BEECH: Investigating Safety, Tolerability and Efficacy of AZD5363 When Combined With Paclitaxel in Breast Cancer Patients

Sponsor

AstraZeneca (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT01625286

Collaborator

(none)

148

Enrollment

Locations

Arms

122.9

Anticipated Duration (Months)

3.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced or Metastatic Breast Cancer ER+ve Advanced or Metastatic Breast Cancer	Drug: AZD5363 when combined with weekly paclitaxel. Drug: AZD5363 when combined with weekly paclitaxel. Drug: AZD5363when combined with weekly paclitaxel. Drug: A placebo in combination with weekly paclitaxel.	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

148 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Study of AZD5363 Combined With Paclitaxel in Patients With Advanced or Metastatic Breast Cancer. Comprising a Safety Run-In and a Placebo-controlled Randomised Expansion in ER+ve Patients Stratified by PIK3CA Mutation Status

Actual Study Start Date :

Oct 3, 2012

Actual Primary Completion Date :

Jan 28, 2017

Anticipated Study Completion Date :

Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: Intermittent schedule (2/5) See intervention description below.	Drug: AZD5363 when combined with weekly paclitaxel. 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.
Experimental: Part A: Intermittent schedule (4/3) See intervention description below.	Drug: AZD5363 when combined with weekly paclitaxel. 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.
Active Comparator: Part B: AZD5363 combined with paclitaxel See intervention description below.	Drug: AZD5363when combined with weekly paclitaxel. 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.
Placebo Comparator: Part B: paclitaxel combined with placebo See intervention description below.	Drug: A placebo in combination with weekly paclitaxel. 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.

Outcome Measures

Primary Outcome Measures

Dose-limiting Toxicity (DLT) Events - Part A [During Part A DLT evaluation period (Cycle 1, up to 28 days)]
An Adverse Event (AE) or laboratory abnormality considered to be related to study drug, that starts at any time during the DLT evaluation period (Cycle 1) and is dose limiting
Progression Free Survival (PFS) - Part B [From randomisation date to date of objective disease progression or death (by any cause) whichever came first, assessed every 12 wks (median total treatment duration AZD5363=325.5 days; Placebo=245 days)]
Time from randomisation to date of objective disease progression or death (by any cause in the absence of progression). Progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a >= 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, and an absolute increase of >=5mm, or progression of non-target lesions or the appearance of new lesions.

Secondary Outcome Measures

Change in Tumour Size at 12 Weeks [RECIST tumour assessments every 12 weeks]
Percentage change from baseline to week 12 in sum of longest diameters of target lesions as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1). Based on patients with measurable disease who had sufficient data available to either calculate or impute a change at 12 weeks
Objective Response Rate (ORR) at Week 12 [RECIST tumour assessments every 12 weeks]
Percentage of patients who have at least one visit response of Complete Response or Partial Response prior to any evidence of progression at week 12 as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm; Objective Response Rate (ORR) = CR + PR
Best Objective Response (BOR) [From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).]
Number of patients, taking their BOR, which is their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.
Overall Objective Response Rate [From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).]
Percentage of patients, taking their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm. Overall Response Rate (ORR) = CR + PR
Number of Subjects Without Progression Disease at Week 12 - Part A [up to 12 weeks]
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 as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.
Duration of Response (DOR) - Part B [From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).]
Date of first documentation of response (Complete Response/Partial Response) until the date of disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.. If a subject does not progress following a response, then their DOR will use the PFS censoring time.
Durable Response Rate (DRR) - Part B [From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).]
Percentage of patients who have a Complete Response (CR) or Partial Response (PR) lasting continuously for at least 24 weeks as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: PR, >=30% decrease in the sum of the longest diameter of target lesions; CR, disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.
Overall Survival - Part B [From date of randomisation, assessed every 12 weeks, up until the time of final statistical analysis. (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).]
The interval between the date of randomisation and the date of patient death due to any cause. All Part B patients were analysed, number of deaths is presented.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Provision of informed consent.
Female patient.
Aged at least 18 years.
Histological or cytological confirmation of breast cancer with evidence of advanced or metastatic disease (must be ER+ve, HER2-ve, in Part B).
World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.

Exclusion Criteria:

Clinically significant abnormalities of glucose metabolism.
Spinal cord compression or brain metastases unless asymptomatic, treated and stable (not requiring steroids).
Evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses or active infections including hepatitis B, C and HIV.
Any prior exposure to agents which inhibit AKT as the primary pharmacological activity.
Part A: more than two prior courses of chemotherapy (including taxanes) for advanced or metastatic breast cancer.

