Phase III Study of BKM120/Placebo With Fulvestrant in Postmenopausal Patients With Hormone Receptor Positive HER2-negative Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitor (BELLE-2)

• ClinicalTrials.gov Identifier: NCT01610284
• Recruitment Status: Completed
• First Posted: June 4, 2012
• Results First Posted: June 18, 2020
• Last Update Posted: August 25, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: May 11, 2012
• First Posted Date: June 4, 2012
• Results First Submitted Date: April 15, 2020
• Results First Posted Date: June 18, 2020
• Last Update Posted Date: August 25, 2020
• Actual Study Start Date: August 7, 2012
• Actual Primary Completion Date: April 29, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2020)

Progression Free Survival (PFS) Based on Local Investigator Assessment - Full Analysis Set (FAS) in Full Population, Main Study Cohort and PI3K Unknown Cohort [ Time Frame: Date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to approximately 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.

Original Primary Outcome Measures (submitted: June 1, 2012)

Progression free survival (PFS) [ Time Frame: up to approx. 8.3 months ]

PFS is defined as the time from the date of randomization until the date of the first radiologically documented disease progression or death due to any cause. PFS is based on local investigator assessment. Patients will be followed up for the duration of the study and for an expected average of every 8 weeks after randomisation. Patients will be assessed

Current Secondary Outcome Measures (submitted: June 3, 2020)

• Overall Survival (OS) - Full Analysis Set (FAS) in Full Population, Main Study Cohort and PI3K Unknown Cohort [ Time Frame: Every 3 months following end of treatment visit, assessed for approximately 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 for the duration of the study and for an expected average of every 3 months after end of treatment.
• Overall Response Rate (ORR) - Full Analysis Set (FAS) in Full Population, Main Study Cohort and PI3K Unknown Cohort [ Time Frame: From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 5 years ]
  Overall Response Rate (ORR) is defined as the percentage 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. 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. Only descriptive analysis performed.
• Clinical Benefit Rate (CBR) - Full Analysis Set (FAS) in Full Population, Main Study Cohort and PI3K Unknown Cohort [ Time Frame: From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 5 years ]
  Clinical Benefit Rate (CBR) is defined as the percentage 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 24 weeks based on local investigator's assessment according to RECIST 1.1. CBR was analyzed in the full population. Only descriptive analysis performed.
• Number of Participants With On-Treatments Adverse Events, Serious Adverse Events and Deaths [ Time Frame: From first dose of study treatment to 30 days after last dose of study treatment, assessed for approximately 5 years ]
  Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths. Only descriptive analysis performed.
• Plasma Concentration-time Profiles of BKM120 in Combination With Fulvestrant at Cycle 2 Day 1 [ Time Frame: Cycle2 Day1 (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours post-dose). Each cycle is 28 days. ]
  Plasma samples were collected from the first 200 BKM120-treated patients on Cycle 2 Day 1 (at pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h and 24h [before Cycle 2 Day 2 dose] post-dose). Each cycle is 28 days. Only descriptive analysis performed.
• Predose Trough Concentration-time Profile of BKM120 in Combination With Fulvestrant Over Time - Pharmacokinetic Analysis Set (PAS) [ Time Frame: Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1. Each cycle is 28 days. ]
  Pre-dose samples were collected for trough concentrations at Cycle 2 Day 1, Cycle 2 Day 15 and Cycle 3 Day 1. Each cycle is 28 days. Only descriptive analysis performed.
• Median Time to Definitive Deterioration of the ECOG Performance Status - Full Analysis Set (FAS) [ Time Frame: Up to approx 27 months ]
  Time to definitive deterioration of the ECOG PS was defined as the time between the date of randomization and the date of the assessment at which definitive deterioration was seen. Only descriptive analysis performed.
• Health-related Quality of Life (HRQoL):Time to 10% Definitive Deterioration in the Global Health Status/Quality of Life Per EORTC-QLQ-C30 [ Time Frame: Cycle 1 day 1, cycle 1 day 15, 6 weeks after randomisation and then every 8 weeks until end of treatment ]
  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. Patients were assessed up to approx. 8.3 months. Only descriptive analysis performed.

Original Secondary Outcome Measures (submitted: June 1, 2012)

