LOTUS: A Study Assessing the Safety and Efficacy of Adding Ipatasertib to Paclitaxel Treatment in Participants With Breast Cancer That Has Spread Beyond the Initial Site, and the Cancer Does Not Have Certain Hormonal Receptors

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02162719
• Collaborator: (none)
• Enrollment: 124
• Locations: 44
• Arms: 2
• Actual Duration (Months): 60.4
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This multicenter, randomized, double-blind study will estimate the efficacy, safety and tolerability of ipatasertib combined with paclitaxel compared with placebo combined with paclitaxel in participants with inoperable locally advanced or metastatic triple-negative breast cancer (mTNBC), as measured by progression-free survival (PFS) in all participants and in participants with phosphatase and tensin homolog (PTEN)-low tumors.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: Ipatasertib; Drug: Paclitaxel; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Phase II, Multi-Center, Placebo-Controlled Study of Ipatasertib (GDC-0068), an Inhibitor of Akt, in Combination With Paclitaxel as Front-Line Treatment for Patients With Metastatic Triple-Negative Breast Cancer
• Actual Study Start Date: Aug 19, 2014
• Actual Primary Completion Date: Jun 7, 2016
• Actual Study Completion Date: Aug 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ipatasertib + Paclitaxel Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Drug: Ipatasertib; Participants received ipatasertib orally 400 milligrams (mg) daily on Days 1-21 of each 28-day cycle.; Other Names: GDC-0068 ; Drug: Paclitaxel; Participants received paclitaxel 80 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, and 15 of each cycle.
Placebo Comparator: Placebo + Paclitaxel Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Drug: Paclitaxel; Participants received paclitaxel 80 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, and 15 of each cycle.; Drug: Placebo; Participants received oral placebo matched to ipatasertib, daily on Days 1-21 of each 28-day cycle.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016)]

   PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first.

2. PFS in Participants With Phosphatase and Tensin Homolog (PTEN)-Low Tumors [Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016)]

   PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first.

Secondary Outcome Measures

1. PFS in Participants With Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Alpha (PIK3CA)/ Protein Kinase B (AKT1)/ PTEN-altered Tumors [Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016)]

   PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first.

2. Overall Survival (OS) [Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019)]

   OS was defined as the time from the date of randomization to the date of death from any cause.

3. OS in Participants With PTEN-Low Tumors [Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019)]

   OS was defined as the time from the date of randomization to the date of death from any cause.

4. OS in Participants With PIK3CA/AKT1/PTEN-altered Tumors [Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019)]

   OS was defined as the time from the date of randomization to the date of death from any cause.

5. Objective Response Rate (ORR) [Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)]

   Confirmed tumor ORR in participants with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of participants who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Participants for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

6. ORR in Participants With PTEN-Low Tumors [Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)]

   Confirmed tumor ORR in participants with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of participants who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Participants for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

7. ORR in Participants With PIK3CA/AKT1/PTEN-altered Tumors [Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)]

   Confirmed tumor ORR in subjects with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of subjects who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Subjects for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

8. Duration of Response [Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)]

   Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1.

9. Duration of Response in Participants With PTEN-Low Tumors [Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)]

   Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1.

10. Duration of Response in Participants With PIK3CA/AKT1/PTEN-altered Tumors [Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)]

    Duration of objective response in participants with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1.

11. Time to Disease Progression [Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)]

    Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1.

12. Time to Disease Progression in Participants With PTEN-Low Tumors [Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)]

    Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1.

13. Time to Disease Progression in Participants With PIK3CA/AKT1/PTEN-altered Tumors [Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)]

    Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1.

14. Safety: Percentage of Participants With Adverse Events [Baseline up to 30 days after the last dose of study drug or until initiation of another anti-cancer therapy, whichever occurs first (up to 3 years, 3 months)]

    An adverse event was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

15. Pharmacokinetic Endpoint: Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) of Ipatasertib [Cycle 1 Day 1, Cycle 1 Day 8]

    PK parameters were not calculated due to sparse PK sampling.

16. Pharmacokinetic Endpoint: Apparent Clearance Following Oral Dosing (CL/F) of Ipatasertib [Cycle 1 Day 1, Cycle 1 Day 8]

    PK parameters were not calculated due to sparse PK sampling.

17. Patient Reported Outcome (PRO) Measure: Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) Score [Baseline (Cycle 1 Day 1) up to Cycle 5 Day 1]

    EORTC QLQ-C30 included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1=Not at all to 4=Very much; 2 questions used 7-point scale [1=very poor to 7=Excellent]). Scores averaged, transformed to 0-100 scale; a higher score=better level of functioning. For symptom scale scores, higher level=severe level of symptoms. "A change of at least 10 points from baseline is considered clinically meaningful (Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality of life score. J Clin Oncol 1998;16:139-44). PRO measures were analyzed from baseline up to cycle 5. Scores from later timepoints were not analyzed due to attrition (in both arms, fewer than 50% of participants remained on treatment beyond cycle 5).

18. PRO Measure: Percentage of Participants With Improved, Worsened, or Remained Stable for Bothersome Side Effects of Treatment Measured by the Scales of the EORTC QLQ-C30 [Baseline (Cycle 1 Day 1) up to Cycle 5 Day 1]

    Subjects reporting >/= 10-point increase compared to baseline (Cycle 1 Day 1) were considered "improved", those reporting <10-point difference were considered "remained stable", and those reporting >/=10-point decrease were considered "worsened". A change of at least 10 points from baseline is considered clinically meaningful (Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality of life score. J Clin Oncol 1998;16:139-44). Patient reported outcome measures were analyzed from baseline up to and including cycle 5. Scores from later timepoints were not analyzed due to attrition (in both arms, fewer than 50% of participants remained on treatment beyond cycle 5).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically documented triple-negative adenocarcinoma of the breast that is inoperable locally advanced or metastatic and is not amenable to resection with curative intent

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen, required prior to randomization

• Measurable disease, according to the RECIST v1.1

• Adequate hematologic and organ function within 14 days before the first study treatment

• For female participants of childbearing potential, agreement (by both participant and partner) to use an effective form of contraception for the duration of the study and for 6 months after last dose of study treatment

Exclusion Criteria:

• Any previous therapy, including chemotherapy or hormonal or targeted therapy, for inoperable locally advanced or metastatic triple-negative adenocarcinoma of the breast. Participants may have received prior neoadjuvant or adjuvant chemotherapy and/or radiation treatment for locally advanced triple negative adenocarcinoma, provided all treatments were completed greater than or equal to (>/=) 6 months prior to Cycle 1 Day 1. Locally recurrent disease must not be amenable to resection with curative intent

