BELLE-3: 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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01633060
• Collaborator: (none)
• Enrollment: 432
• Locations: 197
• Arms: 2
• Actual Duration (Months): 59.6
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study was a multicenter, randomized, double-blind, placebo-controlled Phase III study to determine the efficacy and safety of treatment with Buparlisib plus Fulvestrant vs. Placebo plus Fulvestrant in postmenopausal women with hormone Receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative), aromatase inhibitor (AI)-treated, locally advanced or metastatic breast cancer whose disease progressed on or after mammalian target of rapamycin inhibitor (mTORi)-based treatment.

Patients were randomized in 2:1 ratio to treatment with buparlisib 100 mg daily in combination with fulvestrant 500 mg or placebo daily in combination with fulvestrant 500 mg. Randomization was stratified according to visceral disease status (present or absent).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Fulvestrant; Drug: BKM120; Drug: BKM120 matching placebo	Phase 3

Detailed Description

Novartis decided not to pursue further development of buparlisib program. On 19 Dec 2016, Novartis notified the Investigators about this decision; accordingly the CBKM120F2303 study was terminated.

Study Design

• Study Type: Interventional
• Actual Enrollment: 432 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized, Double Blind, Placebo Controlled Study of BKM120 With Fulvestrant, in Postmenopausal Women With Hormone Receptor-positive HER2-negative AI Treated, Locally Advanced or Metastatic Breast Cancer Who Progressed on or After mTOR Inhibitor Based Treatment
• Actual Study Start Date: Oct 3, 2012
• Actual Primary Completion Date: May 23, 2016
• Actual Study Completion Date: Sep 21, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BKM120 100mg + Fulvestrant BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.	Drug: Fulvestrant; Intramuscular fulvestrant 500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter); Drug: BKM120; BKM120 100 mg once daily
Placebo Comparator: Placebo + Fulvestrant BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.	Drug: Fulvestrant; Intramuscular fulvestrant 500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter); Drug: BKM120 matching placebo; BKM120 matching placebo, once daily

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) Based on Local Investigator Assessment - Full Analysis Set (FAS) [Every 6 weeks after randomization up to a maximum of 4 years]

   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.

Secondary Outcome Measures

1. Overall Survival (OS) - Full Analysis Set (FAS) [Every 6 weeks after randomization up to a maximum of 5 years]

   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.

2. Progression Free Survival (PFS) by PIK3CA Mutational Status [Every 6 weeks after randomization up to a maximum of 5 years]

   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.

3. Overall Survival (OS) by PIK3CA Mutational Status [Every 6 weeks after randomization up to a maximum of 5 years]

   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.

4. Overall Response Rate (ORR) by PIK3CA Mutational Status [Every 6 weeks after randomization up to a maximum of 5 years]

   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.

5. Clinical Benefit Rate (CBR) by PIK3CA Mutational Status [Week 14, Week 24]

   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.

6. Long-term Safety and Tolerability in the Two Treatment Arms - Safety Set (SS) [From first dose of study treatment to 30 days after last dose of study treatment, up to 5 years]

   Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths.

7. Plasma Concentration-time Profiles of BKM120 in Combination With Fulvestrant at Cycle 1 Day 1 - Pharmacokinetic Analysis Set (PAS) [C1D1 1 hour post dose, C1D1 2 hour post dose, C1D1 6 hour post dose and C1D1 9 hour post dose]

   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).

8. Predose Trough Concentration-time Profile of BKM120 in Combination With Fulvestrant Over Time - Pharmacokinetic Analysis Set (PAS) [C1D15, C2D1, C3D1 and C4D1]

   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.

9. 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) [Baseline, Week 6 (C2D15), Week 12 (C4D1), then every 8 weeks until discontinuation (a cycle [C] = 4 weeks) up to 5 years.]

   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.

10. Time to Definitive Deterioration of ECOG Performance Status From Baseline - Full Analysis Set (FAS) [Screening, Baseline (Cycle 1 Day 1) and then at day 1 of each cycle and at the EOT visit]

    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.

