A Study of Sapanisertib, Combination of Sapanisertib With MLN1117, Paclitaxel and Combination of Sapanisertib With Paclitaxel in Women With Endometrial Cancer

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02725268
• Collaborator: European Network of Translational Research in Ovarian Cancer - EUTROC (Other), European Network of Individualized Treatment in Endometrial Cancer - ENITEC (Other)
• Enrollment: 241
• Locations: 78
• Arms: 4
• Actual Duration (Months): 55
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary purpose of this study is to determine if sapanisertib in combination with weekly paclitaxel improves progression-free survival (PFS) compared to weekly paclitaxel alone.

Condition or Disease	Intervention/Treatment	Phase
Endometrial Neoplasms	Drug: Paclitaxel; Drug: Sapanisertib; Drug: MLN1117	Phase 2

Detailed Description

The drugs being evaluated in this study are sapanisertib and MLN1117. Sapanisertib is being evaluated as a single agent and in combination with paclitaxel or MLN1117 to treat women with advanced, recurrent, or persistent endometrial cancer. This study will evaluate the efficacy and safety of each drug or drug combination.

The study will enroll approximately 241 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of 4 treatment groups:

• Paclitaxel 80 mg/m^2

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

• Sapanisertib 30 mg

• Sapanisertib 4 mg + MLN1117 200 mg

Participants will receive either paclitaxel intravenous (IV) weekly, Paclitaxel IV along with sapanisertib orally, sapanisertib orally, or sapanisertib and MLN1117 orally.

This is a multicenter, multinational trial. Participants will make multiple visits to the clinic, with an end of treatment visit (EOT) which will occur 30 to 40 days after receiving their last dose of study drug or before the start of any subsequent anticancer therapy. After EOT, participants will be followed for PFS and overall survival (OS).

Study Design

• Study Type: Interventional
• Actual Enrollment: 241 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Apr 1, 2016
• Actual Primary Completion Date: Jul 2, 2019
• Actual Study Completion Date: Oct 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Paclitaxel 80 mg/m^2 Paclitaxel 80 milligrams per square meter (mg/m^2), IV, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was up to approximately 13 weeks).	Drug: Paclitaxel; Paclitaxel intravenous solution.
Experimental: Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg Paclitaxel 80 mg/m^2, IV, 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 up to approximately 20 weeks).	Drug: Paclitaxel; Paclitaxel intravenous solution.; Drug: Sapanisertib; Sapanisertib capsules.; Other Names: MLN0128 INK128 TAK-228
Experimental: Sapanisertib 30 mg 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 up to approximately 6 weeks).	Drug: Sapanisertib; Sapanisertib capsules.; Other Names: MLN0128 INK128 TAK-228
Experimental: Sapanisertib 4 mg + MLN1117 200 mg 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 up to approximately 8 weeks).	Drug: Sapanisertib; Sapanisertib capsules.; Other Names: MLN0128 INK128 TAK-228 ; Drug: MLN1117; MLN1117 capsules.; Other Names: TAK-117 INK1117

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [Up to approximately 30 months]

   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.

Secondary Outcome Measures

1. Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE) [From the first dose of study drug through 30 days after the last dose of study drug (Up to approximately 54 months)]

   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.

2. Overall Survival (OS) [Up to approximately 54 months]

   OS is defined as the time in months from the date of randomization to the date of death.

3. Time to Tumor Progression (TTP) [Up to 30 months]

   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.

4. Overall Response Rate (ORR) [Up to 30 months]

   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.

5. Clinical Benefit Rate (CBR) [Up to 30 months]

   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.

6. Clinical Benefit Rate (CBR) at Week 16 (CBR-16) [Week 16]

   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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Histologic or cytologic diagnosis of endometrial carcinoma (including endometrioid, serous, mixed adenocarcinoma, clear-cell carcinoma, or carcinosarcoma).

2. Evidence that the endometrial cancer is advanced, recurrent, or persistent and has relapsed or is refractory to curative therapy or established treatments.

3. At least 1 prior platinum-based chemotherapeutic regimen, but not more than 2 prior chemotherapeutic regimens, for management of endometrial carcinoma. Prior treatment may include chemotherapy, chemotherapy/radiation therapy, and/or consolidation/maintenance therapy. Chemotherapy administered in conjunction with primary radiation as a radio-sensitized therapy will be considered a systemic chemotherapy regimen.

4. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded). Each lesion must be greater than or equal to (>=) 10 millimeter (mm) in long axis when measured by computed tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by clinical exam. Lymph nodes must be

= 15 mm in short axis when measured by CT or MRI.

1. Tumor accessible and participant consents to undergo fresh tumor biopsies.

2. Female participants 18 years or older.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

4. Female participants who:

• Are postmenopausal for at least 1 year before the screening visit, OR

• Are surgically sterile, OR

• If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling [example, United States Prescribing Information (USPI), Summary of Product Characteristics (SmPC), etc.]) after the last dose of study drug, OR

• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

1. Clinical laboratory values as specified below within 4 weeks before the first dose of study drug:

• Bone marrow reserve consistent with absolute neutrophil count (ANC) >= 1500 per micro liter (/mcL); platelet count >= 100,000/mcL; hemoglobin A1c (HbA1c) less than (<) 6.5 percent (%).