Part B: any prior chemotherapy for advanced or metastatic breast cancer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Plovdiv		Bulgaria	4004
2	Research Site	Sofia		Bulgaria	1330
3	Research Site	Calgary	Alberta	Canada	T2N 4N2
4	Research Site	Ottawa	Ontario	Canada	K1H 8L6
5	Research Site	Montreal	Quebec	Canada	H4A 3T2
6	Research Site	Quebec		Canada	G1S 4L8
7	Research Site	Brno		Czechia	656 53
8	Research Site	Paris Cedex 5		France	75248
9	Research Site	Pierre Benite CEDEX		France	69310
10	Research Site	Villejuif		France	94805
11	Research Site	Chiba-shi		Japan	260-8717
12	Research Site	Chuo-ku		Japan	104-0045
13	Research Site	Fukuoka-shi		Japan	811-1395
14	Research Site	Mitaka-shi		Japan	181-8611
15	Research Site	Oita-shi		Japan	870-0854
16	Research Site	Osaka-shi		Japan	540-0006
17	Research Site	Seongnam-si		Korea, Republic of	13620
18	Research Site	Seoul		Korea, Republic of	03080
19	Research Site	Seoul		Korea, Republic of	03722
20	Research Site	Seoul		Korea, Republic of	135-710
21	Research Site	Estado de México		Mexico	50080
22	Research Site	Juchitan		Mexico	7000
23	Research Site	Monterrey		Mexico	64460
24	Research Site	Oaxaca		Mexico	68000
25	Research Site	Lima		Peru	15036
26	Research Site	Lima		Peru	L 41
27	Research Site	Lima		Peru	LIMA 27
28	Research Site	Miraflores		Peru	15046
29	Research Site	Singapore		Singapore	119228
30	Research Site	Barcelona		Spain	08025
31	Research Site	Madrid		Spain	08035
32	Research Site	Madrid		Spain	28040
33	Research Site	Madrid		Spain	28041
34	Research Site	Malaga		Spain	29010
35	Research Site	Valencia		Spain	46010
36	Research Site	Glasgow		United Kingdom	G12 0YN
37	Research Site	Leicester		United Kingdom	LE1 5WW
38	Research Site	London		United Kingdom	SW3 6JJ
39	Research Site	Manchester		United Kingdom	M20 4BX
40	Research Site	Plymouth		United Kingdom	PL6 8DH.
41	Research Site	Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

AstraZeneca

Investigators

Study Director: Justin Lindemann, MBChB MBA, AstraZeneca

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.

Responsible Party:

AstraZeneca

ClinicalTrials.gov Identifier:

NCT01625286

Other Study ID Numbers:

D3610C00002
2011-006312-31

First Posted:

Jun 21, 2012

Last Update Posted:

Aug 23, 2022

Last Verified:

Aug 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Keywords provided by AstraZeneca

advanced breast cancer,

metastatic breast cancer,

ER+ve breast cancer,

Estrogen receptor positive breast cancer,

PIK3CA mutated advanced or metastatic breast cancer

AKT inhibitor

Additional relevant MeSH terms:

Breast Neoplasms

Paclitaxel

Albumin-Bound Paclitaxel

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Period Title: Overall Study
STARTED	12	8	5	7	6	54	56
Received AZD5363/Placebo Treatment	12	8	5	7	6	54	55
Did Not Receive AZD5363/Placebo Trt	0	0	0	0	0	0	1
COMPLETED	0	0	0	0	0	0	0
NOT COMPLETED	12	8	5	7	6	54	56

Baseline Characteristics

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo	Total
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	Total of all reporting groups
Overall Participants	12	8	5	7	6	54	56	148
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.2 (9.92)	58.8 (12.78)	56.6 (10.26)	47.1 (9.41)	49.8 (13.12)	54.3 (10.01)	57.4 (11.38)	58.8 (11.24)
Age, Customized (Count of Participants)
<50	5 41.7%	3 37.5%	1 20%	4 57.1%	2 33.3%	19 35.2%	16 28.6%	50 33.8%
>=50 - <65	5 41.7%	2 25%	3 60%	3 42.9%	3 50%	24 44.4%	26 46.4%	66 44.6%
>=65	2 16.7%	3 37.5%	1 20%	0 0%	1 16.7%	11 20.4%	14 25%	32 21.6%
Sex: Female, Male (Count of Participants)
Female	12 100%	8 100%	5 100%	7 100%	6 100%	54 100%	56 100%	148 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
Asian	1 8.3%	0 0%	0 0%	0 0%	0 0%	12 22.2%	15 26.8%	28 18.9%
Black Or African American	1 8.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 0.7%
White	10 83.3%	8 100%	5 100%	7 100%	6 100%	24 44.4%	18 32.1%	78 52.7%
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	15 27.8%	16 28.6%	31 20.9%
Other	0 0%	0 0%	0 0%	0 0%	0 0%	3 5.6%	7 12.5%	10 6.8%

Outcome Measures

1. Primary Outcome

Title	Dose-limiting Toxicity (DLT) Events - Part A
Description	An Adverse Event (AE) or laboratory abnormality considered to be related to study drug, that starts at any time during the DLT evaluation period (Cycle 1) and is dose limiting
Time Frame	During Part A DLT evaluation period (Cycle 1, up to 28 days)

Outcome Measure Data

Analysis Population Description
All Part A patients who either completed the DLT evaluation period with at least 80% of specified dose (of AZD5363 or paxlitaxel) or who experienced a DLT. DLT events were not assessed for Part B participants.

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Measure Participants	11	6	5	7	6	0	0
Number [participants]	0 0%	2 25%	0 0%	0 0%	2 33.3%

2. Primary Outcome

Title	Progression Free Survival (PFS) - Part B
Description	Time from randomisation to date of objective disease progression or death (by any cause in the absence of progression). Progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a >= 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, and an absolute increase of >=5mm, or progression of non-target lesions or the appearance of new lesions.
Time Frame	From randomisation date to date of objective disease progression or death (by any cause) whichever came first, assessed every 12 wks (median total treatment duration AZD5363=325.5 days; Placebo=245 days)

Outcome Measure Data

Analysis Population Description
Intent to Treat (ITT), all randomised patients

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Measure Participants	0	0	0	0	0	54	56
Median (95% Confidence Interval) [Months]	10.9	8.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B AZD5363, Part B Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	A hazard ratio < 1 favours AZD5363

