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

Metastatic Breast Cancer Clinical Trial

— BELLE-3  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01633060
• Other study ID #: CBKM120F2303
• Secondary ID: 2012-002571-34
• Status: Terminated
• Phase: Phase 3
• Start date: October 3, 2012
• Est. completion date: September 21, 2017

Study information

• Verified date: January 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 432
• Est. completion date: September 21, 2017
• Est. primary completion date: May 23, 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• Fulvestrant
Intramuscular fulvestrant 500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)
• BKM120
BKM120 100 mg once daily
• BKM120 matching placebo
BKM120 matching placebo, once daily

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Rio Negro	Viedma
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	San Miguel De Tucuman	Tucuman
Austria	Novartis Investigative Site	Innsbruck	Tyrol
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Belgium	Novartis Investigative Site	Namur
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Varna
Bulgaria	Novartis Investigative Site	Vratsa
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Monteria
Finland	Novartis Investigative Site	Tampere
France	Novartis Investigative Site	Angers Cedex 02
France	Novartis Investigative Site	Clermont-Ferrand
France	Novartis Investigative Site	Limoges cedex	Haute Vienne
France	Novartis Investigative Site	Lyon Cedex
France	Novartis Investigative Site	Nice Cedex 2	Alpes Maritimes
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Reims Cedex	Marne
France	Novartis Investigative Site	Rouen Cedex 1
France	Novartis Investigative Site	Saint-Brieuc Cédex
France	Novartis Investigative Site	Saint-Cloud	Hauts De Seine
France	Novartis Investigative Site	Saint-Herblain Cédex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Fulda
Germany	Novartis Investigative Site	Karlsruhe
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Leer
Germany	Novartis Investigative Site	Magdeburg
Germany	Novartis Investigative Site	Mannheim
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Mühlhausen
Germany	Novartis Investigative Site	Ravensburg
Germany	Novartis Investigative Site	Soest
Germany	Novartis Investigative Site	Tuebingen
Germany	Novartis Investigative Site	Ulm
Germany	Novartis Investigative Site	Velbert
Greece	Novartis Investigative Site	Athens	GR
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Heraklion Crete
Greece	Novartis Investigative Site	Larissa	GR
Greece	Novartis Investigative Site	Marousi	Athens
Greece	Novartis Investigative Site	Patra - RIO	GR
Greece	Novartis Investigative Site	Thesaloniki	Thessaloniki
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Szeged
Hungary	Novartis Investigative Site	Szolnok
Italy	Novartis Investigative Site	Bari	BA
Italy	Novartis Investigative Site	Benevento	BN
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Brindisi	BR
Italy	Novartis Investigative Site	Candiolo	TO
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Cona	FE
Italy	Novartis Investigative Site	Cremona	CR
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Frattamaggiore
Italy	Novartis Investigative Site	Ivrea	TO
Italy	Novartis Investigative Site	L'Aquila	AQ
Italy	Novartis Investigative Site	Lecce	LE
Italy	Novartis Investigative Site	Lecco	LC
Italy	Novartis Investigative Site	Macerata	MC
Italy	Novartis Investigative Site	Meldola	FC
Italy	Novartis Investigative Site	Messina	ME
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Mirano	VE
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Monserrato	CA
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Padova	PD
Italy	Novartis Investigative Site	Parma	PR
Italy	Novartis Investigative Site	Pavia	PV
Italy	Novartis Investigative Site	Pisa	PI
Italy	Novartis Investigative Site	Pordenone	PN
Italy	Novartis Investigative Site	Prato	PO
Italy	Novartis Investigative Site	Reggio Calabria	RC
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Salerno	SA
Italy	Novartis Investigative Site	Sassari	SS
Italy	Novartis Investigative Site	Sora	FR
Italy	Novartis Investigative Site	Torino	TO
Italy	Novartis Investigative Site	Verona	VR
Korea, Republic of	Novartis Investigative Site	Gyeonggi-do	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Lebanon	Novartis Investigative Site	Ashrafieh
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Saida
Netherlands	Novartis Investigative Site	Breda
Netherlands	Novartis Investigative Site	Delft
Netherlands	Novartis Investigative Site	Deventer
Netherlands	Novartis Investigative Site	Hoofddorp
Netherlands	Novartis Investigative Site	Leiden
Netherlands	Novartis Investigative Site	Maastricht	AZ
Netherlands	Novartis Investigative Site	Sittard-Geleen
Netherlands	Novartis Investigative Site	Zwolle
Norway	Novartis Investigative Site	Bergen
Norway	Novartis Investigative Site	Oslo
Poland	Novartis Investigative Site	Olsztyn
Spain	Novartis Investigative Site	Badalona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Castellon	Comunidad Valenciana
Spain	Novartis Investigative Site	Elche	Alicante
Spain	Novartis Investigative Site	Jaen	Andalucia
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	La Laguna	Santa Cruz De Tenerife
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Palma De Mallorca	Islas Baleares
Spain	Novartis Investigative Site	Santa Cruz de Tenerife
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Sweden	Novartis Investigative Site	Kalmar
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Uppsala