• Total bilirubin must be less than or equal to (<=) 1.5 * the upper limit of normal (ULN).

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be <= 2.5

• the upper limit of the normal range. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of metastatic disease in liver.

• Creatinine clearance >= 50 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2) based either on Cockcroft-Gault estimate or based on a 12- or 24-hour urine collection.

• Fasting serum glucose < 130 milligram per deciliter (mg/dL) and fasting triglycerides <= 300 mg/dL.

1. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.

2. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

Exclusion Criteria:

1. Positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug. Women who are lactating and breastfeeding are not eligible.

2. Previous treatment with any weekly taxane regimen.

3. History of severe hypersensitivity reactions to paclitaxel or any of its excipients.

4. Previous treatment with phosphoinositide 3-kinase (PI3K), serine/threonine-specific protein kinase (AKT), dual PI3K/ mammalian (or mechanistic) target of rapamycin (mTOR) inhibitors, target of rapamycin complex 1/2 (TORC1/2) inhibitors or TORC1 inhibitors.

5. Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either intravenous [IV] or oral steroids, excluding inhalers) within 1 week before administration of the first dose of study drug (participants already receiving erythropoietin on a chronic basis for >=4 weeks are eligible).

6. Participants who are taking proton pump inhibitors (PPIs) within 7 days of the first dose of study drug or who require treatment with PPIs throughout the trial or those who are taking H2 receptor antagonists within 24 hours of the first dose of study drug.

7. A prothrombin time (PT) or activated partial thromboplastin time (aPTT) above the ULN or a history of a coagulopathy or bleeding disorder.

8. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.

9. Sensory or motor neuropathy >= Grade 2.

10. Central nervous system (CNS) metastasis, endometrial leiomyosarcoma, or endometrial stromal sarcoma.

11. Manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal disease, or for some other reason that may alter the absorption of sapanisertib or MLN1117. In addition, participants with enteric stomata are also excluded.

12. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active CNS disease, active infection, or any other condition that could compromise participation of the participant in the study.

13. Known human immunodeficiency virus infection.

14. History of any of the following within the last 6 months before administration of the first dose of study drug:

• Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures.

• Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures.

• Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).

• Placement of a pacemaker for control of rhythm.

• New York Heart Association Class III or IV heart failure.

• Pulmonary embolism.

1. Significant active cardiovascular or pulmonary disease before administration of the first dose of study drug, including:

• Uncontrolled hypertension (that is, either systolic blood pressure > 180 millimeter of mercury [mm Hg] or diastolic blood pressure > 95 mm Hg).

• Pulmonary hypertension.

• Uncontrolled asthma or oxygen saturation < 90% by arterial blood gas analysis or pulse oximetry on room air.

• Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention; or history of valve replacement.

• Medically significant (symptomatic) bradycardia.

• History of arrhythmia requiring an implantable cardiac defibrillator.

• Baseline prolongation of the rate-corrected QT interval (QTc; example, repeated demonstration of QTc interval > 480 millisecond [ms], or history of congenital long QT syndrome, or torsades de pointes).

1. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

2. Participants with endometrioid histology and histologically confirmed expression of estrogen receptors (ER) and/or progesterone receptors (PgR) who have not received prior endocrine therapy and for whom endocrine therapy is currently indicated.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Comprehensive Cancer Center	Birmingham	Alabama	United States	35294-3300
2	University of Arizona Cancer Center	Phoenix	Arizona	United States	85013
3	Marin Cancer Care	Greenbrae	California	United States	94904
4	University of California San Diego Medical Center	La Jolla	California	United States	92093-1503
5	University of California at San Francisco (PARENT)	San Francisco	California	United States	94115
6	Stanford School of Medicine	Stanford	California	United States	94305
7	H. Lee Moffitt Cancer Center and Research Institute, Inc	Tampa	Florida	United States	33612-9416
8	Florida Cancer Specialists	West Palm Beach	Florida	United States	33401
9	Augusta University	Augusta	Georgia	United States	30912
10	Franciscan St. Francis Health	Indianapolis	Indiana	United States	46237
11	University of Kansas Medical Center Research Institute, Inc.	Westwood	Kansas	United States	66205
12	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
13	Washington University	Saint Louis	Missouri	United States	63108
14	NYU Langone Medical Center Clinic	New York	New York	United States	10016
15	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065-6094
16	Levine Cancer Institute	Charlotte	North Carolina	United States	28204
17	Oklahoma University Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
18	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
19	University of Pittsburgh Medical Center Cancer Center at Magee-Womens Hospital	Pittsburgh	Pennsylvania	United States	15232
20	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
21	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
22	St George Hospital	Kogarah	New South Wales	Australia	2217
23	Westmead Hospital	Westmead	New South Wales	Australia	2145
24	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
25	Monash Medical Centre Clayton	Clayton	Victoria	Australia	3168
26	Sunshine Hospital	Footscray	Victoria	Australia	3011
27	Cabrini Hospital Malvern	Malvern	Victoria	Australia	3144
28	Peter MacCallum Cancer Centre-East Melbourne	Melbourne	Victoria	Australia	3000
29	UZ Antwerpen	Edegem	Antwerpen	Belgium	2650
30	Cliniques Universitaires Saint-Luc	Bruxelles		Belgium	1200
31	UZ Leuven	Leuven		Belgium	3000
32	Centre Hospitalier Universitaire de Liege Site Sart Tilman	Liege		Belgium	4000
33	GasthuisZusters Antwerpen Sint-Augustinus	Wilrijk		Belgium	2610
34	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
35	Juravinski Cancer Clinic	Hamilton	Ontario	Canada	L8V 5C2
36	LHSC - Victoria Hospital	London	Ontario	Canada	N6A 4L6
37	Ottawa Hospital Cancer Centre	Ottawa	Ontario	Canada	K1H 8L6
38	University Health Network - Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
39	CHUM Hopital Notre-Dame	Montreal	Quebec	Canada	H2X 3E4
40	Universitaetsmedizin Greifswald	Greifswald	Mecklenburg Vorpommern	Germany	17489
41	Medizinische Hochschule Hannover	Hannover	Niedersachsen	Germany	30625
42	Universitaetsklinikum Carl Gustav Carus TU Dresden	Dresden	Sachsen	Germany	01307
43	Universitaetsklinikum Schleswig-Holstein - Campus Luebeck	Luebeck	Schleswig Holstein	Germany	23538
44	Charite - Universitaetsmedizin Berlin - Campus Virchow-Klinikum	Berlin		Germany	13353
45	Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori	Meldola	Forli - Cesena	Italy	47014
46	Spedali Civili di Brescia	Brescia		Italy	25123
47	Ente Ospedaliero Ospedali Galliera	Genova		Italy	16128
48	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano		Italy	20133
49	IEO Istituto Europeo di Oncologia	Milano		Italy	20141
50	Istituto Tumori Napoli Fondazione G. Pascale	Napoli		Italy	80131
51	Azienda Unita Sanitaria Locale di Ravenna	Ravenna		Italy	48121
52	Istituto Nationale Tumori Regina Elena	Roma		Italy	00144
53	Universita degli Studi di Roma "La Sapienza" - Umberto I Policlinico di Roma	Roma		Italy	00161
54	Fondazione Policlinico Universitario Agostino Gemelli	Roma		Italy	00168
55	Maastricht Universitair Medisch Centrum	Maastricht	Limburg	Netherlands	6229 HX
56	Academisch Medisch Centrum	Amsterdam	Noord-holland	Netherlands	1105 AZ
57	Erasmus Medisch Centrum Daniel den Hoed	Rotterdam	Zuid-holland	Netherlands	3015 GD
58	Universitair Medisch Centrum Groningen	Groningen		Netherlands	9700 RB
59	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands	3584 CX
60	Haukeland universitetssykehus, Kvinneklinikken	Bergen		Norway	5021
61	Radiumhospitalet	Oslo		Norway	0310
62	Stavanger University Hospital	Stavanger		Norway	4011
63	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
64	MD Anderson Cancer Centre	Madrid		Spain	28033
65	Hospital Universitario Ramon y Cajal	Madrid		Spain	28034
66	Hospital Universitario Clinico San Carlos	Madrid		Spain	28040
67	Hospital Universitario La Paz	Madrid		Spain	28046
68	Centro Integral Oncologico Clara Campal	Madrid		Spain	28050
69	Instituto Valenciano de Oncologia IVO	Valencia		Spain	46009
70	Bristol Haematology and Oncology Centre	Bristol	Avon	United Kingdom	BS2 8ED
71	Royal Devon and Exeter Hospital (Wonford)	Exeter	Devon	United Kingdom	EX2 5DW
72	University College London Hospitals	London	Greater London	United Kingdom	NW1 2BU
73	Royal Marsden Hospital	London	Greater London	United Kingdom	SW3 6JJ
74	Hammersmith Hospital	London	Greater London	United Kingdom	W12 0HS
75	The Christie	Manchester	Greater Manchester	United Kingdom	M20 4BX
76	Royal Marsden Hospital	Sutton	Surrey	United Kingdom	SM2 5PT
77	University Hospital Coventry	Coventry		United Kingdom	CV2 2DX
78	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.
• European Network of Translational Research in Ovarian Cancer - EUTROC
• European Network of Individualized Treatment in Endometrial Cancer - ENITEC

Investigators

• Study Director: Medical Director Clinical Science, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Mar 2, 2020
• Statistical Analysis Plan - Sep 7, 2018

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02725268
• Other Study ID Numbers: C31004; U1111-1168-1824; 2014-005394-37; 02725268
• First Posted: Mar 31, 2016
• Last Update Posted: Nov 24, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug Therapy
• Additional relevant MeSH terms: Endometrial Neoplasms; Paclitaxel; Serabelisib

Study Results

Participant Flow

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.
Pre-assignment Detail	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.

