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Clinical Trial Results:
A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor), MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of Weekly Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial Cancer

Summary
EudraCT number	2014-005394-37
Trial protocol	BE ES DE NL IT
Global end of trial date	23 Oct 2020

Results information
Results version number	v1
This version publication date	13 Nov 2021
First version publication date	13 Nov 2021
Other versions	v2

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

C31004

ISRCTN number

US NCT number

NCT02725268

WHO universal trial number (UTN)

U1111-1168-1824

Sponsor organisation name

Takeda

Sponsor organisation address

Millennium Pharmaceuticals, Inc., 40 Lansdowne Street, Cambridge, United States, 02139

Public contact

Study Director, Takeda, +1 877-825-3327, TrialDisclosures@takeda.com

Scientific contact

Study Director, Takeda, +1 877-825-3327, TrialDisclosures@takeda.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

23 Oct 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Oct 2020

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial is to determine if sapanisertib in combination with weekly paclitaxel improves progression-free survival (PFS) compared to weekly paclitaxel alone.

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

08 Sep 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 16

Country: Number of subjects enrolled

Belgium: 20

Country: Number of subjects enrolled

Germany: 11

Country: Number of subjects enrolled

Italy: 49

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Norway: 5

Country: Number of subjects enrolled

Spain: 28

Country: Number of subjects enrolled

United Kingdom: 21

Country: Number of subjects enrolled

Canada: 27

Country: Number of subjects enrolled

United States: 59

Worldwide total number of subjects

241

EEA total number of subjects

118

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)

123

From 65 to 84 years

118

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study at 60 investigative sites in Australia, Belgium, Germany, Italy, Netherlands, Norway, Spain, United Kingdom, Canada and the United States from 01 April 2016 to 30 October 2020.

Screening details

The female participants with a diagnosis of endometrial carcinoma were enrolled and randomized into 1:1:1:1 ratio to receive single agent paclitaxel, paclitaxel in combination with sapanisertib, single agent sapanisertib or sapanisertib in combination with MLN1117.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Paclitaxel 80 mg/m^2

Arm description

Paclitaxel 80 milligrams per square meter (mg/m^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 80 mg/m^2 intravenous solution for injection.

Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Arm description

Paclitaxel 80 mg/m^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel intravenous solution for injection.

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib Capsules

Sapanisertib 30 mg

Arm description

Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).

Arm type

Experimental

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib capsules

Sapanisertib 4 mg + MLN1117 200 mg

Arm description

Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).

Arm type

Experimental

Investigational medicinal product name

MLN1117

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

MLN1117 Capsules

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib Capsules

Number of subjects in period 1	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Started	90	90	41	20
Completed	18	20	3	2
Not completed	72	70	38	18
Adverse event, serious fatal	58	59	30	16
Consent Withdrawal by Subject	8	6	8	1
Other Reason: Site Terminated by Sponsor	-	1	-	-
Lost to follow-up	4	3	-	1
Other Reason: Reason not Specified	2	1	-	-

Baseline characteristics

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Reporting group title

Paclitaxel 80 mg/m^2

Reporting group description

Reporting group title

Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Reporting group description

Reporting group title

Sapanisertib 30 mg

Reporting group description

Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).

Reporting group title

Sapanisertib 4 mg + MLN1117 200 mg

Reporting group description

Reporting group values	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg	Total
Number of subjects	90	90	41	20	241
Age categorical
Units: Subjects
In Utero	0	0	0	0	0
Preterm newborn infants (gestional age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days - 23 months)	0	0	0	0	0
Children (2 - 11 years)	0	0	0	0	0
Adolescents (12 - 17 years)	0	0	0	0	0
Adults (18 - 64 years)	44	45	21	13	123
From 65 - 84 years	46	45	20	7	118
85 years and over	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	63.7 ( 7.14 )	64.4 ( 7.63 )	64.0 ( 6.99 )	62.0 ( 10.20 )	-
Gender categorical
Units: Subjects
Male	0	0	0	0	0
Female	90	90	41	20	241
Race/ Ethnicity, Customized
Units: Subjects
White	77	78	37	18	210
Black or African American	3	4	0	1	8
Native Hawaiian or Other Pacific Islander	1	0	1	0	2
Asian	6	3	1	1	11
Other	0	2	2	0	4
Not Reported	3	3	0	0	6
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	3	5	3	4	15
Non-Hispanic and Latino	84	80	37	15	216
Not Reported	3	5	1	1	10
Region of Enrollment
Units: Subjects
Australia	5	6	3	2	16
Belgium	5	10	2	3	20
Germany	6	4	1	0	11
Italy	14	22	9	4	49
Netherlands	2	3	0	0	5
Norway	3	1	1	0	5
Spain	10	7	5	6	28
United Kingdom	9	4	6	2	21
Canada	15	10	2	0	27
United States	21	23	12	3	59
Height
Number analyzed is the number of participants with data available for height at Baseline.
Units: cm
arithmetic mean (standard deviation)	160.60 ( 6.335 )	160.23 ( 5.798 )	159.01 ( 6.471 )	162.67 ( 5.854 )	-
Weight
Number analyzed is the number of participants with data available for weight at Baseline.
Units: kg
arithmetic mean (standard deviation)	73.29 ( 18.783 )	72.13 ( 18.433 )	75.35 ( 17.969 )	71.81 ( 18.613 )	-

End points

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Reporting group title

Paclitaxel 80 mg/m^2

Reporting group description

Reporting group title

Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Reporting group description

Reporting group title

Sapanisertib 30 mg

Reporting group description

Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).