Statistical Test of Hypothesis	p-Value	0.308
	Comments	2-sided p-value
	Method	Regression, Cox
	Comments	Cox PH model including treatment and PIK3CA status as factors/covariates

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 80% 0.60 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Tumour Size at 12 Weeks
Description	Percentage change from baseline to week 12 in sum of longest diameters of target lesions as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1). Based on patients with measurable disease who had sufficient data available to either calculate or impute a change at 12 weeks
Time Frame	RECIST tumour assessments every 12 weeks

Outcome Measure Data

Analysis Population Description
Part A:Full Analysis Set (FAS) Part B: Intent to Treat (ITT)

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Measure Participants	10	7	5	5	4	53	55
Mean (Standard Deviation) [% change from baseline]	-11.0 (33.42)	-15.7 (13.33)	-19.1 (17.73)	-18.3 (37.74)	-10.2 (24.84)	-34.2 (28.91)	-25.4 (35.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B AZD5363, Part B Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.081
	Comments	1-sided p-value
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.9
	Confidence Interval	(2-Sided) 80% -17.1 to -0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Objective Response Rate (ORR) at Week 12
Description	Percentage of patients who have at least one visit response of Complete Response or Partial Response prior to any evidence of progression at week 12 as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm; Objective Response Rate (ORR) = CR + PR
Time Frame	RECIST tumour assessments every 12 weeks

Outcome Measure Data

Analysis Population Description
Part A:Full Analysis Set (FAS) Part B: Intent to Treat (ITT)

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Measure Participants	12	8	5	7	6	54	56
Number [% of participants]	41.7 347.5%	12.5 156.3%	0 0%	0 0%	0 0%	50 92.6%	42.9 76.6%

5. Secondary Outcome

Title	Best Objective Response (BOR)
Description	Number of patients, taking their BOR, which is their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.
Time Frame	From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Measure Participants	12	8	5	7	6	54	56
Complete Response (CR)	0 0%	0 0%	0 0%	0 0%	0 0%	3 5.6%	4 7.1%
Partial Response (PR)	0 0%	2 25%	1 20%	1 14.3%	0 0%	29 53.7%	28 50%
Stable Disease (SD)	7 58.3%	4 50%	3 60%	4 57.1%	3 50%	14 25.9%	14 25%
Progression	4 33.3%	1 12.5%	1 20%	1 14.3%	2 33.3%	6 11.1%	8 14.3%
Not Evaluable (NE)	1 8.3%	1 12.5%	0 0%	1 14.3%	1 16.7%	2 3.7%	2 3.6%

6. Secondary Outcome

Title	Overall Objective Response Rate
Description	Percentage of patients, taking their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm. Overall Response Rate (ORR) = CR + PR
Time Frame	From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).

Outcome Measure Data

Analysis Population Description
Part A:Full Analysis Set (FAS) Part B: Intent to Treat (ITT)

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Measure Participants	12	8	5	7	6	54	56
Number [% of participants]	0 0%	25 312.5%	20 400%	14.3 204.3%	0 0%	59.3 109.8%	57.1 102%

7. Secondary Outcome

Title	Number of Subjects Without Progression Disease at Week 12 - Part A
Description	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 as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description
Part A Full Analysis Set (FAS). Not recorded in Part B.

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Measure Participants	12	8	5	7	6	0	0
Count of Participants [Participants]	6 50%	5 62.5%	3 60%	4 57.1%	2 33.3%

8. Secondary Outcome

Title	Duration of Response (DOR) - Part B
Description	Date of first documentation of response (Complete Response/Partial Response) until the date of disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.. If a subject does not progress following a response, then their DOR will use the PFS censoring time.
Time Frame	From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).

Outcome Measure Data

Analysis Population Description
Part B, all patients with a response in the ITT analysis set. Not collected in Part A

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Measure Participants	0	0	0	0	0	54	56
Median (95% Confidence Interval) [Months]	8.3	8.2

9. Secondary Outcome

Title	Durable Response Rate (DRR) - Part B
Description	Percentage of patients who have a Complete Response (CR) or Partial Response (PR) lasting continuously for at least 24 weeks as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: PR, >=30% decrease in the sum of the longest diameter of target lesions; CR, disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.
Time Frame	From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).

Outcome Measure Data

Analysis Population Description
Part B, ITT analysis set. Not collected in Part A

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Measure Participants	0	0	0	0	0	54	56
Number [% of participants]	48.1 400.8%	37.5 468.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B AZD5363, Part B Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.139
	Comments	1-sided p-value
	Method	Regression, Logistic
	Comments	including treatment and PIK3CA status as factors/covariates

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.53
	Confidence Interval	(2-Sided) 80% 0.93 to 2.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Overall Survival - Part B
Description	The interval between the date of randomisation and the date of patient death due to any cause. All Part B patients were analysed, number of deaths is presented.
Time Frame	From date of randomisation, assessed every 12 weeks, up until the time of final statistical analysis. (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).