Eligibility Criteria

Criteria

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

Key inclusion criteria

• Female patients age 18 years or older

• Histologically and/or cytologically confirmed diagnosis of breast cancer

• Radiologic evidence of inoperable locally advanced or metastatic breast cancer

• Adequate tumor tissue for the analysis of PI3K-related biomarkers

• Human epidermal growth factor receptor-2 (HER2) negative disease, and a known positive hormone receptor status

• Postmenopausal women

• Prior treatment with aromatase inhibitors

• Evidence of progression to the combination of mTORi and endocrine therapy given as the last therapy prior to study entry

• Adequate bone marrow and organ function

• ECOG performance status ≤ 2

Key exclusion criteria

• Previous treatment with PI3K inhibitors, protein kinase B inhibitors or fulvestrant

• More than one chemotherapy line for metastatic disease

• Hypersensitivity to any of the excipients of buparlisib or fulvestrant

• Symptomatic central nervous system metastases

• Concurrent malignancy or malignancy within 3 years of study enrollment

• Certain drugs or radiation within 2-4 weeks of enrollment

• Increasing or chronic treatment (>5 days) with corticosteroids or another immunosuppressive agent

• Certain scores on an anxiety and depression mood questionnaire given at screening

• Acute viral hepatitis or a history of chronic or active hepatitis B virus or hepatitis C virus