• Any radiation treatment to metastatic site within 28 days of Cycle 1, Day 1

• Known Human Epidermal Growth Factor Receptor 2 (HER2) positive, erythrocyte receptor (ER) positive, or progesterone receptor (PR) positive breast cancer

• Previous therapy with Akt, PI3K, and/or mTOR inhibitors

• Major surgical procedure, open biopsy, or significant traumatic injury within 30 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study

• Known presence of the brain or spinal cord metastasis, as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening or prior radiographic assessments

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St Jude Heritage Medical Group	Fullerton	California	United States	92835
2	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
3	Cancer Care Assoc Med Group	Los Angeles	California	United States	90095-1772
4	UCLA Medical Center	Santa Monica	California	United States	90404
5	Holycross Medical Group	Fort Lauderdale	Florida	United States	33308
6	Memorial Healthcare System	Hollywood	Florida	United States	33021
7	Hematology Oncology Associates of the Treasure Coast	Port Saint Lucie	Florida	United States	34952
8	Rush University Medical Center	Chicago	Illinois	United States	60612
9	Cancer Center of Kansas	Wichita	Kansas	United States	67214-3728
10	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
11	Comprehensive Cancer Centers of Nevada	Henderson	Nevada	United States	89014
12	Carolinas Healthcare System	Charlotte	North Carolina	United States	28208
13	The WEST CLINIC, P.C.	Memphis	Tennessee	United States	38119
14	MD Anderson Cancer Center	Houston	Texas	United States	77030
15	Northern Utah Associates	Ogden	Utah	United States	84403
16	Northwest Medical Specialties	Lakewood	Washington	United States	98499
17	West Virginia University Hospitals Inc	Morgantown	West Virginia	United States	26056
18	Sint Augustinus Wilrijk	Wilrijk		Belgium	2610
19	Institut Bergonié Centre Régional de Lutte Contre Le Cancer de Bordeaux Et Sud Ouest	Bordeaux		France	33076
20	Centre Francois Baclesse	Caen		France	14076
21	Centre Régional de Lutte Contre Le Cancer Val D'aurelle Paul Lamarque	Montpellier		France	34298
22	Hopital Saint Louis; Oncologie Medicale	Paris		France	75475
23	Clinique Armoricaine de Radiol	Saint Brieuc		France	22015
24	Istituto Nazionale Tumori Fondazione G. Pascale	Napoli	Campania	Italy	80131
25	Istituto Nazionale dei Tumori; Divisione Oncologia Chirurgica e Ginecologica	Milano	Lombardia	Italy	20133
26	Istituto Oncologico Veneto IRCCS Farmacia Ospedaliera	Padova	Veneto	Italy	35128
27	National Cancer Center	Goyang-si		Korea, Republic of	10408
28	Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of	13605
29	Seoul National University Hospital	Seoul		Korea, Republic of	03080
30	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
31	Asan Medical Center	Seoul		Korea, Republic of	05505
32	Korea University Guro Hospital	Seoul		Korea, Republic of	08308
33	National University Hospital; National University Cancer Institute, Singapore (NCIS)	Singapore		Singapore	119228
34	National Cancer Centre	Singapore		Singapore	169610
35	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
36	Institut Catala d Oncologia Hospital Duran i Reynals	Barcelona		Spain	08908
37	Complejo Hospitalario de Jaen	Jaen		Spain	23007
38	MD Anderson Cancer Center	Madrid		Spain	28033
39	HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio de Farmacia	Madrid		Spain	28050
40	Hospital Virgen del Rocio	Sevilla		Spain	41013
41	China Medical University Hospital	North Dist.		Taiwan	40402
42	Chi Mei Medical Center, Yong kang; Endocrinology	Tainan		Taiwan	710
43	National Taiwan University Hospital	Taipei		Taiwan	10002
44	Chang Gung Medical Foundation - Linkou; Dept of Surgery	Taoyuan		Taiwan	333

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT02162719
• Other Study ID Numbers: GO29227; 2014-000469-35
• First Posted: Jun 13, 2014
• Last Update Posted: Mar 10, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel

Study Results

Participant Flow

Recruitment Details	The study was conducted at 44 centers in 8 countries.
Pre-assignment Detail	A total of 166 participants were screened, out of which 42 participants failed screening. A total of 124 participants were enrolled at 44 sites. Results are reported here up to clinical cut-off date of 31st August 2019.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Period Title: Overall Study
STARTED	62	62
COMPLETED	0	0
NOT COMPLETED	62	62

Baseline Characteristics

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel	Total
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Total of all reporting groups
Overall Participants	62	62	124
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.6 (13.4)	54.4 (10.9)	54.0 (12.2)
Sex: Female, Male (Count of Participants)
Female	62 100%	62 100%	124 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
Hispanic or Latino	2 3.2%	3 4.8%	5 4%
Not Hispanic or Latino	51 82.3%	52 83.9%	103 83.1%
Not Stated	5 8.1%	5 8.1%	10 8.1%
Unknown	4 6.5%	2 3.2%	6 4.8%
Race/Ethnicity, Customized (Number) [Number]
Asian	28 45.2%	30 48.4%	58 46.8%
Black or African American	5 8.1%	3 4.8%	8 6.5%
White	26 41.9%	28 45.2%	54 43.5%
Other	3 4.8%	1 1.6%	4 3.2%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first.
Time Frame	Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

The Intent to treat (ITT) population was defined as all randomized participants allocated to the treatment arm to which they were randomized.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	62	62
Median (90% Confidence Interval) [Months]	6.18 (4.57)	4.93 (3.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipatasertib and Paclitaxel, Placebo and Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0372
	Comments	Stratification variables were adjuvant/neoadjuvant treatment including treatment with or without radiation, disease-free interval from last dose (<=12 vs >12 months vs. no prior chemotherapy), PTEN status of tumor (H-score 0, vs. 1 to 150, vs. >150).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (Stratified Analysis)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 90%; 0.40 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	PFS in Participants With Phosphatase and Tensin Homolog (PTEN)-Low Tumors
Description	PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first.
Time Frame	Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

