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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01633060
Recruitment Status : Terminated (Novartis decided not to pursue further development of buparlisib program (assessment of moderate PFS benefit with know, but manageable, buparlisib profile).)
First Posted : July 4, 2012
Results First Posted : January 9, 2019
Last Update Posted : January 30, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE June 29, 2012
First Posted Date  ICMJE July 4, 2012
Results First Submitted Date  ICMJE September 20, 2018
Results First Posted Date  ICMJE January 9, 2019
Last Update Posted Date January 30, 2019
Actual Study Start Date  ICMJE October 3, 2012
Actual Primary Completion Date May 23, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE 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  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Breast Cancer
Intervention  ICMJE
  • 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  ICMJE
  • 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, Lønning PE, Janni W, O'Regan R, Mouret-Reynier MA, Kalev D, Egle D, Csőszi 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 12, 2017)
432
Original Estimated Enrollment  ICMJE
 (submitted: June 29, 2012)
615
Actual Study Completion Date  ICMJE September 21, 2017
Actual Primary Completion Date May 23, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE 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  ICMJE NCT01633060
Other Study ID Numbers  ICMJE 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  ICMJE
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

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP