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Clinical Trial Results:
A Phase Ib/II Study of GDC-0068 or GDC-0980 with Abiraterone Acetate versus Abiraterone Acetate in Patients with Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy

Summary
EudraCT number	2011-004126-10
Trial protocol	GR CZ ES GB NL FR IT
Global end of trial date	31 Aug 2022

Results information
Results version number	v2(current)
This version publication date	02 Sep 2023
First version publication date	07 Dec 2016
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GO27983

ISRCTN number

US NCT number

NCT01485861

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Aug 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

31 Aug 2022

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of the Phase Ib portion of the study were as follows: To evaluate the safety and tolerability of ipatasertib (GDC-0068), an Akt inhibitor, administered in combination with abiraterone and of apitolisib (GDC-0980), a phosphatidylinositol 3 kinase [PI3K], and/or mammalian target of rapamycin [mTOR] inhibitor, administered in combination with abiraterone. To identify dose-limiting toxicities, estimate the maximum tolerated dose, and identify a recommended Phase II dose of ipatasertib administered in combination with abiraterone and of apitolisib administered in combination with abiraterone. The primary objective of the Phase II portion of the study was to estimate the efficacy as measured by radiographic progression-free survival of ipatasertib (dosed at either 400 milligrams [mg] or 200 mg daily) + abiraterone and prednisone/prednisolone versus placebo + abiraterone and prednisone/prednisolone.

Protection of trial subjects

All study participants were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

11 Jan 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 11

Country: Number of subjects enrolled

Spain: 46

Country: Number of subjects enrolled

United Kingdom: 24

Country: Number of subjects enrolled

Czechia: 22

Country: Number of subjects enrolled

France: 34

Country: Number of subjects enrolled

Greece: 16

Country: Number of subjects enrolled

Italy: 49

Country: Number of subjects enrolled

Romania: 42

Country: Number of subjects enrolled

United States: 54

Worldwide total number of subjects

298

EEA total number of subjects

220

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

201

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 55 centers in 10 countries.

Screening details

The study consisted of 3 stages: Phase Ib determined recommended Phase II doses (RP2D) for ipatasertib and apitolisib in combination with abiraterone and prednisone/prednisolone. Phase II compared ipatasertib (400 mg/200 mg daily) versus placebo each combined with abiraterone and prednisone/prednisolone. The third stage included the safety cohort.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Blinding implementation details

The Phase Ib portion of the study was open-label. In Phase II, participants and investigators were blinded with regard to treatment status (i.e., ipatasertib vs. placebo). The Safety cohort was open-label.

Are arms mutually exclusive

Yes

Phase Ib: Ipatasertib 400 mg

Arm description

Participants received ipatasertib 400 mg orally once daily, abiraterone 1000 mg orally once daily, and prednisone/prednisolone 5 mg twice daily (bid) orally continuously in 28-day treatment cycles until disease progression or intolerable toxicity.

Arm type

Experimental

Investigational medicinal product name

Ipatasertib

Investigational medicinal product code

Other name

GDC-0068

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Ipatasertib was administered orally once daily beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity.

Investigational medicinal product name

Prednisone/Prednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone/prednisolone was to be taken per local clinical practice/investigator recommendation.

Investigational medicinal product name

Abiraterone acetate

Investigational medicinal product code

Other name

Zytiga®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Abiraterone was administered once a day, at the same time that ipatasertib was taken.

Phase Ib: Apitolisib 30 mg

Arm description

Participants received apitolisib 30 mg orally once daily, abiraterone 1000 mg orally once daily, and prednisone/prednisolone 5 mg bid orally continuously in 28-day treatment cycles until disease progression or intolerable toxicity.

Arm type

Experimental

Investigational medicinal product name

Apitolisib

Investigational medicinal product code

Other name

GDC-0980

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Apitolisib was administered daily beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity.

Investigational medicinal product name

Prednisone/Prednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone/prednisolone was to be taken per local clinical practice/investigator recommendation.

Investigational medicinal product name

Abiraterone acetate

Investigational medicinal product code

Other name

Zytiga®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Abiraterone was administered once a day, at the same time that ipatasertib was taken.

Phase II: Ipatasertib 400 mg + Abiraterone

Arm description

Participants received ipatasertib 400 mg orally once daily, abiraterone 1000 mg orally once daily, and prednisone/prednisolone 5 mg bid orally continuously in 28-day treatment cycles until disease progression or intolerable toxicity.

Arm type

Experimental

Investigational medicinal product name

Ipatasertib

Investigational medicinal product code

Other name

GDC-0068

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Ipatasertib was administered orally once daily beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity.

Investigational medicinal product name

Prednisone/Prednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone/prednisolone was to be taken per local clinical practice/investigator recommendation.

Investigational medicinal product name

Abiraterone acetate

Investigational medicinal product code

Other name

Zytiga®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Abiraterone was administered once a day, at the same time that ipatasertib was taken.

Phase II: Ipatasertib 200 mg + Abiraterone

Arm description

Participants received ipatasertib 200 mg orally once daily, abiraterone 1000 mg once orally daily, and prednisone/prednisolone 5 mg bid orally continuously in 28-day treatment cycles until disease progression or intolerable toxicity.

Arm type

Experimental

Investigational medicinal product name

Ipatasertib

Investigational medicinal product code

Other name

GDC-0068

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Ipatasertib was administered orally once daily beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity.

Investigational medicinal product name

Prednisone/Prednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone/prednisolone was to be taken per local clinical practice/investigator recommendation.

Investigational medicinal product name

Abiraterone acetate

Investigational medicinal product code

Other name

Zytiga®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Abiraterone was administered once a day, at the same time that ipatasertib was taken.

Phase II: Placebo + Abiraterone

Arm description

Participants received placebo (matched to ipatasertib 400 mg or 200) orally once daily, abiraterone 1000 mg orally once daily, and prednisone/prednisolone 5 mg bid orally continuously in 28-day treatment cycles until disease progression or intolerable toxicity.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Placebo (for Ipatasertib 400 mg or 200 mg) was administered daily beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity.

Investigational medicinal product name

Prednisone/Prednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone/prednisolone was to be taken per local clinical practice/investigator recommendation.

Investigational medicinal product name

Abiraterone acetate

Investigational medicinal product code

Other name

Zytiga®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Abiraterone was administered once a day, at the same time that ipatasertib was taken.

Safety Cohort: Ipatasertib 400 mg + Abiraterone

Arm description

Participants received ipatasertib 400 mg orally once daily and/or prednisone/prednisolone 5 mg orally once daily or bid and/or abiraterone 1000 mg orally once daily according to the following schedule: ipatasertib in the morning during Cycle 1, Days 1-7; ipatasertib in the morning plus prednisone/prednisolone once at night during Cycle 1, Day 8; ipatasertib in the morning plus prednisone/prednisolone bid (morning and night) during Cycle 1, Days 9-11; ipatasertib in the morning plus prednisone/prednisolone bid (morning and night) and abiraterone in the morning during Cycle 1, Days 12-18; ipatasertib in the evening plus prednisone/prednisolone bid (morning and night) and abiraterone at the same time as ipatasertib during Cycle 1, Days 19-25; Cycle 2 and beyond ipatasertib once daily in the morning or evening, abiraterone at the same time as ipatasertib, and prednisone/prednisolone bid.

Arm type

Experimental

Investigational medicinal product name

Ipatasertib

Investigational medicinal product code

Other name

GDC-0068

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Ipatasertib was administered orally once daily beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity.

Investigational medicinal product name

Abiraterone acetate

Investigational medicinal product code

Other name

Zytiga®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Abiraterone was administered once a day, at the same time that ipatasertib was taken starting at Cycle 1, Day 18 and then continuously until disease progression or intolerable toxicity.

Investigational medicinal product name

Prednisone/Prednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone/prednisolone was to be taken per local clinical practice/investigator recommendation starting on Cycle 1, Day 8.

Number of subjects in period 1	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone	Safety Cohort: Ipatasertib 400 mg + Abiraterone
Started	14	6	84	86	83	25
Completed	0	0	1	0	0	0
Not completed	14	6	83	86	83	25
Physician decision	1	1	-	-	-	-
Consent withdrawn by subject	4	1	6	3	4	6
Study Ended	-	-	7	8	6	-
Discontinuation of Survival Follow-up	-	-	-	-	-	2
Death	1	-	67	71	68	2
Adverse event	-	4	-	-	-	1
Unspecified	3	-	-	1	-	5
Progression of disease	5	-	1	-	-	9
Lost to follow-up	-	-	2	3	5	-

Baseline characteristics

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Reporting group title

Phase Ib: Ipatasertib 400 mg

Reporting group description

Reporting group title

Phase Ib: Apitolisib 30 mg

Reporting group description

Reporting group title

Phase II: Ipatasertib 400 mg + Abiraterone

Reporting group description

Reporting group title

Phase II: Ipatasertib 200 mg + Abiraterone

Reporting group description

Reporting group title

Phase II: Placebo + Abiraterone

Reporting group description

Reporting group title

Safety Cohort: Ipatasertib 400 mg + Abiraterone

Reporting group description

Reporting group values	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone	Safety Cohort: Ipatasertib 400 mg + Abiraterone	Total
Number of subjects	14	6	84	86	83	25	273
Age categorical
Units: Subjects
Age continuous
Number of participants analysed for this parameter were 14, 6, 84, 86, 83, respectively.
Units: years
arithmetic mean (standard deviation)	68.1 ( 9.1 )	69.3 ( 9.3 )	66.9 ( 8.5 )	68.8 ( 7.2 )	67.6 ( 7.8 )	73.7 ( 8.8 )	-
Gender categorical
Units: Subjects
Female	0	0	0	0	0	0	0
Male	14	6	84	86	83	25	298

End points

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Reporting group title

Phase Ib: Ipatasertib 400 mg

Reporting group description

Reporting group title

Phase Ib: Apitolisib 30 mg

Reporting group description

Reporting group title

Phase II: Ipatasertib 400 mg + Abiraterone

Reporting group description

Reporting group title

Phase II: Ipatasertib 200 mg + Abiraterone

Reporting group description

Reporting group title

Phase II: Placebo + Abiraterone

Reporting group description

Reporting group title

Safety Cohort: Ipatasertib 400 mg + Abiraterone

Reporting group description

Subject analysis set title

Safety Set Ipatasertib 400 mg + Abiraterone

Subject analysis set type

Safety analysis

Subject analysis set description

The Safety Set for Ipatasertib 400 mg + Abiraterone included all treated participants.

