
 
6.4.5 
Additional 
glucose 
 
 
2-4h 
4-6h 
2-4h 
4-6h 
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h
4-6h
 
 
 
 
 
 
 
2-4h
4-6h
 
 
 
6.4.5 
Glycosylated 
haemoglobin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
X 
X 
 
6.4.12.2
Lipids  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
X 
 
6.4.12.1


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
36(85) 
Figure 6 
Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
Glucose, insulin, 
insulin c-peptide4 
 
Pre  
Pre 
2h 
4h 
6h 
8h 
 
Pre  
Pre  
Pre  
Pre
2-4h
 
 
 
 
 
 
 
Pre
2-4h
 
X 
 
6.4.12.3
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
6.4.5 
Paclitaxel PK 
blood samples1 
 
Pre 
2h 
4h 
8h 
Pre  
 
Pre 1  
Pre 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
AZD5363 PK 
blood samples1 
 
 
Pre 
2h 
4h 
8h 
Pre  
Pre  
Pre  
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Pharmacodynami
c blood samples1 
 
Pre Pre 
2h 
4h 
8h 
Pre  
Pre  
Pre  
Pre Pre  
 
 
 
 
 
 
X 
 
 
X 
 
6.7.1 
Exploratory 
biomarker blood 
samples1 
(optional) 
X 
 
Pre  
 
Pre  
Pre  
Pre Pre  
 
 
 
 
 
 
X 
 
 
X 
 
6.8.1.5 
Exploratory 
biomarker hair 
samples (optional) 
 
 
Pre 
4h 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 
Pharmacogenetics 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.1 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
37(85) 
Figure 6 
Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
RECIST Tumour 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
 
 
6.3.1 
Archival tumour 
sample  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.2 
Paired biopsy 
(optional)  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.3 
Circulating 
tumour cells 
 
Pre  
 
 
 
 
 
 
 
Pre  
 
 
 
 
 
 
Pre 2  
 
 
 
6.8.1.1 
Patient meal 
information 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
6.4.12.4
QoL 
questionnaires 
(Part B only) 
X 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
X 
 
6.5.1 
Survival status 
(Part B only)5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X5 
6.2.3.4 
Subsequent 
cancer therapy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X5 
5.6 
Concomitant 
medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Adverse events 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
6.4.3 
 
1.  
Part A - Safety Run-in phase only: Patients will continue to undergo paclitaxel PK measurements on these occasions. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
38(85) 
2.  
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1).  Part 
B - Randomised expansion only: Patients will continue to undergo RECIST assessments after cessation of study therapies up to disease progression or 
withdrawal of consent.   
3.  
WHO performance status; Part B – Randomised expansion phase only:  Performance status will be assessed at these timepoints during part B 
only. 
4.  
Insulin c-peptide; Part A - Safety Run-in phase only:  Insulin c-peptide will not be analysed during the Part B Randomised expansion. 
5. 
Part B Randomised expansion phase only: Survival status and subsequent cancer therapies will be determined at the 28 day follow-up visit and 
at 12-weekly intervals thereafter.  These visits suggested to coincide with RECIST assessments up to disease progression, and at 12-weekly 
intervals thereafter to death or withdrawal. 
 
Reason for Amendment:  
Please see amendment rationale number 2 regarding replacement of the schedule of assessments relevant to the AZD5363/placebo 
continuous dosing regimen – with a schedule relevant to the intermittent (2 days-on, 4 days-off) dosing regimen.    
Addition of a survival status evaluation for study Part B has been introduced with reference to amendment rationale number 4. 
Reasons for other amendments to timepoints and footnotes are described per assessment for protocol sections 6.4.5 to 6.8.1.6  
detailed later in this document. 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
39(85) 
Section of protocol affected: 
Figure 5.  Schedule of assessments - Schedule 2 
Previous text: 
Figure 6 
Schedule 2: AZD5363/placebo – Intermittent Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont. 
AZD5363
Discont. 
28-day 
follow-
up 
Details 
in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ       -28 to 
0 
1 
2 
3 
5 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosed (i.v.) 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosed (bd) 
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 Xĺ
 
Xĺ
 
Xĺ 
 
 
 Xĺ
 
 
 
 
ActivityĻ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent - 
PIK3CA screen (Part 
B only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
PIK3CA mutation 
testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Informed consent - 
study 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Demography& 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Previous/concomitant 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Previous cancer 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
40(85) 
Figure 6 
Schedule 2: AZD5363/placebo – Intermittent Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont. 
AZD5363
Discont. 
28-day 
follow-
up 
Details 
in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ       -28 to 
0 
1 
2 
3 
5 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosed (i.v.) 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosed (bd) 
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 Xĺ
 
Xĺ
 
Xĺ 
 
 
 Xĺ
 
 
 
 
Inclusion / exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Physical examination X 
X 
 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.6 
Height and weight 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.7 
WHO performance 
status 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.8 
Vital signs 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
6.4.11 
12-lead ECG 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.9 
MUGA / 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X3  
 
X 
 
6.4.10 
Haematology, 
Clinical chemistry 
Urinalysis 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
6.4.5 
Glycosylated 
haemoglobin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3  
X 
X 
 
6.4.12.2
Lipids  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3  
 
X 
 
6.4.12.1
Glucose, insulin, 
insulin c-peptide,  
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
6.4.12.3


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
41(85) 
Figure 6 
Schedule 2: AZD5363/placebo – Intermittent Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont. 
AZD5363
Discont. 
28-day 
follow-
up 
Details 
in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ       -28 to 
0 
1 
2 
3 
5 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosed (i.v.) 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosed (bd) 
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 Xĺ
 
Xĺ
 
Xĺ 
 
 
 Xĺ
 
 
 
 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
6.4.5 
Paclitaxel PK blood 
samples1 
 
X 
X 
 
 
 
X2  
X2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
AZD5363 PK blood 
samples1 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Pharmacodynamic 
blood samples1 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
6.7.1 
Exploratory 
biomarker blood 
samples1 (optional) 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
6.8.1.5 
Exploratory 
biomarker hair 
samples (optional) 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 
Pharmacogenetics 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.1 
RECIST Tumour 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3  
 
 
 
6.3.1 
Archival tumour 
sample  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.2 
Paired biopsy 
(optional)  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.3 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
42(85) 
Figure 6 
Schedule 2: AZD5363/placebo – Intermittent Dosing. 
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont. 
AZD5363
Discont. 
28-day 
follow-
up 
Details 
in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ       -28 to 
0 
1 
2 
3 
5 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
Paclitaxel dosed (i.v.) 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
AZD5363 dosed (bd) 
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 Xĺ
 
Xĺ
 
Xĺ 
 
 
 Xĺ
 
 
 
 
Circulating tumour 
cells 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X3  
 
 
 
6.8.1.1 
Patient meal 
information 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
6.4.12.4
QoL questionnaires 
(Part B only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3  
 
X 
 
6.5.1 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5.6 
Subsequent cancer 
therapy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
5.6 
Adverse events 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
6.4.3 
 
1   
PK, PD and Biomarker samplings are shown as cumulative timepoints. Please refer to individual study segment tables given in sections 6.6.2 (PK) and 
6.8.1.6 (PD/biomarkers) 
2.  
Part A - Safety Run-in phase only: Patients will continue to undergo paclitaxel PK measurements on these occasions.  
3.  
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1). Part 
B Randomised expansion only: Patients will continue to undergo RECIST assessments after cessation of study therapies up to disease progression or 
withdrawal of consent 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
43(85) 
Revised text: 
Figure 7 
Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ -28 to 0 1 
2 
3 
5 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ  
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
ActivityĻ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
- PIK3CA screen 
(Part B only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
PIK3CA mutation 
testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Informed consent 
- study 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Demography& 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Previous/concomi
tant therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Previous cancer 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Inclusion / 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
Physical 
examination 
X 
Pre  
 
Pre Pre  
 
 
 
 
Pre  
 
 
 
 
 
 
Pre  
X 
X 
 
6.4.6 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
44(85) 
Figure 7 
Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ -28 to 0 1 
2 
3 
5 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ  
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
Height and 
weight 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.7 
WHO 
performance 
status 
X 
Pre X3 X3 X3 X3  
X3  
 
X3 X3  
X3  
X3  
X3  
X3  
X3 
X3 
 
6.4.8 
Vital signs 
X 
Pre Pre 
1h 
2h 
6h 
 
Post Pre  
Pre  
 
Pre Pre  
Post  
Post  
Post  
X 
 
X 
X 
 
6.4.11 
12-lead ECG 
X 
Pre Pre 
1h 
2h 
6h 
Pre Post Pre  
 
 
 
 
Post  
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.9 
MUGA / 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
X5  
 
 
 
 
 
 
X2  
 
X 
 
6.4.10 
Haematology, 
Clinical 
chemistry 
Urinalysis 
X 
Pre Pre  
Pre  
Pre  
Pre  
Pre  
Pre Pre  
Pre  
Pre  
 
Pre X 
X 
 
6.4.5 
Additional 
glucose6 
 
 
2-4h 
4-
6h 
 
2-4h 
4-6h 
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h
4-6h
 
 
 
 
 
 
 
2-4h
4-6h
 
 
 
6.4.5 
Glycosylated 
haemoglobin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2  
X 
X 
 
6.4.12.2
Lipids  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2  
 
X 
 
6.4.12.1


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
45(85) 
Figure 7 
Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ -28 to 0 1 
2 
3 
5 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ  
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
Glucose, insulin, 
insulin c-peptide3 
 
Pre Pre 
2h 
4h 
6h 
8h 
 
Pre 
2h 
4h 
6h 
8h 
 
Pre  
Pre  
Pre  
Pre 
2-4h 
 
 
 
 
 
 
 
Pre 
2-4h
 
X 
 
6.4.12.3
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
6.4.5 
Paclitaxel PK 
blood samples1 
 
Pre 
2h 
4h 
8h 
Pre  
 
 
Pre 1  
Pre 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
AZD5363 PK 
blood samples1 
 
 
Pre 
2h 
4h 
8h 
Pre Pre  
Pre  
Pre  
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Pharmacodynami
c blood samples1 
 
Pre Pre 
2h 
4h 
8h 
Pre Pre  
Pre  
Pre  
Pre Pre  
 
 
 
 
 
 
X 
 
 
X 
 
6.7.1 
Exploratory 
biomarker blood 
samples1 
(optional) 
X 
 
Pre  
 
 
Pre  
Pre  
Pre Pre  
 
 
 
 
 
 
X 
 
 
X 
 
6.8.1.5 
Exploratory 
biomarker hair 
samples 
(optional) 
 
 
Pre 
4h 
 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 
Pharmacogenetic
s (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.1 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
46(85) 
Figure 7 
Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ -28 to 0 1 
2 
3 
5 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ  
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
RECIST Tumour 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2  
 
 
 
6.3.1 
Archival tumour 
sample  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.2 
Paired biopsy 
(optional)  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.3 
Circulating 
tumour cells 
 
Pre  
 
 
 
 
 
 
 
 
Pre  
 
 
 
 
 
 
Pre 
2 
 
 
 
 
6.8.1.1 
Patient meal 
information 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
6.4.12.4
QoL 
questionnaires 
(Part B only) 
X 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2  
 
X 
 
6.5.1 
Survival status 
(Part B only)6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
6.2.3.4 
Subsequent 
cancer therapy6 
  
  
  
  
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
X 
X6 
5.6 
Concomitant 
medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Adverse events 
X 
 
  
  
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
 
6.4.3 
 
1.  
Part A - Safety Run-in phase only: Patients will continue to undergo paclitaxel PK measurements on these occasions.  


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
47(85) 
2.  
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1). Part 
B Randomised expansion only: Patients will continue to undergo RECIST assessments after cessation of study therapies up to disease progression or 
withdrawal of consent.   
3.  
WHO performance status; Part B – Randomised expansion phase only:  Performance status will be assessed at these timepoints during part B 
only. 
4. 
Insulin c-peptide; Part A - Safety Run-in phase only:  Insulin c-peptide will not be analysed during Part B. 
5. 
Part A Safety Run-in phase only: Patients will undergo the Cycle 2 Week 1 Day 1 MUGA / Echocardiogram assessment during Part A only.  
This assessment timepoint will not be conducted during the Part B Randomised expansion. 
6. 
Part B Randomised expansion only: Survival status and subsequent cancer therapies will be determined at the 28 day follow-up visit and at 12-
weekly intervals thereafter.  These visits suggested to coincide with RECIST assessments up to disease progression, and at 12-weekly intervals 
thereafter to death or withdrawal. 
 
Reason for Amendment:  
Sample timepoints (pre-, post- dosing and number of hours post-dosing where applicable) have been specified in the schedules of 
assessments for clarity following feedback received from study sites. 
Addition of a survival status evaluation for study Part B has been introduced with reference to amendment rationale number 4. 
Reasons for other amendments to timepoints and footnotes are described per assessment for protocol sections 6.4.5 to 6.8.1.6 
detailed later in this document. 
 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
48(85) 
Section of protocol affected: 
Section 4.2.  Exclusion criteria.  Bullet point 3. 
Previous text: 
3. 
Participation in another clinical study with an investigational product (IP) during the last 
30 days. 
Revised text: 
3. 
Participation in another clinical study with an investigational product (IP) within 30 
days of the first dose of AZD5363 or matching placebo. 
Reason for Amendment:  
For additional clarity that the exclusion timescales relates to commencement of study 
treatment.  
 
Section of protocol affected: 
Section 4.2.  Exclusion criteria.  Bullet point 8. 
Previous text: 
8. 
Exposure to potent inhibitors or inducers of CYP3A4 or CYP2D6 or substrates of 
CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John’s 
Wort). 
Revised text: 
8. 
Exposure to potent inhibitors or inducers of CYP3A4 or substrates of CYP3A4 or 
CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John’s 
Wort). 
Reason for Amendment:  
The original text was incorrect due to a typographic error in a source document.  This 
amendment reflects that CYP2D6 is not inducible, and exposure to inhibitors of CYP2D6 
should not be an exclusion.  However, AZD5363 is a moderate competitive inhibitor of 
CYP2D6, therefore substrates of CYP2D6 are restricted. 
 
Section of protocol affected: 
Section 4.2.  Exclusion criteria.  Bullet point 11. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
49(85) 
Previous text: 
11. 
Last dose of anticancer therapy - other than for advanced or metastatic breast cancer 
(chemotherapy, radiation therapy, surgery, immunotherapy, endocrine therapy, targeted 
therapy, biologic therapy, or tumour embolisation) must be more than 21 days (more 
than 6 weeks for nitrosurea or mitomycin C) prior to the first dose of study treatment.  If 
sufficient wash-out time has not occurred due to schedule or PK properties, a longer 
wash-out period will be required as agreed by AZ and the investigator. 
Revised text: 
11. 
Last dose of anticancer therapy - other than for advanced or metastatic breast cancer 
(chemotherapy, radiation therapy, surgery, immunotherapy, endocrine therapy, targeted 
therapy, biologic therapy, or tumour embolisation) within 21 days (within 6 weeks for 
nitrosurea or mitomycin C) before the first dose of study treatment.  If sufficient 
wash-out time has not occurred due to schedule or PK properties, a longer wash-out 
period will be required as agreed by AZ and the investigator. 
Reason for Amendment:  
To align wording to conform more precisely as an exclusion criterion. 
 
Section of protocol affected: 
Section 4.2.  Exclusion criteria.  Part A  Safety Run-in.  Bullet point 2. 
Previous text: 
2. 
If patients have received prior treatment with anthracyclines or mitoxantrone, 
cumulative exposure must be less than 360 mg/m2 for doxorubicin, 720 mg/m2 for 
epirubicin or 72 mg/m2 for mitoxantrone. 
Revised text: 
2. 
If patients have received prior treatment with anthracyclines or mitoxantrone, 
cumulative exposure must be less than 360 mg/m2 for doxorubicin, 650mg/m2 for 
doxorubicin liposomal formulation, 720 mg/m2 for epirubicin or 72 mg/m2 for 
mitoxantrone. 
Reason for Amendment:  
Specification of exclusion limits for liposomal doxorubicin has been provided following a 
question raised by a study site. 
 
Section of protocol affected: 
Section 5.2.  Patient enrolment, randomisation and initiation of investigational product. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
50(85) 
Previous text: 
The Principal Investigator will: 
1. 
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed. 
2. 
Obtain a unique enrolment number, beginning with ‘E#’. The E-code is a 7-digit number 
comprising the centre number, the dosing schedule and the patient number within that 
particular centre.  This number is the patient’s unique identifier and is used to identify 
the patient on the electronic case report form (eCRF), and should be entered in to the 
patient medical records.  The E-code will be in the format E000WXYZ.  Where 000W= 
site number, X = schedule (1 = Part A continuous, 2 = part A intermittent, 3 = Part B), Y 
& Z = patient number (per schedule) e.g., the first patient screened at centre 0001, to the 
Part A continuous dosing schedule would be assigned the E-code - E0001101, the 
second patient - E0001102; the first patient at this site in the Part A intermittent dosing 
schedule would be E0001201.  
Once a candidate patient has been identified and consented, the site should obtain the 
enrolment number as follows: 
 Part A: For the safety run-in phase, the study site will notify the AstraZeneca Study 
Team that a patient has been consented by completion and e-mailing of a registration 
form.  AstraZeneca will reply, providing the E  number.  For Part A this will include 
notification of which dosing schedule the patient is allocated to.  
Part B:  For the randomised expansion phase, the study site will contact the Interactive 
Voice/Web Response System (IVRS/IWRS) by telephone or using the web to notify that 
a patient has consented.  IVRS/IWRS will provide the E  number. 
Further guidance on this process will be provided in a separate patient allocation process 
document.  
All screened patients are assigned an E-code and will be listed on the patient enrolment 
and identification log irrespective of whether or not they subsequently receive study 
therapy.  If a patient withdraws from participation in the study, their E-code will not be 
reused and the patient will not be allowed to re-enter the study.   
For the Randomised Expansion part, if the patient is not randomised the site should 
notify IVRS/IWRS via a Discontinuation Call to enable the termination of the  
3. 
Determine patient eligibility. See Sections 4.1 and 4.2 
4. 
As patients become eligible for the study they will be assigned separate four digit 
identification codes.  The first digit will indicate the schedule/phase.  The second and 
third digits will be an escalating patient number, commencing at 001.  


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
51(85) 
Part A: For the safety run-in phase, the study site will notify the AstraZeneca Study 
Team that a patient is eligible by completion and e-mailing of a registration form.  
AstraZeneca will reply, providing the identification code.  The first patient entering 
cohort 1 of schedule 1 (continuous dosing) will be numbered 1001, the second will be 
1002 and so on.  Patients assigned to schedule 2 (intermittent dosing) will be 2001, 2002 
onwards.   
Part B:  For the randomised expansion phase, the study site will contact the IVRS/IWRS 
by telephone or using the web to confirm whether the patient is/is not eligible and, if 
eligible, to report the PIK3CA mutation status: ‘positive’ or ‘not detected’ (see section 
5.2.1) to enable stratification.  IVRS/IWRS will provide the randomised identification 
code.  Patients that are PIK3CA mutation positive will be numbered 3001, 3002 
onwards.  Those that are PIK3CA mutation not detected will be numbered 4001, 4002 
onwards.  The treatment randomisation will not be indicated under this system. 
It is requested that sites obtain the randomised identification code on the day that the 
patient is ready to commence treatment.   
Further guidance on this process will be provided in a separate patient allocation process 
document.  Procedures will be provided in an IVRS/IWRS user manual that will be 
provided to each centre. 
If a patient withdraws from participation in the study, then her identification code cannot 
be reused. 
Revised text: 
The Principal Investigator will: 
1. 
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed. 
2. 
Obtain a unique enrolment (‘E’) number – which will be automatically generated by 
the RAVE system once initial patient information has been entered.  This E-code is 
a 7-digit number comprising the country code, centre number, the dosing schedule and 
the patient number within that particular centre.  This number is the patient’s unique 
identifier and is used to identify the patient on the electronic case report form (eCRF), 
and should be entered in to the patient medical records.  The E-code will be in the 
format EAB0WXYZ.  Where AB = country code, 0W= site number, X = schedule (1 = 
Part A intermittent [2-on 5-off], 2 = Part A intermittent [4-on 3-off], 3 = Part B), Y & 
Z = patient number (per schedule)  
e.g., the first patient screened in the UK (country code = 28) at centre 01, to 
the Part A intermittent 2-on 5-off dosing schedule would be assigned the E-
code – E2801101, the second patient – E2801102.  The first patient at this site 
in the Part A intermittent 4-on 3-off dosing schedule would be E2801201.  


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
52(85) 
Once a candidate patient has been identified and consented, the site should provide 
notification as follows: 
Part A: For the safety run-in phase, the study site will notify the AstraZeneca Study 
Team that a patient has been consented by completion and e-mailing of a registration 
form.  AstraZeneca will reply, providing confirmation of the dosing schedule that the 
patient has been assigned to. Upon entry of this into the appropriate database in 
the eCRF, the patient E-code will be generated automatically by the RAVE system. 
Part B:  For the randomised expansion phase, the study site will contact the Interactive 
Voice/Web Response System (IVRS/IWRS) by telephone or using the web to notify that 
a patient has consented. 
Further guidance on this process will be provided in a separate patient allocation process 
document.  
All screened patients are assigned an E-code and will be listed on the patient enrolment 
and identification log irrespective of whether or not they subsequently receive study 
therapy.  If a patient withdraws from participation in the study, their E-code will not be 
reused and the patient will not be allowed to re-enter the study.   
For the Randomised Expansion part, if the patient is not randomised the site should 
notify IVRS/IWRS via a Screening Failure call to enable the termination of the patient 
in the system. 
3. 
Determine patient eligibility. See Sections 4.1 and 4.2 
4. 
As patients become eligible for the study they will be assigned separate four digit 
identification codes.  The first digit will indicate the schedule/phase.  The second and 
third digits will be an escalating patient number, commencing at 001.  
Part A: For the safety run-in phase, the study site will notify the AstraZeneca Study 
Team that a patient is eligible by completion and e-mailing of a registration form.  
AstraZeneca will reply, providing the identification code.  The first patient entering 
cohort 1 of schedule 1 (intermittent 2-on 5-off dosing) will be numbered 1001, the 
second will be 1002 and so on.  Patients assigned to schedule 2 (intermittent 4-on 3-off 
dosing) will be 2001, 2002 onwards.   
Part B:  For the randomised expansion phase, the study site will notify the IVRS/IWRS, 
by telephone or using the web, that the patient is eligible and to report the PIK3CA 
mutation status: ‘positive’ or ‘not detected’ (see section 5.2.1) to enable stratification.  
IVRS/IWRS will provide the Randomisation identification code.  Patients that are 
PIK3CA tumour-mutation positive will be numbered 3001, 3002 onwards.  Those that 
are PIK3CA tumour-mutation not detected will be numbered 4001, 4002 onwards.  The 
treatment randomisation will not be revealed to the study site. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
53(85) 
It is requested that sites obtain the Randomisation identification code on the day that 
the patient is ready to commence treatment.   
Further guidance on this process will be provided in a separate patient allocation process 
document.  Procedures will be provided in an IVRS/IWRS user manual that will be 
provided to each centre. 
If a patient withdraws from participation in the study, then her Randomisation 
identification code cannot be reused. 
Reason for Amendment:  
For references to intermittent dosing schedules: 2 days-on / 5 days- off, and 4 days-on / 3 
days-off, please see amendment rationale number 2. 
Patient E-code numbering has been revised following implementation of AstraZeneca 
requirement for incorporation of country-specific codes in patient identifiers. 
Other changes have been made following further guidance for accuracy and clarity in 
describing use of the IVRS/IWRS system. 
 
Section of protocol affected: 
Section 5.2.1.   Procedure for identification of tumour PIK3CA mutation status and 
stratification.   
Previous text: 
Patient stratification by PIK3CA mutation status (Part B) 
Patients will be stratified to PIK3CA mutation positive’ or ‘PIK3CA mutation not detected’ 
arms prior to randomisation.  
Patients assigned a PIK3CA mutation status of ‘Unknown’ will not be eligible to participate in 
Part B. In cases where an archival tumour sample is not received in time to be analysed by the 
central laboratory during screening, defined status may be derived from the blood sample 
alone, or it may be applicable to utilise the status from a prior, locally-conducted tumour 
analysis, see above. 
If a patient is initially stratified to the ‘Not detected’ arm based upon a blood sample alone, or 
blood sample plus locally–conducted tumour analysis, and a subsequent, delayed, tumour 
sample is ‘positive’  the stratification will not be changed but the discrepancy will be noted.  
Any requirement to assign additional patient places to either stratification arm will be 
determined on an as needed basis, dependent upon the number of discrepant patients. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
54(85) 
Revised text: 
Patient stratification by PIK3CA mutation status (Part B) 
Patients will be allocated to ‘PIK3CA mutation positive’ or ‘PIK3CA mutation not detected’ 
strata prior to randomisation.  
Patients assigned a PIK3CA mutation status of ‘Unknown’ will not be eligible to participate in 
Part B. In cases where an archival tumour sample is not received in time to be analysed by the 
central laboratory during screening, defined status may be derived from the blood sample 
alone, or it may be applicable to utilise the status from a prior, locally-conducted tumour 
analysis, see above. 
If a patient is initially stratified to the ‘Not detected’ stratum based upon a blood sample 
alone, (or blood sample plus locally–conducted tumour analysis) and a ‘positive’ central 
tumour sample analysis is received after stratification, the site will contact the 
IVRS/IWRS Customer Care department by telephone or using the web to provide 
notification of this new information.  IVRS/IWRS records will be revised to show a 
corrected PIK3CA mutation status of ‘Positive’.   
In the event of any correction to a patient’s allocated mutation status post-stratification: 
x
there will be no revision to the patient stratum allocation or numbering in RAVE. 
x
AZ will coordinate with IVRS/IWRS to ensure that the allocation of patient places 
per stratum is adjusted, as necessaary, to ensure that the minimum number 
required in each will be achieved 
x
for final data analysis the corrected mutation status will be used to assign the 
patient to the relevant stratum.  
Reason for Amendment:  
Clarification of patient stratification terminology – replacing ‘arm‘ with ‘stratum’.  
Statement of process and procedure in the event that the initially recorded PIK3CA tumour-
mutation status of a patient is revised following subsequent tumour sample analysis. 
 
Section of protocol affected: 
Section 5.5.3  Doses and treatment regimens 
Previous text: 
AZD5363 / matching placebo:  


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
55(85) 
A twice daily regimen of an oral formulation given on a continuous or intermittent weekly 
dosing schedule.   
Where possible all doses of AZD5363/placebo should be taken, at approximately the same 
times each day, in a fasted state (water to drink only) from at least 2 hours prior to the dose to 
at least 1 hour post-dose. Please also refer to Restrictions (section 5.1) for further guidance 
regarding patient fasting status on study assessment days. 
Revised text: 
AZD5363 / matching placebo: 
A twice daily regimen of an oral formulation given on one of two intermittent weekly dosing 
schedules.   
During Study Part A, patients will receive AZD5363 in capsule form only.  During Study 
Part B, patients may receive AZD5363/placebo as capsules or as dose-equivalent tablets.  
A tablet formulation may be applied in all sites or in selected sites only.  
Where possible, all doses of AZD5363/placebo should be taken, at approximately the same 
times each day, in a fasted state (water to drink only) from at least 2 hours prior to the dose to 
at least 1 hour post-dose.  Please also refer to Restrictions (section 5.1) for further guidance 
regarding patient fasting status on study assessment days. 
Reason for Amendment:  
Reference to dosing schedules - please see amendment rationale number 2. 
Reference to dosing formulation - please see amendment rationale number 7. 
 
Section of protocol affected: 
Section 5.5.3  Doses and treatment regimens 
Previous text: 
Treatment Schedules: 
Under both the continuous and intermittent dosing schedules, first receipt of paclitaxel will be 
on Cycle 1, Day 1; first receipt of AZD5363/placebo will be on Day 2.  
Thereafter, under the intermittent dosing schedule, weekly AZD5363 regimens will continue 
to start on the day after receipt of paclitaxel. 
 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
56(85) 
 
Cycle 1 
Cycle 2 onwards 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 1 
Week 2 
Week 3 
Week 4 
Paclitaxel. Dose dayĺ 
Day 1 
Day 1 
Day 1 
None 
Day 1 
Day 1 
Day 1 
None 
Continuous. 
Dose days ĺ 
Day 2 to Day 28 
Day 1 to Day 28 
AZD5363  
Intermittent. 
Dose days ĺ 
D2 to D5 D2 to D5
D2 to D5
None 
D2 to D5
D2 to D5 D2 to D5 
None 
 
Revised text: 
Under both intermittent dosing schedules, first receipt of paclitaxel will be on Cycle 1, Day 1; 
first receipt of AZD5363/placebo will be on Day 2.  
Thereafter, weekly AZD5363 regimens will continue to start on the day after receipt of 
paclitaxel. 
 
Cycle 1 
Cycle 2 onwards 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 1 
Week 2 
Week 3 
Week 4 
Paclitaxel. Dose dayĺ 
Day 1 
Day 1 
Day 1 
None 
Day 1 
Day 1 
Day 1 
None 
2-on 5-off 
dose days ĺ D2 & D3 D2 & D3 D2 & D3
None 
D2 & D3 D2 & D3 D2 & D3 
None 
AZD5363  
4-on 3-off 
dose days ĺ 
D2 to D5 D2 to D5
D2 to D5
None 
D2 to D5
D2 to D5 D2 to D5 
None 
 
Reason for Amendment:  
Please see amendment rationale number 2. 
 
Section of protocol affected: 
Section 5.5.5.  Safety Run-In: Starting dose and dose escalation scheme. 
Previous text: 
For Study Part A; administration of AZD5363 will commence, when combined with 
paclitaxel, at cohort 1 of each schedule at doses of: 
x
Continuous dosing: 320 mg bd (640 mg daily). 
x
Intermittent dosing (4 days of treatment followed by 3 days off-treatment: 360 mg bd 
(720 mg daily). 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
57(85) 
These starting doses are below the AZD5363 monotherapy doses of: 400 mg bd (continuous 
dosing schedule) and 480 mg bd (intermittent dosing schedule) deemed tolerable in the 
ongoing Phase I multiple-ascending dose study (D3610C00001) in patients with advanced 
solid malignancies at the time of initiating Part A.   
Patients will be enrolled to ensure a minimum of three and a maximum of six evaluable 
patients per dose escalation cohort.  For procedures and definitions associated with dose 
escalation, see Section 5.10. 
Revised text: 
For Study Part A; administration of AZD5363 will commence, when combined with 
paclitaxel, at cohort 1 of each schedule at doses of: 
x
Intermittent dosing (2 days of treatment followed by 5 days off-treatment: 560 mg 
bd (1120 mg daily). 
x
Intermittent dosing (4 days of treatment followed by 3 days off-treatment: 360 mg bd 
(720 mg daily). 
These starting doses are at or below the AZD5363 monotherapy doses of: 640 mg bd (2-on 5-
off dosing schedule) and 480 mg bd (4-on 3-off dosing schedule) deemed tolerable in the 
ongoing Phase I multiple-ascending dose study (D3610C00001) in patients with advanced 
solid malignancies at the time of initiating each of the dosing schedules in Part A.   
Patients will be enrolled to ensure a minimum of three and a maximum of six evaluable 
patients per dose escalation cohort.  For procedures and definitions associated with dose 
escalation, see Section 5.10. 
Reason for Amendment:  
Please see amendment rationale number 2. 
 
Section of protocol affected: 
Section 5.5.6  Randomised expansion: Selected Dose 
Previous text: 
Study Part B will be conducted at a dose and schedule of AZD5363, when combined with 
paclitaxel, selected from Part A 
Revised text: 
Study Part B will be conducted at a dose and schedule of AZD5363, when combined with 
paclitaxel, selected from Part A.  


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
58(85) 
During the conduct of Part B, the SRC will continue to evaluate the status of patients 
ongoing in Part A (see section 5.10.2).  If emerging findings suggest that the AZD5363 
dosing schedule that was not selected to commence Part B may present a more 
favourable alternative - in terms of safety, tolerability and/or efficacy – they may elect to 
re-start Part B under this schedule in consultation with AstraZeneca.     
In this circumstance, recruitment to the original dose schedule for Part B would cease, 
and 100 patients would be recruited to the new dose schedule. 
Reason for Amendment:  
With reference to amendment rationale number 6; this addition allows for the Part B dose 
and/or schedule of AZD5363/placebo to be revised under guidance from the Safety Review 
Committee within the parameters of assessments conducted under Part A. 
 
Section of protocol affected: 
Section 5.6.  Concomitant and post-study treatment(s).  Paragraph 1. 
Previous text: 
Information on any treatment received by the patient, with reasons for its provision, will be 
recorded in the eCRF from 4 weeks prior to starting study treatment up to 28 days after the 
last dose of AZD5363/placebo or until objective progression, whichever is the latest.  If 
medically feasible, patients taking regular medication - with the exception of potent inhibitors 
or inducers or substrates of CYP3A4 or substrates of CYP2D6 - (see Section 4.2 Exclusion 8 
and Appendix G), should be maintained on it throughout the study period. 
Revised text: 
Information on any treatment received by the patient, with reasons for its provision, will be 
recorded in the eCRF from 4 weeks prior to starting study treatment up to 28 days after the 
last dose of AZD5363/placebo or until objective progression, whichever is the latest.  For 
Part B of the study, anti-cancer medications should continue to be recorded at 12-weekly 
intervals to death or withdrawal (see Section 6.2.3.4).  If medically feasible, patients taking 
regular medication - with the exception of potent inhibitors or inducers or substrates of 
CYP3A4 or substrates of CYP2D6 - (see Section 4.2 Exclusion 8 and Appendix G), should be 
maintained on it throughout the study period. 
Reason for Amendment:  
Please see amendment rationale number 4. 
 
Section of protocol affected: 
Section 5.8.  Discontinuation of investigational product.  Paragraph 1. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
59(85) 
Previous text: 
Patients may be discontinued from IP at any time, without prejudice to further treatment. If a 
patient discontinues IP for reasons other than death, then they should still continue in the 
study up to objective disease progression assessed by RECIST 1.1, unless they withdraw 
consent from the study. 
Revised text: 
Patients may be discontinued from IP at any time, without prejudice to further treatment. If a 
patient discontinues IP for reasons other than death, then they should still continue in the 
study up to objective disease progression assessed by RECIST 1.1 in Part A, and also up to 
death in Part B (see section 6.2.3.4), unless they withdraw consent from the study. 
Reason for Amendment:  
Please see amendment rationale number 4. 
 
Section of protocol affected: 
Section 5.10.2.  Safety Review Committee and Dose Escalation Process. Paragraph 5, bullet 
point 5. 
Previous text (with reference to cohort dose selection in study part A): 
…… 6 evaluable patients must be assessed at that dose level.  The SRC may elect to assess up 
to a further 6 evaluable patients at the identified MTD to confirm the dose selection.  To 
determine the NTD 2 patients, of up to 6 patients, must experience DLTs at that dose level. 
Revised text: 
…… 6 evaluable patients must be assessed at that dose level.  The SRC may elect to assess up 
to a further 6 evaluable patients at the identified RD or MTD to confirm the dose selection.  
To determine the NTD 2 patients, of up to 6 patients, must experience DLTs at that dose level. 
Reason for Amendment:  
This amendment allows for the Safety Review Committee in Part A to request evaluation of 
additional patients to confirm a recommended dose to take forward to Part B.  This inclusion 
has been made to allow for greater surety, if required, in dose selection.   
 
