A Phase III Study of BKM120 With Fulvestrant in Patients With HR+,HER2-, AI Treated, Locally Advanced or Metastatic Breast Cancer Who Progressed on or After mTORi (BELLE-3)

• ClinicalTrials.gov Identifier: NCT01633060
• Recruitment Status: Terminated
• First Posted: July 4, 2012
• Results First Posted: January 9, 2019
• Last Update Posted: January 30, 2019
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Metastatic Breast Cancer
• Interventions: Drug: Fulvestrant; Drug: BKM120; Drug: BKM120 matching placebo
• Enrollment: 432

Participant Flow

Recruitment Details	This study was conducted at 201 centers in 22 countries worldwide (Argentina, Austria, Belgium, Bulgaria, Canada, Colombia, Finland, France, Germany, Greece, Hungary, Italy, Republic of Korea, Lebanon, The Netherlands, Norway, Poland, Spain, Sweden, Thailand, UK and USA).
Pre-assignment Details	At least 420 patients were planned to be enrolled, randomized in a 2:1 ratio (two buparlisib, one placebo). A total of 432 patients were actually enrolled and analyzed (buparlisib arm: N=289; placebo arm: N=143). Not completed: in Randomization Phase=Randomized and not Treated; in Treatment Phase=Discontinued study treatment per Protocol.

Arm/Group Title	BKM120 100mg + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description	BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
Period Title: Randomization Phase
Started [1]	289 [1]	143 [1]
Completed [2]	288	140
Not Completed	1	3
Reason Not Completed
Protocol deviation	1	2
Technical problem	0	1
[1] All randomized patients; [2] Randomized and treated
Period Title: Treatment Phase
Started [1]	288	140
FAS - ctDNA PIK3CA Mutant [2]	100	35
FAS - ctDNA PIK3CA Non-mutant [3]	132	81
Safety Set (SS) [4]	288	140
Pharmacokinetic Analysis Set (PAS) [5]	63	0
Completed	0	0
Not Completed	288	140
Reason Not Completed
Adverse Event	24	3
Lost to Follow-up	1	0
Physician Decision	16	7
Progressive Disease	210	120
Protocol Deviation	1	0
Study Terminated by sponsor	7	3
Subject/guardian decision	25	4
Death	4	3
[1] All patients in FAS that were treated; [2] All patients in FAS with ctDNA sample and PIK3CA mutation; [3] All patients in FAS with ctDNA sample and no PIK3CA mutation; [4] At least 1 dose of study treatment and a 1 post baseline safety assessment; [5] At least one dose of Buparlisib and had at least 1 evaluable buparlisib concentration measurement
Period Title: Post-Treatment Efficacy Follow-Up Phase
Started [1]	16 [2]	2 [2]
Completed	0	0
Not Completed	16	2
Reason Not Completed
Adverse Event	2	0
Physician Decision	1	0
Progressive Disease	10	1
Study terminated by sponsor	1	0
Subject/Guardian Decision	1	1
Death	1	0
[1] All patients who discontinued treatment and entered Post-Treatment Efficacy Follow-Up Phase; [2] All patients who entered Post-Treatment Efficacy Fup Phase

Baseline Characteristics

Arm/Group Title		BKM120 100mg + Fulvestrant	Placebo + Fulvestrant	Total
Arm/Group Description		BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.	Total of all reporting groups
Overall Number of Baseline Participants		289	143	432
Baseline Analysis Population Description		Full Analysis Set (FAS)
Age, Continuous [1]; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	289 participants	143 participants	432 participants
		60.5 (9.76)	61.5 (9.23)	60.8 (9.59)
		[1] Measure Analysis Population Description: Full Analysis Set (FAS)
Sex: Female, Male [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	289 participants	143 participants	432 participants
	Female	289 100.0%	143 100.0%	432 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
		[1] Measure Analysis Population Description: Full Analysis Set (FAS)
Race (NIH/OMB) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	289 participants	143 participants	432 participants
	American Indian or Alaska Native	4 1.4%	1 0.7%	5 1.2%
	Asian	20 6.9%	9 6.3%	29 6.7%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	4 1.4%	4 2.8%	8 1.9%
	White	249 86.2%	121 84.6%	370 85.6%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	12 4.2%	8 5.6%	20 4.6%
		[1] Measure Analysis Population Description: Full Analysis Set (FAS)

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) Based on Local Investigator Assessment - Full Analysis Set (FAS)
Description	Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm. Patients were followed up for approximately every 6 weeks after randomization.
Time Frame	Every 6 weeks after randomization up to a maximum of 4 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) based on Primary Analysis.