Outcome Measure Data

Analysis Population Description
Part B Intent to Treat (ITT). Not collected in Part A

Arm/Group Title	Part A Schedule 1 560 mg bd	Part A Schedule 1 640 mg bd	Part A Schedule 2 360 mg bd	Part A Schedule 2 400 mg bd	Part A Schedule 2 480 mg bd	Part B AZD5363	Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly	(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
Measure Participants	0	0	0	0	0	54	56
Median (95% Confidence Interval) [months]	32.8	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B AZD5363, Part B Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	A hazard ratio < 1 favours AZD5363

Statistical Test of Hypothesis	p-Value	0.482
	Comments	2-sided p-value
	Method	Log Rank
	Comments	Cox PH model including treatment and PIK3CA status as factors/covariates

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 80% 0.48 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

	Part A Schedule 1 560 mg bd		Sched 1 - AZD5363 640 mg bd		Sched 2 - AZD5363 360 mg bd		Sched 2 - AZD5363 400 mg bd		Part A Schedule 2 480 mg bd		Part B AZD5363		Part B Placebo
Time Frame	Time of signature of informed consent throughout the treatment period up to and including the follow-up period (median follow-up AZD5363 16.9 months; Placebo 15.2 months)
Adverse Event Reporting Description	The 5% threshold is applied to treatment schedule in Part A and then the Part A AEs are labelled as MedDRA v20.0 (schedule 1) or MedDRA v18.1 (schedule 2). The 5% threshold is applied to each Part B treatment arm and then the Part B AEs are labelled as MedDRA v19.1 One patient in the placebo group did not receive placebo treatment (hence n=56 for All Cause Mortality but n=55 for SAEs and Other AEs)