Arm/Group Title	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Arm/Group 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).	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).	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).	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).
Period Title: Overall Study
STARTED	90	90	41	20
Started	90	90	41	20
Completed	18	20	3	2
COMPLETED	18	20	3	2
NOT COMPLETED	72	70	38	18

Baseline Characteristics

Arm/Group Title	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg	Total
Arm/Group 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).	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).	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).	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).	Total of all reporting groups
Overall Participants	90	90	41	20	241
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.7 (7.14)	64.4 (7.63)	64.0 (6.99)	62.0 (10.20)	63.9 (7.57)
Sex: Female, Male (Count of Participants)
Female	90 100%	90 100%	41 100%	20 100%	241 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 3.3%	5 5.6%	3 7.3%	4 20%	15 6.2%
Not Hispanic or Latino	84 93.3%	80 88.9%	37 90.2%	15 75%	216 89.6%
Unknown or Not Reported	3 3.3%	5 5.6%	1 2.4%	1 5%	10 4.1%
Race/Ethnicity, Customized (Count of Participants)
White	77 85.6%	78 86.7%	37 90.2%	18 90%	210 87.1%
Black or African American	3 3.3%	4 4.4%	0 0%	1 5%	8 3.3%
Native Hawaiian or other Pacific Islander	1 1.1%	0 0%	1 2.4%	0 0%	2 0.8%
Asian	6 6.7%	3 3.3%	1 2.4%	1 5%	11 4.6%
Other	0 0%	2 2.2%	2 4.9%	0 0%	4 1.7%
Not Reported	3 3.3%	3 3.3%	0 0%	0 0%	6 2.5%
Region of Enrollment (Count of Participants)
Australia	5 5.6%	6 6.7%	3 7.3%	2 10%	16 6.6%
Belgium	5 5.6%	10 11.1%	2 4.9%	3 15%	20 8.3%
Germany	6 6.7%	4 4.4%	1 2.4%	0 0%	11 4.6%
Italy	14 15.6%	22 24.4%	9 22%	4 20%	49 20.3%
Netherlands	2 2.2%	3 3.3%	0 0%	0 0%	5 2.1%
Norway	3 3.3%	1 1.1%	1 2.4%	0 0%	5 2.1%
Spain	10 11.1%	7 7.8%	5 12.2%	6 30%	28 11.6%
United Kingdom	9 10%	4 4.4%	6 14.6%	2 10%	21 8.7%
Canada	15 16.7%	10 11.1%	2 4.9%	0 0%	27 11.2%
United States	21 23.3%	23 25.6%	12 29.3%	3 15%	59 24.5%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	160.60 (6.335)	160.23 (5.798)	159.01 (6.471)	162.67 (5.854)	160.36 (6.16)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	73.29 (18.783)	72.13 (18.433)	75.35 (17.969)	71.81 (18.613)	73.11 (18.418)

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
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.
Time Frame	Up to approximately 30 months

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants. For a participant 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.

Arm/Group Title	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Arm/Group 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).	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).	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).	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).
Measure Participants	90	90	41	20
Median (95% Confidence Interval) [months]	3.7	5.6	2.1	2.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.178
	Comments	The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.092
	Comments	The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.85
	Confidence Interval	(2-Sided) 95%; 1.19 to 2.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 4 mg + MLN1117 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.147
	Comments	The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.57
	Confidence Interval	(2-Sided) 95%; 1.47 to 4.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

2. Secondary Outcome

Title	Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE)
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.
Time Frame	From the first dose of study drug through 30 days after the last dose of study drug (Up to approximately 54 months)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of study drug.

Arm/Group Title	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Arm/Group 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).	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).	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).	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).
Measure Participants	87	86	41	20
Count of Participants [Participants]	87 96.7%	86 95.6%	41 100%	20 100%

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time in months from the date of randomization to the date of death.
Time Frame	Up to approximately 54 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Arm/Group 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).	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).	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).	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).
Measure Participants	90	90	41	20
Median (95% Confidence Interval) [months]	12.7	13.8	12.5	11.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.968
	Comments	The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.145
	Comments	The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.50
	Confidence Interval	(2-Sided) 95%; 0.95 to 2.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 4 mg + MLN1117 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.243
	Comments	The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.54
	Confidence Interval	(2-Sided) 95%; 0.87 to 2.73
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

4. Secondary Outcome

Title	Time to Tumor Progression (TTP)
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.
Time Frame	Up to 30 months

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants. For a participant who has not progressed, TTP was censored at the last response assessment that is SD or better.