Subject analysis set title

Safety Set Ipatasertib 200 mg + Abiraterone

Subject analysis set type

Safety analysis

Subject analysis set description

There were 2 participants who had been randomized to the Placebo + Abiraterone arm, but received 200 mg ipatasertib for 5 days, and are thus counted in the Ipatasertib 200 mg + Abiraterone for the safety population.

Subject analysis set title

Safety Set Placebo + Abiraterone

Subject analysis set type

Safety analysis

Subject analysis set description

Primary: Phase Ib: Percentage of Participants With Dose-Limiting Toxicity (DLTs)

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End point title

Phase Ib: Percentage of Participants With Dose-Limiting Toxicity (DLTs) ^[1] ^[2]

End point description

DLT: 1 of the following toxicities, at least possibly related to ipatasertib or apitolisib. 1) Grade ≥ 3 non-hematologic, non-hepatic major organ AE; 2) Grade ≥ 3 febrile neutropenia; 3) Grade ≥ 4 neutropenia (absolute neutrophils less than [<] 500 per microliter) lasting greater than (>) 7 days; 4) Grade ≥3 thrombocytopenia associated with acute hemorrhage; 5) Grade ≥4 thrombocytopenia; 6) Grade ≥4 anemia; 7) 1 episode of fasting Grade ≥4 hyperglycemia or 3 episodes of fasting Grade 3 hyperglycemia on separate days within 7 days, as determined by laboratory blood glucose evaluation; 8) Grade ≥3 elevation lasting for > 48 hours for hepatic transaminase or liver-specific alkaline phosphatase or total bilirubin. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.0. Safety population: all participants who had received ipatasertib, apitolisib, placebo, or abiraterone treatment on Day 1 of Cycle 1.

End point type

Primary

End point timeframe

Days 1 to 28 of Cycle 1 (Cycle length = 28 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analyses were planned to be reported.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase Ib arms were planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	14	6
Units: percentage of participants
number (not applicable)	0	0

No statistical analyses for this end point

Primary: Phase Ib: Percentage of Participants with Adverse Events (AEs)

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End point title

Phase Ib: Percentage of Participants with Adverse Events (AEs) ^[3] ^[4]

End point description

An Adverse Event (AE) 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. Safety Population was defined as all participants who had received ipatasertib, apitolisib, placebo, or abiraterone treatment on Day 1 of Cycle 1.

End point type

Primary

End point timeframe

Baseline up until 30 days following the last administration of study treatment or until initiation of another anti-cancer therapy, whichever occurs first (up to approximately 10 months).

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analyses were planned to be reported.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase Ib arms were planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	14	6
Units: percentage of participants
number (not applicable)	100.0	100.0

No statistical analyses for this end point

Primary: Phase II: Radiographic Progression Free Survival (rPFS) - ITT Population

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End point title

Phase II: Radiographic Progression Free Survival (rPFS) - ITT Population ^[5]

End point description

rPFS: Time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments via CT scan and bone scans, or death on study from any cause, whichever occurred first. Progression was defined as follows: Soft tissue mass (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1): at least 20% increase in sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. Bone: ≥ 2 new bone lesions plus 2 additional at confirmation on a second bone scan ≥ 4 weeks later (< 12 weeks after randomization). ≥ 2 new bone lesions consistent with progression, without need for confirmatory bone scan (≥ 12 weeks after randomization). ITT Population was defined as all randomised participants with the participants allocated to the treatment arm according to the randomisation.

End point type

Primary

End point timeframe

Screening up to radiographic progression or death, whichever occurred first (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	84	86	83
Units: months
median (confidence interval 90%)	8.18 (6.67 to 10.87)	8.31 (6.44 to 10.48)	6.37 (4.60 to 8.34)

Unstratified analysis:Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1606

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

90%

sides

2-sided

lower limit

0.56

upper limit

1.04

Unstratified analysis:Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.53

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.89

Confidence interval

level

90%

sides

2-sided

lower limit

0.66

upper limit

1.2

Stratified analysis:Ipatasertib 400 mg v Placebo

Statistical analysis description

Strata were: prior enzalutamide (Yes vs. No), progression factor (prostate-specific antigen [PSA] only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one).

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1689

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.75

Confidence interval

level

90%

sides

2-sided

lower limit

0.54

upper limit

1.05

Stratified analysis:Ipatasertib 200 mg v Placebo

Statistical analysis description

Strata were: prior enzalutamide (Yes vs. No), progression factor (PSA only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one).

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7484

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.94

Confidence interval

level

90%

sides

2-sided

lower limit

0.69

upper limit

1.28

Primary: Phase Ib: Recommended Phase II Dose (RP2D) of Ipatasertib and Apitolisib

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End point title

Phase Ib: Recommended Phase II Dose (RP2D) of Ipatasertib and Apitolisib ^[6] ^[7]

End point description

RP2D is a dose of a drug which would be used in Phase II stage of the study. RP2D was to be determined based on maximum tolerated dose (MTD) in Phase Ib stage of the study. The highest dose level (in 3+3 escalation scheme) with an acceptable safety profile and with a minimum of 6 participants at which fewer than one-third of participants experienced a DLT was declared the MTD and RP2D. Safety Population was defined as all participants who had received ipatasertib, apitolisib, placebo, or abiraterone treatment on Day 1 of Cycle 1.

End point type

Primary

End point timeframe

Days 1 to 28 of Cycle 1 (Cycle length = 28 days)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analyses were planned to be reported.
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase Ib arms were planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	14	0 ^[8]
Units: milligrams
number (not applicable)	400

Notes
[8] - Based on safety analysis, further testing of apitolisib arm was discontinued.

No statistical analyses for this end point

Primary: Phase II: rPFS in Participants With Institute of Cancer Research (ICR) Phosphatase and Tensin Homolog (PTEN) Loss

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End point title

Phase II: rPFS in Participants With Institute of Cancer Research (ICR) Phosphatase and Tensin Homolog (PTEN) Loss ^[9]

End point description

rPFS: Time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments via CT scan and bone scans, or death on study from any cause, whichever occurred first. Progression was defined as follows: Soft tissue mass (RECIST 1.1): at least 20% increase in sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. Bone: ≥ 2 new bone lesions plus 2 additional at confirmation on 2nd bone scan ≥ 4 weeks later (< 12 weeks after randomization). ≥ 2 new bone lesions consistent with progression, without need for confirmatory bone scan (≥ 12 weeks after randomization). PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analyzed=participants with PTEN loss.

End point type

Primary

End point timeframe

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	25	25	21
Units: months
median (confidence interval 90%)	11.53 (6.67 to 13.73)	11.10 (6.34 to 16.36)	4.60 (4.40 to 6.37)

Unstratified analysis:Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0064

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.39

Confidence interval

level

90%

sides

2-sided

lower limit

0.22

upper limit

0.7

Unstratified analysis:Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Placebo + Abiraterone v Phase II: Ipatasertib 200 mg + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0285

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.46

Confidence interval

level

90%

sides

2-sided

lower limit

0.25

upper limit

0.83

Secondary: Phase Ib: Time to Cmax (tmax) of Ipatasertib When Co-Administered With Abiraterone

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End point title

Phase Ib: Time to Cmax (tmax) of Ipatasertib When Co-Administered With Abiraterone ^[10]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with ipatasertib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg
Number of subjects analysed	14
Units: hours
median (full range (min-max))
Cycle 1, Day 1 (n=14)	2.00 (0.97 to 4.05)
Cycle 1, Day 15 (n=12)	2.02 (1.00 to 6.00)

No statistical analyses for this end point

Secondary: Phase Ib: Maximum Plasma Concentration (Cmax) of Ipatasertib When Co-Administered With Abiraterone

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End point title

Phase Ib: Maximum Plasma Concentration (Cmax) of Ipatasertib When Co-Administered With Abiraterone ^[11]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with ipatasertib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg
Number of subjects analysed	14
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 (n=14)	269 ( 41.3 )
Cycle 1, Day 15 (n=12)	466 ( 36.2 )

No statistical analyses for this end point

Secondary: Phase Ib: Cmax of G-037720 (Metabolite of Ipatasertib)

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End point title

Phase Ib: Cmax of G-037720 (Metabolite of Ipatasertib) ^[12]

End point description

G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation. Analysis was performed on Pharmacokinetic Analysis Population (only ipatasertib arm) which included all participants who had evaluable PK data. Here, "n" signifies the number of participants with PK data available for specified timepoint.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with ipatasertib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg
Number of subjects analysed	14
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 (n=14)	117 ( 64.4 )
Cycle 1, Day 15 (n=12)	326 ( 42.4 )

No statistical analyses for this end point

Secondary: Phase Ib: tmax of G-037720 (Metabolite of Ipatasertib)

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End point title

Phase Ib: tmax of G-037720 (Metabolite of Ipatasertib) ^[13]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with ipatasertib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg
Number of subjects analysed	14
Units: hours
median (full range (min-max))
Cycle 1, Day 1 (n=14)	2.00 (1.00 to 4.05)
Cycle 1, Day 15 (n=12)	2.10 (1.00 to 6.00)

No statistical analyses for this end point

Secondary: Phase Ib: Accumulation Ratio of Ipatasertib When Co-Administered With Abiraterone

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End point title

Phase Ib: Accumulation Ratio of Ipatasertib When Co-Administered With Abiraterone ^[14]

End point description

Accumulation Ratio was caculated as AUC0-24 (Cycle 1 Day 15) divided by AUC0-24 (Cycle 1 Day 1). Analysis was performed on Pharmacokinetic Analysis Population which included all participants who had evaluable PK data Number of participants analyzed=participants with PK data available on both Day 1 and Day 15 of Cycle 1.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with ipatasertib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg
Number of subjects analysed	12
Units: ratio
geometric mean (geometric coefficient of variation)	1.82 ( 40.9 )

No statistical analyses for this end point

Secondary: Phase Ib: Total Body Clearance (CL/F) of Ipatasertib When Co-Administered With Abiraterone

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End point title

Phase Ib: Total Body Clearance (CL/F) of Ipatasertib When Co-Administered With Abiraterone ^[15]

End point description

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Analysis was performed on Pharmacokinetic Analysis Population which included all participants who had evaluable PK data. Numer of participants analyzed=participants with PK data available on Day 15 of Cycle 1.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 15 of Cycle 1 (cycle length = 28 days)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with ipatasertib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg
Number of subjects analysed	12
Units: milliliter per hour (mL/h)
geometric mean (geometric coefficient of variation)	99600 ( 50.7 )

No statistical analyses for this end point

Secondary: Phase Ib: Area Under The Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of Ipatasertib When Co-Administered With Abiraterone

