Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01923168
• Collaborator: (none)
• Enrollment: 340
• Locations: 87
• Arms: 3
• Actual Duration (Months): 39.9
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of the study was to determine whether treatment with a PI3K inhibitor plus letrozole led to an increase in pathologic clinical response and Objective Response Rate compared to treatment with placebo plus letrozole in patients with Breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: alpelisib; Drug: buparlisib; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 340 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized, Double-blind Placebo Controlled, Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women With Hormone Receptor-positive HER2-negative Breast Cancer
• Actual Study Start Date: Mar 11, 2014
• Actual Primary Completion Date: Jul 7, 2017
• Actual Study Completion Date: Jul 8, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alpelisib + Letrozole Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Drug: alpelisib; BYL719 + Letrozole; Other Names: BYL719
Experimental: Buparlisib + Letrozole Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.	Drug: buparlisib; BKM120 + Letrozole; Other Names: BKM120
Placebo Comparator: Placebo + Letrozole Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.	Drug: Placebo; Placebo (of BYL719 or BKM120) + Letrozole; Other Names: BYL719 Placebo, BKM120 Placebo

Outcome Measures

Primary Outcome Measures

1. Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Mutant Cohort [After 24 weeks of treatment]

   Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.

2. Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Wild-type Cohort [After 24 weeks of treatment]

   Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.

3. Objective Response Rate Per Investigator Assessment According to RECIST 1.1 for Alpelisib vs. Placebo - PIK3CA Mutant Cohort [After 24 weeks of treatment]

   Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1. BOR was assessed per MRI or Ultrasound and defined as per RECIST 1.1 as CR for a disappearance of all non-nodal target lesions (TL)/non-target lesions (NTL) and a reduction in short axis to < 10 mm of any pathological lymph nodes assigned as TL/NTL and no new lesion; as PR if not qualifying for CR but with a decrease from baseline ≥ 30% in the sum of diameter of all TL, no progression of NTL and no new lesion.

4. Objective Response Rate According to RECIST 1.1 Per Investigator Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort [After 24 weeks of treatment]

   Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1. BOR was assessed per MRI or Ultrasound and defined as per RECIST 1.1 as CR for a disappearance of all non-nodal target lesions (TL)/non-target lesions (NTL) and a reduction in short axis to < 10 mm of any pathological lymph nodes assigned as TL/NTL and no new lesion; as PR if not qualifying for CR but with a decrease from baseline ≥ 30% in the sum of diameter of all TL, no progression of NTL and no new lesion.

Secondary Outcome Measures

1. pCR and Objective Response Rate According to RECIST 1.1 Criteria Per Investigator Assessment for Alpelisib vs. Placebo in PIK3CA Mutant Cohort Based on ctDNA [After 24 weeks of treatment]

   pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment

2. pCR and Objective Response Rate According to RECIST 1.1 Criteria Per Investigator Assessment for Alpelisib vs. Placebo in PIK3CA Wild-type Cohort Based on ctDNA [After 24 weeks of treatment]

   pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment

3. Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Mutant Cohort [After 24 weeks of treatment]

   Breast conserving surgery is defined for participants who underwent surgery and did not have a mastectomy. The row "no surgery" provides the number of patients who did not undergo surgery at all for various reasons.

4. Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort [After 24 weeks of treatment]

   Breast conserving surgery is defined as the percentage of participants with no mastectomy following completion of 24 weeks of treatment. Breast conserving surgery is defined for participants who underwent surgery and did not have a mastectomy. The row "no surgery" provides the number of patients who did not undergo surgery at all for various reasons.

5. Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Responders as Per pCR [Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)]

   Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Responders as Per pCR

6. Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Non-responders as Per pCR [Baseline, Cycle 1 Day 15 (each cycle is 28 days ) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)]

   Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Non-responders as Per pCR.

7. Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Responders as Per pCR [Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)]

   Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: responders as per pCR

8. Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Non-responders as Per pCR [Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)]

   Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: non-responders as per pCR

9. Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Mutant Cohort [At the time of surgery (expected after 24 weeks of treatment)]

   Preoperative endocrine prognostic index (PEPI) response as per central assessment for alpelisib vs. placebo - PIK3CA mutant cohort. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of the surgical specimen (Ellis et al, Contemp Clin Trials 2008). The PEPI score ranges from 0 to to 12, and a higher score means a worse outcome. PEPI response is defined as a PEPI score of 0.

10. Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort [At the time of surgery (expected after 24 weeks of treatment)]

    Preoperative endocrine prognostic index (PEPI) response as per central assessment for alpelisib vs. placebo - PIK3CA wild-type cohort. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of the surgical specimen (Ellis et al, Contemp Clin Trials 2008). The PEPI score ranges from 0 to to 12, and a higher score means a worse outcome. PEPI response is defined as a PEPI score of 0.

11. Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1 [0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for alpelisib plasma concentration

12. Alpelisib PK Parameter: Cmax at Cycle 1 Day 1 [Cycle 1 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for alpelisib plasma concentration

13. Alpelisib and PK Parameter: Tmax at Cycle 1 Day 1 [Cycle 1 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for alpelisib plasma concentration

14. Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1 [0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for alpelisib plasma concentration

15. Alpelisib PK Parameter: Cmax at Cycle 4 Day 1 [Cycle 4 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for alpelisib plasma concentration

16. Alpelisib PK Parameter: Tmax at Cycle 4 Day 1 [Cycle 4 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for alpelisib plasma concentration

17. Letrozole and PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1 [0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for Letrozole plasma concentration

18. Letrozole PK Parameter: Cmax at Cycle 1 Day 1 [Cycle 1 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for letrozole plasma concentration

19. Letrozole PK Parameter: Tmax at Cycle 1 Day 1 [Cycle 1 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for letrozole plasma concentration

20. Letrozole PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1 [0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for Letrozole plasma concentration

21. Letrozole PK Parameter: Cmax at Cycle 4 Day 1 [Cycle 4 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for letrozole plasma concentration

22. Letrozole PK Parameter: Tmax at Cycle 4 Day 1 [Cycle 4 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for letrozole plasma concentration

23. Buparlisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1 [0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for Buparlisib plasma concentration

24. Buparlisib PK Parameter: Cmax at Cycle 1 Day 1 [Cycle 1 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for buparlisib plasma concentration

25. Buparlisib PK Parameter: Tmax at Cycle 1 Day 1 [Cycle 1 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for buparlisib plasma concentration

26. Buparlisib PK Parameter: AUClast at Cycle 4 Day 1 [0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for Buparlisib plasma concentration

27. Buparlisb PK Parameter: Cmax at Cycle 4 Day 1 [Cycle 4 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for buparlisib plasma concentration

28. Buparlisib PK Parameter: Tmax at Cycle 4 Day 1 [Cycle 4 Day 1 (each cycle is 28 days)]

    Summary of primary PK parameters for buparlisib plasma concentration

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Patient is an adult, female ≥ 18 years old at the time of informed consent

2. Patient has a histologically and/or cytologically confirmed diagnosis of breast cancer

3. Patient is postmenopausal.

4. Patient has T1c-T3, any N, M0, operable breast cancer

5. Patients must have measurable disease

6. Patient has diagnostic biopsy available for the analysis of PIK3CA mutation and Ki67 level.

7. Patient has estrogen-receptor and/or progesterone positive breast cancer as per local laboratory testing

8. Patient has HER2 negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0 or 1+ as per local laboratory testing

Exclusion Criteria:

1. Patient has locally recurrent or metastatic disease

2. Patient has received any systemic therapy (e.g. chemotherapy, targeted therapy, immunotherapy) or radiotherapy for current breast cancer disease before randomization.

