Sapanisertib in Combination With Fulvestrant in Women With Advanced or Metastatic Breast Cancer After Aromatase Inhibitor Therapy

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02756364
• Collaborator: (none)
• Enrollment: 141
• Locations: 53
• Arms: 3
• Actual Duration (Months): 39.9
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary purpose of this study is to compare the progression free survival (PFS) of participants treated with the combination of fulvestrant plus daily sapanisertib and fulvestrant plus weekly sapanisertib versus participants treated with single-agent fulvestrant.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: Fulvestrant; Drug: Sapanisertib	Phase 2

Detailed Description

The drug being tested in this study is called sapanisertib. Sapanisertib is being tested to treat postmenopausal women with advanced or metastatic estrogen receptor (ER) positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer that has progressed during or after aromatase inhibitor (AI) therapy. This study will evaluate the efficacy and safety of combination of fulvestrant + daily sapanisertib and fulvestrant + weekly sapanisertib compared with fulvestrant alone.

The study will enroll approximately 153 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

• Fulvestrant 500 mg

• Fulvestrant 500 mg + Sapanisertib 4 mg

• Fulvestrant 500 mg + Sapanisertib 30 mg

All participants will receive either fulvestrant 500 mg intramuscularly (IM), fulvestrant 500 mg + sapanisertib 4 mg daily or fulvestrant 500 mg + sapanisertib 30 mg weekly.

This multicenter trial will be conducted Spain and the USA. Participants will make multiple visits to the clinic, and end of treatment (EOT) visit 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 progression free survival (PFS) and overall survival (OS).

Study Design

• Study Type: Interventional
• Actual Enrollment: 141 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Phase 2 Study of MLN0128 (A TORC1/2 Inhibitor) in Combination With Fulvestrant in Women With ER-Positive/HER2-Negative Advanced or Metastatic Breast Cancer That Has Progressed During or After Aromatase Inhibitor Therapy
• Actual Study Start Date: Jul 28, 2016
• Actual Primary Completion Date: Nov 25, 2019
• Actual Study Completion Date: Nov 25, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Fulvestrant 500 mg Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).	Drug: Fulvestrant; Fulvestrant IM injection.
Experimental: Fulvestrant 500 mg + Sapanisertib 4 mg Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).	Drug: Fulvestrant; Fulvestrant IM injection.; Drug: Sapanisertib; Sapanisertib capsule.; Other Names: MLN0128
Experimental: Fulvestrant 500 mg + Sapanisertib 30 mg Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).	Drug: Fulvestrant; Fulvestrant IM injection.; Drug: Sapanisertib; Sapanisertib capsule.; Other Names: MLN0128

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [Up to 40 months]

   PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Evaluation Criteria in Solid Tumors (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. Overall Survival (OS) [Up to 164 weeks]

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

2. Time to Progression (TTP) [Up to 40 months]

   TTP was defined as the time from the date of randomization to the date of first documentation of progression. Per RECIST v1.1, PD was defined as at least a 20% increase in the sum of the 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.

3. Objective Response Rate (ORR) [Up to 40 months]

   ORR was defined as the percentage of participants who achieve a best response of complete response (CR) or partial response (PR) according to RECIST v1.1 criteria. 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.

4. Clinical Benefit Rate (CBR) [Up to 40 months]

   CBR was defined as the percentage of participants who achieved a best response of CR, PR, or stable disease (SD) of any duration. 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.

5. Percentage of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE) [Up to 164 weeks]

   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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Female participants aged 18 years or older who are postmenopausal.

2. Histologically proven diagnosis of breast cancer with evidence of metastatic disease or locoregional recurrence.

3. Histological confirmation and documentation of estrogen receptor (ER)-positive status (≥1% positive stained cells).

4. Histological or cytological confirmation and documentation of human epidermal growth factor receptor-2 (HER2)-negative status by local laboratory testing using criteria in the American Society of Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline update.

5. Measurable disease defined as either of the following:

• At least 1 extra-osseous lesion that could be accurately measured in at least 1 dimension.