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End point title

Phase Ib: Area Under The Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of Ipatasertib When Co-Administered With Abiraterone ^[16]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with ipatasertib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg
Number of subjects analysed	14
Units: ng/mL*hours
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 (n=14)	1710 ( 54.7 )
Cycle 1, Day 15 (n=12)	3290 ( 37.0 )

No statistical analyses for this end point

Secondary: Phase Ib: Cmax of Apitolisib When Co-Administered With Abiraterone

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End point title

Phase Ib: Cmax of Apitolisib When Co-Administered With Abiraterone ^[17]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with apitolisib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 (n=6)	190 ( 35.2 )
Cycle 1, Day 15 (n=2)	193 ( 16.2 )

No statistical analyses for this end point

Secondary: Phase Ib: Accumulation Ratio of G-037720 (Metabolite of Ipatasertib)

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End point title

Phase Ib: Accumulation Ratio of G-037720 (Metabolite of Ipatasertib) ^[18]

End point description

G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation. Accumulation Ratio was caculated as AUC0-24 (Cycle 1 Day 15) divided by AUC0-24 (Cycle 1 Day 1). Analysis was performed on Pharmacokinetic Analysis Population (only ipatasertib arm) which included all participants who had evaluable PK data. Number of participants analyzed=participants with PK data available on both Day 1 and Day 15 of Cycle 1.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with ipatasertib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg
Number of subjects analysed	12
Units: ratio
geometric mean (geometric coefficient of variation)	2.79 ( 54.4 )

No statistical analyses for this end point

Secondary: Phase Ib: AUC0-24 of G-037720 (Metabolite of Ipatasertib)

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End point title

Phase Ib: AUC0-24 of G-037720 (Metabolite of Ipatasertib) ^[19]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with ipatasertib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg
Number of subjects analysed	14
Units: ng/mL*hour
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 (n=14)	839 ( 70.3 )
Cycle 1, Day 15 (n=12)	2850 ( 71.7 )

No statistical analyses for this end point

Secondary: Phase Ib: tmax of Apitolisib When Co-Administered With Abiraterone

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End point title

Phase Ib: tmax of Apitolisib When Co-Administered With Abiraterone ^[20]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with apitolisib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	6
Units: hours
median (full range (min-max))
Cycle 1, Day 1 (n=6)	2.02 (1.00 to 4.10)
Cycle 1, Day 15 (n=2)	2.04 (2.00 to 2.08)

No statistical analyses for this end point

Secondary: Phase Ib: tmax of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

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End point title

Phase Ib: tmax of Abiraterone When Co- Administered With Ipatasertib or GDC-0980 ^[21]

End point description

Analysis was performed on Pharmacokinetic Analysis Population which included all participants who had evaluable PK data. Here, "n" signifies the number of participants with PK data available for specified timepoint.Cycle 1, Day 1 (n=14,6)

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase Ib arms were planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	14	6
Units: hours
median (full range (min-max))
Cycle 1, Day 1 (n=14,6)	2.05 (2.00 to 6.45)	2.01 (1.00 to 4.03)
Cycle 1, Day 15 (n=12,2)	2.17 (2.00 to 6.00)	3.04 (2.00 to 4.08)

No statistical analyses for this end point

Secondary: Phase Ib: Cmax of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

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End point title

Phase Ib: Cmax of Abiraterone When Co- Administered With Ipatasertib or GDC-0980 ^[22]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase Ib arms were planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	14	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 (n=14,6)	151 ( 123.6 )	88.2 ( 218 )
Cycle 1, Day 15 (n=12,2)	140 ( 124.4 )	52.7 ( 182 )

No statistical analyses for this end point

Secondary: Phase Ib: AUC0-24 of Apitolisib When Co-Administered With Abiraterone

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End point title

Phase Ib: AUC0-24 of Apitolisib When Co-Administered With Abiraterone ^[23]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arm treated with apitolisib in Phase Ib was planned to be included in the analysis.

End point values	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	6
Units: ng/mL*hours
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 (n=6)	1600 ( 47.5 )
Cycle 1, Day 15 (n=2)	1640 ( 5.65 )

No statistical analyses for this end point

Secondary: Phase Ib: AUC0-24 of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

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End point title

Phase Ib: AUC0-24 of Abiraterone When Co- Administered With Ipatasertib or GDC-0980 ^[24]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase Ib arms were planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	12	6
Units: ng/mL*hr
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 (n=12,6)	749 ( 92.0 )	475 ( 203.4 )
Cycle 1, Day 15 (n=6,1)	961 ( 87.2 )	220 ( 99999 )

No statistical analyses for this end point

Secondary: Phase Ib: Plasma Half-Life of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

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End point title

Phase Ib: Plasma Half-Life of Abiraterone When Co- Administered With Ipatasertib or GDC-0980 ^[25]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase Ib arms were planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	10	5
Units: hours
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1 (n=10,5)	5.25 ( 13.0 )	7.68 ( 26.2 )
Cycle 1, Day 15 (n=6,1)	6.92 ( 23.5 )	14.70 ( 99999 )

No statistical analyses for this end point

Secondary: Phase II: Overall Survival - ITT Population

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End point title

Phase II: Overall Survival - ITT Population ^[26]

End point description

Overall survival was defined as the interval between the date of screening and death due to any cause. Overall survival was estimated using Kaplan Meier method. The ITT Population was defined as all randomised participants with the participants allocated to the treatment arm according to the randomisation.

End point type

Secondary

End point timeframe

Screening up to death (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 8.9 years overall]) (cycle length = 28 days)

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	84	86	83
Units: months
median (confidence interval 95%)	18.27 (16.66 to 24.21)	17.31 (13.83 to 22.41)	18.37 (13.80 to 20.96)

Stratified analysis:Ipatasertib 400 mg v Placebo

Statistical analysis description

Strata were: prior enzalutamide (Yes vs. No), progression factor (PSA only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one).

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5164

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

1.27

Unstratified analysis:Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.417

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

1.22

Unstratified analysis:Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Placebo + Abiraterone v Phase II: Ipatasertib 200 mg + Abiraterone

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6712

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.3

Stratified analysis:Ipatasertib 200 mg v Placebo

Statistical analysis description

Strata were: prior enzalutamide (Yes vs. No), progression factor (PSA only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one).

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8955

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.44

Secondary: Phase Ib: Accumulation Ratio of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

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End point title

Phase Ib: Accumulation Ratio of Abiraterone When Co- Administered With Ipatasertib or GDC-0980 ^[27]

End point description

Accumulation Ratio was caculated as AUC0-24 (Cycle 1 Day 15) divided by AUC0-24 (Cycle 1 Day 1). Analysis was performed on Pharmacokinetic Analysis Population which included all participants who had evaluable PK data. Number of participants analyzed=participants with PK data available on both Day 1 and Day 15 of Cycle 1. 99999 = Geometric Coefficient of Variation could not be estimated as only 1 participant was evaluated.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase Ib arms were planned to be included in the analysis.

End point values	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg
Number of subjects analysed	12	1
Units: ratio
geometric mean (geometric coefficient of variation)	0.823 ( 70.7 )	0.882 ( 99999 )

No statistical analyses for this end point

Secondary: Phase II: Overall Survival in Participants With ICR IHC PTEN Loss

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End point title

Phase II: Overall Survival in Participants With ICR IHC PTEN Loss ^[28]

End point description

Overall survival was defined as the interval between the date of randomization and death from any cause. Overall survival was estimated using Kaplan Meier method. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analyzed=participants with PTEN loss.

End point type

Secondary

End point timeframe

Screening up to death (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 8.9 years overall]) (cycle length = 28 days)

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	25	25	21
Units: months
median (confidence interval 95%)	17.12 (12.32 to 28.02)	28.45 (13.24 to 33.28)	17.28 (11.30 to 20.96)

Unstratified analysis:Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0157

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

0.87

Unstratified analysis:Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1472

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

1.19

Secondary: Phase II: Percentage of Participants With PSA Progression - ITT Population

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End point title

Phase II: Percentage of Participants With PSA Progression - ITT Population ^[29]

End point description

PSA progression was defined as per Prostate Cancer Working Group 2 criteria. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 nanogram per milliliter (ng/mL) from the baseline value, or a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the nadir if PSA decreases from baseline after treatment, which was confirmed by a second value obtained ≥ 3 weeks later. The ITT Population was defined as all randomised participants with the participants allocated to the treatment arm according to the randomisation.

End point type

Secondary

End point timeframe

Screening up to PSA progression (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	84	86	83
Units: percentage of participants
number (not applicable)	57.1	69.8	72.3

No statistical analyses for this end point

Secondary: Phase II: Percentage of Participants With PSA Progression in Participants With ICR PTEN Loss

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End point title

Phase II: Percentage of Participants With PSA Progression in Participants With ICR PTEN Loss ^[30]

End point description

PSA progression was defined as per Prostate Cancer Working Group 2 criteria. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the baseline value, or a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the nadir if PSA decreases from baseline after treatment, which was confirmed by a second value obtained ≥ 3 weeks later. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analyzed=participants with PTEN loss.

End point type

Secondary

End point timeframe

Screening up to PSA progression (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	25	25	21
Units: percentage of participants
number (not applicable)	72.0	64.0	66.7

No statistical analyses for this end point

Secondary: Phase II: Time to PSA Progression in Participants With ICR PTEN Loss

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End point title

Phase II: Time to PSA Progression in Participants With ICR PTEN Loss ^[31]

End point description

Time to PSA progression: Time from screening to the first occurrence of PSA progression, as determined by investigator. PSA progression was defined as per Prostate Cancer Working Group 2 criteria. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the baseline value, or a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the nadir if PSA decreases from baseline after treatment, which was confirmed by a second value obtained ≥ 3 weeks later. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analyzed=participants with PTEN loss.

End point type

Secondary

End point timeframe

Screening up to PSA progression (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	25	25	21
Units: months
median (confidence interval 90%)	3.71 (2.99 to 8.18)	2.92 (2.07 to 7.39)	2.79 (1.02 to 4.67)

Unstratified analysis:Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2716

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.65

Confidence interval

level

90%

sides

2-sided

lower limit

0.35

upper limit

1.22

Unstratified analysis:Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2906

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.68

Confidence interval

level

90%

sides

2-sided

lower limit

0.37

upper limit

1.25

Secondary: Phase II: Time to PSA Progression - ITT Population

Top of page

End point title

Phase II: Time to PSA Progression - ITT Population ^[32]

End point description

Time to PSA progression: Time from screening to the first occurrence of PSA progression, as determined by investigator. PSA progression was defined as per Prostate Cancer Working Group 2 criteria. PSA progression is defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the baseline value, or a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the nadir if PSA decreases from baseline after treatment, which was confirmed by a second value obtained ≥ 3 weeks later. The ITT Population was defined as all randomised participants with the participants allocated to the treatment arm according to the randomisation.