Thailand	Novartis Investigative Site	Bangkok
United Kingdom	Novartis Investigative Site	Blackburn	Lancashire
United Kingdom	Novartis Investigative Site	Edinburgh
United Kingdom	Novartis Investigative Site	Ipswich	Suffolk
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Nottingham
United States	University Cancer & Blood Center, LLC	Athens	Georgia
United States	Emory University School of Medicine/Winship Cancer Institute Emory	Atlanta	Georgia
United States	University of Maryland Medical Center Univ Maryland	Baltimore	Maryland
United States	Montefiore Medical Center Montefiore	Bronx	New York
United States	Ironwood Cancer and Research Centers SC	Chandler	Arizona
United States	Texas Oncology P A SC-Austin	Dallas	Texas
United States	Texas Oncology P A Texas Oncology - Fort Worth (3	Dallas	Texas
United States	Texas Oncology PA Dallas Presbyterian Hospital SC	Dallas	Texas
United States	Texas Oncology Texas Oncology - Sammons	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Rocky Mountain Cancer Centers SC	Denver	Colorado
United States	Texas Tech University Health Science Center Dept of Texas Tech	El Paso	Texas
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	Compassionate Cancer Care Medical Group CCCMG	Fountain Valley	California
United States	Moanalua Medical Center. Attn: Oncology Dept	Honolulu	Hawaii
United States	The Methodist Hospital Cancer Center	Houston	Texas
United States	Clinical Research Alliance	Lake Success	New York
United States	Clinical Research Alliance BKM120F2303	Lake Success	New York
United States	Cedars Sinai Medical Center SC-5	Los Angeles	California
United States	Los Angeles Hematology/Oncology Medical Group Onc Dept.	Los Angeles	California
United States	University of California at Los Angeles UCLA SC	Los Angeles	California
United States	Mercy Medical Research Institute SC	Manchester	Missouri
United States	The West Clinic Dept. of the West Clinic	Memphis	Tennessee
United States	Crescent City Research Consortium, LLC SC	Metairie	Louisiana
United States	University of South Alabama / Mitchell Cancer Institute Univ South AL	Mobile	Alabama
United States	Pacific Cancer Care	Monterey	California
United States	Morristown Memorial Hospital Morristown Mem	Morristown	New Jersey
United States	Edward Hospital Edward Hospital	Naperville	Illinois
United States	John Ochsner Heart and Vascular Institute Clinical Trials Ochsner 2	New Orleans	Louisiana
United States	LSU Health Sciences Center Feist-Weiller Cancer Center	New Orleans	Louisiana
United States	Lsu Health Sciences Center/ Lsu School of Medicine Lsu	New Orleans	Louisiana
United States	University of Pittsburgh Cancer Institute Dept of Magee Women's Hospital	Pittsburgh	Pennsylvania
United States	Northwest Cancer Specialists Compass Oncology -BKM	Portland	Oregon
United States	Oregon Health and Science University SC-5	Portland	Oregon
United States	Northwest Medical Specialties	Tacoma	Washington
United States	US Oncology, P.A.	Tyler	Texas
United States	CINJ at Cooper University Hospital Dept of Onc	Voorhees	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  Bulgaria,  Canada,  Colombia,  Finland,  France,  Germany,  Greece,  Hungary,  Italy,  Korea, Republic of,  Lebanon,  Netherlands,  Norway,  Poland,  Spain,  Sweden,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS) Based on Local Investigator Assessment - Full Analysis Set (FAS)	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.	Every 6 weeks after randomization up to a maximum of 4 years
Secondary	Overall Survival (OS) - Full Analysis Set (FAS)	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.	Every 6 weeks after randomization up to a maximum of 5 years
Secondary	Progression Free Survival (PFS) by PIK3CA Mutational Status	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.	Every 6 weeks after randomization up to a maximum of 5 years
Secondary	Overall Survival (OS) by PIK3CA Mutational Status	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.	Every 6 weeks after randomization up to a maximum of 5 years
Secondary	Overall Response Rate (ORR) by PIK3CA Mutational Status	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.	Every 6 weeks after randomization up to a maximum of 5 years
Secondary	Clinical Benefit Rate (CBR) by PIK3CA Mutational Status	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.	Week 14, Week 24
Secondary	Long-term Safety and Tolerability in the Two Treatment Arms - Safety Set (SS)	Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths.	From first dose of study treatment to 30 days after last dose of study treatment, up to 5 years
Secondary	Plasma Concentration-time Profiles of BKM120 in Combination With Fulvestrant at Cycle 1 Day 1 - Pharmacokinetic Analysis Set (PAS)	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).	C1D1 1 hour post dose, C1D1 2 hour post dose, C1D1 6 hour post dose and C1D1 9 hour post dose
Secondary	Predose Trough Concentration-time Profile of BKM120 in Combination With Fulvestrant Over Time - Pharmacokinetic Analysis Set (PAS)	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.	C1D15, C2D1, C3D1 and C4D1
Secondary	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)	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.	Baseline, Week 6 (C2D15), Week 12 (C4D1), then every 8 weeks until discontinuation (a cycle [C] = 4 weeks) up to 5 years.
Secondary	Time to Definitive Deterioration of ECOG Performance Status From Baseline - Full Analysis Set (FAS)	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.	Screening, Baseline (Cycle 1 Day 1) and then at day 1 of each cycle and at the EOT visit