3. Patient with type 1 diabetes mellitus or not adequately controlled type 2 diabetes mellitus

4. History of acute pancreatitis within 1 year of study entry

5. Uncontrolled hypertension

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham/ Kirklin Clinic Univ AL - PI	Birmingham	Alabama	United States	35294-0006
2	Highlands Oncology Group	Fayetteville	Arkansas	United States	72703
3	Los Angeles Hematology/Oncology Medical Group Onc Dept.	Los Angeles	California	United States	90017
4	University of California at Los Angeles UCLA SC	Los Angeles	California	United States	90095
5	University of California San Francisco BYL719A2201 - SC	San Francisco	California	United States	94115
6	Emory University School of Medicine/Winship Cancer Institute SC	Atlanta	Georgia	United States	30322
7	Mercy Medical Center Medical Oncology & Hematology	Baltimore	Maryland	United States	21202
8	Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Johns Hopkins Med. BYL719A2201	Baltimore	Maryland	United States	21231
9	Dana Farber Cancer Institute BYL719A2201	Boston	Massachusetts	United States	02215
10	Mayo Clinic - Rochester BYL719A2201 - SC	Rochester	Minnesota	United States	55905
11	Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
12	Duke University Medical Center Duke University Medical Center	Durham	North Carolina	United States	27710
13	Northwest Cancer Specialists Vancouver Loc	Portland	Oregon	United States	97210
14	Vanderbilt Ingram Cancer Center Vanderbilt Health 100 Oaks	Nashville	Tennessee	United States	37203
15	Texas Oncology, P.A.	Bedford	Texas	United States	76022
16	Presbyterian Hospital of Dallas TexasOncology@PresbyterianHosp	Dallas	Texas	United States	75231
17	Texas Oncology Texas Oncology - Sammons	Dallas	Texas	United States	75246
18	Texas Oncology Houston Memorial City SC	Houston	Texas	United States	77024
19	Cancer Care Centers of South Texas HOAST CCC of So. TX- San Antonio(2)	San Antonio	Texas	United States	78229
20	Cancer Therapy & Research Center UT Health Science Center InstituteForDrugDevelopment(5)	San Antonio	Texas	United States	78229
21	Virginia Oncology Associates SC	Norfolk	Virginia	United States	23502
22	Seattle Cancer Care Alliance SC-3	Seattle	Washington	United States	98105
23	Northwest Medical Specialties Dept.ofNW Med. Specialties	Tacoma	Washington	United States	98405
24	Novartis Investigative Site	Kingswood	New South Wales	Australia	2747
25	Novartis Investigative Site	Innsbruck	Tyrol	Austria	6020
26	Novartis Investigative Site	Dornbirn	Vorarlberg	Austria	6830
27	Novartis Investigative Site	Leoben		Austria	A-8700
28	Novartis Investigative Site	Rankweil		Austria	A-6830
29	Novartis Investigative Site	Salzburg		Austria	5020
30	Novartis Investigative Site	Vienna		Austria	A-1090
31	Novartis Investigative Site	Villach		Austria	9500
32	Novartis Investigative Site	Wien		Austria	A-1090
33	Novartis Investigative Site	Edegem	Antwerpen	Belgium	2650
34	Novartis Investigative Site	Leuven		Belgium	3000
35	Novartis Investigative Site	Sint Niklaas		Belgium	9100
36	Novartis Investigative Site	Goiania	GO	Brazil	74605-070
37	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul	Brazil	90610-000
38	Novartis Investigative Site	Ribeirao Preto	SP	Brazil	14048-900
39	Novartis Investigative Site	Sao Paulo	SP	Brazil	01317-002
40	Novartis Investigative Site	Sao Paulo	SP	Brazil	03102-002
41	Novartis Investigative Site	Shumen		Bulgaria	9700
42	Novartis Investigative Site	Sofia		Bulgaria	1303
43	Novartis Investigative Site	Varna		Bulgaria	9010
44	Novartis Investigative Site	Vancouver	British Columbia	Canada	V5Z 4E6
45	Novartis Investigative Site	Montreal	Quebec	Canada	H2W 1T8
46	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1E2
47	Novartis Investigative Site	Quebec		Canada	G1S 4L8
48	Novartis Investigative Site	Medellin	Antioquia	Colombia
49	Novartis Investigative Site	Bogota		Colombia
50	Novartis Investigative Site	Olomouc	CZE	Czechia	775 20
51	Novartis Investigative Site	Praha		Czechia	12808
52	Novartis Investigative Site	Berlin		Germany	13125
53	Novartis Investigative Site	Erlangen		Germany	91054
54	Novartis Investigative Site	Essen		Germany	45136
55	Novartis Investigative Site	Kiel		Germany	24105
56	Novartis Investigative Site	Koeln		Germany	51067
57	Novartis Investigative Site	Hong Kong SAR		Hong Kong
58	Novartis Investigative Site	Haifa		Israel	3525408
59	Novartis Investigative Site	Ramat Gan		Israel	5265601
60	Novartis Investigative Site	Tel Aviv		Israel	64239
61	Novartis Investigative Site	Brescia	BS	Italy	25127
62	Novartis Investigative Site	Cremona	CR	Italy	26100
63	Novartis Investigative Site	Macerata	MC	Italy	62100
64	Novartis Investigative Site	Milano	MI	Italy	20141
65	Novartis Investigative Site	Napoli		Italy	80131
66	Novartis Investigative Site	Nagoya-city	Aichi	Japan	467-8602
67	Novartis Investigative Site	Hiroshima-city	Hiroshima	Japan	730-8518
68	Novartis Investigative Site	Osaka-city	Osaka	Japan	540-0006
69	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-8677
70	Novartis Investigative Site	Koto-ku	Tokyo	Japan	135 8550
71	Novartis Investigative Site	Niigata		Japan	951-8566
72	Novartis Investigative Site	Ashrafieh		Lebanon	166830
73	Novartis Investigative Site	Beirut		Lebanon
74	Novartis Investigative Site	Saida		Lebanon	652
75	Novartis Investigative Site	Delft		Netherlands	2625 AD
76	Novartis Investigative Site	Den Haag		Netherlands	2545 CH
77	Novartis Investigative Site	Leiden		Netherlands	2300 RC
78	Novartis Investigative Site	Tilburg		Netherlands	5022 GC
79	Novartis Investigative Site	Sevilla	Andalucia	Spain	41017
80	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
81	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya	Spain	08907
82	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46010
83	Novartis Investigative Site	La Coruna	Galicia	Spain	15006
84	Novartis Investigative Site	San Sebastián	Pais Vasco	Spain	20014
85	Novartis Investigative Site	Madrid		Spain	28007
86	Novartis Investigative Site	Madrid		Spain	28040
87	Novartis Investigative Site	Madrid		Spain	28050

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Feb 7, 2017
• Study Protocol - Oct 18, 2016

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01923168
• Other Study ID Numbers: CBYL719A2201; 2013-001862-41
• First Posted: Aug 15, 2013
• Last Update Posted: Sep 14, 2018
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: BYL719; alpelisib; Breast Cancer; BKM120; buparlisib; Pathological Complete Response; neoadjuvant; hormone receptor-positive; HER2 negative; Objective Response Rate
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Recruitment Details	A total of approximately 320 patients were planned to be randomized: this was based on 60 patients per arm in each cohort (PIK3CA mutant and PIK3CA wild-type) for the alpelisib+letrozole and placebo+letrozole arms, plus the estimated number of patients randomized to buparlisib+letrozole arm at the time this arm was discontinued.

Arm/Group Title	Alpelisib + Letrozole	Buparlisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Period Title: Overall Study
STARTED	131	83	126
COMPLETED	94	44	109
NOT COMPLETED	37	39	17

Baseline Characteristics

Arm/Group Title	Alpelisib + Letrozole	Buparlisib + Letrozole	Placebo + Letrozole	Total
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.	Total of all reporting groups
Overall Participants	131	83	126	340
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.3 (8.53)	65.2 (8.61)	63.1 (8.31)	64.1 (8.49)
Sex: Female, Male (Count of Participants)
Female	131 100%	83 100%	126 100%	340 100%
Male	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	117 89.3%	68 81.9%	105 83.3%	290 85.3%
Asian	7 5.3%	4 4.8%	10 7.9%	21 6.2%
Black or African American	3 2.3%	3 3.6%	5 4%	11 3.2%
Other	3 2.3%	6 7.2%	3 2.4%	12 3.5%
Unknown	1 0.8%	2 2.4%	3 2.4%	6 1.8%

Outcome Measures

1. Primary Outcome

Title	Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Mutant Cohort
Description	Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.
Time Frame	After 24 weeks of treatment

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	60	67
Number (80% Confidence Interval) [Percentage of Participants]	1.7 1.3%	3.0 3.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alpelisib + Letrozole, Placebo + Letrozole
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian double criteria
Statistical Test of Hypothesis	p-Value	0.282
	Comments
	Method	Posterior mean diff. & credible interval
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 80%; -4.5 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Wild-type Cohort
Description	Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.
Time Frame	After 24 weeks of treatment