End point type

Secondary

End point timeframe

Screening up to PSA progression (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	84	86	83
Units: months
median (confidence interval 90%)	5.55 (4.17 to 7.39)	3.78 (2.79 to 5.49)	3.71 (2.79 to 4.67)

Unstratified analysis:Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0665

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.7

Confidence interval

level

90%

sides

2-sided

lower limit

0.51

upper limit

0.97

Stratified analysis:Ipatasertib 200 mg v Placebo

Statistical analysis description

Strata were: prior enzalutamide (Yes vs. No), progression factor (PSA only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one).

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.789

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.95

Confidence interval

level

90%

sides

2-sided

lower limit

0.7

upper limit

1.31

Stratified analysis:Ipatasertib 400 mg v Placebo

Statistical analysis description

Strata were: prior Enzalutamide (Yes vs. No), progression factor (PSA only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one).

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.071

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.7

Confidence interval

level

90%

sides

2-sided

lower limit

0.5

upper limit

0.97

Unstratified analysis:Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Placebo + Abiraterone v Phase II: Ipatasertib 200 mg + Abiraterone

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9319

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.99

Confidence interval

level

90%

sides

2-sided

lower limit

0.73

upper limit

1.33

Secondary: Phase II: Percentage of Participants With PSA Response - ITT Population

Top of page

End point title

Phase II: Percentage of Participants With PSA Response - ITT Population ^[33]

End point description

PSA response was defined as a > 50% decrease in PSA from baseline, which was to be confirmed after ≥ 4 weeks by a confirmatory PSA measurement. The ITT Population was defined as all randomised participants with the participants allocated to the treatment arm according to the randomisation.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose (assessed at baseline, Day 1 of every cycle [starting from Cycle 2] till 30 days after last dose [up to overall 3.6 years]) (cycle length = 28 days)

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	84	86	83
Units: percentage of participants
number (confidence interval 90%)	36.9 (28.11 to 46.40)	33.7 (25.29 to 42.93)	34.9 (26.25 to 43.75)

Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8675

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

-1.22

Confidence interval

level

90%

sides

2-sided

lower limit

-13.24

upper limit

10.8

Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7913

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

1.97

Confidence interval

level

90%

sides

2-sided

lower limit

-10.25

upper limit

14.18

Secondary: Phase II: Percentage of Participants With PSA Response in Participants With ICR PTEN Loss

Top of page

End point title

Phase II: Percentage of Participants With PSA Response in Participants With ICR PTEN Loss ^[34]

End point description

PSA response was defined as a > 50% decrease in PSA from baseline, which was to be confirmed after ≥ 4 weeks by a confirmatory PSA measurement. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analyzed=participants with PTEN loss.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose (assessed at baseline, Day 1 of every cycle [starting from Cycle 2] till 30 days after last dose [up to overall 3.6 years]) (cycle length = 28 days)

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	25	25	21
Units: percentage of participants
number (confidence interval 90%)	40.0 (24.57 to 58.32)	44.0 (26.99 to 61.06)	28.6 (13.24 to 46.41)

Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4176

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

11.43

Confidence interval

level

90%

sides

2-sided

lower limit

-11.43

upper limit

58.32

Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2802

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

15.43

Confidence interval

level

90%

sides

2-sided

lower limit

-7.58

upper limit

38.44

Secondary: Phase II: Percentage of Participants With Objective Response in Participants With ICR PTEN Loss

Top of page

End point title

Phase II: Percentage of Participants With Objective Response in Participants With ICR PTEN Loss ^[35]

End point description

Objective response was defined as having a CR or PR according to a RECIST 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analyzed=participants with PTEN loss and evaluable for this endpoint.

End point type

Secondary

End point timeframe

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	9	15	7
Units: percentage of participants
number (confidence interval 90%)	11.1 (1.16 to 39.09)	26.7 (12.18 to 50.00)	14.3 (1.49 to 50.00)

Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8489

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

-3.17

Confidence interval

level

90%

sides

2-sided

lower limit

-30.93

upper limit

24.58

Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5186

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

12.38

Confidence interval

level

90%

sides

2-sided

lower limit

-16.36

upper limit

41.12

Secondary: Phase II: Percentage of Participants With Objective Response - ITT Population

Top of page

End point title

Phase II: Percentage of Participants With Objective Response - ITT Population ^[36]

End point description

Objective response was defined as having a confirm response (CR) or partial response (PR) according to a RECIST 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. The ITT Population was defined as all randomised participants with the participants allocated to the treatment arm according to the randomisation. Number of participants analysed=participants who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	37	39	35
Units: percentage of participants
number (confidence interval 90%)	32.4 (20.56 to 46.41)	23.1 (13.69 to 35.63)	22.9 (11.91 to 36.46)

Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9821

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

0.22

Confidence interval

level

90%

sides

2-sided

lower limit

-15.89

upper limit

16.33

Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3646

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

9.58

Confidence interval

level

90%

sides

2-sided

lower limit

-7.65

upper limit

26.8

Secondary: Phase II: Duration of Tumor Response - ITT Population

Top of page

End point title

Phase II: Duration of Tumor Response - ITT Population ^[37]

End point description

Duration of tumor response: time period from 1st documentation of objective response (CR/PR) (whichever status was recorded first) to date of 1st occurrence of investigator documented disease progression or death. CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR: at least 30% decrease in sum of diameters of target lesions (taking as reference baseline sum diameters), no progression in non-target lesions, and no new lesions. Progression: increase by at least 20% in sum of longest diameters of each target lesion, taking as reference smallest sum of longest diameters or appearance of one or more new lesions. Duration of tumor response was estimated using Kaplan Meier method. Number of participants analysed=participants from ITT population who had achieved an objective response. Here, 99999 reflects that data was not evaluable due to insufficient number of events.

End point type

Secondary

End point timeframe

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	12	9	8
Units: months
median (confidence interval 90%)	8.77 (3.75 to 99999)	99999 (6.47 to 99999)	99999 (2.76 to 99999)

Unstratified analysis:Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Placebo + Abiraterone v Phase II: Ipatasertib 400 mg + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.678

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.31

Confidence interval

level

90%

sides

2-sided

lower limit

0.45

upper limit

3.8

Stratified analysis:Ipatasertib 200 mg v Placebo

Statistical analysis description

Strata were: prior enzalutamide (Yes vs. No), progression factor (PSA only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one).

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4227

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

2.46

Confidence interval

level

90%

sides

2-sided

lower limit

0.36

upper limit

16.59

Stratified analysis:Ipatasertib 400 mg v Placebo

Statistical analysis description

Strata were: prior enzalutamide (Yes vs. No), progression factor (PSA only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one).

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7733

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

90%

sides

2-sided

lower limit

0.17

upper limit

3.5

Unstratified analysis:Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8372

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.85

Confidence interval

level

90%

sides

2-sided

lower limit

0.24

upper limit

3.02

Secondary: Phase II: Percentage of Participants With Circulating Tumor Cells (CTC) Reduction Response - ITT Population

Top of page

End point title

Phase II: Percentage of Participants With Circulating Tumor Cells (CTC) Reduction Response - ITT Population ^[38]

End point description

CTC reduction response was defined as participants with a reduction in CTCs of ≥ 30% compared to baseline. The ITT Population was defined as all randomised participants with the participants allocated to the treatment arm according to the randomisation. Number of participants analysed=participants with CTC > 0 cells/7.5 milliliters (mL) at baseline.

End point type

Secondary

End point timeframe

Baseline, on Day 1 of Cycle 2, on Day 1 of Cycle 3, and at the treatment completion visit (up to overall 3.6 years) (cycle length=28 days)

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	58	62	63
Units: percentage of participants
number (confidence interval 90%)	67.2 (56.44 to 77.37)	71.0 (61.07 to 80.32)	63.5 (52.41 to 73.60)

Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6652

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

3.75

Confidence interval

level

90%

sides

2-sided

lower limit

-10.47

upper limit

17.97

Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3734

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

7.48

Confidence interval

level

90%

sides

2-sided

lower limit

-6.29

upper limit

21.24

Secondary: Phase II: Duration of Tumor Response in Participants with ICR PTEN Loss

Top of page

End point title

Phase II: Duration of Tumor Response in Participants with ICR PTEN Loss ^[39]

End point description

Time from 1st documentation of objective response (CR/PR) to 1st occurrence of investigator documented disease progression or death. CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR: at least 30% decrease in sum of diameters of target lesions, no progression in non-target lesions, and no new lesions. Progression: increase by at least 20% in sum of longest diameters of each target lesion, taking as reference smallest sum of longest diameters or appearance of one or more new lesions. Estimated using Kaplan Meier method. PTEN status was assessed by RUO IHC assay. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analysed = participants from PTEN loss population who had achieved an objective response. 0.0000/9999/99999 = not estimable due to low number of events

End point type

Secondary

End point timeframe

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	1	4	1
Units: months
median (confidence interval 90%)	8.77 (0.0000 to 99999)	9999 (0.99 to 99999)	9999 (0.0000 to 99999)

Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6171

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

999.99

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

99999

Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3173

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

999.99

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

99999

Secondary: Phase II: Percentage of Participants With CTC Reduction Response in Participants With ICR PTEN Loss

Top of page

End point title

Phase II: Percentage of Participants With CTC Reduction Response in Participants With ICR PTEN Loss ^[40]

End point description

CTC reduction response was defined as participants with a reduction in CTCs of ≥ 30% compared to baseline. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analyzed=participants with PTEN loss and CTC > 0 cells/7.5 mL at baseline.

End point type

Secondary

End point timeframe

Baseline, on Day 1 of Cycle 2, on Day 1 of Cycle 3, and at the treatment completion visit (up to overall 3.6 years) (cycle length=28 days)

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	20	20	17
Units: percentage of participants
number (confidence interval 90%)	75.0 (55.80 to 87.42)	75.0 (55.80 to 87.42)	70.6 (50.00 to 85.95)

Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7633

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

4.41

Confidence interval

level

90%

sides

2-sided

lower limit

-19.76

upper limit

28.58

Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7633

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

4.41

Confidence interval

level

90%

sides

2-sided

lower limit

-19.76

upper limit

28.58

Secondary: Phase II: Percentage of Participants With CTC Conversion - ITT Population

Top of page

End point title

Phase II: Percentage of Participants With CTC Conversion - ITT Population ^[41]

End point description

CTC conversion was defined as a decline to < 5 cells/7.5 milliliter (mL) post baseline among participants with CTC ≥ 5 cells/7.5 mL at baseline. The ITT Population was defined as all randomised participants with the participants allocated to the treatment arm according to the randomisation. Number of participants analysed=participants with CTC ≥ 5 cells/7.5 mL at baseline.