Reporting group title

Sapanisertib 4 mg + MLN1117 200 mg

Reporting group description

Primary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS)

End point description

PFS is defined as the time in months from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST v1.1, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. ITT population included all randomized participants. For a participants who had not progressed and was last known to be alive, PFS was censored at the last response assessment that is stable disease (SD) or better.

End point type

Primary

End point timeframe

Up to approximately 30 months

End point values	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Number of subjects analysed	90	90	41	20
Units: months
median (confidence interval 95%)	3.7 (2.3 to 4.5)	5.6 (3.8 to 6.2)	2.1 (1.9 to 3.5)	2.0 (1.5 to 3.3)

Statistical Analysis 1 for PFS

Statistical analysis description

The hazard ratio was obtained using a stratified Cox proportional hazard model adjusted for histological subtype, lines of prior chemotherapy and prior taxane therapy. A hazard ratio of <1 was considered statistically significant.

Comparison groups

Paclitaxel 80 mg/m^2 v Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.178 ^[2]

Method

Stratified Log-rank Test

Parameter type

Hazard ratio (HR)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

1.12

Notes
[1] - null
[2] - The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Statistical Analysis 2 for PFS

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 30 mg

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.092 ^[4]

Method

Stratified Log-rank Test

Parameter type

Hazard ratio (HR)

Point estimate

1.85

Confidence interval

level

95%

sides

2-sided

lower limit

1.19

upper limit

2.86

Notes
[3] - null
[4] - The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Statistical Analysis 3 for PFS

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 4 mg + MLN1117 200 mg

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.147 ^[6]

Method

Stratified Log-rank Test

Parameter type

Hazard ratio (HR)

Point estimate

2.57

Confidence interval

level

95%

sides

2-sided

lower limit

1.47

upper limit

4.49

Notes
[5] - null
[6] - The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Secondary: Number of Participants who Experienced at Least One Treatment-emergent Adverse Event (TEAE)

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End point title

Number of Participants who Experienced at Least One Treatment-emergent Adverse Event (TEAE)

End point description

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. Safety population included all participant who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

From the first dose of study drug through 30 days after the last dose of study drug (Up to approximately 54 months)

End point values	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Number of subjects analysed	87	86	41	20
Units: participants	87	86	41	20

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS is defined as the time in months from the date of randomization to the date of death. ITT population included all randomized participants. Participants without documentation of death at the time of analysis were censored at the date last known to be alive.

End point type

Secondary

End point timeframe

Up to approximately 54 months

End point values	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Number of subjects analysed	90	90	41	20
Units: months
median (confidence interval 95%)	12.7 (9.8 to 19.6)	13.8 (9.9 to 19.1)	12.5 (9.0 to 15.7)	11.1 (2.7 to 17.5)

Statistical Analysis 1 for OS

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.968 ^[8]

Method

Stratified Log-rank Test

Parameter type

Hazard ratio (HR)

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.5

Notes
[7] - null
[8] - The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Statistical Analysis 2 for OS

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 30 mg

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.145 ^[10]

Method

Stratified Log-rank Test

Parameter type

Hazard ratio (HR)

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

2.37

Notes
[9] - null
[10] - The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Statistical Analysis 3 for OS

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 4 mg + MLN1117 200 mg

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.243 ^[12]

Method

Stratified Log-rank Test

Parameter type

Hazard ratio (HR)

Point estimate

1.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

2.73

Notes
[11] - null
[12] - The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Secondary: Time to Tumor Progression (TTP)

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End point title

Time to Tumor Progression (TTP)

End point description

TTP is defined as the time in months from the date of randomization to the date of first documentation of progression. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. ITT population included all randomized participants . For a participants who had not progressed, TTP was censored at the last response assessment that is SD or better.