Arm/Group Title	Part A Schedule 1 560 mg bd		Sched 1 - AZD5363 640 mg bd		Sched 2 - AZD5363 360 mg bd		Sched 2 - AZD5363 400 mg bd		Part A Schedule 2 480 mg bd		Part B AZD5363		Part B Placebo
Arm/Group Description	Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.		(2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.		(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.		(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.		Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.		(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly		(4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/8 (0%)		1/5 (20%)		1/7 (14.3%)		0/6 (0%)		13/54 (24.1%)		15/56 (26.8%)
Serious Adverse Events
	Part A Schedule 1 560 mg bd		Sched 1 - AZD5363 640 mg bd		Sched 2 - AZD5363 360 mg bd		Sched 2 - AZD5363 400 mg bd		Part A Schedule 2 480 mg bd		Part B AZD5363		Part B Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/12 (25%)		3/8 (37.5%)		0/5 (0%)		1/7 (14.3%)		4/6 (66.7%)		13/54 (24.1%)		8/55 (14.5%)
Blood and lymphatic system disorders
Anaemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Febrile neutropenia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Neutropenia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Febrile neutropenia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	0/55 (0%)	0
Anaemia	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Gastrointestinal disorders
Diarrhoea	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Abdominal pain	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Ascites	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Diarrhoea	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	0/55 (0%)	0
Periodontal disease	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Vomiting	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	1/55 (1.8%)	1
Diarrhoea	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Vomiting	1/12 (8.3%)	1	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
General disorders
Pyrexia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	3	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Asthenia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Pyrexia	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Immune system disorders
Drug hypersensitivity	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Infections and infestations
Lower respiratory tract infection bacterial	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Pneumonia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Urinary tract infection	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Catheter site cellulitis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Cellulitis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Device related infection	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Pneumonia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/54 (7.4%)	7	1/55 (1.8%)	1
Pyelonephritis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Urinary tract infection bacterial	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Urosepsis	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Injury, poisoning and procedural complications
Concussion	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Upper limb fracture	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	0/55 (0%)	0
Hyperglycaemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Hyponatraemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Salivary gland cancer	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Lethargy	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Renal and urinary disorders
Renal failure	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Acute kidney injury	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Pleural effusion	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	2
Pulmonary embolism	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Stridor	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Skin and subcutaneous tissue disorders
Drug eruption	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Rash pruritic	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Other (Not Including Serious) Adverse Events
	Part A Schedule 1 560 mg bd		Sched 1 - AZD5363 640 mg bd		Sched 2 - AZD5363 360 mg bd		Sched 2 - AZD5363 400 mg bd		Part A Schedule 2 480 mg bd		Part B AZD5363		Part B Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/12 (100%)		8/8 (100%)		5/5 (100%)		7/7 (100%)		6/6 (100%)		50/54 (92.6%)		48/55 (87.3%)
Blood and lymphatic system disorders
Anaemia	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	2/6 (33.3%)	2	0/54 (0%)	0	0/55 (0%)	0
Neutropenia	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	4	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Anaemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	18/54 (33.3%)	32	15/55 (27.3%)	20
Leukopenia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	5/54 (9.3%)	16	1/55 (1.8%)	2
Neutropenia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	7/54 (13%)	21	7/55 (12.7%)	26
Anaemia	6/12 (50%)	17	4/8 (50%)	16	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Leukopenia	1/12 (8.3%)	1	1/8 (12.5%)	3	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Neutropenia	3/12 (25%)	20	3/8 (37.5%)	23	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Normochromic normocytic anaemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Febrile neutropenia	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Thrombocytopenia	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	3
Cardiac disorders
Palpitations	1/12 (8.3%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	1/55 (1.8%)	1
Pericardial effusion	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Left ventricular dysfunction	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Ear and labyrinth disorders
Ear pain	1/12 (8.3%)	2	1/8 (12.5%)	2	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	2	0/55 (0%)	0
Tinnitus	1/12 (8.3%)	1	2/8 (25%)	2	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	8	0/55 (0%)	0
Vertigo	2/12 (16.7%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	2/55 (3.6%)	2
Ear canal erythema	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Hypoacusis	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Eye disorders
Lacrimation increased	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	1/7 (14.3%)	2	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Dry eye	2/12 (16.7%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	2	2/54 (3.7%)	2	1/55 (1.8%)	1
Lacrimation increased	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Photopsia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Conjunctival pallor	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Visual acuity reduced	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Vitreous detachment	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Gastrointestinal disorders
Abdominal distension	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	3	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Constipation	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	4	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Diarrhoea	0/12 (0%)	0	0/8 (0%)	0	5/5 (100%)	31	6/7 (85.7%)	34	6/6 (100%)	101	0/54 (0%)	0	0/55 (0%)	0
Dry mouth	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	1/7 (14.3%)	2	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Dyspepsia	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	1/7 (14.3%)	1	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Gastrointestinal sounds abnormal	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	8	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Mouth ulceration	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	2	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Nausea	0/12 (0%)	0	0/8 (0%)	0	3/5 (60%)	8	2/7 (28.6%)	5	5/6 (83.3%)	15	0/54 (0%)	0	0/55 (0%)	0
Odynophagia	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	2/55 (3.6%)	2
Vomiting	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	3	2/7 (28.6%)	2	4/6 (66.7%)	9	0/54 (0%)	0	0/55 (0%)	0
Abdominal distension	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	3/55 (5.5%)	3
Abdominal pain	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	4	5/55 (9.1%)	6
Abdominal pain upper	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	5/54 (9.3%)	6	0/55 (0%)	0
Constipation	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	7/55 (12.7%)	8
Diarrhoea	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	41/54 (75.9%)	228	15/55 (27.3%)	32
Dyspepsia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	5/54 (9.3%)	6	8/55 (14.5%)	8