End point type

Secondary

End point timeframe

Baseline, on Day 1 of Cycle 2, on Day 1 of Cycle 3, and at the treatment completion visit (up to overall 3.6 years) (cycle length=28 days)

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	41	47	48
Units: percentage of participants
number (confidence interval 90%)	43.9 (31.18 to 57.87)	46.8 (34.48 to 59.72)	41.7 (29.59 to 54.55)

Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6139

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

5.14

Confidence interval

level

90%

sides

2-sided

lower limit

-11.6

upper limit

21.88

Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8317

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

2.24

Confidence interval

level

90%

sides

2-sided

lower limit

-15.07

upper limit

19.54

Secondary: Phase II: Percentage of Participants With Pain Progression in Participants With ICR PTEN Loss

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End point title

Phase II: Percentage of Participants With Pain Progression in Participants With ICR PTEN Loss ^[42]

End point description

Pain progression was defined as ≥ 2 point-increase from baseline on the modified Brief Pain Inventory – short form (mBPI-sf). The mBPI-sf consists of four questions that assess pain intensity (worst, least, average, right now) and seven items within one question that assess the impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each item was assessed on 0-10 scale with 0 being no pain to 10 being worst imaginable pain. Total score was the average of individual item (range 0-10). PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analyzed=participants with PTEN loss.

End point type

Secondary

End point timeframe

Screening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	25	25	21
Units: percentage of participants
number (not applicable)	40.0	28.0	33.3

No statistical analyses for this end point

Secondary: Phase II: Percentage of Participants With Pain Progression - ITT Population

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End point title

Phase II: Percentage of Participants With Pain Progression - ITT Population ^[43]

End point description

Pain progression was defined as ≥ 2 point-increase from baseline on the modified Brief Pain Inventory – short form (mBPI-sf). The mBPI-sf consists of four questions that assess pain intensity (worst, least, average, right now) and seven items within one question that assess the impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each item was assessed on 0-10 scale with 0 being no pain to 10 being worst imaginable pain. Total score was the average of individual item (range 0-10). The ITT Population was defined as all randomised participants with the participants allocated to the treatment arm according to the randomisation.

End point type

Secondary

End point timeframe

Screening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	84	86	83
Units: percentage of participants
number (not applicable)	33.3	34.9	34.9

No statistical analyses for this end point

Secondary: Phase II: Percentage of Participants With CTC Conversion in Participants With ICR PTEN Loss

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End point title

Phase II: Percentage of Participants With CTC Conversion in Participants With ICR PTEN Loss ^[44]

End point description

CTC conversion was defined as a decline to < 5 cells/7.5 milliliter (mL) post baseline among participants with CTC ≥ 5 cells/7.5 mL at baseline. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analyzed=participants with PTEN loss and CTC ≥ 5 cells/7.5 mL at baseline.

End point type

Secondary

End point timeframe

Baseline, on Day 1 of Cycle 2, on Day 1 of Cycle 3, and at the treatment completion visit (up to overall 3.6 years) (cycle length=28 days)

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	12	18	22
Units: percentage of participants
number (confidence interval 90%)	66.7 (39.84 to 84.58)	22.2 (10.60 to 41.88)	31.8 (18.11 to 50.00)

Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4989

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

-9.6

Confidence interval

level

90%

sides

2-sided

lower limit

-32.54

upper limit

13.35

Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0505

Method

Chi-squared

Parameter type

Difference in response rates

Point estimate

34.85

Confidence interval

level

90%

sides

2-sided

lower limit

7.14

upper limit

62.56

Secondary: Phase II: Time to Pain Progression in Participants With ICR PTEN Loss

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End point title

Phase II: Time to Pain Progression in Participants With ICR PTEN Loss ^[45]

End point description

Time to pain progression was defined as the time from screening till first occurrence of pain progression. Pain progression: ≥ 2 point-increase from baseline on the modified Brief Pain Inventory – short form (mBPI-sf). The mBPI-sf consists of 4questions that assess pain intensity (worst, least, average, right now) and seven items within one question that assess the impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each item was assessed on 0-10 scale with 0 being no pain to 10 being worst imaginable pain. Total score was the average of individual item (range 0-10). PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as “ICR PTEN loss”. Number of participants analyzed=participants with PTEN loss. Here, "99999" reflects that the data was not evaluable because of insufficient number of events.

End point type

Secondary

End point timeframe

Screening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	25	25	21
Units: months
median (confidence interval 90%)	16.49 (7.59 to 16.49)	99999 (8.28 to 99999)	6.93 (5.65 to 99999)

Unstratified analysis:Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7383

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.84

Confidence interval

level

90%

sides

2-sided

lower limit

0.35

upper limit

2.02

Unstratified analysis:Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8271

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.89

Confidence interval

level

90%

sides

2-sided

lower limit

0.39

upper limit

2.06

Secondary: Phase II: Time to Pain Progression - ITT Population

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End point title

Phase II: Time to Pain Progression - ITT Population ^[46]

End point description

Time to pain progression was defined as the time from screening till first occurrence of pain progression. Pain progression was defined as ≥ 2 point-increase from baseline on the modified Brief Pain Inventory – short form (mBPI-sf). The mBPI-sf consists of four questions that assess pain intensity (worst, least, average, right now) and seven items within one question that assess the impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each item was assessed on 0-10 scale with 0 being no pain to 10 being worst imaginable pain. Total score was the average of individual item (range 0-10). The ITT Population was defined as all randomised participants with the participants allocated to the treatment arm according to the randomisation. Here, "99999" reflects that the data was not evaluable because of insufficient number of events.

End point type

Secondary

End point timeframe

Screening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase II arms were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone
Number of subjects analysed	84	86	83
Units: months
median (confidence interval 90%)	13.90 (8.61 to 99999)	16.16 (8.54 to 99999)	15.15 (11.07 to 99999)

Unstratified analysis:Ipatasertib 400 mg v Placebo

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8483

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.95

Confidence interval

level

90%

sides

2-sided

lower limit

0.61

upper limit

1.47

Stratified analysis:Ipatasertib 200 mg v Placebo

Statistical analysis description

Strata were: prior enzalutamide (Yes vs. No), progression factor (PSA only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one).

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8647

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.05

Confidence interval

level

90%

sides

2-sided

lower limit

0.67

upper limit

1.63

Stratified analysis:Ipatasertib 400 mg v Placebo

Statistical analysis description

Strata were: prior enzalutamide (Yes vs. No), progression factor (PSA only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one).

Comparison groups

Phase II: Ipatasertib 400 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8847

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.04

Confidence interval

level

90%

sides

2-sided

lower limit

0.66

upper limit

1.65

Unstratified analysis:Ipatasertib 200 mg v Placebo

Comparison groups

Phase II: Ipatasertib 200 mg + Abiraterone v Phase II: Placebo + Abiraterone

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.785

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.08

Confidence interval

level

90%

sides

2-sided

lower limit

0.7

upper limit

1.65

Secondary: Phase II: Percentage of Participants With Adverse Events (AEs)

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End point title

Phase II: Percentage of Participants With Adverse Events (AEs)

End point description

An Adverse Event (AE) 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. The Safety Population was defined as all participants who had received ipatasertib, apitolisib, placebo, or abiraterone treatment.

End point type

Secondary

End point timeframe

Baseline up until 30 days following the last administration of study treatment or until initiation of another anti-cancer therapy, whichever occurred first (up to approximately 8.9 years)

End point values	Safety Set Ipatasertib 400 mg + Abiraterone	Safety Set Ipatasertib 200 mg + Abiraterone	Safety Set Placebo + Abiraterone
Number of subjects analysed	84	88	81
Units: percentage of participants
number (not applicable)	98.8	96.6	93.8

No statistical analyses for this end point

Secondary: Phase II: Ipatasertib Plasma Concentrations When Co-Administered With Abiraterone

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End point title

Phase II: Ipatasertib Plasma Concentrations When Co-Administered With Abiraterone ^[47]

End point description

The Pharmacokinetic (PK) Analysis Population was defined as all participants who had evaluable PK data. Data were only analyzed in ipatasertib treatment arms. Total number analyzed represents all participants with evaluations at one or more time points. Here, "n" signifies the number of participants with PK data available for specified timepoint.

End point type

Secondary

End point timeframe

Phase II: Cycle 1, Day 1: 1, 4 hours postdose; Cycle 1, Day 15: predose, 2, 4 hours postdose; Cycle 2, Day 1: predose, 1-4 hours postdose (cycle length = 28 days)

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arms treated with ipatasertib in Phase II were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone
Number of subjects analysed	83	86
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1: 1 hour postdose (n=43, 47)	101 ( 359.5 )	63.4 ( 187.2 )
Cycle 1, Day 1: 4 hours postdose (n=72, 76)	180 ( 103.4 )	87.0 ( 71.6 )
Cycle 1, Day 15: predose (n=74, 81)	53.1 ( 97.2 )	24.5 ( 61.9 )
Cycle 1, Day 15: 2 hours postdose (n=69, 77)	213 ( 174.3 )	140 ( 103.7 )
Cycle 1, Day 15: 4 hours postdose (n=72, 77)	272 ( 137.9 )	139 ( 69.3 )
Cycle 2, Day 1: predose (n=73, 82)	46.7 ( 138.6 )	25.3 ( 49.8 )
Cycle 2, Day 1: 1-4 hours postdose (n=70, 82)	243 ( 94.4 )	145 ( 80.9 )

No statistical analyses for this end point

Secondary: Phase II: G-037720 (Metabolite of Ipatasertib) Plasma Concentrations

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End point title

Phase II: G-037720 (Metabolite of Ipatasertib) Plasma Concentrations ^[48]

End point description

End point type

Secondary

End point timeframe

Phase II: Cycle 1, Day 1: 1, 4 hours postdose; Cycle 1, Day 15: predose, 2, 4 hours postdose; Cycle 2, Day 1: predose, 1-4 hours postdose (cycle length = 28 days)

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the arms treated with ipatasertib in Phase II were planned to be included in the analysis.

