Breast Cancer
Conditions
Keywords
BKM120, paclitaxel, breast cancer, metastatic, locally advanced, PI3K, PIK3CA, PTEN
Brief summary
This study evaluated whether the addition of daily BKM120 to weekly paclitaxel was effective and safe in treating patients with HER2- locally advanced or metastatic breast cancer.
Detailed description
Based on the efficacy results at the time of the interim analyses, the DMC recommended stopping the study at Phase II during the interim as it met the protocol pre-specified futility criteria. Consequently, the Phase III portion of the study was not conducted.
Interventions
DRUGPaclitaxel
intravenous paclitaxel 80 mg/m2 per week given until progression
Buparlisib maching plaxcebo were supplied as 100 mg and 50 mg hard gelatin capsules. Buparlisib placebo was dosed on a flat scale of mg/day and was not adjusted to body weight or body surface area.
DRUGBKM120
Buparlisib (BKM120) were supplied as 100 mg and 50 mg hard gelatin capsules. Buparlisib was dosed on a flat scale of mg/day and was not adjusted to body weight or body surface area.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Breast cancer that is locally advanced or metastatic * HER2 negative disease, and a known hormone receptor status - ER/PgR (common breast cancer classification tests) * A tumor sample must be shipped to a central lab for identification of biomarkers (PI3K activation status) before randomization * Adequate bone marrow and organ function * Measurable or non-measurable disease
Exclusion criteria
* Prior chemotherapy for locally advanced or metastatic disease * Previous treatment with PI3K or AKT inhibitors * Patient has symptomatic CNS metastases * Concurrent malignancy or malignancy within 3 years of study enrollment * Hematopoietic colony-stimulating growth factors or radiation within 2-4 weeks prior to starting study drug * Increasing or chronic treatment (\> 5 days) with corticosteroids or another immunosuppressive agent * Active heart (cardiac) disease as defined in the protocol * Known hypersensitivity or contraindications to use paclitaxel * Pregnant or nursing (lactating) woman * Certain scores on an anxiety and depression mood questionaire given at screening * Other protocol defined criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS)Assessed by Local Investigator's Assessment (Phase ll) | Every 8 weeks from randomization until disease progression up to 10 months after futility was analyzed | PFS was defined as the time from the date of randomization to the date of the event, defined as the first radiologically documented disease progression or death due to any cause. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (Phase ll) | every 8 weeks after randomization Up to 3 months after end of Treatment | Percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST v1.1. According to this criteria, CR = at least two determinations of CR at least 4 weeks apart before progression; PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Duration of Response (Phase Lll) | every 8 weeks after randomization Up to 3 months after end of Treatment | time from the date of the first documented response (CR or PR, which had to be confirmed subsequently) to the date of the first radiologically documented disease progression or death due to disease |
| Time to Response (Phase Lll) | every 8 weeks after randomization Up to 3 months after end of Treatment | time from date of randomization until first documented response (CR or PR, which has to be confirmed subsequently). |
| Overall Survival by Kaplan-Meier Estimate (Phase ll) | every 3 months until death, lost to follow-up, or withdrawal of consent to survival follow-up, up to 10 months after futility was analyzed | Overall survival (OS) was 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 contact. |
| Plasma Concentration-time Profiles of BKM120 - Pharmacokinetics (PK) (Phase Lll) | Cycle 1 day 1, 15, 16, 22 and Cycle 2 day 1. | Summary statistics for PK: plasma concentration-time profiles of BKM120 and appropriate individual PK parameters based on population PK model , if deemed appropriate; each cycle = 28 days |
| Time to Definitive Deterioration of ECOG Performance Status (Phase Lll) | every 4 weeks | Time to definitive deterioration of the ECOG performance status from baseline |
| Clinical Benefit Rate (CBR) (Phase ll) | every 8 weeks after randomization Up to 3 months after end of Treatment | CBR was defined as the percentage of patients with an overall response of CR or PR or SD or non-CR/non-PD lasting more than 24 weeks based on local Investigator's assessment according to RECIST v1.1. |
Countries
Australia, Austria, Belgium, Brazil, Canada, Czechia, France, Germany, Hong Kong, Hungary, Israel, Italy, Japan, Netherlands, Russia, Singapore, South Africa, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
416 patients randomized patients, 405 received the study treatment & 403 had at least 1 post-baseline safety assessment. Randomization of patients was stopped following DMC decision & all but 5 still benefiting from the treatment were discontinued. The DMC decision was based on pre-defined futility criteria at time of the adaptive interim analysis.
Pre-assignment details
A total of approximately 524 patients were to be randomized in a 1:1 ratio to one of the two treatment arms irrespective of the adaptation decision to continue in the full or PI3K pathway activated subpopulation. Randomization was stratified by PI3K activation and Hormone Receptor status.