• Active cardiac disease or a history of cardiac dysfunction

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of South Alabama / Mitchell Cancer Institute Univ South AL	Mobile	Alabama	United States	36688
2	Ironwood Cancer and Research Centers SC	Chandler	Arizona	United States	85224
3	Highlands Oncology Group	Fayetteville	Arkansas	United States	72703
4	Compassionate Cancer Care Medical Group CCCMG	Fountain Valley	California	United States	92708
5	Los Angeles Hematology/Oncology Medical Group Onc Dept.	Los Angeles	California	United States	90017
6	Cedars Sinai Medical Center SC-5	Los Angeles	California	United States	90048
7	University of California at Los Angeles UCLA SC	Los Angeles	California	United States	90095
8	Pacific Cancer Care	Monterey	California	United States	93940
9	Rocky Mountain Cancer Centers SC	Denver	Colorado	United States	80218
10	University Cancer & Blood Center, LLC	Athens	Georgia	United States	30607
11	Emory University School of Medicine/Winship Cancer Institute Emory	Atlanta	Georgia	United States	30322
12	Moanalua Medical Center. Attn: Oncology Dept	Honolulu	Hawaii	United States	96817
13	Edward Hospital Edward Hospital	Naperville	Illinois	United States	60540
14	Crescent City Research Consortium, LLC SC	Metairie	Louisiana	United States	70006
15	Lsu Health Sciences Center/ Lsu School of Medicine Lsu	New Orleans	Louisiana	United States	70115
16	John Ochsner Heart and Vascular Institute Clinical Trials Ochsner 2	New Orleans	Louisiana	United States	70121
17	LSU Health Sciences Center Feist-Weiller Cancer Center	New Orleans	Louisiana	United States	70122-2822
18	University of Maryland Medical Center Univ Maryland	Baltimore	Maryland	United States	21201
19	Mercy Medical Research Institute SC	Manchester	Missouri	United States	63021
20	Morristown Memorial Hospital Morristown Mem	Morristown	New Jersey	United States	07962
21	CINJ at Cooper University Hospital Dept of Onc	Voorhees	New Jersey	United States	08043
22	Montefiore Medical Center Montefiore	Bronx	New York	United States	10467
23	Clinical Research Alliance BKM120F2303	Lake Success	New York	United States	11042
24	Clinical Research Alliance	Lake Success	New York	United States	11042
25	Northwest Cancer Specialists Compass Oncology -BKM	Portland	Oregon	United States	97210
26	Oregon Health and Science University SC-5	Portland	Oregon	United States	97239
27	University of Pittsburgh Cancer Institute Dept of Magee Women's Hospital	Pittsburgh	Pennsylvania	United States	15232
28	The West Clinic Dept. of the West Clinic	Memphis	Tennessee	United States	38120
29	Texas Oncology PA Dallas Presbyterian Hospital SC	Dallas	Texas	United States	75231
30	Texas Oncology Texas Oncology - Sammons	Dallas	Texas	United States	75246
31	Texas Oncology P A SC-Austin	Dallas	Texas	United States	75251
32	Texas Oncology P A Texas Oncology - Fort Worth (3	Dallas	Texas	United States	75251
33	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
34	Texas Tech University Health Science Center Dept of Texas Tech	El Paso	Texas	United States	79905
35	The Methodist Hospital Cancer Center	Houston	Texas	United States	77030
36	US Oncology, P.A.	Tyler	Texas	United States	75702
37	Northwest Medical Specialties	Tacoma	Washington	United States	98405
38	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1050AAK
39	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000KZE
40	Novartis Investigative Site	San Miguel De Tucuman	Tucuman	Argentina	T4000IAK
41	Novartis Investigative Site	Rio Negro	Viedma	Argentina	8500
42	Novartis Investigative Site	Innsbruck	Tyrol	Austria	6020
43	Novartis Investigative Site	Linz		Austria	4010
44	Novartis Investigative Site	Salzburg		Austria	5020
45	Novartis Investigative Site	Wien		Austria	A-1090
46	Novartis Investigative Site	Bruxelles		Belgium	1000
47	Novartis Investigative Site	Leuven		Belgium	3000
48	Novartis Investigative Site	Liege		Belgium	4000
49	Novartis Investigative Site	Namur		Belgium	5000
50	Novartis Investigative Site	Plovdiv		Bulgaria	4000
51	Novartis Investigative Site	Plovdiv		Bulgaria	4004
52	Novartis Investigative Site	Sofia		Bulgaria	1303
53	Novartis Investigative Site	Sofia		Bulgaria	1527
54	Novartis Investigative Site	Sofia		Bulgaria	1756