The ITT population included all randomized participants allocated to the treatment arm to which they were randomized. Participants with PTEN-low tumors were evaluated for this endpoint.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	25	23
Median (90% Confidence Interval) [Months]	6.18 (3.65)	3.65 (2.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipatasertib and Paclitaxel, Placebo and Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1753
	Comments	Stratification variables were adjuvant/neoadjuvant treatment including treatment with or without radiation, disease-free interval from last dose (<=12 vs >12 months vs. no prior chemotherapy), PTEN status of tumor (H-score 0, vs. 1 to 150, vs. >150).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (Stratified Analysis)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 90%; 0.30 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	PFS in Participants With Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Alpha (PIK3CA)/ Protein Kinase B (AKT1)/ PTEN-altered Tumors
Description	PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first.
Time Frame	Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all randomized participants allocated to the treatment arm to which they were randomized. Participants with PIK3CA/AKT1/PTEN-altered tumors were evaluated for this endpoint.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	26	16
Median (90% Confidence Interval) [Months]	9.03 (4.57)	4.93 (3.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipatasertib and Paclitaxel, Placebo and Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3636
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (Unstratified Analysis)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 90%; 0.46 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from the date of randomization to the date of death from any cause.
Time Frame	Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all randomized participants allocated to the treatment arm to which they were randomized.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	62	62
Median (95% Confidence Interval) [months]	25.8 (18.6)	16.9 (14.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipatasertib and Paclitaxel, Placebo and Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3607
	Comments	Stratification variables were adjuvant/neoadjuvant treatment including treatment with/without radiation, disease-free interval from last dose (<=12 vs >12 months vs. no prior chemotherapy), PTEN status of tumor (H-score 0, vs. 1 to 150, vs. >150).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (Stratified Analysis)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.50 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	OS in Participants With PTEN-Low Tumors
Description	OS was defined as the time from the date of randomization to the date of death from any cause.
Time Frame	Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all randomized participants allocated to the treatment arm to which they were randomized. Participants with PTEN-low tumors were evaluated for this endpoint.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	25	23
Median (95% Confidence Interval) [months]	23.1 (18.3)	15.8 (9.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipatasertib and Paclitaxel, Placebo and Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4422
	Comments	Stratification variables were adjuvant/neoadjuvant treatment including treatment with/without radiation, disease-free interval from last dose (<=12 vs >12 months vs. no prior chemotherapy), PTEN status of tumor (H-score 0, vs. 1 to 150, vs. >150).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (Stratified Analysis)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.32 to 1.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	OS in Participants With PIK3CA/AKT1/PTEN-altered Tumors
Description	OS was defined as the time from the date of randomization to the date of death from any cause.
Time Frame	Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all randomized participants allocated to the treatment arm to which they were randomized. Participants with PIK3CA/AKT1/PTEN-altered tumors were evaluated for this endpoint.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	26	16
Median (95% Confidence Interval) [months]	25.8 (18.6)	22.1 (8.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipatasertib and Paclitaxel, Placebo and Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7599
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (Unstratified Analysis)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.52 to 2.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	Confirmed tumor ORR in participants with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of participants who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Participants for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time Frame	Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

The Intent to treat (ITT) population was defined as all randomized participants allocated to the treatment arm to which they were randomized.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	62	62
Number (90% Confidence Interval) [Percentage of Participants]	40.3 (30.64) 65%	32.3 (23.35) 52.1%

8. Secondary Outcome

Title	ORR in Participants With PTEN-Low Tumors
Description	Confirmed tumor ORR in participants with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of participants who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Participants for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time Frame	Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all randomized participants allocated to the treatment arm to which they were randomized. Participants with PTEN-Low Tumors were evaluated for this endpoint.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	25	23
Number (90% Confidence Interval) [Percentage of Participants]	48.0 (30.73) 77.4%	26.1 (12.02) 42.1%

9. Secondary Outcome

Title	ORR in Participants With PIK3CA/AKT1/PTEN-altered Tumors
Description	Confirmed tumor ORR in subjects with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of subjects who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Subjects for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time Frame	Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all randomized participants allocated to the treatment arm to which they were randomized. Participants with PIK3CA/AKT1/PTEN-altered tumors were evaluated for this endpoint.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	26	16
Number (90% Confidence Interval) [Percentage of Participants]	50.0 (34.24) 80.6%	43.8 (23.53) 70.6%

10. Secondary Outcome

Title	Duration of Response
Description	Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1.
Time Frame	Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all randomized participants allocated to the treatment arm to which they were randomized. Only participants who achieved a confirmed objective response were included in the analysis.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	25	20
Median (90% Confidence Interval) [months]	7.85	7.43

11. Secondary Outcome

Title	Duration of Response in Participants With PTEN-Low Tumors
Description	Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1.
Time Frame	Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants allocated to the treatment arm to which they were randomized. Participants with PTEN-low tumors were evaluated for this endpoint. Only participants who achieved a confirmed objective response were included in the analysis.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	12	6
Median (90% Confidence Interval) [Months]	6.54	7.49

12. Secondary Outcome

Title	Duration of Response in Participants With PIK3CA/AKT1/PTEN-altered Tumors
Description	Duration of objective response in participants with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1.
Time Frame	Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants allocated to the treatment arm to which they were randomized. Participants with PIK3CA/AKT1/PTEN-altered tumors were evaluated for this endpoint. Only participants who achieved a confirmed objective response were included in the analysis.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	13	7
Median (90% Confidence Interval) [Months]	11.24	6.06

13. Secondary Outcome

Title	Time to Disease Progression
Description	Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1.
Time Frame	Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants allocated to the treatment arm to which they were randomized.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	62	62
Median (90% Confidence Interval) [Months]	6.18 (4.57)	4.96 (3.61)

14. Secondary Outcome

Title	Time to Disease Progression in Participants With PTEN-Low Tumors
Description	Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1.
Time Frame	Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants allocated to the treatment arm to which they were randomized. Participants with PTEN low tumors were evaluated for this endpoint.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	25	23
Median (90% Confidence Interval) [Months]	6.18 (3.65)	3.94 (2.53)

15. Secondary Outcome

Title	Time to Disease Progression in Participants With PIK3CA/AKT1/PTEN-altered Tumors
Description	Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1.
Time Frame	Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants allocated to the treatment arm to which they were randomized. Participants with PIK3CA/AKT1/PTEN-altered tumors were evaluated for this endpoint.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	26	16
Median (90% Confidence Interval) [Months]	9.03 (4.57)	4.93 (3.58)

16. Secondary Outcome

Title	Safety: Percentage of Participants With Adverse Events
Description	An adverse event was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Time Frame	Baseline up to 30 days after the last dose of study drug or until initiation of another anti-cancer therapy, whichever occurs first (up to 3 years, 3 months)

Outcome Measure Data

Analysis Population Description

The Safety population included all treated participants with participants allocated to the treatment arm associated with the regimen that they actually received.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	61	62
Number [Percentage of Participants]	100.0 161.3%	96.8 156.1%

17. Secondary Outcome

Title	Pharmacokinetic Endpoint: Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) of Ipatasertib
Description	PK parameters were not calculated due to sparse PK sampling.
Time Frame	Cycle 1 Day 1, Cycle 1 Day 8

Outcome Measure Data

Analysis Population Description

The PK Analysis population was defined as all participants who had evaluable PK data.