• The lesion must have measured ≥20 mm with conventional imaging techniques or ≥10 mm with spiral CT or MRI. Lymph nodes must be ≥1.5 cm in the short axis to be considered measurable.

• Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable disease as defined above. Note: Participants with sclerotic/osteoblastic bone lesions only, in the absence of measurable disease, were not eligible.

1. Progressive Disease (PD) during prior aromatase inhibitor (AI) therapy.

2. Have a history of brain metastasis provided that all of the following criteria are met:

• Brain metastases have been treated.

• No evidence of PD for ≥3 months before the first dose of study drug.

• No hemorrhage after treatment.

• Off dexamethasone treatment for ≥4 weeks before the first dose of study drug.

• No ongoing requirement for dexamethasone or anti-epileptic drugs.

1. Eastern cooperative oncology group (ECOG) performance status of 0 or 1.

2. 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) ≥1.510^9/L; platelet count ≥10010^9/L; hemoglobin (Hgb) ≥9 g/dL.

• Total bilirubin ≤1.5the upper limit of the normal range (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5ULN (≤5*ULN if liver metastases are present).

• Creatinine clearance ≥40 mL/min based on Cockcroft-Gault estimate or based on a 12- or 24-hour urine collection.

• Fasting serum glucose ≤130 mg/dL and fasting triglycerides ≤300 mg/dL.

Exclusion Criteria:

1. Prior therapy with mechanistic target of rapamycin (mTOR), phosphoinositide-3-kinase (PI3K), or dual PI3K-mTOR inhibitors, serine/threonine-specific protein kinase (AKT) inhibitors, or fulvestrant.

2. Prior treatment with >1 line of chemotherapy for metastatic breast cancer or for locoregional recurrence that was not amenable to resection or radiation therapy with curative intent.

3. Experienced PD on >2 endocrine therapies for metastatic breast cancer or for locoregional recurrence that was not amenable to resection or radiation therapy with curative intent.

4. Life-threatening metastatic visceral disease (defined as extensive hepatic involvement or symptomatic pulmonary lymphangitic spread).