Arm/Group Title	BKM120 100mg + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed	289	143
Median (95% Confidence Interval); Unit of Measure: Months
	3.9; (2.8 to 4.2)	1.8; (1.5 to 2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BKM120 100mg + Fulvestrant, Placebo + Fulvestrant
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Comparison of progression-free survival (PFS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(1-Sided) 95%; 0.53
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Overall Survival (OS) - Full Analysis Set (FAS)
Description	Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive. Patients were followed up approximately every 6 weeks after randomization and every 3 months during survival follow-up.
Time Frame	Every 6 weeks after randomization up to a maximum of 5 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) based on Primary Analysis.

Arm/Group Title	BKM120 100mg + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed	289	143
Median (95% Confidence Interval); Unit of Measure: Months
	21.2; (18.2 to 23.4)	22.1 [1]; (17.3 to NA)

[1]

NA: Not estimable (preliminary OS analyses). Final OS analyses not done due to early study termination (OS data collection stopped early)

3. Secondary Outcome

Title	Progression Free Survival (PFS) by PIK3CA Mutational Status
Description	Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm. Patients were followed up for approximately every 6 weeks after randomization.
Time Frame	Every 6 weeks after randomization up to a maximum of 5 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) -ctDNA PIK3CA mutant, Full Analysis Set (FAS) - ctDNA PIK3CA non-mutant based on Primary Analysis.

Arm/Group Title		BKM120 100mg + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:		BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed		289	143
Median (95% Confidence Interval); Unit of Measure: Months
FAS ctDNA PIK3CA mutant	Number Analyzed	100 participants	35 participants
		4.2; (2.8 to 6.7)	1.6; (1.4 to 2.8)
FAS ctDNA PIK3CA non-mutant	Number Analyzed	132 participants	81 participants
		3.9; (2.8 to 4.3)	2.7; (1.5 to 3.6)

4. Secondary Outcome

Title	Overall Survival (OS) by PIK3CA Mutational Status
Description	Overall Survival (OS) by PIK3CA mutational status based on ctDNA is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive. Patients were followed up approximately every 6 weeks after randomization and every 3 months during survival follow-up.
Time Frame	Every 6 weeks after randomization up to a maximum of 5 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) -ctDNA PIK3CA mutant, Full Analysis Set (FAS) - ctDNA PIK3CA non-mutant based on Primary Analysis.

Arm/Group Title		BKM120 100mg + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:		BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed		289	143
Median (95% Confidence Interval); Unit of Measure: Months
FAS ctDNA PIK3CA mutant	Number Analyzed	100 participants	35 participants
		21.8; (14.7 to 25.8)	NA [1]; (14.5 to NA)
FAS ctDNA PIK3CA non-mutant	Number Analyzed	132 participants	81 participants
		21.4 [1]; (17.3 to NA)	21.4 [1]; (17.3 to NA)

[1]

NA: Not estimable (preliminary OS analyses). Final OS analyses not done due to early study termination (OS data collection stopped early)

5. Secondary Outcome

Title	Overall Response Rate (ORR) by PIK3CA Mutational Status
Description	Overall Response Rate (ORR) is defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1. ORR was analyzed in the full population and by PIK3CA mutational status based on ctDNA. Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target/non target lesions: Complete Response (CR), disappearance of all target/non target lesions (all lymph nodes assigned as non-target lesions must be non-pathological in size (< 10 mm short axis)); Partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions ; Overall Response (OR)= CR+PR. Patients were followed up for the duration of the study and for approximately every 6 weeks after randomization.
Time Frame	Every 6 weeks after randomization up to a maximum of 5 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), Full Analysis Set (FAS) -ctDNA PIK3CA mutant, Full Analysis Set (FAS) - ctDNA PIK3CA non-mutant based on Primary Analysis.