Arm/Group Title	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Arm/Group 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).	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).	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).	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).
Measure Participants	90	90	41	20
Median (95% Confidence Interval) [months]	3.7	5.7	2.3	2.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.170
	Comments	The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.224
	Comments	The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.67
	Confidence Interval	(2-Sided) 95%; 1.04 to 2.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 4 mg + MLN1117 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.244
	Comments	The p-value was obtained using stratified log-rank test with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.28
	Confidence Interval	(2-Sided) 95%; 1.32 to 3.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

5. Secondary Outcome

Title	Overall Response Rate (ORR)
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.
Time Frame	Up to 30 months

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least 1 dose of study drug.

Arm/Group Title	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Arm/Group 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).	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).	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).	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).
Measure Participants	87	86	41	20
Number [percentage of participants]	18.4 20.4%	24.4 27.1%	4.9 12%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.39
	Confidence Interval	(2-Sided) 95%; 0.66 to 2.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio and 95% confidence intervals were obtained using a stratified Cochran-Mantel-Haenszel (CMH) model with histological subtype, lines of prior chemotherapy and prior taxane therapy (original stratification values).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 95%; 0.04 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	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).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 4 mg + MLN1117 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; 0.00 to 0.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	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).

6. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
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.
Time Frame	Up to 30 months

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least 1 dose of study drug.

Arm/Group Title	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Arm/Group 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).	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).	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).	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).
Measure Participants	87	86	41	20
Number [percentage of participants]	57.5 63.9%	80.2 89.1%	34.1 83.2%	35.0 175%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.02
	Confidence Interval	(2-Sided) 95%; 1.53 to 5.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	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).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.18 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	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).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 4 mg + MLN1117 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95%; 0.15 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments	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).

7. Secondary Outcome

Title	Clinical Benefit Rate (CBR) at Week 16 (CBR-16)
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.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least 1 dose of study drug.

Arm/Group Title	Paclitaxel 80 mg/m^2	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg	Sapanisertib 30 mg	Sapanisertib 4 mg + MLN1117 200 mg
Arm/Group 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).	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).	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).	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).
Measure Participants	87	86	41	20
Number [percentage of participants]	36.8 40.9%	51.2 56.9%	17.1 41.7%	5.0 25%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.62
	Confidence Interval	(2-Sided) 95%; 0.89 to 7.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	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).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; 0.05 to 0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	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).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Paclitaxel 80 mg/m^2, Sapanisertib 4 mg + MLN1117 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	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).