5. Poorly controlled diabetes mellitus defined as hemoglobin A1c (glycosylated hemoglobin; HbA1c) >7%; participants with a history of transient glucose intolerance due to corticosteroid administration may be eligible if all other inclusion/exclusion criteria are met.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Southern Cancer Center, PC	Mobile	Alabama	United States	36608
2	CBCC Global Research 6501 Truxtun Avenue Bakersfield, CA	Bakersfield	California	United States	93309
3	St. Jude Hospital Yorba Linda DBA St. Joseph Heritage Healthcare	Fullerton	California	United States	92835
4	UCSD Moores Cancer Center	La Jolla	California	United States	92037
5	UCLA Hematology/Oncology David Geffen School of Medicine	Los Angeles	California	United States	90095-7077
6	North County Oncology	Oceanside	California	United States	92056
7	Torrance Health Association	Redondo Beach	California	United States	90277
8	PHC-SLO Oncology and Hematology	San Luis Obispo	California	United States	93401
9	Cancer Center of Santa Barbara With Sansum Clinic	Santa Barbara	California	United States	93105
10	University of Colorado Cancer Center-Anschutz Cancer Pavilion (ACP)	Aurora	Colorado	United States	80045
11	St. Mary'S Hospital Regional Cancer Center	Grand Junction	Colorado	United States	81501
12	Rocky mountain cancer centers LLP	Lakewood	Colorado	United States	80228
13	Holy Cross Hospital- Bienes Cancer Center	Fort Lauderdale	Florida	United States	33308
14	Memorial Healthcare System	Hollywood	Florida	United States	33021
15	Orlando Health Inc.	Orlando	Florida	United States	33806
16	Ft. Wayne Medical Oncology and Hematology, Inc	Fort Wayne	Indiana	United States	46804
17	New England Cancer Specialists	Scarborough	Maine	United States	04074
18	Health Partners Institute Park Nicollet Frauenshuh Cancer Center	Saint Louis Park	Minnesota	United States	55426
19	Comprehensive Cancer Centers of Nevada	Henderson	Nevada	United States	89074
20	New Jersey Hematology & Oncology Associates	Brick	New Jersey	United States	8724
21	Northern Westchester Hospital Cancer Treatment & Wellness Center	Mount Kisco	New York	United States	10549
22	Oregon Health and Science University	Portland	Oregon	United States	97239
23	Texas Oncology, P.A.	Austin	Texas	United States	78745
24	Texas Oncology - Presbyterian Hospital	Dallas	Texas	United States	75231
25	Texas Oncology, P.A.	Dallas	Texas	United States	75246
26	Texas Oncology- South Second Street	McAllen	Texas	United States	78503
27	Cancer Care Centers of South Texas	San Antonio	Texas	United States	78217
28	Texas Oncology,PA. Tyler TX, 75702	Tyler	Texas	United States	75702
29	Virginia Cancer Specialist PC	Leesburg	Virginia	United States	20176
30	West Virginia University School of Medicine	Morgantown	West Virginia	United States	26505
31	Consorci Sanitari de Terrassa	Terrassa	Barcelona	Spain	08827
32	Onkologikoa	San Sebastian	Guipuzcoa	Spain	20014
33	Hospital Universitari Son Espases	Palma de Mallorca	Islas Baleares	Spain	07120
34	Hospital Son Llatzer	Palma de Mallorca	Islas Baleares	Spain	07198
35	Hospital Universitario Puerta del Hierro	Majadahonda	Madrid	Spain	28220
36	Clinica Universidad de Navarra	Pamplona	Navarra	Spain	31008
37	Hospital Universitario Sant Joan de Reus	Reus	Tarragona	Spain	43204
38	Complejo Hospitalario Universitario A Coruna	A Coruna		Spain	15006
39	Centro Oncologico de Galicia	A Coruna		Spain	15009
40	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
41	Hospital Clinic i Provincial	Barcelona		Spain	08036
42	Hospital De la Santa Creu i Sant Pau	Barcelona		Spain	08041
43	Hospital San Pedro de Alcantara	Caceres		Spain	10003
44	Hospital Universitari Arnau de Vilanova de Lleida	Lleida		Spain	25198
45	Hospital General Universitario Gregorio Maranon	Madrid		Spain	28009
46	Hospital Universitario Ramon y Cajal	Madrid		Spain	28034
47	Hospital Clinico San Carlos	Madrid		Spain	28040
48	Hospital General Universitario Morales Messeguer	Murcia		Spain	30008
49	Hospital Clinico Universitario Virgen de la Arrixaca	Murcia		Spain	30120
50	Hospital Universitario Virgen de la Macarena	Sevilla		Spain	41009
51	Fundacion Instituto Valenciano de Oncologia	Valencia		Spain	46009
52	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
53	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Oct 2, 2017
• Statistical Analysis Plan - Dec 4, 2018

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02756364
• Other Study ID Numbers: C31006; 2015-003612-20; U1111-1174-2165
• First Posted: Apr 29, 2016
• Last Update Posted: Dec 19, 2020
• Last Verified: Nov 1, 2020

• 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: Breast Neoplasms; Fulvestrant

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 50 investigative sites in Spain and the United States from 28 July 2016 to 25 November 2019. After all data was collected and participants were transitioned to post-trial access, the Sponsor stopped the study site, defined as 'Site terminated by the Sponsor'.
Pre-assignment Detail	Female participants with a diagnosis of estrogen receptor (ER)-positive/human epidermal growth factor receptor-2 (HER2)-negative advanced or metastatic breast cancer that has progressed during or after aromatase inhibitor therapy were enrolled in 1:1:1 ratio to receive fulvestrant, fulvestrant + sapanisertib QD and fulvestrant + sapanisertib QW.