55	Novartis Investigative Site	Varna		Bulgaria	9010
56	Novartis Investigative Site	Vratsa		Bulgaria	3000
57	Novartis Investigative Site	Montreal	Quebec	Canada	H2W 1T8
58	Novartis Investigative Site	Montreal	Quebec	Canada	H3A 1A1
59	Novartis Investigative Site	Bogota		Colombia
60	Novartis Investigative Site	Monteria		Colombia
61	Novartis Investigative Site	Tampere		Finland	FIN-33521
62	Novartis Investigative Site	Nice Cedex 2	Alpes Maritimes	France	06189
63	Novartis Investigative Site	Limoges cedex	Haute Vienne	France	87000
64	Novartis Investigative Site	Saint-Cloud	Hauts De Seine	France	92210
65	Novartis Investigative Site	Reims Cedex	Marne	France	51056
66	Novartis Investigative Site	Angers Cedex 02		France	49055
67	Novartis Investigative Site	Clermont-Ferrand		France	63011
68	Novartis Investigative Site	Lyon Cedex		France	69373
69	Novartis Investigative Site	Paris		France	75231
70	Novartis Investigative Site	Rouen Cedex 1		France	76038
71	Novartis Investigative Site	Saint-Brieuc Cédex		France	22015
72	Novartis Investigative Site	Saint-Herblain Cédex		France	44805
73	Novartis Investigative Site	Koeln	Nordrhein-Westfalen	Germany	50937
74	Novartis Investigative Site	Berlin		Germany	12203
75	Novartis Investigative Site	Bonn		Germany	53111
76	Novartis Investigative Site	Dresden		Germany	01307
77	Novartis Investigative Site	Erlangen		Germany	91054
78	Novartis Investigative Site	Essen		Germany	45136
79	Novartis Investigative Site	Essen		Germany	45147
80	Novartis Investigative Site	Frankfurt		Germany	60389
81	Novartis Investigative Site	Fulda		Germany	36043
82	Novartis Investigative Site	Karlsruhe		Germany	76135
83	Novartis Investigative Site	Kiel		Germany	24103
84	Novartis Investigative Site	Leer		Germany	26789
85	Novartis Investigative Site	Magdeburg		Germany	39120
86	Novartis Investigative Site	Mannheim		Germany	68165
87	Novartis Investigative Site	Muenchen		Germany	80637
88	Novartis Investigative Site	Muenchen		Germany	81377
89	Novartis Investigative Site	Mühlhausen		Germany	99974
90	Novartis Investigative Site	Ravensburg		Germany	88214
91	Novartis Investigative Site	Soest		Germany	59494
92	Novartis Investigative Site	Tuebingen		Germany	72076
93	Novartis Investigative Site	Ulm		Germany	89081
94	Novartis Investigative Site	Velbert		Germany	42551
95	Novartis Investigative Site	Marousi	Athens	Greece	15123
96	Novartis Investigative Site	Athens	GR	Greece	151 23
97	Novartis Investigative Site	Larissa	GR	Greece	411 10
98	Novartis Investigative Site	Patra - RIO	GR	Greece	265 04
99	Novartis Investigative Site	Thesaloniki	Thessaloniki	Greece	54622
100	Novartis Investigative Site	Athens		Greece	18547
101	Novartis Investigative Site	Athens		Greece	GR-115 22
102	Novartis Investigative Site	Heraklion Crete		Greece	711 10
103	Novartis Investigative Site	Budapest		Hungary	1134
104	Novartis Investigative Site	Budapest		Hungary	H-1122
105	Novartis Investigative Site	Szeged		Hungary	H-6720
106	Novartis Investigative Site	Szolnok		Hungary	H-5000
107	Novartis Investigative Site	L'Aquila	AQ	Italy	67100
108	Novartis Investigative Site	Bari	BA	Italy	70124
109	Novartis Investigative Site	Benevento	BN	Italy	82100
110	Novartis Investigative Site	Brindisi	BR	Italy	72100
111	Novartis Investigative Site	Brescia	BS	Italy	25123
112	Novartis Investigative Site	Monserrato	CA	Italy	09042
113	Novartis Investigative Site	Cremona	CR	Italy	26100
114	Novartis Investigative Site	Catania	CT	Italy	95100
115	Novartis Investigative Site	Meldola	FC	Italy	47014
116	Novartis Investigative Site	Cona	FE	Italy	44100
117	Novartis Investigative Site	Firenze	FI	Italy	50134
118	Novartis Investigative Site	Sora	FR	Italy	03039
119	Novartis Investigative Site	Lecco	LC	Italy	23900
120	Novartis Investigative Site	Lecce	LE	Italy	73100
121	Novartis Investigative Site	Monza	MB	Italy	20900
122	Novartis Investigative Site	Macerata	MC	Italy	62100
123	Novartis Investigative Site	Messina	ME	Italy	98158
124	Novartis Investigative Site	Milano	MI	Italy	20121
125	Novartis Investigative Site	Milano	MI	Italy	20132
126	Novartis Investigative Site	Milano	MI	Italy	20141
127	Novartis Investigative Site	Modena	MO	Italy	41124