End point type

Secondary

End point timeframe

Up to 30 months

End point values	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Number of subjects analysed	90	90	41	20
Units: months
median (confidence interval 95%)	3.7 (2.5 to 5.4)	5.7 (3.8 to 7.2)	2.3 (1.9 to 4.2)	2.2 (1.8 to 3.7)

Statistical Analysis 1 for TTP

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.17 ^[14]

Method

Stratified Log-rank Test

Parameter type

Hazard ratio (HR)

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.11

Notes
[13] - null
[14] - The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Statistical Analysis 2 for TTP

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 30 mg

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.224 ^[16]

Method

Stratified Log-rank Test

Parameter type

Hazard ratio (HR)

Point estimate

1.67

Confidence interval

level

95%

sides

2-sided

lower limit

1.04

upper limit

2.68

Notes
[15] - null
[16] - The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Statistical Analysis 3 for TTP

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 4 mg + MLN1117 200 mg

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.244 ^[18]

Method

Stratified Log-rank Test

Parameter type

Hazard ratio (HR)

Point estimate

2.28

Confidence interval

level

95%

sides

2-sided

lower limit

1.32

upper limit

3.96

Notes
[17] - null
[18] - The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Secondary: Overall Response Rate (ORR)

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End point title

Overall Response Rate (ORR)

End point description

ORR is defined as the percentage of participants who achieved a best response of a complete response (CR) or partial response (PR). Per RECIST v1.1, CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. Safety population included participants who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

Up to 30 months

End point values	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Number of subjects analysed	87	86	41	20
Units: percentage of participants
number (not applicable)	18.4	24.4	4.9	0

Statistical Analysis 1 for ORR

Statistical analysis description

The odds ratio and 95% confidence intervals were obtained using a stratified CMH model with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Comparison groups

Paclitaxel 80 mg/m^2 v Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Number of subjects included in analysis

173

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

Method

Parameter type

Odds ratio (OR)

Point estimate

1.39

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

2.9

Notes
[19] - null

Statistical Analysis 2 for ORR

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 30 mg

Number of subjects included in analysis

128

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

Method

Parameter type

Odds ratio (OR)

Point estimate

0.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.04

upper limit

1.14

Notes
[20] - null

Statistical Analysis 3 for ORR

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 4 mg + MLN1117 200 mg

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

Method

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[21] - null

Secondary: Clinical Benefit Rate (CBR)

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End point title

Clinical Benefit Rate (CBR)

End point description

CBR is defined as the percentage of participants with CR or PR or SD (SD of any duration). Per RECIST v1.1, CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Safety population included participants who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

Up to 30 months

End point values	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Number of subjects analysed	87	86	41	20
Units: percentage of participants
number (not applicable)	57.5	80.2	34.1	35.0

Statistical Analysis 1 for CBR

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Number of subjects included in analysis

173

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

Method

Parameter type

Odds ratio (OR)

Point estimate

3.02

Confidence interval

level

95%

sides

2-sided

lower limit

1.53

upper limit

5.96

Notes
[22] - null

Statistical Analysis 2 for CBR

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 30 mg

Number of subjects included in analysis

128

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

Method

Parameter type

Odds ratio (OR)

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

0.86

Notes
[23] - null

Statistical Analysis 3 for CBR

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 4 mg + MLN1117 200 mg

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

Method

Parameter type

Odds ratio (OR)

Point estimate

0.43

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

1.21

Notes
[24] - null

Secondary: Clinical Benefit Rate (CBR) at Week 16 (CBR-16)

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End point title

Clinical Benefit Rate (CBR) at Week 16 (CBR-16)

End point description

CBR-16 is defined as the percentage of participants who achieved CR or PR of any duration or have SD with a duration of at least 16 weeks. Per RECIST v1.1, CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Safety population included participants who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

Week 16

End point values	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Number of subjects analysed	87	86	41	20
Units: percentage of participants
number (not applicable)	36.8	51.2	17.1	5.0

Statistical Analysis 1 for CBR-16

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Number of subjects included in analysis

173

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

Method

Parameter type

Odds ratio (OR)

Point estimate

2.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

7.67

Notes
[25] - null

Statistical Analysis 2 for CBR-16

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 30 mg

Number of subjects included in analysis

128

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

Method

Parameter type

Odds ratio (OR)

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

0.51

Notes
[26] - null

Statistical Analysis 3 for CBR-16

Statistical analysis description

Comparison groups

Paclitaxel 80 mg/m^2 v Sapanisertib 4 mg + MLN1117 200 mg

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

Method

Parameter type

Odds ratio (OR)

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.67

Notes
[27] - null

Adverse events

Top of page

Timeframe for reporting adverse events

Up to the end of study (approximately up to 54 months)

Adverse event reporting additional description

At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Paclitaxel 80 mg/m^2

Reporting group description

Reporting group title

Sapanisertib 4 mg + MLN1117 200 mg

Reporting group description

Reporting group title

Sapanisertib 30 mg

Reporting group description

Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).