Arm/Group Title		BKM120 100mg + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:		BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed		289	143
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
Full Analysis Set (FAS)	Number Analyzed	289 participants	143 participants
		7.6; (4.8 to 11.3)	2.1; (0.4 to 6.0)
FAS ctDNA PIK3CA mutant	Number Analyzed	100 participants	35 participants
		10.0; (4.9 to 17.6)	0; (0.0 to 10.0)
FAS ctDNA PIK3CA non-mutant	Number Analyzed	132 participants	81 participants
		7.6; (3.7 to 13.5)	3.7; (0.8 to 10.4)

6. Secondary Outcome

Title	Clinical Benefit Rate (CBR) by PIK3CA Mutational Status
Description	Clinical Benefit Rate (CBR) is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 14 or 24 weeks based on local investigator's assessment according to RECIST 1.1. CBR was analyzed in the full population and by PIK3CA mutational status based on ctDNA. Patients were followed up for the duration of the study and approximately every 6 weeks after randomization.
Time Frame	Week 14, Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), Full Analysis Set (FAS) -ctDNA PIK3CA mutant, Full Analysis Set (FAS) - ctDNA PIK3CA non-mutant based on Primary Analysis.

Arm/Group Title		BKM120 100mg + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:		BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed		289	143
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
CBR>=14wks(FAS)	Number Analyzed	289 participants	143 participants
		33.2; (27.8 to 39.0)	20.3; (14.0 to 27.8)
CBR>=24wks(FAS)	Number Analyzed	289 participants	143 participants
		24.6; (19.7 to 29.9)	15.4; (9.9 to 22.4)
CBR>=14wks(FAS ctDNA PIK3CA mutant)	Number Analyzed	100 participants	35 participants
		38.0; (28.5 to 48.3)	14.3; (4.8 to 30.3)
CBR>=24wks(FAS ctDNA PIK3CA mutant)	Number Analyzed	100 participants	35 participants
		30.0; (21.2 to 40.0)	11.4; (3.2 to 26.7)
CBR>=14wks(FAS ctDNA PIK3CA non-mutant)	Number Analyzed	132 participants	81 participants
		36.4; (28.2 to 45.2)	21.0; (12.7 to 31.5)
CBR>= 24wks(FAS ctDNA PIK3CA non-mutant)	Number Analyzed	132 participants	81 participants
		25.8; (18.5 to 34.1)	14.8; (7.9 to 24.4)

7. Secondary Outcome

Title	Long-term Safety and Tolerability in the Two Treatment Arms - Safety Set (SS)
Description	Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths.
Time Frame	From first dose of study treatment to 30 days after last dose of study treatment, up to 5 years

Outcome Measure Data

Analysis Population Description

Safety Set (SS) based on Final Analysis

Arm/Group Title	BKM120 100mg + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed	288	140
Measure Type: Number; Unit of Measure: Percentage of Participants
AEs	97.9	92.9
SAEs	25.7	18.6
Deaths	42.7	48.6

8. Secondary Outcome

Title	Plasma Concentration-time Profiles of BKM120 in Combination With Fulvestrant at Cycle 1 Day 1 - Pharmacokinetic Analysis Set (PAS)
Description	Plasma samples were collected from the first 100 BKM120-treated patients on Cycle 1 Day 1 (at 1h, 2h, and 6h post-dose and a recommended 9h post-dose sample).
Time Frame	C1D1 1 hour post dose, C1D1 2 hour post dose, C1D1 6 hour post dose and C1D1 9 hour post dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS) based on Primary Analysis