Section of protocol affected: 
Section 5.10.6.  Definition of a dose-limiting toxicity. 




Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
61(85) 
approximately 3-monthly intervals.  Based on this coded review, the independent SRC 
may recommend one of: a) continuation of recruitment without change; or b) an 
amendment to the dose and schedule of AZD5363/placebo eg, from a 4 days on, 3 days 
off schedule to a 2 days on, 5 days off schedule or to continue at the same schedule at a 
reduced dose of AZD5363/placebo; or c) termination of recruitment on the grounds that 
the combination is considered to be insufficiently well tolerated. 
The independent SRC will consist of: 
x
AstraZeneca Physician, independent of the AZD5363 programme, who will chair 
the committee - or delegate 
x
AstraZeneca Global Safety Physician, independent of the AZD5363 programme. 
x
Two external Investigators independent of the study 
The independent SRC Remit document for this study will define the exact membership 
and who should be present for decisions to be made. 
The first review of coded safety data will occur when data are available from 
approximately 15 patients who have received at least 28 days of treatment.  
In the event that AstraZeneca adopts the recommendation to explore an alternative dose 
or schedule, any patients already recruited to the study at this point will continue to 
receive AZD5363/placebo as per their current dose and schedule provided that they are 
tolerating the treatment and the investigator believes they are gaining benefit.  
Alternatively, the investigator may elect to change the dose/schedule of patients 
recruited prior to the dose change to the new dose/schedule.  After a change to the 
schedule of AZD5363/placebo, approximately 100 new patients will be recruited to 
receive AZD5363/placebo as per the new schedule. There will be no more than 2 changes 
made to dose or schedule during the randomised phase of the study.  
Reason for Amendment:  
Please see amendment rationale number 6. 
 
Section of protocol affected: 
New – Section 6.2.3.4.  Survival follow-up. 
Previous text: 
Not applicable. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
62(85) 
New text: 
Part B. Randomised Expansion only.  Overall Survival status will be obtained for all 
randomised patients.  Survival contacts will be made and entered into the database every 
12 weeks (± 1week) post-permanent discontinuation of study treatment and at data cut 
off.  The patient does not have to attend the clinic for the survival assessments to be 
carried out; these can either be done via a telephone call, or through review of the 
patient’s notes, or through the use of public records.  If the site becomes aware that a 
patient has died prior to the primary analysis, the relevant eCRF on the database should 
be completed at that time. 
To aid the interpretation of the survival analysis, anti-cancer therapies administered 
following the discontinuation of study treatment will be recorded on the eCRF. 
Survival status will continue to be collected until 50% of randomized patients have died.  
Optionally, continuation until 75% of randomized patients have died may be considered. 
Reason for Amendment:  
Please see amendment rationale number 4. 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
63(85) 
Please note:  The following amendments to sections 6.4.5 to 6.8.1.6 describe changes to 
patient assessments and sample collection.   The primary rationale for these changes is to 
align samples/assessments with revised study therapy dosing timepoints due to 
replacement of the AZD5363/placebo continuous dosing schedule with an intermittent 
(2days-on, 5 days-off) schedule (see amendment rationale number 2).  For clarity of 
review the full original/revised text has not been provided.  Instead, amendments are 
described per section, with new items identified in bold text.   Any change not associated 
with the schedule replacement will be outlined separately.   
 
Section of protocol affected: 
Section 6.4.5.  Laboratory safety assessment. 
Amendments: 
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis.  
Continuous dosing schedule.   Sample timepoints: Day 1 of  - Cycle 1, Weeks 2, 3 and 
4; Cycle 2 onwards Week 1. 
Replaced by – 
Intermittent dosing schedule (2/5).   Sample timepoints: Day 2 of  - Cycle 1, Weeks 2, 
3 and 4; and Cycle 2 onwards Week 1. 
 
Serum/plasma glucose samples for additional measurements for potential abnormalities of 
glucose metabolism.  
Continuous dosing schedule.   Sample timepoints: 2-4 hours post-dose on Day 1 of  - 
Cycle 1, Weeks 2, 3 and 4; Cycle 2 onwards Week 1. 
Replaced by – 
Intermittent dosing schedule (2/5).   Sample timepoints: 2-4hours and 4-6 hours post- 
dose on Day 2 of  - Cycle 1, Weeks 2, 3 and 4; and Cycle 2 onwards Week 1. 
Additional amendment - 
Intermittent dosing schedule (4/3)  Part B only.  Additional 4-6 hours post-dose 
sample to be taken at all timepoints.  
New text - 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
64(85) 
Note:  It is acceptable for these additional blood glucose samples to be analysed at 
a hospital ward or clinical unit, where measurement can be provided in units of 
mg/dL, mmol/L or equivalent, rather than at the designated local laboratory. 
Reason for Amendment:  
For general revision to timepoints, please see amendment rationale number 2. 
With reference to additional blood glucose samples to be taken between 4 to 6 hours, 
following receipt of the morning dose of AZD5363.  This change was implemented to aid 
review of glucose levels and management of potential abnormalities of glucose metabolism 
over the period of maximum concentration of circulating AZD5363 identified under 
pharmacokinetic analysis.   
The additional note clarifies that bedside glucose measurements can be done, where 
appropriate, to aid in rapid evaluation of patient status.  
 
Section of protocol affected: 
Section 6.4.6.  Physical examination. 
Amendment: 
Intermittent doing schedule 2/5.   Assessment timepoint added – Cycle 1, Week 1, Day 3. 
Reason for Amendment:  
This timepoint to assess patient’s physical status on last day of receipt of AZD5363/placebo  - 
to correspond with Day 5 assessment conducted for the intermittent 4/3 schedule.  
 
Section of protocol affected: 
Section 6.4.8.  WHO performance status. 
Amendment: 
Intermittent dosing schedules 4/3 and 2/5.  Part B.  Assessment timepoints added – Cycle 1, 
Week 1, Days 2 and 3; Weeks 2 and 3, Day 1;  Week 4 Day 2.  Cycle 2, Weeks 1 to 4, Day 
1.  Cycle 3 onwards Week 1 Day 1.  At discontinuation of AZD5363/placebo and 
paclitaxel. 
Reason for Amendment:  
Please see amendment rationale number 5. 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
65(85) 
Section of protocol affected: 
Section 6.4.10.  MUGA scan / Echocardiogram. 
Amendment: 
Intermittent dosing schedules 4/3 (Part B) and 2/5 (Parts A and B).  Assessment timepoint 
removed – Cycle 2, Week 1, Day 1. 
Reason for Amendment:  
On review, AstraZeneca identified that this assessment timepoint did not provide sufficient 
value for review of patient safety to merit continuation.  It will therefore be removed for all 
new schedules; but retained for completion of the Part A intermittent 4/3 schedule. 
 
Section of protocol affected: 
Section 6.4.11.  Vital signs: Pulse and blood pressure. 
Amendment: 
Continuous and intermittent (4/3) dosing schedule.  Assessment  timepoint Cycle 1, 
Week 4, Day 1. 
Replaced by – 
Intermittent dosing schedules (2/5) and (4/3).  Assessment  timepoint Cycle 1, Week 4 
Day 2. 
Reason for Amendment:  
To align all Cycle 1, Week 4, patient assessments under Day 2 – to minimise inconvenience 
for patients. 
 
Section of protocol affected: 
Section 6.4.12.3.  Glucose, insulin and insulin c-peptide. 
Amendment: 
Continuous dosing schedule.   Sample timepoints: Day 1 of: Cycle 1 Weeks 2, 3 and 4; 
and Cycle 2 onwards Week 1. 
Replaced by – 
Intermittent dosing schedule (2/5).   Sample timepoints: Day 2 of: Cycle 1 Weeks 2, 3 
and 4; and Cycle 2 onwards Week 1. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
66(85) 
Additional amendment - 
Insulin c-peptide measurements are removed from the Part B assessment schedules.. 
Reason for Amendment:  
For realignment of sample schedule - please see amendment rationale number 2. 
Removal of insulin c-peptide assessment was agreed following AstraZeneca review of critical 
analyses, which indicated that sufficient data on c-peptide has been generated in the AZD5363 
clinical programme conducted to date. 
 
Section of protocol affected: 
Section 6.4.12.4.  Patient meal information 
Amendment: 
Continuous dosing schedule.   Sample timepoints: Day 1 of: Cycle 1 Weeks 2, 3 and 4; 
and Cycle 2 onwards Week 1. 
Replaced by – 
Intermittent dosing schedule (2/5).   Sample timepoints: Day 2 of: Cycle 1 Weeks 2, 3 
and 4; and Cycle 2 onwards Week 1. 
Additional amendment - 
Intermittent doing schedule 2/5.   Additional  assessment timepoint added – Cycle 1, 
Week 1, Day 3. 
Reason for Amendment:  
For realignment of sample schedule - please see amendment rationale number 2. 
Additional timepoint to record patient’s meal intake on last day of receipt of 
AZD5363/placebo - to correspond with Day 5 assessment conducted for the intermittent 4/3 
schedule. 
 
Section of protocol affected: 
Section 6.6.2.  Pharmacokinetic sampling schedule: Paclitaxel  


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
67(85) 
Amendment: 
Continuous dosing schedule.   Paclitaxel PK sample timepoint: Day 1 of: Cycle 1 
Week 3. 
Replaced by – 
Intermittent dosing schedule (2/5).   Paclitaxel PK sample timepoint: Day 1 of: Cycle 1 
Week 3. 
Additional amendment - 
Continuous dosing schedule.   Paclitaxel PK sample timepoint: Day 1 of: Cycle 1 
Week 2 will not appear under intermittent dosing schedule (2/5). 
New text - 
Note:  Timing of paclitaxel PK sampling on Day 1 is from start of the infusion; 
e.g. if paclitaxel infusion commences at 9am, the 2, 4 and 8 hour samples should 
be taken at 11am, 1pm and 5pm respectively. 
Reason for Amendment:  
For realignment of sample schedule - please see amendment rationale number 2. 
Following a request for clarification from a study site – the additional text provides guidance 
regarding timing of paclitaxel sample timing relative to the start of paclitaxel infusion. 
 
Section of protocol affected: 
Section 6.6.2.  Pharmacokinetic sampling schedule: AZD5363. 
Amendment: 
Continuous dosing schedule.   AZD5363 PK sample timepoints: Day 1 of  - Cycle 1, 
Weeks 2, 3 and 4. 
Replaced by – 
Intermittent dosing schedule (2/5).   AZD5363 PK sample timepoints: Day 2 of  - 
Cycle 1, Weeks 2, 3 and 4. 
Reason for Amendment:  
Please see amendment rationale number 2. 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
68(85) 
Section of protocol affected: 
Section 6.6.2.  Pharmacokinetic sampling schedule: Tables 
Amendment: 
Separate tables defining sample timepoints under the continuous dosing schedule have been 
removed. 
Reason for Amendment:  
Continuous dosing schedule no longer applicable – please see amendment rationale number 2.  
 
Section of protocol affected: 
Sections 6.8.1 and 6.8.1.6.  Exploratory biomarker research: venous blood for analysis of 
exploratory biomarkers. 
Amendment: 
Continuous dosing schedule.   Sample timepoints: Day 1 of  - Cycle 1, Weeks 2, 3 and 
4; Cycle 2 Week 1. 
Replaced by – 
Intermittent dosing schedule (2/5).   Sample timepoints: Day 2 of  - Cycle 1, Weeks 2, 
3 and 4; and Cycle 2 Week 1. 
Reason for Amendment:  
Please see amendment rationale number 2. 
 
Section of protocol affected: 
Sections 6.8.1 and 6.8.1.6.  Exploratory biomarker research: eyebrow hairs for analysis of 
exploratory biomarkers. 
Amendment: 
Continuous dosing schedule.   Sample timepoint: Cycle 1, Week 2, Day 1. 
Replaced by – 
Intermittent dosing schedule (2/5).   Sample timepoints: Cycle 1, Week 1, Day 3. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
69(85) 
Reason for Amendment:  
Please see amendment rationale number 2; to correspond with Day 5 assessment conducted 
for the intermittent 4/3 schedule. 
 
Section of protocol affected: 
Section 6.8.1.6.  Pharmacodynamic and exploratory biomarker sampling schedule: Tables 
Amendment: 
Separate tables defining sample timepoints under the continuous dosing schedule have been 
removed. 
Reason for Amendment:  
Continuous dosing schedule no longer applicable – please see amendment rationale number 2. 
 
Section of protocol affected: 
Section  7.1.  Volume of blood. 
Previous text: 
The volume of blood that will be drawn from each patient will vary, dependent upon the 
dosing schedule and phase of the study: 
x
The volume of blood to be drawn from each patient during screening and Cycle 1 should  
not exceed 35 mL and 360 mL respectively 
x
The total volume of blood to be drawn from each patient in the study, assuming they 
complete screening, 6 cycles of combination treatment and a discontinuation visit should 
not exceed 710 mL.   
Safety laboratory assessments will be performed locally at each centre’s laboratory by means 
of their established methods.  The number of samples/blood volumes is therefore subject to 
site-specific change.  
In both phases of the study, extra blood samples may also be collected if, for example, 
additional samples are required for repeat safety assessments or additional PK assessment.   


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
70(85) 
The maximum volume of blood to be drawn from each patient in this study is as follows: 
Table 6 
Estimated Maximum volume of blood to be drawn per patient  
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Haematology 
5 
15 
75 
 
Clinical chemistry 
10 
15 
150 
 
Additional Glucose 
2 
9 
18 
 
Lipids 
5 
3 
15 
 
Glucose, insulin and 
insulin c-peptide 
5 
24 
120 
CTCs 
10 
4 
40 
PIK3CA mutation 
10 
1 
10 
Pharmacokinetic 
4 
23 
92 
Pharmacodynamic 
8.1 (3 x 2.7) 
16 
129.6 
Pharmacogenetics (optional) 
5 
1 
5 
Exploratory Biomarker (optional) 
5 
11 
55 
Total 
 
 
709.6 
Note:  Maximum is taken to reflect Part A, continuous dosing schedule: 6 Cycles plus a 
discontinuation visit. 
 
Revised text: 
The volume of blood that will be drawn from each patient will vary, dependent upon the 
dosing schedule and phase of the study: 
x
The volume of blood to be drawn from each patient during screening and Cycle 1 should 
not exceed 35 mL and 380 mL respectively 
x
The total volume of blood to be drawn from each patient in the study, assuming they 
complete screening, 6 cycles of combination treatment and discontinuation visits should 
not exceed 750 mL.   
Safety laboratory assessments will be performed locally at each centre’s laboratory by means 
of their established methods.  The number of samples/blood volumes is therefore subject to 
site-specific change.  
In both phases of the study, extra blood samples may also be collected if, for example, 
additional samples are required for repeat safety assessments or additional PK assessment.   


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
71(85) 
The maximum volume of blood to be drawn from each patient in this study is as follows: 
Table 5 
Estimated Maximum volume of blood to be drawn per patient  
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Haematology 
5 
17 
85 
 
Clinical chemistry 
10 
17 
170 
 
Additional Glucose 
2 
20 
40 
 
Lipids and glycosylated 
haemoglobin 
5 
5 
25 
 
Glucose and insulin 
5 
25 
125 
CTCs 
10 
4 
40 
PIK3CA mutation 
10 
1 
10 
Pharmacokinetic 
4 
16 
64 
Pharmacodynamic 
8.1 (3 x 2.7) 
16 
129.6 
Pharmacogenetics (optional) 
5 
1 
5 
Exploratory Biomarker (optional) 
5 
11 
55 
Total 
 
 
748.6 
Note:  Maximum is taken to reflect Part A, 4-on 3-off dosing schedule: 6 Cycles plus 
discontinuation visits.   
Reason for Amendment:  
Amendments reflect: Additional glucose 4-6 hour post-dose samples, revision of the reference 
treatment schedule from continuous to intermittent 4 days-on, 3 days-off, AZD5363/placebo 
dosing - and correction of an omission under the original protocol, which had failed to include 
sample volumes collected during Cycles 4 to 6. 
 
Section of protocol affected: 
Section: 11.1.  Calculation or derivation of efficacy variables. 
Amendment: 
Section 11.1.5 - Progression-free Survival (PFS) has been moved to section position 11.1.1.  
All subsequent section numbers have been revised accordingly.   
Reason for Amendment:  
Progression-free survival is now the primary endpoint, hence its derivation now appears as the 
first item in section 11.1.  Please see amendment rationale number 3. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
72(85) 
Section of protocol affected: 
11.1.1. (originally section 11.1.5).  Progression-free Survival (PFS).  Paragraph 1. 
Previous text: 
PFS is defined as the time from start of treatment until objective disease progression as 
defined by RECIST 1.1 or death (by any cause in the absence of progression).  
Revised text: 
The primary outcome variable for Part B of the study is PFS.  PFS is defined as the time 
from start of treatment until objective disease progression as defined by RECIST 1.1 or death 
(by any cause in the absence of progression). 
Reason for Amendment:  
Please see amendment rationale number 3. 
 
Section of protocol affected: 
Section 11.1.2 (originally section 11.1.1) Change in tumour size at 12 weeks.  Paragraph 1. 
Previous text: 
The primary outcome variable for Part B of the study is change in tumour size at 12 weeks.  
This is based on RECIST measurements taken at baseline and at week 12.  Tumour size is the 
sum of the longest diameters of the TLs that have been selected at baseline.  Baseline for 
RECIST is defined to be the last evaluable assessment prior to starting treatment.  The change 
in tumour size will be assessed using the log (ratio) of the week 12 tumour size over the 
baseline tumour size for each subject.  More details on TLs selection and assessment during 
the treatment can be found in Appendix F of the protocol. 
Revised text: 
Change in tumour size at 12 weeks is based on RECIST measurements taken at baseline and 
at week 12.  Tumour size is the sum of the longest diameters of the TLs that have been 
selected at baseline.  Baseline for RECIST is defined to be the last evaluable assessment prior 
to starting treatment.  The change in tumour size will be assessed using the log (ratio) of the 
week 12 tumour size over the baseline tumour size for each subject.  More details on TLs 
selection and assessment during the treatment can be found in Appendix F of the protocol. 
Reason for Amendment:  
Please see amendment rationale numbers 3 and 8. 
 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
73(85) 
Section of protocol affected: 
New – Section 11.1.6.   Overall survival.   
Previous text: 
Not applicable. 
New  text: 
11.1.6  
Overall survival 
Overall survival is defined as the interval between the date of randomisation and the 
date of patient death due to any cause.  Patients who have not died at the time of the 
statistical analysis or who are lost to follow-up or withdraw consent, will be censored at 
the time they were last known to be alive. 
Reason for Amendment:  
Please see amendment rationale numbers 4 and 8. 
 
Section of protocol affected: 
Section 12.1.1.  Efficacy analysis set. 
Previous text: 
All efficacy data in Part B of the study (change in tumour size at 12 weeks, PFS, ORR, DoR 
and percentage of patients without progression at 12 weeks) will be analysed on an intention-
to-treat basis (ITT). This will include all randomised patients, wherever possible, and compare 
treatment groups on the basis of randomised treatment, regardless of the treatment they 
actually received. 
To be considered 'evaluable' for the primary efficacy analysis, a patient must have: 
x
Baseline and week 12 (r1 week) tumour measurements; or 
x
Evidence of progression prior to week 12; or 
x
In the absence of the week 12 measurements and no evidence of progression, RECIST 
measurements at baseline and 1 visit after or prior to the week 12 visit such that a 
prediction for the week 12 result can be made (see section 11.1.1 for details) 
For the Part A safety run-in, the efficacy analysis set will include all patients who received at 
least one dose of study treatment. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
74(85) 
Revised text: 
All efficacy data in Part B of the study (PFS, change in tumour size at 12 weeks, ORR, DoR 
percentage of patients without progression at 12 weeks and OS) will be analysed on an 
intention-to-treat basis (ITT).  This will include all randomised patients, wherever possible, 
and compare treatment groups on the basis of randomised treatment, regardless of the 
treatment they actually received. 
For the Part B randomised expansion; in the event that the dose/schedule is changed 
following recommendation by the SRC, and the total number of patients has been 
increased to compensate for patients recruited prior to the change, the primary analyses 
will be performed on the subset of the efficacy analysis set randomised to the new 
dose/schedule. 
For the Part A safety run-in, the efficacy analysis set will include all patients who received at 
least one dose of study treatment. 
Reason for Amendment:  
Please see amendment rationale numbers 3, 4 and 6. 
 
Section of protocol affected: 
Section 12.2.  Methods of statistical analyses 
Previous text: 
A comprehensive statistical analysis plan (SAP) will be prepared prior to enrolment of 
patients in the study. 
The primary outcome variable for Part B of change in tumour size at 12 weeks, and the 
secondary outcome variable of PFS, will be analysed formally.  All Part A data, other Part B 
efficacy and safety data will be summarised descriptively. 
For the primary and secondary analysis the null hypothesis is that there is no treatment effect, 
i.e., there is no difference in terms of change in tumour size at 12 weeks between patients 
treated with AZD5363 + paclitaxel and patients treated with matching placebo + paclitaxel. 
No adjustments for multiplicity will be made. 
Details of sensitivity analyses and imputation methods for missing data will be fully 
documented in the SAP. 
There are potentially a number of different analysis points for the study.  The table below 
details which data will be analysed at each time point. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
75(85) 
Analysis 
Trigger 
Data type included 
End of safety run-in 
All patients in Part A followed 
up for at least 12 weeks  
Safety, efficacy (week 12 response 
rate, best response), PK, PD 
Randomised expansion 
interim analysis 
40 patients randomised and 
completed 12 week follow up 
period (or progressed prior to 12 
weeks) 
Change in tumour size, response 
rate at 12 weeks, best objective 
response (No PIK3CA mutation 
subgroup analysis) 
Randomised expansion 
primary analysis 
60 patients randomised and 
completed 12 weeks follow up 
period (or progressed prior to 12 
weeks) 
All efficacy other than PFS 
(including PIK3CA mutation 
subgroup analyses), safety, PK, PD 
Randomised expansion 
progression free survival 
analysis 
Recruitment to Part B complete 
and 45 progression events 
occurred 
PFS (overall and in PIK3CA 
mutation - positive subgroup), RR 
and duration, safety 
Safety update 
When last patient discontinues 
study treatment 
Reduced set of safety outputs 
PFS analysis and safety update will be combined if last patient has discontinued by the time the PFS events are 
reached. 
 
Randomisation in Part B of the study will be stratified by PIK3CA mutation status determined 
by analysis of tumour tissue (or result from a prior tumour analysis) and a blood sample (see 
sections 5.2.1 and 6.2.2).   
A mutation detected in either the blood or tissue samples will result in a patient being 
classified as being in the mutation-positive group for this analysis.  Concordance between 
tumour tissue and blood sample mutation results will be explored. In the event of conflicting 
results in a substantial number of patients, the impact of the different methods on the efficacy 
analyses will be explored. 
Revised text: 
A comprehensive statistical analysis plan (SAP) will be prepared prior to enrolment of 
patients in the study. 
The primary outcome variable for Part B of PFS, and the secondary outcome variables, will 
be analysed formally.  All Part A data and safety data will be summarised descriptively. 
The secondary outcome variable of OS will be formally analysed if there is sufficient 
data to warrant formal statistical analysis (ie enough OS events at the primary analysis 
to analyse OS). 
During Part B; in the event that the SRC and AstraZeneca agrees that an alternative 
dose or schedule should be explored with a consequent increase in the number of 
patients to be enrolled, the above analyses will be performed for the patients randomised 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
76(85) 
after the last change in dose or schedule (for SRC roles and responsibilities reference 
section 5.11.2).  These analyses will be considered as primary, and data from patients 
randomised prior to the change in dose or schedule will be summarised descriptively. 
For the primary and secondary analysis the null hypothesis is that there is no treatment effect, 
i.e., there is no difference in terms of PFS between patients treated with AZD5363 + 
paclitaxel and patients treated with matching placebo + paclitaxel. 
No adjustments for multiplicity will be made. 
Details of sensitivity analyses and imputation methods for missing data will be fully 
documented in the SAP. 
There are potentially a number of different analysis points for the study.  The table below 
details which data will be analysed at each time point.  
Analysis 
Trigger 
Data type included 
End of safety run-in 
All patients in Part A followed 
up for at least 12 weeks  
Safety, efficacy (week 12 response 
rate, best response), PK, PD 
Randomised expansion 1st 
interim analysis 
40 patients randomised and 
completed 12 week follow up 
period (or progressed prior to 12 
weeks) 
Change in tumour size, response 
rate at 12 weeks, best objective 
response (No PIK3CA mutation-
positive subgroup analysis), 
safety. 
Randomised expansion 2nd 
interim analysis 
38 progression events in the 
overall population and 30 
PIK3CA mutation-positive 
patients randomised and 
completed 12 week follow up 
period (or progressed prior to 12 
weeks) 
All efficacy other than survival 
for the overall population 
(including PIK3CA mutation-
positive subgroup analyses for 
change in tumour size, 
response rate at 12 weeks, 
BOR), safety,  
Randomised expansion 
progression primary 
analysis 
Recruitment to Part B complete 
and 76 progression events 
occurred in the overall 
population and 38 progression 
events occurred in the PIK3CA  
mutation-positive patients. 
All efficacy, PFS (overall and in 
PIK3CA mutation - positive 
subgroup), safety, PK, PD. 
Randomised expansion 
overall survival analysis 
 
At 50% maturity.   
A further analysis at 75% 
maturity may be considered. 
OS (overall and in PIK3CA 
mutation - positive subgroup), 
safety. 
Safety update 
When last patient discontinues 
study treatment 
Reduced set of safety outputs 
PFS analysis and safety update will be combined if last patient has discontinued by the time the PFS events are 
reached. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
77(85) 
 
Randomisation in Part B of the study will be stratified by PIK3CA mutation status determined 
by analysis of tumour tissue (or result from a prior tumour analysis) and a blood sample (see 
sections 5.2.1 and 6.2.2).   
A mutation detected in either the blood or tissue samples will result in a patient being 
classified as being in the mutation-positive group for this analysis.  Concordance between 
tumour tissue and blood sample mutation results will be explored. In the event of conflicting 
results in a substantial number of patients, the impact of the different methods on the efficacy 
analyses will be explored. 
Reason for Amendment:  
Please see amendment rationale numbers 3, 4 and 8. 
 
Section of protocol affected: 
Section: 12.2.  Methods of statistical analyses. 
Amendment: 
Subsection 12.2.2, Progression Free Survival, has been moved to subsection position 12.2.1.   
Reason for Amendment:  
Progression-free survival is now the primary endpoint, hence its derivation now appears as the 
first item in section 12.2.  Please see amendment rationale numbers 3 and 8. 
 
Section of protocol affected: 
Section 12.2.1 (originally section 12.2.2).  Progression Free Survival.  Paragraph 1. 
Previous text: 
The secondary endpoint of PFS will be analysed for the patients in Part B when recruitment to 
Part B has completed and approximately 45 PFS events in the overall population have 
occurred.  Waiting until recruitment has completed to this part of the study will ensure that as 
many as possible of the PFS events included in the analysis come from a mixture of PIK3CA 
mutation positive and not detected patients.  This aims to safeguard against the possibility that 
the progression events could be largely from the mutation not detected patients if that stratum 
recruits substantially quicker than the other.  PFS will not be presented for patients in Part A 
of the study.  PFS will be analysed for the overall population and for the subgroup of PIK3CA 
mutation patients, using separate Cox proportional-hazards models allowing for the effect of 
treatment and including a term for PIK3CA mutation status in the overall analysis (mutation 
positive or not detected). 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
78(85) 
Revised text: 
The primary endpoint of PFS will be analysed for the patients in Part B when recruitment to 
Part B has completed and 76 PFS events in the overall population, and 38 in the PIK3CA 
mutation-positive subgroup, have occurred.  Waiting until recruitment has completed to this 
part of the study will ensure that as many as possible of the PFS events included in the 
analysis come from a mixture of PIK3CA mutation positive and not detected patients.  This 
aims to safeguard against the possibility that the progression events could be largely from the 
mutation not detected patients if that stratum recruits substantially quicker than the other.  PFS 
will not be presented for patients in Part A of the study.  PFS will be analysed for the overall 
population and for the subgroup of PIK3CA mutation patients, using separate Cox 
proportional-hazards models allowing for the effect of treatment and including a term for 
PIK3CA mutation status in the overall analysis (mutation positive or not detected). 
Reason for Amendment:  
Please see amendment rationale numbers 3 and 8. 
 
Section of protocol affected: 
Section 12.2.2 (originally section 12.2.1).  Change in tumour size at 12 weeks.  Paragraph 1. 
Previous text: 
The primary endpoint for Part B, of change in tumour size at week 12 (or progression if prior 
to week 12), will be assessed in all patients in this part and separately within the PIK3CA 
mutation-positive subgroup of patients.  Change in tumour size will be assessed as the log of 
the ratio of week 12 tumour size over the baseline tumour size measurement for each patient 
as these data have been assumed to be log-normally distributed (see section 11.1.1). 
Revised text: 
The secondary endpoint for Part B, of change in tumour size at week 12 (or progression if 
prior to week 12), will be assessed in all patients in this part and separately within the PIK3CA 
mutation-positive subgroup of patients.  Change in tumour size will be assessed as the log of 
the ratio of week 12 tumour size over the baseline tumour size measurement for each patient 
as these data have been assumed to be log-normally distributed (see section 11.1.1). 
Reason for Amendment:  
Please see amendment rationale number 3. 
 
Section of protocol affected: 
New – Section 12.2.2.   Overall survival.  (Note: subsequent subsections have been re-
numbered accordingly).   


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
79(85) 
Previous text: 
Not applicable. 
New  text: 
12.2.2  
Overall survival 
The analysis population for OS will be the ITT population. 
OS on AZD5363 in combination with weekly paclitaxel compared to weekly paclitaxel 
plus placebo will also be analysed using the same methods as for PFS.  This analysis will 
be performed after 50% of patients have died.  If fewer than 50% of patients have died 
at the time of the primary PFS analysis, then the OS data will only be summarized at 
that time. 
A further analysis after 75% of patients have died may be considered. 
Reason for Amendment:  
Please see amendment rationale numbers 3, 4 and 8. 
 
Section of protocol affected: 
12.2.4 (originally 12.2.3):  Response rate at 12 weeks and best objective tumour response 
Previous text: 
Response rate at 12 weeks and best response during the study will be tabulated by randomised 
treatment (AZD5363 + paclitaxel or placebo + paclitaxel) in Part B and by dose and schedule 
for the Part A patients.  These will present frequencies of confirmed complete responses and 
partial responses in addition to unconfirmed complete and partial responses, stable disease, 
progressive disease and not evaluable.  In addition, the proportion of patients known to be 
progression-free at 12 weeks will be presented. This is defined as the number of patients with 
complete response, partial response or stable disease at 12 weeks (do not have to be 
confirmed). 
These data will not be analysed formally. 
A tabulation of response rate at 12 weeks, best response during the study and proportion 
progression free at 12 weeks by treatment group by PIK3CA mutation status will also be 
presented to assess if the response rate is different in the PIK3CA mutation-positive and 
PIK3CA mutation-not detected subgroups. 
Revised text: 
Response rate at 12 weeks and best response during the study will be tabulated by randomised 
treatment (AZD5363 + paclitaxel or placebo + paclitaxel) in Part B and by dose and schedule 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
80(85) 
for the Part A patients.  These will present frequencies of confirmed complete responses and 
partial responses in addition to unconfirmed complete and partial responses, stable disease, 
progressive disease and not evaluable.  In addition, the proportion of patients known to be 
progression-free at 12 weeks will be presented. This is defined as the number of patients with 
complete response, partial response or stable disease at 12 weeks (do not have to be 
confirmed). 
Response rate will be analysed for the overall population and for the subgroup of 
PIK3CA mutation-positive patients using separate logistic regression models allowing for 
the effect of treatment and including a term for PIK3CA mutation status in the overall 
analysis. 
A tabulation of response rate at 12 weeks, best response during the study and proportion 
progression free at 12 weeks by treatment group by PIK3CA mutation status will also be 
presented to assess if the response rate is different in the PIK3CA mutation-positive and 
PIK3CA mutation-not detected subgroups. 
Reason for Amendment:  
Please see amendment rationale numbers 3 and 8. 
 
Section of protocol affected: 
12.3.  Interim analyses 
Previous text: 
An interim analysis will be performed when 40 patients have been recruited to Part B and 
followed up for 12 weeks (or progressed prior to 12 weeks).  The analysis will be primarily 
based on changes in tumour size at 12 weeks, but additional summaries of response rate at 12 
weeks, proportion progression-free at 12 weeks and best objective response during the study 
will support the change in tumour size data at the interim analysis.  The analysis and data 
presentations will be performed on the overall population, no PIK3CA mutation subgroup 
analysis will be performed as the number of patients expected to be recruited with a PIK3CA 
mutation positive tumour by that stage is likely to be low. 
The purpose of the interim analysis is to provide the opportunity for an early trigger to 
commence setting up a phase IIb study, if the results are strong enough, such that once the 
primary analysis is completed to confirm the interim result, the phase IIb study could 
commence with minimal delay.  Therefore, as safety data will be analysed on the full dataset 
at the primary analysis, it is proposed not to include safety data at the interim analysis.  It is 
not considered necessary to adjust the significance level to account for this additional analysis 
of the data, given that this analysis will not form the basis of any stop or acceleration 
decisions. In addition, the results obtained will be interpreted with caution, bearing in mind 
the increased risk of false positive results that this additional analysis introduces. 


Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
81(85) 
Revised text: 
The 1st interim analysis will be performed when 40 patients have been recruited to Part B and 
followed up for 12 weeks (or progressed prior to 12 weeks).  The analysis will be primarily 
based on changes in tumour size at 12 weeks, but additional summaries of response rate at 12 
weeks, proportion progression-free at 12 weeks and best objective response during the study 
will support the change in tumour size data at the interim analysis.  The analysis and data 
presentations will be performed on the overall population, no PIK3CA mutation subgroup 
analysis will be performed as the number of patients expected to be recruited with a PIK3CA 
mutation positive tumour by that stage is likely to be low. 
A 2nd interim analysis will be conducted when at least 38 PFS events across both PIK3CA 
mutation subgroups have been achieved and 30 PIK3CA mutation-positive patients have  
completed 12 week follow up period (or progressed prior to 12 weeks).   
The 2nd interim analysis will be conducted upon all efficacy outputs other than survival 
for the overall population (including PIK3CA mutation-positive subgroup analyses for 
change in tumour size, response rate at 12 weeks, BOR) and safety. 
The purpose of the interim analyses is to provide the opportunity for an early trigger to 
commence setting up a phase IIb study, if the results are strong enough, such that once the 
primary analysis is completed to confirm the interim result, the phase IIb study could 
commence with minimal delay.  It is not considered necessary to adjust the significance level 
to account for this additional analysis of the data, given that this analysis will not form the 
basis of any stop or acceleration decisions. In addition, the results obtained will be interpreted 
with caution, bearing in mind the increased risk of false positive results that this additional 
analysis introduces. 
Reason for Amendment:  
Please see amendment rationale numbers 3 and 8. 
 
Section of protocol affected: 
12.4.  Determination of sample size 
Previous text: 
Part B - Randomised expansion 
The primary endpoint of change in tumour size at week 12 will be assessed by calculating the 
log of the ratio of the week 12 (r1 week) tumour size measurement over the baseline tumour 
size measurement for each patient.  If the patient has documented evidence of objective 
disease progression prior to week 12, then this will be used as the week 12 measurement. 