Arm/Group Title	Ipatasertib and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	61
Number [h*ng/mL/mg]	NA

18. Secondary Outcome

Title	Pharmacokinetic Endpoint: Apparent Clearance Following Oral Dosing (CL/F) of Ipatasertib
Description	PK parameters were not calculated due to sparse PK sampling.
Time Frame	Cycle 1 Day 1, Cycle 1 Day 8

Outcome Measure Data

Analysis Population Description

The PK Analysis population was defined as all participants who had evaluable PK data.

Arm/Group Title	Ipatasertib and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	61
Number [ml/hr]	NA

19. Secondary Outcome

Title	Patient Reported Outcome (PRO) Measure: Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) Score
Description	EORTC QLQ-C30 included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1=Not at all to 4=Very much; 2 questions used 7-point scale [1=very poor to 7=Excellent]). Scores averaged, transformed to 0-100 scale; a higher score=better level of functioning. For symptom scale scores, higher level=severe level of symptoms. "A change of at least 10 points from baseline is considered clinically meaningful (Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality of life score. J Clin Oncol 1998;16:139-44). PRO measures were analyzed from baseline up to cycle 5. Scores from later timepoints were not analyzed due to attrition (in both arms, fewer than 50% of participants remained on treatment beyond cycle 5).
Time Frame	Baseline (Cycle 1 Day 1) up to Cycle 5 Day 1

Outcome Measure Data

Analysis Population Description

The PRO Analysis population was defined as the ITT population with a baseline and at least one post baseline PRO assessment. Data presented below is only for participants included in the actual analysis.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	57	53
Appetite loss:Cycle 2	7.60 (28.18)	-0.63 (24.88)
Appetite loss:Cycle 3	9.42 (21.84)	-3.88 (24.35)
Appetite loss:Cycle 4	5.44 (23.91)	-4.17 (25.25)
Appetite loss:Cycle 5	0.00 (18.08)	-1.11 (25.50)
Cognitive Functioning: Cycle 2 Day 1	1.17 (14.04)	0.63 (17.28)
Cognitive Functioning: Cycle 3 Day 1	-1.81 (19.64)	-1.81 (19.64)
Cognitive Functioning: Cycle 4 Day 1	-3.40 (15.95)	0.00 (20.32)
Cognitive Functioning: Cycle 5 Day 1	0.00 (13.80)	-4.44 (19.54)
Constipation: Cycle 2 Day 1	5.85 (24.50)	0.63 (25.73)
Constipation: Cycle 3 Day 1	2.90 (19.66)	1.59 (22.03)
Constipation: Cycle 4 Day 1	1.39 (16.78)	0.83 (30.65)
Constipation: Cycle 5 Day 1	2.78 (14.64)	1.11 (20.50)
Diarrhoea: Cycle 2 Day 1	17.54 (30.28)	1.89 (15.21)
Diarrhoea: Cycle 3 Day 1	23.91 (34.90)	3.88 (18.13)
Diarrhoea: Cycle 4 Day 1	19.73 (34.64)	0.83 (15.99)
Diarrhoea: Cycle 5 Day 1	21.90 (37.87)	1.11 (16.34)
Dyspnea: Cycle 2 Day 1	2.92 (19.19)	0.00 (18.67)
Dyspnea: Cycle 3 Day 1	5.07 (23.27)	2.44 (22.84)
Dyspnea: Cycle 4 Day 1	3.40 (25.68)	5.13 (22.35)
Dyspnea: Cycle 5 Day 1	5.56 (25.82)	4.76 (23.51)
Emotional Functioning: Cycle 2 Day 1	12.09 (15.90)	4.72 (16.87)
Emotional Functioning: Cycle 3 Day 1	7.37 (17.18)	3.88 (20.36)
Emotional Functioning: Cycle 4 Day 1	8.22 (16.53)	2.71 (21.47)
Emotional Functioning: Cycle 5 Day 1	8.73 (16.30)	1.39 (17.79)
Fatigue: Cycle 2 Day 1	7.99 (22.69)	-1.36 (16.98)
Fatigue: Cycle 3 Day 1	9.18 (22.63)	1.42 (19.44)
Fatigue: Cycle 4 Day 1	7.94 (20.91)	1.85 (21.64)
Fatigue: Cycle 5 Day 1	10.32 (20.35)	1.67 (20.59)
Financial difficulties Cycle 2 Day 1	3.57 (21.72)	0.00 (20.87)
Financial difficulties Cycle 3 Day 1	0.72 (22.76)	-3.88 (24.35)
Financial difficulties Cycle 4 Day 1	3.40 (23.81)	-0.83 (29.71)
Financial difficulties Cycle 5 Day 1	2.78 (25.67)	1.11 (26.96)
Nausea/Vomiting Cycle 2 Day 1	9.06 (19.43)	2.83 (15.24)
Nausea/Vomiting Cycle 3 Day 1	6.52 (14.26)	3.10 (14.21)
Nausea/Vomiting Cycle 4 Day 1	6.80 (17.32)	3.75 (17.50)
Nausea/Vomiting Cycle 5 Day 1	3.70 (7.03)	0.00 (23.16)
Pain Cycle 2 Day 1	-3.80 (22.93)	-7.86 (23.02)
Pain Cycle 3 Day 1	-4.71 (26.45)	-7.36 (26.80)
Pain Cycle 4 Day 1	1.36 (28.63)	-3.33 (31.62)
Pain Cycle 5 Day 1	0.00 (26.13)	-5.56 (25.27)
Physical Functioning Cycle 2 Day 1	-4.53 (14.23)	-0.16 (12.96)
Physical Functioning Cycle 3 Day 1	-5.94 (15.54)	-1.71 (13.88)
Physical Functioning Cycle 4 Day 1	-9.12 (13.92)	-3.17 (16.54)
Physical Functioning Cycle 5 Day 1	-8.56 (13.47)	-4.44 (14.26)
Global health status Cycle 2 Day 1	-4.68 (22.33)	4.72 (18.38)
Global health status Cycle 3 Day 1	-8.15 (21.55)	3.29 (21.37)
Global health status Cycle 4 Day 1	-8.50 (21.62)	-1.46 (26.61)
Global health status Cycle 5 Day 1	-6.48 (22.55)	-5.00 (21.62)
Role Functioning Cycle 2 Day 1	-5.85 (20.04)	0.63 (22.40)
Role Functioning Cycle 3 Day 1	-10.51 (24.43)	-2.71 (22.69)
Role Functioning Cycle 4 Day 1	-13.95 (25.76)	-6.25 (26.34)
Role Functioning Cycle 5 Day 1	-11.57 (21.76)	-7.22 (21.30)
Social Functioning Cycle 2 Day 1	-2.05 (26.92)	0.00 (23.34)
Social Functioning Cycle 3 Day 1	-2.17 (23.99)	-3.49 (26.11)
Social Functioning Cycle 4 Day 1	-7.14 (27.00)	-5.83 (23.74)
Social Functioning Cycle 5 Day 1	-4.76 (31.72)	-9.44 (24.24)
Insomnia Cycle 2 Day 1	2.92 (31.67)	-5.03 (24.80)
Insomnia Cycle 3 Day 1	2.90 (25.17)	-3.10 (25.00)
Insomnia Cycle 4 Day 1	7.48 (28.27)	5.83 (31.02)
Insomnia Cycle 5 Day 1	1.85 (34.68)	-5.56 (29.14)