Reporting group title

Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Reporting group description

Serious adverse events	Paclitaxel 80 mg/m^2	Sapanisertib 4 mg + MLN1117 200 mg	Sapanisertib 30 mg	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg
Total subjects affected by serious adverse events
subjects affected / exposed	23 / 87 (26.44%)	7 / 20 (35.00%)	14 / 41 (34.15%)	47 / 86 (54.65%)
number of deaths (all causes)	58	16	30	59
number of deaths resulting from adverse events	0	0	0	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	1 / 20 (5.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant ascites
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Embolism
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoedema
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	1 / 41 (2.44%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Fatigue
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	1 / 20 (5.00%)	1 / 41 (2.44%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	1 / 20 (5.00%)	1 / 41 (2.44%)	3 / 86 (3.49%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	1 / 41 (2.44%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Vaginal haemorrhage
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	3 / 86 (3.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	3 / 86 (3.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	3 / 86 (3.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood glucose increased
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	1 / 20 (5.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	1 / 20 (5.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Waist circumference increased
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Foot fracture
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	1 / 41 (2.44%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract stoma complication
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial tachycardia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	1 / 41 (2.44%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal hernia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	0 / 20 (0.00%)	1 / 41 (2.44%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain lower
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Discoloured vomit
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspepsia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	1 / 41 (2.44%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	0 / 20 (0.00%)	1 / 41 (2.44%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	1 / 41 (2.44%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	2 / 20 (10.00%)	2 / 41 (4.88%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 0	2 / 2	5 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	0 / 20 (0.00%)	1 / 41 (2.44%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	2 / 20 (10.00%)	2 / 41 (4.88%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 0	4 / 4	5 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	0 / 20 (0.00%)	1 / 41 (2.44%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Skin and subcutaneous tissue disorders
Rash
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	1 / 41 (2.44%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	1 / 41 (2.44%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fistula
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	1 / 41 (2.44%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	1 / 20 (5.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Kidney infection
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	3 / 86 (3.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	3 / 86 (3.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	1 / 41 (2.44%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal infection
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	2 / 86 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Glucose tolerance impaired
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	1 / 20 (5.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	1 / 41 (2.44%)	0 / 86 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	0 / 20 (0.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Paclitaxel 80 mg/m^2	Sapanisertib 4 mg + MLN1117 200 mg	Sapanisertib 30 mg	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	85 / 87 (97.70%)	20 / 20 (100.00%)	41 / 41 (100.00%)	86 / 86 (100.00%)
Vascular disorders
Deep vein thrombosis
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	1 / 20 (5.00%)	0 / 41 (0.00%)	5 / 86 (5.81%)
occurrences all number	3	1	0	5