Clinical Study Protocol Amendment 2 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 24 April 2013 
85(85) 
Reason for Amendment:  
Following investigational site feedback, this management plan for elevated plasma glucose 
levels (also provided separately as a study aide) has been incorporated in to Appendix H for 
completeness of information. 
 


 
 
Clinical Study Protocol Amendment 
 
Amendment Number 
3 
 
Drug Substance 
AZD5363 
 
Study Code 
D3610C00002 
 
Date 
09 May 2014 
 
Protocol Dated 
30 April 2013 
 
 
 
 
 
 
 
 
 
 
A Phase I/II, Multicentre, Study Comprising a Safety Run-In of AZD5363 
when Combined with Paclitaxel in Patients with Advanced or Metastatic 
Breast Cancer; Followed by a Randomised Expansion of AZD5363 when 
Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-
Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA 
Mutation Status (BEECH). 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
Sponsor: 
AstraZeneca AB, 151 85 Södertälje, Sweden. 
Centres affected by the Amendment: 
This amendment affects all centres in the study 
The protocol for the study is to be amended as follows:  
Changed or additional text is indicated in bold, where applicable. Deleted text is indicated as 
scored through. 
Administrative changes - due to, for example, correction of typographical errors or 
renumbering of subsequent sections following addition of new sections - have been amended 
as applicable and have been included in the revised protocol but will not be listed separately in 
this amendment. 
The protocol amendments defined within this document primarily relate to the areas detailed, 
with rationales, below.  Other amendments are described separately in the body of this 
document. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
2(79) 
1. 
Part B Inclusion Criteria:  

Addition of requirement for patients to be negative for presence of Human 
Epidermal Growth Factor Receptor 2 (HER2) for entry to Part B of this study.  This 
change was to reflect that HER2 – positive patients would be de-facto excluded 
from the study due to non-allowance of anti-HER2 agents in combination, and is for 
the purposes of clarity rather than significantly altering the intended patient 
population. 

Removal of requirement for patients to have received prior endocrine therapy for 
entry to Part B.  This change was made following Investigators’ identification that 
this criterion prevented access to study treatment for otherwise applicable patients.  
On review, AstraZeneca concluded that receipt of prior endocrine therapy would 
not present a critical factor in the interpretation of trial outcomes and that allowing 
entry of patients without such prior therapies would not confer additional risks to 
patient safety or welfare. 
2. 
Part B Patient Stratification: Allowance included for patients to be allocated to 
PIK3CA tumour mutation ‘positive’ or ‘not detected’ strata based upon central 
laboratory analysed and/or pre-existing local laboratory analyses.  Allowance is also 
given for patients to be allocated to the ‘not detected’ stratum as a default option 
where no PIK3CA tumour mutation status results available at the time of planned 
start of standard care / study treatment.  This change was made in response to 
Investigators concerns that the period required for provision and analysis of both a 
patient’s blood and tissue samples for central determination of their PIK3CA tumour 
mutation status could result in a clinically unacceptable delay to the commencement 
of study and standard of care treatment (i.e would take longer than the time required 
to complete other screening procedures).  This change therefore allows Investigators 
to ensure that patients may be stratified and commmence study therapy without 
incurring delay;  based upon the best available information, or in the absence of 
information. Additional changes to enrolment procedures are also included to ensure 
that appropriate numbers of patients with/without PIK3CA mutation of their tumour 
are included in the study and that randomisation balance is maintained within each of 
these two study strata: 

In instances where a patient may be allocated to the ‘not-detected’ stratum, 
and the PIK3CA tumour mutation is subsequently identified as ‘positive’, 
the patient’s status will be amended accordingly in the study database and 
the corrected status utilised for all analyses. 

In the event that recruitment to one stratum is completed before the other, 
this change will provide clarity regarding a process to close the completed 
stratum to further recruitment and to pre-screen patients for mutation status 
applicable to the remaining, open, stratum 
3. 
Efficacy Variable: Durable Response Rate added as new efficacy variable.  This 
change was made to enable an assessment of the proportion of patients who had a 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
3(79) 
sustained response of at least 24 weeks.  Whilst the primary outcome of the study is 
the standard endpoint of progression-free survival, from which a positive result may 
be obtained if patients benefit from an extended duration of stable disease; durable 
response rate allows analysis of the presence and durable effect of any anti-tumour 
activity arising from the combination of AZD5363 with paclitaxel chemotherapy 
which could not be measured by assessing only response rate. 
4. 
Part B Patient Assessments: Reduction in the number of patient assessments, and 
the number of days on which patients are required to attend for evaluation.  This 
change was made in response to Investigators’ observations that the originally 
proposed schedule of assessments presented a potential burden to both patients and 
site staff.  Whilst all assessments are acceptable and essential for the Phase I (Part A) 
evaluation, the data that the removed assessments would provide were - on further 
review- not considered fundamental for the Phase II evaluation of Part B; nor were 
they essential for the purposes of maintaining patient safety.   
It was also noted that the schedule of assessments during Cycle 1, Week 1 – requiring 
patients to attend on Day 3 (and 5 for those on the 4 days-on, 3 days-off regimen) 
post commencement of dosing - resulted in it being necessary to initiate the study on 
particular days of the week in order to avoid assessments being required on non-
working days.  This restricted the ability of study sites to provide the most 
appropriate timetable for patient attendance for initiation and subsequent evaluations.  
On consideration of the above, AstraZeneca has concluded that it is appropriate to 
remove Part B patient evaluations on Cycle 1 Week 1 Days 3 and 5 and on Week 4 of 
Cycles 1 and 2; with some re-assignment of specific assessments.  This was based on 
the judgement that sufficient data will be collected during Part A at these timepoints 
to support study endpoints and objectives, when combined with a reduced and 
revised evaluation set from Part B.  It was considered that anticipated benefit in ease 
of study conduct for sites and patients mitigated against reduction in overall data 
collection. 
5. 
Data Monitoring Committee.  Inclusion of an AstraZeneca internal Data 
Monitoring Committee (AZDMC).  This change was made following a review of 
interim data analysis requirements for study Part B.  From this it was identified that 
blinded data evaluation alone by the Safety Review Committee may be insufficient to 
adequately evaluate patient safety and initial efficacy indicators in the event of any 
outcomes that may require amendment to study conduct.  In addition, the introduction 
of the AZDMC would ensure that the AZ personnel directly involved in the running 
of the study would not be involved in reviewing the data from the interim analyses 
and therefore limits any potential for bias in study conduct after each of the interim 
analyses. 
The members of the AZDMC will be AstraZeneca personnel independent of the 
AZD5363 project team.  Their remit will be to evaluate unblinded data outputs 
following Part B 1st and 2nd interim analyses and provide the project team with 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
4(79) 
recommendations for action with respect to study conduct and the management of 
patients treated under the auspices of the study protocol. 
 
It is the judgement of the AstraZeneca Project Team that none of the protocol changes detailed 
in this document present any additional risk or hazard to participating patients welfare or 
safety.    


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
5(79) 
Amendments 
 
Section of protocol affected: 
Protocol Synopsis: Secondary objectives / Part B Randomised expansion  
Previous text: 
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel compared 
with weekly paclitaxel plus placebo by assessment of best objective response and duration of 
response. 
Revised text: 
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel compared 
with weekly paclitaxel plus placebo by assessment of best objective response, durable 
response rate and duration of response. 
Reason for Amendment:  
Please refer to amendment rationale number 3. 
 
Section of protocol affected: 
Protocol Synopsis: Study Design / Part B: Randomised Expansion 
Additional text (following paragraph 2): 
Patients may be stratified based upon PIK3CA status determined by a central laboratory 
(Quintiles) and/or an existing PIK3CA status determined by local analysis.  In instances 
where the period required for provision and analysis of both a patient’s blood and tissue 
samples for central determination of their PIK3CA tumour mutation status would result 
in a clinically unacceptable delay to the commencement of study and standard of care 
treatment (i.e will take longer than the time required to complete other screening 
procedures), the patient may be stratified to the ‘not-detected’ arm by default in the 
absence of a known status. In such cases, where the PIK3CA tumour mutation status is 
subsequently identified as ‘positive’, the record of the patient’s status will be amended 
accordingly in the study database and the corrected status utilised for all analyses. 
 
Reason for Amendment:  
Please refer to amendment rationale number 2. 
Section of protocol affected: 
Protocol Synopsis: Target Population 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
6(79) 
Previous text: 
Part B. Randomised expansion:  Female patients, 18 years or older, with ER+ve advanced or 
metastatic breast cancer.  For inclusion in Part B, patients must not have received any prior 
chemotherapy in the advanced or metastatic settings. 
Revised text: 
Part B. Randomised expansion:  Female patients, 18 years or older, with ER+ve, HER2-ve, 
advanced or metastatic breast cancer.  For inclusion in Part B, patients must not have received 
any prior chemotherapy in the advanced or metastatic settings. 
Reason for Amendment:  
Please refer to amendment rationale number 1. 
Section of protocol affected: 
List of Abbreviations and Definitions of Terms 
Additional text lines: 
Abbreviation or 
special term 
Explanation 
AZDMC 
AstraZeneca Data Monitoring Committee 
DRR 
Durable Response Rate 
HER2 
Human Epidermal Growth Factor Receptor 2  
ISRC 
Independent Safety Monitoring Committee 
 
Reason for Amendment:  
Additional abbreviations associated with protocol amendment items. 
Section of protocol affected: 
Section 2.2  
Secondary objectives / Part B. Randomised expansion (bullet point 2) 
Previous text: 
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel compared 
with weekly paclitaxel plus placebo by assessment of ORR at 12 weeks, best objective 
response (BOR) and DoR and Durable Response Rate (DRR). 
Revised text: 
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel compared 
with weekly paclitaxel plus placebo by assessment of ORR at 12 weeks, best objective 
response (BOR) and, DoR and Durable Response Rate (DRR). 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
7(79) 
Reason for Amendment:  
Please refer to amendment rationale number 3. 
Section of protocol affected: 
Section 3.1.2 Part B: Randomised expansion (bullet point 2) 
Previous text: 
The patient population will be female, aged 18 years or older, with ER+ve advanced or 
metastatic breast cancer, and incorporating a subgroup who have PIK3CA mutation-positive 
tumour(s).  For inclusion in Part B, patients must not have received any prior chemotherapy 
for breast cancer in the advanced or metastatic setting.  Prior (neo)adjuvant chemotherapy is 
allowed (if (neo) adjuvant taxane, there must have been a minimum of 12 months from 
completion of therapy to relapse). 
Revised text: 
The patient population will be female, aged 18 years or older, with ER+ve, HER2-ve, 
advanced or metastatic breast cancer, and incorporating a subgroup who have PIK3CA 
mutation-positive tumour(s).  For inclusion in Part B, patients must not have received any 
prior chemotherapy for breast cancer in the advanced or metastatic setting.  Prior 
(neo)adjuvant chemotherapy is allowed (if (neo) adjuvant taxane, there must have been a 
minimum of 12 months from completion of therapy to relapse). 
Reason for Amendment:  
Please refer to amendment rationale number 1. 
 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
8(79) 
Section of protocol affected: 
Section 3.1.4 Assessment Schedule 
Previous text: 
Figure 6 
Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
ActivityĻ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent - 
PIK3CA screen 
(Part B only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
PIK3CA mutation 
testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Informed consent - 
study 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Demography& 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Previous/concomit
ant therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Previous cancer 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
9(79) 
Figure 6 
Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
Inclusion / 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.0 
Physical 
examination 
X 
Pre  
Pre 
Pre  
 
 
 
 
Pre  
 
 
 
 
 
 
Pre  
X 
X 
 
6.4.6 
Height and weight X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.7 
WHO 
performance 
status3 
X 
Pre X3 
X3 
X3 
 
X3 
 
 
X3 
X3 
 
X3 
 
X3 
 
X3 
 
X3 
 
X3 
X3 
 
6.4.8 
Vital signs 
X 
Pre Pre 
1h 
2h 
6h 
Post Pre  
Pre  
 
Pre Pre  
Post  
Post  
Post  
X 
 
X 
X 
 
6.4.11 
12-lead ECG 
X 
Pre Pre 
1h 
2h 
6h 
Pre 
Pre  
 
 
 
 
Post  
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.9 
MUGA / 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
X 
 
6.4.10 
Haematology, 
Clinical chemistry 
Urinalysis 
X 
Pre Pre Pre 
 
Pre 
 
Pre 
 
Pre  
Pre Pre  
Pre  
Pre  
 
Pre X 
X 
 
6.4.5 
Additional glucose  
 
2-4h 
4-6h 
2-4h 
4-6h 
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h
4-6h
 
 
 
 
 
 
 
2-4h
4-6h
 
 
 
6.4.5 
Glycosylated 
haemoglobin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
X 
X 
 
6.4.12.2 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
10(79) 
Figure 6 
Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
Lipids  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
X 
 
6.4.12.1 
Glucose, insulin, 
insulin c-peptide4 
 
Pre  
Pre 
2h 
4h 
6h 
8h 
 
Pre 
 
Pre 
 
Pre  
Pre 
2-4h
 
 
 
 
 
 
 
Pre 
2-4h
 
X 
 
6.4.12.3 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
6.4.5 
Paclitaxel PK 
blood samples1 
 
Pre 
2h 
4h 
8h 
Pre  
 
Pre 1  
Pre 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
AZD5363 PK 
blood samples1 
 
 
Pre 
2h 
4h 
8h 
Pre 
 
Pre 
 
Pre 
 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Pharmacodynamic 
blood samples1 
 
Pre Pre 
2h 
4h 
8h 
Pre 
 
Pre 
 
Pre 
 
Pre Pre  
 
 
 
 
 
 
X 
 
 
X 
 
6.7.1 
Exploratory 
biomarker blood 
samples1 
(optional) 
X 
 
Pre  
 
Pre 
 
Pre 
 
Pre Pre  
 
 
 
 
 
 
X 
 
 
X 
 
6.8.1.5 
Exploratory 
biomarker hair 
samples (optional) 
 
 
Pre 
4h 
Pre 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
11(79) 
Figure 6 
Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363 
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
Pharmacogenetics 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.1 
RECIST Tumour 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
 
 
6.3.1 
Archival tumour 
sample  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.2 
Paired biopsy 
(optional)  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.3 
Circulating tumour 
cells 
 
Pre  
 
 
 
 
 
 
 
Pre  
 
 
 
 
 
 
Pre 2  
 
 
 
6.8.1.1 
Patient meal 
information 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
6.4.12.4 
QoL 
questionnaires 
(Part B only) 
X 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
X 
 
6.5.1 
Survival status 
(Part B only)5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X5 
6.2.3.4 
Subsequent cancer 
therapy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X5 
5.6 
Concomitant 
medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Adverse events 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
6.4.3 
1.  
Part A - Safety Run-in phase only: Patients will continue to undergo paclitaxel PK measurements on these occasions. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
12(79) 
2.  
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1).  Part 
B - Randomised expansion only: Patients will continue to undergo RECIST assessments after cessation of study therapies up to disease progression or 
withdrawal of consent.   
3.  
WHO performance status; Part B – Randomised expansion phase only:  Performance status will be assessed at these timepoints during part B only. 
4.  
Insulin c-peptide; Part A - Safety Run-in phase only:  Insulin c-peptide will not be analysed during the Part B Randomised expansion. 
5. 
Part B Randomised expansion phase only: Survival status and subsequent cancer therapies will be determined at the 28 day follow-up visit and at 12-
weekly intervals thereafter.  These visits suggested to coincide with RECIST assessments up to disease progression, and at 12-weekly intervals thereafter 
to death or withdrawal. 
 
Figure 7 
Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details 
in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
5 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
ActivityĻ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
- PIK3CA screen 
(Part B only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
PIK3CA mutation 
testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Informed consent 
- study 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Demography& 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
13(79) 
Figure 7 
Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details 
in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
5 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
Previous/concomi
tant therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Previous cancer 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Inclusion / 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
Physical 
examination 
X 
Pre  
 
Pre Pre  
 
 
 
 
Pre  
 
 
 
 
 
 
Pre  
X 
X 
 
6.4.6 
Height and weight X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.7 
WHO 
performance 
status 
X 
Pre X3 X3 X3 
X3  
X3  
 
X3 
X3 
 
X3 
 
X3 
 
X3 
 
X3 
 
X3 
X3 
 
6.4.8 
Vital signs 
X 
Pre Pre 
1h 
2h 
6h 
 
Post Pre  
Pre  
 
Pre Pre  
Post  
Post  
Post  
X 
 
X 
X 
 
6.4.11 
12-lead ECG 
X 
Pre Pre 
1h 
2h 
6h 
Pre Post Pre  
 
 
 
 
Post  
 
 
 
 
 
 
X 
 
X 
X 
 
6.4.9 
MUGA / 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
X5 
 
 
 
 
 
 
 
X2 
 
 
X 
 
6.4.10 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
14(79) 
Figure 7 
Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details 
in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
5 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
Haematology, 
Clinical chemistry 
Urinalysis 
X 
Pre Pre  
Pre  
Pre  
Pre  
Pre  
Pre Pre  
Pre  
Pre  
 
Pre X 
X 
 
6.4.5 
Additional 
glucose 
 
 
2-4h 
4-6h 
 
2-4h 
4-6h 
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h
4-6h
 
 
 
 
 
 
 
2-4h
4-6h
 
 
 
6.4.5 
Glycosylated 
haemoglobin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
X 
X 
 
6.4.12.
2 
Lipids  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
X 
 
6.4.12.
1 
Glucose, insulin, 
insulin c-peptide3  
 
Pre Pre 
2h 
4h 
6h 
8h 
 
Pre 
2h 
4h 
6h 
8h 
 
Pre  
Pre  
Pre  
Pre 
2-4h 
 
 
 
 
 
 
 
Pre 
2-4h
 
X 
 
6.4.12.
3 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
6.4.5 
Paclitaxel PK 
blood samples1 
 
Pre 
2h 
4h 
8h 
Pre  
 
 
Pre 1  
Pre 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
AZD5363 PK 
blood samples1 
 
 
Pre 
2h 
4h 
8h 
Pre Pre  
Pre  
Pre  
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
15(79) 
Figure 7 
Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details 
in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
5 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
Pharmacodynamic 
blood samples1 
 
Pre Pre 
2h 
4h 
8h 
Pre Pre  
Pre  
Pre  
Pre Pre  
 
 
 
 
 
 
X 
 
 
X 
 
6.7.1 
Exploratory 
biomarker blood 
samples1 
(optional) 
X 
 
Pre  
 
 
Pre  
Pre  
Pre Pre  
 
 
 
 
 
 
X 
 
 
X 
 
6.8.1.5 
Exploratory 
biomarker hair 
samples (optional) 
 
 
Pre 
4h 
 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 
Pharmacogenetics 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.1 
RECIST Tumour 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
 
 
6.3.1 
Archival tumour 
sample  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.2 
Paired biopsy 
(optional)  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.3 
Circulating 
tumour cells 
 
Pre  
 
 
 
 
 
 
 
 
Pre  
 
 
 
 
 
 
Pre 2  
 
 
 
6.8.1.1 
Patient meal 
information 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
6.4.12.
4 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
16(79) 
Figure 7 
Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details 
in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
Week Day  ĺ  -28 to 0 1 
2 
3 
5 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2
1 
2 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
QoL 
questionnaires 
(Part B only) 
X 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
X 
 
6.5.1 
Survival status 
(Part B only)6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
6.2.3.4 
Subsequent 
cancer therapy6 
  
  
  
  
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
X 
X6 
5.6 
Concomitant 
medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Adverse events 
X 
 
  
  
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
 
6.4.3 
1.  
Part A - Safety Run-in phase only: Patients will continue to undergo paclitaxel PK measurements on these occasions.  
2.  
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1). Part 
B Randomised expansion only: Patients will continue to undergo RECIST assessments after cessation of study therapies up to disease progression or 
withdrawal of consent.   
3.  
WHO performance status; Part B – Randomised expansion phase only:  Performance status will be assessed at these timepoints during part B only. 
4. 
Insulin c-peptide; Part A - Safety Run-in phase only:  Insulin c-peptide will not be analysed during Part B. 
5. 
Part A Safety Run-in phase only: Patients will undergo the Cycle 2 Week 1 Day 1 MUGA / Echocardiogram assessment during Part A only.  This 
assessment timepoint will not be conducted during the Part B Randomised expansion. 
 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
17(79) 
Revised text: Note 1 – the following tables now represent patient assessments as applicable to Part A of the study only.  These 
assessments remain unchanged from protocol edition 2.  All changes are therefore relevant to removal of assessments applicable to 
Part B alone (which are now shown in new Figure 9).  For clarity of presentation, the revised schedules of assessment and 
footnotes are shown below without marked deletions.  The individual changes are described in the relevant sections identified 
under the ‘Details in Section:’ column. 
Note 2 - a ’12 weekly’ column has been included to more clearly identify assessments relevant to the set of evaluations conducted at 
12-weekly intervals and to delineate these from assessments conducted routinely at the start of each Cycle.  
Schedule of Assessments: Part A  
 Figure 6 
Part A Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
12 
weekly
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
 
Week Day  ĺ   -28 to 0 1 
2 
3 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
 
ActivityĻ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PIK3CA mutation 
testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Informed consent - 
study 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Demography & 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Previous/concomit
ant therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
18(79) 
 Figure 6 
Part A Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
12 
weekly
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
 
Week Day  ĺ   -28 to 0 1 
2 
3 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
 
Previous cancer 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Inclusion / 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
Physical 
examination 
X 
Pre  
Pre Pre  
 
 
 
 
Pre  
 
 
 
 
 
 
Pre 
 
 
X 
X 
 
6.4.6 
Height and weight X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
6.4.7 
WHO performance 
status 
X 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.8 
Vital signs 
X 
Pre Pre 
1h 
2h 
6h 
Post Pre  
Pre  
 
Pre 
Pre  
Post  
Post  
Post  
X 
 
 
X 
X 
 
6.4.11 
12-lead ECG 
X 
Pre Pre 
1h 
2h 
6h 
Pre Pre  
 
 
 
 
Post  
 
 
 
 
 
 
X 
 
 
X 
X 
 
6.4.9 
MUGA / 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
 
X 
 
6.4.10 
Haematology, 
Clinical chemistry 
Urinalysis 
X 
Pre Pre Pre  
Pre  
Pre 
 
Pre 
 
Pre Pre  
Pre  
Pre 
 
 
Pre  
X 
X 
 
6.4.5 
Additional glucose  
 
2-4h 
4-6h 
2-4h 
4-6h 
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h
4-6h
 
 
 
 
 
 
 
2-4h
4-6h
 
 
 
 
6.4.5 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
19(79) 
 Figure 6 
Part A Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
12 
weekly
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
 
Week Day  ĺ   -28 to 0 1 
2 
3 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
 
Glycosylated 
haemoglobin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
X 
X 
 
6.4.12.2
Lipids  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
 
X 
 
6.4.12.1
Glucose, insulin, 
insulin c-peptide 
 
Pre  
Pre 
2h 
4h 
6h 
8h 
 
Pre 
 
 
Pre 
 
 
Pre 
 
Pre 
2-4h
 
 
 
 
 
 
 
 
Pre 
2-4h
 
 
 
X 
 
6.4.12.3
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
6.4.5 
Paclitaxel PK 
blood samples 
 
Pre 
2h 
4h 
8h 
Pre  
 
Pre  
Pre   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
AZD5363 PK 
blood samples 
 
 
Pre 
2h 
4h 
8h 
Pre  
Pre  
Pre 
 
Pre 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Pharmacodynamic 
blood samples 
 
Pre Pre 
2h 
4h 
8h 
Pre  
Pre  
Pre 
 
Pre 
Pre  
 
 
 
 
 
 
X 
 
 
 
X 
 
6.7.1 
Exploratory 
biomarker blood 
samples (optional) 
X 
 
Pre  
 
Pre  
Pre 
 
Pre 
Pre  
 
 
 
 
 
 
X 
 
 
 
X 
 
6.8.1.5 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
20(79) 
 Figure 6 
Part A Schedule 1: AZD5363/placebo – Intermittent Dosing: 2 days on 5 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
12 
weekly
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
 
Week Day  ĺ   -28 to 0 1 
2 
3 
1 
2 
1 
2 
1
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X 
X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
 
Exploratory 
biomarker hair 
samples (optional) 
 
 
Pre 
4h 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 
Pharmacogenetics 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.1 
RECIST Tumour 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
 
 
 
6.3.1 
Archival tumour 
sample  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.2 
Paired biopsy 
(optional)  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.3 
Circulating tumour 
cells 
 
Pre  
 
 
 
 
 
 
 
Pre  
 
 
 
 
 
 
Pre2  
Pre1 
 
 
 
6.8.1.1 
Patient meal 
information 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
6.4.12.4
Subsequent cancer 
therapy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
X 
X 
 
Concomitant 
medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
5.6 
 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
21(79) 
1.  
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1).   
2.  
Circulating tumour cell samples will be collected on Cycle 3 Week 1 Day 1 and then only at 12-weekly assessments thereafter (see footnote 1 above). 
 
 
 Figure 7 
Part A Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
12 
weekly 
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
 
Week Day  
ĺ                 
-28 to 0 1 
2 
3 
5 
1 
2 
1 
2 1
2 
1 
2 
1 
2 
1 
2 
1 2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
 
ActivityĻ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PIK3CA mutation 
testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Informed consent 
- study 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Demography& 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Previous/concomi
tant therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Previous cancer 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Inclusion / 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
22(79) 
 Figure 7 
Part A Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
12 
weekly 
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
 
Week Day  
ĺ                 
-28 to 0 1 
2 
3 
5 
1 
2 
1 
2 1
2 
1 
2 
1 
2 
1 
2 
1 2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
 
Physical 
examination 
X 
Pre  
 
Pre Pre  
 
 
 
 
Pre  
 
 
 
 
 
 
Pre  
 
X 
X 
 
6.4.6 
Height and 
weight 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
6.4.7 
WHO 
performance 
status 
X 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.8 
Vital signs 
X 
Pre Pre 
1h 
2h 
6h 
 
Post Pre  
Pre  
 
Pre Pre  
Post  
Post  
Post  
X 
 
 
X 
X 
 
6.4.11 
12-lead ECG 
X 
Pre Pre 
1h 
2h 
6h 
Pre Post Pre  
 
 
 
 
Post  
 
 
 
 
 
 
X 
 
 
X 
X 
 
6.4.9 
MUGA / 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X1 
 
X 
 
6.4.10 
Haematology, 
Clinical chemistry 
Urinalysis 
X 
Pre Pre  
Pre  
Pre 
 
Pre  
Pre  
Pre 
Pre  
Pre  
Pre  
 
Pre  
X 
X 
 
6.4.5 
Additional 
glucose 
 
 
2-4h 
4-6h 
 
2-4h 
4-6h 
 
2-4h 
4-6h 
 
2-4h
4-6h
 
2-4h
4-6h
 
2-4h 
4-6h
 
 
 
 
 
 
 
2-4h
4-6h
 
 
 
 
6.4.5 
Glycosylated 
haemoglobin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
X 
X 
 
6.4.12.2


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
23(79) 
 Figure 7 
Part A Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
12 
weekly 
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
 
Week Day  
ĺ                 
-28 to 0 1 
2 
3 
5 
1 
2 
1 
2 1
2 
1 
2 
1 
2 
1 
2 
1 2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
 
Lipids  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
 
X 
 
6.4.12.1
Glucose, insulin, 
insulin c-peptide  
 
Pre Pre 
2h 
4h 
6h 
8h 
 
Pre 
2h 
4h 
6h 
8h 
 
Pre 
 
 
Pre  
Pre  
Pre 
2-4h 
 
 
 
 
 
 
 
 
Pre 
2-4h
 
 
 
X 
 
6.4.12.3
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
6.4.5 
Paclitaxel PK 
blood samples 
 
Pre 
2h 
4h 
8h 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
AZD5363 PK 
blood samples 
 
 
Pre 
2h 
4h 
8h 
Pre Pre  
Pre 
 
Pre  
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Pharmacodynami
c blood samples 
 
Pre Pre 
2h 
4h 
8h 
Pre Pre  
Pre 
 
Pre  
Pre Pre  
 
 
 
 
 
 
X 
 
 
 
X 
 
6.7.1 
Exploratory 
biomarker blood 
samples (optional) 
X 
 
Pre  
 
 
Pre 
 
Pre  
Pre Pre  
 
 
 
 
 
 
X 
 
 
 
X 
 
6.8.1.5 
Exploratory 
biomarker hair 
samples 
(optional) 
 
 
Pre 
4h 
 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
24(79) 
 Figure 7 
Part A Schedule 2: AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
12 
weekly 
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section:
Week ĺ 
 
1 
2 
3 
4 
1 
2 
3 
4 
1 
 
 
 
 
 
Week Day  
ĺ                 
-28 to 0 1 
2 
3 
5 
1 
2 
1 
2 1
2 
1 
2 
1 
2 
1 
2 
1 2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X Xĺ X 
 
Xĺ
 
Xĺ
 
 
 
Xĺ
 
Xĺ
 
Xĺ 
 
 
 
Xĺ
 
 
 
 
 
Pharmacogenetics 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.1 
RECIST Tumour 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
 
 
 
6.3.1 
Archival tumour 
sample  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.2 
Paired biopsy 
(optional)  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.3 
Circulating 
tumour cells 
 
Pre  
 
 
 
 
 
 
 
 
Pre  
 
 
 
 
 
 
Pre 2  
Pre 1 
 
 
 
6.8.1.1 
Patient meal 
information 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
6.4.12.4
Subsequent 
cancer therapy 
  
  
  
  
 
  
  
  
  
    
  
  
  
  
  
  
  
    
  
 
  
X 
X 
5.6 
Concomitant 
medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Adverse events 
X 
 
  
  
 
  
  
  
  
    
  
  
  
  
  
  
  
    
  
 
  
  
 
6.4.3 
 
1.  
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1).  
2. 
Circulating tumour cell samples will be collected on Cycle 3 Week 1 Day 1 and then only at 12-weekly assessments thereafter (see footnote 1 above). 
 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
25(79) 
Reason for Amendment:  
Revision to reflect Part A assessments only - Please refer to amendment rationale number 4. 
Addition of a ’12 weekly’ column followed feedback received from study sites that delineation of evaluations between  those to be 
conducted at the start of each cycle from Cycle 3 onwards and those to be conducted at 12-weekly intervals from baseline, was 
insufficiently clear in the original protocol versions.       
Section of protocol affected: 
Section 3.1.4 Assessment Schedule 
Additional figure: 
Note: The following table represents patient assessments applicable to Part B of the study only.  This is a new entry associated with 
a revision to original figures 6 and 7 to represent patient assessments applicable to Part A only. 
 Figure 8 
Part B Schedules 1 and 2.  AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off and 2 days on 5 days 
off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
12 weekly 
 
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
1 
2 
3 
1 
 
 
 
 
 
Week Day  ĺ            -28 to 0 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ
 
 
 
 
 
ActivityĻ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent - 
PIK3CA screen  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4  /  
5.2.1 
PIK3CA mutation testing1  X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
26(79) 
 Figure 8 
Part B Schedules 1 and 2.  AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off and 2 days on 5 days 
off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
12 weekly 
 
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
1 
2 
3 
1 
 
 
 
 
 
Week Day  ĺ            -28 to 0 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ
 
 
 
 
 
Informed consent - study X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Demography& baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Previous/concomitant 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Previous cancer therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Inclusion / exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
Physical examination 
X 
Pre  
Pre  
 
 
Pre  
 
 
 
 
Pre  
 
X 
X 
 
6.4.6 
Height and weight 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
6.4.7 
WHO performance status X 
Pre X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
6.4.8 
Vital signs 
X 
Pre Pre 
1h 
2h 
6h 
Pre  
Pre  
Pre  
Post  
Post  
X 
 
 
X 
X 
 
6.4.11 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
27(79) 
 Figure 8 
Part B Schedules 1 and 2.  AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off and 2 days on 5 days 
off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
12 weekly 
 
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
1 
2 
3 
1 
 
 
 
 
 
Week Day  ĺ            -28 to 0 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ
 
 
 
 
 
12-lead ECG 
X 
Pre Pre 
1h 
2h 
6h 
Pre  
 
 
Post  
 
 
 
 
X 
 
 
X 
X 
 
6.4.9 
MUGA / Echocardiogram X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
X 
 
6.4.10 
Haematology, Clinical 
chemistry Urinalysis 
X 
Pre Pre 
 
Pre 
 
Pre 
 
Pre 
Pre  
Pre  
 
Pre  
X 
X 
 
6.4.5 
Glycosylated 
haemoglobin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
X 
X 
 
6.4.12.2 
Lipids  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
X 
 
6.4.12.1 
Glucose, insulin, 
 
Pre Pre 
2h 
4h 
6h 
8h 
 
Pre 
2h 
4h 
 
Pre 
2h 
4h 
 
Pre 
2h 
4h 
 
 
 
 
 
Pre 
2-
4h 
 
 
 
X 
 
6.4.12.3 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
6.4.5 
Paclitaxel PK blood 
samples 
 
Pre 
2h 
4h 
8h 
Pre 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
28(79) 
 Figure 8 
Part B Schedules 1 and 2.  AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off and 2 days on 5 days 
off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
12 weekly 
 
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
1 
2 
3 
1 
 
 
 
 
 
Week Day  ĺ            -28 to 0 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ
 
 
 
 
 
AZD5363 PK blood 
samples 
 
 
Pre 
2h 
4h 
8h 
 
Pre 
 
Pre 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2 
Pharmacodynamic blood 
samples 
 
Pre Pre 
2h 
4h 
8h 
 
 
 
Pre 
4h 
Pre  
 
 
 
 
X 
 
 
 
X 
 
6.7.1 
Exploratory biomarker 
blood samples (optional) 
X 
 
Pre 
 
 
 
 
Pre  
 
 
 
 
X 
 
 
 
X 
 
6.8.1.5 
Exploratory biomarker 
hair samples (optional) 
 
 
Pre 
4h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.4 
Pharmacogenetics 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.1 
RECIST Tumour 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
 
6.3.1 
Archival tumour sample  X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.2 
Paired biopsy (optional)  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
6.8.1.3 
Circulating tumour cells 
 
Pre  
 
 
 
 
Pre  
 
 
 
 
Pre 3  
Pre 2 
 
 
 
6.8.1.1 
Patient meal information  
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
6.4.12.4 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
29(79) 
 Figure 8 
Part B Schedules 1 and 2.  AZD5363/placebo – Intermittent Dosing: 4 days on 3 days off and 2 days on 5 days 
off  
Cycle ĺ 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
onward
12 weekly 
 
Pac’xel 
Discont.
AZD5363
Discont. 
28-day 
follow-up
Details in 
Section: 
Week ĺ 
 
1 
2 
3 
1 
2 
3 
1 
 
 
 
 
 
Week Day  ĺ            -28 to 0 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
 
 
 
 
 
Paclitaxel dosing  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xĺ
 
 
 
 
 
 
AZD5363 dosing  
 
 
X 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ 
 
Xĺ
 
 
 
 
 
QoL questionnaires  
X 
Pre  
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
X 
 
6.5.1 
Survival status4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
6.2.3.4 
Subsequent cancer 
therapy4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
X 
X4 
5.6 
Concomitant medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Adverse events 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
6.4.3 
 
1.  
Note: PIK3CA mutation testing results is required for patient stratification and randomisation. The blood sample for PIK3CA mutation testing should 
therefore be sent to the central laboratory as soon as possible after consent.  If a patient requires urgent chemotherapy, a patient may be stratified 
/randomised before the PIK3CA result is available provided that the blood sample has been received at the central laboratory.  Please refer to section 5.2. 
2. 
RECIST, MUGA/Echo, CTCs, Glycosylated haemoglobin, lipids and QoL to be conducted every 12 weeks from start of treatment (Cycle 1 Day 1). 
Patients will continue to undergo RECIST assessments after cessation of study therapies up to disease progression or withdrawal of consent.   
3. 
Circulating tumour cell samples will be collected on Cycle 3 Week 1 Day 1 and then only at 12-weekly assessments thereafter (see footnote 2 above). 
4. 
Survival status and subsequent cancer therapies will be determined at the 28 day follow-up visit and at 12-weekly intervals thereafter.  These visits 
suggested to coincide with RECIST assessments up to disease progression, and at 12-weekly intervals thereafter to death or withdrawal.  
Reason for Amendment:  
Please refer to amendment rationale number 4.