128	Novartis Investigative Site	Padova	PD	Italy	35100
129	Novartis Investigative Site	Pisa	PI	Italy	56126
130	Novartis Investigative Site	Pordenone	PN	Italy	33170
131	Novartis Investigative Site	Prato	PO	Italy	59100
132	Novartis Investigative Site	Parma	PR	Italy	43100
133	Novartis Investigative Site	Pavia	PV	Italy	27100
134	Novartis Investigative Site	Reggio Calabria	RC	Italy	89124
135	Novartis Investigative Site	Roma	RM	Italy	00128
136	Novartis Investigative Site	Roma	RM	Italy	00168
137	Novartis Investigative Site	Salerno	SA	Italy	84131
138	Novartis Investigative Site	Sassari	SS	Italy	07100
139	Novartis Investigative Site	Candiolo	TO	Italy	10060
140	Novartis Investigative Site	Ivrea	TO	Italy	10015
141	Novartis Investigative Site	Torino	TO	Italy	10126
142	Novartis Investigative Site	Mirano	VE	Italy	30035
143	Novartis Investigative Site	Verona	VR	Italy	37126
144	Novartis Investigative Site	Frattamaggiore		Italy	80020
145	Novartis Investigative Site	Gyeonggi-do	Korea	Korea, Republic of	10408
146	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	03080
147	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	05505
148	Novartis Investigative Site	Seoul		Korea, Republic of	03722
149	Novartis Investigative Site	Ashrafieh		Lebanon	166830
150	Novartis Investigative Site	Beirut		Lebanon
151	Novartis Investigative Site	Saida		Lebanon	652
152	Novartis Investigative Site	Maastricht	AZ	Netherlands	5800
153	Novartis Investigative Site	Breda		Netherlands	4819 EV
154	Novartis Investigative Site	Delft		Netherlands	NL 2625 AD
155	Novartis Investigative Site	Deventer		Netherlands	7416 SE
156	Novartis Investigative Site	Hoofddorp		Netherlands	2134 TM
157	Novartis Investigative Site	Leiden		Netherlands	2300 RC
158	Novartis Investigative Site	Sittard-Geleen		Netherlands	6162 BG
159	Novartis Investigative Site	Zwolle		Netherlands	8025 AB
160	Novartis Investigative Site	Bergen		Norway	5021
161	Novartis Investigative Site	Oslo		Norway	NO 0450
162	Novartis Investigative Site	Olsztyn		Poland	10226
163	Novartis Investigative Site	Elche	Alicante	Spain	03203
164	Novartis Investigative Site	Jaen	Andalucia	Spain	23007
165	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
166	Novartis Investigative Site	Sevilla	Andalucia	Spain	41009
167	Novartis Investigative Site	Badalona	Catalunya	Spain	08916
168	Novartis Investigative Site	Barcelona	Catalunya	Spain	08003
169	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
170	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
171	Novartis Investigative Site	Castellon	Comunidad Valenciana	Spain	12002
172	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46009
173	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46010
174	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46014
175	Novartis Investigative Site	La Coruna	Galicia	Spain	15006
176	Novartis Investigative Site	Santiago de Compostela	Galicia	Spain	15706
177	Novartis Investigative Site	Palma De Mallorca	Islas Baleares	Spain	07120
178	Novartis Investigative Site	La Laguna	Santa Cruz De Tenerife	Spain	38320
179	Novartis Investigative Site	Barcelona		Spain	08041
180	Novartis Investigative Site	Madrid		Spain	28007
181	Novartis Investigative Site	Madrid		Spain	28034
182	Novartis Investigative Site	Madrid		Spain	28040
183	Novartis Investigative Site	Madrid		Spain	28041
184	Novartis Investigative Site	Madrid		Spain	28046
185	Novartis Investigative Site	Madrid		Spain	28222
186	Novartis Investigative Site	Santa Cruz de Tenerife		Spain	38009
187	Novartis Investigative Site	Kalmar		Sweden	SE-391 85
188	Novartis Investigative Site	Stockholm		Sweden	SE-171 76
189	Novartis Investigative Site	Uppsala		Sweden	751 85
190	Novartis Investigative Site	Bangkok		Thailand	10400
191	Novartis Investigative Site	Blackburn	Lancashire	United Kingdom	BB2 3HH
192	Novartis Investigative Site	Ipswich	Suffolk	United Kingdom	IP4 5PD
193	Novartis Investigative Site	Edinburgh		United Kingdom	EH4 2XU
194	Novartis Investigative Site	London		United Kingdom	SM2 5PT
195	Novartis Investigative Site	London		United Kingdom	SW3 6JJ
196	Novartis Investigative Site	Manchester		United Kingdom	M20 2BX
197	Novartis Investigative Site	Nottingham		United Kingdom	NG5 1PB