Hypertension
Additional description: null
subjects affected / exposed	9 / 87 (10.34%)	1 / 20 (5.00%)	2 / 41 (4.88%)	5 / 86 (5.81%)
occurrences all number	18	1	2	5
Hypotension
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	0 / 20 (0.00%)	0 / 41 (0.00%)	6 / 86 (6.98%)
occurrences all number	2	0	0	6
General disorders and administration site conditions
Asthenia
Additional description: null
subjects affected / exposed	7 / 87 (8.05%)	10 / 20 (50.00%)	9 / 41 (21.95%)	26 / 86 (30.23%)
occurrences all number	7	14	10	39
Chills
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	1 / 20 (5.00%)	0 / 41 (0.00%)	5 / 86 (5.81%)
occurrences all number	1	1	0	7
Fatigue
Additional description: null
subjects affected / exposed	39 / 87 (44.83%)	7 / 20 (35.00%)	18 / 41 (43.90%)	40 / 86 (46.51%)
occurrences all number	54	7	24	65
Oedema peripheral
Additional description: null
subjects affected / exposed	18 / 87 (20.69%)	1 / 20 (5.00%)	2 / 41 (4.88%)	10 / 86 (11.63%)
occurrences all number	23	1	2	13
Peripheral swelling
Additional description: null
subjects affected / exposed	5 / 87 (5.75%)	2 / 20 (10.00%)	0 / 41 (0.00%)	5 / 86 (5.81%)
occurrences all number	6	2	0	5
Pyrexia
Additional description: null
subjects affected / exposed	12 / 87 (13.79%)	4 / 20 (20.00%)	5 / 41 (12.20%)	13 / 86 (15.12%)
occurrences all number	18	6	7	20
Reproductive system and breast disorders
Vaginal haemorrhage
Additional description: null
subjects affected / exposed	6 / 87 (6.90%)	0 / 20 (0.00%)	0 / 41 (0.00%)	4 / 86 (4.65%)
occurrences all number	7	0	0	5
Respiratory, thoracic and mediastinal disorders
Cough
Additional description: null
subjects affected / exposed	21 / 87 (24.14%)	1 / 20 (5.00%)	8 / 41 (19.51%)	19 / 86 (22.09%)
occurrences all number	30	1	9	29
Dyspnoea
Additional description: null
subjects affected / exposed	18 / 87 (20.69%)	3 / 20 (15.00%)	6 / 41 (14.63%)	25 / 86 (29.07%)
occurrences all number	20	3	7	35
Epistaxis
Additional description: null
subjects affected / exposed	6 / 87 (6.90%)	0 / 20 (0.00%)	1 / 41 (2.44%)	11 / 86 (12.79%)
occurrences all number	8	0	1	13
Oropharyngeal pain
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	0 / 20 (0.00%)	3 / 41 (7.32%)	4 / 86 (4.65%)
occurrences all number	3	0	3	5
Pulmonary embolism
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	0 / 20 (0.00%)	3 / 41 (7.32%)	9 / 86 (10.47%)
occurrences all number	3	0	3	9
Psychiatric disorders
Anxiety
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	1 / 20 (5.00%)	3 / 41 (7.32%)	7 / 86 (8.14%)
occurrences all number	3	1	3	7
Depression
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	0 / 20 (0.00%)	5 / 41 (12.20%)	3 / 86 (3.49%)
occurrences all number	3	0	5	3
Insomnia
Additional description: null
subjects affected / exposed	6 / 87 (6.90%)	1 / 20 (5.00%)	1 / 41 (2.44%)	17 / 86 (19.77%)
occurrences all number	6	1	1	17
Investigations
Alanine aminotransferase increased
Additional description: null
subjects affected / exposed	5 / 87 (5.75%)	6 / 20 (30.00%)	1 / 41 (2.44%)	7 / 86 (8.14%)
occurrences all number	5	9	2	7
Aspartate aminotransferase increased
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	6 / 20 (30.00%)	2 / 41 (4.88%)	7 / 86 (8.14%)
occurrences all number	3	8	3	8
Blood alkaline phosphatase increased
Additional description: null
subjects affected / exposed	4 / 87 (4.60%)	0 / 20 (0.00%)	4 / 41 (9.76%)	5 / 86 (5.81%)
occurrences all number	4	0	5	8
Blood creatinine increased
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	4 / 20 (20.00%)	3 / 41 (7.32%)	6 / 86 (6.98%)
occurrences all number	5	4	6	7
Blood glucose increased
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	2 / 20 (10.00%)	0 / 41 (0.00%)	0 / 86 (0.00%)
occurrences all number	0	3	0	0
Gamma-glutamyltransferase increased
Additional description: null
subjects affected / exposed	6 / 87 (6.90%)	0 / 20 (0.00%)	5 / 41 (12.20%)	9 / 86 (10.47%)
occurrences all number	8	0	7	15
Neutrophil count decreased
Additional description: null
subjects affected / exposed	8 / 87 (9.20%)	0 / 20 (0.00%)	0 / 41 (0.00%)	9 / 86 (10.47%)
occurrences all number	10	0	0	22
Platelet count decreased
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	2 / 20 (10.00%)	1 / 41 (2.44%)	2 / 86 (2.33%)
occurrences all number	2	2	1	2
Protein total decreased
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	1 / 20 (5.00%)	3 / 41 (7.32%)	1 / 86 (1.16%)
occurrences all number	1	1	3	1
Weight decreased
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	3 / 20 (15.00%)	7 / 41 (17.07%)	17 / 86 (19.77%)
occurrences all number	2	3	7	20