20. Secondary Outcome

Title	PRO Measure: Percentage of Participants With Improved, Worsened, or Remained Stable for Bothersome Side Effects of Treatment Measured by the Scales of the EORTC QLQ-C30
Description	Subjects reporting >/= 10-point increase compared to baseline (Cycle 1 Day 1) were considered "improved", those reporting <10-point difference were considered "remained stable", and those reporting >/=10-point decrease were considered "worsened". A change of at least 10 points from baseline is considered clinically meaningful (Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality of life score. J Clin Oncol 1998;16:139-44). Patient reported outcome measures were analyzed from baseline up to and including cycle 5. Scores from later timepoints were not analyzed due to attrition (in both arms, fewer than 50% of participants remained on treatment beyond cycle 5).
Time Frame	Baseline (Cycle 1 Day 1) up to Cycle 5 Day 1

Outcome Measure Data

Analysis Population Description

The PRO Analysis population was defined as the ITT population with a baseline and at least one post baseline PRO assessment. Data presented below is only for participants included in the actual analysis.

Arm/Group Title	Ipatasertib and Paclitaxel	Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
Measure Participants	57	53
Improved Appetite Loss: Cycle 2	10.5 16.9%	18.9 30.5%
Maintained Appetite Loss: Cycle 2	64.9 104.7%	66.0 106.5%
Worsened Appetite Loss: Cycle 2	24.6 39.7%	15.1 24.4%
Improved Appetite Loss: Cycle 3	8.7 14%	27.9 45%
Maintained Appetite Loss: Cycle 3	56.5 91.1%	53.5 86.3%
Worsened Appetite Loss: Cycle 3	34.8 56.1%	18.6 30%
Improved Appetite Loss: Cycle 4	10.2 16.5%	30.0 48.4%
Maintained Appetite Loss: Cycle 4	65.3 105.3%	57.5 92.7%
Worsened Appetite Loss: Cycle 4	24.5 39.5%	12.5 20.2%
Improved Appetite Loss: Cycle 5	8.6 13.9%	26.7 43.1%
Maintained Appetite Loss: Cycle 5	80.0 129%	53.3 86%
Worsened Appetite Loss: Cycle 5	11.4 18.4%	20.0 32.3%
Improved Diarrhea: Cycle 2	3.5 5.6%	7.5 12.1%
Maintained Diarrhea: Cycle 2	50.9 82.1%	79.2 127.7%
Worsened Diarrhea: Cycle 2	45.6 73.5%	13.2 21.3%
Improved Diarrhea: Cycle 3	8.7 14%	9.3 15%
Maintained Diarrhea: Cycle 3	39.1 63.1%	69.8 112.6%
Worsened Diarrhea: Cycle 3	52.2 84.2%	20.9 33.7%
Improved Diarrhea: Cycle 4	10.2 16.5%	10.0 16.1%
Maintained Diarrhea: Cycle 4	38.8 62.6%	77.5 125%
Worsened Diarrhea: Cycle 4	51.0 82.3%	12.5 20.2%
Improved Diarrhea: Cycle 5	14.3 23.1%	10.0 16.1%
Maintained Diarrhea: Cycle 5	34.3 55.3%	76.7 123.7%
Worsened Diarrhea: Cycle 5	51.4 82.9%	13.3 21.5%
Improved Fatigue: Cycle 2	21.1 34%	34.0 54.8%
Maintained Fatigue: Cycle 2	29.85 48.1%	30.2 48.7%
Worsened Fatigue: Cycle 2	49.1 79.2%	35.8 57.7%
Improved Fatigue: Cycle 3	23.9 38.5%	34.9 56.3%
Maintained Fatigue: Cycle 3	15.2 24.5%	30.2 48.7%
Worsened Fatigue: Cycle 3	60.9 98.2%	34.9 56.3%
Improved Fatigue: Cycle 4	24.5 39.5%	28.2 45.5%
Maintained Fatigue: Cycle 4	28.6 46.1%	28.2 45.5%
Worsened Fatigue: Cycle 4	46.9 75.6%	43.6 70.3%
Improved Fatigue: Cycle 5	20.0 32.3%	30.0 48.4%
Maintained Fatigue: Cycle 5	20.0 32.3%	43.3 69.8%
Worsened Fatigue: Cycle 5	60.0 96.8%	26.7 43.1%
Improved Nausea/Vomiting Cycle 2	3.5 5.6%	11.3 18.2%
Maintained Nausea/Vomiting Cycle 2	61.4 99%	64.2 103.5%
Worsened Nausea/Vomiting Cycle 2	35.1 56.6%	24.5 39.5%
Improved Nausea/Vomiting Cycle 3	4.3 6.9%	9.3 15%
Maintained Nausea/Vomiting Cycle 3	65.2 105.2%	62.8 101.3%
Worsened Nausea/Vomiting Cycle 3	30.4 49%	27.9 45%
Improved Nausea/Vomiting Cycle 4	2.0 3.2%	7.5 12.1%