Adverse Events

Time Frame	Up to the end of study (approximately up to 54 months)
Adverse Event Reporting 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.
Arm/Group Title	Paclitaxel 80 mg/m^2		Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg		Sapanisertib 30 mg		Sapanisertib 4 mg + MLN1117 200 mg
Arm/Group 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).		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).		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).		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).
All Cause Mortality
	Paclitaxel 80 mg/m^2		Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg		Sapanisertib 30 mg		Sapanisertib 4 mg + MLN1117 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/90 (64.4%)		59/90 (65.6%)		30/41 (73.2%)		16/20 (80%)
Serious Adverse Events
	Paclitaxel 80 mg/m^2		Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg		Sapanisertib 30 mg		Sapanisertib 4 mg + MLN1117 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/87 (26.4%)		47/86 (54.7%)		14/41 (34.1%)		7/20 (35%)
Blood and lymphatic system disorders
Febrile neutropenia	2/87 (2.3%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Anaemia	0/87 (0%)		2/86 (2.3%)		0/41 (0%)		0/20 (0%)
Cardiac disorders
Acute myocardial infarction	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Atrial tachycardia	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Tachycardia	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Gastrointestinal disorders
Nausea	0/87 (0%)		2/86 (2.3%)		2/41 (4.9%)		2/20 (10%)
Vomiting	0/87 (0%)		2/86 (2.3%)		2/41 (4.9%)		2/20 (10%)
Intestinal obstruction	3/87 (3.4%)		1/86 (1.2%)		1/41 (2.4%)		0/20 (0%)
Small intestinal obstruction	2/87 (2.3%)		1/86 (1.2%)		1/41 (2.4%)		0/20 (0%)
Abdominal pain	2/87 (2.3%)		0/86 (0%)		1/41 (2.4%)		0/20 (0%)
Colitis	0/87 (0%)		2/86 (2.3%)		0/41 (0%)		0/20 (0%)
Intestinal perforation	0/87 (0%)		1/86 (1.2%)		1/41 (2.4%)		0/20 (0%)
Large intestinal obstruction	2/87 (2.3%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Subileus	2/87 (2.3%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Abdominal distension	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Abdominal hernia	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Abdominal pain lower	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Constipation	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Diarrhoea	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Discoloured vomit	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Dyspepsia	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Faecaloma	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Haematemesis	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Ileus	0/87 (0%)		0/86 (0%)		1/41 (2.4%)		0/20 (0%)
General disorders
General physical health deterioration	3/87 (3.4%)		3/86 (3.5%)		1/41 (2.4%)		1/20 (5%)
Fatigue	0/87 (0%)		2/86 (2.3%)		1/41 (2.4%)		1/20 (5%)
Pyrexia	1/87 (1.1%)		1/86 (1.2%)		1/41 (2.4%)		0/20 (0%)
Malaise	0/87 (0%)		2/86 (2.3%)		0/41 (0%)		0/20 (0%)
Pain	1/87 (1.1%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Asthenia	0/87 (0%)		0/86 (0%)		1/41 (2.4%)		0/20 (0%)
Death	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Non-cardiac chest pain	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Hepatobiliary disorders
Hepatic failure	2/87 (2.3%)		0/86 (0%)		1/41 (2.4%)		0/20 (0%)
Hyperbilirubinaemia	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Infections and infestations
Sepsis	1/87 (1.1%)		3/86 (3.5%)		0/41 (0%)		0/20 (0%)
Pneumonia	0/87 (0%)		3/86 (3.5%)		0/41 (0%)		0/20 (0%)
Urinary tract infection	0/87 (0%)		1/86 (1.2%)		1/41 (2.4%)		0/20 (0%)
Abdominal abscess	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Bacteraemia	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Cellulitis	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Cystitis	0/87 (0%)		0/86 (0%)		1/41 (2.4%)		0/20 (0%)
Enterocolitis infectious	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Gastroenteritis	0/87 (0%)		0/86 (0%)		0/41 (0%)		1/20 (5%)
Kidney infection	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Pyelonephritis	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Staphylococcal infection	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Urosepsis	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Vaginal infection	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Injury, poisoning and procedural complications
Foot fracture	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Lower limb fracture	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Overdose	0/87 (0%)		0/86 (0%)		1/41 (2.4%)		0/20 (0%)