Gastrooesophageal reflux disease	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	3/55 (5.5%)	3
Mouth ulceration	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/54 (7.4%)	5	1/55 (1.8%)	1
Nausea	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	21/54 (38.9%)	33	13/55 (23.6%)	19
Stomatitis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	15/54 (27.8%)	26	4/55 (7.3%)	4
Toothache	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	4/54 (7.4%)	6	1/55 (1.8%)	1
Vomiting	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	14/54 (25.9%)	20	8/55 (14.5%)	10
Abdominal pain	1/12 (8.3%)	1	3/8 (37.5%)	4	1/5 (20%)	1	0/7 (0%)	0	2/6 (33.3%)	2	0/54 (0%)	0	0/55 (0%)	0
Abdominal pain upper	3/12 (25%)	3	2/8 (25%)	4	0/5 (0%)	0	2/7 (28.6%)	2	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Constipation	4/12 (33.3%)	5	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Diarrhoea	11/12 (91.7%)	66	7/8 (87.5%)	57	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Dry mouth	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Dyspepsia	1/12 (8.3%)	2	1/8 (12.5%)	2	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Gastrointestinal pain	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Gingival bleeding	1/12 (8.3%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Haemorrhoids	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	2/55 (3.6%)	2
Mouth ulceration	1/12 (8.3%)	1	1/8 (12.5%)	2	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Stomatitis	2/12 (16.7%)	3	2/8 (25%)	5	0/5 (0%)	0	2/7 (28.6%)	2	3/6 (50%)	10	0/54 (0%)	0	0/55 (0%)	0
Vomiting	4/12 (33.3%)	17	2/8 (25%)	6	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Nausea	8/12 (66.7%)	23	5/8 (62.5%)	6	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Colitis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Rectal tenesmus	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Aphthous ulcer	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Dysphagia	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Flatulence	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
General disorders
Asthenia	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	4	6/7 (85.7%)	11	3/6 (50%)	3	0/54 (0%)	0	0/55 (0%)	0
Device breakage	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Fatigue	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	4	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Malaise	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Oedema peripheral	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	2/7 (28.6%)	3	2/6 (33.3%)	2	0/54 (0%)	0	0/55 (0%)	0
Peripheral swelling	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Pyrexia	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	0/7 (0%)	0	2/6 (33.3%)	3	0/54 (0%)	0	0/55 (0%)	0
Asthenia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	7/54 (13%)	8	7/55 (12.7%)	16
Fatigue	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	16/54 (29.6%)	20	11/55 (20%)	14
Influenza like illness	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	3/55 (5.5%)	3
Malaise	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/54 (7.4%)	4	4/55 (7.3%)	8
Oedema peripheral	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	8/54 (14.8%)	10	8/55 (14.5%)	11
Peripheral swelling	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	2/55 (3.6%)	2
Pyrexia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	14/54 (25.9%)	15	3/55 (5.5%)	3
Asthenia	6/12 (50%)	12	5/8 (62.5%)	22	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Chest pain	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Fatigue	2/12 (16.7%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Influenza like illness	2/12 (16.7%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Non-cardiac chest pain	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	2/55 (3.6%)	2
Oedema peripheral	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Peripheral swelling	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Pyrexia	1/12 (8.3%)	1	3/8 (37.5%)	3	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Suprapubic pain	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Catheter site related reaction	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Face oedema	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	1/55 (1.8%)	1
Hyperthermia	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Hepatobiliary disorders
Hepatomegaly	0/12 (0%)	0	1/8 (12.5%)	2	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	1/55 (1.8%)	1
Hepatic pain	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Hepatocellular injury	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Immune system disorders
Drug hypersensitivity	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/54 (7.4%)	5	2/55 (3.6%)	3
Infections and infestations
Gastroenteritis viral	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Hordeolum	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Nasopharyngitis	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Rhinitis	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Upper respiratory tract infection	0/12 (0%)	0	0/8 (0%)	0	3/5 (60%)	3	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Urinary tract infection bacterial	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	1/7 (14.3%)	2	1/6 (16.7%)	2	0/54 (0%)	0	0/55 (0%)	0
Cellulitis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	3/55 (5.5%)	3
Cystitis	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	4	1/55 (1.8%)	1
Herpes zoster	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	3/55 (5.5%)	3
Nasopharyngitis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	7/54 (13%)	11	5/55 (9.1%)	7
Oral candidiasis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/54 (7.4%)	5	1/55 (1.8%)	1
Oral herpes	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	6	3/55 (5.5%)	3
Paronychia	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/54 (7.4%)	4	0/55 (0%)	0
Upper respiratory tract infection	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	7/54 (13%)	13	5/55 (9.1%)	5
Urinary tract infection	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	8/54 (14.8%)	12	5/55 (9.1%)	6
Vulvovaginal candidiasis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	0/55 (0%)	0
Cellulitis	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Fungal infection	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Influenza	2/12 (16.7%)	4	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	2/54 (3.7%)	2	2/55 (3.6%)	2
Nasopharyngitis	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Pyelonephritis acute	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Sinusitis	1/12 (8.3%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Upper respiratory tract infection	1/12 (8.3%)	1	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Upper respiratory tract infection bacterial	1/12 (8.3%)	1	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	4	0/54 (0%)	0	0/55 (0%)	0
Urinary tract infection bacterial	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Vaginal infection	1/12 (8.3%)	1	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Varicella	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Viral upper respiratory tract infection	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	0/55 (0%)	0
Bacterial infection	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Conjunctivitis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	2/54 (3.7%)	2	0/55 (0%)	0
Folliculitis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/54 (1.9%)	1	1/55 (1.8%)	1
Viral infection	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/54 (1.9%)	2	1/55 (1.8%)	1
Herpes virus infection	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Pharyngitis	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	2
Rash pustular	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Lower respiratory tract infection bacterial	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Injury, poisoning and procedural complications
Infusion related reaction	0/12 (0%)	0	1/8 (12.5%)	1	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Lumbar vertebral fracture	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Infusion related reaction	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	0/55 (0%)	0
Muscle strain	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Wound	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Investigations
Ejection fraction decreased	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	1/55 (1.8%)	1
Transaminases increased	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Alanine aminotransferase increased	0/12 (0%)	0	2/8 (25%)	3	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	13/54 (24.1%)	22	4/55 (7.3%)	5