Arm/Group Title	Arm A: Fulvestrant 500 mg	Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD	Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
Arm/Group Description	Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
Period Title: Overall Study
STARTED	46	47	48
Treated Participants	46	47	47
COMPLETED	0	0	0
NOT COMPLETED	46	47	48

Baseline Characteristics

Arm/Group Title	Arm A: Fulvestrant 500 mg	Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD	Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW	Total
Arm/Group Description	Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).	Total of all reporting groups
Overall Participants	46	47	48	141
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.3 (10.10)	60.3 (10.92)	57.9 (12.04)	59.5 (11.05)
Sex: Female, Male (Count of Participants)
Female	46 100%	47 100%	48 100%	141 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 10.9%	4 8.5%	7 14.6%	16 11.3%
Not Hispanic or Latino	37 80.4%	41 87.2%	40 83.3%	118 83.7%
Unknown or Not Reported	4 8.7%	2 4.3%	1 2.1%	7 5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 2.2%	0 0%	1 2.1%	2 1.4%
White	44 95.7%	45 95.7%	44 91.7%	133 94.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 2.2%	2 4.3%	3 6.3%	6 4.3%
Region of Enrollment (Count of Participants)
Spain	23 50%	34 72.3%	33 68.8%	90 63.8%
United States	23 50%	13 27.7%	15 31.3%	51 36.2%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Evaluation Criteria in Solid Tumors (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 40 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants.

Arm/Group Title	Arm A: Fulvestrant 500 mg	Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD	Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
Arm/Group Description	Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
Measure Participants	46	47	48
Median (95% Confidence Interval) [months]	3.5	7.2	5.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Fulvestrant 500 mg, Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.537
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.47 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR obtained by stratified Cox proportional hazard model with treatment arm, original interactive response technology (IRT) stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Fulvestrant 500 mg, Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.849
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR obtained by stratified Cox proportional hazard model with treatment arm, original IRT stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from the date of randomization to the date of death.
Time Frame	Up to 164 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants.

Arm/Group Title	Arm A: Fulvestrant 500 mg	Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD	Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
Arm/Group Description	Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
Measure Participants	46	47	48
Median (95% Confidence Interval) [months]	30.5	NA	34.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Fulvestrant 500 mg, Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.276
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.36 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR obtained by stratified Cox proportional hazard model with treatment arm, original IRT stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Fulvestrant 500 mg, Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.470
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.47 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR obtained by stratified Cox proportional hazard model with treatment arm, original IRT stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.

3. Secondary Outcome

Title	Time to Progression (TTP)
Description	TTP was defined as the time from the date of randomization to the date of first documentation of progression. Per RECIST v1.1, PD was defined as at least a 20% increase in the sum of the 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 40 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants.

Arm/Group Title	Arm A: Fulvestrant 500 mg	Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD	Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
Arm/Group Description	Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
Measure Participants	46	47	48
Median (95% Confidence Interval) [months]	3.5	7.2	5.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Fulvestrant 500 mg, Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.495
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR obtained by stratified Cox proportional hazard model with treatment arm, original IRT stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Fulvestrant 500 mg, Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.646
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR obtained by stratified Cox proportional hazard model with treatment arm, original IRT stratification factors as covariates. A hazard ratio of <1 was considered statistically significant.

4. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	ORR was defined as the percentage of participants who achieve a best response of complete response (CR) or partial response (PR) according to RECIST v1.1 criteria. 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 40 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Arm A: Fulvestrant 500 mg	Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD	Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
Arm/Group Description	Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
Measure Participants	46	47	47
Number [percentage of participants]	10.9 23.7%	21.3 45.3%	12.8 26.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Fulvestrant 500 mg, Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
	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	2.23
	Confidence Interval	(2-Sided) 95%; 0.68 to 7.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio and 95% CIs were obtained using a stratified Cochran-Mantel-Haenszel model with the original IRT stratification factors (visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to CDK4/6 inhibitors).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Fulvestrant 500 mg, Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
	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	1.22
	Confidence Interval	(2-Sided) 95%; 0.34 to 4.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio and 95% CIs were obtained using a stratified Cochran-Mantel-Haenszel model with the original IRT stratification factors (visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to CDK4/6 inhibitors).

5. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	CBR was defined as the percentage of participants who achieved a best response of CR, PR, or stable disease (SD) of any duration. 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.
Time Frame	Up to 40 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Arm A: Fulvestrant 500 mg	Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD	Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
Arm/Group Description	Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
Measure Participants	46	47	47
Number [percentage of participants]	60.9 132.4%	74.5 158.5%	66.0 137.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Fulvestrant 500 mg, Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD
	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	2.56
	Confidence Interval	(2-Sided) 95%; 0.94 to 6.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio and 95% CIs were obtained using a stratified Cochran-Mantel-Haenszel model with the original IRT stratification factors (visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to CDK4/6 inhibitors).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Fulvestrant 500 mg, Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
	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	1.75
	Confidence Interval	(2-Sided) 95%; 0.69 to 4.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio and 95% CIs were obtained using a stratified Cochran-Mantel-Haenszel model with the original IRT stratification factors (visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to CDK4/6 inhibitors).

6. Secondary Outcome

Title	Percentage 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	Up to 164 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Arm A: Fulvestrant 500 mg	Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD	Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
Arm/Group Description	Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).	Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
Measure Participants	46	47	47
Number [percentage of participants]	89.1 193.7%	100.0 212.8%	100.0 208.3%

Adverse Events

Time Frame	Up to 164 weeks
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. All-cause Mortality or data for deaths were collected in FAS population. Adverse events were collected in Safety Analysis Set.
Arm/Group Title	Arm A: Fulvestrant 500 mg		Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD		Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
Arm/Group Description	Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks).		Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively).		Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
All Cause Mortality
	Arm A: Fulvestrant 500 mg		Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD		Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/46 (43.5%)		15/47 (31.9%)		18/48 (37.5%)
Serious Adverse Events
	Arm A: Fulvestrant 500 mg		Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD		Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/46 (17.4%)		13/47 (27.7%)		8/47 (17%)