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01633060
• Other Study ID Numbers: CBKM120F2303; 2012-002571-34
• First Posted: Jul 4, 2012
• Last Update Posted: Jan 30, 2019
• Last Verified: Jan 1, 2019

• 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: BKM120; fulvestrant; breast cancer; metastatic; locally advanced; AI treated; mTOR inhibitor; PI3K; PIK3CA; PTEN; HER2-; HR+
• Additional relevant MeSH terms: Breast Neoplasms; Fulvestrant

Study Results

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 Detail	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	289	143
COMPLETED	288	140
NOT COMPLETED	1	3
Period Title: Randomization Phase
STARTED	288	140
FAS - ctDNA PIK3CA Mutant	100	35
FAS - ctDNA PIK3CA Non-mutant	132	81
Safety Set (SS)	288	140
Pharmacokinetic Analysis Set (PAS)	63	0
COMPLETED	0	0
NOT COMPLETED	288	140
Period Title: Randomization Phase
STARTED	16	2
COMPLETED	0	0
NOT COMPLETED	16	2

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 Participants	289	143	432
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.5 (9.76)	61.5 (9.23)	60.8 (9.59)
Sex: Female, Male (Count of Participants)
Female	289 100%	143 100%	432 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of 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%
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%
Unknown or Not Reported	12 4.2%	8 5.6%	20 4.6%

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.
Measure Participants	289	143
Median (95% Confidence Interval) [Months]	3.9	1.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BKM120 100mg + Fulvestrant, Placebo + Fulvestrant
	Comments
	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
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(1-Sided) 95%; 0.53 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
Measure Participants	289	143
Median (95% Confidence Interval) [Months]	21.2	22.1

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.
Measure Participants	289	143
FAS ctDNA PIK3CA mutant	4.2	1.6
FAS ctDNA PIK3CA non-mutant	3.9	2.7

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.
Measure Participants	289	143
FAS ctDNA PIK3CA mutant	21.8	NA
FAS ctDNA PIK3CA non-mutant	21.4	21.4

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.
Measure Participants	289	143
Full Analysis Set (FAS)	7.6 2.6%	2.1 1.5%
FAS ctDNA PIK3CA mutant	10.0 3.5%	0 0%
FAS ctDNA PIK3CA non-mutant	7.6 2.6%	3.7 2.6%

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.
Measure Participants	289	143
CBR>=14wks(FAS)	33.2 11.5%	20.3 14.2%
CBR>=24wks(FAS)	24.6 8.5%	15.4 10.8%
CBR>=14wks(FAS ctDNA PIK3CA mutant)	38.0 13.1%	14.3 10%
CBR>=24wks(FAS ctDNA PIK3CA mutant)	30.0 10.4%	11.4 8%
CBR>=14wks(FAS ctDNA PIK3CA non-mutant)	36.4 12.6%	21.0 14.7%
CBR>= 24wks(FAS ctDNA PIK3CA non-mutant)	25.8 8.9%	14.8 10.3%

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.
Measure Participants	288	140
AEs	97.9 33.9%	92.9 65%
SAEs	25.7 8.9%	18.6 13%
Deaths	42.7 14.8%	48.6 34%

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.
Measure Participants	63
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.
Measure Participants	63
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.
Measure Participants	289	143
EORTC QLQ-30 - Global QoL score	5.3	6.3
EORTC QLQ-30 - PF scale score	11.8	10.1
EORTC QLQ-30 - EF scale score	10.0	10.0
EORTC QLQ-30 - SF scale score	10.0	11.5

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.
Measure Participants	289	143
Median (95% Confidence Interval) [Months]	18.3	12.0