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) for the PIK3CA wild-type cohort comprised all randomized participants who were assigned to the PIK3CA wild-type cohort based on tumor tissue for the randomization.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	71	59
Number (80% Confidence Interval) [Percentage of Participants]	2.8 2.1%	1.7 2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alpelisib + Letrozole, Placebo + Letrozole
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian double criteria
Statistical Test of Hypothesis	p-Value	0.697
	Comments
	Method	Posterior mean difference
	Comments	Posterior mean difference
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 80%; -1.9 to 4.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Objective Response Rate Per Investigator Assessment According to RECIST 1.1 for Alpelisib vs. Placebo - PIK3CA Mutant Cohort
Description	Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1. BOR was assessed per MRI or Ultrasound and defined as per RECIST 1.1 as CR for a disappearance of all non-nodal target lesions (TL)/non-target lesions (NTL) and a reduction in short axis to < 10 mm of any pathological lymph nodes assigned as TL/NTL and no new lesion; as PR if not qualifying for CR but with a decrease from baseline ≥ 30% in the sum of diameter of all TL, no progression of NTL and no new lesion.
Time Frame	After 24 weeks of treatment

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	60	67
Number (80% Confidence Interval) [Percentage of Participants]	43.3 33.1%	44.8 54%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alpelisib + Letrozole, Placebo + Letrozole
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian double criteria
Statistical Test of Hypothesis	p-Value	0.435
	Comments
	Method	Posterior mean diff. & credible interval
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 80%; -12.5 to 9.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Objective Response Rate According to RECIST 1.1 Per Investigator Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort
Description	Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1. BOR was assessed per MRI or Ultrasound and defined as per RECIST 1.1 as CR for a disappearance of all non-nodal target lesions (TL)/non-target lesions (NTL) and a reduction in short axis to < 10 mm of any pathological lymph nodes assigned as TL/NTL and no new lesion; as PR if not qualifying for CR but with a decrease from baseline ≥ 30% in the sum of diameter of all TL, no progression of NTL and no new lesion.
Time Frame	After 24 weeks of treatment

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) for the PIK3CA wild-type cohort comprised all randomized participants who were assigned to the PIK3CA wild-type cohort based on tumor tissue for the randomization.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	71	59
Number (80% Confidence Interval) [Percentage of Participants]	63.4 48.4%	61.0 73.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alpelisib + Letrozole, Placebo + Letrozole
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian double criteria
Statistical Test of Hypothesis	p-Value	0.611
	Comments
	Method	Posterior mean diff. & credible interval
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.4
	Confidence Interval	(2-Sided) 80%; -8.4 to 13.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	pCR and Objective Response Rate According to RECIST 1.1 Criteria Per Investigator Assessment for Alpelisib vs. Placebo in PIK3CA Mutant Cohort Based on ctDNA
Description	pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment
Time Frame	After 24 weeks of treatment

Outcome Measure Data

Analysis Population Description

The FAS comprised all randomized participants. This analysis was to be done in patients with PIK3CA mutation based on Circulating tumor DNA (ctDNA). Data could not be reported as the ctDNA analysis was not done after the primary endpoint was negative.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	0	0

6. Secondary Outcome

Title	pCR and Objective Response Rate According to RECIST 1.1 Criteria Per Investigator Assessment for Alpelisib vs. Placebo in PIK3CA Wild-type Cohort Based on ctDNA
Description	pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment
Time Frame	After 24 weeks of treatment

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised all randomized participants in the study. This analysis was to be done in PIK3CA wild-type patients based on Circulating tumor DNA (ctDNA). Data could not be reported in this table as the ctDNA analysis was not done after the primary endpoint was negative.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	0	0

7. Secondary Outcome

Title	Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Mutant Cohort
Description	Breast conserving surgery is defined for participants who underwent surgery and did not have a mastectomy. The row "no surgery" provides the number of patients who did not undergo surgery at all for various reasons.
Time Frame	After 24 weeks of treatment

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization. PIK3CA mutation is based on tumor tissue.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	60	67
Breast conserving surgery	56.7 43.3%	50.7 61.1%
No Surgery	15.0 11.5%	9.0 10.8%

8. Secondary Outcome

Title	Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort
Description	Breast conserving surgery is defined as the percentage of participants with no mastectomy following completion of 24 weeks of treatment. Breast conserving surgery is defined for participants who underwent surgery and did not have a mastectomy. The row "no surgery" provides the number of patients who did not undergo surgery at all for various reasons.
Time Frame	After 24 weeks of treatment

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) for the PIK3CA wild-type cohort comprised all randomized participants who were assigned to the PIK3CA wild-type cohort based on tumor tissue for the randomization. PIK3CA mutation is based on tumor tissue.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	71	59
Breast conserving surgery	50.7 38.7%	62.7 75.5%
No Surgery	18.3 14%	8.5 10.2%

9. Secondary Outcome

Title	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Responders as Per pCR
Description	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Responders as Per pCR
Time Frame	Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)

Outcome Measure Data

Analysis Population Description

The FAS for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization. Only responders as per pCR were considered for this analysis. No patient had data reported at end of trial (EOT), hence the percent change from baseline at EOT could not be reported.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	1	2
Baseline	5.0	11.0
C1D15: % change from Baseline	-80.0	80.0