Maintained Nausea/Vomiting Cycle 4	73.5 118.5%	67.5 108.9%
Worsened Nausea/Vomiting Cycle 4	24.5 39.5%	25.0 40.3%
Improved Nausea/Vomiting Cycle 5	0 0%	16.7 26.9%
Maintained Nausea/Vomiting Cycle 5	77.8 125.5%	60.0 96.8%
Worsened Nausea/Vomiting Cycle 5	22.2 35.8%	23.3 37.6%
Improved Cognitive Functioning Cycle 2	22.8 36.8%	17.0 27.4%
Maintained Cognitive Function Cycle 2	61.4 99%	60.4 97.4%
Worsened Cognitive Function Cycle 2	15.8 25.5%	22.6 36.5%
Improved Cognitive Functioning Cycle 3	26.1 42.1%	16.3 26.3%
Maintained Cognitive Functioning Cycle 3	47.8 77.1%	53.5 86.3%
Worsened Cognitive Functioning Cycle 3	26.1 42.1%	30.2 48.7%
Improved Cognitive Functioning Cycle 4	20.4 32.9%	22.5 36.3%
Maintained Cognitive Functioning Cycle 4	51.0 82.3%	52.5 84.7%
Worsened Cognitive Functioning Cycle 4	28.6 46.1%	25.0 40.3%
Improved Cognitive Functioning Cycle 5	19.4 31.3%	20.0 32.3%
Maintained Cognitive Functioning Cycle 5	58.3 94%	46.7 75.3%
Worsened Cognitive Functioning Cycle 5	22.2 35.8%	33.3 53.7%
Improved Constipation Cycle 2	8.8 14.2%	17.0 27.4%
Maintained Constipation Cycle 2	73.7 118.9%	64.2 103.5%
Worsened Constipation Cycle 2	17.5 28.2%	18.9 30.5%
Improved Constipation Cycle 3	10.9 17.6%	9.5 15.3%
Maintained Constipation Cycle 3	71.7 115.6%	71.4 115.2%
Worsened Constipation Cycle 3	17.4 28.1%	19.0 30.6%
Improved Constipation Cycle 4	10.4 16.8%	15.0 24.2%
Maintained Constipation Cycle 4	75.0 121%	60.0 96.8%
Worsened Constipation Cycle 4	14.6 23.5%	25.0 40.3%
Improved Constipation Cycle 5	5.6 9%	13.3 21.5%
Maintained Constipation Cycle 5	80.6 130%	73.3 118.2%
Worsened Constipation Cycle 5	13.9 22.4%	13.3 21.5%
Improved Dyspnea Cycle 2	5.3 8.5%	15.4 24.8%
Maintained Dyspnea Cycle 2	77.2 124.5%	69.2 111.6%
Worsened Dyspnea Cycle 2	17.5 28.2%	15.4 24.8%
Improved Dyspnea Cycle 3	6.5 10.5%	14.6 23.5%
Maintained Dyspnea Cycle 3	67.4 108.7%	68.3 110.2%
Worsened Dyspnea Cycle 3	26.1 42.1%	17.1 27.6%
Improved Dyspnea Cycle 4	10.2 16.5%	12.8 20.6%
Maintained Dyspnea Cycle 4	69.4 111.9%	61.5 99.2%
Worsened Dyspnea Cycle 4	20.4 32.9%	25.6 41.3%
Improved Dyspnea Cycle 5	8.3 13.4%	14.3 23.1%
Maintained Dyspnea Cycle 5	69.4 111.9%	60.7 97.9%
Worsened Dyspnea Cycle 5	22.2 35.8%	25.0 40.3%
Improved Emotional Functioning Cycle 2	50.9 82.1%	35.8 57.7%
Maintained Emotional Functioning Cycle 2	43.9 70.8%	50.9 82.1%
Worsened Emotional Functioning Cycle 2	5.3 8.5%	13.2 21.3%
Improved Emotional Functioning Cycle 3	45.7 73.7%	37.2 60%
Maintained Emotional Functioning Cycle 3	45.7 73.7%	41.9 67.6%
Worsened Emotional Functioning Cycle 3	8.7 14%	20.9 33.7%
Improved Emotional Functioning Cycle 4	42.9 69.2%	30.0 48.4%
Maintained Emotional Functioning Cycle 4	49.0 79%	45.0 72.6%
Worsened Emotional Functioning Cycle 4	8.2 13.2%	25.0 40.3%
Improved Emotional Functioning Cycle 5	42.9 69.2%	36.7 59.2%
Maintained Emotional Functioning Cycle 5	48.6 78.4%	36.7 59.2%
Worsened Emotional Functioning Cycle 5	8.6 13.9%	26.7 43.1%
Improved Financial Difficulties Cycle 2	10.7 17.3%	13.5 21.8%
Maintained Financial Difficulties Cycle 2	73.2 118.1%	73.1 117.9%
Worsened Financial Difficulties Cycle 2	16.1 26%	13.5 21.8%
Improved Financial Difficulties Cycle 3	13.0 21%	18.6 30%
Maintained Financial Difficulties Cycle 3	73.9 119.2%	72.1 116.3%
Worsened Financial Difficulties Cycle 3	13.0 21%	9.3 15%
Improved Financial Difficulties Cycle 4	10.2 16.5%	17.5 28.2%
Maintained Financial Difficulties Cycle 4	73.5 118.5%	70.0 112.9%
Worsened Financial Difficulties Cycle 4	16.3 26.3%	12.5 20.2%
Improved Financial Difficulties Cycle 5	13.9 22.4%	20.0 32.3%