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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	123/288 (42.7%)		68/140 (48.6%)		191/428 (44.6%)
Serious Adverse Events
	BKM120 100 mg + Fulvestrant		Placebo + Fulvestrant		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/288 (25.7%)		26/140 (18.6%)		100/428 (23.4%)
Blood and lymphatic system disorders
Anaemia	1/288 (0.3%)		1/140 (0.7%)		2/428 (0.5%)
Febrile neutropenia	2/288 (0.7%)		0/140 (0%)		2/428 (0.5%)
Haemolytic anaemia	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Cardiac disorders
Angina pectoris	2/288 (0.7%)		0/140 (0%)		2/428 (0.5%)
Atrial fibrillation	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Cardiac arrest	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Cardiac failure acute	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Cardiac tamponade	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Intracardiac mass	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Pericardial effusion	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Ear and labyrinth disorders
Vertigo	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Eye disorders
Amaurosis	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Diplopia	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Eyelid ptosis	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Optic atrophy	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Vision blurred	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Gastrointestinal disorders
Abdominal pain	1/288 (0.3%)		1/140 (0.7%)		2/428 (0.5%)
Ascites	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Diarrhoea	3/288 (1%)		1/140 (0.7%)		4/428 (0.9%)
Gastrointestinal haemorrhage	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Haematemesis	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Ileus	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Intestinal perforation	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Nausea	1/288 (0.3%)		2/140 (1.4%)		3/428 (0.7%)
Oesophageal haemorrhage	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Vomiting	4/288 (1.4%)		1/140 (0.7%)		5/428 (1.2%)
General disorders
Asthenia	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Death	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Facial pain	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Fatigue	1/288 (0.3%)		1/140 (0.7%)		2/428 (0.5%)
General physical health deterioration	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Malaise	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Non-cardiac chest pain	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Pyrexia	0/288 (0%)		2/140 (1.4%)		2/428 (0.5%)
Hepatobiliary disorders
Bile duct obstruction	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Bile duct stenosis	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Hepatic function abnormal	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Hepatotoxicity	2/288 (0.7%)		0/140 (0%)		2/428 (0.5%)
Jaundice	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Infections and infestations
Clostridial infection	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Clostridium difficile infection	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Cystitis	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Infective thrombosis	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Peritonitis	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Pneumonia	4/288 (1.4%)		0/140 (0%)		4/428 (0.9%)
Respiratory tract infection	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Urinary tract infection	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Viral infection	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Injury, poisoning and procedural complications
Ankle fracture	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Electric injury	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Femur fracture	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Head injury	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Spinal cord injury thoracic	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Wrist fracture	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Investigations
Alanine aminotransferase increased	5/288 (1.7%)		0/140 (0%)		5/428 (1.2%)
Aspartate aminotransferase increased	6/288 (2.1%)		0/140 (0%)		6/428 (1.4%)
Gamma-glutamyltransferase increased	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Transaminases increased	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Weight decreased	2/288 (0.7%)		0/140 (0%)		2/428 (0.5%)
Metabolism and nutrition disorders
Decreased appetite	1/288 (0.3%)		1/140 (0.7%)		2/428 (0.5%)
Dehydration	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Diabetes mellitus inadequate control	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Hypercalcaemia	1/288 (0.3%)		1/140 (0.7%)		2/428 (0.5%)
Hyperglycaemia	3/288 (1%)		0/140 (0%)		3/428 (0.7%)
Hyperuricaemia	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Hyponatraemia	2/288 (0.7%)		0/140 (0%)		2/428 (0.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Back pain	1/288 (0.3%)		2/140 (1.4%)		3/428 (0.7%)
Flank pain	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Muscular weakness	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Musculoskeletal chest pain	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Musculoskeletal pain	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Osteonecrosis of jaw	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Pain in extremity	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Malignant pleural effusion	1/288 (0.3%)		1/140 (0.7%)		2/428 (0.5%)
