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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)

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ClinicalTrials.gov Identifier: NCT01610284
Recruitment Status : Completed
First Posted : June 4, 2012
Last Update Posted : January 27, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Fulvestrant Drug: BKM120 Drug: BKM120 matching placebo Phase 3

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1149 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 Locally Advanced or Metastatic Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment
Actual Study Start Date : August 7, 2012
Actual Primary Completion Date : April 29, 2015
Actual Study Completion Date : April 19, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Fulvestrant

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




Primary Outcome Measures :
  1. Progression Free Survival (PFS) based on Local Investigator assessment - Full Analysis Set (FAS) [ Time Frame: up to approx. 8.3 months ]
    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.


Secondary Outcome Measures :
  1. Overall Survival (OS) - Full Analysis Set (FAS) [ Time Frame: up to approx. 32 months ]
    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 will be followed up for the duration of the study and for an expected average of every 3 months after end of treatment.

  2. Overall Response Rate (ORR) [ Time Frame: up to approx. 8.3 months ]
    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. 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.

  3. Clinical Benefit Rate (CBR) - Full Analysis Set (FAS) [ Time Frame: up to approx. 8.3 months ]
    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 24 weeks based on local investigator's assessment according to RECIST 1.1. CBR was analyzed in the full population. Only descriptive analysis performed.

  4. Number of Participants with On-Treatments Adverse Events, Serious Adverse Events, and Death [ Time Frame: at minimum at each study visit and up to approx. 10 months ]
    Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths. Only descriptive analysis performed.

  5. 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.

  6. 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.

  7. 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.

    Time to definitive deterioration of the ECOG PS by at least one category of the score from baseline was assessed for the two treatment arms in the FAS-Full population and all the subsets. The survival distributions were presented descriptively using Kaplan-Meier curves. Summary statistics from the Kaplan-Meier distributions were determined, including the median time to definitive deterioration along with 95% CI. Only descriptive analysis performed.


  8. 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 will be assessed up to approx. 8.3 months. Only descriptive analysis performed.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01610284


Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01610284    
Other Study ID Numbers: CBKM120F2302
2011-005524-17 ( EudraCT Number )
First Posted: June 4, 2012    Key Record Dates
Last Update Posted: January 27, 2020
Last Verified: January 2020
Individual Participant Data (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


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Breast cancer
Hormone receptor positive
HER2-negative
Metastatic
Locally advanced
PI3K
Fulvestrant
Refractory
Aromatase inhibitor
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Fulvestrant
Hormones
Aromatase Inhibitors
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action