Arm/Group Title	BKM120 100mg + Fulvestrant
Arm/Group Description:	BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed	63
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter (ng/mL)
C1D1 - 1 hour post dose	425.178; (149.6%)
C1D1 - 2 hour post dose	615.441; (70.9%)
C1D1 - 6 hour post dose	314.094; (41.9%)
C1D1 - 9 hour post dose	302.899; (58.3%)

9. Secondary Outcome

Title	Predose Trough Concentration-time Profile of BKM120 in Combination With Fulvestrant Over Time - Pharmacokinetic Analysis Set (PAS)
Description	Pre-dose samples were collected for trough concentrations at Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1 and Cycle 4 Day 1.
Time Frame	C1D15, C2D1, C3D1 and C4D1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS) based on Primary Analysis

Arm/Group Title	BKM120 100mg + Fulvestrant
Arm/Group Description:	BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed	63
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter (ng/mL)
C1D15	939.978; (36.8%)
C2D1	880.074; (38.4%)
C3D1	777.026; (131.0%)
C4D1	1088.074; (27.0%)

10. Secondary Outcome

Title	Health-related Quality of Life (HRQoL):Time to 10% Definitive Deterioration in the Global Health Status/Quality of Life Per EORTC-QLQ-C30 - Full Analysis Set (FAS)
Description	The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is defined as the time from the randomization date to the date of an event, which is defined as a worsening (decrease) in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study or death due to any cause. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high /healthy level of functioning, a high score for the global health status / QoL represents a high QoL.
Time Frame	Baseline, Week 6 (C2D15), Week 12 (C4D1), then every 8 weeks until discontinuation (a cycle [C] = 4 weeks) up to 5 years.

Outcome Measure Data

Analysis Population Description

Full Analysis (FAS) based on Primary Analysis

Arm/Group Title	BKM120 100mg + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed	289	143
Median (95% Confidence Interval); Unit of Measure: Months
EORTC QLQ-30 - Global QoL score	5.3; (4.4 to 8.1)	6.3; (3.0 to 9.9)
EORTC QLQ-30 - PF scale score	11.8 [1]; (8.1 to NA)	10.1; (7.5 to 14.6)
EORTC QLQ-30 - EF scale score	10.0 [1]; (6.2 to NA)	10.0 [1]; (4.9 to NA)
EORTC QLQ-30 - SF scale score	10.0; (6.2 to 20.2)	11.5; (6.4 to 14.6)

[1]

NA: Not estimable (preliminary OS analyses). Final OS analyses not done due to early study termination (OS data collection stopped early)

11. Secondary Outcome

Title	Time to Definitive Deterioration of ECOG Performance Status From Baseline - Full Analysis Set (FAS)
Description	The Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. The ECOG Performance Scores has 5 grades: 0 = fully active, able to carry on all pre-disease performance without restriction, 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work, 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours, 3 = capable of only limited self-care, confined to bed or chair more than 50% of waking hours, 4 = completely disabled, cannot carry on any self-care, totally confined to bed or chair and 5 = dead. Definitive deterioration is defined as no improvement in the ECOG status following observation of the deterioration.
Time Frame	Screening, Baseline (Cycle 1 Day 1) and then at day 1 of each cycle and at the EOT visit

Outcome Measure Data

Analysis Population Description

Full Analysis (FAS) based on Primary Analysis

Arm/Group Title	BKM120 100mg + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
Overall Number of Participants Analyzed	289	143
Median (95% Confidence Interval); Unit of Measure: Months
	18.3 [1]; (6.9 to NA)	12.0; (6.4 to 14.2)

[1]

NA: Not estimable (preliminary OS analyses). Final OS analyses not done due to early study termination (OS data collection stopped early)