• Overall survival (OS) [ Time Frame: up to approx. 32 months ]
  Time from date of randomization to the date of death from any causPatients will be followed up for the duration of the study and for an expected average of every 3 months after end of treatment.
• Overall response rate (ORR) [ Time Frame: up to approx. 8.3 months ]
  Proportion of patients with best overall response of complete response (CR) or partial response (PR) based according to RECIST 1.1.Patients will be followed up for the duration of the study and for an expected average of every 8 weeks after randomisation.
• Clinical benefit rate (CBR) [ Time Frame: up to approx. 8.3 months ]
  Proportion of patients with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) lasting more than 24 weeks as defined in RECIST 1.1. Patients will be followed up for the duration of the study and for an expected average of every 8 weeks after randomisation.
• Type, frequency and severity of adverse events [ Time Frame: at minimum at each study visit and up to approx. 10 months ]
  Safety will be determined by type, frequency and severity of adverse events per CTCAEv4.03 and type, frequency and severity of laboratory toxicities per CTCAEv4.03. Patients will be followed up for the duration of the study.
• Plasma concentration of BKM120 and Fulvestrant (Pharmacokinetics) [ Time Frame: Cycle 1 day 1, Cycle 1 day 15, cycle 2 day 1, cycle 2 day 2, cycle 2 day 15, cycle 3 day 1, cycle 4 day 1, cycle 5 day 1 and cycle 6 day 1 ]
  PK parameters; Patients will be assessed up to approx. 6 months after randomisation date. cycle = 28 days
• Time profile of BKM120 and Fulvestrant (Pharmacokinetics) [ Time Frame: Cycle 1 day 1, Cycle 1 day 15, cycle 2 day 1, cycle 2 day 2, cycle 2 day 15, cycle 3 day 1, cycle 4 day 1, cycle 5 day 1 and cycle 6 day 1 ]
  PK parameters; Patients will be assessed up to approx. 6 months after randomisation date. cycle = 28 days
• Patient reported outcomes for global health status/QOL [ Time Frame: Cycle 1 day 1, cycle 1 day 15, 6 weeks after randomisation and then every 8 weeks until end of treatment ]
  Time to definitive deterioration in global health status/QOL; Change from baseline in global health status/Quality of Life (QOL). Patients will be assessed up to approx. 8.3 months

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase III Study of BKM120/Placebo With Fulvestrant in Postmenopausal Patients With Hormone Receptor Positive HER2-negative Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitor
• Official Title: A Phase III Randomized, Double Blind Placebo Controlled Study of BKM120 With Fulvestrant, in Postmenopausal Women With Hormone Receptor-positive HER2-negative Locally Advanced or Metastatic Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment
• Brief Summary: This study was a multi-center, randomized, double-blind, placebo controlled Phase III study to determine the efficacy and safety of treatment with buparlisib plus fulvestrant versus fulvestrant plus placebo in postmenopausal women with hormone Receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative), locally advanced or metastatic breast cancer (MBC) whose disease has progressed on or after aromatase inhibitor (AI) treatment.

Detailed Description

Patients were randomized (1:1) to receive buparlisib (100 mg/day) or placebo with fulvestrant (500 mg); randomization was stratified by PI3K pathway activation status (activated, non-activated, unknown determined in archival tumor tissue) and visceral disease status (present or absent). Tumor evaluation was performed 6 weeks after the randomization date and then every 8 weeks until radiological progression (based on Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1).

Novartis made the decision not to pursue further development of buparlisib and to terminate the ongoing studies in the program. Accordingly, on 19-Dec-2016, Novartis notified all the Investigators about the decision not to pursue further development of buparlisib in Breast Cancer. As a result, the CBKM120F2302 study was terminated on 19-Apr-2019 (last subject last visit).

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• 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
• Drug: BKM120 matching placebo
  BKM120 matching placebo, once daily

Study Arms

• Experimental: BKM120 100mg + Fulvestrant
  BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.
  Interventions:

  • Drug: Fulvestrant
  • Drug: BKM120
• Placebo Comparator: Placebo + Fulvestrant
  BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
  Interventions:

  • Drug: Fulvestrant
  • Drug: BKM120 matching placebo

Publications *

• Campone M, Im SA, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Cortes J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Le Mouhaer S, Sankaran B, Bourdeau L, El-Hashimy M, Sellami D, Baselga J. Buparlisib plus fulvestrant versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: Overall survival results from BELLE-2. Eur J Cancer. 2018 Nov;103:147-154. doi: 10.1016/j.ejca.2018.08.002. Epub 2018 Sep 18.
• Baselga J, Im SA, Iwata H, Cortes J, De Laurentiis M, Jiang Z, Arteaga CL, Jonat W, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Takahashi M, Vuylsteke P, Hachemi S, Dharan B, Di Tomaso E, Urban P, Massacesi C, Campone M. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):904-916. doi: 10.1016/S1470-2045(17)30376-5. Epub 2017 May 30. Erratum In: Lancet Oncol. 2019 Feb;20(2):e71-e72.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 3, 2020): 1147
• Original Estimated Enrollment (submitted: June 1, 2012): 842
• Actual Study Completion Date: April 19, 2019
• Actual Primary Completion Date: April 29, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Locally advanced or metastatic breast cancer
• HER2-negative and hormone receptor-positive status (common breast cancer classification tests)
• Postmenopausal woman
• A tumor sample must be shipped to a Novartis designated laboratory for identification of biomarkers (PI3K activation status)
• Progression or recurrence of breast cancer while on or after aromatase inhibitor treatment
• Measurable disease or non measurable disease bone lesions in the absence of measurable disease as per RECIST 1.1
• Adequate bone marrow and organ function defined by laboratory values

Key Exclusion Criteria:

• Previous treatment with PI3K inhibitors, AKT inhibitors, mTOR inhibitor or fulvestrant
• More than one prior chemotherapy line for metastatic disease
• Symptomatic brain metastases
• Increasing or chronic treatment (> 5 days) with corticosteroids or another immunosuppressive agent
• Active heart (cardiac) disease as defined in the protocol
• Certain scores on an anxiety and depression mood questionnaires

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Netherlands, Peru, Poland, Russian Federation, Singapore, Slovakia, South Africa, Spain, Switzerland, Taiwan, Thailand, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01610284
• Other Study ID Numbers: CBKM120F2302; 2011-005524-17 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: August 2020