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
30(79) 
Section of protocol affected: 
Section 4.1 
Inclusion criteria / Part B Randomised Expansion. 
Previous text: 
Part B. Randomised Expansion: 
1. 
Patients with histological or cytologic diagnosis of ER+ve breast cancer with 
evidence of relapsed advanced or metastatic disease.  Lesions should not be 
amenable to surgery or radiation of curative intent and must be considered unlikely 
to be rendered eligible for surgery by treatment with paclitaxel in this study. 
2. 
Patients who relapsed more than 12 months after completing adjuvant endocrine 
therapy, or who have not had adjuvant endocrine therapy, must have received prior 
endocrine therapy for advanced or metastatic disease.* 
Patients who relapsed on adjuvant endocrine therapy, or within 12 months of 
completing adjuvant endocrine therapy, may enter the study without prior endocrine 
therapy for advanced or metastatic disease.*  
3. 
Provision of archival tumour sample for PIK3CA mutation testing. 
4. 
Provision of baseline plasma sample for PIK3CA mutation testing. 
5. 
At least one tumour lesion, not previously irradiated, that can be measured 
accurately at baseline as 10 mm in the longest diameter (except lymph nodes 
which must have short axis 15 mm) with computed tomography (CT) or magnetic 
resonance imaging (MRI) which is suitable for accurate repeated measurements. 
* For guidance when evaluating inclusion criteria under item 2 above. 
The following patients would be eligible for inclusion:  
x
Relapsed whilst on adjuvant endocrine therapy 
x
Relapsed <12 months after completing adjuvant endocrine therapy (with or without 
receiving endocrine therapy in the advanced or metastatic setting)  
x
Relapsed >12 months after completing adjuvant endocrine therapy and has 
received endocrine therapy in the advanced or metastatic setting 
The following patients would not be eligible for inclusion:  
x
Adjuvant endocrine therapy- naive 
x
Relapsed >12 months after completing adjuvant endocrine therapy and has not 
received endocrine therapy in the advanced or metastatic setting 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
31(79) 
 
Revised text: 
Part B. Randomised Expansion: 
1. 
Patients with histological or cytologic diagnosis of ER+ve and HER2-ve breast 
cancer with evidence of relapsed advanced or metastatic disease.  Lesions should 
not be amenable to surgery or radiation of curative intent and must be considered 
unlikely to be rendered eligible for surgery by treatment with paclitaxel in this 
study. 
2. 
Blank (inclusion criterion removed)  Patients who relapsed more than 12 months 
after completing adjuvant endocrine therapy, or who have not had adjuvant 
endocrine therapy, must have received prior endocrine therapy for advanced or 
metastatic disease.* 
Patients who relapsed on adjuvant endocrine therapy, or within 12 months of completing 
adjuvant endocrine therapy, may enter the study without prior endocrine therapy for 
advanced or metastatic disease.*  
3. 
Provision of archival tumour sample for PIK3CA mutation testing. 
4. 
Provision of baseline plasma sample for PIK3CA mutation testing. 
5. 
At least one tumour lesion, not previously irradiated, that can be measured 
accurately at baseline as 10 mm in the longest diameter (except lymph nodes 
which must have short axis 15 mm) with computed tomography (CT) or magnetic 
resonance imaging (MRI) which is suitable for accurate repeated measurements. 
* For guidance when evaluating inclusion criteria under item 2 above. 
The following patients would be eligible for inclusion:  
x
Relapsed whilst on adjuvant endocrine therapy 
x
Relapsed <12 months after completing adjuvant endocrine therapy (with or without 
receiving endocrine therapy in the advanced or metastatic setting)  
x
Relapsed >12 months after completing adjuvant endocrine therapy and has received 
endocrine therapy in the advanced or metastatic setting 
The following patients would not be eligible for inclusion:  
x
Adjuvant endocrine therapy  naive 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
32(79) 
x
Relapsed >12 months after completing adjuvant endocrine therapy and has not 
received endocrine therapy in the advanced or metastatic setting 
Reason for Amendment:  
Please refer to amendment rationale number 1. 
Section of protocol affected: 
Section 4.2 
Exclusion criteria (criterion 9) 
Previous text: 
9. 
Clinically significant abnormalities of glucose metabolism as defined by any of the 
following: 

Diagnosis of diabetes mellitus type I or II (irrespective of management). 

Glycosylated haemoglobin (HbA1C) 8.0% at screening (64 mmol/mol) 
(conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-
HbA1C (%) – 2.15] x 10.929) 

Fasting Plasma Glucose   7.0mmol/L (126 mg/dL) at screening. Fasting is 
defined as no caloric intake for at least 8 hours. 
Revised text: 
9. 
Clinically significant abnormalities of glucose metabolism as defined by any of the 
following including diagnosis of diabetes mellitus type I or II (irrespective of 
management), defined according to the American Diabetes Association 
Guidelines 2014 (ADA 2014) which include the criteria: 
Diagnosis of diabetes mellitus type I or II (irrespective of management). 

Glycosylated haemoglobin (HbA1C) 8.0 6.5% at screening (64 48mmol/mol) 
(conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-
HbA1C (%) – 2.15] x 10.929) 

Fasting Plasma Glucose   7.0mmol/L (126 mg/dL) at screening. Fasting is 
defined as no caloric intake for at least 8 hours. 
Reason for Amendment:  
Further clarity to description of exclusion of patients with type I or II diabetes mellitus.  Re-
alignment of HbA1C limit criterion to conform to current American Diabetes Association 
Guidelines for definition of diabetes, and as adopted by the European Diabetes Association. 
 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
33(79) 
Section of protocol affected: 
Section 5.2.1 Procedure for identification of tumour PIK3CA mutation status and 
stratification. 
Previous text: 
Determination of PIK3CA mutation status 
Blood (for cfDNA) and most recent archival tumour samples should be provided at screening 
for determination of  PIK3CA mutation status (see section 6.2.2) 
Where possible, samples should be collected no later than two weeks prior to intended first 
dosing date.  Samples will be analysed by Quintiles on behalf of AstraZeneca and the results 
reported to the study site within 7-14 days of transfer.  
Patients will be designated as:‘PIK3CA mutation positive’ or ‘PIK3CA mutation not detected’. 
Where a sample cannot be analysed, or the analysis is flawed/indeterminate, a status of 
‘unknown’ will be reported.  The results from both the blood and tumour analyses will be 
utilised to derive a single ‘defined’ PIK3CA mutation status for each patient with reference to 
the algorithm below.  
Part A. Safety Run-In: Defined PIK3CA mutation status is not a requirement for 
commencement of treatment, but should be recorded prior to completion of Cycle 1. 
Part B. Randomised Expansion: Defined PIK3CA mutation status is required prior to 
commencement of treatment for stratification of patients to PIK3CA mutation-positive and 
mutation–not detected groups (see ‘Patient stratification by PIK3CA mutation status’ below).  
If it is not possible to obtain one, or both, sample types at screening, the missing sample(s) 
must be provided no later than the end of Cycle 1. 
 
 
Sample type - Tissue 
 
PIK3CA mutation 
resultĺĻ 
Positive (+ve) 
Not detected 
(ND) 
Unknown / 
unavailable (U) 
Positive (+ve) 
+ve 
+ve 
+ve 
Not detected (ND) 
+ve 
ND 
ND 
Sample 
type - 
Blood 
Unknown (U) 
+ve 
ND 
U 
 
Note: 
Pre-existing PIK3CA mutation status, where generated from a relevant tumour 
sample as part of local clinical practice, will also be recorded. These data may be 
utilised, if necessary, on study completion to assist in confirmation of mutation 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
34(79) 
status where there is a discrepancy between blood and tumour PIK3CA mutation 
results from the central analysis.  
Where an archival tumour sample cannot be provided in sufficient time for analysis 
by Quintiles to support determination of defined PIK3CA mutation status (Part B) 
or the result is ‘unknown’ (Part A or B), mutation status derived from a prior 
locally-conducted analysis may be utilised.  This, however, will only be acceptable 
where the analytical methodology/kit has been approved in advance by 
AstraZeneca. 
Patient stratification by PIK3CA mutation status (Part B) 
Patients will be allocated to ‘PIK3CA mutation positive’ or ‘PIK3CA mutation not detected’ 
strata prior to randomisation.  
Patients assigned a PIK3CA mutation status of ‘Unknown’ will not be eligible to participate in 
Part B. In cases where an archival tumour sample is not received in time to be analysed by the 
central laboratory during screening, defined status may be derived from the blood sample 
alone, or it may be applicable to utilise the status from a prior, locally-conducted tumour 
analysis, see above. 
If a patient is initially stratified to the ‘Not detected’ stratum based upon a blood sample alone, 
(or blood sample plus locally–conducted tumour analysis) and a ‘positive’ central tumour 
sample analysis is received after stratification, the site will contact the IVRS/IWRS Customer 
Care department by telephone or using the web to provide notification of this new 
information.  IVRS/IWRS records will be revised to show a corrected PIK3CA mutation status 
of ‘Positive’.   
In the event of any correction to a patient’s allocated mutation status post-stratification: 
x
there will be no revision to the patient stratum allocation or numbering in 
RAVE. 
x
AZ will coordinate with IVRS/IWRS to ensure that the allocation of patient 
places per stratum is adjusted, as necessaary, to ensure that the minimum 
number required in each will be achieved 
x
for final data analysis the corrected mutation status will be used to assign the 
patient to the relevant stratum.  
 
Revised text: 
Determination of PIK3CA mutation status 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
35(79) 
Blood (for cfDNA) and most recent archival tumour samples should be provided at screening 
for determination of  PIK3CA mutation status (see section 6.2.2).  For Part B, in the event 
that recruitment to one stratum is completed before the other, it will be necessary to pre-
screen patients for mutation status applicable to the remaining open stratum (see section 
5.2.2 and Figure 9). 
Where possible, samples should be collected no later than two weeks prior to intended first 
dosing date.  Samples will be analysed by Quintiles on behalf of AstraZeneca and the results 
reported to the study site within 7-14 days of transfer.  
Patients will be designated as:‘PIK3CA mutation positive’ or ‘PIK3CA mutation not detected’. 
Where a sample cannot be analysed, or the analysis is flawed/indeterminate, a status of 
‘unknown’ will be reported.  The results from both the blood and tumour analyses will be 
utilised to derive a single ‘defined’ PIK3CA mutation status for each patient with reference to 
the following algorithm below.  
 
 
Sample type - Tissue 
 
PIK3CA mutation 
resultĺĻ 
Positive (+ve) 
Not detected 
(ND) 
Unknown / 
unavailable (U) 
Positive (+ve) 
+ve 
+ve 
+ve 
Not detected (ND) 
+ve 
ND 
ND 
Sample 
type - 
Blood 
Unknown (U) 
+ve 
ND 
U 
 
Part A. Safety Run-In: Defined PIK3CA mutation status is not a requirement for 
commencement of treatment, but should be recorded prior to completion of Cycle 1. 
Part B. Randomised Expansion: Defined PIK3CA mutation status is required prior to 
commencement of treatment for stratification of patients to PIK3CA mutation positive and 
mutation not detected groups (see ‘Patient stratification by PIK3CA mutation status’ below).  
If it is not possible to obtain one, or both, sample types at screening, the missing sample(s) 
must be provided no later than the end of Cycle 1. 
 
 
Sample type  Tissue 
 
PIK3CA mutation 
resultĺĻ 
Positive (+ve) 
Not detected 
(ND) 
Unknown / 
unavailable (U) 
Positive (+ve) 
+ve 
+ve 
+ve 
Not detected (ND) 
+ve 
ND 
ND 
Sample 
type  
Blood 
Unknown (U) 
+ve 
ND 
U 
 
Note: 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
36(79) 
Pre existing PIK3CA mutation status, where generated from a relevant tumour 
sample as part of local clinical practice, will also be recorded. These data may be 
utilised, if necessary, on study completion to assist in confirmation of mutation 
status where there is a discrepancy between blood and tumour PIK3CA mutation 
results from the central analysis.  
Where an archival tumour sample cannot be provided in sufficient time for analysis 
by Quintiles to support determination of defined PIK3CA mutation status (Part B) 
or the result is ‘unknown’ (Part A or B), mutation status derived from a prior 
locally conducted analysis may be utilised.  This, however, will only be acceptable 
where the analytical methodology/kit has been approved in advance by 
AstraZeneca. 
Patients must be stratified to either the PIK3CA mutation-positive or mutation–not 
detected arm prior to randomisation and commencement of treatment.  
All efforts should be made to provide plasma and tumour tissue samples for PIK3CA 
mutation analysis during the screening period*.  However, patients may be stratified in 
the absence of mutation status results from one or both sample types (see below) where 
the investigator considers this necessary to minimise delay to commencement of 
standard treatment with paclitaxel.  Any samples not collected during screening must be 
provided for analysis no later than the end of Cycle 1. 
Investigators may register a patient’s PIK3CA tumour mutation status via IVRS/IWRS 
to enable stratification and randomisation - at a time appropriate to start of study 
therapy.  PIK3CA tumour mutation status will be identified and stratification may be 
conducted under the following conditions, dependent upon availability of PIK3CA 
mutation results from either mandated central laboratory (Quintiles) analysis or pre-
existing local tumour tissue analysis (please also refer to Figure 9): 
Patient stratification by PIK3CA mutation status (Part B) 
Patients will be allocated to ‘PIK3CA mutation positive’ or ‘PIK3CA mutation not detected’ 
strata prior to randomisation.  
Patients assigned a PIK3CA mutation status of ‘Unknown’ will not be eligible to participate in 
Part B. In cases where an archival tumour sample is not received in time to be analysed by the 
central laboratory during screening, defined status may be derived from the blood sample 
alone, or it may be applicable to utilise the status from a prior, locally conducted tumour 
analysis, see above. 
Patient will be identified as PIK3CA ‘positive’ in either/both of the following cases:  

Available centrally analysed plasma and/or tumour tissue sample results are 
PIK3CA ‘positive’ (Note: where both sample types have been sent for central 
analysis, stratification may be based on the first result to be returned). 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
37(79) 

Locally analysed plasma and/or tumour tissue result is positive for any 
PIK3CA mutation.  
Patient will be identified as PIK3CA ‘not detected’ in either of the following cases**:  

Available centrally analysed plasma and tumour tissue sample results are 
PIK3CA ‘not detected’ and any locally analysed tumour tissue sample result is 
negative for PIK3CA mutation.   

Centrally analysed plasma or tumour tissue sample results are awaited, but not 
yet available, and no locally analysed tumour tissue sample results are 
available, at the planned time of stratification.  In this case the patient may be 
stratified to the ‘not detected’ group by default.  Note - at least the plasma 
sample must have been received by the central laboratory before the patient 
may be stratified/randomised. 
* In the event that only one stratum is open to recruitment, see section 5.2.2 and Figure 9 
scenario 2, patients will be separately evaluated for PIK3CA mutation status prior to 
screening to determine eligibility.  In such a case, the status derived for eligible patients 
will be carried forward to be recorded under the screening assessment. 
**If  Where a patient is initially stratified to the ‘Not detected’ stratum based upon a blood 
sample alone, (or blood sample plus locally–conducted tumour analysis) in the absence of 
one or more sample analyses, and a ‘positive’ central tumour sample analysis result is 
received after stratification, the site will contact the IVRS/IWRS Customer Care department 
by telephone or using the web to provide notification of this new information.  IVRS/IWRS 
records will be revised to show a corrected PIK3CA mutation status of ‘Positive’.   
In the event of any correction to a patient’s allocated mutation status post-stratification: 
x
there will be no revision to the patient stratum allocation or numbering in RAVE. 
x
AZ will coordinate with IVRS/IWRS to ensure that the allocation of patient places per 
stratum is adjusted, as necessary, to ensure that the minimum number required and 
radomisation balance within each will be achieved. 
x
for final data analysis the corrected mutation status will be used to assign the patient to 
the relevant stratum. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
38(79) 
 
PIK3CA mutation 
results status ĺ 
Report via 
IVRS/IWRS: ĺ  
Patient completed screening and is scheduled to start 
study treatment 
Any central or local 
result = ’Positive’ 
Available central / 
local results = ’Not 
detected’/’negative’ 
No results available 
Report mutation 
status as ’Positive’ 
Report mutation 
status as ’Not 
detected’ 
When all central 
results available - 
No further action 
Report change of 
status via  IVRS/IWRS
If confirmed status = 
’Positive’ 
If confirmed status = 
’Not detected’ 
No further action 
 




Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
40(79) 
consent for PIK3CA tumour mutation pre-screening assessment will be provided for 
this.  Those patients whose mutation status aligns with the actively recruiting stratum 
will be invited to consent to participate in the BEECH study.  Further mutation status 
analysis during screening will not be required in these cases see Figure 9. 
Reason for Amendment:  
Identification of scenarios under which one Part B stratum could close before the other, and 
notification of the requirement for patients then to be pre-screened for PIK3CA tumour 
mutation status to determine eligibility to the open stratum.  Please refer to amendment 
rationale number 2. 
With reference to the AZDMC, please refer to amendment rationale number 5. 
Section of protocol affected: 
Section 5.5.3 Doses and treatment regimens / Treatment Schedules (third paragrph note) 
Previous text: 
Note:  
AZD5363/placebo should not be taken on any week that the paclitaxel infusion is not 
administered – either due to a scheduled off-drug week or unscheduled omission or 
delay.  Where paclitaxel is ceased entirely, AZD5363/placebo may be continued on a 
weekly schedule at the investigator’s discretion. 
Revised text: 
Note:  
AZD5363/placebo should not be taken on any week that the paclitaxel infusion is not 
administered – either due to a scheduled off-drug week or unscheduled omission or 
delay.  Where paclitaxel is ceased entirely, it is recommended that AZD5363/placebo 
may be is continued on a weekly schedule at the investigator’s discretion (see section 
5.5.4). 
Reason for Amendment:  
Following Investigator comments regarding preferred clinical management of patients 
remaining on AZD5363/placebo after having ceased paclitaxel.  This change provides further 
emphasis upon a recommendation to continue such patients under a weekly AZD5363/placebo 
treatment schedule – i.e. 4 weeks per cycle rather than 3 weeks on-treatment followed by 1 
week-off.   
 
Section of protocol affected: 
Section 5.5.4 Dose modifications / AZD5363/placebo 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
41(79) 
Additional text (new 3rd paragraph): 
If paclitaxel is permanently ceased, and the investigator elects to continue provision of 
AZD5363/placebo, it is recommended that the 3 weeks-on, 1 week-off dosing schedule is 
changed to a weekly dosing schedule – i.e AZD5363/placebo may be taken on every week 
during a cycle, with no requirement for an off-treatment week.  This change remains at 
the discretion of the investigator. Please note that irrespective of any change to the 
overall inter-weekly treatment schedule, the intra-weekly schedule (eg 4 days-on, 3 days-
off or 2 days-on, 5 days-off) should be retained. 
Reason for Amendment:  
Please see rationale provided for changes to Section 5.5.3 above. 
 
Section of protocol affected: 
Section 5.10.2 Safety Review Committee and Dose Escalation Process  
Additional text (new final paragraph): 
The SRC will continue to evaluate Part A patients after the dose decision for the last 
cohort has been made, up to a point at which all patients have completed three treatment 
cycles or have withdrawn from the study prior to the end of Cycle 3.  No further routine 
evaluations will then be performed by the Part A SRC; although members may be 
requested to attend ad-hoc meetings for discussion of specific safety issues that may 
arise. 
Reason for Amendment:  
Following agreement with the Part A Safety Review Committee, this addition provides clarity 
regarding the processes and timelines for their evaluation of patient safety up to and following 
completion of Part A recruitment. 
 
Section of protocol affected: 
Section 5.11.2 Safety Review Committee (Part B) 
Previous text: 
During the Part B Randomised Phase of the study, an independent SRC will monitor safety 
and tolerability in the study by means of coded (A vs B) reviews of safety data at 
approximately 3-monthly intervals.  Based on this coded review, the independent SRC may 
recommend one of: a) continuation of recruitment without change; or b) an amendment to the 
dose and schedule of AZD5363/placebo eg, from a 4 days on, 3 days off schedule to a 2 days 
on, 5 days off schedule or to continue at the same schedule at a reduced dose of 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
42(79) 
AZD5363/placebo; or c) termination of recruitment on the grounds that the combination is 
considered to be insufficiently well tolerated. 
The independent SRC will consist of: 
x
AstraZeneca Physician, independent of the AZD5363 programme, who will chair the 
committee - or delegate 
x
AstraZeneca Global Safety Physician, independent of the AZD5363 programme. 
x
Two external Investigators independent of the study 
The independent SRC Remit document for this study will define the exact membership and 
who should be present for decisions to be made. 
The first review of coded safety data will occur when data are available from approximately 
15 patients who have received at least 28 days of treatment.  
In the event that AstraZeneca adopts the recommendation to explore an alternative dose or 
schedule, any patients already recruited to the study at this point will continue to receive 
AZD5363/placebo as per their current dose and schedule provided that they are tolerating the 
treatment and the investigator believes they are gaining benefit.  Alternatively, the investigator 
may elect to change the dose/schedule of patients recruited prior to the dose change to the new 
dose/schedule.  After a change to the schedule of AZD5363/placebo, approximately 100 new 
patients will be recruited to receive AZD5363/placebo as per the new schedule. There will be 
no more than 2 changes made to dose or schedule during the randomised phase of the study. 
Revised text: 
During the Part B Randomised Phase of the study, an independent SRC (ISRC) will monitor 
safety and tolerability in the study by means of coded (A vs B) reviews of safety data at 
approximately 3 to 6-monthly intervals.  Based on this coded review, the independent ISRC 
may recommend one of: a) continuation of recruitment without change; or b) an amendment 
to the dose and schedule of AZD5363/placebo eg, from a 4 days on, 3 days off schedule to a 2 
days on, 5 days off schedule or to continue at the same schedule at a reduced dose of 
AZD5363/placebo; or c) termination of recruitment on the grounds that the combination is 
considered to be insufficiently well tolerated. 
The independent ISRC will consist of: 
x
AstraZeneca Physician, independent of the AZD5363 programme, who will chair the 
committee  or delegate 
x
AstraZeneca Global Safety Physician, independent of the AZD5363 programme. 
x
Two external Investigators independent of the study 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
43(79) 
The independent ISRC Remit document for this study will define the exact membership and 
who should be present for decisions to be made. 
The first review of coded safety data will occur when data are available from approximately 
15 patients who have received at least 28 days of treatment.  
In the event that AstraZeneca adopts the recommendation to explore an alternative dose or 
schedule, any patients already recruited to the study at this point will continue to receive 
AZD5363/placebo as per their current dose and schedule provided that they are tolerating the 
treatment and the investigator believes they are gaining benefit.  Alternatively, the investigator 
may elect to change the dose/schedule of patients recruited prior to the dose change to the new 
dose/schedule.  After a change to the schedule of AZD5363/placebo, approximately 100 new 
patients will be recruited to receive AZD5363/placebo as per the new schedule. There will be 
no more than 2 changes made to dose or schedule during the randomised phase of the study 
Reason for Amendment:  
Redefinition of frequency of ISRC meetings from approximately 3 monthly to 3-6 monthly.  
This change was made to allow flexibility of timing of ISRC reviews in response to varying 
patient recruitment rates at differing stages during conduct of Part B.   
Removal of option for independent AZ Physician chair to appoint a delegate to attend ISRC 
meetings.  This change was made to correspond with guidance incorporated in to the standard 
AZ SRC remit parameters. 
 
Section of protocol affected: 
Section 6.2.1 Enrolment procedures 
Previous text: 
Written informed consent must be obtained prior to conduct of any study specific assessments. 
Procedures that are part of standard care may occur before informed consent is obtained. 
A list of procedures and assessments described in the Study Plans (Figure 6: Intermittent 
dosing 2-on 5-off; Figure 7: Intermittent dosing 4-on 3-off) for the screening visit must be 
completed within 4 weeks (-28 days) of enrolment. At screening, consenting patients will be 
assessed to ensure that they meet inclusion and exclusion criteria (Sections 4.1 and 4.2). 
Demographic data and other characteristics will be recorded at screening and will include: 
date of birth, gender, race, menstrual status and smoking history. 
Part B. Randomised Expansion: Each patient’s PIK3CA mutation status must be determined at 
screening from a blood and archival tumour sample to enable the patient to be stratified as 
PIK3CA mutation positive or not detected prior to randomisation (see section 5.2.1): 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
44(79) 
x
Patients will be stratified to the PIK3CA mutation positive arm where either one of the 
sample-type analyses is positive.  Patients will be stratified to the not-detected arm 
where both sample type analyses are negative. 
x
It is requested that all efforts are made to ensure that archival tumour tissue is provided 
for this stratification analysis.  Where tissue cannot be made available in a timely 
manner, PIK3CA mutation stratification may be conducted on the blood sample 
analysis alone.  In this event, tumour tissue must be provided for retrospective PIK3CA 
mutation analysis prior to completion of treatment Cycle 1.   
x
Where a patient has been assigned to the not-detected arm from blood sample analysis 
alone but the retrospective tumour tissue analysis is PIK3CA mutation positive - the 
patient will remain stratified to the not-detected arm.  The discrepancy will be noted 
and an additional patient allocation may be made for this arm.   
x
In the event that one stratification arm (PIK3CA mutation positive or not-detected) 
completes recruitment before the other, new candidate patients will be requested to 
provide separate, initial, informed consent to obtain a blood and/or tumour tissue 
sample to screen for PIK3CA mutation status.  Patients with status appropriate for 
entry to the open stratification arm will be invited to provide informed consent for 
entry to the study. 
Revised text: 
Written informed consent must be obtained prior to conduct of any study specific assessments. 
Procedures that are part of standard care may occur before informed consent is obtained. 
A list of procedures and assessments described in the Study Plans (Part A - Figure 6: 
Intermittent dosing 2-on 5-off; Figure 7: Intermittent dosing 4-on 3-off, Part B – Figure 8) 
for the screening visit must be completed within 4 weeks (-28 days) of enrolment. At 
screening, consenting patients will be assessed to ensure that they meet inclusion and 
exclusion criteria (Sections 4.1 and 4.2). 
Demographic data and other characteristics will be recorded at screening and will include: 
date of birth, gender, race, menstrual status and smoking history. 
Part B. Randomised Expansion: Each patient’s PIK3CA mutation status must should be 
determined at screening from a blood and archival tumour sample to enable the patient to be 
stratified as PIK3CA mutation positive or not detected prior to randomisation (see sections 
5.2.1 and 5.2.2): 
x
Patients will be stratified to the PIK3CA mutation positive arm where either one of the 
sample type analyses is positive.  Patients will be stratified to the not detected arm 
where both sample type analyses are negative. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
45(79) 
x
It is requested that all efforts are made to ensure that archival tumour tissue is provided 
for this stratification analysis.  Where tissue cannot be made available in a timely 
manner, PIK3CA mutation stratification may be conducted on the blood sample 
analysis alone.  In this event, tumour tissue must be provided for retrospective PIK3CA 
mutation analysis prior to completion of treatment Cycle 1.   
x
Where a patient has been assigned to the not detected arm from blood sample analysis 
alone but the retrospective tumour tissue analysis is PIK3CA mutation positive  the 
patient will remain stratified to the not detected arm.  The discrepancy will be noted 
and an additional patient allocation may be made for this arm.   
In the event that one stratification arm (PIK3CA mutation positive or not detected) completes 
recruitment before the other, new candidate patients will be requested to provide separate, 
initial, informed consent to obtain a blood and/or tumour tissue sample to screen for PIK3CA 
mutation status.  Patients with status appropriate for entry to the open stratification arm will be 
invited to provide informed consent for entry to the study. 
Reason for Amendment:  
Addition of new Figure 8, a Part B-specific assessment schedule, reflects changes to the 
schedules of assessments previously described in Section 3.1.4 in relation to amendment 
rationale number 4.  
Revisions to the subset ‘Part B. Randomised Expansion’ reflect changes and additions to 
Sections 5.2.1 and 5.2.2 in relation to amendment rationale number 2.  Deletion of text reflects 
that additional information, now provided in Sections 5.2.1 and 5.2.2, rendered this text, in 
Section 6.2.1, unnecessary.  
 
Section of protocol affected: 
Section 6.2.2 PIK3CA Mutation Status   
Previous text: 
Patient response to treatment will be assessed against the tumour PIK3CA mutation status to 
determine whether the mutation confers any increased tumour sensitivity to AZD5363. 
Blood and most recent archival tumour samples will be collected at screening (see Figure 6 
and Figure 7) with reference to the criteria and restrictions detailed in section 5.2.1.  The 
PIK3CA mutation assay(s) will genotype for a set of mutations that will cover the majority of, 
but not all, mutations in the PIK3CA gene that have been thus far identified in breast cancer 
patients.  Therefore, there may be patients carrying either a rare mutation, not included in the 
assay(s) used, or who have a level of mutation in cfDNA or tumour tissue DNA beyond the 
range of sensitivity of the selected assay(s).  In this case, their mutation will not be identified 
under the protocolled testing.  In acknowledgment of this, patients who are shown not to be 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
46(79) 
‘mutation positive’ in either cfDNA or tumour tissue DNA will be categorised as ‘mutation 
not detected’, rather than a more definitive ‘mutation negative’. 
During Study Part B, PIK3CA mutation status will be utilised to stratify patients to ‘positive’ 
and ‘not detected’ arms (see section 5.2.1). 
Revised text: 
Patient response to treatment will be assessed against the tumour PIK3CA mutation status to 
determine whether the mutation confers any increased tumour sensitivity to AZD5363. 
A 10ml blood sample and most recent archival tumour samples will be collected at screening 
(see Figure 6, and Figure 7 and Figure 8) with reference to the criteria and restrictions 
detailed in section 5.2.1.  The PIK3CA mutation assay(s) will genotype for a set of mutations 
that will cover the majority of, but not all, mutations in the PIK3CA gene that have been thus 
far identified in breast cancer patients.  Therefore, there may be patients carrying either a rare 
mutation, not included in the assay(s) used, or who have a level of mutation in cfDNA or 
tumour tissue DNA beyond the range of sensitivity of the selected assay(s).  In this case, their 
mutation will not be identified under the protocolled testing.  In acknowledgment of this, 
patients who are shown not to be ‘mutation positive’ in either cfDNA or tumour tissue DNA 
will be categorised as ‘mutation not detected’, rather than a more definitive ‘mutation 
negative’. 
During Study Part B, PIK3CA mutation status will be utilised to stratify patients to ‘positive’ 
and ‘not detected’ arms (see sections 5.2.1 and 5.2.2 and Figure 9). 
An optional 20mL blood sample will also be taken, subject to separate patient consent, to 
be utilised for evaluation of innovative PIK3CA mutation analysis platforms.  The 
purpose of this evaluation is to evaluate new analytical options for enhanced specificity, 
accuracy and/or increased speed of sample processing. 
Reason for Amendment:  
Clarification of blood sample volume and inclusion of an optional 20ml sample for evaluation 
of PIK3CA analytical platforms.  This change was made to allow for collection of a voluntary 
blood sample to be used to assess new analytical technologies that may enable more rapid 
and/or more accurate measurement of PIK3CA tumour mutations.  Further clarity is given 
regarding volumes to differentiate between this optional sample and the mandatory blood 
sample for screening PIK3CA analysis. 
 
Section of protocol affected: 
Section 6.2.3 Follow-up procedures 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
47(79) 
Previous text: 
Patients will be followed up as detailed below unless prior withdrawal from the study: 
Part A. Safety Run-in:  Patients will be followed to discontinuation of study drug / completion 
of the 28-day safety follow-up.  
Part B. Randomised Expansion:  Patients will be followed to death. 
Revised text: 
Patients will be followed up as detailed below unless prior withdrawal from the study: 
Part A. Safety Run-in:  Patients will be followed to discontinuation of study drug / completion 
of the 28-day safety follow-up.  
Part B. Randomised Expansion:  Patients will be followed to death, or to cessation of the 
study. 
Reason for Amendment:  
Specification of limitation of follow-up period for study Part B.  
 
Section of protocol affected: 
6.3.1 Tumour assessments (1st paragraph) 
Previous text: 
RECIST 1.1 criteria will be used to assess patient response to treatment by determining 
change in tumour size at 12 weeks, percentage of patients without progressive disease, at 12 
weeks, overall response rate (ORR), BoR, DoR and PFS. The RECIST 1.1 guidelines for 
measurable, non-measurable, target, and non-target lesions (NTL) and the objective tumour 
response criteria (CR, PR, SD or progressive disease [PD]) are presented in Appendix F. 
Revised text: 
RECIST 1.1 criteria will be used to assess patient response to treatment by determining 
change in tumour size at 12 weeks, percentage of patients without progressive disease, at 12 
weeks, overall response rate (ORR), BoR, DRR, DoR and PFS. The RECIST 1.1 guidelines 
for measurable, non-measurable, target, and non-target lesions (NTL) and the objective 
tumour response criteria (CR, PR, SD or progressive disease [PD]) are presented in Appendix 
F. 
Reason for Amendment:  
Please refer to amendment rationale number 3. 
 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
48(79) 
Section of protocol affected: 
6.4.5 Laboratory safety assessment 
Previous text: 
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the Study Plan (see Figure 6 and Figure 7) at the 
following timepoints: 
x
Screening 
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose; Weeks 2, 3 and 4: Day 2 pre-dose. 
2-on 5-off schedule only: Week 1 Day 3 pre-dose 
4-on 3-off schedule only: Week 1 Day 5 pre-dose 
x
Cycle 2: Week 1: Day 2 pre-dose; Weeks 2, 3 and 4: Day 1 pre-dose. 
x
Cycles 3+: Week 1: Day 2 pre-dose up to discontinuation of both study therapies. 
x
Discontinuation of AZD5363/placebo: at any time of the day.   
x
Discontinuation of paclitaxel: at any time of the day.  
x
Urine pregnancy test to be completed at: Screening, Cycle 1 Week 1 Day 1 and on 
discontinuation of study therapies. 
Serum/Plasma glucose to be additionally measured, for evaluation of potential abnormalities 
of glucose metabolism, from samples taken between 2 to 4 hours, and between 4 to 6 hours, 
following receipt of the morning dose of AZD5363 at the following timepoints:  
x
Cycle 1: Week 1: Day 2; Weeks 2, 3 and 4: Day 2. 
2-on 5-off schedule only: Week 1 Day 3  
4-on 3-off schedule only: Week 1 Day 5  
x
Day 2 of every Cycle thereafter up to discontinuation of AZD5363. 
 