Adverse Events

Time Frame	Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment (FPFT) until end of treatment exposure + 30 days safety follow-up.
Adverse Event Reporting Description	Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fields "number of deaths resulting from adverse events" all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
Arm/Group Title	BKM120 100 mg + Fulvestrant	Placebo + Fulvestrant	All Patients
Arm/Group Description	BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol test.	BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.	All Patients
All-Cause Mortality
	BKM120 100 mg + Fulvestrant	Placebo + Fulvestrant	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	123/288 (42.71%)	68/140 (48.57%)	191/428 (44.63%)
Serious Adverse Events
	BKM120 100 mg + Fulvestrant	Placebo + Fulvestrant	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	74/288 (25.69%)	26/140 (18.57%)	100/428 (23.36%)
Blood and lymphatic system disorders
Anaemia † 1	1/288 (0.35%)	1/140 (0.71%)	2/428 (0.47%)
Febrile neutropenia † 1	2/288 (0.69%)	0/140 (0.00%)	2/428 (0.47%)
Haemolytic anaemia † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Cardiac disorders
Angina pectoris † 1	2/288 (0.69%)	0/140 (0.00%)	2/428 (0.47%)
Atrial fibrillation † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Cardiac arrest † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Cardiac failure acute † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Cardiac tamponade † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Intracardiac mass † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Pericardial effusion † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Ear and labyrinth disorders
Vertigo † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Eye disorders
Amaurosis † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Diplopia † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Eyelid ptosis † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Optic atrophy † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Vision blurred † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Gastrointestinal disorders
Abdominal pain † 1	1/288 (0.35%)	1/140 (0.71%)	2/428 (0.47%)
Ascites † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Diarrhoea † 1	3/288 (1.04%)	1/140 (0.71%)	4/428 (0.93%)
Gastrointestinal haemorrhage † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Haematemesis † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Ileus † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Intestinal perforation † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Nausea † 1	1/288 (0.35%)	2/140 (1.43%)	3/428 (0.70%)
Oesophageal haemorrhage † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Vomiting † 1	4/288 (1.39%)	1/140 (0.71%)	5/428 (1.17%)
General disorders
Asthenia † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Death † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Facial pain † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Fatigue † 1	1/288 (0.35%)	1/140 (0.71%)	2/428 (0.47%)
General physical health deterioration † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Malaise † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Non-cardiac chest pain † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Pyrexia † 1	0/288 (0.00%)	2/140 (1.43%)	2/428 (0.47%)
Hepatobiliary disorders
Bile duct obstruction † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Bile duct stenosis † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Hepatic function abnormal † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Hepatotoxicity † 1	2/288 (0.69%)	0/140 (0.00%)	2/428 (0.47%)
Jaundice † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Infections and infestations
Clostridial infection † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Clostridium difficile infection † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Cystitis † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Infective thrombosis † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Peritonitis † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Pneumonia † 1	4/288 (1.39%)	0/140 (0.00%)	4/428 (0.93%)
Respiratory tract infection † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Urinary tract infection † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Viral infection † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Injury, poisoning and procedural complications