Nervous system disorders
Cerebral haemorrhage	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Cerebrovascular accident	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Dizziness	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Epilepsy	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Horner's syndrome	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Hydrocephalus	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Loss of consciousness	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Migraine	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Neuralgia	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Neurological symptom	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Posterior reversible encephalopathy syndrome	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Presyncope	0/288 (0%)		1/140 (0.7%)		1/428 (0.2%)
Resting tremor	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Seizure	2/288 (0.7%)		0/140 (0%)		2/428 (0.5%)
Syncope	2/288 (0.7%)		1/140 (0.7%)		3/428 (0.7%)
Transient ischaemic attack	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Vith nerve paralysis	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Vocal cord paralysis	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Psychiatric disorders
Confusional state	4/288 (1.4%)		1/140 (0.7%)		5/428 (1.2%)
Disorientation	2/288 (0.7%)		0/140 (0%)		2/428 (0.5%)
Mania	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Mental disorder	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Mood altered	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Suicide attempt	3/288 (1%)		0/140 (0%)		3/428 (0.7%)
Renal and urinary disorders
Renal failure	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Urinary retention	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Atelectasis	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Dyspnoea	7/288 (2.4%)		1/140 (0.7%)		8/428 (1.9%)
Pleural effusion	6/288 (2.1%)		0/140 (0%)		6/428 (1.4%)
Respiratory failure	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Social circumstances
Homicide	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Vascular disorders
Circulatory collapse	2/288 (0.7%)		0/140 (0%)		2/428 (0.5%)
Hypertension	2/288 (0.7%)		0/140 (0%)		2/428 (0.5%)
Hypotension	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Venous thrombosis	1/288 (0.3%)		0/140 (0%)		1/428 (0.2%)
Other (Not Including Serious) Adverse Events
	BKM120 100 mg + Fulvestrant		Placebo + Fulvestrant		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	271/288 (94.1%)		113/140 (80.7%)		384/428 (89.7%)
Gastrointestinal disorders
Abdominal pain	16/288 (5.6%)		6/140 (4.3%)		22/428 (5.1%)
Abdominal pain upper	23/288 (8%)		4/140 (2.9%)		27/428 (6.3%)
Constipation	29/288 (10.1%)		13/140 (9.3%)		42/428 (9.8%)
Diarrhoea	76/288 (26.4%)		13/140 (9.3%)		89/428 (20.8%)
Dry mouth	23/288 (8%)		5/140 (3.6%)		28/428 (6.5%)
Dyspepsia	29/288 (10.1%)		2/140 (1.4%)		31/428 (7.2%)
Nausea	100/288 (34.7%)		24/140 (17.1%)		124/428 (29%)
Stomatitis	32/288 (11.1%)		6/140 (4.3%)		38/428 (8.9%)
Vomiting	27/288 (9.4%)		13/140 (9.3%)		40/428 (9.3%)
General disorders
Asthenia	52/288 (18.1%)		15/140 (10.7%)		67/428 (15.7%)
Fatigue	69/288 (24%)		25/140 (17.9%)		94/428 (22%)
Oedema peripheral	18/288 (6.3%)		2/140 (1.4%)		20/428 (4.7%)
Pyrexia	20/288 (6.9%)		8/140 (5.7%)		28/428 (6.5%)
Infections and infestations
Urinary tract infection	15/288 (5.2%)		3/140 (2.1%)		18/428 (4.2%)
Investigations
Alanine aminotransferase increased	113/288 (39.2%)		10/140 (7.1%)		123/428 (28.7%)
Aspartate aminotransferase increased	108/288 (37.5%)		14/140 (10%)		122/428 (28.5%)
Gamma-glutamyltransferase increased	26/288 (9%)		5/140 (3.6%)		31/428 (7.2%)
Weight decreased	27/288 (9.4%)		7/140 (5%)		34/428 (7.9%)
Metabolism and nutrition disorders
Decreased appetite	47/288 (16.3%)		9/140 (6.4%)		56/428 (13.1%)
Hyperglycaemia	104/288 (36.1%)		4/140 (2.9%)		108/428 (25.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	21/288 (7.3%)		12/140 (8.6%)		33/428 (7.7%)
Back pain	27/288 (9.4%)		11/140 (7.9%)		38/428 (8.9%)
Bone pain	9/288 (3.1%)		11/140 (7.9%)		20/428 (4.7%)
Muscle spasms	21/288 (7.3%)		5/140 (3.6%)		26/428 (6.1%)
Pain in extremity	19/288 (6.6%)		10/140 (7.1%)		29/428 (6.8%)
Nervous system disorders
Dizziness	35/288 (12.2%)		10/140 (7.1%)		45/428 (10.5%)
Dysgeusia	19/288 (6.6%)		4/140 (2.9%)		23/428 (5.4%)
Headache	27/288 (9.4%)		15/140 (10.7%)		42/428 (9.8%)
Tremor	18/288 (6.3%)		0/140 (0%)		18/428 (4.2%)
Psychiatric disorders
Anxiety	51/288 (17.7%)		15/140 (10.7%)		66/428 (15.4%)
Depression	60/288 (20.8%)		11/140 (7.9%)		71/428 (16.6%)
Insomnia	26/288 (9%)		11/140 (7.9%)		37/428 (8.6%)
Mood altered	15/288 (5.2%)		2/140 (1.4%)		17/428 (4%)
Respiratory, thoracic and mediastinal disorders
Cough	27/288 (9.4%)		9/140 (6.4%)		36/428 (8.4%)
Dyspnoea	22/288 (7.6%)		12/140 (8.6%)		34/428 (7.9%)
Skin and subcutaneous tissue disorders
Dry skin	22/288 (7.6%)		3/140 (2.1%)		25/428 (5.8%)
Pruritus	25/288 (8.7%)		4/140 (2.9%)		29/428 (6.8%)
Rash	37/288 (12.8%)		3/140 (2.1%)		40/428 (9.3%)
Vascular disorders
Hot flush	10/288 (3.5%)		11/140 (7.9%)		21/428 (4.9%)
Hypertension	33/288 (11.5%)		8/140 (5.7%)		41/428 (9.6%)

Limitations/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).

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