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

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

Tracking Information

• First Submitted Date: June 29, 2012
• First Posted Date: July 4, 2012
• Results First Submitted Date: September 20, 2018
• Results First Posted Date: January 9, 2019
• Last Update Posted Date: January 30, 2019
• Actual Study Start Date: October 3, 2012
• Actual Primary Completion Date: May 23, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 8, 2019)

Progression Free Survival (PFS) Based on Local Investigator Assessment - Full Analysis Set (FAS) [ Time Frame: 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.

Original Primary Outcome Measures (submitted: June 29, 2012)

Progression Free Survival (PFS) [ Time Frame: Up to approx. 5.5 months ]

PFS is defined as time from date of randomization to the date of the event, defined as 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 randomization.

Current Secondary Outcome Measures (submitted: January 8, 2019)

• Overall Survival (OS) - Full Analysis Set (FAS) [ Time Frame: 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.
• Progression Free Survival (PFS) by PIK3CA Mutational Status [ Time Frame: 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.
• Overall Survival (OS) by PIK3CA Mutational Status [ Time Frame: 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.
• Overall Response Rate (ORR) by PIK3CA Mutational Status [ Time Frame: 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.
• Clinical Benefit Rate (CBR) by PIK3CA Mutational Status [ Time Frame: 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.
• Long-term Safety and Tolerability in the Two Treatment Arms - Safety Set (SS) [ Time Frame: 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.
• Plasma Concentration-time Profiles of BKM120 in Combination With Fulvestrant at Cycle 1 Day 1 - Pharmacokinetic Analysis Set (PAS) [ Time Frame: 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).
• Predose Trough Concentration-time Profile of BKM120 in Combination With Fulvestrant Over Time - Pharmacokinetic Analysis Set (PAS) [ Time Frame: 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.
• 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) [ Time Frame: 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.
• Time to Definitive Deterioration of ECOG Performance Status From Baseline - Full Analysis Set (FAS) [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: June 29, 2012)

• Overall survival (OS) [ Time Frame: Up to approx. 21 months ]
  Time from date of randomization to the date of death from any cause. Patients 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. 5.5 months ]
  Proportion of patients with best overall response of complete response (CR) or partial response (PR). ORR will be assessed according to RECIST 1.1 criteria. Patients will be followed up for the duration of the study and for an expected average of every 8 weeks after randomization.
• Clinical benefit rate (CBR) [ Time Frame: Up to approx. 5.5 months ]
  Proportion of patients with best overall response of complete response (CR) or partial response (PR). ORR will be assessed according to RECIST 1.1 criteria. Patients will be followed up for the duration of the study and for an expected average of every 8 weeks after randomization.
• Type, frequency and severity of adverse events [ Time Frame: at minimum at each study visit and up to approx. 8 months ]
  Safety will be determine 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-time profiles of BKM120 - pharmacokinetics (PK) [ Time Frame: C1D1, C1D15, C2D1,C3D1 and C4D1 (a cycle [C] = 4 weeks), D = Day ]
  Plasma concentration-time profiles of BKM120 and appropriate individual PK parameters.
• Patient reported outcome for global health status/QoL [ Time Frame: C1D1, C2D15, C4D1, then every 8 weeks until discontinuation (a cycle [C] = 4 weeks). ]
  Time to definitive deterioration in the global health status/QoL scale score. Change from baseline in the global health status/QOL scale score. Patients will be assessed up to approx. 5.5 months.

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

Descriptive Information

• Brief Title: 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
• 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

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).

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

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: September 12, 2017): 432
• Original Estimated Enrollment (submitted: June 29, 2012): 615
• Actual Study Completion Date: September 21, 2017
• Actual Primary Completion Date: May 23, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

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, Austria, Belgium, Bulgaria, Canada, Colombia, Finland, France, Germany, Greece, Hungary, Italy, Korea, Republic of, Lebanon, Netherlands, Norway, Poland, Spain, Sweden, Thailand, United Kingdom, United States
• Removed Location Countries: Russian Federation

Administrative Information

• NCT Number: NCT01633060
• Other Study ID Numbers: CBKM120F2303; 2012-002571-34 ( 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: Undecided

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: January 2019