10. Secondary Outcome

Title	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Non-responders as Per pCR
Description	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Non-responders as Per pCR.
Time Frame	Baseline, Cycle 1 Day 15 (each cycle is 28 days ) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization. Only non-responders as per pCR are considered for this analysis.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	59	65
Baseline	14.0	13.0
C1D15 % change from Baseline	-62.5	-60.0
EOT % change from Baseline	-51.2	-60.0

11. Secondary Outcome

Title	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Responders as Per pCR
Description	Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: responders as per pCR
Time Frame	Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)

Outcome Measure Data

Analysis Population Description

FAS for PIK3CA wild-type cohort comprised all rand. Parts. assigned to PIK3CA wild-type cohort based on tumor tissue for rand. Only responders as per pCR were considered for this analysis. No patient had data reported at C1D15 & EOT for Placebo, hence percent change from baseline could not be reported.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	2	1
Baseline	16.5	20.0
C1D15: % change from Baseline	-80.0
EOT % change from Baseline	-45.0

12. Secondary Outcome

Title	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Non-responders as Per pCR
Description	Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: non-responders as per pCR
Time Frame	Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) for the PIK3CA wild-type cohort comprised all randomized participants who were assigned to the PIK3CA wild-type cohort based on tumor tissue for the randomization. Only non-responders as per pCR are considered for this analysis.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	69	58
Baseline	16.0	18.0
C1D15 % change from Baseline	-60.0	-52.0
EOT % change from Baseline	-60.0	-71.1

13. Secondary Outcome

Title	Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Mutant Cohort
Description	Preoperative endocrine prognostic index (PEPI) response as per central assessment for alpelisib vs. placebo - PIK3CA mutant cohort. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of the surgical specimen (Ellis et al, Contemp Clin Trials 2008). The PEPI score ranges from 0 to to 12, and a higher score means a worse outcome. PEPI response is defined as a PEPI score of 0.
Time Frame	At the time of surgery (expected after 24 weeks of treatment)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	60	67
Number [Number of participants]	1 0.8%	0 0%

14. Secondary Outcome

Title	Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort
Description	Preoperative endocrine prognostic index (PEPI) response as per central assessment for alpelisib vs. placebo - PIK3CA wild-type cohort. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of the surgical specimen (Ellis et al, Contemp Clin Trials 2008). The PEPI score ranges from 0 to to 12, and a higher score means a worse outcome. PEPI response is defined as a PEPI score of 0.
Time Frame	At the time of surgery (expected after 24 weeks of treatment)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) for the PIK3CA wild-type cohort comprised all randomized participants who were assigned to the PIK3CA wild-type cohort based on tumor tissue for the randomization.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	71	59
Number [Number of participants]	1 0.8%	1 1.2%

15. Secondary Outcome

Title	Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1
Description	Summary of primary PK parameters for alpelisib plasma concentration
Time Frame	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

The BYL FPAS included participants who received at least 1 dose of alpelisib, had at least 1 evaluable post-treatment alpelisib concentration, received adequate doses of alpelisib and letrozole prior to full PK assessment, did not vomit within 4 hours of alpelisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Alpelisib + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
Measure Participants	5
AUC0-24	30800 (20.6)
AUClast	27300 (68.6)

16. Secondary Outcome

Title	Alpelisib PK Parameter: Cmax at Cycle 1 Day 1
Description	Summary of primary PK parameters for alpelisib plasma concentration
Time Frame	Cycle 1 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

The BYL FPAS included participants who received at least 1 dose of alpelisib, had at least 1 evaluable post-treatment alpelisib concentration, received adequate doses of alpelisib and letrozole prior to full PK assessment, did not vomit within 4 hours of alpelisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Alpelisib + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
Measure Participants	5
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	3160 (25.3)

17. Secondary Outcome

Title	Alpelisib and PK Parameter: Tmax at Cycle 1 Day 1
Description	Summary of primary PK parameters for alpelisib plasma concentration
Time Frame	Cycle 1 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

Alpelisib Pharmacokinetic Analysis Set (BYL PAS): The BYL PAS included all participants who received at least one dose of alpelisib and had at least one evaluable post-treatment alpelisib concentration measurement.

Arm/Group Title	Alpelisib + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
Measure Participants	5
Median (Full Range) [HR]	2.93

18. Secondary Outcome

Title	Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1
Description	Summary of primary PK parameters for alpelisib plasma concentration
Time Frame	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

The BYL FPAS included participants who received at least 1 dose of alpelisib, had at least 1 evaluable post-treatment alpelisib concentration, received adequate doses of alpelisib and letrozole prior to full PK assessment, did not vomit within 4 hours of alpelisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Alpelisib + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
Measure Participants	5
AUC0-24	38000 (13.2)
AUClast	38000 (13.1)

19. Secondary Outcome

Title	Alpelisib PK Parameter: Cmax at Cycle 4 Day 1
Description	Summary of primary PK parameters for alpelisib plasma concentration
Time Frame	Cycle 4 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

Alpelisib Pharmacokinetic Analysis Set (BYL PAS): The BYL PAS included all participants who received at least one dose of alpelisib and had at least one evaluable post-treatment alpelisib concentration measurement.

Arm/Group Title	Alpelisib + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
Measure Participants	5
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	3260 (26.7)

20. Secondary Outcome

Title	Alpelisib PK Parameter: Tmax at Cycle 4 Day 1
Description	Summary of primary PK parameters for alpelisib plasma concentration
Time Frame	Cycle 4 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

Alpelisib Pharmacokinetic Analysis Set (BYL PAS): The BYL PAS included all participants who received at least one dose of alpelisib and had at least one evaluable post-treatment alpelisib concentration measurement.