Urinary tract stoma complication	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Investigations
Blood glucose increased	0/87 (0%)		0/86 (0%)		0/41 (0%)		1/20 (5%)
Electrocardiogram QT prolonged	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Platelet count decreased	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Transaminases increased	0/87 (0%)		0/86 (0%)		0/41 (0%)		1/20 (5%)
Waist circumference increased	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Metabolism and nutrition disorders
Dehydration	0/87 (0%)		2/86 (2.3%)		0/41 (0%)		0/20 (0%)
Hyperglycaemia	0/87 (0%)		0/86 (0%)		1/41 (2.4%)		0/20 (0%)
Hypokalaemia	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Glucose tolerance impaired	0/87 (0%)		0/86 (0%)		0/41 (0%)		1/20 (5%)
Musculoskeletal and connective tissue disorders
Back pain	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Fistula	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		1/20 (5%)
Malignant ascites	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Metastases to central nervous system	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Nervous system disorders
Cerebrovascular accident	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Encephalopathy	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Ischaemic stroke	0/87 (0%)		0/86 (0%)		1/41 (2.4%)		0/20 (0%)
Spinal cord compression	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Syncope	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Psychiatric disorders
Confusional state	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Renal and urinary disorders
Acute kidney injury	1/87 (1.1%)		1/86 (1.2%)		1/41 (2.4%)		0/20 (0%)
Haematuria	1/87 (1.1%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Urinary tract obstruction	1/87 (1.1%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Hydronephrosis	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Renal failure	0/87 (0%)		0/86 (0%)		1/41 (2.4%)		0/20 (0%)
Reproductive system and breast disorders
Vaginal haemorrhage	0/87 (0%)		2/86 (2.3%)		0/41 (0%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/87 (0%)		3/86 (3.5%)		0/41 (0%)		0/20 (0%)
Dyspnoea	0/87 (0%)		3/86 (3.5%)		0/41 (0%)		0/20 (0%)
Pneumonitis	0/87 (0%)		3/86 (3.5%)		0/41 (0%)		0/20 (0%)
Respiratory failure	0/87 (0%)		2/86 (2.3%)		0/41 (0%)		0/20 (0%)
Acute respiratory failure	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Dyspnoea exertional	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Hypoxia	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Pleural effusion	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Skin and subcutaneous tissue disorders
Rash	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Vascular disorders
Hypotension	1/87 (1.1%)		0/86 (0%)		0/41 (0%)		0/20 (0%)
Lymphoedema	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Embolism	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Paclitaxel 80 mg/m^2		Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg		Sapanisertib 30 mg		Sapanisertib 4 mg + MLN1117 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/87 (97.7%)		86/86 (100%)		41/41 (100%)		20/20 (100%)
Blood and lymphatic system disorders
Anaemia	32/87 (36.8%)		48/86 (55.8%)		5/41 (12.2%)		6/20 (30%)
Neutropenia	10/87 (11.5%)		19/86 (22.1%)		1/41 (2.4%)		1/20 (5%)
Leukopenia	8/87 (9.2%)		12/86 (14%)		0/41 (0%)		1/20 (5%)
Cardiac disorders
Tachycardia	1/87 (1.1%)		6/86 (7%)		3/41 (7.3%)		0/20 (0%)
Ear and labyrinth disorders
Vertigo	2/87 (2.3%)		4/86 (4.7%)		0/41 (0%)		2/20 (10%)
Gastrointestinal disorders
Nausea	29/87 (33.3%)		53/86 (61.6%)		30/41 (73.2%)		16/20 (80%)
Diarrhoea	31/87 (35.6%)		48/86 (55.8%)		15/41 (36.6%)		13/20 (65%)
Vomiting	20/87 (23%)		24/86 (27.9%)		31/41 (75.6%)		15/20 (75%)
Constipation	25/87 (28.7%)		20/86 (23.3%)		14/41 (34.1%)		5/20 (25%)
Abdominal pain	13/87 (14.9%)		22/86 (25.6%)		6/41 (14.6%)		4/20 (20%)
Stomatitis	4/87 (4.6%)		22/86 (25.6%)		10/41 (24.4%)		2/20 (10%)
Abdominal pain upper	6/87 (6.9%)		13/86 (15.1%)		4/41 (9.8%)		4/20 (20%)
Dyspepsia	5/87 (5.7%)		13/86 (15.1%)		3/41 (7.3%)		1/20 (5%)
Gastrooesophageal reflux disease	4/87 (4.6%)		10/86 (11.6%)		3/41 (7.3%)		3/20 (15%)
Dry mouth	2/87 (2.3%)		8/86 (9.3%)		2/41 (4.9%)		2/20 (10%)
Abdominal distension	5/87 (5.7%)		6/86 (7%)		1/41 (2.4%)		0/20 (0%)
Abdominal pain lower	4/87 (4.6%)		3/86 (3.5%)		0/41 (0%)		3/20 (15%)
Haemorrhoids	5/87 (5.7%)		2/86 (2.3%)		1/41 (2.4%)		0/20 (0%)
General disorders
Fatigue	39/87 (44.8%)		40/86 (46.5%)		18/41 (43.9%)		7/20 (35%)