White blood cell count decreased
Additional description: null
subjects affected / exposed	5 / 87 (5.75%)	0 / 20 (0.00%)	1 / 41 (2.44%)	9 / 86 (10.47%)
occurrences all number	13	0	1	20
Cardiac disorders
Tachycardia
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	3 / 41 (7.32%)	6 / 86 (6.98%)
occurrences all number	1	0	3	7
Nervous system disorders
Dizziness
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	2 / 20 (10.00%)	3 / 41 (7.32%)	14 / 86 (16.28%)
occurrences all number	3	2	4	17
Dysgeusia
Additional description: null
subjects affected / exposed	10 / 87 (11.49%)	2 / 20 (10.00%)	6 / 41 (14.63%)	15 / 86 (17.44%)
occurrences all number	10	2	6	16
Headache
Additional description: null
subjects affected / exposed	4 / 87 (4.60%)	1 / 20 (5.00%)	6 / 41 (14.63%)	13 / 86 (15.12%)
occurrences all number	6	1	6	15
Neuropathy peripheral
Additional description: null
subjects affected / exposed	12 / 87 (13.79%)	0 / 20 (0.00%)	3 / 41 (7.32%)	22 / 86 (25.58%)
occurrences all number	23	0	3	32
Paraesthesia
Additional description: null
subjects affected / exposed	6 / 87 (6.90%)	1 / 20 (5.00%)	1 / 41 (2.44%)	9 / 86 (10.47%)
occurrences all number	7	1	1	12
Peripheral sensory neuropathy
Additional description: null
subjects affected / exposed	7 / 87 (8.05%)	0 / 20 (0.00%)	0 / 41 (0.00%)	8 / 86 (9.30%)
occurrences all number	11	0	0	15
Taste disorder
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	0 / 20 (0.00%)	2 / 41 (4.88%)	6 / 86 (6.98%)
occurrences all number	2	0	2	7
Tremor
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	1 / 20 (5.00%)	3 / 41 (7.32%)	5 / 86 (5.81%)
occurrences all number	2	1	3	6
Blood and lymphatic system disorders
Anaemia
Additional description: null
subjects affected / exposed	32 / 87 (36.78%)	6 / 20 (30.00%)	5 / 41 (12.20%)	48 / 86 (55.81%)
occurrences all number	57	10	6	93
Leukopenia
Additional description: null
subjects affected / exposed	8 / 87 (9.20%)	1 / 20 (5.00%)	0 / 41 (0.00%)	12 / 86 (13.95%)
occurrences all number	15	3	0	19
Neutropenia
Additional description: null
subjects affected / exposed	10 / 87 (11.49%)	1 / 20 (5.00%)	1 / 41 (2.44%)	19 / 86 (22.09%)
occurrences all number	13	4	3	42
Ear and labyrinth disorders
Vertigo
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	2 / 20 (10.00%)	0 / 41 (0.00%)	4 / 86 (4.65%)
occurrences all number	2	4	0	7
Gastrointestinal disorders
Abdominal distension
Additional description: null
subjects affected / exposed	5 / 87 (5.75%)	0 / 20 (0.00%)	1 / 41 (2.44%)	6 / 86 (6.98%)
occurrences all number	5	0	2	11
Abdominal pain
Additional description: null
subjects affected / exposed	13 / 87 (14.94%)	4 / 20 (20.00%)	6 / 41 (14.63%)	22 / 86 (25.58%)
occurrences all number	16	6	10	25
Abdominal pain lower
Additional description: null
subjects affected / exposed	4 / 87 (4.60%)	3 / 20 (15.00%)	0 / 41 (0.00%)	3 / 86 (3.49%)
occurrences all number	5	3	0	5
Abdominal pain upper
Additional description: null
subjects affected / exposed	6 / 87 (6.90%)	4 / 20 (20.00%)	4 / 41 (9.76%)	13 / 86 (15.12%)
occurrences all number	7	5	5	16
Constipation
Additional description: null
subjects affected / exposed	25 / 87 (28.74%)	5 / 20 (25.00%)	14 / 41 (34.15%)	20 / 86 (23.26%)
occurrences all number	33	5	15	33
Diarrhoea
Additional description: null
subjects affected / exposed	31 / 87 (35.63%)	13 / 20 (65.00%)	15 / 41 (36.59%)	48 / 86 (55.81%)
occurrences all number	49	16	24	122
Dry mouth
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	2 / 20 (10.00%)	2 / 41 (4.88%)	8 / 86 (9.30%)
occurrences all number	2	2	2	10
Dyspepsia
Additional description: null
subjects affected / exposed	5 / 87 (5.75%)	1 / 20 (5.00%)	3 / 41 (7.32%)	13 / 86 (15.12%)
occurrences all number	5	1	3	14
Gastrooesophageal reflux disease
Additional description: null
subjects affected / exposed	4 / 87 (4.60%)	3 / 20 (15.00%)	3 / 41 (7.32%)	10 / 86 (11.63%)
occurrences all number	5	3	3	11
Haemorrhoids
Additional description: null
subjects affected / exposed	5 / 87 (5.75%)	0 / 20 (0.00%)	1 / 41 (2.44%)	2 / 86 (2.33%)
occurrences all number	5	0	1	2
Nausea
Additional description: null
subjects affected / exposed	29 / 87 (33.33%)	16 / 20 (80.00%)	30 / 41 (73.17%)	53 / 86 (61.63%)
occurrences all number	44	23	64	83
Stomatitis
Additional description: null
subjects affected / exposed	4 / 87 (4.60%)	2 / 20 (10.00%)	10 / 41 (24.39%)	22 / 86 (25.58%)
occurrences all number	5	2	11	34
Vomiting
Additional description: null
subjects affected / exposed	20 / 87 (22.99%)	15 / 20 (75.00%)	31 / 41 (75.61%)	24 / 86 (27.91%)
occurrences all number	38	30	62	43