Arm/Group Title	Alpelisib + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
Measure Participants	5
Median (Full Range) [hr]	2.99

21. Secondary Outcome

Title	Letrozole and PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1
Description	Summary of primary PK parameters for Letrozole plasma concentration
Time Frame	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

The LZ FPAS included participants who received at least 1 dose of letrozole, had at least 1 evaluable post-treatment letrozole concentration, received adequate doses of letrozole prior to full PK assessment, did not vomit within 4 hours of letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	5	15
AUC0-24	433 (36.3)	427 (28.8)
AUClast	314 (96.9)	347 (49.6)

22. Secondary Outcome

Title	Letrozole PK Parameter: Cmax at Cycle 1 Day 1
Description	Summary of primary PK parameters for letrozole plasma concentration
Time Frame	Cycle 1 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

The LZ FPAS included participants who received at least 1 dose of letrozole, had at least 1 evaluable post-treatment letrozole concentration, received adequate doses of letrozole prior to full PK assessment, did not vomit within 4 hours of letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	5	15
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	30.2 (33.2)	28 (42.3)

23. Secondary Outcome

Title	Letrozole PK Parameter: Tmax at Cycle 1 Day 1
Description	Summary of primary PK parameters for letrozole plasma concentration
Time Frame	Cycle 1 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

The LZ FPAS included participants who received at least 1 dose of letrozole, had at least 1 evaluable post-treatment letrozole concentration, received adequate doses of letrozole prior to full PK assessment, did not vomit within 4 hours of letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	5	15
Median (Full Range) [hr]	1.03	2.25

24. Secondary Outcome

Title	Letrozole PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1
Description	Summary of primary PK parameters for Letrozole plasma concentration
Time Frame	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

Letrozole Pharmacokinetic Analysis Set (LZ PAS): The LZ PAS included all participants who received at least one dose of letrozole and had at least one evaluable post-treatment letrozole concentration measurement.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	5	15
AUC0-24	1280 (18)	1810 (33.1)
AUClast	1280 (17.9)	1440 (66.7)

25. Secondary Outcome

Title	Letrozole PK Parameter: Cmax at Cycle 4 Day 1
Description	Summary of primary PK parameters for letrozole plasma concentration
Time Frame	Cycle 4 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

The LZ FPAS included participants who received at least 1 dose of letrozole, had at least 1 evaluable post-treatment letrozole concentration, received adequate doses of letrozole prior to full PK assessment, did not vomit within 4 hours of letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	5	15
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	75.6 (6.84)	103 (30)

26. Secondary Outcome

Title	Letrozole PK Parameter: Tmax at Cycle 4 Day 1
Description	Summary of primary PK parameters for letrozole plasma concentration
Time Frame	Cycle 4 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

The LZ FPAS included participants who received at least 1 dose of letrozole, had at least 1 evaluable post-treatment letrozole concentration, received adequate doses of letrozole prior to full PK assessment, did not vomit within 4 hours of letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Alpelisib + Letrozole	Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.	Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Measure Participants	5	15
Median (Full Range) [hr]	2	1.17

27. Secondary Outcome

Title	Buparlisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1
Description	Summary of primary PK parameters for Buparlisib plasma concentration
Time Frame	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

The BKM FPAS included participants who received at least 1 dose of buparlisib, had at least 1 evaluable post-treatment concentration, received adequate doses of buparlisib and letrozole prior to full PK assessment, did not vomit within 4 hours of buparlisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Buparlisib + Letrozole
Arm/Group Description	Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.
Measure Participants	10
AUC0-24	6420 (60)
AUClast	4820 (123)

28. Secondary Outcome

Title	Buparlisib PK Parameter: Cmax at Cycle 1 Day 1
Description	Summary of primary PK parameters for buparlisib plasma concentration
Time Frame	Cycle 1 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

The BKM FPAS included participants who received at least 1 dose of buparlisib, had at least 1 evaluable post-treatment concentration, received adequate doses of buparlisib and letrozole prior to full PK assessment, did not vomit within 4 hours of buparlisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Buparlisib + Letrozole
Arm/Group Description	Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	760 (86.7)

29. Secondary Outcome

Title	Buparlisib PK Parameter: Tmax at Cycle 1 Day 1
Description	Summary of primary PK parameters for buparlisib plasma concentration
Time Frame	Cycle 1 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

Buparlisib Pharmacokinetic Analysis Set (BKM PAS): The BKM PAS included all participants who received at least one dose of buparlisib and had at least one evaluable post-treatment buparlisib concentration measurement.

Arm/Group Title	Buparlisib + Letrozole
Arm/Group Description	Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.
Measure Participants	10
Median (Full Range) [hr]	1.03

30. Secondary Outcome

Title	Buparlisib PK Parameter: AUClast at Cycle 4 Day 1
Description	Summary of primary PK parameters for Buparlisib plasma concentration
Time Frame	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

BKM FPAS: The BKM FPAS included participants who received at least 1 dose of buparlisib, had at least 1 evaluable post-treatment concentration, received adequate doses of buparlisib and letrozole prior to full PK assessment, did not vomit within 4 hours of buparlisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Arm/Group Title	Buparlisib + Letrozole
Arm/Group Description	Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.
Measure Participants	10
Median (Full Range) [ng*hr/mL]	10400

31. Secondary Outcome

Title	Buparlisb PK Parameter: Cmax at Cycle 4 Day 1
Description	Summary of primary PK parameters for buparlisib plasma concentration
Time Frame	Cycle 4 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

Buparlisib Pharmacokinetic Analysis Set (BKM PAS): The BKM PAS included all participants who received at least one dose of buparlisib and had at least one evaluable post-treatment buparlisib concentration measurement.