Maintained Financial Difficulties Cycle 5	66.7 107.6%	63.3 102.1%
Worsened Financial Difficulties Cycle 5	19.4 31.3%	16.7 26.9%
Improved Pain Cycle 2	35.1 56.6%	35.8 57.7%
Maintained Pain Cycle 2	40.4 65.2%	45.3 73.1%
Worsened Pain Cycle 2	24.6 39.7%	18.9 30.5%
Improved Pain Cycle 3	37.0 59.7%	39.5 63.7%
Maintained Pain Cycle 3	39.1 63.1%	39.5 63.7%
Worsened Pain Cycle	23.9 38.5%	20.9 33.7%
Improved Pain Cycle 4	32.7 52.7%	37.5 60.5%
Maintained Pain Cycle 4	32.7 52.7%	35.0 56.5%
Worsened Pain Cycle 4	34.7 56%	27.5 44.4%
Improved Pain Cycle 5	33.3 53.7%	33.3 53.7%
Maintained Pain Cycle 5	30.6 49.4%	40.0 64.5%
Worsened Pain Cycle 5	36.1 58.2%	26.7 43.1%
Improved Physical Functioning Cycle 2	7.0 11.3%	13.2 21.3%
Maintained Physical Functioning Cycle 2	68.4 110.3%	75.5 121.8%
Worsened Physical Functioning Cycle 2	24.6 39.7%	11.3 18.2%
Improved Physical Functioning Cycle 3	8.7 14%	16.3 26.3%
Maintained Physical Functioning Cycle 3	67.4 108.7%	60.5 97.6%
Worsened Physical Functioning Cycle 3	23.9 38.5%	23.3 37.6%
Improved Physical Functioning Cycle 4	4.1 6.6%	17.5 28.2%
Maintained Physical Functioning Cycle 4	55.1 88.9%	57.5 92.7%
Worsened Physical Functioning Cycle 4	40.8 65.8%	25.0 40.3%
Improved Physical Functioning Cycle 5	8.3 13.4%	16.7 26.9%
Maintained Physical Functioning Cycle 5	44.4 71.6%	46.7 75.3%
Worsened Physical Functioning Cycle 5	47.2 76.1%	36.7 59.2%
Improved Global Health Status/QoL Cycle 2	19.3 31.1%	26.4 42.6%
Maintained Global Health Status/QoL Cycle 2	45.6 73.5%	58.5 94.4%
Worsened Global Health Status/QoL Cycle 2	35.1 56.6%	15.1 24.4%
Improved Global Health Status/QoL Cycle 3	17.4 28.1%	25.6 41.3%
Maintained Global Health Status/QoL Cycle 3	37.0 59.7%	60.5 97.6%
Worsened Global Health Status/QoL Cycle 3	45.7 73.7%	14.0 22.6%
Improved Global Health Status/QoL Cycle 4	14.3 23.1%	25.0 40.3%
Maintained Global Health Status/QoL Cycle 4	51.0 82.3%	42.5 68.5%
Worsened Global Health Status/QoL Cycle 4	34.7 56%	32.5 52.4%
Improved Global Health Status/QoL Cycle 5	11.1 17.9%	20.0 32.3%
Maintained Global Health Status/QoL Cycle 5	58.3 94%	46.7 75.3%
Worsened Global Health Status/QoL Cycle 5	30.6 49.4%	33.3 53.7%
Improved Role Functioning Cycle 2	17.5 28.2%	24.5 39.5%
Maintained Role Functioning Cycle 2	52.6 84.8%	45.3 73.1%
Worsened Role Functioning Cycle 2	29.8 48.1%	30.2 48.7%
Improved Role Functioning Cycle 3	13.0 21%	27.9 45%
Maintained Role Functioning Cycle 3	47.8 77.1%	46.5 75%
Worsened Role Functioning Cycle 3	39.1 63.1%	25.6 41.3%
Improved Role Functioning Cycle 4	12.2 19.7%	25.0 40.3%
Maintained Role Functioning Cycle 4	38.8 62.6%	37.5 60.5%
Worsened Role Functioning Cycle 4	49.0 79%	37.5 60.5%
Improved Role Functioning Cycle 5	11.1 17.9%	16.7 26.9%
Maintained Role Functioning Cycle 5	47.2 76.1%	40.0 64.5%
Worsened Role Functioning Cycle 5	41.7 67.3%	43.3 69.8%
Improved Social Functioning Cycle 2	21.1 34%	22.6 36.5%
Maintained Social Functioning Cycle 2	49.1 79.2%	49.1 79.2%
Worsened Social Functioning Cycle 2	29.8 48.1%	28.3 45.6%
Improved Social Functioning Cycle 3	17.4 28.1%	16.3 26.3%
Maintained Social Functioning Cycle 3	52.2 84.2%	53.5 86.3%
Worsened Social Functioning Cycle 3	30.4 49%	30.2 48.7%
Improved Social Functioning Cycle 4	16.3 26.3%	10.0 16.1%
Maintained Social Functioning Cycle 4	49.0 79%	47.5 76.6%
Worsened Social Functioning Cycle 4	34.7 56%	42.5 68.5%
Improved Social Functioning Cycle 5	17.1 27.6%	13.3 21.5%
Maintained Social Functioning Cycle 5	48.6 78.4%	36.7 59.2%
Worsened Social Functioning Cycle 5	34.3 55.3%	50.0 80.6%