Revised text: 
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the Study Plans (see Figure 6, and Figure 7 and Figure 
8) at the following timepoints: 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
49(79) 
x
Screening 
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose; Weeks 2 and 3 and 4: Day 2 pre-
dose. 
Part A only - 2-on 5-off schedule only : Week 1 Day 3 pre-dose; Week 4 Day 
2 pre-dose. 
Part A only - 4-on 3-off schedule only: Week 1 Day 5 pre-dose; Week 4 Day 
2 pre-dose. 
x
Cycle 2: Week 1: Day 2 pre-dose; Weeks 2 and 3 and 4: Day 1 pre-dose. 
Part A only - both schedules: Week 4 Day 1 pre-dose. 
x
Cycles 3+: Week 1: Day 2 pre-dose up to discontinuation of both study therapies. 
x
Discontinuation of AZD5363/placebo: at any time of the day.   
x
Discontinuation of paclitaxel: at any time of the day.  
x
Urine pregnancy test to be completed at: Screening, Cycle 1 Week 1 Day 1 and on 
discontinuation of study therapies. 
Part A only (additional glucose assessments will not be conducted in Part B) - 
Serum/Plasma glucose to be additionally measured, for evaluation of potential abnormalities 
of glucose metabolism, from samples taken between 2 to 4 hours, and between 4 to 6 hours, 
following receipt of the morning dose of AZD5363 at the following timepoints:  
x
Cycle 1: Week 1: Day 2; Weeks 2, 3 and 4: Day 2. 
2-on 5-off schedule only: Week 1 Day 3  
4-on 3-off schedule only: Week 1 Day 5  
x
Day 2 of every Cycle thereafter up to discontinuation of AZD5363. 
 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.4.6 Physical examination 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
50(79) 
Previous text: 
A complete physical examination will include an assessment of the following: general 
appearance, respiratory, cardiovascular, abdomen skin, head and neck (including ears, eyes, 
nose and throat), lymph nodes, thyroid, abdomen, musculo-skeletal (including spine and 
extremities) and neurological systems. 
Physical examinations will be conducted at the times indicated in the Study Plan (see Figure 6 
and Figure 7) at the following timepoints: 
x
Screening. 
x
Cycle 1: Week 1 and 2: Day 1 pre-dose. 
2-on 5-off schedule only: Week 1 Day 3 pre-dose 
4-on 3-off schedule only: Week 1 Day 5 pre-dose 
x
Cycles 2+: Week 1: Day 1 pre-dose. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 
x
Discontinuation of paclitaxel: at any time of the day. 
 
Revised text: 
A complete physical examination will include an assessment of the following: general 
appearance, respiratory, cardiovascular, abdomen skin, head and neck (including ears, eyes, 
nose and throat), lymph nodes, thyroid, abdomen, musculo-skeletal (including spine and 
extremities) and neurological systems. 
Physical examinations will be conducted at the times indicated in the Study Plans (see Figure 
6, and Figure 7 and Figure 8) at the following timepoints: 
x
Screening. 
x
Cycle 1: Week 1 and 2: Day 1 pre-dose. 
Part A only - 2-on 5-off schedule only: Week 1 Day 3 pre-dose 
Part A only - 4-on 3-off schedule only: Week 1 Day 5 pre-dose 
x
Cycles 2+: Week 1: Day 1 pre-dose. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
51(79) 
x
Discontinuation of paclitaxel: at any time of the day. 
 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.4.8 WHO Performance status 
Previous text: 
Performance status will be assessed at the times indicated in the Study Plan (see Figure 6 and 
Figure 7) at the following timepoints (assessment may be conducted at any time of the day 
unless otherwise indicated): 
Part A and Part B: 
x
Screening 
x
Cycle 1: Week 1: Day 1 pre-dose,  
Part B only: 
x
Cycle 1: Week 1 Days 2 and 3; Weeks 2 and 3 Day 1; Week 4 Day 2. 
4-on 3-off schedule only: Week 1 Day 5 
x
Cycle 2: Weeks 1, 2, 3 and 4: Day 1. 
x
Cycles 3+: Week 1: Day 1. 
x
Discontinuation of AZD5363/placebo. 
x
Discontinuation of paclitaxel. 
 
Revised text: 
Performance status will be assessed at the times indicated in the Study Plans (see Figure 6, 
and Figure 7 and Figure 8) at the following timepoints (assessment may be conducted at any 
time of the day unless otherwise indicated): 
Part A and Part B: 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
52(79) 
x
Screening 
x
Cycle 1: Week 1: Day 1 pre-dose,  
Part B only: 
x
Cycle 1: Week 1 Days 2 and 3; Weeks 2 and 3 Day 1; Week 4 Day 2. 
4 on 3 off schedule only: Week 1 Day 5 
x
Cycle 2: Weeks 1, 2, and 3 and 4: Day 1. 
x
Cycles 3+: Week 1: Day 1. 
x
Discontinuation of AZD5363/placebo. 
x
Discontinuation of paclitaxel. 
 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.4.9 Resting ECG 
Previous text: 
ECG measurements will be conducted at the study site or other local institution as applicable.  
At each timepoint, at approximately the same time of day, a standard 12-lead ECG should be 
performed after the patient has been resting in a semi-supine position for at least 5 minutes.  A 
paper speed of 25mm/second, covering at least 6 sequential beats, is recommended. Three 
ECGs per timepoint should be conducted within a 5-minute period. 
ECG measurements should be conducted as indicated in the Study Plan (see Figure 6 and 
Figure 7) at the following timepoints: 
x
Screening. 
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose, 1, 2, 6 and 24 hours post-dose; 
Week 2: Day 1 pre-dose. 
4-on 3-off schedule only: Week1 Day 5 post-dose. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
53(79) 
x
Cycle 2: Week 1: Day 1 post-dose. 
x
Cycles 3+: Week 1: Day 1 at any time of the day.   
x
Discontinuation of AZD5363/placebo: at any time of the day.   
x
Discontinuation of paclitaxel: at any time of the day. 
 
Revised text: 
ECG measurements will be conducted at the study site or other local institution as applicable.  
At each timepoint, at approximately the same time of day, a standard 12-lead ECG should be 
performed after the patient has been resting in a semi-supine position for at least 5 minutes.  A 
paper speed of 25mm/second, covering at least 6 sequential beats, is recommended. Three 
ECGs per timepoint should be conducted within a 5-minute period. 
ECG measurements should be conducted as indicated in the Study Study Plans (see Figure 6, 
and Figure 7 and Figure 8) at the following timepoints: 
x
Screening. 
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose, 1, 2, and 6 and 24 hours post-dose; 
Week 2: Day 1 pre-dose. 
Part A only - Cycle 1: Week 1 Day 3 pre-dose; 4-on 3-off schedule only: 
Cycle 1: Week1 Day 5 post-dose. 
x
Cycle 2: Week 1: Day 1 post-dose. 
x
Cycles 3+: Week 1: Day 1 at any time of the day.   
x
Discontinuation of AZD5363/placebo: at any time of the day.   
x
Discontinuation of paclitaxel: at any time of the day. 
 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.4.10 MUGA scan / Echocardiogram 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
54(79) 
Previous text: 
A MUGA scan or echocardiogram to assess LVEF will be conducted at the times indicated in 
the Study Plans (see Figure 6, and Figure 7) at the following timepoints: 
x
Screening. 
Part A -  4-on 3-off schedule only: Cycle 2: Week 1: Day 1 (±1 week).  
x
Every 12 weeks from baseline thereafter: at any time of the day.  
x
Where clinically indicated.  
x
Discontinuation of AZD5363/placebo: at any time of the day.   
Revised text:  
A MUGA scan or echocardiogram to assess LVEF will be conducted at the times indicated in 
the Study Plans (see Figure 6, and Figure 7 and Figure 8) at the following timepoints: 
x
Screening. 
Part A only -  4-on 3-off schedule only: Cycle 2: Week 1: Day 1 (±1 week).  
x
Every 12 weeks from baseline (Cycle 1, Week 1, day 1) thereafter: at any time of the 
day.  
x
Where clinically indicated.  
x
Discontinuation of AZD5363/placebo: at any time of the day.   
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.4.11  
Vital signs: Pulse and blood pressure 
Previous text: 
Supine blood pressure and pulse rate will be measured after 10 minutes rest. 
Assessments  will be conducted at the times indicated in the Study Plan (see Figure 6 and 
Figure 7) at the following timepoints: 
x
Screening 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
55(79) 
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose; 1, 2, and 6 hours post-dose; Weeks 
2 and 3 Day 1 pre-dose; Week 4 Day 2 pre-dose. 
2-on 5-off schedule only: Week 1 Day 3 post-dose 
4-on 3-off schedule only: Week 1 Day 5 post-dose 
x
Cycle 2: Week 1: Day 1 pre-dose; Weeks 2, 3 and 4: Day 1 post-dose. 
x
Cycles 3+: Week 1: Day 1 at any time of the day. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 
x
Discontinuation of paclitaxel: at any time of the day. 
 
Revised text: 
Supine blood pressure and pulse rate will be measured after 10 minutes rest. 
Assessments  will be conducted at the times indicated in the Study Plans (see Figure 6, and 
Figure 7 and Figure 8) at the following timepoints: 
x
Screening 
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose; 1, 2, and 6 hours post-dose; Weeks 
2 and 3 Day 1 pre-dose; Week 4 Day 2 pre dose. 
Part A only  - 2-on 5-off schedule only: Week 1 Day 3 post-dose, Week 4 Day 
2 pre-dose. 
Part A only  - 4-on 3-off schedule only: Week 1 Day 5 post-dose, Week 4 Day 
2 pre-dose. 
x
Cycle 2: Week 1: Day 1 pre-dose; Weeks 2, and 3 and 4: Day 1 post-dose. 
Part A only – both schedules: Week 4 Day 1 post-dose 
x
Cycles 3+: Week 1: Day 1 at any time of the day. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 
x
Discontinuation of paclitaxel: at any time of the day. 
 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
56(79) 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.4.12.1 
Lipids 
Previous text: 
Blood samples for determination of triglycerides, HDL, LDL and cholesterol will be taken at 
the times indicated in the Study Plan (see Figure 6 and Figure 7) at the following timepoints: 
x
Screening. 
x
Every 12 weeks from baseline: at any time of the day.  Up to cessation of 
AZD5363/placebo.  
x
Discontinuation of AZD5363/placebo: at any time of the day. 
Revised text: 
Blood samples for determination of triglycerides, HDL, LDL and cholesterol will be taken at 
the times indicated in the Study Plans (see Figure 6, and Figure 7 and Figure 8) at the 
following timepoints: 
x
Screening. 
x
Every 12 weeks from baseline (Cycle 1, Week 1, Day 1):: at any time of the day.  Up 
to cessation of AZD5363/placebo.  
x
Discontinuation of AZD5363/placebo: at any time of the day. 
 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.4.12.3 
Glucose, insulin and insulin c-peptide* 
Previous text: 
Blood samples for determination of glucose insulin and insulin c-peptide will be taken at the 
times indicated in the Study Plan (see Figure 6 and Figure 7) at the following timepoints: 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
57(79) 
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre-dose; 2, 4, 6 and 8 hours post-dose.  
Weeks 2, 3 and 4: Day 2 pre-dose. 
2-on 5-off schedule only: Week 1 Day 3 pre-dose, 2, 4, 6 and 8 hours post-dose 
4-on 3-off schedule only: Week 1 Day 5 pre-dose, 2, 4, 6 and 8 hours post-dose 
x
Cycles 2+: Week 1: Day 2 pre-dose and between 2 to 4 hours post-dose. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 
* Note:  Insulin c-peptide will be measured during study Part A only.  During Part B glucose 
and insulin only will be determined. 
Revised text: 
Blood samples for determination of glucose insulin and insulin c-peptide will be taken at the 
times indicated in the Study Plans (see Figure 6, and Figure 7 and Figure 8) at the following 
timepoints: 
Part A:  
x
Cycle 1: Week 1: Day 1 pre-dose; Day 2 pre dose; 2, 4, 6 and 8 hours post dose.  
Weeks 2, 3 and 4: Day 2 pre-dose. 
2-on 5-off schedule only: Week 1 Day 3 pre-dose, 2, 4, 6 and 8 hours post-dose 
4-on 3-off schedule only: Week 1 Days 2 and 5; pre-dose, 2, 4, 6 and 8 hours post-
dose. 
x
Cycles 2+: Week 1: Day 2 pre-dose and between 2 to 4 hours post-dose. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 
Part B: 
x
Cycle 1: Week 1: Day 1 pre-dose, Day 2 pre-dose; 2, 4 and 8 hours post-dose; Weeks 
2 and 3: Day 2 pre-dose, 2 and 4 hours post-dose. 
x
Cycle 2: Week 1: Day 2 pre-dose and 2 and 4 hours post-dose. 
x
Cycles 3+: Week 1: Day 2 pre-dose and between 2 to 4 hours post-dose. 
x
Discontinuation of AZD5363/placebo: at any time of the day. 
* Note:  Insulin c-peptide will be measured during study Part A only.  During Part B glucose 
and insulin only will be determined. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
58(79) 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.4.12.4 
Patient meal information. 
Previous text: 
The times and types of meals (tickbox) received by patients will be recorded on the days that 
the patient attends the study site and receives AZD5363/placebo at the following timepoints: 
x
Cycle 1: Week 1: Day 2.  Weeks 2, 3 and 4: Day 2. 
2-on 5-off schedule only: Week 1 Day 3  
4-on 3-off schedule only: Week 1 Day 5  
x
Cycles 2+: Week 1 Day 2. 
 
Revised text: 
The times and types of meals (tickbox) received by patients will be recorded on the days that 
the patient attends the study site and receives AZD5363/placebo at the following timepoints: 
x
Cycle 1: Week 1: Day 2.  Weeks 2, and 3 and 4: Day 2. 
Part A only - 2-on 5-off schedule only: Week 1 Day 3, Week 4 Day 2  
Part A only - 4-on 3-off schedule only: Week 1 Day 5, Week 4 Day 2 
x
Cycles 2+: Week 1 Day 2. 
 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.5.1 Quality of Life: EORTC QLQ C-30 and BR-23 questionnaires (Part B: 
Randomised expansion only). ( 4th Paragraph) 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
59(79) 
Previous text: 
During the Randomised Expansion phase only; patients will be requested to complete both 
questionnaires at the times indicated in the Study Plan (see Figure 6 and Figure 7) at the 
following timepoints: 
x
Screening. 
x
Cycle 1: Week 1: Day 1: pre-dose. 
x
Every 12 weeks from baseline: at any time of the day and after cessation of study 
therapies up to disease progression or withdrawal of consent.   
x
Discontinuation of AZD5363/placebo: at any time of the day. 
 
Revised text: 
During the Randomised Expansion phase only; patients will be requested to complete both 
questionnaires at the times indicated in the Study Plan (see Figure 6 and Figure 78) at the 
following timepoints: 
x
Screening. 
x
Cycle 1: Week 1: Day 1: pre-dose. 
x
Every 12 weeks from baseline (Cycle 1 Week 1 Day 1): at any time of the day and 
after cessation of study therapies up to disease progression or withdrawal of consent.   
x
Discontinuation of AZD5363/placebo: at any time of the day. 
 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.6.2 Pharmacokinetic sampling schedule  
Previous text: 
Code:  
P = Samples for paclitaxel PK.   


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
60(79) 
A = Samples for AZD5363 PK 
Note: Timing of paclitaxel PK sampling on Day 1 is from start of the infusion; e.g if paclitaxel 
infusion commences at 9am, the 2, 4 and 8 hour samples should be taken at 11am, 1pm and 
5pm respectively. 
Table 2 
PK sampling schedule:  Safety Run-in Phase. 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Time relative 
to first dose 
in cycle 
Day 1 
Day 2 
Day 3 
Day 5* 
Day 2 
Day 2 
Day 2 
Predose 
P 
P 
A 
 
A 
 
A* 
P 
A 
P 
A 
 
A 
2 hours  
P 
 
A 
 
 
 
 
 
4 hours  
P 
 
A 
 
 
 
 
 
8 hours  
P 
 
A 
 
 
 
 
 
* 4-on 3-off dosing schedule only 
Table 3 
PK sampling schedule:  Randomised Expansion Phase. 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Time relative 
to first dose 
in cycle 
Day 1 
Day 2 
Day 3 
Day 5* 
Day 2 
Day 2 
Day 2 
Predose 
P 
P 
A 
 
A 
 
A* 
 
A 
 
A 
 
A 
2 hours  
P 
 
A 
 
 
 
 
 
4 hours  
P 
 
A 
 
 
 
 
 
8 hours  
P 
 
A 
 
 
 
 
 
* 4-on 3-off dosing schedule only 
Revised text: 
Code:  


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
61(79) 
P = Samples for paclitaxel PK.   
A = Samples for AZD5363 PK 
Note: Timing of paclitaxel PK sampling on Day 1 is from start of the infusion; e.g if paclitaxel 
infusion commences at 9am, the 2, 4 and 8 hour samples should be taken at 11am, 1pm and 
5pm respectively. 
Table 2 
PK sampling schedule:  Part A Safety Run-in Phase. 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Time relative 
to first dose 
in cycle 
Day 1 
Day 2 
Day 3 
Day 5* 
Day 2 
Day 2 
Day 2 
Predose 
P 
P 
A 
 
A 
 
A* 
P 
A 
P 
A 
 
A 
2 hours  
P 
 
A 
 
 
 
 
 
4 hours  
P 
 
A 
 
 
 
 
 
8 hours  
P 
 
A 
 
 
 
 
 
* 4-on 3-off dosing schedule only 
Table 3 
PK sampling schedule:  Part B Randomised Expansion Phase. 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Time relative 
to first dose 
in cycle 
Day 1 
Day 2 
Day 3 
Day 5* 
Day 2 
Day 2 
Day 2 
Predose 
P 
P 
A 
 
A 
 
A* 
 
A 
 
A 
 
A 
2 hours  
P 
 
A 
 
 
 
 
 
4 hours  
P 
 
A 
 
 
 
 
 
8 hours  
P 
 
A 
 
 
 
 
 
* 4 on 3 off dosing schedule only 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
62(79) 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.7.1 Collection of pharmacodynamic markers (First paragraph) 
Previous text: 
Venous blood samples (8.1 mL) to provide platelet-rich plasma will be taken for assessment 
of pharmacodynamic (PD) markers at the times presented in the Study Plan (see Figure 6 and 
Figure 7) at the timepoints shown in Table 4. 
Revised text: 
Venous blood samples (8.1 mL) to provide platelet-rich plasma will be taken for assessment 
of pharmacodynamic (PD) markers at the times presented in the Study Plans (see Figure 6, 
and Figure 7 and Figure 8) at the timepoints shown in Table 4 and Table 5. 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.8.1.4 
Collection of eyebrow hairs (optional) (1st paragraph) 
Previous text: 
Four eyebrow hairs will be taken at the times presented in the Study Plan (see Figure 6 and 
Figure 7) on each of the timepoints presented in Table 4 below. 
Revised text: 
Four eyebrow hairs will be taken at the times presented in the Study Plans (see Figure 6, and 
Figure 7 and Figure 8) at the timepoints shown in Table 4 and Table 5. 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.8.1.5  
Collection of exploratory blood-borne biomarkers (optional) (1st 
paragraph) 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
63(79) 
Previous text: 
5mL venous blood will be taken at the times presented in the Study Plan (see Figure 6 and 
Figure 7) on each of the timepoints presented in Table 4 below.  
Revised text: 
5mL venous blood will be taken at the times presented in the Study Plans (see Figure 6, and 
Figure 7 and Figure 8) at the timepoints shown in Table 4 and Table 5. 
Reason for Amendment:  
Please refer to amendment rationale number 4. 
 
Section of protocol affected: 
Section 6.8.1.6 
Pharmacodynamic and exploratory biomarker sampling schedule 
Previous text: 
The following samples will be taken on each of the timepoints presented below. 
Code:  
PD = venous blood for determination of pharmacodynamic parameters.  
B = venous blood for analysis of exploratory biomarkers.  
BH  = 4 eyebrow hairs for analysis of exploratory biomarkers. 
Table 4 
PD and exploratory biomarker sampling schedule:   
Screen 
Cycle 1 
Cycle 2+ 
AZD5363 
Disc 
 
Week 1 
Week 2 Week 3 Week 4 Week 1
 
Time 
relative to 
first dose 
in cycle 
 
Day 1 
Day 2 
Day 3 
Day 5*
Day 2 
Day 2 
Day 2 
Day1 
 
Any time 
B 
 
 
 
 
 
 
 
 
B PD 
Predose 
 
PD  
B PD 
BH   
PD BH† PD* 
BH* 
B PD    
B PD    
B PD  
B PD 
 
2 hours  
 
 
PD  
 
 
 
 
 
 
 
4 hours  
 
 
PD BH 
 
 
 
 
 
 
 
8 hours  
 
 
PD  
 
 
 
 
 
 
 
* 4-on 3-off dosing schedule only 
† 2-on 5-off dosing schedule only 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
64(79) 
Revised text: 
The following samples will be taken on each of the timepoints presented below. 
Code:  
PD = venous blood for determination of pharmacodynamic parameters.  
B = venous blood for analysis of exploratory biomarkers.  
BH  = 4 eyebrow hairs for analysis of exploratory biomarkers. 
Table 4 
Part A Safety Run-in Phase: PD and exploratory biomarker sampling 
schedule:   
Screen 
Cycle 1 
Cycle 2+ 
AZD5363 
Disc 
 
Week 1 
Week 2 Week 3 Week 4 Week 1
 
Time 
relative to 
first dose 
in cycle 
 
Day 1 
Day 2 
Day 3 
Day 5*
Day 2 
Day 2 
Day 2 
Day1 
 
Any time 
B 
 
 
 
 
 
 
 
 
B PD 
Predose 
 
PD  
B PD 
BH   
PD BH† PD* 
BH* 
B PD    
B PD    
B PD  
B PD 
 
2 hours  
 
 
PD  
 
 
 
 
 
 
 
4 hours  
 
 
PD BH 
 
 
 
 
 
 
 
8 hours  
 
 
PD  
 
 
 
 
 
 
 
* 4-on 3-off dosing schedule only 
† 2-on 5-off dosing schedule only 
Table 5 
Part B Randomised Expansion Phase:  PD and exploratory biomarker 
sampling schedule. 
Screen 
Cycle 1 
Cycle 2+ 
AZD5363 
Disc 
 
Week 1 
Week 3 
Week 1 
 
Time relative to 
first dose in 
cycle 
 
Day 1 
Day 2 
Day 2 
Day1 
 
Any time 
B 
 
 
 
B PD 
B PD 
Predose 
 
PD  
B PD BH   
PD    
 
 
2 hours  
 
 
PD  
 
 
 
4 hours  
 
 
PD BH 
PD 
 
 
8 hours  
 
 
PD  
 
 
 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
65(79) 
 
Reason for Amendment:  
Separation of assessments to be conducted under study Parts A and B for clarity.  Please refer 
to amendment rationale number 4. 
 
Section of protocol affected: 
Section 7.1  
Volume of blood 
Previous text: 
The volume of blood that will be drawn from each patient will vary, dependent upon the 
dosing schedule and phase of the study: 
x
The volume of blood to be drawn from each patient during screening and Cycle 1 
should not exceed 35 mL and 380 mL respectively 
x
The total volume of blood to be drawn from each patient in the study, assuming they 
complete screening, 6 cycles of combination treatment and discontinuation visits 
should not exceed 750 mL.   
Safety laboratory assessments will be performed locally at each centre’s laboratory by means 
of their established methods.  The number of samples/blood volumes is therefore subject to 
site-specific change.  
In both phases of the study, extra blood samples may also be collected if, for example, 
additional samples are required for repeat safety assessments or additional PK assessment.   
The maximum volume of blood to be drawn from each patient in this study is as follows: 
Table 5 
Estimated Maximum volume of blood to be drawn per patient  
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Haematology 
5 
17 
85 
 
Clinical chemistry 
10 
17 
170 
 
Additional Glucose 
2 
20 
40 
 
Lipids and glycosylated 
haemoglobin 
5 
5 
25 
 
Glucose, insulin and 
insulin c-peptide 
5 
25 
125 
CTCs 
10 
4 
40 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
66(79) 
Table 5 
Estimated Maximum volume of blood to be drawn per patient  
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
PIK3CA mutation 
10 
1 
10 
Pharmacokinetic 
4 
16 
64 
Pharmacodynamic 
8.1 (3 x 2.7) 
16 
129.6 
Pharmacogenetics (optional) 
5 
1 
5 
Exploratory Biomarker (optional) 
5 
11 
55 
Total 
 
 
748.6 
Note:  Maximum is taken to reflect Part A, 4-on 3-off dosing schedule: 6 Cycles plus 
discontinuation visits.   
Revised text: 
The volume of blood that will be drawn from each patient will vary, dependent upon the 
dosing schedule and phase of the study: 
x
The volume of blood to be drawn from each patient during screening and Cycle 1 
should not exceed 35 55 mL and 380 mL respectively in Part A and 55mL and 
240mL respectively in Part B. 
x
The total volume of blood to be drawn from each patient in the study, assuming they 
complete screening, 6 cycles of combination treatment and discontinuation visits 
should not exceed 750 mL in Part A and 615ml in Part B.   
Safety laboratory assessments will be performed locally at each centre’s laboratory by means 
of their established methods.  The number of samples/blood volumes is therefore subject to 
site-specific change.  
In both phases of the study, extra blood samples may also be collected if, for example, 
additional samples are required for repeat safety assessments or additional PK assessment.   
The maximum volume of blood to be drawn from each patient in this study is as follows: 
Table 56 
Part A Safety Run-in Phase: Estimated Maximum volume of blood to be 
drawn per patient  
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Haematology 
5 
17 
85 
 
Clinical chemistry 
10 
17 
170 
 
Additional Glucose 
2 
20 
40 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
67(79) 
Table 56 
Part A Safety Run-in Phase: Estimated Maximum volume of blood to be 
drawn per patient  
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
 
Lipids and glycosylated 
haemoglobin 
5 
5 
25 
 
Glucose, insulin and 
insulin c-peptide 
5 
25 
125 
CTCs 
10 
4 
40 
PIK3CA mutation 
10 
1 
10 
PIK3CA analytical development 
20 
1 
20 
Pharmacokinetic 
4 
1613 
6452 
Pharmacodynamic 
8.1 (3 x 2.7) 
16 
129.6 
Pharmacogenetics (optional) 
5 
1 
5 
Exploratory Biomarker (optional) 
5 
11 
55 
Total 
 
 
748.6756.6 
Note:  Maximum is taken to reflect Part A, 4-on 3-off dosing schedule: 6 Cycles plus 
discontinuation visits.  
Table 7 
Part B Randomised Phase: Estimated Maximum volume of blood to be 
drawn per patient  
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Haematology 
5 
14 
70 
 
Clinical chemistry 
10 
14 
140 
 
Lipids and glycosylated 
haemoglobin 
5 
4 
20 
 
Glucose and insulin  
5 
24 
120 
CTCs 
10 
4 
40 
PIK3CA mutation 
10 
1 
10 
PIK3CA analytical development 
20 
1 
20 
Pharmacokinetic 
4 
10 
40 
Pharmacodynamic 
8.1 (3 x 2.7) 
13 
105.3 
Pharmacogenetics (optional) 
5 
1 
5 
Exploratory Biomarker (optional) 
5 
8 
40 
Total 
 
 
610.3 




Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
69(79) 
analysis then they will be censored at 0 days for PFS.  Symptomatic deterioration will not be 
regarded as a progression event. 
Reason for Amendment:  
Paragraph 1: Revision from ‘start of treatment’ to ‘date of randomisation’ – for consistency 
with other analytical timepoints within this protocol. 
Paragraph 2: Additional text – to clarify criteria for PFS analytical evaluability for patients 
that progress or die having not attended for two or more prior RECIST assessments.   
 
Section of protocol affected: 
Section 11.1.5 Duration of response (DoR) 
Previous text: 
Duration of response is defined as the date of first documentation of response (CR/PR) until 
the date of disease progression as defined by RECIST 1.1 or death (by any cause in the 
absence of disease progression). 
Revised text: 
Duration of response is defined as the date of first documentation of response (CR/PR) until 
the date of disease progression as defined by RECIST 1.1 or death (by any cause in the 
absence of disease progression). 
If a subject does not progress following a response, then their duration of response will 
use the PFS censoring time. 
Reason for Amendment:  
Clarification of criteria for determining DoR in the event that a patient that has responded 
does not subsequently progress prior to study closure. 
 
Section of protocol affected: 
New Section 11.1.6 
Durable Response Rate 
Additional text: 
Durable Response Rate (DRR) is defined as the percentage of patients who have a 
complete or partial response lasting continuously for at least 24 weeks. 
Reason for Amendment:  
Please refer to amendment rationale number 3. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
70(79) 
Please note – subsequent section numbering revised upwards, following addition of this new 
section. 
 
Section of protocol affected: 
Section 12.1.1 Efficacy analysis set (1st paragraph) 
Previous text: 
All efficacy data in Part B of the study (PFS, change in tumour size at 12 weeks, ORR, DRR 
DoR and percentage of patients without progression at 12 weeks and OS) will be analysed on 
an intention-to-treat basis (ITT).  This will include all randomised patients, wherever possible, 
and compare treatment groups on the basis of randomised treatment, regardless of the 
treatment they actually received. 
Revised text: 
All efficacy data in Part B of the study (PFS, change in tumour size at 12 weeks, ORR, DoR 
percentage of patients without progression at 12 weeks and OS) will be analysed on an 
intention-to-treat basis (ITT).  This will include all randomised patients, wherever possible, 
and compare treatment groups on the basis of randomised treatment, regardless of the 
treatment they actually received. 
Reason for Amendment:  
Please refer to amendment rationale number 3. 
 
Section of protocol affected: 
New Section 12.2.5 
Durable Response Rate 
Additional text: 
Durable Response rate will be tabulated by randomised treatment (AZD5363 + 
paclitaxel or placebo + paclitaxel) 
Durable Response rate will be analysed for the overall population and for the subgroup 
of PIK3CA mutation-positive patients using separate logistic regression models allowing 
for the effect of treatment and including a term for PIK3CA mutation status in the 
overall analysis. 
Reason for Amendment:  
Please refer to amendment rationale number 3. 
Please note – subsequent section numbering revised upwards following addition of this new 
section. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
71(79) 
 
Section of protocol affected: 
Section 12.2.6 (Revised to 12.2.7)  
Safety (1st paragraph) 
Previous text: 
Safety data will not be analysed formally.  All patients who receive at least 1 dose of study 
treatment will be included in the assessment of the safety profile (safety analysis set).  Safety 
and tolerability data will be presented by treatment received for patients in Part B and by dose 
and schedule for patients in Part A.  For Part B, the main set of safety tables will consist of the 
overall population in the randomised expansion, but a reduced set of key safety outputs will 
also be repeated on patients with PIK3CA mutation positive tumours (as according to 
stratification levels determined at randomisation) to assess if the safety profile remains 
consistent within these patients. 
Revised text: 
Safety data will not be analysed formally.  All patients who receive at least 1 dose of study 
treatment will be included in the assessment of the safety profile (safety analysis set).  Safety 
and tolerability data will be presented by treatment received for patients in Part B and by dose 
and schedule for patients in Part A.  For Part B, the main set of safety tables will consist of the 
overall population in the randomised expansion, but a reduced set of key safety outputs will 
also be repeated on patients with PIK3CA mutation positive tumours (as according to 
stratification levels determined at randomisation confirmed PIK3CA tumour mutation 
status) to assess if the safety profile remains consistent within these patients. 
Reason for Amendment:  
Correction to state that population of the patient Safety analysis set for patients with PIK3CA 
mutation-positive tumours will be determined by confirmed mutation status – i.e. following 
full central laboratory analyses.  Please refer to amendment rationale number 2. 
 
Section of protocol affected: 
Section 12.2.7 (Revised to 12.2.8)  
Pharmacokinetics  
Previous text: 
Part A Safety Run-in AZD5363 and paclitaxel pharmacokinetics 
Plasma concentrations of AZD5363 and paclitaxel will be summarised by nominal sample 
time.  Plasma concentrations and derived PK parameters will be summarised by dose level and 
schedule.  Plasma concentrations at each time point will be summarised according to dose and 
schedule by the following summary statistics: 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
72(79) 
x
The geometric mean (gmean, calculated as exp [ȝ], where ȝ is the mean of the data on 
a logarithmic scale) 
x
Coefficient of variation (CV, calculated as 100 ¥ [exp(s2)-1], where s is the standard 
deviation of the data on a log scale) 
x
Gmean ± standard deviation (calculated as exp[ȝ±s]) 
x
Arithmetic mean calculated using untransformed data 
x
Standard Deviation calculated using untransformed data 
x
Minimum 
x
Maximum 
x
Number of observations 
In the calculation of plasma concentration summary statistics, plasma concentrations below 
the lower limit of quantification (LLOQ) will be set to zero at pre-dose. Summary statistics 
will be presented according to the following rules: 
x
If, at a given time point, 50% or less of the plasma concentrations are non-quantifiable 
(NQ), the geometric mean (gmean), CV, gmean ± standard deviation (SD), arithmetic 
mean, SD and median will be calculated by substituting the LLOQ for values which 
are NQ.  The minimum at that time point will be reported as NQ. 
x
If more than 50%, but not all, of the concentrations are NQ, the gmean, CV, gmean ± 
SD, arithmetic mean and SD will be reported as not calculable (NC).  The minimum 
and median at that time point will be reported as NQ. 
x
If all the concentrations are NQ, the gmean, arithmetic mean, median, minimum and 
maximum will be reported as NQ and the CV, gmean ± SD and SD as NC. 
x
If the calculation of the gmean - SD results in a value less than the LLOQ, NQ will be 
displayed. 
Part B Randomised expansion  
The plasma concentrations determined using the sparse PK sampling scheme, at sampling 
timepoints, will be listed but not summarised. 
Revised text: 
Part A Safety Run in AZD5363 and paclitaxel pharmacokinetics 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
73(79) 
Plasma concentrations of AZD5363 and paclitaxel will be summarised by nominal sample 
time.  Plasma concentrations and derived PK parameters will be summarised by dose level and 
schedule.  Plasma concentrations at each time point will be summarised according to dose and 
schedule by the following summary statistics: 
x
The geometric mean (gmean, calculated as exp [ȝ], where ȝ is the mean of the data on 
a logarithmic scale) 
x
Coefficient of variation (CV, calculated as 100 ¥ [exp(s2) 1], where s is the standard 
deviation of the data on a log scale) 
x
Gmean ± standard deviation (calculated as exp[ȝ±s]) 
x
Arithmetic mean calculated using untransformed data 
x
Standard Deviation calculated using untransformed data 
x
Minimum 
x
Maximum 
x
Number of observations 
In the calculation of plasma concentration summary statistics, plasma concentrations below 
the lower limit of quantification (LLOQ) will be set to zero at pre dose. Summary statistics 
will be presented according to the following rules: 
x
If, at a given time point, 50% or less of the plasma concentrations are non quantifiable 
(NQ), the geometric mean (gmean), CV, gmean ± standard deviation (SD), arithmetic 
mean, SD and median will be calculated by substituting the LLOQ for values which 
are NQ.  The minimum at that time point will be reported as NQ. 
x
If more than 50%, but not all, of the concentrations are NQ, the gmean, CV, gmean ± 
SD, arithmetic mean and SD will be reported as not calculable (NC).  The minimum 
and median at that time point will be reported as NQ. 
x
If all the concentrations are NQ, the gmean, arithmetic mean, median, minimum and 
maximum will be reported as NQ and the CV, gmean ± SD and SD as NC. 
x
If the calculation of the gmean  SD results in a value less than the LLOQ, NQ will be 
displayed. 
Part B Randomised expansion  
The plasma concentrations determined using the sparse PK sampling scheme, at sampling 
timepoints, will be listed but not summarised. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
74(79) 
The plasma concentrations, determined using the sparse PK sampling scheme data will 
be analyzed using population non-linear mixed effects approach (Beal and Sheiner 1988-
1998). If data from the current study proves limited and is identified as insufficient to 
define the pharmacokinetics (large standard errors, non-identifiable PK profile), 
additional data will be included from previous clinical studies. Parameters will include 
AUCss, Cmaxss, CL/F and other PK parameters will be determined where appropriate 
and possible.  
Once the population PK model is defined, covariates (age, weight, renal function etc) 
relationship and it's clinical relevant to the model will be explored.  
The population PK analysis of data from this study will form part of the overall 
population analysis for the AZD5363 programme and is described in a population PK 
analysis plan associated with this programme. 
Reason for Amendment:  
Clarification and simplification of parameters for analysis of pharmacokinetic data.   
Inclusion of an option to combine data with outputs from other AZD5363 clinical studies in 
the event that PK outputs from D3610C00002 prove to be insufficient to enable a sufficiently 
robust evaluation. 
 