Cardiac disorders
Angina pectoris	0/46 (0%)		0/47 (0%)		1/47 (2.1%)
Endocrine disorders
Hypercalcaemia of malignancy	0/46 (0%)		0/47 (0%)		1/47 (2.1%)
Gastrointestinal disorders
Vomiting	0/46 (0%)		2/47 (4.3%)		1/47 (2.1%)
Diarrhoea	0/46 (0%)		2/47 (4.3%)		0/47 (0%)
Nausea	0/46 (0%)		0/47 (0%)		1/47 (2.1%)
Stomatitis	0/46 (0%)		1/47 (2.1%)		0/47 (0%)
General disorders
Pyrexia	0/46 (0%)		2/47 (4.3%)		0/47 (0%)
Hepatobiliary disorders
Cholelithiasis	0/46 (0%)		0/47 (0%)		1/47 (2.1%)
Hepatic failure	1/46 (2.2%)		0/47 (0%)		0/47 (0%)
Infections and infestations
Pyelonephritis acute	0/46 (0%)		0/47 (0%)		2/47 (4.3%)
Appendicitis	0/46 (0%)		0/47 (0%)		1/47 (2.1%)
Cellulitis	0/46 (0%)		0/47 (0%)		1/47 (2.1%)
Pneumonia	1/46 (2.2%)		0/47 (0%)		0/47 (0%)
Urinary tract infection	0/46 (0%)		0/47 (0%)		1/47 (2.1%)
Investigations
Alanine aminotransferase increased	0/46 (0%)		1/47 (2.1%)		0/47 (0%)
Aspartate aminotransferase increased	0/46 (0%)		1/47 (2.1%)		0/47 (0%)
Metabolism and nutrition disorders
Diabetic metabolic decompensation	0/46 (0%)		1/47 (2.1%)		0/47 (0%)
Failure to thrive	1/46 (2.2%)		0/47 (0%)		0/47 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/46 (2.2%)		0/47 (0%)		0/47 (0%)
Pain in extremity	1/46 (2.2%)		0/47 (0%)		0/47 (0%)
Nervous system disorders
Encephalopathy	1/46 (2.2%)		0/47 (0%)		0/47 (0%)
Headache	1/46 (2.2%)		0/47 (0%)		0/47 (0%)
Spinal cord compression	1/46 (2.2%)		0/47 (0%)		0/47 (0%)
Psychiatric disorders
Disorientation	1/46 (2.2%)		0/47 (0%)		0/47 (0%)
Renal and urinary disorders
Acute kidney injury	1/46 (2.2%)		0/47 (0%)		0/47 (0%)
Renal failure	0/46 (0%)		1/47 (2.1%)		0/47 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	2/46 (4.3%)		0/47 (0%)		0/47 (0%)
Pneumonitis	0/46 (0%)		2/47 (4.3%)		0/47 (0%)
Respiratory failure	2/46 (4.3%)		0/47 (0%)		0/47 (0%)
Pneumonia aspiration	0/46 (0%)		1/47 (2.1%)		0/47 (0%)
Respiratory arrest	0/46 (0%)		1/47 (2.1%)		0/47 (0%)
Vascular disorders
Peripheral ischaemia	0/46 (0%)		1/47 (2.1%)		0/47 (0%)
Other (Not Including Serious) Adverse Events
	Arm A: Fulvestrant 500 mg		Arm B: Fulvestrant 500 mg + Sapanisertib 4 mg QD		Arm C: Fulvestrant 500 mg + Sapanisertib 30 mg QW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/46 (82.6%)		47/47 (100%)		47/47 (100%)
Blood and lymphatic system disorders
Anaemia	3/46 (6.5%)		3/47 (6.4%)		2/47 (4.3%)
Ear and labyrinth disorders
Tinnitus	0/46 (0%)		3/47 (6.4%)		0/47 (0%)
Gastrointestinal disorders
Nausea	9/46 (19.6%)		23/47 (48.9%)		41/47 (87.2%)
Vomiting	4/46 (8.7%)		14/47 (29.8%)		33/47 (70.2%)
Diarrhoea	1/46 (2.2%)		24/47 (51.1%)		13/47 (27.7%)
Stomatitis	3/46 (6.5%)		16/47 (34%)		15/47 (31.9%)
Constipation	8/46 (17.4%)		4/47 (8.5%)		6/47 (12.8%)
Dry mouth	1/46 (2.2%)		12/47 (25.5%)		3/47 (6.4%)
Abdominal pain upper	1/46 (2.2%)		5/47 (10.6%)		9/47 (19.1%)
Abdominal pain	3/46 (6.5%)		4/47 (8.5%)		4/47 (8.5%)
Dyspepsia	0/46 (0%)		4/47 (8.5%)		3/47 (6.4%)
Gastritis	0/46 (0%)		3/47 (6.4%)		2/47 (4.3%)