Ankle fracture † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Electric injury † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Femur fracture † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Head injury † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Spinal cord injury thoracic † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Wrist fracture † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Investigations
Alanine aminotransferase increased † 1	5/288 (1.74%)	0/140 (0.00%)	5/428 (1.17%)
Aspartate aminotransferase increased † 1	6/288 (2.08%)	0/140 (0.00%)	6/428 (1.40%)
Gamma-glutamyltransferase increased † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Transaminases increased † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Weight decreased † 1	2/288 (0.69%)	0/140 (0.00%)	2/428 (0.47%)
Metabolism and nutrition disorders
Decreased appetite † 1	1/288 (0.35%)	1/140 (0.71%)	2/428 (0.47%)
Dehydration † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Diabetes mellitus inadequate control † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Hypercalcaemia † 1	1/288 (0.35%)	1/140 (0.71%)	2/428 (0.47%)
Hyperglycaemia † 1	3/288 (1.04%)	0/140 (0.00%)	3/428 (0.70%)
Hyperuricaemia † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Hyponatraemia † 1	2/288 (0.69%)	0/140 (0.00%)	2/428 (0.47%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Back pain † 1	1/288 (0.35%)	2/140 (1.43%)	3/428 (0.70%)
Flank pain † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Muscular weakness † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Musculoskeletal chest pain † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Musculoskeletal pain † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Osteonecrosis of jaw † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Pain in extremity † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Malignant pleural effusion † 1	1/288 (0.35%)	1/140 (0.71%)	2/428 (0.47%)
Nervous system disorders
Cerebral haemorrhage † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Cerebrovascular accident † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Dizziness † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Epilepsy † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Horner's syndrome † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Hydrocephalus † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Loss of consciousness † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Migraine † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Neuralgia † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Neurological symptom † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Posterior reversible encephalopathy syndrome † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Presyncope † 1	0/288 (0.00%)	1/140 (0.71%)	1/428 (0.23%)
Resting tremor † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Seizure † 1	2/288 (0.69%)	0/140 (0.00%)	2/428 (0.47%)
Syncope † 1	2/288 (0.69%)	1/140 (0.71%)	3/428 (0.70%)
Transient ischaemic attack † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Vith nerve paralysis † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Vocal cord paralysis † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Psychiatric disorders
Confusional state † 1	4/288 (1.39%)	1/140 (0.71%)	5/428 (1.17%)
Disorientation † 1	2/288 (0.69%)	0/140 (0.00%)	2/428 (0.47%)
Mania † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Mental disorder † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Mood altered † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Suicide attempt † 1	3/288 (1.04%)	0/140 (0.00%)	3/428 (0.70%)
Renal and urinary disorders
Renal failure † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Urinary retention † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Atelectasis † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Dyspnoea † 1	7/288 (2.43%)	1/140 (0.71%)	8/428 (1.87%)
Pleural effusion † 1	6/288 (2.08%)	0/140 (0.00%)	6/428 (1.40%)
Respiratory failure † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Social circumstances
Homicide † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Vascular disorders
Circulatory collapse † 1	2/288 (0.69%)	0/140 (0.00%)	2/428 (0.47%)
Hypertension † 1	2/288 (0.69%)	0/140 (0.00%)	2/428 (0.47%)
Hypotension † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
Venous thrombosis † 1	1/288 (0.35%)	0/140 (0.00%)	1/428 (0.23%)