Skin and subcutaneous tissue disorders
Alopecia
Additional description: null
subjects affected / exposed	31 / 87 (35.63%)	0 / 20 (0.00%)	1 / 41 (2.44%)	27 / 86 (31.40%)
occurrences all number	37	0	1	30
Dry skin
Additional description: null
subjects affected / exposed	6 / 87 (6.90%)	1 / 20 (5.00%)	0 / 41 (0.00%)	8 / 86 (9.30%)
occurrences all number	6	1	0	8
Pruritus
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	1 / 20 (5.00%)	6 / 41 (14.63%)	11 / 86 (12.79%)
occurrences all number	3	1	7	16
Rash
Additional description: null
subjects affected / exposed	5 / 87 (5.75%)	0 / 20 (0.00%)	4 / 41 (9.76%)	17 / 86 (19.77%)
occurrences all number	7	0	5	27
Rash maculo-papular
Additional description: null
subjects affected / exposed	5 / 87 (5.75%)	0 / 20 (0.00%)	1 / 41 (2.44%)	2 / 86 (2.33%)
occurrences all number	6	0	2	2
Renal and urinary disorders
Dysuria
Additional description: null
subjects affected / exposed	5 / 87 (5.75%)	1 / 20 (5.00%)	0 / 41 (0.00%)	6 / 86 (6.98%)
occurrences all number	5	1	0	6
Haematuria
Additional description: null
subjects affected / exposed	7 / 87 (8.05%)	0 / 20 (0.00%)	0 / 41 (0.00%)	8 / 86 (9.30%)
occurrences all number	9	0	0	10
Proteinuria
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	0 / 20 (0.00%)	0 / 41 (0.00%)	5 / 86 (5.81%)
occurrences all number	4	0	0	7
Musculoskeletal and connective tissue disorders
Arthralgia
Additional description: null
subjects affected / exposed	11 / 87 (12.64%)	0 / 20 (0.00%)	0 / 41 (0.00%)	22 / 86 (25.58%)
occurrences all number	14	0	0	29
Back pain
Additional description: null
subjects affected / exposed	14 / 87 (16.09%)	3 / 20 (15.00%)	3 / 41 (7.32%)	11 / 86 (12.79%)
occurrences all number	16	3	3	18
Groin pain
Additional description: null
subjects affected / exposed	0 / 87 (0.00%)	2 / 20 (10.00%)	0 / 41 (0.00%)	1 / 86 (1.16%)
occurrences all number	0	2	0	1
Muscular weakness
Additional description: null
subjects affected / exposed	4 / 87 (4.60%)	1 / 20 (5.00%)	0 / 41 (0.00%)	9 / 86 (10.47%)
occurrences all number	5	1	0	9
Myalgia
Additional description: null
subjects affected / exposed	12 / 87 (13.79%)	1 / 20 (5.00%)	1 / 41 (2.44%)	10 / 86 (11.63%)
occurrences all number	18	1	1	14
Pain in extremity
Additional description: null
subjects affected / exposed	7 / 87 (8.05%)	1 / 20 (5.00%)	1 / 41 (2.44%)	16 / 86 (18.60%)
occurrences all number	7	1	1	21
Infections and infestations
Nasopharyngitis
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	0 / 20 (0.00%)	2 / 41 (4.88%)	5 / 86 (5.81%)
occurrences all number	3	0	2	7
Sinusitis
Additional description: null
subjects affected / exposed	5 / 87 (5.75%)	0 / 20 (0.00%)	0 / 41 (0.00%)	3 / 86 (3.49%)
occurrences all number	7	0	0	4
Upper respiratory tract infection
Additional description: null
subjects affected / exposed	7 / 87 (8.05%)	0 / 20 (0.00%)	1 / 41 (2.44%)	6 / 86 (6.98%)
occurrences all number	7	0	1	7
Urinary tract infection
Additional description: null
subjects affected / exposed	9 / 87 (10.34%)	3 / 20 (15.00%)	6 / 41 (14.63%)	19 / 86 (22.09%)
occurrences all number	13	3	6	24
Metabolism and nutrition disorders
Decreased appetite
Additional description: null
subjects affected / exposed	16 / 87 (18.39%)	8 / 20 (40.00%)	20 / 41 (48.78%)	33 / 86 (38.37%)
occurrences all number	25	11	27	45
Dehydration
Additional description: null
subjects affected / exposed	1 / 87 (1.15%)	2 / 20 (10.00%)	6 / 41 (14.63%)	8 / 86 (9.30%)
occurrences all number	1	7	7	13
Hyperglycaemia
Additional description: null
subjects affected / exposed	8 / 87 (9.20%)	5 / 20 (25.00%)	15 / 41 (36.59%)	17 / 86 (19.77%)
occurrences all number	12	7	34	30
Hypoalbuminaemia
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	1 / 20 (5.00%)	4 / 41 (9.76%)	8 / 86 (9.30%)
occurrences all number	6	2	5	13
Hypocalcaemia
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	2 / 20 (10.00%)	1 / 41 (2.44%)	6 / 86 (6.98%)
occurrences all number	6	4	2	7
Hypokalaemia
Additional description: null
subjects affected / exposed	6 / 87 (6.90%)	0 / 20 (0.00%)	3 / 41 (7.32%)	11 / 86 (12.79%)
occurrences all number	11	0	4	18
Hypomagnesaemia
Additional description: null
subjects affected / exposed	11 / 87 (12.64%)	1 / 20 (5.00%)	7 / 41 (17.07%)	19 / 86 (22.09%)
occurrences all number	29	1	10	25
Hyponatraemia
Additional description: null
subjects affected / exposed	3 / 87 (3.45%)	2 / 20 (10.00%)	4 / 41 (9.76%)	6 / 86 (6.98%)
occurrences all number	6	2	6	8
Hypophosphataemia
Additional description: null
subjects affected / exposed	2 / 87 (2.30%)	1 / 20 (5.00%)	2 / 41 (4.88%)	12 / 86 (13.95%)
occurrences all number	4	2	2	28