Adverse Events

Time Frame	Baseline up to 30 days after the last dose of study drug or until initiation of another anti-cancer therapy, whichever occurs first (up to 3 years, 3 months)
Arm/Group Title	Ipatasertib and Paclitaxel		Placebo and Paclitaxel
Arm/Group Description	Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.		Participants randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
All Cause Mortality
	Ipatasertib and Paclitaxel		Placebo and Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/61 (67.2%)		46/62 (74.2%)
Serious Adverse Events
	Ipatasertib and Paclitaxel		Placebo and Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/61 (29.5%)		12/62 (19.4%)
Blood and lymphatic system disorders
Pancytopenia	0/61 (0%)	0	1/62 (1.6%)	1
Febrile Neutropenia	2/61 (3.3%)	2	0/62 (0%)	0
Gastrointestinal disorders
Constipation	0/61 (0%)	0	1/62 (1.6%)	1
Diarrhoea	3/61 (4.9%)	3	0/62 (0%)	0
Nausea	1/61 (1.6%)	2	0/62 (0%)	0
Pancreatitis	1/61 (1.6%)	1	0/62 (0%)	0
General disorders
Death	0/61 (0%)	0	1/62 (1.6%)	1
Pyrexia	2/61 (3.3%)	3	1/62 (1.6%)	1
Hepatobiliary disorders
Cholestasis	0/61 (0%)	0	1/62 (1.6%)	1
Infections and infestations
Atypical Pneumonia	1/61 (1.6%)	1	0/62 (0%)	0
Cystitis	0/61 (0%)	0	1/62 (1.6%)	1
Gastroenteritis	0/61 (0%)	0	1/62 (1.6%)	1
Influenza	0/61 (0%)	0	1/62 (1.6%)	1
Pneumonia	3/61 (4.9%)	3	0/62 (0%)	0
Retroperitoneal Infection	1/61 (1.6%)	1	0/62 (0%)	0
Tuberculosis	1/61 (1.6%)	1	0/62 (0%)	0
Upper Respiratory Tract Infection	1/61 (1.6%)	1	0/62 (0%)	0
Wound Infection	1/61 (1.6%)	1	0/62 (0%)	0
Vascular device infection	1/61 (1.6%)	1	0/62 (0%)	0
Investigations
Neutrophil Count Decreased	1/61 (1.6%)	1	0/62 (0%)	0
Metabolism and nutrition disorders
Cell Death	0/61 (0%)	0	1/62 (1.6%)	1
Decreased Appetite	1/61 (1.6%)	1	0/62 (0%)	0
Hyponatraemia	0/61 (0%)	0	1/62 (1.6%)	1
Musculoskeletal and connective tissue disorders
Bone Pain	0/61 (0%)	0	1/62 (1.6%)	1
Muscular weakness	0/61 (0%)	0	1/62 (1.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Triple negative breast cancer	0/61 (0%)	0	1/62 (1.6%)	1
Nervous system disorders
Spinal Cord Compression	1/61 (1.6%)	1	0/62 (0%)	0
Psychiatric disorders
Depression	1/61 (1.6%)	1	0/62 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/61 (0%)	0	1/62 (1.6%)	2
Pleural effusion	0/61 (0%)	0	1/62 (1.6%)	1
Vascular disorders
Embolism	1/61 (1.6%)	1	0/62 (0%)	0
Other (Not Including Serious) Adverse Events
	Ipatasertib and Paclitaxel		Placebo and Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/61 (100%)		59/62 (95.2%)
Blood and lymphatic system disorders
Anaemia	9/61 (14.8%)	17	8/62 (12.9%)	11
Leukopenia	2/61 (3.3%)	3	4/62 (6.5%)	6
Neutropenia	13/61 (21.3%)	38	15/62 (24.2%)	36
Eye disorders
Dry Eye	4/61 (6.6%)	5	3/62 (4.8%)	3
Gastrointestinal disorders
Abdominal Pain	9/61 (14.8%)	13	7/62 (11.3%)	9
Abdominal Pain Upper	4/61 (6.6%)	4	4/62 (6.5%)	5
Constipation	12/61 (19.7%)	17	9/62 (14.5%)	11
Diarrhoea	56/61 (91.8%)	205	13/62 (21%)	19
Dry Mouth	2/61 (3.3%)	3	5/62 (8.1%)	5
Dyspepsia	8/61 (13.1%)	11	6/62 (9.7%)	6
Flatulence	4/61 (6.6%)	4	2/62 (3.2%)	2
Gastritis	4/61 (6.6%)	5	0/62 (0%)	0
Nausea	32/61 (52.5%)	67	21/62 (33.9%)	28
Stomatitis	11/61 (18%)	14	5/62 (8.1%)	6
Vomiting	17/61 (27.9%)	39	14/62 (22.6%)	15
General disorders
Asthenia	17/61 (27.9%)	41	7/62 (11.3%)	7
Chest Discomfort	4/61 (6.6%)	4	1/62 (1.6%)	1
Chest Pain	4/61 (6.6%)	5	6/62 (9.7%)	6
Fatigue	18/61 (29.5%)	26	20/62 (32.3%)	32
Mucosal Inflammation	4/61 (6.6%)	7	4/62 (6.5%)	5
Oedema Peripheral	7/61 (11.5%)	9	5/62 (8.1%)	6
Pyrexia	11/61 (18%)	13	7/62 (11.3%)	9
Infections and infestations
Nasopharyngitis	8/61 (13.1%)	12	5/62 (8.1%)	6
Upper Respiratory Tract Infection	10/61 (16.4%)	15	4/62 (6.5%)	10
Urinary Tract Infection	5/61 (8.2%)	6	4/62 (6.5%)	4
Influenza	4/61 (6.6%)	6	1/62 (1.6%)	1
Rhinitis	4/61 (6.6%)	5	1/62 (1.6%)	1
Investigations
Alanine Aminotransferase Increased	3/61 (4.9%)	5	4/62 (6.5%)	4
Aspartate Aminotransferase Increased	5/61 (8.2%)	8	3/62 (4.8%)	6
Neutrophil Count Decreased	8/61 (13.1%)	19	9/62 (14.5%)	20
Metabolism and nutrition disorders
Decreased appetite	12/61 (19.7%)	15	11/62 (17.7%)	15
Hypercholesterolaemia	6/61 (9.8%)	6	1/62 (1.6%)	2
Hyperglycaemia	5/61 (8.2%)	10	2/62 (3.2%)	3
Hypokalaemia	4/61 (6.6%)	7	2/62 (3.2%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	12/61 (19.7%)	16	5/62 (8.1%)	5
Back Pain	7/61 (11.5%)	10	6/62 (9.7%)	7
Musculoskeletal Chest Pain	4/61 (6.6%)	9	4/62 (6.5%)	4
Musculoskeletal Pain	3/61 (4.9%)	4	4/62 (6.5%)	4
Myalgia	17/61 (27.9%)	42	15/62 (24.2%)	25
Pain in Extremity	5/61 (8.2%)	8	2/62 (3.2%)	2
Bone pain	4/61 (6.6%)	6	1/62 (1.6%)	1
Nervous system disorders
Dizziness	11/61 (18%)	19	9/62 (14.5%)	10
Dysgeusia	4/61 (6.6%)	4	5/62 (8.1%)	5
Headache	11/61 (18%)	15	13/62 (21%)	14
Hypoaesthesia	4/61 (6.6%)	6	0/62 (0%)	0
Neuropathy Peripheral	12/61 (19.7%)	17	14/62 (22.6%)	18
Paraesthesia	6/61 (9.8%)	10	7/62 (11.3%)	10
Peripheral Sensory Neuropathy	16/61 (26.2%)	33	10/62 (16.1%)	16
Psychiatric disorders
Anxiety	2/61 (3.3%)	3	4/62 (6.5%)	6
Insomnia	13/61 (21.3%)	19	8/62 (12.9%)	9
Depression	4/61 (6.6%)	4	2/62 (3.2%)	2
Respiratory, thoracic and mediastinal disorders
Cough	9/61 (14.8%)	11	8/62 (12.9%)	12
Epistaxis	7/61 (11.5%)	8	2/62 (3.2%)	2
Dyspnoea	9/61 (14.8%)	13	5/62 (8.1%)	6
Productive cough	4/61 (6.6%)	4	2/62 (3.2%)	2
Skin and subcutaneous tissue disorders
Alopecia	33/61 (54.1%)	37	29/62 (46.8%)	34
Dermatitis Acneiform	10/61 (16.4%)	17	5/62 (8.1%)	5
Nail Disorder	4/61 (6.6%)	7	4/62 (6.5%)	4
Onycholysis	4/61 (6.6%)	4	1/62 (1.6%)	1
Pruritus	9/61 (14.8%)	14	5/62 (8.1%)	5
Rash	17/61 (27.9%)	28	13/62 (21%)	17
Rash Maculo-Papular	1/61 (1.6%)	1	4/62 (6.5%)	7
Vascular disorders
Flushing	4/61 (6.6%)	4	3/62 (4.8%)	3
Hot Flush	5/61 (8.2%)	5	3/62 (4.8%)	3
Hypertension	3/61 (4.9%)	3	4/62 (6.5%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the study but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.