Asthenia	7/87 (8%)		26/86 (30.2%)		9/41 (22%)		10/20 (50%)
Pyrexia	12/87 (13.8%)		13/86 (15.1%)		5/41 (12.2%)		4/20 (20%)
Oedema peripheral	18/87 (20.7%)		10/86 (11.6%)		2/41 (4.9%)		1/20 (5%)
Peripheral swelling	5/87 (5.7%)		5/86 (5.8%)		0/41 (0%)		2/20 (10%)
Chills	1/87 (1.1%)		5/86 (5.8%)		0/41 (0%)		1/20 (5%)
Infections and infestations
Urinary tract infection	9/87 (10.3%)		19/86 (22.1%)		6/41 (14.6%)		3/20 (15%)
Upper respiratory tract infection	7/87 (8%)		6/86 (7%)		1/41 (2.4%)		0/20 (0%)
Nasopharyngitis	2/87 (2.3%)		5/86 (5.8%)		2/41 (4.9%)		0/20 (0%)
Sinusitis	5/87 (5.7%)		3/86 (3.5%)		0/41 (0%)		0/20 (0%)
Investigations
Weight decreased	2/87 (2.3%)		17/86 (19.8%)		7/41 (17.1%)		3/20 (15%)
Gamma-glutamyltransferase increased	6/87 (6.9%)		9/86 (10.5%)		5/41 (12.2%)		0/20 (0%)
Alanine aminotransferase increased	5/87 (5.7%)		7/86 (8.1%)		1/41 (2.4%)		6/20 (30%)
Aspartate aminotransferase increased	3/87 (3.4%)		7/86 (8.1%)		2/41 (4.9%)		6/20 (30%)
Neutrophil count decreased	8/87 (9.2%)		9/86 (10.5%)		0/41 (0%)		0/20 (0%)
Blood creatinine increased	3/87 (3.4%)		6/86 (7%)		3/41 (7.3%)		4/20 (20%)
White blood cell count decreased	5/87 (5.7%)		9/86 (10.5%)		1/41 (2.4%)		0/20 (0%)
Blood alkaline phosphatase increased	4/87 (4.6%)		5/86 (5.8%)		4/41 (9.8%)		0/20 (0%)
Platelet count decreased	2/87 (2.3%)		2/86 (2.3%)		1/41 (2.4%)		2/20 (10%)
Protein total decreased	1/87 (1.1%)		1/86 (1.2%)		3/41 (7.3%)		1/20 (5%)
Blood glucose increased	0/87 (0%)		0/86 (0%)		0/41 (0%)		2/20 (10%)
Metabolism and nutrition disorders
Decreased appetite	16/87 (18.4%)		33/86 (38.4%)		20/41 (48.8%)		8/20 (40%)
Hyperglycaemia	8/87 (9.2%)		17/86 (19.8%)		15/41 (36.6%)		5/20 (25%)
Hypomagnesaemia	11/87 (12.6%)		19/86 (22.1%)		7/41 (17.1%)		1/20 (5%)
Hypokalaemia	6/87 (6.9%)		11/86 (12.8%)		3/41 (7.3%)		0/20 (0%)
Dehydration	1/87 (1.1%)		8/86 (9.3%)		6/41 (14.6%)		2/20 (10%)
Hypophosphataemia	2/87 (2.3%)		12/86 (14%)		2/41 (4.9%)		1/20 (5%)
Hypoalbuminaemia	3/87 (3.4%)		8/86 (9.3%)		4/41 (9.8%)		1/20 (5%)
Hyponatraemia	3/87 (3.4%)		6/86 (7%)		4/41 (9.8%)		2/20 (10%)
Hypocalcaemia	2/87 (2.3%)		6/86 (7%)		1/41 (2.4%)		2/20 (10%)
Musculoskeletal and connective tissue disorders
Arthralgia	11/87 (12.6%)		22/86 (25.6%)		0/41 (0%)		0/20 (0%)
Back pain	14/87 (16.1%)		11/86 (12.8%)		3/41 (7.3%)		3/20 (15%)
Pain in extremity	7/87 (8%)		16/86 (18.6%)		1/41 (2.4%)		1/20 (5%)
Myalgia	12/87 (13.8%)		10/86 (11.6%)		1/41 (2.4%)		1/20 (5%)
Muscular weakness	4/87 (4.6%)		9/86 (10.5%)		0/41 (0%)		1/20 (5%)
Groin pain	0/87 (0%)		1/86 (1.2%)		0/41 (0%)		2/20 (10%)
Nervous system disorders
Neuropathy peripheral	12/87 (13.8%)		22/86 (25.6%)		3/41 (7.3%)		0/20 (0%)
Dysgeusia	10/87 (11.5%)		15/86 (17.4%)		6/41 (14.6%)		2/20 (10%)
Headache	4/87 (4.6%)		13/86 (15.1%)		6/41 (14.6%)		1/20 (5%)
Dizziness	3/87 (3.4%)		14/86 (16.3%)		3/41 (7.3%)		2/20 (10%)
Paraesthesia	6/87 (6.9%)		9/86 (10.5%)		1/41 (2.4%)		1/20 (5%)
Peripheral sensory neuropathy	7/87 (8%)		8/86 (9.3%)		0/41 (0%)		0/20 (0%)
Tremor	2/87 (2.3%)		5/86 (5.8%)		3/41 (7.3%)		1/20 (5%)
Taste disorder	2/87 (2.3%)		6/86 (7%)		2/41 (4.9%)		0/20 (0%)
Psychiatric disorders
Insomnia	6/87 (6.9%)		17/86 (19.8%)		1/41 (2.4%)		1/20 (5%)
Anxiety	3/87 (3.4%)		7/86 (8.1%)		3/41 (7.3%)		1/20 (5%)
Depression	3/87 (3.4%)		3/86 (3.5%)		5/41 (12.2%)		0/20 (0%)
Renal and urinary disorders
Haematuria	7/87 (8%)		8/86 (9.3%)		0/41 (0%)		0/20 (0%)
Dysuria	5/87 (5.7%)		6/86 (7%)		0/41 (0%)		1/20 (5%)
Proteinuria	1/87 (1.1%)		5/86 (5.8%)		0/41 (0%)		0/20 (0%)
Reproductive system and breast disorders
Vaginal haemorrhage	6/87 (6.9%)		4/86 (4.7%)		0/41 (0%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	18/87 (20.7%)		25/86 (29.1%)		6/41 (14.6%)		3/20 (15%)
Cough	21/87 (24.1%)		19/86 (22.1%)		8/41 (19.5%)		1/20 (5%)
Epistaxis	6/87 (6.9%)		11/86 (12.8%)		1/41 (2.4%)		0/20 (0%)
Pulmonary embolism	3/87 (3.4%)		9/86 (10.5%)		3/41 (7.3%)		0/20 (0%)
Oropharyngeal pain	3/87 (3.4%)		4/86 (4.7%)		3/41 (7.3%)		0/20 (0%)
Skin and subcutaneous tissue disorders
Alopecia	31/87 (35.6%)		27/86 (31.4%)		1/41 (2.4%)		0/20 (0%)
Rash	5/87 (5.7%)		17/86 (19.8%)		4/41 (9.8%)		0/20 (0%)
Pruritus	3/87 (3.4%)		11/86 (12.8%)		6/41 (14.6%)		1/20 (5%)
Dry skin	6/87 (6.9%)		8/86 (9.3%)		0/41 (0%)		1/20 (5%)
Rash maculo-papular	5/87 (5.7%)		2/86 (2.3%)		1/41 (2.4%)		0/20 (0%)
Vascular disorders
Hypertension	9/87 (10.3%)		5/86 (5.8%)		2/41 (4.9%)		1/20 (5%)
Deep vein thrombosis	3/87 (3.4%)		5/86 (5.8%)		0/41 (0%)		1/20 (5%)
Hypotension	2/87 (2.3%)		6/86 (7%)		0/41 (0%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.