Arm/Group Title	Buparlisib + Letrozole
Arm/Group Description	Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.
Measure Participants	10
Median (Full Range) [ng/mL]	610

32. Secondary Outcome

Title	Buparlisib PK Parameter: Tmax at Cycle 4 Day 1
Description	Summary of primary PK parameters for buparlisib plasma concentration
Time Frame	Cycle 4 Day 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

Buparlisib Pharmacokinetic Analysis Set (BKM PAS): The BKM PAS included all participants who received at least one dose of buparlisib and had at least one evaluable post-treatment buparlisib concentration measurement.

Arm/Group Title	Buparlisib + Letrozole
Arm/Group Description	Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.
Measure Participants	10
Median (Full Range) [hr]	3

Adverse Events

Time Frame	All Adverse Events reported in this record are on-treatment events (from first dose of study treatment to last dose of study treatment + 30 days, duration expected to be a total of approximately 25 weeks).
Adverse Event Reporting Description	Adverse Events, Serious Adverse Events based on Safety Set population defined as all patients who received at least one dose of study treatment
Arm/Group Title	Alpelisib + Letrozole		Buparlisib + Letrozole		Placebo + Letrozole
Arm/Group Description	Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.		Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.		Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
All Cause Mortality
	Alpelisib + Letrozole		Buparlisib + Letrozole		Placebo + Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/130 (0.8%)		0/81 (0%)		1/125 (0.8%)
Serious Adverse Events
	Alpelisib + Letrozole		Buparlisib + Letrozole		Placebo + Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/130 (16.2%)		22/81 (27.2%)		6/125 (4.8%)
Cardiac disorders
Atrial fibrillation	0/130 (0%)		2/81 (2.5%)		0/125 (0%)
Cardiac disorder	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Cardiac failure	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Stress cardiomyopathy	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Eye disorders
Iritis	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Gastrointestinal disorders
Colitis	1/130 (0.8%)		2/81 (2.5%)		0/125 (0%)
Diarrhoea	1/130 (0.8%)		1/81 (1.2%)		0/125 (0%)
Nausea	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Stomatitis	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Vomiting	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
General disorders
Disease progression	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
General physical health deterioration	2/130 (1.5%)		1/81 (1.2%)		0/125 (0%)
Generalised oedema	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Malaise	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Oedema peripheral	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Pyrexia	2/130 (1.5%)		0/81 (0%)		0/125 (0%)
Sudden death	0/130 (0%)		0/81 (0%)		1/125 (0.8%)
Hepatobiliary disorders
Hepatotoxicity	0/130 (0%)		3/81 (3.7%)		0/125 (0%)
Hypertransaminasaemia	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Immune system disorders
Hypersensitivity	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Infections and infestations
Appendicitis	0/130 (0%)		0/81 (0%)		1/125 (0.8%)
Gastroenteritis	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Respiratory tract infection	1/130 (0.8%)		0/81 (0%)		1/125 (0.8%)
Sepsis	1/130 (0.8%)		1/81 (1.2%)		0/125 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Contusion	0/130 (0%)		0/81 (0%)		1/125 (0.8%)
Post procedural haematoma	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Investigations
Alanine aminotransferase increased	0/130 (0%)		7/81 (8.6%)		0/125 (0%)
Aspartate aminotransferase increased	0/130 (0%)		6/81 (7.4%)		0/125 (0%)
Blood bilirubin increased	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Ejection fraction decreased	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Metabolism and nutrition disorders
Dehydration	2/130 (1.5%)		0/81 (0%)		0/125 (0%)
Hypercalcaemia	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Hyperglycaemia	7/130 (5.4%)		0/81 (0%)		0/125 (0%)
Hyperuricaemia	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Hyponatraemia	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Nervous system disorders
Syncope	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Transient ischaemic attack	0/130 (0%)		0/81 (0%)		1/125 (0.8%)
Renal and urinary disorders