Section of protocol affected: 
Section 12.2.8 (Revised to 12.2.9)  
Pharmacodynamics and PK/PD relationships 
Previous text: 
Biomarker levels at various time points in addition to changes from baseline will be plotted 
and summarized appropriately; by treatment group for Part B, and by dose and schedule for 
Part A. 
The relationship between biomarkers, PK parameters and clinical efficacy endpoints may be 
explored by graphical presentations and modelling techniques, the details of which will be 
documented in a separate analysis plan. 
Revised text: 
Biomarker levels at various time points in addition to changes from baseline will be plotted 
and summarized appropriately; by treatment group for Part B, and by dose and schedule for 
Part A. 
The relationship between biomarkers, PK parameters and clinical efficacy endpoints may be 
explored by graphical presentations and population modelling techniques, the details of 
which will be documented in a separate population PK/PD analysis plan. 


Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
75(79) 
Reason for Amendment:  
Further clarification of parameters for PK/PD analytical populations.  
 
Section of protocol affected: 
Section 12.5 Data monitoring committee 
Previous text: 
Not applicable  
Revised text: 
Not applicable  
In addition to the ISRC (see section 5.11.2) Part B of the study will utilise an 
AstraZeneca internal Data Monitoring Committee (AZDMC), that is independent of the 
AZD5363 project team, to evaluate unblinded data outputs following the 1st and 2nd 
interim analyses (see section 12.3). The AZDMC will provide the project team with 
recommendations for action with respect to study conduct and the management of 
patients treated under the auspices of the study protocol. The AZDMC may recommend 
that the study should continue as planned, be terminated or modified in some way. It is 
then the responsibility of AZ to act as appropriate upon AZDMC recommendations 
concerning safety and study conduct. 
The AZDMC is constituted of: 
 
x
Head of Early Clinical Development, or delegate, who serves as the 
chairperson of the AZDMC 
x
Head of Biometrics in Early Clinical Development  
x
Head of Innovative Medicines and Early Development 
x
Head of Regulatory in Global Medicines Development 
x
Head of Patient Safety in Global Medicines Development 
The AZDMC charter for this study will define the remit of the committee.  
Reason for Amendment:  
Please refer to amendment rationale number 5. 
 
Section of protocol affected: 
Section 13.1 Medical emergencies and AstraZeneca contacts (table of contacts) 




Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
77(79) 
Reason for Amendment:  
To reflect changes in the AstraZeneca project team personnel.  
 
Section of protocol affected: 
Section 14 
 List of references 
Additional text: 
ADA 2014 
American Diabetes Association; Clinical Practice Recommendations 2014.  Diabetes care 
January 2014 Volume 37, Supplement 1. Retrieved from http://www.diabetes.org/. 
Beal and Sheiner 1988-1998 
Beal, SL, and Sheiner, LB (1988-1998). NONMEM Users Guides. Part I-VIII.NONMEM 
Project Group C255, University of California at San Francisco. 
Reason for Amendment:  
Additional literature references in support of revisions incorporated in protocol Edition 3; 
refer to Sections 4.2 and 12.2.8. 
 
Section of protocol affected: 
Appendix G 
Guidance Regarding Cautions and Restrictions for Prior and Concomitant 
Medications 
Previous text: 
Separate document provided 
Revised text: 
Separate document provided 
Reason for Amendment:  
Following a thorough review of allowance/exclusion of concomitant medications for 
AZD5363 clincal studies, and based upon emerging information and with reference to the 
revised Washington School of Pharmacy Drug Interaction Database, several revisions and 
additions were made to Appendix G.   Due to the number of these updates, a track-changed 
version of the Appendix is made separately available for ease of reference. 
 




Clinical Study Protocol Amendment 3 
Drug Substance AZD5363 
Study Code D3610C00002 
Date 09 May 2014 
79(79) 
Section of protocol affected: 
Appendix H 
Instructions for Study Drug Dose Modification (general) 
Previous text: 
References to: ‘Guidance for the Management of Adverse Events in Studies of AZD5363’ 
Revised text: 
References to: ‘Investigators’ Guide for the Management of Toxicities and Adverse Events’ 
Reason for Amendment:  
This change reflects that an original project-level guide for management of adverse events was  
replaced by a study-specific investigator aide to management of adverse events and toxicities.  
 


Clinical Study Protocol Amendment
Amendment Number
4
Drug Substance
AZD5363
Study Code
D3610C00002
Date
29 April 2015
Protocol Dated
13 May 2014
A Phase I/II, Multicentre, Study Comprising a Safety Run-In of AZD5363 
when Combined with Paclitaxel in Patients with Advanced or Metastatic 
Breast Cancer; Followed by a Randomised Expansion of AZD5363 when 
Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-
Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA 
Mutation Status (BEECH).
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden.
Centres affected by the Amendment:
This amendment affects all centres in the study.
Primary reason for amendment:
To allow the use of the tablet formulation of AZD5363 in Part A patients.  
In response to feedback from Investigators and emerging clinical data, other substantial 
changes have also been made to the protocol. These changes will simplify procedures, aid 
participation and adherence to the protocol, without compromising patient care.
Persons who initiated the Amendment:
AstraZeneca clinical study team. 
For details of all revised text in each section of the protocol, refer to the revised protocol (and 
tracked change version of the revised protocol) submitted with this amendment. 


Clinical Study Protocol Amendment 4
Drug Substance AZD5363
Study Code D3610C00002
Date 29 April 2015
2(6)
Where deleted, additional or amended protocol text is included in this amendment document it 
has been presented in italic script to aid ease of identification.
Primary protocol change in this amendment: 
1.
5.5.3 Doses and treatment regimens: Changes have been made to the text to 
permit the use of dose-equivalent tablets in Part A of the study, as current wording 
specifies capsules only.  This is supported by data generated from study 
D3610C00007 and is presented in Edition 6 of the Investigator’s Brochure.  The 
data show the comparability of PK exposure and safety between the original capsule
(of the kind that has been dosed to patients in Part A of the study) and the new 
tablet formulation of AZD5363.  
Other substantial protocol changes in this amendment:
1.
Part B Patient Assessments: Changes to and an overall reduction in the number of 
patient assessments and the number of days on which patients are required to attend 
clinic for evaluation.  This change was made in response to Investigators’ 
observations that the schedule of assessments as documented in Revised Protocol 
Edition 3 presented a substantial burden to both patients and site staff. 
After thorough consideration, AstraZeneca has concluded that it is appropriate to 
remove some and re-assign other Part B patient assessments associated with PK/PD, 
biomarker and safety assessments. The removal and reassignment of the former 
were based on the review of the objectives of Part B and the essential data required 
to address these objectives. The change of safety assessments was based on the
judgement that sufficient safety data has been collected during Part A and the early 
stages of Part B of the study along with associated studies in the clinical 
development programme for AZD5363.  The available data are considered to
support a reduction in assessments without compromising patient care. 
These changes are reflected in the following aspects of the protocol:
a)
Updates to the 3.1.4 Schedule of Assessments Part B (Figure 8) and Sections 
6.4 to 6.9 to reflect all changes in this amendment.
b)
Consent to provide a plasma blood sample for biomarker analysis will no 
longer be optional; instead, the consent will be mandatory and included in the 
main study consent form. This sample has also been renamed ctDNA blood 
sample to clarify the intention and use of the sample.
c)
Removal of the obligation for patients to use urine dipsticks at home during 
cycle 1 in Part B of the study to monitor for presence of glycosuria. Emerging 
data have shown that glucose levels as a result of study treatment tend to peak 
at 2 to 4 hrs after ingestion of AZD5363 and are not associated with clinical 
sequelae. Patients will be monitored for hyperglycemia whilst in the clinic in 
the 2-4 hours after dosing of the study treatment during the first cycle of study 


Clinical Study Protocol Amendment 4
Drug Substance AZD5363
Study Code D3610C00002
Date 29 April 2015
3(6)
treatment.  Monitoring will be achieved via the assessment of serum glucose 
levels.  Additional monitoring in subsequent cycles may be instigated at the 
discretion of the investigator based on findings from the glucose sampling 
conducted during the first cycle of treatment.
d)
Updates to language related to analytical procedures (PK samples) and length 
of storage (CTC sample).
e)
Reductions to the volume of blood to be drawn, given the overall reduction in 
the number of assessments.
f)
Clarification concerning the acceptable time window around clinic visits.
2.
4.2 Exclusion Criteria: Change and clarification of Exclusion Criterion 4. 
Exclusion criterion 4 has been revised to:   
Receipt of any investigational drug within 30 days or 5 half-lives, whichever is 
shorter, of the first dose of AZD5363 or matching placebo. [Note: that this criterion 
does not apply where the investigational drug was an established or marketed 
breast cancer medication administered previously as part of a clinical trial, e.g., as 
a comparator in a randomised study.]
This change has been made as patients requiring first-line chemotherapy for 
advanced or metastatic breast cancer often have rapidly progressive disease or 
disease impairing organ function and for which therapy without delay is warranted.  
This is at odds with the previously mandated 30 day washout period for the prior 
therapy and this stipulation has been removed.  The 5 half-life washout has been 
retained to ensure patient safety in relation to potential drug interactions and to 
reduce the risk of confounding interpretation of safety and efficacy data collected in 
Part B of the study.  Where the safety and efficacy profile of an established breast 
cancer therapy is well established and the drug has a long half-life (e.g. fulvestrant) 
the 5 half-life stipulation is also removed to reflect real-world clinical practice and 
patient need.
3.
4.2 Exclusion Criteria: Removal of Exclusion Criterion 11. 
This criterion has been removed as it applied to patients with primary tumour types 
other than breast cancer (which was in error as only patients with breast cancer may 
be entered into the study) and incorrectly differentiated between early disease and 
advanced or metastatic disease.  The target population will commonly include 
women recurring with aggressive disease during or after adjuvant therapy for early 
disease.  This criterion is also subsumed within the revised exclusion criterion 4 
above and therefore redundant.


Clinical Study Protocol Amendment 4
Drug Substance AZD5363
Study Code D3610C00002
Date 29 April 2015
4(6)
4.
5.2.1.1 Determination of PIK3CA mutation status and 5.2.2 Procedures for 
allocation and randomisation: New text added to these sections.
5.2.1.1: Alternatively, based on data from the interim analysis(es), it may be 
decided to permit unselected accrual to continue with the result that the number of 
patients in the two strata will be imbalanced (see section 5.2.2).  In this instance, 
prospective screening will not be required however it will remain necessary to 
determine mutation status for all patients to enable sub-group analyses.
5.2.2: When one stratum is complete (i.e. the minimum of 50 patients corrected for 
any post-screening revised mutation status have been randomised to a stratum), 
based on results from one or more of the interim analyses or results of other studies 
of AZD5363 or agents that act on the PIK3CA pathway, AstraZeneca may elect to 
permit accrual to the completed stratum to continue or re-open.  This may result in 
imbalanced accrual between the two strata as a result of competitive accrual.  The 
total sample size of approximately 100 patients will not be affected.
This text has been added to the protocol as the field of research relating to the 
PIK3CA pathway is rapidly evolving and it is anticipated that, during the 
recruitment period of this study, data may emerge to indicate that exploring the 
hypothesis of enhanced sensitivity to AZD5363 arising from PIK3CA mutation is 
no longer a valid exercise.  If this becomes the case, forcing the enrichment of the 
study population with patients whose tumour bears the mutation may no longer be 
necessary. 
Other protocol changes in this amendment:
1.
Section 1.1.3 Clinical Information: Data presented were no longer the most up to 
date information. The reader is now referred to the Investigator’s Brochure which 
details the emerging data thus far. 
2.
Section 1.4.4 and 1.4.5 Patient risks: Text has been included regarding the risk of 
hypersensitivity reactions due to AZD5363. This change has been made as a result 
of emerging information as documented in Investigator’s Brochure Edition 6.
3.
Section 2.2. Part A and B Secondary Objectives: Addition of the secondary 
objective to assess the toxicity burden associated with diarrhoea. This change has 
been made to reflect the intention and use of the current data collection. This data 
collection is also further documented in section 6.4.3.
4.
Section 2.3 Exploratory Objectives: Clarification that the CTC assessment may 
also include characterisation of these samples. 
5.
Section 3.1.1 Asian Patient evaluation: Change of Japanese population to ‘Asian’ 
to allow sub-analyses and evaluation of emerging data from this population as 
centres in other Asian countries may be included in the study.


Clinical Study Protocol Amendment 4
Drug Substance AZD5363
Study Code D3610C00002
Date 29 April 2015
5(6)
6.
4.1 Inclusion Criteria: Part B Criterion 1. Patients with histological or cytologic 
diagnosis of ER+ve and HER2-ve breast cancer with evidence of relapsed advanced 
or metastatic disease.  Lesions should not be amenable to surgery or radiation of 
curative intent and must be considered unlikely to be rendered eligible for surgery 
by treatment with paclitaxel in this study. Clarification and simplification of this 
criterion.
7.
4.2 Exclusion Criteria: Removal of text within Exclusion Criterion 20.  Aspartate 
aminotransferase (AST) >2.5 times ULN if no demonstrable liver metastases or >5 
times ULN in the presence of liver metastases.  Elevated Alkaline phosphatase 
(ALP) is not exclusionary if due to the presence of bone metastasis and liver 
function is otherwise considered adequate in the investigator’s judgement.
This latter part of the criterion has been removed as this current wording is 
confusing and does not describe an exclusion criterion. 
8.
5.1 Restrictions during the study: Restriction 4 is no longer applicable to Part B 
of the study and is therefore amended accordingly.
9.
5.2 Patient enrolment process: Clarification that for Part B a separate patient 
allocation process document is not available, sufficient detail is given within section 
5.2. Correction to the description of the allocation of randomisation identification 
codes.
10.
5.5 Treatments. Table 1: Dosage form and strength of the investigational product 
updated to reflect Administrative Change Number 1, dated 8th December 2014.
11.
5.5.3 Dose and Treatment Regimens: Removal of text relating to re-dosing study 
drug if vomiting occurs after ingestion. This deletion has been made to reduce the 
possibility of overdose.
12.
5.5.3 Dose and Treatment Regimens and 3.1.2 Treatment Schedules:
Clarification to the text relating to the dosing schedule of AZD5363 study treatment 
once paclitaxel has been permanently discontinued.
13.
5.5.4 Dose modifications: Clarification to the text regarding the suspension of 
study treatment before permanent discontinuation. Appendix H has also been 
updated respectively.
14.
5.5.4 Dose modifications: Permissible dose modifications during Part B have been 
updated to reflect the available formulation strengths of the new tablet formulation 
of the investigational product.
15.
Update to the statistical section of the protocol to ensure consistency with all the 
changes in this protocol amendment.


Clinical Study Protocol Amendment 4
Drug Substance AZD5363
Study Code D3610C00002
Date 29 April 2015
6(6)
16.
Minor clarifications to format or language that support the protocol (but do not 
change meaning).
17.
Other minor updates relating to study personnel, contact details and timelines.
18.
Changes to the number of participating centres and countries.
19.
Update to Appendix B to provide further information on Adverse Event reporting.
It is the judgement of the AstraZeneca Project Team that none of the protocol changes detailed 
in this document present any additional risk or hazard to the welfare or safety of participating 
patients. The changes made to this protocol do not affect the overall risk-benefit profile to the 
patient.


Clinical Study Protocol Amendment
Amendment Number
5
Drug Substance
AZD5363
Study Code
D3610C00002
Date
30 May 2017
Protocol Dated
29 April 2015
A Phase I/II, Multicentre, Study Comprising a Safety Run-In of AZD5363 
when Combined with Paclitaxel in Patients with Advanced or Metastatic 
Breast Cancer; Followed by a Randomised Expansion of AZD5363 when 
Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-
Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA 
Mutation Status (BEECH).
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden.
Centres affected by the Amendment:
This amendment affects all centres in the study.
Reason for Amendment:
To clarify the steps that should be followed if an early clinical database closure is warranted 
based on data generated by the study. To clarify the information that should be recorded for 
patients who continue to take study medication after the formal closure of the database has 
been triggered by the primary analysis, if required.  To clarify the procedure for long-term 
collection of survival data. To update the estimated date of the last patient completed.
Persons who initiated the Amendment:
AstraZeneca Clinical Project Team
Section of protocol affected:
Protocol Synopsis


Clinical Study Protocol Amendment 5
Drug Substance AZD5363
Study Code D3610C00002
Date 30 May 2017
2(3)
Previous text:
Estimated date of last patient completed Q1 2017
Revised text:
Estimated date of last patient completed Q4 2017
Additional Section 
Section 3.1.5
Early Closure of the Database.
In the event of an early closure of the database, patients are permitted to continue to receive 
study treatment if, in the opinion of the investigator, they are continuing to receive benefit 
from study treatment. For patients who do continue to receive treatment, investigators will 
continue to follow them for safety assessments as per the study plan (Figure 8) and in 
accordance with Section 6.4.3 Recording of Adverse Events. All SAEs must continue to be 
reported to AZ Patient Safety within the usual timelines until 28 days after study treatment is 
discontinued. All non-safety assessments will stop once the decision to close the clinical 
database has been communicated.
Any patients who are still receiving study medication, will be switched from IVRS/IWRS 
supply to a manual supply and the IVRS/IWRS will be closed, in line with the database 
closure.
Patients will not be considered formally withdrawn from the study until they stop taking study 
medication.
Survival status will not continue to be collected if the database is closed early. If this occurs, 
the overall survival analysis and safety update may be conducted using all available data the 
time of the database closure.
Section 5.5.1 Identity of investigational product(s)
Additional text:
Any patients who are still receiving study medication, will be switched from IVRS/IWRS 
supply to a manual supply and the IVRS/IWRS will be closed, in line with the database 
closure.
Section 5.9 Withdrawal from the Study
Additional text:
Patients will not be considered formally withdrawn from the study until they stop taking study 
medication.
Section 6.2.3.4 Survival follow-up


Clinical Study Protocol Amendment 5
Drug Substance AZD5363
Study Code D3610C00002
Date 30 May 2017
3(3)
Previous text:
Survival status will continue to be collected until 50% of randomized patients have died.
Optionally, continuation until 75% of randomized patients have died may be considered.
Revised text:
Survival status will continue to be collected until 50% of randomized patients have died (or 
the database is closed, if this occurs earlier). Optionally, continuation until 75% of 
randomized patients have died may be considered.
Section 12.2 Methods of statistical analyses Table 12 Footnote
Previous text:
PFS analysis and safety update will be combined if last patient has discontinued by the time 
the PFS events are reached
Revised text:
PFS analysis and safety update will be combined if last patient has discontinued by the time 
the PFS events are reached. The overall survival analysis and safety update may be conducted 
using all available data at the time of database closure if earlier.


Clinical Study Protocol Amendment
Amendment Number
6
Drug Substance
AZD5363 (Capivasertib)
Study Code
D3610C00002
Date
11 February 2020
Protocol Dated
30 May 2017
A Phase I/II, Multicentre, Study Comprising a Safety Run-In of AZD5363 
when Combined with Paclitaxel in Patients with Advanced or Metastatic 
Breast Cancer; Followed by a Randomised Expansion of AZD5363 when 
Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-
Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA 
Mutation Status (BEECH).
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden.
Centres affected by the Amendment:
This amendment affects all centres in the study.
Reason for Amendment:
To introduce the INN: AZD5363 is now called Capivasertib
This has been amended in the cover of the clinical study protocol and in the introduction
section of this clinical study protocol
To add information for tablet formulation switch and explain dose modifications:
AZD5363 (Capivasertib) tablet formulation is being replaced with the new commercial
formulation currently being used in the phase III program. The phase I/II tablet formulation 
will no longer be manufactured. There will be new strengths introduced 160 mg and 200 mg, 
instead of 80 mg. Section 5.5.4 Dose modifications has been updated to reflect this and 
provide guidance on how to dose reduce.
To update Section 13.1 Medical emergency and AstraZeneca contacts


Clinical Study Protocol Amendment 6
Drug Substance AZD5363
Study Code D3610C00002
Date 11 February 2020
2(7)
To update Appendix H Instruction for Study Drug Dose Modification (provide the new
guidance on the management of events of hyperglycemia)
Persons who initiated the Amendment:
AstraZeneca Clinical Project Team 
Section of protocol affected:
Cover of the protocol
Previous text:
Clinical Study Protocol
Drug Substance
AZD5363
Revised text:
Clinical Study Protocol
Drug Substance
AZD5363 (Capivasertib)
Section 1.1.1 Investigational agent
Previous text:
AZD5363 is a potent, selective inhibitor of the kinase activity of the serine/threonine 
AKT/PKB (protein kinase B) that is being developed as a potential treatment for solid and 
haematological malignancies.
Revised text:
AZD5363 (capivasertib) is a potent, selective inhibitor of the kinase activity of the 
serine/threonine AKT/PKB (protein kinase B) that is being developed as a potential treatment 
for solid and haematological malignancies.
Section 3.1.5 Early closure of the database
Additional text:
If the database is not closed early; patients may continue to receive study treatment after final 
database closure if, in the opinion of the investigator, they are receiving benefit from study 
treatment


Clinical Study Protocol Amendment 6
Drug Substance 
Study Code D3610C00002
Date 11 February 2020
3(7)
Section 5.5.1 Identity of investigational product(s)
Additional text:
The investigational product, AZD5363, was manufactured within a dosage unit strength range 
of 5 to 165 mg capsules and 80 to 320 mg tablets. At the time of this CSP amendment 6, 
AZD5363 is manufactured as 160 and 200 mg tablets only.
Section 5.5.4 Dose modification
Additional text:
From Edition 6 of this protocol, dose reduction should be to a minimum dose of 200 mg bd 
(the manufacturing of 80 mg tablets has been terminated, and there will be no tablet 
combinations available to make a 240 mg dose, hence the 200 mg will be the dose reduction 
going forward from this CSP amendment 6)
Section 5.5.4 Dose modification
Previous text:
All dose modifications and interruptions (including any missed doses due to AEs), and the 
reasons for the dose modifications/interruptions are to be recorded in the CRF.
Revised text:
All dose modifications and interruptions (including any missed doses due to AEs), and the 
reasons for the dose modifications/interruptions are to be recorded in the CRF. At the time of 
this CSP amendment 6 the CRF is closed, thus all information will be recorded in patient’s 
source documentation.
Section 7.2 Handling, storage and destruction of biological samples
Previous text:
Biological samples for future research will be retained by AstraZeneca Alderley Park, UK for
a maximum of 15 years following the Last Patient’s Last Visit in the study.  The results from
future analysis will not be reported in the CSR but separately in a Scientific Report.
Revised text:
Biological samples for future research will be retained by AstraZeneca Biobank for a
maximum of 15 years following the Last Patient’s Last Visit in the study.  The results from
future analysis will not be reported in the CSR but separately in a Scientific Report.






Clinical Study Protocol Amendment 6
Drug Substance 
Study Code D3610C00002
Date 11 February 2020
6(7)
Revised text:
Hyperglycemia toxicity guidelines
These are general recommendations therefore due consideration should be given to baseline 
values and fasting condition (and time since food if applicable) when interpreting glucose 
results. In diabetic patients, it may be beneficial to rule out concomitant aetiologies that could 
be associated with hyperglycaemia (e.g. infections, dehydration, vascular events, 
glucocorticoids). Patients should be made aware of symptoms of hyperglycaemia (eg, 
polydipsia and polyuria). Dose modification guidelines for capivasertib-related hyperglycemia 
are shown below. In addition, for all grades, patients may receive education on lifestyle 
changes (eg, a diabetic diet) and consider beginning home glucose monitoring (eg, fasting 
self-blood glucose monitoring [SBGM] once-daily) at the discretion of the investigator. If 
glucose home monitoring is instituted, the capivasertib/placebo treatment decision should be 
based on the morning fasting glucose value obtained prior to the dose of capivasertib/placebo. 
It is recommended that approaches to the management of capivasertib-induced 
hyperglycaemia include advice from a diabetologist where appropriate (eg, diabetic patients). 
Metformin is currently the preferred oral antidiabetic recommended for the management of 
hyperglycaemia occurring in patients participating in studies of capivasertib. If a second agent 
is required, consideration should be given to the intermittent schedule of capivasertib and the 
pattern of glucose changes (eg. sulphonylureas should be avoided due to their risk of 
hypoglycaemia secondary to their mechanism of action).
Table 1 provides guidance on the management of events of hyperglycemia.
Table 1 Glucose intervention plan
NCI CTCAE v4 Toxicity Grade 
Action
Grade 1
(fasting glucose >uln – 160mg/dl; fasting
glucose >uln – 8.9 mmol/L)
Maintain same capivasertib dose level.
Grade 2
(fasting glucose >160 – 250mg/dl; fasting
glucose >8.9 – 13.9 mmol/L)
Asymptomatic:

Maintain same capivasertib dose level.

Treatment as per local guidelines, consider
the use of oral antidiabetic (eg, metformin)
on capivasertib/placebo dosing days
Symptomatic: Appropriate clinical management as
per local guidelines.

Interrupt capivasertib until resolution of
symptoms and fasting blood glucose is ≤160
mg/dL or ≤8.9 mmol/L (treatment can be
interrupt up to 21 days)

Restart at same dose level maintaining
appropriate antidiabetic treatment (eg
addition of/higher dose of oral metformin)

Consider consult with the diabetologist


Clinical Study Protocol Amendment 6
Drug Substance 
Study Code D3610C00002
Date 11 February 2020
7(7)
Grade 3
(glucose > 250 - 500mg/dl; glucose >13.9
– 27.8 mmol/L; hospitalization indicated)
Hold capivasertib up to 21 days, until resolution of
symptoms.Consult with diabetologist.

If fasting blood glucose decreases to ≤160
mg/dL or ≤8.9 mmol/L within 21 days and
under appropriate anti-diabetic treatment,
resume capivasertib at 1 lower dose level.

If fasting blood glucose does not decrease to
≤160 mg/dL or ≤8.9 mmol/L within 21 days
following appropriate antidiabetic treatment,
permanently discontinue capivasertib
Grade 4
(glucose > 500mg/dl: glucose > 27.8
mmol/L; life-threatening consequences)
Appropriate clinical management of hyperglycemia
per local guidelines. Consider consult with the
diabetologist.
Consider permanent cessation of capivasertib/placebo
NCI CTCAE v4, National Cancer Institute Common Terminology Criteria for Adverse Events
Use of Metformin and other hypoglycemics
Metformin is currently the preferred oral antidiabetic recommended for the management of
hyperglycaemia occurring in patients participating in studies of capivasertib. Investigators
should exercise caution in the dosing and management of patients receiving the
metformin/capivasertib combination and must be vigilant for signs of renal impairment and
metformin toxicity, such as lactic acidosis and hypoglycaemia, namely: lethargy, hypotension,
poor urine output, drowsiness, irritation, tachypnoea, sweating, diarrhoea, and vomiting. If a
second agent is required, consideration should be given to the intermittent schedule of
capivasertib and the pattern of glucose changes (eg, sulphonylureas should be avoided due to 
the
risk of hypoglycemia secondary to their mechanism of action).
Due to the potential interaction of metformin and capivasertib due to inhibition of OCT2, 
when
taking both capivasertib and metformin concurrently, patients should attend the clinic for
monitoring of serum creatinine at least once per week for the first 3 weeks after initiation of
metformin, then every 3 weeks thereafter.
Metformin should only be given on the days when capivasertib is also administered (the half-
life
of capivasertib is approximately 7-15 hours), and should be withdrawn when treatment with
capivasertib is withdrawn, unless otherwise clinically indicated.
Consider withholding of metformin on the days patients are due to have imaging with contrast
(in order to reduce the already low risk of lactic acidosis) per local guidelines.

SAP_001.pdf: 


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Statistical Analysis Plan
Study Code
D3610C00002 (B)
Edition Number
3.0
Date
03/02/2017
A Phase I/II, Multicentre, Study Comprising a Safety Run-In of AZD5363 
when Combined with Paclitaxel in Patients with Advanced or Metastatic 
Breast Cancer; Followed by a Randomised Expansion of AZD5363 when 
Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-
Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA
Mutation Status (BEECH).






Statistical Analysis Plan 
Study Code D3610C00002 (B)
Edition Number 3.0
Date 03/02/2017
4
TABLE OF CONTENTS
                                          PAGE
TITLE PAGE...........................................................................................................1
SIGNATURE OF STUDY STATISTICIAN ..........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN....................................3
TABLE OF CONTENTS.........................................................................................4
LIST OF ABBREVIATIONS..................................................................................7
1.
STUDY DETAILS...................................................................................................9
1.1
Study objectives .......................................................................................................9
1.1.1
Primary objective.....................................................................................................9
1.1.2
Secondary objective(s).............................................................................................9
1.1.3
Exploratory objectives ...........................................................................................10
1.2
Study designs .........................................................................................................10
1.3
Number of subjects ................................................................................................11
2.
ANALYSIS SETS..................................................................................................12
2.1
Definition of analysis sets......................................................................................12
2.1.1
Intention to treat (ITT)...........................................................................................12
2.1.2
Safety analysis set ..................................................................................................12
2.1.3
Pharmacokinetic (PK) analysis set.........................................................................12
2.1.4
Pharmacodynamic (PD) analysis set......................................................................13
2.2
Violations and deviations.......................................................................................14
3.
PRIMARY AND SECONDARY VARIABLES...................................................14
3.1
Derivation of RECIST visit responses...................................................................14
3.1.1
Target lesions (TLs)...............................................................................................15
3.1.2
Overall visit response.............................................................................................19
3.2
Outcome variables..................................................................................................20
3.2.1
Primary outcome variable: Progression free survival (PFS)..................................20
3.2.2
Secondary outcome variables.................................................................................21
3.2.2.1
Objective Response Rate (ORR)............................................................................23
3.2.2.2
Duration of Response (DoR)..................................................................................23
3.2.2.3
Durable Response Rate (DRR) ..............................................................................23
3.2.2.4
Overall survival......................................................................................................23
3.2.2.5
Response rate at 12 weeks and best objective tumour response............................24
3.2.2.6
Proportion of patients without progressive disease at 12 weeks............................24
3.3
Health Related Quality of Life (HRQoL) ..............................................................24
3.4
Safety Variables .....................................................................................................28


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3.4.1
Adverse events .......................................................................................................28
3.4.2
Other Significant events (OAE).............................................................................28
3.4.3
Laboratory variables ..............................................................................................28
3.4.4
ECG........................................................................................................................30
3.4.5
Calculation or derivation of safety variables .........................................................30
3.4.6
Visit windows for other safety assessments...........................................................31
3.4.7
Duration of Exposure.............................................................................................32
3.4.8
Dose Intensity ........................................................................................................32
3.5
Derivation of pharmacokinetics variables: ............................................................34
3.6
Derivation of pharmacodynamic variables ............................................................35
3.7
Derivation of other exploratory biomarker research variables ..............................35
4.
ANALYSIS METHODS........................................................................................35
4.1
General principles ..................................................................................................35
4.2
Analyses.................................................................................................................36
4.2.1
Subgroup analyses..................................................................................................37
4.2.2
Primary variable – Progression Free Survival (PFS).............................................38
4.2.3
Secondary variables ...............................................................................................40
4.2.3.1
Change in tumour size at 12 weeks........................................................................40
4.2.3.2
Overall Survival .....................................................................................................41
4.2.3.3
Objective Response Rate (ORR)............................................................................42
4.2.3.4
Duration of Response (DoR)..................................................................................43
4.2.3.5
Durable Response Rate (DRR) ..............................................................................43
4.2.3.6
Health related quality of life (HR QoL) data.........................................................43
4.2.4
Safety .....................................................................................................................44
4.2.4.1
Adverse Events ......................................................................................................44
4.2.4.2
Laboratory parameters ...........................................................................................47
4.2.4.3
Vital Signs..............................................................................................................48
4.2.4.4
ECG parameters and echocardiogram data............................................................48
4.2.5
Treatment Exposure...............................................................................................49
4.2.6
Demography...........................................................................................................50
4.2.7
Pharmacokinetics ...................................................................................................50
4.2.8
Exploratory outcome variables ..............................................................................51
5.
INTERIM ANALYSES .........................................................................................52
6.
CHANGES OF ANALYSIS FROM PROTOCOL ...............................................53
7.
REFERENCES.......................................................................................................53
8.
APPENDIX (NOT APPLICABLE).......................................................................53


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Study Code D3610C00002 (B)
Edition Number 3.0
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LIST OF TABLES
Table 1 
Summary of outcome variables and analysis sets ....................................13
Table 2  
TL visit responses.....................................................................................15
Table 3
Example of scaling ...................................................................................16
Table 4  
Overall visit responses..............................................................................19
Table 5  
Visit Response..........................................................................................26
Table 6  
Best QoL Response ..................................................................................26
Table 7 
Day Ranges for lab assessments...............................................................29
Table 8 
Day Ranges for Serum/Plasma glucose assessments ...............................29
Table 9 
Formal statistical analyses planned for the primary and secondary 
endpoints...................................................................................................36
LIST OF FIGURES
Figure 1  
Study design .............................................................................................11
Figure 2  
Illustrative Example 1 – Paclitaxel dosing ...............................................33
Figure 3  
Illustrative Example 2 – AZD5363/placebo dosing .................................34


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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event 
AZ
AstraZeneca
BOR
Best Objective Response
BP
Blood Pressure
CP&P
Clinical Pharmacology & Pharmacometrics 
CR
Complete Response
CTC
Common Terminology Criteria
CTCs
Circulating Tumour Cells
CTCAE
Common Terminology Criteria for Adverse Event
CV
Coefficient of variation
DBP
Diastolic Blood Pressure
DoR
Duration of Response
ECG
Electrocardiogram
ER 
Estrogen Receptor
GSK3β
Glycogen synthase kinase
HDL
High Density Lipoprotein
HR
Hazard Ratio
IP
Investigational Product 
ITT
Intention to Treat
IVRS
Interactive Voice Response System
LLOQ
Lower Limit of Quantification
LVEF
Left ventricular ejection fraction
NE
Not Evaluable
NQ
Non-quantifiable
NTL
Non-Target Lesion
OAE
Other Significant Adverse Event 
ORR
Objective Response Rate
PD
Progression of Disease
PK/PDc
Pharmacokinetic/Pharmacodynamic
PFS
Progression Free Survival