1 Term from vocabulary, MedDRA (19.1); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	BKM120 100 mg + Fulvestrant	Placebo + Fulvestrant	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	271/288 (94.10%)	113/140 (80.71%)	384/428 (89.72%)
Gastrointestinal disorders
Abdominal pain † 1	16/288 (5.56%)	6/140 (4.29%)	22/428 (5.14%)
Abdominal pain upper † 1	23/288 (7.99%)	4/140 (2.86%)	27/428 (6.31%)
Constipation † 1	29/288 (10.07%)	13/140 (9.29%)	42/428 (9.81%)
Diarrhoea † 1	76/288 (26.39%)	13/140 (9.29%)	89/428 (20.79%)
Dry mouth † 1	23/288 (7.99%)	5/140 (3.57%)	28/428 (6.54%)
Dyspepsia † 1	29/288 (10.07%)	2/140 (1.43%)	31/428 (7.24%)
Nausea † 1	100/288 (34.72%)	24/140 (17.14%)	124/428 (28.97%)
Stomatitis † 1	32/288 (11.11%)	6/140 (4.29%)	38/428 (8.88%)
Vomiting † 1	27/288 (9.38%)	13/140 (9.29%)	40/428 (9.35%)
General disorders
Asthenia † 1	52/288 (18.06%)	15/140 (10.71%)	67/428 (15.65%)
Fatigue † 1	69/288 (23.96%)	25/140 (17.86%)	94/428 (21.96%)
Oedema peripheral † 1	18/288 (6.25%)	2/140 (1.43%)	20/428 (4.67%)
Pyrexia † 1	20/288 (6.94%)	8/140 (5.71%)	28/428 (6.54%)
Infections and infestations
Urinary tract infection † 1	15/288 (5.21%)	3/140 (2.14%)	18/428 (4.21%)
Investigations
Alanine aminotransferase increased † 1	113/288 (39.24%)	10/140 (7.14%)	123/428 (28.74%)
Aspartate aminotransferase increased † 1	108/288 (37.50%)	14/140 (10.00%)	122/428 (28.50%)
Gamma-glutamyltransferase increased † 1	26/288 (9.03%)	5/140 (3.57%)	31/428 (7.24%)
Weight decreased † 1	27/288 (9.38%)	7/140 (5.00%)	34/428 (7.94%)
Metabolism and nutrition disorders
Decreased appetite † 1	47/288 (16.32%)	9/140 (6.43%)	56/428 (13.08%)
Hyperglycaemia † 1	104/288 (36.11%)	4/140 (2.86%)	108/428 (25.23%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	21/288 (7.29%)	12/140 (8.57%)	33/428 (7.71%)
Back pain † 1	27/288 (9.38%)	11/140 (7.86%)	38/428 (8.88%)
Bone pain † 1	9/288 (3.13%)	11/140 (7.86%)	20/428 (4.67%)
Muscle spasms † 1	21/288 (7.29%)	5/140 (3.57%)	26/428 (6.07%)
Pain in extremity † 1	19/288 (6.60%)	10/140 (7.14%)	29/428 (6.78%)
Nervous system disorders
Dizziness † 1	35/288 (12.15%)	10/140 (7.14%)	45/428 (10.51%)
Dysgeusia † 1	19/288 (6.60%)	4/140 (2.86%)	23/428 (5.37%)
Headache † 1	27/288 (9.38%)	15/140 (10.71%)	42/428 (9.81%)
Tremor † 1	18/288 (6.25%)	0/140 (0.00%)	18/428 (4.21%)
Psychiatric disorders
Anxiety † 1	51/288 (17.71%)	15/140 (10.71%)	66/428 (15.42%)
Depression † 1	60/288 (20.83%)	11/140 (7.86%)	71/428 (16.59%)
Insomnia † 1	26/288 (9.03%)	11/140 (7.86%)	37/428 (8.64%)
Mood altered † 1	15/288 (5.21%)	2/140 (1.43%)	17/428 (3.97%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	27/288 (9.38%)	9/140 (6.43%)	36/428 (8.41%)
Dyspnoea † 1	22/288 (7.64%)	12/140 (8.57%)	34/428 (7.94%)
Skin and subcutaneous tissue disorders
Dry skin † 1	22/288 (7.64%)	3/140 (2.14%)	25/428 (5.84%)
Pruritus † 1	25/288 (8.68%)	4/140 (2.86%)	29/428 (6.78%)
Rash † 1	37/288 (12.85%)	3/140 (2.14%)	40/428 (9.35%)
Vascular disorders
Hot flush † 1	10/288 (3.47%)	11/140 (7.86%)	21/428 (4.91%)
Hypertension † 1	33/288 (11.46%)	8/140 (5.71%)	41/428 (9.58%)
1 Term from vocabulary, MedDRA (19.1); † Indicates events were collected by systematic assessment

Limitations and Caveats

The primary efficacy analysis was completed by 23May16 (primary PFS analysis cutoff date). The study was later terminated and the final safety analysis was conducted up to 08Sep17. One CRF was collecting on 21Sep2017 for survival follow up (LPLV).

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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 the pooled data (ie, data from all sites) in the clinical trial.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300
• EMail: Novartis.email@novartis.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Di Leo A, Johnston S, Lee KS, Ciruelos E, Lonning PE, Janni W, O'Regan R, Mouret-Reynier MA, Kalev D, Egle D, Csoszi T, Bordonaro R, Decker T, Tjan-Heijnen VCG, Blau S, Schirone A, Weber D, El-Hashimy M, Dharan B, Sellami D, Bachelot T. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Jan;19(1):87-100. doi: 10.1016/S1470-2045(17)30688-5. Epub 2017 Dec 7. Erratum In: Lancet Oncol. 2018 Mar;19(3):e137.

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT01633060
• Other Study ID Numbers: CBKM120F2303; 2012-002571-34 ( EudraCT Number )
• First Submitted: June 29, 2012
• First Posted: July 4, 2012
• Results First Submitted: September 20, 2018
• Results First Posted: January 9, 2019
• Last Update Posted: January 30, 2019