End point values	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone
Number of subjects analysed	82	86
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1, Day 1: 1 hour postdose (n=35, 40)	34.7 ( 223.1 )	13.9 ( 268.9 )
Cycle 1, Day 1: 4 hours postdose (n=69, 75)	101 ( 61.8 )	42.9 ( 96.6 )
Cycle 1, Day 15: predose (n=73, 80)	44.1 ( 92.4 )	20.4 ( 59.2 )
Cycle 1, Day 15: 2 hours postdose (n=69, 77)	121 ( 159.4 )	78.0 ( 93.0 )
Cycle 1, Day 15: 4 hours postdose (n=72, 76)	178 ( 134.0 )	101 ( 61.0 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline up until 30 days following the last administration of study treatment or until initiation of another anti-cancer therapy, whichever occurred first (up to approximately 10.7 years)

Adverse event reporting additional description

The Safety Population was defined as all participants who had received ipatasertib, apitolisib, placebo, or abiraterone treatment.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

23.1, 25.1

Reporting group title

Phase Ib: Ipatasertib 400 mg

Reporting group description

Participants received ipatasertib 400 mg orally daily, abiraterone 1000 mg orally daily, and prednisone/prednisolone 5 mg bid orally continuously in 28-day treatment cycles until disease progression or intolerable toxicity.

Reporting group title

Phase Ib: Apitolisib 30 mg

Reporting group description

Participants received apitolisib 30 mg orally daily, abiraterone 1000 mg orally daily, and prednisone/prednisolone 5 mg bid orally continuously in 28-day treatment cycles until disease progression or intolerable toxicity.

Reporting group title

Phase II: Ipatasertib 400 mg + Abiraterone

Reporting group description

Reporting group title

Phase II: Ipatasertib 200 mg + Abiraterone

Reporting group description

Participants received ipatasertib 200 mg orally daily, abiraterone 1000 mg orally daily, and prednisone/prednisolone 5 mg bid orally continuously in 28-day treatment cycles until disease progression or intolerable toxicity.

Reporting group title

Phase II: Placebo + Abiraterone

Reporting group description

Participants received placebo (for ipatasertib 400 mg or 200) orally daily, abiraterone 1000 mg orally daily, and prednisone/prednisolone 5 mg bid orally continuously in 28-day treatment cycles until disease progression or intolerable toxicity.