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Abbreviation or 
special term
Explanation
PIK3CA
Phosphoinositide-3-kinase, catalytic, alpha polypeptide
PR
Partial Response
PR
ECG intervals measured from the beginning of the P wave to beginning of 
the QRS complex.
PRAS40
Proline-rich AKT substrate of 40 kDaltons
PTEN
Phosphatase and Tensin Homolog
QoL
Quality of Life
QT
ECG interval measured from onset of the QRS complex to the end of the T 
wave
QTc
QT interval corrected for heart rate
QTcB
interval duration corrected for changes on heart rate using Bazett's formula
QTcF
interval duration corrected for changes on heart rate using Friderica’s 
formula
RECIST 1.1
Response Evaluation Criteria In Solid Tumours, version 1.1
R-R
the interval between successive Rs, where R is a point corresponding to the 
peak of the QRS complex of the ECG wave
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Stable Disease
SD
Standard Deviation
ULN
Upper Limit of Normal


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1.
STUDY DETAILS
This statistical analysis plan (SAP) covers the Phase II (Part B) of the study only. The Phase I 
safety run-in part (Part A) of the study is not covered in this SAP.
1.1
Study objectives
1.1.1
Primary objective
The primary objective of the second part (Part B) of this study is:
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel compared 
with weekly paclitaxel plus placebo by assessment of progression free survival (PFS) in the 
overall advanced or metastatic ER+ve breast cancer population and in the PIK3CA mutation-
positive sub-population.
1.1.2
Secondary objective(s)
The secondary objectives of the second part (Part B) of this study are:
!
To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel 
compared with weekly paclitaxel plus placebo by assessment of objective response 
rate (ORR) at 12 weeks, best objective response (BOR), durable response rate 
(DRR) and duration of response (DoR).
!
To assess the relative anti-tumour activity of AZD5363 when combined with 
weekly paclitaxel vs. weekly paclitaxel plus placebo by comparison of change in 
tumour size at 12 weeks (target lesion assessment using Response Evaluation 
Criteria In Solid Tumours [RECIST 1.1]).
!
To compare overall survival (OS) in patients treated with AZD5363 in combination 
with weekly paclitaxel compared with weekly paclitaxel plus placebo by assessment 
of time to death.
!
To further assess the safety and tolerability of AZD5363 when combined with
weekly paclitaxel compared with weekly paclitaxel plus placebo.
!
To investigate the effect on patients’ quality of life (QoL) of AZD5363 when 
combined with weekly paclitaxel compared with weekly paclitaxel alone by change
from baseline, utilising a patient-completed QoL questionnaire.
!
To assess the pharmacokinetics (PK) of AZD5363 when combined with paclitaxel.
!
To assess the PK of paclitaxel alone and when combined with AZD5363.
!
To assess the Pharmacokinetic /Pharmacodynamic (PK/PDc) relationship between 
plasma AZD5363 exposure and plasma concentrations of biomarkers (including 


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phospo-PRAS40, total PRAS40, pAKT and pGSK3β) anti-tumour activity 
(assessed by RECIST 1.1).
!
To assess the toxicity burden associated with diarrhoea in relation to the number of 
episodes, duration of episodes and variations in intensity within episodes of the 
event's occurrence.
1.1.3
Exploratory objectives
!
To investigate the relationship between plasma AZD5363 exposure and plasma
concentration of exploratory biomarkers and efficacy. Biomarkers may include, but 
are not restricted to, somatic mutation or amplification of genes on the PI3 Kinase 
and related pathways in circulating tumour plasma DNA (ctDNA).
!
To obtain a preliminary assessment of AZD5363 treatment effect by quantitative 
change in circulating tumour cells (CTCs).
!
To investigate the concordance of PIK3CA mutation status between per-patient
analyses of blood and archival tumour tissue samples.
!
To explore changes in WHO performance status in patients treated with AZD5363 
in combination with weekly paclitaxel compared with weekly paclitaxel plus 
placebo.
!
To collect optional matched pre-and post- treatment tumour biopsy samples to
conduct assessment of the PDc effect of therapy compared to baseline.
!
To collect and store archival tumour samples and analyse surplus blood or tissue,
for potential future exploratory research into factors that may influence
development of cancer and/or response to AZD5363 (where response is defined
broadly to include efficacy, tolerability or safety).  Biomarkers may include, but are 
not restricted to, somatic mutation or amplification of genes on the PI3 kinase and 
related pathways, PTEN protein expression and AKT protein expression. This
exploratory analysis will be reported separately.
!
To obtain blood samples for DNA extraction for future exploratory research into
genes/genetic variation that may influence response (ie, distribution, safety,
tolerability and efficacy) to AZD5363 treatment and/or susceptibility to cancer.
This exploratory analysis will be reported separately.
1.2
Study designs 
A double-blind, stratified and randomised evaluation of AZD5363 when combined with 
weekly paclitaxel vs. weekly paclitaxel plus placebo. Approximately 100 female patients, with 
ER+ve advanced or metastatic breast cancer will be enrolled in this phase, of which 


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approximately 50 must have a tumour detectable as carrying a PIK3CA mutation. The dose 
and schedule of AZD5363 will be selected as an outcome from the safety run-in, Part A. 
All enrolled patients will be stratified to either the PIK3CA mutation ‘detected’ or ‘not 
detected’ group by the outcome of two tests (tissue and blood (ctDNA)). If a patient is 
detected as having the PIK3CA mutation in both or either of the two tests, they will be 
assigned to the mutation detected strata. If the mutation is not detected in both of the two tests,
(or should one test be not detected and the other is either unknown or not completed for any 
reason) the patient will be assigned to the not detected strata. This will be referred to as the 
protocol definition of PIK3CA mutational status.  Patients within each stratum will be 
randomised to 28-day cycles comprising either of:
!
Paclitaxel 90 mg/m2 IV once weekly plus AZD5363 capsules taken orally, twice 
daily.
!
Paclitaxel 90 mg/m2 IV once weekly plus AZD5363-matching placebo capsules 
taken orally, twice daily.
The overall study plan for PART B is shown in Figure 1.
Figure 1
Study design
1.3
Number of subjects
For this part of study (PART B), the sample size calculation was based on the primary 
endpoint of progression free survival (PFS). A sample size is determined for each PIK3CA
mutation status strata and irrespective of PIK3CA status (i.e. an overall sample size to 
compare treatment groups). 
 


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2.
ANALYSIS SETS
2.1
Definition of analysis sets
The main analysis sets are defined below for this study:
2.1.1
Intention to treat (ITT)
The intention to treat analysis set (ITT) will include all randomised patients. The ITT analysis 
set will be the primary analysis set for the analysing the efficacy parameters. Patients in the 
ITT analysis set will be analysed according to the treatment they were randomised to receive 
by the interactive voice response system (IVRS) regardless of the treatment they actually 
received. 
2.1.2
Safety analysis set
The safety analysis set will include all patients who received at least 1 dose of 
AZD5363/matching placebo.  Any patient who only receives one or more doses of paclitaxel 
and does not commence dosing with AZD5363/matching placebo will not be included in the 
assessment of safety data.
The safety analysis set will be the primary set used for the safety analyses. Patients in the 
safety analysis set will be analysed by actual treatment initially received. If patients were 
dose reduced during the study, all data will be summarised/analysed based on the initial dose 
of study treatment received.  However, some listings such as adverse event (AE) listings may 
give the actual dose the patient received at the time of the AE (e.g. dose interruption etc).
2.1.3
Pharmacokinetic (PK) analysis set
The AZD5363 PK analysis set will comprise all patients who received at least one dose of 
AZD5363 and have who have reportable plasma concentration data for AZD5363 and have no 
important adverse events that would impact PK data (e.g. vomiting).  


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The paclitaxel PK analysis set will comprise all patients who received at least one dose of 
paclitaxel and have who have reportable plasma concentration data for paclitaxel and have no 
important adverse events that would impact PK data (e.g. vomiting).  
2.1.4
Pharmacodynamic (PD) analysis set
The PD analysis set will comprise all patients who received at least one dose of AZD5363 
and/or paclitaxel and have who have reportable PD data with no important protocol deviations 
that may impact PD.  
A summary of outcome variables and analysis sets is defined in Table 1.
Table 1
Summary of outcome variables and analysis sets
Outcomes variables 
Analysis set
Efficacy (Primary)
Progression free survival (PFS)
ITT
Efficacy (Secondary):
Objective Response Rate (ORR)
Best Objective Response (BOR), Duration of Response (DoR), 
Durable Response Rate (DRR)
Change in tumour size 
Overall Survival
Quality of Life (QoL)
ITT
Pharmacokinetics (Secondary)
Plasma Concentration of AZD5363
Plasma Concentration of paclitaxel
PK
Pharmacodynamics (Secondary)
Biomarker: phospo-PRAS40, total PRAS40, pAKT and pGSK3β
PD
Safety and tolerability (Secondary):
AEs including specific safety data (i.e. Skin reactions, diarrhoea 
score)
Laboratory data (haematology, clinical chemistry, urinalysis); Vital 
signs, ECG, Physical examination, cardiac examination
Safety
Biomarkers (Exploratory)
Circulating tumour cells (CTCs).
PD


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2.2
Violations and deviations
Protocol deviations are recorded directly on the eCRF, the important protocol deviations will 
be identified prior to data base lock by the study team. All important protocol deviations will 
be listed summarised on the basis of randomised treatment group. 
None of the deviations will lead to any patients being excluded from any of the analysis sets 
described in Section 2.1 (with the exception of the PK analysis sets, if the deviation/AE (e.g. 
vomiting) is considered to impact upon PK). If the deviations are serious enough to have the 
potential to impact the primary analysis, sensitivity analyses may be performed.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Derivation of RECIST visit responses 
For all subjects, the RECIST tumour response data will be used to determine each subject’s 
visit response according to RECIST version 1.1.  It will also be used to determine if and when 
a subject has progressed in accordance with RECIST and also their best objective response. 
Baseline radiological tumour assessments are to be performed no more than 28 days before 
the start of randomised treatment.  Tumour assessments are then performed every 12 weeks 
following the start of treatment until objective disease progression (using RECIST v1.1).  
At each visit, an overall visit response will be determined programmatically - using the 
information from TLs, NTLs and new lesions.  RECIST outcomes will be calculated using a 
computer program.  
Patients with at least one lesion, not previously irradiated and not chosen for an optional fresh 
biopsy during the study screening period, that can be accurately measured at baseline as 
≥10mm in longest diameter (except lymph nodes which must have short axis ≥15mm) by 
computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate 
repeat assessment will be included in this study.
Measurable disease:
A lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in 
the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or 
MRI and which is suitable for accurate repeated measurements.
Non-measurable disease:
!
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15 mm short axis at baseline).
!
Previously irradiated lesions


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3.1.1
Target lesions (TLs) 
A subject can have a maximum of 5 measurable lesions recorded at baseline and these are 
referred to as the target lesions.  If more than one baseline scan is recorded then measurements 
from the one that is closest to and prior to randomisation will be used to define the baseline 
sum of TLs.
Baseline assessments should be performed no more than 28 days before the start of study 
treatment, and ideally should be performed as close as possible to the start of study treatment.
Note: For patients who do not have measurable disease at entry (i.e. no TLs), evaluation of 
overall visit responses will be based on the overall non-target lesion (NTL) assessment and the 
absence/presence of new lesions. If a patient does not have measurable disease at baseline 
then the TL visit response will be not applicable (NA).
Table 2  
TL visit responses
Visit Responses
Description
Complete Response (CR)
Disappearance of all target lesions.  Any pathological lymph nodes 
selected as target lesions must have a reduction in short axis to 
<10mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters as long as criteria 
for PD are not met.
Progressive disease (PD)
A ≥ 20% increase in the sum of diameters of target lesions and an 
absolute increase of ≥ 5mm, taking as reference the smallest sum of 
diameters since treatment started including the baseline sum of 
diameters.
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase
to qualify for PD
Not Evaluable (NE)
All target lesion measurements are missing or had a lesion 
intervention at this visit, or >1/3 target lesion measurements are 
missing and sum of diameters of non-missing target lesions does not 
qualify for PD.
Not applicable (NA)
No target lesions are recorded at baseline
Rounding of TL data:
For calculation of PD and PR for TLs percentage changes from baseline and previous 
minimum should be rounded to 1 decimal place before assigning a target lesion response.  For 
example 19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%.  


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Missing TL data: 
  
 
 
 
 
 
 
 
 
 
 
 
#
∃


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Lymph nodes
TL Visit responses subsequent to CR
A CR response can only be followed by CR, PD or NE.  If a CR has occurred then the 
following rules at the subsequent visits must be applied:
!
 
 
 
 
TL too big to measure:
If a target lesion becomes too big to measure this should be indicated in the database and a 
size (‘x’) above which it cannot be accurately measured should be recorded.  If using a value 
of x in the calculation of target lesion response would not give an overall visit response of PD, 
then this will be flagged and reviewed by the study team blinded to treatment assignment.  It 
is expected that a visit response of PD will remain in the vast majority of cases.  
TL too small to measure:
If a target lesion becomes too small to measure a value of 5mm will be entered into the 
database and used in TL calculations, unless the radiologist has indicated and entered a 
smaller value that can be reliably measured.  If a target lesion response of PD results then this 
will be reviewed by the study team blinded to treatment assignment.
Irradiated lesions/ lesion intervention/ curative surgery:
Previously irradiated lesions (i.e. lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment.


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Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolisation/ curative surgery), should be handled in the 
following way and once a lesion has had intervention then it should be treated as having 
intervention for the remainder of the study noting that an intervention will most likely shrink 
the size of tumours:
!
 
 
 
 
 
 
  
 
 
 
 
 
 
   
Lesions that split in two:
If a TL splits in two, then the longest diameters (LDs) of the split lesions should be summed 
and reported as the LD for the lesion that split.
Lesions that merge:
If two target lesions merge, then the LD of the merged lesion should be recorded for one of 
the TL sizes and the other TL size should be recorded as 0 cm.
Change in method of assessment of target lesions:
CT and MRI are the only methods of assessment that can be used within the trial, with CT 
being the preferred method. If a change in method of assessment occurs between CT and MRI 
this will be considered acceptable and no adjustment within the programming is needed.  
 
 


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Non-Target Lesions (NTLs) and new lesions
Non-target lesion response will be derived based on the Investigator’s overall assessment of 
NTLs as follows:  
Progressive disease:
Unequivocal progression of existing NTLs, which may be due to an 
important progression in one lesion only or in several lesions.
Complete response: 
Disappearance of all NTLs present at baseline with all lymph nodes 
non-pathological in size (<10mm short axis).
Non-CR/Non-PD: 
Persistence of one or more NTLs with no evidence of progression.
Not evaluable: 
Only relevant when one or some of the NTLs have not been assessed 
and in the Investigator’s opinion they are not able to provide an 
evaluable overall NTL assessment. 
Not applicable:
Only relevant if there are no NTLs at baseline.
New lesions will be identified via a Yes/No tick box.  The absence and presence of new 
lesions at each visit should be listed alongside the TL and NTL visit responses.
A new lesion indicates progression so the overall visit response will be PD irrespective of the 
TL and NTL response.
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and 
the new lesion details are blank this is not evidence that no new lesions are present and should 
be treated as NE in the derivation of overall visit response.   
3.1.2
Overall visit response
Table 4 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response. 
Table 4  
Overall visit responses
TARGET
NON-TARGET
NEW LESIONS
OVERALL VISIT 
RESPONSE
CR
CR (or NA)
No (or NE)
CR
CR
Non-CR/Non-PD or 
NE
No (or NE)
PR
PR
Non-PD or NE
No (or NE)
PR
SD
Non-PD or NE
No (or NE)
SD
PD
Any
Any
PD


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Table 4  
Overall visit responses
TARGET
NON-TARGET
NEW LESIONS
OVERALL VISIT 
RESPONSE
Any
PD
Any
PD
Any
Any
Yes
PD
NE
Non-PD or NE
No (or NE)
NE
NA
CR
No (or NE)
CR
NA
Non-CR/Non-PD
No
SD
NA
NE
No (or NE)
NE
NA
Non-PD
NE
SD
3.2
Outcome variables
3.2.1
Primary outcome variable: Progression free survival (PFS)
PFS is defined as the time from the date of randomisation until the date of objective disease 
progression (as per RECIST 1.1) or death (by any cause in the absence of progression) 
regardless of whether the patient withdraws from randomised therapy or receives another anti-
cancer therapy prior to progression. Patients who have not progressed or died at the time of 
analysis will be censored at the time of the latest date of assessment from their last evaluable 
RECIST assessment. 
 
 
 
 
PFS will be calculated using a programming algorithm using the data collected on objective 
tumour assessment.
The PFS time will always be derived based on scan/assessment dates not visit dates. RECIST 
assessments/scans contributing towards a particular visit may be performed on different dates. 
The following rules will be applied:
!
Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression
!
When censoring a patient for PFS the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment


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3.2.2
Secondary outcome variables
Change in tumour size at 12 weeks.
Change in tumour size at 12 weeks is based on RECIST target lesion measurements taken at 
baseline and at week 12 for patients with measurable disease only. Tumour size is the sum of 
the longest diameters of the target lesions.  Target lesions are measurable tumour lesions.  
Baseline for RECIST is defined to be the last evaluable assessment prior to starting treatment.  
More details on target lesions and measurements can be found in Appendix F of the protocol.
Subjects who progress before week 12 should have had a tumour assessment performed at the 
time of progression prior to treatment discontinuation and unblinding.  The tumour size from 
their latest progression assessment will be used instead of the week 12 assessment for these 
subjects.
Patients who discontinue study treatment for reasons other than objective disease progression 
should have tumour assessments scans performed as scheduled in the protocol and the tumour 
size from the week 12 assessment will be used in this analysis.
Handling Missing TLs measures 
Target lesion imputation: 
 
Apply a window around the week 12 visit: 
Whenever tumour size data for the week 12 visit (Note: or visit at which progression was 
documented if before week 12) is available then this should be used in the analysis.  A 
windowing rule will be applied and will follow the protocol allowed visit window; therefore 
any RECIST scan performed within ± 1 week of the protocol scheduled visit will be used for 
that visit. 
Assess level of missing data and change TSA analysis if appropriate:  
If after target lesion imputation and applying a window around the week 12 visit there remains 
reasonable amount of missing tumour size measurement data, a non-parametric method will 
be considered for the TSA analysis, assigning patients who have died with the worst rank and 
ranking other imputed data.  What constitutes a reasonable amount of data will be judged on a 
case-by-case basis but > 10% missing data would be cause for consideration. 
Following imputation, the blinded data will be assessed for normality and if appropriate, a 
decision to use a non-parametric method as the primary TSA analysis may still be made after 
an assessment of the combined actual and imputed data


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If, after applying the above considerations to the missing data, there is still missing tumour 
size measurement data (tsm data) at week 12, the recommendation would be to follow the 
imputation process outlined below for each individual patient where data is missing (applied 
prior to blind review). 
 
 
 
 
 
 
 
 
 
All imputed data should be derived within the reporting dataset with a corresponding flag 
against the imputed value to show that this value has been programmatically derived
Best percentage change in tumour size.
The best percentage change in tumour size from baseline will be reported, i.e. the maximum 
reduction from baseline or the minimum increase from baseline in the absence of a reduction 
from baseline based on all post baseline assessments. 
If following the scaling up rules, best percentage change cannot be calculated due to missing 
data, and a patient has no post baseline assessments, then the following imputation rules 
should be applied:
a)
 
 
 
 
b)
 


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c)
 
All imputed data should be derived within the reporting dataset with a corresponding flag 
against the imputed value to show that this value has been programmatically derived.
3.2.2.1
Objective Response Rate (ORR)
ORR is defined as the percentage of patients with at least one investigator-assessed visit response 
of CR or PR and will based on a subset of all randomised patients with measurable disease at 
baseline per the site investigator. The response does not need to be confirmed.  Data obtained 
up until progression, or last evaluable assessment in the absence of progression, will be 
included in the assessment of ORR. Patients who discontinue randomised treatment without 
progression, receive a subsequent anti-cancer therapy and then respond will not be included as 
responders in the ORR. The denominator for ORR will be the Efficacy analysis set (ITT 
population), excluding any patients who do not have measurable disease at baseline as per the 
RECIST 1.1 criteria.
Section 3.1 gives details about the derivation of objective tumour response (CR and PR).
3.2.2.2
Duration of Response (DoR)
Duration of response will be defined as the time from the date of first documented response 
until date of documented progression or death in the absence of disease progression, the end
of response should coincide with the date of progression or death from any cause used for the 
PFS endpoint. If a subject does not progress following a response, then their duration of 
response will use the PFS censoring time.
3.2.2.3
Durable Response Rate (DRR)
Durable response rate (DRR) is defined as the proportion of patients with complete or partial 
response lasting continuously for at least 24 weeks (with a window of +/- 1 week) from time 
of onset of response.
The denominator for DRR will be the Efficacy analysis set (ITT population), excluding any 
patients who do not have measurable disease at baseline as per the RECIST 1.1 criteria.
3.2.2.4
Overall survival
Overall survival is defined as the time from the date of randomisation until the date of death 
due to any cause, regardless of whether the patient withdraws from randomised therapy or 
receives another anti-cancer therapy (i.e date of death or censoring – date of randomisation + 
1). Any patient not known to have died or who are lost to follow-up or withdraw consent at 
the time of analysis will be censored based on the last recorded date on which the patient was 
known to be alive.
If there are no survival or death data available at the data cut-off date, then the last date the 
patient is known to be alive will be calculated from the last assessment date of all modules 


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(except the visit module) on the database and patient will treated as censored patients at last 
recorded date. 
3.2.2.5
Response rate at 12 weeks and best objective tumour response
Response rate at 12 weeks (with a window of +/- 1 week) is defined as the percentage of 
patients who have a week 12 visit response of CR or PR (as defined by RECIST 1.1), 
regardless of whether the responses are confirmed or not.
Best objective tumour response will be based on RECIST measurements taken throughout the 
whole study and will classify patients as complete and partial responses, stable disease, 
progressive disease and not evaluable.  It is the best response a patient has had following first 
dose but prior to starting any subsequent cancer therapy and up to and including RECIST 
progression or the last evaluable assessment in the absence of RECIST progression. 
BoR will be determined programmatically based on RECIST using all site investigator data up 
until the first progression event.  The denominator will be consistent with that used in the 
ORR analysis.
For patients whose progression event is death, BoR will be calculated based upon all 
evaluable RECIST assessments prior to death.
 
3.2.2.6
Proportion of patients without progressive disease at 12 weeks
The proportion of patients without progressive disease at 12 weeks is defined as the 
percentage of patients with a 12 week visit response (with a window of +/- 1 week) of CR, PR 
or SD (as defined by RECIST 1.1) with no evidence of previous progression.  If the week 12 
response is missing or NE but the next evaluable response is SD or better then the patient will be 
defined as having NPD at 12 weeks.
The denominator for patients without progressive disease at 12 weeks will be all randomised 
patients.
3.3
Health Related Quality of Life (HRQoL) 
The EORTC QLQ-C30 + BR-23 questionnaires will be used to identify and analyse global 
health status/ quality of life and disease-related symptoms according to EORTC scoring 
manual. 
EORTC QLQ-C30 is a 30-item generic instrument designed specifically to assess quality of 
life (QoL). The structure of questionnaire is defined as:


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5 functional scales (physical, role, cognitive, emotional, and social)
3 symptom scales (fatigue, pain, and nausea/vomiting)
A global health scale (Global health status/QoL)
5 single items assessing common physical symptoms of cancer (dyspnoea, loss of
appetite, insomnia, constipation, and diarrhoea)
A single item assessing the financial effect of cancer. 
The raw scores for each of the 30 items of the QLQC-30 will be converted into scores for each 
of the 15 domains on a scale from 0 to 100. The scoring algorithm for the QLQC-30 (from the 
EORTC scoring manual for QLQC-30) will be used to generate the domain scores. 
In case of Functioning and Global QoL scales, higher scores indicate better function whereas 
for symptomatic scales higher scores indicate worse symptoms.
The BR-23 breast cancer–specific questionnaire includes 23 questions to assess function 
(body image, sexuality, and future perspective) and symptoms (Systemic therapy side effects, 
Breast symptoms, Arm symptoms, Upset by hair loss) specific to breast cancer.
Seven domain scores will be derived on a 0 to 100 scale as per the EORTC manual.
The compliance rate and evaluability rate will be calculated at baseline and each subsequent 
assessment for each of the HRQoL and disease related symptoms scores.
The compliance rate and evaluability rate will be calculated as –
Compliance Rate = (The number of evaluable forms/ the number of expected forms) x 100.
Evaluability Rate = (The number of evaluable forms / the number of received forms) x 100.
Only patients who have a baseline score will have their scores included in any analysis.
The pre-dose of day-1 of Cycle 1 is defined as baseline for both EORTC + BR23 
questionnaires.
!
HRQoL measurement prior to dosing with study treatment (AZD5363/placebo and
Paclitaxel) will be considered as baseline values. For each of the HRQoL and 
disease-related symptoms scores, a change in score from baseline of at least 10 
points can be considered as a clinically relevant or a minimally important
difference.  A visit response will be calculated for each subscale as detailed in Table 
5.


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Table 5  
Visit Response
Score
Change from baseline
Visit Response
Symptom scales / 
items
≤-10
Improved 
>-10, <10
No change
≥10, or missing questionnaire
due to “Subject too sick, other
than disease under investigation” or 
“Subject too affected by symptoms of 
disease under investigation”
Worsened
Missing for reasons other than
those above
Not evaluable 
Functional scales, 
Global
health status
≥10
Improved 
>-10, <10
No change
≤-10, or missing questionnaire
due to “Subject too sick, other
than disease under investigation” or 
“Subject too affected by symptoms of 
disease under investigation”
Worsened
Missing for reasons other than
those above
Not evaluable 
  
For each patient, a best overall QoL response will be calculated for each of the HRQoL and 
disease related symptoms as detailed in Table 6.
Table 6  
Best QoL Response
Score
Definition
Best QoL Response
Any
Two visit responses of ‘improved’ a minimum 
of 21 days apart without an intervening visit 
response of ‘worsened’
Improved 
Does not qualify for overall score response of 
“improved”. Two visit responses of either “no 
change”, or “improved” and “no change” a 
minimum of 21 days apart without an
Intervening visit response of “worsened”.
No change


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Table 6  
Best QoL Response
Score
Definition
Best QoL Response
Does not qualify for overall score response of 
“improved” or “no change”. Either (1) A visit 
response of “worsened” without a response of 
“improved” or “no change” within 21 days; or 
(2) Died within 12 weeks of last evaluable 
PRO assessment. 
Worsened
Dose not qualify for one of the above
Not evaluable
Time-to-deterioration will only be reported and analysed, should initial review of the 
summary outputs for the QoL data indicate that it would be meaningful.  
If conducted, time to deterioration for each of the HRQoL scale and disease related symptoms 
score will be calculated.  For each endpoint separately, patients should be considered non-
evaluable if any of the following apply
!
The subject does not have any evaluable baseline data
!
The subject does not have any evaluable post-baseline data
!
The subject’s baseline score is so close to the maximum/minimum subscale score 
that it would be impossible for them to experience a deterioration (e.g. maximum 
score – baseline score < deterioration threshold)
A deterioration time is defined as the first visit response of worsened without a visit response 
of no change or improved within the following 21 days. If a subject has no QoL data after the 
first visit which deterioration has occurred, the subject will still be considered to have 
deteriorated.  Subjects who die or are unable to complete the questionnaires will also be 
considered to have deteriorated if it occurs within 12 weeks of last evaluable HRQoL 
assessment. 
Time to deterioration is calculated as the time from randomisation to date of the first 
assessment at which deterioration started.  Subjects who do not deteriorate will be censored at 
the time of their last evaluable subscale score for the specific subscale being analysed.  If 
subject does not have an evaluable post baseline score for the subscale, the subject will be 
censored for time to deterioration at day 1.  Any subject who cannot possibly worsen 
compared to baseline will be censored for time to worsening at day 1.
Handling missing HRQoL data
For each score, if less than 50% of the individual items are missing, the score will be divided 
by the number of non-missing items and multiplied by the total number of items comprising 
the score. If more than 50% of the items are missing, that scale score will be treated as 


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missing. Missing single items are treated as missing.  The reason for any missing 
questionnaire will be identified and recorded.
If there are cases in which more than one questionnaire has been completed on the same day, 
and provided different answers, the questionnaire with the worst overall score will be used.  
3.4
Safety Variables  
Safety and tolerability will be assessed using reports of adverse events (including SAEs), 
deaths, vital signs (including blood pressure [BP], and pulse), cardiac monitoring (including 
12-lead ECGs and LVEF (by MUGA or cardiac ECHO) , physical examination, lipids 
(Triglycerides, HDL, LDL and Cholesterol ), laboratory findings ( including Haematology, 
Clinical Chemistry and Urinalysis).  These parameters will be collected for all patients. 
Adverse events will be collected throughout the study, from time of signature of informed 
consent until 28 days after the last dose of AZD5363/placebo. The detailed definitions and 
calculation of the safety and tolerability variables are given in section 6.4 and 11.2 of CSP. 
Appropriate summaries of these data will be presented as described in Section 4.2.4.
3.4.1
Adverse events
All AEs will be coded using latest available version of the Medical Dictionary for Regulatory
Activities (MedDRA).  AE will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.
3.4.2
Other Significant events (OAE)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review
the list of AEs that were not reported as a SAE and/or a Discontinuation of Investigational
Product due to Adverse Event. Based on the expert’s judgement, significant adverse events of
particular clinical importance may, after consultation with the Global Patient Safety Physician,
be considered OAEs and reported as such in the CSR. A similar review of laboratory, vital
signs and ECG data will be performed for identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain
events that lead to intervention (other than those already classified as serious), dose reduction
or significant additional treatment.
3.4.3
Laboratory variables 
Blood and urine samples for determination of haematology, clinical chemistry, and urinalysis
will be collected as outlined in CSP section 6.4.5. Laboratory values will be graded according 
to CTCAE version 4.0. Neutrophils and glucose values with a grade >= 4 will be used to 
determine tolerability for the go-no go criteria.
The baseline value of each laboratory variable will be derived, as described in the Clinical 
Study Protocol; values captured up to 3 days before baseline visit will be considered suitable 
for a baseline value. If multiple records are present between -3 days and baseline visit (cycle 1 
day 1) then the last value obtained prior to the first dose of study medication will be 


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considered as baseline.  Alternatively, if two visits are equally eligible to assess patient status 
at baseline (e.g., screening and baseline assessments both prior to first dose with no washout 
or other intervention in the screening period), the average can be taken as a baseline value.
The post-baseline non-missing values of laboratory parameter closest to the scheduled visit
date will be considered as the visit value. If two assessments are equidistant from a scheduled
visit, then the earlier of the two will be used.  The visit will be missing if no assessment was
reported within the specified visit window around the scheduled date.
Designation of visits for Lab data assessment are given in table below (Table 7):
Table 7
Day Ranges for lab assessments  
Cycle No.
Visit day
Target day
Day Range
Screening
-1
-28 – -1 
1
Day 1 (Baseline)
1
-3 – 1 (prior to dose)
1
Day 2
2
2 – 3
1
Day 5
5
4 – 7 
1
Day 9
9
8 – 12
1
Day 16
16
13 – 19 
1
Day 23
23
20 – 26 
2
Day 2
30
27 – 33
2
Day 8
36
34 – 39  
2
Day 15
43
40 – 46 
2
Day 22
50
47 – 54 
3
Day 2
58
55 – 72
4
Day 2
86
73 – 100
Y
Day 1
X
X-13 – X+14 
Where Y = 5, 6 ……….. and X = (Y-1)*28+1
Table 8
Day Ranges for Serum/Plasma glucose assessments
Cycle No.
Visit day
Target day
Day Range
Screening
-1
-28 – -1 
1
Day 1 (Baseline)
1
-3 – 1 (prior to dose)
1
Day 2
2
2 – 3
1
Day 5
5
4 – 7 
1
Day 9
9
8 – 12


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Table 8
Day Ranges for Serum/Plasma glucose assessments
Cycle No.
Visit day
Target day
Day Range
1
Day 16
16
13 – 19 
1
Day 23
23
20 – 26 
2
Day 2
30
27 – 44
3
Day 2
58
45 – 71
Y
Day 2
X
X-13 – X+14 
Where Y = 5, 6 ……….. and X = (Y-1)*28+1
3.4.4
ECG 
A 12-lead ECG will be performed as per intermittent dosing described in protocol section 
6.4.9. The following parameters will be recorded for each ECG: date and time of ECG, heart 
rate (beats/min), PR, R-R, QRS, QT (ms), QTc (ms), sinus rhythm (yes/no), and overall 
evaluation (normal/abnormal).
3.4.5
Calculation or derivation of safety variables
ECG Changes
QTc will be calculated using both Bazett’s (QTcB) and Fridericia’s (QTcF) formulae as 
follows:
!
    QTcB = 
QT
 RR
1000
!
   QTcF = 
QT
 RR
1000

Where QT and RR is in msec.
Creatinine clearance
Creatinine clearance will be calculated using the Cockcroft and Gault formula below, from 
creatinine:
For creatinine values in mol/L
Men: [(140 – age) x weight (kg) x 1.23] / creatinine (μmol/L)
Women: [(140 – age) x weight (kg) x 1.04] / creatinine (μmol/L)
Corrected calcium will be calculated using the formula below, from total calcium and 
albumin: 


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Corr. Calcium = Total Calcium (mmol/L) + ([40 – Albumin (g/L)] x 0.02)
Baseline for laboratory variables will be defined as last non missing measurement prior to the 
first dose of medication and change from baseline will be calculated for each scheduled visit 
using the formula:
Change = [(Post dose measurement - baseline measurement)]
And percentage change from baseline using,
Percentage change = [(Post dose measurement - baseline measurement) / Baseline 
measurement] *100
3.4.6
Visit windows for other safety assessments
For physical examination, weight, ECG, vital signs, LVEF, lipids, glycosylated haemoglobin, 
glucose, insulin and insulin c-peptide the following conventions should apply to define visit 
response.
The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarised.  Inclusion within the time window should be based on the actual 
date and not the intended date of the visit.
!
All unscheduled visit data should have the potential to be included in the 
summaries.
!
The window for the visits following baseline will be constructed in such a way that 
the upper limit of the interval falls half way between the two visits.
!
For summaries showing the maximum or minimum values, the maximum/minimum 
value recorded on treatment will be used (regardless of where it falls in an interval).
!
Listings should display all values contributing to a time point for a patient.
!
For visit based summaries:
!
If there is more than one value per patient within a time window then the 
closest value should be summarised, or the earlier in the event the values are 
equidistant from the nominal visit date.  
!
For summaries at a patient level, all values should be included, regardless of 
whether they appear in a corresponding visit based summary, when deriving a 
patient level statistic such as a maximum.
Unless otherwise stated, baseline will be defined as the last non-missing measurement prior to 
dosing with study treatment (AZD5363/placebo or Paclitaxel). For laboratory data and vital 
signs data, any assessments made on day 1 will be considered pre-dose. Where safety data are 


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summarised over time, study day will be calculated in relation to date of first treatment 
(AZD5363 or placebo).
Handling missing safety data
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “< x” (i.e., below the lower limit of quantification) or > x (i.e., above the upper limit 
of quantification) will be imputed as “x” in the calculation of summary statistics but displayed 
as “< x” or “> x” in the listings.
3.4.7
Duration of Exposure
Total duration of exposure will be calculated as 
For AZD5363 drug:
Date (last day of week of last dose of AZD5363) – Date (first dose of AZD5363) + 1
For paclitaxel: 
For patients who discontinued paclitaxel therapy during the 1st or 2nd week of a dosing cycle 
Date (last day of week of last dose of paclitaxel) – Date (first dose of paclitaxel) + 1
Otherwise 
Date (last day of cycle of last dose of paclitaxel) – Date (first dose of paclitaxel) + 1
3.4.8
Dose Intensity 
Dose intensity of AZD5363 and paclitaxel will be addressed by considering relative dose 
intensity (RDI) and Percent intended dose (PID), defined as follows:
RDI = 100% * d/D
where d is the actual cumulative dose delivered up to the earlier of progression (or a censoring 
event) or the actual last day of dosing and D is the intended cumulative dose up to the earlier 
of progression (or a censoring event) or the actual last day of dosing plus the protocol-defined 
post-dose rest period. 
PID = 100% * d1/D1
Where d1 is the actual cumulative dose delivered up to progression (or a censoring event) and 
D1 is the intended cumulative dose up to progression (or a censoring event).  D1 is the total
dose that would be delivered, if there were no modifications to dose or schedule.
RDI and PID for AZD5363 and paclitaxel will be calculated for the entire intended treatment 
period (censored at data cut-off).