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Were there any global substantial amendments to the protocol? Yes

08 Feb 2016

The primary purpose of this amendment was to revise dosing regimens for sapanisertib, Added EudraCT number and Millennium corporate identification to Title page. Updated study overview diagram, schedule of events section. Added alternative names for sapanisertib and MLN1117. Decreased the dose of sapanisertib in Arms B and D from 8 mg to 4 mg. Added the combination of sapanisertib + MLN1117 for the investigator to consider when assessing whether AE is possibly related to study drug. Revised maximum dose reduction from 2 to 3 for sapanisertib. Revised paclitaxel, sapanisertib dose reduction guidelines. Added magnetic resonance imaging (MRI) as an optional method of disease assessment Clarified that PK samples was to be collected from participants in Arm B, C, and D only. Added description suspected expected SAEs reporting. Updated Product Complaint contact information.

19 May 2016

The primary purpose of this amendment was to revise the study population to exclude participants with a known severe hypersensitivity reaction to prior paclitaxel exposure, active hepatitis B and hepatitis C in D infections and were lactating and breastfeeding to have a positive serum pregnancy test. Added an exclusion criterion regarding history of severe hypersensitivity reaction to paclitaxel.

17 Apr 2017

The primary purpose of this amendment was to update the dosing conditions for the subjects receiving weekly sapanisertib in Arm C, to update the pharmacokinetic (PK) sampling schedule to reflect the dosing change in Arm C, to clarify the procedure and/or timing for collection and clinical laboratory evaluations, to clarify the sapanisertib and paclitaxel dosing instructions, to update the window for obtaining informed consent and to update the procedure for reporting drug exposure during pregnancy with birth events. Added a PK sample collection at 3 to 6 hours postdose on Cycle 1 Day 1 for participants receiving weekly sapanisertib in Arm C. Replaced references relating to QD or QD5D dosing with appropriate dosing instructions. Clarified that informed consent may be signed more than 28 days before Cycle 1 Day 1.

25 Sep 2017

The primary purpose of this amendment was to update those sections affected by nonclinical data for sapanisertib metabolism by specific cytochrome P (CYP) isoforms. Removed the exclusion criterion relating to treatment with strong CYP inhibitors or inducers. Updated the list of concomitant medications prohibited during the study. Updated the description of potential drug-drug interactions in Arm D. Updated the list of CYP inhibitors or inducers. Removed dietary restrictions related to CYP inhibitors and inducers.

22 Jan 2018

The primary purpose of this amendment was to update the sample size of the study to reflect changes in study design and the closure of enrollment into Arms C and D. Update the Global Clinical Lead of the study. Added the sensitivity analysis of efficacy endpoints may be performed.

01 Mar 2020

The primary purpose of this amendment was to remove in-home glucose monitoring., long-term follow up (PFS follow up and/or OS follow up) for participants after end of treatment. Update the Global Clinical Lead 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 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor), MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of Weekly Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression Free Survival (PFS)

Primary: Progression Free Survival (PFS)

Secondary: Number of Participants who Experienced at Least One Treatment-emergent Adverse Event (TEAE)

Secondary: Number of Participants who Experienced at Least One Treatment-emergent Adverse Event (TEAE)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Time to Tumor Progression (TTP)

Secondary: Time to Tumor Progression (TTP)

Secondary: Overall Response Rate (ORR)

Secondary: Overall Response Rate (ORR)

Secondary: Clinical Benefit Rate (CBR)

Secondary: Clinical Benefit Rate (CBR)

Secondary: Clinical Benefit Rate (CBR) at Week 16 (CBR-16)

Secondary: Clinical Benefit Rate (CBR) at Week 16 (CBR-16)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor), MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of Weekly Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression Free Survival (PFS)

Primary: Progression Free Survival (PFS)

Secondary: Number of Participants who Experienced at Least One Treatment-emergent Adverse Event (TEAE)

Secondary: Number of Participants who Experienced at Least One Treatment-emergent Adverse Event (TEAE)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Time to Tumor Progression (TTP)

Secondary: Time to Tumor Progression (TTP)

Secondary: Overall Response Rate (ORR)

Secondary: Overall Response Rate (ORR)

Secondary: Clinical Benefit Rate (CBR)

Secondary: Clinical Benefit Rate (CBR)

Secondary: Clinical Benefit Rate (CBR) at Week 16 (CBR-16)

Secondary: Clinical Benefit Rate (CBR) at Week 16 (CBR-16)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor), MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of Weekly Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial Cancer