Reporting group title

Safety Cohort: Ipatasertib 400 mg + Abiraterone

Reporting group description

Serious adverse events	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone	Safety Cohort: Ipatasertib 400 mg + Abiraterone
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 14 (64.29%)	5 / 6 (83.33%)	43 / 84 (51.19%)	42 / 88 (47.73%)	18 / 81 (22.22%)	6 / 25 (24.00%)
number of deaths (all causes)	1	0	67	72	67	2
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	3 / 84 (3.57%)	2 / 88 (2.27%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 3	0 / 2	0 / 0	0 / 1
Prostatic adenoma
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small cell carcinoma
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic aneurysm rupture
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic venous thrombosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
Death
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Asthenia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	2 / 84 (2.38%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Prostatitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute pulmonary oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Haematocrit decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Subdural haematoma
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Accidental overdose
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrioventricular block
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Dizziness
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular encephalopathy
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haematoma
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Coagulopathy
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	2 / 88 (2.27%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemolytic uraemic syndrome
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Chorioretinopathy
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	2 / 84 (2.38%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	2 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngo-oesophageal diverticulum
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Toxic skin eruption
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	1 / 14 (7.14%)	2 / 6 (33.33%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 84 (2.38%)	0 / 88 (0.00%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decubitus ulcer
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 84 (2.38%)	1 / 88 (1.14%)	1 / 81 (1.23%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephropathy toxic
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureteric obstruction
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder perforation
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureteric stenosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 84 (1.19%)	2 / 88 (2.27%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteolysis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma muscle
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pyelonephritis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	3 / 84 (3.57%)	5 / 88 (5.68%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	1 / 3	0 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	3 / 88 (3.41%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	5 / 84 (5.95%)	1 / 88 (1.14%)	1 / 81 (1.23%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 6	0 / 2	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 14 (7.14%)	2 / 6 (33.33%)	2 / 84 (2.38%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 2	2 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ketoacidosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic metabolic decompensation
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase Ib: Ipatasertib 400 mg	Phase Ib: Apitolisib 30 mg	Phase II: Ipatasertib 400 mg + Abiraterone	Phase II: Ipatasertib 200 mg + Abiraterone	Phase II: Placebo + Abiraterone	Safety Cohort: Ipatasertib 400 mg + Abiraterone
Total subjects affected by non serious adverse events
subjects affected / exposed	14 / 14 (100.00%)	6 / 6 (100.00%)	82 / 84 (97.62%)	79 / 88 (89.77%)	76 / 81 (93.83%)	25 / 25 (100.00%)
Vascular disorders
Hot flush
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	10 / 84 (11.90%)	5 / 88 (5.68%)	7 / 81 (8.64%)	0 / 25 (0.00%)
occurrences all number	1	1	10	5	7	0
Hypertension
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	11 / 84 (13.10%)	12 / 88 (13.64%)	9 / 81 (11.11%)	1 / 25 (4.00%)
occurrences all number	1	0	15	13	12	1
Hypotension
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	3 / 84 (3.57%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences all number	1	1	3	1	1	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	9 / 14 (64.29%)	1 / 6 (16.67%)	22 / 84 (26.19%)	25 / 88 (28.41%)	24 / 81 (29.63%)	5 / 25 (20.00%)
occurrences all number	11	1	36	37	32	7
Asthenia
subjects affected / exposed	4 / 14 (28.57%)	1 / 6 (16.67%)	23 / 84 (27.38%)	20 / 88 (22.73%)	13 / 81 (16.05%)	2 / 25 (8.00%)
occurrences all number	4	1	36	24	15	4
Gait disturbance
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences all number	1	0	0	1	1	0
Mucosal inflammation
subjects affected / exposed	3 / 14 (21.43%)	0 / 6 (0.00%)	3 / 84 (3.57%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences all number	3	0	4	1	1	0
Thirst
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0	0
Pyrexia
subjects affected / exposed	1 / 14 (7.14%)	3 / 6 (50.00%)	12 / 84 (14.29%)	12 / 88 (13.64%)	9 / 81 (11.11%)	4 / 25 (16.00%)
occurrences all number	1	3	28	16	13	5
Pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	7 / 84 (8.33%)	9 / 88 (10.23%)	2 / 81 (2.47%)	1 / 25 (4.00%)
occurrences all number	0	1	7	14	2	1
Oedema peripheral
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	10 / 84 (11.90%)	9 / 88 (10.23%)	7 / 81 (8.64%)	0 / 25 (0.00%)
occurrences all number	2	0	13	11	7	0
Oedema
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 84 (1.19%)	1 / 88 (1.14%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences all number	1	0	1	1	0	1
Reproductive system and breast disorders
Penile pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0	0
Pelvic pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	7 / 84 (8.33%)	5 / 88 (5.68%)	0 / 81 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	8	7	0	1
Respiratory, thoracic and mediastinal disorders
Dry throat
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0	0
Cough
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	7 / 84 (8.33%)	6 / 88 (6.82%)	7 / 81 (8.64%)	1 / 25 (4.00%)
occurrences all number	1	0	13	7	7	1
Dysphonia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 84 (1.19%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	1	3	0	0
Dyspnoea exertional
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	1	0	0	0
Dyspnoea
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	11 / 84 (13.10%)	9 / 88 (10.23%)	6 / 81 (7.41%)	3 / 25 (12.00%)
occurrences all number	0	1	13	10	7	5
Oropharyngeal pain
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	3 / 84 (3.57%)	2 / 88 (2.27%)	1 / 81 (1.23%)	1 / 25 (4.00%)
occurrences all number	2	1	3	2	1	1
Wheezing
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	1	0	0	0
Sinus congestion
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	1	0	0	0
Rhinorrhoea
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	2 / 84 (2.38%)	4 / 88 (4.55%)	2 / 81 (2.47%)	0 / 25 (0.00%)
occurrences all number	1	1	2	4	4	0
Pleural effusion
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	1	0	0
Psychiatric disorders
Restlessness
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0	0
Insomnia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	9 / 84 (10.71%)	10 / 88 (11.36%)	5 / 81 (6.17%)	2 / 25 (8.00%)
occurrences all number	0	0	11	10	5	2
Depression
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	3 / 84 (3.57%)	3 / 88 (3.41%)	1 / 81 (1.23%)	1 / 25 (4.00%)
occurrences all number	2	0	3	3	1	1
Anxiety
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	3 / 84 (3.57%)	5 / 88 (5.68%)	3 / 81 (3.70%)	2 / 25 (8.00%)
occurrences all number	1	0	3	5	3	2
Agitation
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	1	0
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	2 / 84 (2.38%)	0 / 88 (0.00%)	1 / 81 (1.23%)	1 / 25 (4.00%)
occurrences all number	2	0	2	0	1	1
Aspartate aminotransferase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	5 / 84 (5.95%)	4 / 88 (4.55%)	1 / 81 (1.23%)	3 / 25 (12.00%)
occurrences all number	1	0	8	5	1	10
Blood urine present
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	7 / 84 (8.33%)	4 / 88 (4.55%)	1 / 81 (1.23%)	1 / 25 (4.00%)
occurrences all number	0	0	7	5	2	1
Weight decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 84 (3.57%)	3 / 88 (3.41%)	1 / 81 (1.23%)	3 / 25 (12.00%)
occurrences all number	0	0	6	4	1	3
Blood triglycerides increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	1	0	0	2
Alanine aminotransferase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	4 / 84 (4.76%)	2 / 88 (2.27%)	1 / 81 (1.23%)	3 / 25 (12.00%)
occurrences all number	0	0	8	2	1	12
Injury, poisoning and procedural complications
Meniscus injury
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0	0
Fall
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 84 (1.19%)	2 / 88 (2.27%)	3 / 81 (3.70%)	3 / 25 (12.00%)
occurrences all number	0	0	1	4	3	3
Nervous system disorders
Dysgeusia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	6 / 84 (7.14%)	0 / 88 (0.00%)	3 / 81 (3.70%)	2 / 25 (8.00%)
occurrences all number	1	0	8	0	3	2
Dizziness
subjects affected / exposed	3 / 14 (21.43%)	0 / 6 (0.00%)	11 / 84 (13.10%)	6 / 88 (6.82%)	5 / 81 (6.17%)	1 / 25 (4.00%)
occurrences all number	4	0	16	8	5	1
Somnolence
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	3 / 84 (3.57%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	3	2	0	0
Lethargy
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 84 (1.19%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences all number	0	1	1	1	1	0
Hypoaesthesia
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences all number	2	0	0	9	1	0
Headache
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	9 / 84 (10.71%)	5 / 88 (5.68%)	6 / 81 (7.41%)	1 / 25 (4.00%)
occurrences all number	3	0	14	5	9	1
Paraesthesia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 84 (3.57%)	5 / 88 (5.68%)	3 / 81 (3.70%)	0 / 25 (0.00%)
occurrences all number	0	0	3	9	3	0
Taste disorder
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0	0
Tremor
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	0	1	0	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	19 / 84 (22.62%)	18 / 88 (20.45%)	8 / 81 (9.88%)	2 / 25 (8.00%)
occurrences all number	2	1	25	37	13	4
Pancytopenia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0	0
Eye disorders
Vision blurred
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	3 / 81 (3.70%)	0 / 25 (0.00%)
occurrences all number	1	0	0	1	4	0
Gastrointestinal disorders
Dry mouth
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	3 / 84 (3.57%)	0 / 88 (0.00%)	4 / 81 (4.94%)	0 / 25 (0.00%)
occurrences all number	2	1	3	0	4	0
Diarrhoea
subjects affected / exposed	9 / 14 (64.29%)	4 / 6 (66.67%)	65 / 84 (77.38%)	42 / 88 (47.73%)	20 / 81 (24.69%)	17 / 25 (68.00%)
occurrences all number	14	6	198	72	36	63
Constipation
subjects affected / exposed	1 / 14 (7.14%)	2 / 6 (33.33%)	8 / 84 (9.52%)	18 / 88 (20.45%)	16 / 81 (19.75%)	0 / 25 (0.00%)
occurrences all number	1	2	8	26	22	0
Cheilosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0	0
Abdominal pain lower
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	2 / 84 (2.38%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	3	2	0	0
Abdominal pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	9 / 84 (10.71%)	10 / 88 (11.36%)	3 / 81 (3.70%)	2 / 25 (8.00%)
occurrences all number	1	0	12	13	3	2
Abdominal pain upper
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	8 / 84 (9.52%)	4 / 88 (4.55%)	5 / 81 (6.17%)	0 / 25 (0.00%)
occurrences all number	0	0	10	5	7	0
Vomiting
subjects affected / exposed	9 / 14 (64.29%)	3 / 6 (50.00%)	27 / 84 (32.14%)	24 / 88 (27.27%)	12 / 81 (14.81%)	5 / 25 (20.00%)
occurrences all number	14	3	42	69	24	12
Tongue discolouration
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0	0
Retching
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	1	0	0	0	0
Rectal haemorrhage
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	3	0	0
Oral disorder
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0	0
Nausea
subjects affected / exposed	6 / 14 (42.86%)	4 / 6 (66.67%)	45 / 84 (53.57%)	31 / 88 (35.23%)	21 / 81 (25.93%)	12 / 25 (48.00%)
occurrences all number	11	4	74	44	30	24
Eructation
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 84 (1.19%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	1	1	0	0
Dyspepsia
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	9 / 84 (10.71%)	7 / 88 (7.95%)	3 / 81 (3.70%)	3 / 25 (12.00%)
occurrences all number	1	1	9	8	3	6
Flatulence
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 84 (3.57%)	5 / 88 (5.68%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	3	5	0	0
Skin and subcutaneous tissue disorders
Night sweats
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	3 / 84 (3.57%)	0 / 88 (0.00%)	1 / 81 (1.23%)	1 / 25 (4.00%)
occurrences all number	1	0	4	0	1	1
Onycholysis
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 84 (0.00%)	1 / 88 (1.14%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	1	0	0
Hyperhidrosis
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	1 / 84 (1.19%)	0 / 88 (0.00%)	3 / 81 (3.70%)	0 / 25 (0.00%)
occurrences all number	1	1	2	0	4	0
Haemorrhage subcutaneous
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0	0
Ecchymosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences all number	1	0	0	1	1	0
Rash
subjects affected / exposed	1 / 14 (7.14%)	3 / 6 (50.00%)	10 / 84 (11.90%)	5 / 88 (5.68%)	3 / 81 (3.70%)	2 / 25 (8.00%)
occurrences all number	1	5	16	7	3	3
Rash maculo-papular
subjects affected / exposed	2 / 14 (14.29%)	2 / 6 (33.33%)	4 / 84 (4.76%)	1 / 88 (1.14%)	1 / 81 (1.23%)	7 / 25 (28.00%)
occurrences all number	3	3	9	2	1	14
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	2 / 84 (2.38%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	1	4	2	0	0
Renal pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 84 (1.19%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	1	0	0	0
Urinary incontinence
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	3 / 84 (3.57%)	2 / 88 (2.27%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	3	2	0	0
Hypertonic bladder
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0	0
Haematuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	10 / 84 (11.90%)	6 / 88 (6.82%)	5 / 81 (6.17%)	1 / 25 (4.00%)
occurrences all number	0	0	16	13	6	1
Dysuria
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	8 / 84 (9.52%)	2 / 88 (2.27%)	2 / 81 (2.47%)	2 / 25 (8.00%)
occurrences all number	1	0	9	4	2	2
Pollakiuria
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	3 / 84 (3.57%)	9 / 88 (10.23%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	1	3	11	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	17 / 84 (20.24%)	17 / 88 (19.32%)	21 / 81 (25.93%)	3 / 25 (12.00%)
occurrences all number	4	1	33	30	27	3
Back pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	18 / 84 (21.43%)	20 / 88 (22.73%)	20 / 81 (24.69%)	1 / 25 (4.00%)
occurrences all number	1	0	25	41	28	3
Bone pain
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	12 / 84 (14.29%)	12 / 88 (13.64%)	18 / 81 (22.22%)	1 / 25 (4.00%)
occurrences all number	1	1	20	15	20	1
Flank pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	2 / 84 (2.38%)	3 / 88 (3.41%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	0	2	3	0	0
Muscle spasms
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 84 (3.57%)	6 / 88 (6.82%)	2 / 81 (2.47%)	0 / 25 (0.00%)
occurrences all number	0	0	5	6	2	0
Muscular weakness
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	1 / 84 (1.19%)	7 / 88 (7.95%)	3 / 81 (3.70%)	0 / 25 (0.00%)
occurrences all number	1	1	1	8	3	0
Musculoskeletal chest pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	7 / 84 (8.33%)	5 / 88 (5.68%)	7 / 81 (8.64%)	0 / 25 (0.00%)
occurrences all number	1	0	19	8	10	0
Myalgia
subjects affected / exposed	4 / 14 (28.57%)	1 / 6 (16.67%)	6 / 84 (7.14%)	3 / 88 (3.41%)	5 / 81 (6.17%)	0 / 25 (0.00%)
occurrences all number	5	1	8	3	5	0
Neck pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	2 / 84 (2.38%)	4 / 88 (4.55%)	3 / 81 (3.70%)	1 / 25 (4.00%)
occurrences all number	2	0	2	4	3	1
Pain in extremity
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	13 / 84 (15.48%)	13 / 88 (14.77%)	8 / 81 (9.88%)	4 / 25 (16.00%)
occurrences all number	3	0	15	24	14	4
Pain in jaw
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	3 / 84 (3.57%)	1 / 88 (1.14%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences all number	2	0	4	1	1	0
Infections and infestations
Fungal urethritis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	14 / 84 (16.67%)	7 / 88 (7.95%)	6 / 81 (7.41%)	3 / 25 (12.00%)
occurrences all number	3	0	16	12	9	3
Nasopharyngitis
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	5 / 84 (5.95%)	7 / 88 (7.95%)	3 / 81 (3.70%)	0 / 25 (0.00%)
occurrences all number	2	0	6	9	3	0
Influenza
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	5 / 84 (5.95%)	4 / 88 (4.55%)	3 / 81 (3.70%)	0 / 25 (0.00%)
occurrences all number	0	0	5	4	3	0
Metabolism and nutrition disorders
Hypocalcaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	6 / 84 (7.14%)	4 / 88 (4.55%)	4 / 81 (4.94%)	1 / 25 (4.00%)
occurrences all number	1	0	9	5	5	1
Hypertriglyceridaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 84 (1.19%)	3 / 88 (3.41%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	1	4	0	0
Hyperkalaemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 84 (1.19%)	0 / 88 (0.00%)	1 / 81 (1.23%)	0 / 25 (0.00%)
occurrences all number	0	1	1	0	1	0
Hyperglycaemia
subjects affected / exposed	6 / 14 (42.86%)	2 / 6 (33.33%)	19 / 84 (22.62%)	7 / 88 (7.95%)	5 / 81 (6.17%)	8 / 25 (32.00%)
occurrences all number	7	4	26	12	8	18
Failure to thrive
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0	0
Hypovolaemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0	0
Decreased appetite
subjects affected / exposed	5 / 14 (35.71%)	1 / 6 (16.67%)	21 / 84 (25.00%)	21 / 88 (23.86%)	12 / 81 (14.81%)	2 / 25 (8.00%)
occurrences all number	5	1	31	28	13	3
Hypokalaemia
subjects affected / exposed	0 / 14 (0.00%)	2 / 6 (33.33%)	8 / 84 (9.52%)	6 / 88 (6.82%)	7 / 81 (8.64%)	4 / 25 (16.00%)
occurrences all number	0	2	20	13	9	7
Dehydration
subjects affected / exposed	3 / 14 (21.43%)	2 / 6 (33.33%)	3 / 84 (3.57%)	2 / 88 (2.27%)	2 / 81 (2.47%)	2 / 25 (8.00%)
occurrences all number	3	2	3	2	2	2
Increased appetite
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	0 / 81 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0	0
Hypomagnesaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	6 / 84 (7.14%)	1 / 88 (1.14%)	2 / 81 (2.47%)	0 / 25 (0.00%)
occurrences all number	0	0	6	1	2	0
Hypoglycaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 84 (0.00%)	0 / 88 (0.00%)	1 / 81 (1.23%)	2 / 25 (8.00%)
occurrences all number	0	0	0	0	1	2

More information

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Were there any global substantial amendments to the protocol? Yes

30 Jan 2012

The following major changes were made in Amendment: 1) For Phase Ib, the exclusion criteria were changed: Participants who had received selected prior anti-cancer therapies (cytochrome P 17 inhibitors including abiraterone, inhibtors of Akt, PI3K/mTOR) were allowed. 2) For Phase Ib and II, participants who had received previous therapies with ketoconazole and/or MDV3100 (i.e., enzalutamide) were allowed to enroll. 3) The definition of DLT with respect to liver parameters was modified. 4) The number of sites participating in this study was increased from approximately 50 to approximately 70 sites. 5) Prednisolone was added as an alternative to prednisone. 6) Denosumab was added to the list of allowed concomitant therapies.