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Examples of dose intensity:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.5
Derivation of pharmacokinetics variables:
PK concentration data will be summarised and displayed graphically in the CSR. Details of 
sample collections are provided in CSP section 6.6.
The pharmacokinetic analysis, i.e. derivation of pharmacokinetic variables will be performed 
by Quantitative Clinical Pharmacology, AstraZeneca using Population PK methods. These 
analyses will be described in a separate modeling analysis plan, and the results will not be 
reported in the CSR. 


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3.6
Derivation of pharmacodynamic variables
pPRAS40, total PRAS40, pAKT, pGSK3β, CTC count from platelet rich plasma samples will 
be reported in the Clinical Study Report (CSR). Other exploratory biomarker research will be 
reported separately from the CSR.
3.7
Derivation of other exploratory biomarker research variables
Results from the other exploratory biomarker and pharmacogenetic research, including 
matched tumour biopsy samples and investigating the relationship between AZD5363 
exposure and these exploratory biomarkers, are out of scope of this SAP, and will be reported 
separately from the CSR.
4.
ANALYSIS METHODS
4.1
General principles
The data cut off for primary analysis will be performed when recruitment to Part B has 
completed and 76 PFS events in the overall population, and 38 events in the PIK3CA mutation
detected subgroup, have occurred.
The secondary outcome variable of OS will be formally analysed if there is sufficient data to 
warrant formal statistical analysis (ie enough OS events at the primary analysis to analyse 
OS).
In each of the following groups and sub-groups (ITT population):
i.
overall (regardless of PIK3CA status) 
ii.
PIK3CA mutation detected stratum
iii.
PIK3CA mutation not detected stratum
the hypotheses described below will be tested.  The assignment of mutation status is described 
in more detail in section 1.2.
H0: No treatment difference in terms of PFS between AZD5363 plus paclitaxel and 
AZD5363 matching placebo plus paclitaxel (i.e. HR =1)
H1: There exists a treatment difference in term of PFS between AZD5363 plus paclitaxel 
and AZD5363 matching placebo plus paclitaxel (i.e. HR ≠1)
Each of i, ii and iii will be tested at the 1 sided 10% significance level and the corresponding 
confidence interval (2-sided 80% CI) will be provided. No adjustments for multiplicity will be 
performed for multiple subgroups or interim analyses. The above hypotheses are considered as 
the primary analyses.
 


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AZD5363 + paclitaxel is hereafter referred to as AZD5363, and AZD5363 matching placebo 
+ paclitaxel is hereafter referred to as placebo. Since patients were randomised into this study 
based on the stratification factor PIK3CA mutation status (detected or not detected), all 
statistical analysis modelling in the overall population will include a term for this stratification 
covariate. 
For stratification based on PIK3CA mutation, changes to stratum allocation after
randomization will be discussed in the CSR. Analysis will be based on confirmed stratum
allocation (for example if the baseline status was ‘PIK3CA not detected’, but the patient’s
tissue/blood(ctDNA) was subsequently determined to be ‘PIK3CA detected’ , analysis will 
proceed based on the patients last known PIK3CA status or that determined from the 
allocations recorded in the IVRS randomization procedure). 
Summaries of the safety and efficacy data will be produced using standard summary statistics. 
For continuous variables, these statistics will include (but not be limited to) the mean, 
standard deviation, median, minimum and maximum. For categorical data, these statistics will 
consist of frequencies and associated percentages. Missing safety and efficacy data will not be 
included in the numerator of the percentage calculation.
Measures of location (minimum and maximum) will be reported to the same degree of 
precision as the raw data, other measure of location (mean, median) will be reported to one 
further degree of precision. Measures of spread (standard deviation, standard error) will be 
reported to two further degree of precision. Where confidence intervals are provided, unless 
otherwise stated, they will have been calculated using an assumption of normal distribution.
All safety and efficacy data will be listed.
4.2
Analyses
Table 9 summarises all formal statistical analyses planned for this study:
Table 9
Formal statistical analyses planned for the primary and secondary 
endpoints
Endpoint Analysed 
Analyses
Progression free survival (PFS)  
Primary Analysis: Cox proportional hazards model with 
covariates for PIK3CA mutation status in the overall 
population and repeated for subgroup of PIK3CA mutation
detected patients and PIK3CA not detected patients
separately.
Sensitivity analysis: 
Evaluation-time bias assessment
Attrition bias assessment


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Table 9
Formal statistical analyses planned for the primary and secondary 
endpoints
Endpoint Analysed 
Analyses
Overall Survival (OS)
Cox proportional hazards model with covariates for
PIK3CA mutation status in the overall population and 
repeated for subgroup of PIK3CA mutation detected 
patients and PIK3CA not detected patients separately.
Tumour Size (TS)
ANCOVA with covariates for PIK3CA mutation status, 
time from randomisation to baseline tumour assessment 
and baseline tumour size in the overall population and 
repeated for subgroup of PIK3CA mutation detected 
patients and PIK3CA not detected patients separately.
Duration response rate (DRR)
Logistic regression with covariates for PIK3CA mutation 
status in the overall population and repeated for subgroup 
of PIK3CA mutation detected patients and PIK3CA not 
detected patients separately.
Objective response rate (ORR)
Main Analysis: Logistic regression with covariates 
forPIK3CA mutation status in the overall population and 
repeated for subgroup of PIK3CA mutation detected 
patients and PIK3CA not detected patients separately.
* Some analyses specified above will be repeated based on determination of PIK3CA status 
via ctDNA samples only and via tissue samples only.
4.2.1
Subgroup analyses
The following subgroups have been defined for the primary analysis:
!
PIK3CA mutation status (detected/not detected in ctDNA or tissue samples)
!
PIK3CA mutation (detected/not detected in ctDNA samples only)
!
PIK3CA mutation (detected/not detected in tissue only)
!
Age (<=65, >65)
!
Region (Asian/Not Asian)
!
Visceral disease (Yes/No)
!
Prior taxane use in adjuvant/neoadjuvant setting (Yes/No)


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Where variables are not categorical (e.g. age), cut-offs have been defined to determine 
subgroup classification. Statistical analysis will be performed when there are a minimum of 10 
patients/events in a subgroup.
Mutation PIK3CA status (detected/not detected) and sample type (tissue/ctDNA) will be 
summarised and listed. To investigate the concordance between the results of the two sample 
types, an analysis will be done using kappa statistics with 95% confidence intervals. 
4.2.2
Primary variable – Progression Free Survival (PFS)
Primary analysis
PFS will be summarised using Kaplan-Meier (KM) methods.  Estimates of median PFS with 
CIs and proportion of patients progression-free at 6 months and 1 year will be presented by 
treatment group for the overall analysis and in the analysis of PIK3CA mutation detected
patients and PIK3CA not detected group.  In addition, an analysis of PFS will be conducted on 
the subset of patients who have PIK3CA mutation detected by blood (ctDNA) only.
Kaplan Meier plots of PFS will be presented for the following scenarios by treatment 
(AZD5363 or placebo): 
a.
overall population by treatment regardless of PIK3CA mutation status, 
b. by PIK3CA mutation (detected/not detected) as specified in the protocol (any 
method) and treatment, 
c.
by PIK3CA mutation (detected/not detected in ctDNA samples only) and 
treatment, 
d. by PIK3CA mutation (detected/not detected in tissue samples only) and 
treatment, 
e.
by PIK3CA mutation (detected only) in ctDNA and tissue samples,
f.
by PIK3CA mutation (not detected only) in ctDNA and tissue samples.
g. by PIK3CA mutation (detected/not detected) by protocol definition and by 
overall treatment regardless of PIK3CA mutation status (i.e. overlay of a and b 
above)
The primary analysis of progression free survival for all randomised patients (ITT) will be 
performed by Cox proportional hazard model using SAS® PROC PHREG with the Efron 
method to control for ties. PFS will be analysed for the overall population and for the 
subgroup of PIK3CA mutation detected patients and PIK3CA mutation not detected patients,
using the protocol defined definition and based on ctDNA only.  PFS will be analysed using 
separate Cox proportional-hazards models allowing for the effect of treatment and including a 
term for PIK3CA mutation status in the overall analysis (mutation detected or not detected).


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The hazard ratios in the overall population and in the PIK3CA mutation detected and PIK3CA
mutation not detected subgroups (HR; AZD5363 + paclitaxel: placebo + paclitaxel) for 
treatment will be estimated 
A forest plot will be used to display (on a single plot) the HRs and 2 sided 80% confidence 
intervals for the overall population subset by PIK3CA mutation status and the subgroups 
detailed in section 4.2.1.
Proportionality assumption
The assumption of proportionality, for all time to event analyses, will be assessed firstly by 
examining plots of complementary log-log (event times) versus log (time) and, if this raises 
concerns, subsequently fitting a time dependent covariate (adding a treatment-by-time or 
treatment-by-ln(time) interaction term) to the model to assess the extent to which this 
represents random variation. If a lack of proportionality is evident then the HR can still be 
meaningfully interpreted as an average HR over time unless there is extensive crossing of 
thetime to event curves.
Sensitivity analysis
The following sensitivity analyses will be performed on PFS data using the ITT.
Evaluation-time bias assessment
For PFS, a supportive analysis will be performed to assess time assessment bias via an
Evaluation-time bias approach (Sellke et al. 1983, Sun et al. 2010). This will be 
performed using a validated SAS program for generation of the p-value. The most 
pragmatic and preferred approach to assessing evaluation-time bias is to analyse, using 
standard log-rank , the midpoint between the time of progression and the previous 
visit, this approach has been shown to be robust to even highly asymmetric assessment 
schedules. 
To support this analysis, the mean of patient-level average inter-assessment times will 
be tabulated for each treatment.
Attrition bias assessment
A further analysis of the primary endpoint will be conducted, whereby patients who 
received subsequent anti-cancer therapies prior to progression (or death in the absence 
of progression) will be censored at the time patients received subsequent therapies, 
while patients who progress or die following two or more missed visits will not be 
censored. The analysis will use the same approach as the primary analysis model 
(outlined within Section 4.2.2). A list of relevant anti-cancer therapies will be provided 
by the study team prior to database lock (DBL). In support of this analysis, a Kaplan-
Meier plot where the roles of events and censored observations are reversed will be 
presented to assess the impact of rate and nature of censoring on final results. 


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Additional supportive summaries/graphs
A summary of the number of patients who have incomplete PFS follow-up, i.e. were alive and 
progression free at the date of data cut-off and had not had a RECIST assessment within 12 
weeks of the data cut-off will be provided by treatment group. Additionally, summary 
statistics will be given for the number of days from censoring to data cut-off for all censored 
patients.
A summary of the median duration of follow-up will also be presented. Each patient’s 
duration of follow-up will be defined as the number of days from randomisation to the date of 
last contact. Duration of follow-up will be summarised using medians:
!
In censored (not progressed) patients only: Time from randomisation to date of 
censoring (date last known to be non-progressor) and
!
In all patients: Time from randomisation to the date of progression/date of death or 
to the date of censoring for censored patients.
Duration of follow-up will be presented for the overall population, and the PIK3CA detected 
and not detected strata (protocol defined).  All of the collected RECIST data will be listed for 
all randomised patients. 
4.2.3
Secondary variables
4.2.3.1
Change in tumour size at 12 weeks
The absolute values and percentage change in target lesion tumour size from baseline will be 
summarised using descriptive statistics and presented at each time point and by randomised
treatment group.
The number and percentage of subjects in each treatment group whose week 12 data is 
imputed will also be presented.  
At blind review, plots of the residuals from fitting an ANCOVA model (including covariates 
for baseline tumour size, time from randomisation to baseline assessment and PIK3CA
mutation status) to the percentage change from baseline at week 12 will be produced.  If the 
residuals appear to follow a normal distribution then the same model will be used in the final 
analysis with an additional term for treatment. The model will be repeated in each of the 
PIK3CA mutation subgroup (protocol definition) analyses. In each case, the results to be 
presented include: the adjusted least square means for each treatment, the difference in least 
square means between treatments, 
 
 


Statistical Analysis Plan 
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In each case, the results to be presented include: 
the adjusted geometric least square means for each treatment (back transformed to the original 
scale), the ratio of the geometric least square means,
Should neither of the above parametric models produce normally distributed residuals, a non-
parametric approach will be applied instead. The recommended method is an ANCOVA 
model on the ranked percentage change in tumour size, including a covariate for baseline 
tumour size, time from randomisation to baseline assessment, treatment and PIK3CA status.  
The ranking will be of the analysis data set following appropriate imputation.  The subject 
with the greatest reduction in target lesion tumour size will be assigned the lowest rank, with 
smaller changes and increases in tumour sizes taking increasing ranks. Deaths will be assigned 
the highest rank. The model will be repeated in each of the PIK3CA mutation subgroup 
analyses.
If a non-parametric analysis is performed, the p-value from the ANCOVA model will be 
presented together with the Hodges Lehmann estimate of the median difference and 
 The median percentage 
change and range will be presented for each treatment group, together with the number of 
subjects and percentage of subjects in each treatment group whose 12 week data is imputed 
(imputation as described above or using a regression method) in the non-parametric analysis.
Tumour size is also to be presented graphically using waterfall plots for each treatment group, 
to present each subject’s week 12 percentage change in tumour size as a separate bar, with the 
bars ordered from the largest increase to the largest decrease.  The waterfall plot will be 
repeated separately by PIK3CA mutation status at entry (protocol definition) and treatment 
group. A reference line at the –30% change in tumour size level will be added to the plots, 
which correspond with the definitions of ‘complete or partial’ response. In these waterfall 
plots, the subjects whose week 12 percentage change in tumour size is based on an imputation
(imputation as described above or using a regression method), due to missing target lesion 
data, will be clearly identified (by different coloured bars/symbols on the waterfall plot). A 
waterfall plot by treatment group of best percentage change will also be reported, repeated for 
mutation subgroups (PIK3CA detected and not detected, based on the protocol definition).
4.2.3.2
Overall Survival
The analysis population for OS will be the ITT. OS on AZD5363 in combination with weekly 
paclitaxel compared to weekly paclitaxel plus placebo will also be analysed using the same 
methods as for PFS.  Estimates of median OS with CIs will be presented by treatment group 


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for the overall analysis and in the analysis of PIK3CA mutation detected patients and PIK3CA
not detected group.  In addition, an analysis of PFS will be conducted on the subset of patients 
who have PIK3CA mutation detected/not detected by blood (ctDNA) only.
Cox proportional hazard models will be conducted on the overall analysis and in the analysis 
of PIK3CA mutation detected patients and PIK3CA not detected group (protocol definition) 
only.
Analysis will occur when a sufficient number of events are available in the overall population, 
i.e. when 50% of patients have died. An additional analysis after 75% of patients have died 
may also be carried out. If fewer than 50% of patients have died at the time of the primary 
PFS analysis, then the OS data will only be summarised at that time. Analyses of PFS and OS 
at other time points may be performed as deemed appropriate. 
Kaplan Meier plots of OS will be presented for the same scenarios that are outlined in points a 
b and g for the primary analysis above.
4.2.3.3
Objective Response Rate (ORR)
Objective response rate (ORR) as defined in section 3.2.2.1 will be reported and analyzed over 
the whole study and reported at week 12 in the ITT. 
A tabulation of response rate at 12 weeks and proportion progression free at 12 weeks will be 
presented for the overall population, PIK3CA detected and PIK3CA not detected.
Best overall response will be presented by treatment group at time of PFS analysis.  
Frequencies and percentages will be presented for complete responses and partial response, 
stable disease, progressive disease and not evaluable.  Summaries will be repeated based on 
the overall population, PIK3CA detected, PIK3CA not detected, PIK3CA detected (blood 
(ctDNA)) and PIK3CA not detected (blood (ctDNA)).
Objective tumour response rates will be compared between the two treatment arms for 
scenarios i – iii outlined in the primary analysis above using a logistic regression model 
allowing for the effect of treatment and adjusted for PIK3CA mutation status in the overall 
population.  The analysis will also be repeated based on PIK3CA mutation detected/not 
detected by blood (ctDNA) only.
The objective tumour response rate will be estimated for each arm. If there is an imbalance in 
the covariates, adjusted response rates will also be presented. These are the counterparts of 
lsmeans from linear models and require conditioning on one arm’s observed response rate. An 
estimate statement would be used that weights log-odds in line with the prevalence of the 
covariates.


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4.2.3.4
Duration of Response (DoR)
Duration of response (DoR) is defined in section 3.2.2.2 will be presented by using Kaplan 
Meier plots and KM estimates. Kaplan Meier plots of DoR will be presented for scenarios a, b 
and g detailed in the primary analysis description above.  DoR in the responding patients will 
be presented as individual line plots for each patient, with lines indicating the DoR and 
symbols indicating whether the response had ended (progressed) or censored at the data cut 
off.  
Supporting summary tables will be presented on the overall population and on the analysis of 
PIK3CA mutation detected patients and PIK3CA not detected group (protocol definition).
4.2.3.5
Durable Response Rate (DRR)
Durable response rate (DRR) as defined in section 3.2.2.3 will be reported and analyzed in the 
ITT population set. Frequencies and percentages will be presented for patient with durable 
response (complete or partial response lasting continuously for at least 24 weeks). 
Durable response rate (DRR) will be compared between the two treatment arms in overall 
population, PIK3CA mutation detected, PIK3CA mutation not detected, detected in blood 
(ctDNA) only and not detected in blood (ctDNA) only subgroups using a logistic regression 
model allowing for the effect of treatment and adjusting for PIK3CA mutation status in the 
overall analysis.
4.2.3.6
Health related quality of life (HR QoL) data 
Heath related quality of life (HR QoL) is defined in section 3.3. Tables of summary statistics 
will be provided for the 15 domains of the QLQC-30 and any further domains of the BR-23. 
Responses from individual items will be listed only. Where sufficient data are available then 
summary statistics (frequencies and percentages) will be presented by treatment group for the 
following:
!
Summary of compliance of subjects to the PRO instruments.
!
Summary of subjects best QoL response
!
Summary statistics (n, mean, median, SD, minimum, maximum) for domain scores 
over time
!
Summary statistics (n, mean median, SD, minimum, maximum, q1, q3) for change 
from baseline in domain scores and categories of change from baseline
Time-to-deterioration will only be reported and analysed, should initial review of the 
summary outputs for the QoL data indicate that it would be meaningful.  In case that sufficient 
data is collected, and further analysis is required a log-rank test would be implemented to 
estimate the hazard ratios and corresponding confidence intervals of the effect of treatment. 


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PROC LIFETEST would be used to estimate these measures. Breslow method of handling of 
ties would be used. For further exploration, a repeated-measures ANOVA method may be 
implemented taking treatment effect as a factor and each of the PRO scores as the continuous 
response thus estimating the effect of treatment on the changes in score. 
4.2.4
Safety
Safety data will be listed and summarised only. No formal statistical analyses will be 
performed on the safety data.  All safety data will be summarised by initial treatment group 
(AZD5363 or placebo) including patients who have dose modification. However, some 
listings such as AEs listings will display the actual dose the patient received at onset of an AE. 
A reduced set of safety outputs will be replicated for patients having PIK3CA mutation
detected and mutation not detected status (using the protocol definition).
4.2.4.1
Adverse Events
All AEs occurred will be summarised (percentages and frequencies) by actual treatment group 
(AZD5363 and Placebo) using MedDRA system organ class, preferred term and maximum 
CTCAE grade (version 4.0). 
Any AE occurring before the first dose of IP (i.e., before Cycle 1 Week 1 Day 2) will be 
included in the data listings but will not be included in the summary tables of adverse events. 
Any AE occurring within the defined 28 day follow-up period after discontinuation of study 
therapy (AZD5363/placebo and paclitaxel) will be included in the AE listings and summaries. 
AEs occurring after the 28-day follow-up period after discontinuation of IP will be listed, but 
not included in the summaries. AE occurred before first dose of IP or after 28 days follow-up 
period will be flagged in AE listings.
All reported AEs will be listed along with the date of onset, date of resolution (if AE is
resolved), investigator’s assessment of severity and relationship to study drug. Frequencies
and percentages of patients reporting each preferred term will be presented (i.e. multiple
events per patient will not be accounted for apart from on the episode level summaries).
The following tables of summaries will also be produced:
!
Summary information (the number and percent of patients by treatment) will be 
tabulated for all AEs and all AEs (by episode)
!
All AEs
!
All AEs with causality related to study medication (AZD5363/Paclitaxel/both)
!
All serious adverse events (SAEs)
!
All SAEs with causality related to study medication (AZD5363/Paclitaxel/both)


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!
AE leading to study medication (AZD5363/Paclitaxel/both) interrupted
!
AEs leading to discontinuation of study medication (AZD5363/Paclitaxel/both)
!
AEs leading to discontinuation of AZD5363/Paclitaxel/both, causally related to 
AZD5363/Paclitaxel/both
!
AEs leading to dose reduction of study medication (AZD5363/Paclitaxel)
!
AEs with an outcome of death
!
AEs with an outcome of death, causally related to study medication 
(AZD5363/Paclitaxel/both)
!
AEs with CTCAE grade 3 or higher
!
AEs with CTCAE grade 3 or higher, causally related to study medication 
(AZD5363/Paclitaxel/both)
!
Other significant AEs
!
Other significant AEs causally related to study medication 
(AZD5363/Paclitaxel/both)
An overall summary of the number and percentage of patients in each category will be 
presented, as will an overall summary of the number of episodes in each category. With the 
exception of Other Significant AEs, all the above categories will be summarised for each 
initial treatment group by system organ class and preferred term. In addition, a truncated 
adverse event table of most common AEs, showing all events that occurs in at least 5% of 
patients overall will be summarised by preferred term, by decreasing frequency. 
AEs will be assigned CTCAE grades (National cancer institute (NCI) CTCAE version 4.0) 
and summaries of the number and percentage of patients will be provided by maximum
CTCAE grade, preferred term and initial treatment group. Fluctuations observed in CTCAE 
grades during study will be listed.
In addition, serious adverse events, other significant adverse events, adverse events leading to 
discontinuation of treatment, adverse events leading to dose interruption of AZD5363/placebo 
and paclitaxel adverse events with causality AZD5363/placebo and adverse events of special 
interest will be flagged in the relevant listing. Key patient information for serious adverse 
events and adverse events leading to death will be listed.
A summary of deaths (categorised as related to disease under investigation, AE 
outcome=death or both, AE with outcome=death >=28 days after last treatment and Patient 
with unknown reason for death) will be provided by number and percentage of patients by 
initial treatment group and a corresponding listing will also be produced. In this table, patients 


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who died more than 28 days following their last dose of AZD5363/Placebo and did not die 
from disease progression, it is assumed they died from an AE. 
Burden of adverse event of diarrhoea
The burden of AE of diarrhoea will be determined for each patient in the safety population 
and summarised.
                          
                                                                                                            
 
 
 
 
 
 
 
 
 
 
 
 
Grouped adverse events of special interest
Preferred terms used to identify adverse events of special interest will be listed and 
documented in the Study Master File. Groupings of AE will be based on preferred terms 
provided by the medical team prior to unblinding.
Grouped summary tables of certain MedDRA preferred terms will be produced. For each 
‘grouped’ term, the number (%) of patients experiencing any of the specified terms will be 
presented by maximum CTCAE grade. Time to onset of first AE for each grouped term and 
preferred term within it will also be produced. A listing of the preferred terms in each 
grouping will be provided. Changes observed in CTCAE grade during study will be listed 
only.


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Additional summaries of the above-mentioned grouped AE categories will include number 
(%) of patients who have:
!
At least one adverse event of special interest presented by outcome
!
At least one adverse event of special interest by CTCAE grade
!
At least one adverse event of special interest causally related to study medication 
(AZD5363/placebo, paclitaxel, AZD5363/placebo and paclitaxel)
!
At least one adverse event of special interest leading to discontinuation of 
AZD5363/placebo.
Go/no-go Criteria
 
 
 
4.2.4.2
Laboratory parameters
All laboratory data (absolute value), change from baseline and percentage change from 
baseline values will be listed and summarised using descriptive statistics at each scheduled 
assessment time by treatment groups. 
For all laboratory variables, which are included in the CTCAE version 4.0, the CTCAE grade 
will be calculated and summarised using frequency counts and percentages in the form of 
shifts from baseline to maximum grade post baseline. 
For urinalysis, shift table comparing baseline to maximum value by treatment will be 
presented (i.e. using number of patients with results of negative, trace or positive). 


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Clinically significant laboratory values will be listed. Laboratory parameters will be 
summarised and listed by treatment groups.
Frequencies and percentages will be presented for:
!
Elevated Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) by 
maximum total bilirubin during the study.
−ALT <= 1x , > 1x – 3x, > 3x – 5x, > 5x – 10x, > 10x – 20x and > 20x ULN
during the study
−AST <= 1x, > 1x – 3x, > 3x – 5x, > 5x – 10x, > 10x – 20x and > 20x ULN
during the study
−Total bilirubin <= 1x, > 1x - 1.5x, > 1.5x – 2x, > 2x ULN during the study
!
Narratives will be provided for patients who have ALT >3x ULN plus Total 
Bilirubin >2x ULN or AST >3x ULN plus Total Bilirubin >2x ULN at any visit.
Individual patient data where ALT or AST plus bilirubin are elevated at any time will be 
listed.
Box-plots of absolute values and change from baseline in all hematological and clinical 
chemistry variables will be presented for scenarios i – iii outlined in the primary analysis 
above.
For glucose, screening values (fasted only) will be listed. All other glucose assessments will 
be reported as separately regardless of the fasting/non-fasting status assigned to them. In the 
clinical chemistry shift tables, CTCAE grading will be used on all glucose assessments 
regardless of fasting status. It is acknowledged that while CTCAE grading is intended for 
fasted samples, the use of this grading on all assessments is a conservative approach which 
allows comparison of the placebo and active treatment groups.   
4.2.4.3
Vital Signs
Vital signs (SBP, DBP and pulse) will be listed and summarised using descriptive statistics 
over time in terms of absolute values and changes from baseline at each scheduled time point 
by treatment group using descriptive statistics.  Box-plots for absolute values and change from
baseline for SBP, DBP and pulse will be presented graphically for scenarios i – iii outlined in 
the primary analysis above.
4.2.4.4
ECG parameters and echocardiogram data
Overall evaluation of ECG will be summarised by cycle using frequency counts and 
percentage of patients for each treatment group as normal or abnormal, and the relevance of 
the abnormality will be summarised by “clinically significant” or “not clinically significant”. 


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In addition, a shift table comparing baseline (normal, abnormal - not clinically significant, 
abnormal - clinically significant) to last observation on treatment will also be presented. 
Continuous ECG measurements will be summarised over time in terms of absolute values and 
change from baseline at each scheduled measurement by dose group. 
The baseline value for each parameter is defined as the last available value before the first 
dose of study treatment in cycle 1.
The number and percentage of patients with increases of QTcB and QTcF of >30msec and 
>60msec from baseline, and QTcB and QTcF values of >450msec, >480msec and >500msec 
will be produced.
Left ventricular ejection fraction (LVEF) will be summarised over time in terms of absolute 
values and changes from baseline at each scheduled measurement by treatment group.
Box and whisker plots of absolute values and change from baseline for all continuous ECG 
variables and LVEF will be presented for scenarios i – iii outlined in the primary analysis 
above. A listing of echocardiography will be provided by treatment group.
4.2.5
Treatment Exposure
The following summaries related to study treatment and dose reductions /interruptions/
discontinuation will be generated:
!
Total exposure of AZD5363/placebo and paclitaxel
!
Actual exposure of AZD5363/placebo and paclitaxel
!
Duration of therapy at starting dose of AZD5363/placebo and paclitaxel
!
Total number and duration of dose interruptions and modifications of 
AZD5363/placebo
!
Total number and duration of dose interruptions, delays and reductions of paclitaxel
!
Time to dose discontinuation of AZD5363/placebo and paclitaxel
!
Time to first dose interruptions of AZD5363/placebo and paclitaxel
!
Time to first dose reduction of AZD5363/placebo and paclitaxel
!
Time to first dose delay of paclitaxel
!
Reasons for dose reduction, dose interruptions, and dose modifications of
AZD5363/placebo


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!
Reasons for dose reduction, dose interruptions, and dose delays of paclitaxel
!
Number (%) of patients summarised by total number cycles received of 
AZD5363/Placebo and paclitaxel.
!
PID and RDI of AZD5363/placebo (entire intended treatment period and according 
to defined treatment periods in weeks)
!
PID and RDI of paclitaxel (entire intended treatment period and according to 
defined treatment periods in weeks)
For patients on study treatment at the time of the analysis, the data cut off (DCO) date will be 
used to calculate exposure.
All treatment information data will be listed by treatment group.
4.2.6
Demography
Information collected at baseline will be summarised by randomised treatment group. A 
subset of demography outputs will be repeated for subjects who have PIK3CA mutation 
detected/not detected status.  
4.2.7
Pharmacokinetics
In the calculation of plasma concentration summary statistics, values below the lower limit of 
quantification (LLOQ) will be handled according to the following rules:
!
If, at a given time point, 50% or less of the plasma concentrations are non-
quantifiable (NQ), the geometric mean (gmean), coefficient of variation (CV), 
gmean ± standard deviation (SD), arithmetic mean, SD and median will be 
calculated by substituting the LLOQ for values which are NQ. The minimum at that 
time point will be reported as NQ.
!
If more than 50%, but not all, of the concentrations are NQ, the gmean, CV, gmean 
± SD, arithmetic mean and SD will be reported as not calculable (NC). The 
minimum and median at that time point will be reported as NQ.
!
If all the concentrations are NQ, the gmean, arithmetic mean, median, minimum and 
maximum will be reported as NQ and the CV, gmean ± SD and SD as NC.
!
If the calculation of the gmean - SD results in a value less than the LLOQ, NQ will 
be displayed.
The plasma concentrations determined using sparse PK sampling scheme, at sampling time 
points, will be summarised and listed. Box plots will be produced for the PK concentration 
data on the original raw scale.  The geometric mean may also be displayed graphically on the 
linear and log linear scale.


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4.2.8
Exploratory outcome variables
The exploratory analyses discussed in the following sections will be included in the CSR, 
unless otherwise stated.
WHO performance status
WHO performance status will be listed only in the CSR.
Biomarkers Analysis
All biomarker analysis will be performed on the ITT analysis set patients for whom data is 
available. The following biomarkers will be reported in the CSR for all measured timepoints. 
1. PRP data:
!
phospo-PRAS40
!
Total PRAS40
!
pAKT
!
pGSK3β
For each biomarker there will be two baseline results defined; one before the first dose of 
paclitaxel and one before the first dose of AZD5363. The absolute value and percentage 
change from baselines will be summarised at each time point, by dose and schedule. Standard 
summary statistics n, mean, standard deviation, median, minimum and maximum will be 
presented.
Box plots of percentage change from baseline (pre-paclitaxel) of each biomarker will be 
presented by treatment and timepoint. Line plots of mean absolute values over time split by 
treatment may be produced as well as line plots of individual patient’s absolute values over 
time split by treatment.
2. CTC count
The absolute values will be summarised at each time point, by treatment. Standard summary 
statistics n, mean, standard deviation, median, minimum and maximum will be presented. The 
number of patients with < 5 vs ≥ 5 CTCs per 7.5 mL of whole blood will be presented.  
Line plots of individual patient’s absolute values will also be plotted by timepoint split by 
treatment.
If there are sufficient data, the association between CTC count at baseline (< 5 vs ≥ 5 CTCs 
per 7.5 mL) with outcome (PFS) by treatment may be explored.  For the patients with 
increased baseline CTCs (≥ 5 CTCs per 7.5 mL), the association between CTC decrease to <5 


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per 7.5ml vs not at Cycle 2 Week 1 Day 1 and Cycle 3 Week 1 Day 1 with outcome (PFS) by 
treatment may be explored.
5.
INTERIM ANALYSES
The first interim analysis will be done when the recruitment of 40 patients have been 
completed and followed up for 12 weeks (or progressed or died prior to 12 weeks). The 
interim analysis will be based on efficacy variables i.e. change in tumour size at 12 weeks.  
The description of statistical analysis at the interim will be same as section 4.2.
Additionally, the following variables will be summarised (frequency and percentage) by 
treatment groups for overall population.
!
Response rate at week 12
!
Best Objective response 
!
Percentage of patients without progression
The above stated analysis will be performed for overall population, PIK3CA mutation-positive 
patients and non-detected patient population separately.
The second interim analysis will be conducted when at least 38 PFS events across both 
PIK3CA mutation subgroups have been achieved and 30 PIK3CA mutation detected patients 
have completed 12 week follow up period (or progressed prior to 12 weeks).
The 2nd interim analysis will be conducted upon the following efficacy endpoints for the 
overall population, PIK3CA mutation detected and PIK3CA mutation not detected subgroups :
!
Change in tumour size at week 12
!
Progression-free survival
!
Duration of response
Additionally the following variables will be summarised:
!
Progression status
!
Progression free survival
!
Best objective response
More details on the interim analysis can be found in the interim SAP.


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6.
CHANGES OF ANALYSIS FROM PROTOCOL
The following changes have been made from the analysis outlined in the protocol:
1. The analysis of HR QoL C30/BR23 has been restricted to compliance, best QoL, 
summary of domain scores, change from baseline, and change from baseline
categorical status. The rationale for this change is to enable the exploration of the 
data in the relevant populations of interest. From this initial exploration, further 
outputs outlined in the protocol may be produced should they be deemed 
necessary.
7.
REFERENCES
Sellke et al. 1983
Sellke, T. and Siegmund, D. Sequential analysis of the proportional hazards model. 
Biometrika 70: 315-326, 1983
Sun et al. 2010 
Sun X, Chen C. Comparison of Finkelstein’s Method With the Conventional Approach for 
Interval-Censored Data Analysis. Stat Biopharm Research 2010. 2:97-108.
8.
APPENDIX (NOT APPLICABLE)


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