Odynophagia	0/46 (0%)		1/47 (2.1%)		3/47 (6.4%)
General disorders
Asthenia	11/46 (23.9%)		13/47 (27.7%)		21/47 (44.7%)
Fatigue	10/46 (21.7%)		17/47 (36.2%)		11/47 (23.4%)
Pyrexia	3/46 (6.5%)		4/47 (8.5%)		4/47 (8.5%)
Injection site pain	5/46 (10.9%)		2/47 (4.3%)		2/47 (4.3%)
Malaise	0/46 (0%)		1/47 (2.1%)		4/47 (8.5%)
Pain	1/46 (2.2%)		3/47 (6.4%)		1/47 (2.1%)
Infections and infestations
Urinary tract infection	2/46 (4.3%)		7/47 (14.9%)		7/47 (14.9%)
Nasopharyngitis	4/46 (8.7%)		5/47 (10.6%)		3/47 (6.4%)
Upper respiratory tract infection	2/46 (4.3%)		5/47 (10.6%)		1/47 (2.1%)
Respiratory tract infection	3/46 (6.5%)		2/47 (4.3%)		1/47 (2.1%)
Investigations
Weight decreased	1/46 (2.2%)		11/47 (23.4%)		6/47 (12.8%)
Aspartate aminotransferase increased	2/46 (4.3%)		6/47 (12.8%)		6/47 (12.8%)
Alanine aminotransferase increased	2/46 (4.3%)		6/47 (12.8%)		4/47 (8.5%)
Gamma-glutamyltransferase increased	1/46 (2.2%)		5/47 (10.6%)		3/47 (6.4%)
Blood cholesterol increased	0/46 (0%)		5/47 (10.6%)		1/47 (2.1%)
Electrocardiogram QT prolonged	1/46 (2.2%)		3/47 (6.4%)		1/47 (2.1%)
Neutrophil count decreased	0/46 (0%)		3/47 (6.4%)		2/47 (4.3%)
Metabolism and nutrition disorders
Hyperglycaemia	10/46 (21.7%)		27/47 (57.4%)		26/47 (55.3%)
Decreased appetite	5/46 (10.9%)		15/47 (31.9%)		19/47 (40.4%)
Dehydration	0/46 (0%)		1/47 (2.1%)		3/47 (6.4%)
Musculoskeletal and connective tissue disorders
Back pain	7/46 (15.2%)		6/47 (12.8%)		2/47 (4.3%)
Pain in extremity	6/46 (13%)		3/47 (6.4%)		4/47 (8.5%)
Arthralgia	5/46 (10.9%)		4/47 (8.5%)		3/47 (6.4%)
Bone pain	4/46 (8.7%)		2/47 (4.3%)		4/47 (8.5%)
Myalgia	0/46 (0%)		2/47 (4.3%)		4/47 (8.5%)
Musculoskeletal chest pain	3/46 (6.5%)		1/47 (2.1%)		1/47 (2.1%)
Musculoskeletal pain	4/46 (8.7%)		0/47 (0%)		1/47 (2.1%)
Flank pain	0/46 (0%)		0/47 (0%)		3/47 (6.4%)
Nervous system disorders
Headache	9/46 (19.6%)		4/47 (8.5%)		10/47 (21.3%)
Dysgeusia	0/46 (0%)		8/47 (17%)		7/47 (14.9%)
Dizziness	1/46 (2.2%)		4/47 (8.5%)		5/47 (10.6%)
Somnolence	0/46 (0%)		4/47 (8.5%)		0/47 (0%)
Tremor	0/46 (0%)		3/47 (6.4%)		1/47 (2.1%)
Psychiatric disorders
Anxiety	5/46 (10.9%)		5/47 (10.6%)		2/47 (4.3%)
Depression	3/46 (6.5%)		4/47 (8.5%)		3/47 (6.4%)
Insomnia	0/46 (0%)		3/47 (6.4%)		4/47 (8.5%)
Renal and urinary disorders
Dysuria	0/46 (0%)		2/47 (4.3%)		3/47 (6.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	7/46 (15.2%)		5/47 (10.6%)		2/47 (4.3%)
Cough	5/46 (10.9%)		7/47 (14.9%)		1/47 (2.1%)
Skin and subcutaneous tissue disorders
Pruritus	0/46 (0%)		15/47 (31.9%)		8/47 (17%)
Rash	0/46 (0%)		14/47 (29.8%)		7/47 (14.9%)
Dry skin	2/46 (4.3%)		3/47 (6.4%)		3/47 (6.4%)
Alopecia	2/46 (4.3%)		2/47 (4.3%)		3/47 (6.4%)
Erythema	0/46 (0%)		3/47 (6.4%)		2/47 (4.3%)
Rash maculo-papular	0/46 (0%)		3/47 (6.4%)		1/47 (2.1%)
Vascular disorders
Hypertension	7/46 (15.2%)		4/47 (8.5%)		5/47 (10.6%)
Hot flush	5/46 (10.9%)		1/47 (2.1%)		1/47 (2.1%)

Limitations/Caveats

[Not Specified]

More Information

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.