Aspartate aminotransferase increased	0/12 (0%)	0	2/8 (25%)	9	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	11/54 (20.4%)	19	4/55 (7.3%)	6
Blood alkaline phosphatase increased	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	3/55 (5.5%)	5
Blood cholesterol increased	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	6	2/55 (3.6%)	2
Blood creatinine increased	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	0/55 (0%)	0
Gamma-glutamyltransferase increased	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	2/55 (3.6%)	4
Lymphocyte count decreased	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	1/55 (1.8%)	1
Neutrophil count decreased	0/12 (0%)	0	2/8 (25%)	5	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	4/54 (7.4%)	8	3/55 (5.5%)	5
Weight decreased	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	5/54 (9.3%)	5	3/55 (5.5%)	3
White blood cell count decreased	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	4/55 (7.3%)	18
Blood alkaline phosphatase increased	1/12 (8.3%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Blood cholesterol increased	1/12 (8.3%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Blood creatinine increased	1/12 (8.3%)	6	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Blood glucose increased	3/12 (25%)	5	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	1/55 (1.8%)	1
Electrocardiogram QT prolonged	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	2/55 (3.6%)	2
Gamma-glutamyltransferase increased	1/12 (8.3%)	1	2/8 (25%)	3	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Thyroxine decreased	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Weight decreased	2/12 (16.7%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Blood bilirubin increased	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	1/55 (1.8%)	1
Haemoglobin decreased	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Liver palpable	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	2/7 (28.6%)	2	3/6 (50%)	3	0/54 (0%)	0	0/55 (0%)	0
Hyperglycaemia	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Decreased appetite	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	10/54 (18.5%)	11	3/55 (5.5%)	4
Hyperglycaemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	15/54 (27.8%)	48	6/55 (10.9%)	13
Hypertriglyceridaemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	6/54 (11.1%)	8	5/55 (9.1%)	5
Hypocalcaemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	3/55 (5.5%)	4
Hypokalaemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	4/55 (7.3%)	11
Hypomagnesaemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	4/55 (7.3%)	6
Decreased appetite	4/12 (33.3%)	8	3/8 (37.5%)	3	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Hypercholesterolaemia	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Hyperglycaemia	5/12 (41.7%)	39	3/8 (37.5%)	15	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Hypocalcaemia	1/12 (8.3%)	1	2/8 (25%)	3	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Hypokalaemia	1/12 (8.3%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Hypomagnesaemia	1/12 (8.3%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Hyponatraemia	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Hypokalaemia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Calcium deficiency	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Cell death	0/12 (0%)	0	1/8 (12.5%)	8	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	1/7 (14.3%)	1	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Joint swelling	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Muscle spasms	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Musculoskeletal pain	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Arthralgia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	7/54 (13%)	8	5/55 (9.1%)	12
Back pain	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	8/54 (14.8%)	10	5/55 (9.1%)	5
Bone pain	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	3/55 (5.5%)	3
Muscle spasms	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	6	2/55 (3.6%)	3
Musculoskeletal pain	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	6/54 (11.1%)	7	5/55 (9.1%)	7
Myalgia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	5/54 (9.3%)	6	12/55 (21.8%)	24
Pain in extremity	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	4/55 (7.3%)	5
Arthralgia	2/12 (16.7%)	3	1/8 (12.5%)	1	0/5 (0%)	0	1/7 (14.3%)	1	2/6 (33.3%)	2	0/54 (0%)	0	0/55 (0%)	0
Back pain	4/12 (33.3%)	5	3/8 (37.5%)	4	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Bone pain	1/12 (8.3%)	1	1/8 (12.5%)	2	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Muscle spasms	1/12 (8.3%)	1	2/8 (25%)	5	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Musculoskeletal chest pain	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	2/54 (3.7%)	2	1/55 (1.8%)	1
Musculoskeletal discomfort	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Musculoskeletal pain	3/12 (25%)	5	1/8 (12.5%)	2	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Myalgia	2/12 (16.7%)	2	2/8 (25%)	3	0/5 (0%)	0	3/7 (42.9%)	5	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Neck pain	1/12 (8.3%)	2	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Pain in extremity	1/12 (8.3%)	2	2/8 (25%)	2	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Osteoarthritis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Spinal pain	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Flank pain	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	0/55 (0%)	0
Groin pain	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Nervous system disorders
Dysgeusia	0/12 (0%)	0	2/8 (25%)	2	2/5 (40%)	2	1/7 (14.3%)	4	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Headache	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	2/7 (28.6%)	2	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Lethargy	0/12 (0%)	0	1/8 (12.5%)	1	1/5 (20%)	6	0/7 (0%)	0	2/6 (33.3%)	3	2/54 (3.7%)	5	2/55 (3.6%)	2
Neuropathy peripheral	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	2	2/7 (28.6%)	3	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Neurotoxicity	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	3/7 (42.9%)	3	2/6 (33.3%)	3	0/54 (0%)	0	0/55 (0%)	0
Paraesthesia	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	1/7 (14.3%)	1	2/6 (33.3%)	2	0/54 (0%)	0	0/55 (0%)	0
Peripheral sensory neuropathy	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Presyncope	0/12 (0%)	0	1/8 (12.5%)	1	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Dizziness	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	4/55 (7.3%)	5
Dysgeusia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	11/54 (20.4%)	13	7/55 (12.7%)	8
Headache	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	8/54 (14.8%)	14	10/55 (18.2%)	12
Neuralgia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	3/55 (5.5%)	3
Neuropathy peripheral	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	13/54 (24.1%)	22	18/55 (32.7%)	26
Neurotoxicity	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	5/54 (9.3%)	9	3/55 (5.5%)	3
Paraesthesia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	6/54 (11.1%)	8	2/55 (3.6%)	2
Peripheral sensory neuropathy	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	14/54 (25.9%)	17	10/55 (18.2%)	11
Dizziness	3/12 (25%)	4	5/8 (62.5%)	7	0/5 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	3	0/54 (0%)	0	0/55 (0%)	0
Headache	2/12 (16.7%)	7	4/8 (50%)	4	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Migraine	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Neuralgia	1/12 (8.3%)	1	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Neuropathy peripheral	4/12 (33.3%)	13	2/8 (25%)	7	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Neurotoxicity	5/12 (41.7%)	6	3/8 (37.5%)	3	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Paraesthesia	1/12 (8.3%)	1	2/8 (25%)	3	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Peripheral sensory neuropathy	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Radicular pain	1/12 (8.3%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Somnolence	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/54 (1.9%)	1	1/55 (1.8%)	1
Myoclonus	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Parosmia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Sciatica	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Tremor	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	4	0/54 (0%)	0	0/55 (0%)	0
Ageusia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Visual field defect	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Psychiatric disorders