Participants by arm
| Arm | Count |
|---|---|
| BKM120 and Paclitaxel Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received study drug plus paclitaxel | 207 |
| Placebo and Paclitaxel Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received placebo plus paclitaxel | 209 |
| Total | 416 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 43 | 15 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Parent/guardian decision | 14 | 9 |
| Overall Study | Physician Decision | 23 | 9 |
| Overall Study | Progressive disease | 59 | 82 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Study terminated by sponsor | 61 | 83 |
| Overall Study | Untreated | 4 | 7 |
Baseline characteristics
| Characteristic | BKM120 and Paclitaxel | Placebo and Paclitaxel | Total |
|---|---|---|---|
| Age, Continuous | 54.1 Years STANDARD_DEVIATION 11.13 | 55.6 Years STANDARD_DEVIATION 10.48 | 54.9 Years STANDARD_DEVIATION 10.89 |
| Sex: Female, Male Female | 207 Participants | 209 Participants | 416 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 196 / 202 | 188 / 201 |
| serious Total, serious adverse events | 61 / 202 | 42 / 201 |
Outcome results
Primary
Progression-free Survival (PFS)Assessed by Local Investigator's Assessment (Phase ll)
PFS was defined as the time from the date of randomization to the date of the event, defined as the first radiologically documented disease progression or death due to any cause. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Every 8 weeks from randomization until disease progression up to 10 months after futility was analyzed
Population: FAS per Expert Report: All pts randomized to study treatment. Per ITT principle, pts were analyzed according to treatment \& strata. FAS was primary population for analysis of efficacy endpoints at interim. 338 pts were randomized (between 16-Aug-2012 \& 07-Jun-2014) in 1:1 ratio to buparlisib + paclitaxel arm N=168 or placebo + paclitaxel arm N=170.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BKM120 and Paclitaxel | Progression-free Survival (PFS)Assessed by Local Investigator's Assessment (Phase ll) | 8.0 Months |
| Placebo and Paclitaxel | Progression-free Survival (PFS)Assessed by Local Investigator's Assessment (Phase ll) | 9.2 Months |
95% CI: [0.82, 1.68]
Secondary
Clinical Benefit Rate (CBR) (Phase ll)
CBR was defined as the percentage of patients with an overall response of CR or PR or SD or non-CR/non-PD lasting more than 24 weeks based on local Investigator's assessment according to RECIST v1.1.
Time frame: every 8 weeks after randomization Up to 3 months after end of Treatment
Population: FAS per Expert Report: All pts randomized to study treatment. Per ITT principle, pts were analyzed according to treatment \& strata. FAS was primary population for analysis of efficacy endpoints at interim. 338 pts were randomized (between 16-Aug-2012 \& 07-Jun-2014) in 1:1 ratio to buparlisib + paclitaxel arm N=168 or placebo + paclitaxel arm N=170.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BKM120 and Paclitaxel | Clinical Benefit Rate (CBR) (Phase ll) | 26.2 Percentage of participants |
| Placebo and Paclitaxel | Clinical Benefit Rate (CBR) (Phase ll) | 32.9 Percentage of participants |
Secondary
Duration of Response (Phase Lll)
time from the date of the first documented response (CR or PR, which had to be confirmed subsequently) to the date of the first radiologically documented disease progression or death due to disease
Time frame: every 8 weeks after randomization Up to 3 months after end of Treatment
Population: PFS, ORR and CBR were analyzed and reported at the interim analysis. Given the study met the futility analysis per protocol, the duration of response was removed as a secondary endpoint in the final analysis and consequently not analyzed.
Secondary
Overall Response Rate (Phase ll)
Percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST v1.1. According to this criteria, CR = at least two determinations of CR at least 4 weeks apart before progression; PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: every 8 weeks after randomization Up to 3 months after end of Treatment
Population: FAS per Expert Report: All pts randomized to study treatment. Per ITT principle, pts were analyzed according to treatment \& strata. FAS was primary population for analysis of efficacy endpoints at interim. 338 pts were randomized (between 16-Aug-2012 \& 07-Jun-2014) in 1:1 ratio to buparlisib + paclitaxel arm N=168 or placebo + paclitaxel arm N=170.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BKM120 and Paclitaxel | Overall Response Rate (Phase ll) | 22.6 Percentage of participants |
| Placebo and Paclitaxel | Overall Response Rate (Phase ll) | 27.1 Percentage of participants |
Secondary
Overall Survival by Kaplan-Meier Estimate (Phase ll)
Overall survival (OS) was 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 contact.
Time frame: every 3 months until death, lost to follow-up, or withdrawal of consent to survival follow-up, up to 10 months after futility was analyzed
Population: Full analysis set (FAS) comprises all patients who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BKM120 and Paclitaxel | Overall Survival by Kaplan-Meier Estimate (Phase ll) | 29.5 Months |
| Placebo and Paclitaxel | Overall Survival by Kaplan-Meier Estimate (Phase ll) | NA Months |
Secondary
Plasma Concentration-time Profiles of BKM120 - Pharmacokinetics (PK) (Phase Lll)
Summary statistics for PK: plasma concentration-time profiles of BKM120 and appropriate individual PK parameters based on population PK model , if deemed appropriate; each cycle = 28 days
Time frame: Cycle 1 day 1, 15, 16, 22 and Cycle 2 day 1.
Population: PFS, ORR and CBR were analyzed and reported at the interim analysis. Given the study met the futility analysis per protocol, the plasma concentration-time profiles was removed as a secondary endpoint in the final analysis and consequently not analyzed.
Secondary
Time to Definitive Deterioration of ECOG Performance Status (Phase Lll)
Time to definitive deterioration of the ECOG performance status from baseline
Time frame: every 4 weeks
Population: PFS, ORR and CBR were analyzed and reported at the interim analysis. Given the study met the futility analysis per protocol, the time to definitive deterioration of ECOG performance status was removed as a secondary endpoint in the final analysis and consequently not analyzed.
Secondary
Time to Response (Phase Lll)
time from date of randomization until first documented response (CR or PR, which has to be confirmed subsequently).
Time frame: every 8 weeks after randomization Up to 3 months after end of Treatment
Population: PFS, ORR and CBR were analyzed and reported at the interim analysis. Given the study met the futility analysis per protocol, time to response was removed as a secondary endpoint in the final analysis and consequently not analyzed.