Ureterolithiasis	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/130 (1.5%)		0/81 (0%)		0/125 (0%)
Epistaxis	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Hypoxia	0/130 (0%)		0/81 (0%)		1/125 (0.8%)
Pleural effusion	2/130 (1.5%)		0/81 (0%)		0/125 (0%)
Pulmonary embolism	0/130 (0%)		0/81 (0%)		1/125 (0.8%)
Skin and subcutaneous tissue disorders
Angioedema	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Pruritus	2/130 (1.5%)		0/81 (0%)		0/125 (0%)
Rash	3/130 (2.3%)		2/81 (2.5%)		0/125 (0%)
Rash maculo-papular	2/130 (1.5%)		2/81 (2.5%)		0/125 (0%)
Skin necrosis	0/130 (0%)		1/81 (1.2%)		0/125 (0%)
Vascular disorders
Deep vein thrombosis	1/130 (0.8%)		0/81 (0%)		0/125 (0%)
Other (Not Including Serious) Adverse Events
	Alpelisib + Letrozole		Buparlisib + Letrozole		Placebo + Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	126/130 (96.9%)		80/81 (98.8%)		106/125 (84.8%)
Cardiac disorders
Tachycardia	3/130 (2.3%)		5/81 (6.2%)		1/125 (0.8%)
Ear and labyrinth disorders
Vertigo	5/130 (3.8%)		5/81 (6.2%)		6/125 (4.8%)
Eye disorders
Vision blurred	9/130 (6.9%)		3/81 (3.7%)		0/125 (0%)
Gastrointestinal disorders
Abdominal distension	3/130 (2.3%)		6/81 (7.4%)		4/125 (3.2%)
Abdominal pain	7/130 (5.4%)		5/81 (6.2%)		4/125 (3.2%)
Abdominal pain upper	5/130 (3.8%)		7/81 (8.6%)		4/125 (3.2%)
Constipation	5/130 (3.8%)		7/81 (8.6%)		13/125 (10.4%)
Diarrhoea	66/130 (50.8%)		29/81 (35.8%)		19/125 (15.2%)
Dry mouth	14/130 (10.8%)		5/81 (6.2%)		4/125 (3.2%)
Dyspepsia	11/130 (8.5%)		11/81 (13.6%)		6/125 (4.8%)
Nausea	57/130 (43.8%)		37/81 (45.7%)		23/125 (18.4%)
Stomatitis	42/130 (32.3%)		18/81 (22.2%)		5/125 (4%)
Vomiting	23/130 (17.7%)		6/81 (7.4%)		6/125 (4.8%)
General disorders
Asthenia	21/130 (16.2%)		16/81 (19.8%)		17/125 (13.6%)
Chills	7/130 (5.4%)		8/81 (9.9%)		5/125 (4%)
Fatigue	53/130 (40.8%)		30/81 (37%)		42/125 (33.6%)
Mucosal dryness	7/130 (5.4%)		2/81 (2.5%)		0/125 (0%)
Oedema peripheral	9/130 (6.9%)		4/81 (4.9%)		4/125 (3.2%)
Pyrexia	12/130 (9.2%)		1/81 (1.2%)		3/125 (2.4%)
Infections and infestations
Urinary tract infection	15/130 (11.5%)		7/81 (8.6%)		7/125 (5.6%)
Viral upper respiratory tract infection	5/130 (3.8%)		5/81 (6.2%)		13/125 (10.4%)
Injury, poisoning and procedural complications
Procedural pain	2/130 (1.5%)		5/81 (6.2%)		9/125 (7.2%)
Investigations
Alanine aminotransferase increased	14/130 (10.8%)		49/81 (60.5%)		3/125 (2.4%)
Aspartate aminotransferase increased	11/130 (8.5%)		44/81 (54.3%)		2/125 (1.6%)
Blood bilirubin increased	2/130 (1.5%)		6/81 (7.4%)		1/125 (0.8%)
Blood creatinine increased	12/130 (9.2%)		1/81 (1.2%)		4/125 (3.2%)
Blood glucose increased	12/130 (9.2%)		3/81 (3.7%)		2/125 (1.6%)
Gamma-glutamyltransferase increased	5/130 (3.8%)		6/81 (7.4%)		1/125 (0.8%)
Weight decreased	16/130 (12.3%)		10/81 (12.3%)		3/125 (2.4%)
Metabolism and nutrition disorders
Decreased appetite	40/130 (30.8%)		25/81 (30.9%)		10/125 (8%)
Hyperglycaemia	69/130 (53.1%)		38/81 (46.9%)		8/125 (6.4%)
Hypokalaemia	9/130 (6.9%)		1/81 (1.2%)		0/125 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	11/130 (8.5%)		13/81 (16%)		34/125 (27.2%)
Back pain	1/130 (0.8%)		7/81 (8.6%)		11/125 (8.8%)
Muscle spasms	13/130 (10%)		5/81 (6.2%)		5/125 (4%)
Musculoskeletal pain	2/130 (1.5%)		4/81 (4.9%)		7/125 (5.6%)
Myalgia	6/130 (4.6%)		4/81 (4.9%)		13/125 (10.4%)
Nervous system disorders
Dizziness	7/130 (5.4%)		22/81 (27.2%)		19/125 (15.2%)
Dysgeusia	24/130 (18.5%)		11/81 (13.6%)		7/125 (5.6%)
Headache	26/130 (20%)		10/81 (12.3%)		16/125 (12.8%)
Memory impairment	2/130 (1.5%)		5/81 (6.2%)		2/125 (1.6%)
Paraesthesia	8/130 (6.2%)		2/81 (2.5%)		4/125 (3.2%)
Tremor	0/130 (0%)		8/81 (9.9%)		1/125 (0.8%)
Psychiatric disorders
Anxiety	10/130 (7.7%)		16/81 (19.8%)		10/125 (8%)
Depression	5/130 (3.8%)		12/81 (14.8%)		3/125 (2.4%)
Insomnia	15/130 (11.5%)		8/81 (9.9%)		17/125 (13.6%)
Reproductive system and breast disorders
Breast pain	4/130 (3.1%)		8/81 (9.9%)		10/125 (8%)
Respiratory, thoracic and mediastinal disorders
Cough	9/130 (6.9%)		8/81 (9.9%)		9/125 (7.2%)
Skin and subcutaneous tissue disorders
Alopecia	28/130 (21.5%)		3/81 (3.7%)		7/125 (5.6%)
Dry skin	19/130 (14.6%)		14/81 (17.3%)		4/125 (3.2%)
Pruritus	22/130 (16.9%)		18/81 (22.2%)		9/125 (7.2%)
Rash	58/130 (44.6%)		31/81 (38.3%)		10/125 (8%)
Rash maculo-papular	22/130 (16.9%)		9/81 (11.1%)		3/125 (2.4%)
Vascular disorders
Hot flush	8/130 (6.2%)		12/81 (14.8%)		31/125 (24.8%)
Hypertension	16/130 (12.3%)		10/81 (12.3%)		8/125 (6.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.