Depressed mood	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Insomnia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	3/55 (5.5%)	3
Anxiety	1/12 (8.3%)	2	1/8 (12.5%)	2	0/5 (0%)	0	2/7 (28.6%)	2	0/6 (0%)	0	2/54 (3.7%)	2	2/55 (3.6%)	2
Insomnia	1/12 (8.3%)	3	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Sleep disorder	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Confusional state	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/54 (1.9%)	1	0/55 (0%)	0
Depression	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	2/54 (3.7%)	2	0/55 (0%)	0
Hallucination	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Irritability	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Dysuria	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	4	2/55 (3.6%)	2
Proteinuria	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	1/55 (1.8%)	1
Acute kidney injury	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Dysuria	1/12 (8.3%)	2	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Renal failure	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Haematuria	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	2	1/54 (1.9%)	1	2/55 (3.6%)	2
Urinary incontinence	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/54 (1.9%)	2	0/55 (0%)	0
Reproductive system and breast disorders
Breast discharge	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Pelvic pain	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Vaginal discharge	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Menorrhagia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	1/7 (14.3%)	1	2/6 (33.3%)	2	0/54 (0%)	0	0/55 (0%)	0
Dysphonia	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Productive cough	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Rhinorrhoea	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	2/7 (28.6%)	2	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Cough	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	11/54 (20.4%)	13	8/55 (14.5%)	11
Dyspnoea	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	6/54 (11.1%)	6	9/55 (16.4%)	14
Dyspnoea exertional	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	2/55 (3.6%)	2
Epistaxis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	5/54 (9.3%)	5	1/55 (1.8%)	1
Oropharyngeal pain	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/54 (7.4%)	6	6/55 (10.9%)	6
Productive cough	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	5/54 (9.3%)	5	2/55 (3.6%)	2
Cough	5/12 (41.7%)	6	3/8 (37.5%)	4	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Dysphonia	2/12 (16.7%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Dyspnoea	2/12 (16.7%)	3	1/8 (12.5%)	1	0/5 (0%)	0	2/7 (28.6%)	2	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Dyspnoea exertional	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Epistaxis	1/12 (8.3%)	1	2/8 (25%)	3	0/5 (0%)	0	2/7 (28.6%)	2	2/6 (33.3%)	3	0/54 (0%)	0	0/55 (0%)	0
Nasal dryness	2/12 (16.7%)	2	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	2	0/54 (0%)	0	0/55 (0%)	0
Nasal obstruction	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Oropharyngeal pain	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Rhinorrhoea	3/12 (25%)	4	3/8 (37.5%)	4	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	1/55 (1.8%)	2
Rhinitis allergic	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	0/12 (0%)	0	0/8 (0%)	0	3/5 (60%)	3	2/7 (28.6%)	2	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Dry skin	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Nail disorder	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Pruritus	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/7 (0%)	0	2/6 (33.3%)	3	0/54 (0%)	0	0/55 (0%)	0
Rash erythematous	0/12 (0%)	0	0/8 (0%)	0	3/5 (60%)	4	0/7 (0%)	0	3/6 (50%)	5	0/54 (0%)	0	0/55 (0%)	0
Rash macular	0/12 (0%)	0	1/8 (12.5%)	1	1/5 (20%)	1	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Rash maculo-papular	0/12 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	2/7 (28.6%)	2	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Swelling face	0/12 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	1/7 (14.3%)	1	0/6 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Alopecia	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	28/54 (51.9%)	28	27/55 (49.1%)	30
Dry skin	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/54 (7.4%)	5	1/55 (1.8%)	2
Erythema	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	4	4/55 (7.3%)	4
Nail discolouration	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	1	5/55 (9.1%)	5
Nail disorder	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	4	3/55 (5.5%)	3
Onycholysis	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/54 (1.9%)	2	5/55 (9.1%)	7
Palmar-plantar erythrodysaesthesia syndrome	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	4/54 (7.4%)	4	4/55 (7.3%)	4
Pruritus	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	5/55 (9.1%)	7
Rash	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	8/54 (14.8%)	8	4/55 (7.3%)	8
Rash erythematous	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	2/55 (3.6%)	3
Rash macular	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	4/54 (7.4%)	8	0/55 (0%)	0
Rash maculo-papular	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	14/54 (25.9%)	18	2/55 (3.6%)	2
Rash papular	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	8	0/55 (0%)	0
Rash pruritic	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	3/54 (5.6%)	3	0/55 (0%)	0
Skin reaction	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	5	0/55 (0%)	0
Alopecia	3/12 (25%)	6	4/8 (50%)	4	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Dry skin	3/12 (25%)	3	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Erythema	1/12 (8.3%)	1	2/8 (25%)	2	0/5 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Melanoderma	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Nail disorder	1/12 (8.3%)	1	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Nail dystrophy	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	2/54 (3.7%)	2	0/55 (0%)	0
Onycholysis	2/12 (16.7%)	2	1/8 (12.5%)	2	0/5 (0%)	0	2/7 (28.6%)	2	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Pruritus	2/12 (16.7%)	5	2/8 (25%)	2	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Rash	1/12 (8.3%)	2	1/8 (12.5%)	5	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Rash erythematous	2/12 (16.7%)	5	1/8 (12.5%)	3	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Rash maculo-papular	1/12 (8.3%)	3	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Rash papular	2/12 (16.7%)	3	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Skin hyperpigmentation	1/12 (8.3%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	2	0/54 (0%)	0	1/55 (1.8%)	1
Dermatitis acneiform	0/12 (0%)	0	1/8 (12.5%)	3	0/5 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Eczema	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/54 (0%)	0	0/55 (0%)	0
Generalised erythema	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	2	0/54 (0%)	0	0/55 (0%)	0
Vascular disorders
Flushing	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	1/55 (1.8%)	1
Hypertension	0/12 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/54 (5.6%)	3	2/55 (3.6%)	10
Hot flush	1/12 (8.3%)	1	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	2/54 (3.7%)	2	0/55 (0%)	0
Hypertension	2/12 (16.7%)	2	0/8 (0%)	0	0/5 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Lymphoedema	0/12 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	2/54 (3.7%)	2	1/55 (1.8%)	1

Limitations/Caveats

QoL, PK/PD & efficacy response modelling were considered non-key secondary endpoints and not disclosed at this time. QoL data was limited and considered exploratory, PK/PD and modelling were not reported in CSR. Diarrhoea burden is reported with AEs

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title	AstraZeneca Clinical
Organization	AstraZeneca
Phone	1-877-240-9479
Email	information.center@astrazeneca.com

Responsible Party:

AstraZeneca

ClinicalTrials.gov Identifier:

NCT01625286

Other Study ID Numbers:

D3610C00002
2011-006312-31

First Posted:

Jun 21, 2012

Last Update Posted:

Aug 23, 2022

Last Verified:

Aug 1, 2022

BEECH: Investigating Safety, Tolerability and Efficacy of AZD5363 When Combined With Paclitaxel in Breast Cancer Patients

Study Details

Study Description

Brief Summary

Detailed Description

The study will be conducted in two parts:

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

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Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

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Results Point of Contact