29 Apr 2012

The amendment was released to clarify the process for unblinding of treatment assignment by the investigator through the interactive voice response system/interactive web response system.

11 Sep 2012

The amendment was released to introduce the following main changes: 1) The study was amended to indicate the recommended dose of ipatasertib (GDC-0068, 400 mg daily) in combination with abiraterone for the Phase II part of the study, on the basis of safety and pharmacokinetic data from the Phase Ib portion. In addition, because of adverse events observed with the combination apitolisib (GDC-0980, 30 mg daily) and abiraterone, further exploration of this combination in the study was discontinued. 2) The design of the Phase II portion of the study was amended accordingly. 3) Updated dose-modification guidelines for the management of hyperglycemia, skin toxicity, gastrointestinal toxicities, and pneumonitis were included.

06 Mar 2013

The following major changes were made in Amendment: 1) Eligibility criteria were modified to exclude patients with poor performance status (Eastern Cooperative Oncology Group [ECOG] 2). 2) Accordingly, the stratification factors in the Phase II portion of the study were changed: randomization was stratified by prior enzalutamide (yes vs. no), progression factor (PSA only vs. other), and number of prior chemotherapy regimens for metastatic disease (one vs. more than one). 3) Dose modification for prednisone was added. 4) Risk of abiraterone on the fetus was added. 5) Dose reduction of ipatasertib/placebo or apitolisib was added as an option for management of fasting Grade ≥ 3 hyperglycemia if fasting glucose levels recovered to Grade less than or equal to 2 within 3 days upon dose interruption. 6) Cases of potential drug-induced liver injury that included an elevated alanine aminotransferase or aspartate aminotransferase in combination with either an elevated bilirubin or clinical jaundice, and suspected transmission of an infectious agent by the study drug were added as protocol defined events of special interest.

27 Nov 2013

The disease inclusion criterion was updated to align with the study title and rationale that participants who progressed from docetaxel-based chemotherapy (including docetaxel and cabazitaxel, sharing the same cytotoxic mechanism) should be eligible.

15 Sep 2017

The amendment was released with the following updates: 1) Facilitate study closure of the Phase Ib portion of the study, while allowing current participants in the Phase II portion of the study to stay on treatment. 2) A section on the Management of Selected Identified and Potential Risks of Ipatasertib was added. 3) Laboratory assessments were streamlined and reduced for ongoing participants. 4) The survival follow-up assessments were removed. 5) The use of the following treatments was removed from the list of prohibited therapies: for apitolisib, proton pump inhibitors (it was recommended that these agents be replaced with an H2-receptor antagonist when feasible), and orally administered H2-receptor antagonists within 10 hours before and 2 hours after apitolisib dose.

24 Apr 2019

The amendment was released with the following updates: 1) Include a new safety cohort to the study. The purpose of the safety cohort was to use new technology, a continuous glucose monitoring device, to assess the impact of ipatasertib monotherapy, ipatasertib plus prednisone/prednisolone, and ipatasertib plus prednisone/prednisolone plus abiraterone on glucose levels. 2) Compare morning versus evening dosing of ipatasertib with regard to its impact on glucose levels. 3) Explore the potential drug-drug interaction between abiraterone and ipatasertib and/or its metabolite, G-037720.

02 Jun 2020

The amendment was released with the following updates: 1) Harmonize the inclusion criteria of fasting total serum glucose and HbA1c between the Safety cohort and the Phase II portion of the study. 2) Implement additional changes concerning safety reporting and management of risks as well as further definition of the retinal disorder central subfield thickness.

02 Jun 2021

The amendment was released to clarify the access to ipatasertib for participants assigned to this treatment after completion of the study.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase Ib/II Study of GDC-0068 or GDC-0980 with Abiraterone Acetate versus Abiraterone Acetate in Patients with Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase Ib: Percentage of Participants With Dose-Limiting Toxicity (DLTs)

Primary: Phase Ib: Percentage of Participants With Dose-Limiting Toxicity (DLTs)

Primary: Phase Ib: Percentage of Participants with Adverse Events (AEs)

Primary: Phase Ib: Percentage of Participants with Adverse Events (AEs)

Primary: Phase II: Radiographic Progression Free Survival (rPFS) - ITT Population

Primary: Phase II: Radiographic Progression Free Survival (rPFS) - ITT Population

Primary: Phase Ib: Recommended Phase II Dose (RP2D) of Ipatasertib and Apitolisib

Primary: Phase Ib: Recommended Phase II Dose (RP2D) of Ipatasertib and Apitolisib

Primary: Phase II: rPFS in Participants With Institute of Cancer Research (ICR) Phosphatase and Tensin Homolog (PTEN) Loss

Primary: Phase II: rPFS in Participants With Institute of Cancer Research (ICR) Phosphatase and Tensin Homolog (PTEN) Loss

Secondary: Phase Ib: Time to Cmax (tmax) of Ipatasertib When Co-Administered With Abiraterone

Secondary: Phase Ib: Time to Cmax (tmax) of Ipatasertib When Co-Administered With Abiraterone

Secondary: Phase Ib: Maximum Plasma Concentration (Cmax) of Ipatasertib When Co-Administered With Abiraterone

Secondary: Phase Ib: Maximum Plasma Concentration (Cmax) of Ipatasertib When Co-Administered With Abiraterone

Secondary: Phase Ib: Cmax of G-037720 (Metabolite of Ipatasertib)

Secondary: Phase Ib: Cmax of G-037720 (Metabolite of Ipatasertib)

Secondary: Phase Ib: tmax of G-037720 (Metabolite of Ipatasertib)

Secondary: Phase Ib: tmax of G-037720 (Metabolite of Ipatasertib)

Secondary: Phase Ib: Accumulation Ratio of Ipatasertib When Co-Administered With Abiraterone

Secondary: Phase Ib: Accumulation Ratio of Ipatasertib When Co-Administered With Abiraterone

Secondary: Phase Ib: Total Body Clearance (CL/F) of Ipatasertib When Co-Administered With Abiraterone

Secondary: Phase Ib: Total Body Clearance (CL/F) of Ipatasertib When Co-Administered With Abiraterone

Secondary: Phase Ib: Area Under The Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of Ipatasertib When Co-Administered With Abiraterone

Secondary: Phase Ib: Area Under The Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of Ipatasertib When Co-Administered With Abiraterone

Secondary: Phase Ib: Cmax of Apitolisib When Co-Administered With Abiraterone

Secondary: Phase Ib: Cmax of Apitolisib When Co-Administered With Abiraterone

Secondary: Phase Ib: Accumulation Ratio of G-037720 (Metabolite of Ipatasertib)

Secondary: Phase Ib: Accumulation Ratio of G-037720 (Metabolite of Ipatasertib)

Secondary: Phase Ib: AUC0-24 of G-037720 (Metabolite of Ipatasertib)

Secondary: Phase Ib: AUC0-24 of G-037720 (Metabolite of Ipatasertib)

Secondary: Phase Ib: tmax of Apitolisib When Co-Administered With Abiraterone

Secondary: Phase Ib: tmax of Apitolisib When Co-Administered With Abiraterone

Secondary: Phase Ib: tmax of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

Secondary: Phase Ib: tmax of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

Secondary: Phase Ib: Cmax of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

Secondary: Phase Ib: Cmax of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

Secondary: Phase Ib: AUC0-24 of Apitolisib When Co-Administered With Abiraterone

Secondary: Phase Ib: AUC0-24 of Apitolisib When Co-Administered With Abiraterone

Secondary: Phase Ib: AUC0-24 of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

Secondary: Phase Ib: AUC0-24 of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

Secondary: Phase Ib: Plasma Half-Life of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

Secondary: Phase Ib: Plasma Half-Life of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

Secondary: Phase II: Overall Survival - ITT Population

Secondary: Phase II: Overall Survival - ITT Population

Secondary: Phase Ib: Accumulation Ratio of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

Secondary: Phase Ib: Accumulation Ratio of Abiraterone When Co- Administered With Ipatasertib or GDC-0980

Secondary: Phase II: Overall Survival in Participants With ICR IHC PTEN Loss

Secondary: Phase II: Overall Survival in Participants With ICR IHC PTEN Loss

Secondary: Phase II: Percentage of Participants With PSA Progression - ITT Population

Secondary: Phase II: Percentage of Participants With PSA Progression - ITT Population

Secondary: Phase II: Percentage of Participants With PSA Progression in Participants With ICR PTEN Loss

Secondary: Phase II: Percentage of Participants With PSA Progression in Participants With ICR PTEN Loss

Secondary: Phase II: Time to PSA Progression in Participants With ICR PTEN Loss

Secondary: Phase II: Time to PSA Progression in Participants With ICR PTEN Loss

Secondary: Phase II: Time to PSA Progression - ITT Population

Secondary: Phase II: Time to PSA Progression - ITT Population

Secondary: Phase II: Percentage of Participants With PSA Response - ITT Population

Secondary: Phase II: Percentage of Participants With PSA Response - ITT Population

Secondary: Phase II: Percentage of Participants With PSA Response in Participants With ICR PTEN Loss

Secondary: Phase II: Percentage of Participants With PSA Response in Participants With ICR PTEN Loss

Secondary: Phase II: Percentage of Participants With Objective Response in Participants With ICR PTEN Loss

Secondary: Phase II: Percentage of Participants With Objective Response in Participants With ICR PTEN Loss

Secondary: Phase II: Percentage of Participants With Objective Response - ITT Population

Secondary: Phase II: Percentage of Participants With Objective Response - ITT Population

Secondary: Phase II: Duration of Tumor Response - ITT Population

Secondary: Phase II: Duration of Tumor Response - ITT Population

Secondary: Phase II: Percentage of Participants With Circulating Tumor Cells (CTC) Reduction Response - ITT Population

Secondary: Phase II: Percentage of Participants With Circulating Tumor Cells (CTC) Reduction Response - ITT Population

Secondary: Phase II: Duration of Tumor Response in Participants with ICR PTEN Loss

Secondary: Phase II: Duration of Tumor Response in Participants with ICR PTEN Loss

Clinical Trial Results:
A Phase Ib/II Study of GDC-0068 or GDC-0980 with Abiraterone Acetate versus Abiraterone Acetate in Patients with Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy