A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4)
© The Author 2016.Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
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Oxford University Press
2017
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| Online Access: | http://hdl.handle.net/20.500.11937/57649 |
| _version_ | 1848760186283491328 |
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| author | Martín, M. Chan, Arlene Dirix, L. O'Shaughnessy, J. Hegg, R. Manikhas, A. Shtivelband, M. Krivorotko, P. Batista López, N. Campone, M. Ruiz Borrego, M. Khan, Q. Beck, J. Ramos Vázquez, M. Urban, P. Goteti, S. Di Tomaso, E. Massacesi, C. Delaloge, S. |
| author_facet | Martín, M. Chan, Arlene Dirix, L. O'Shaughnessy, J. Hegg, R. Manikhas, A. Shtivelband, M. Krivorotko, P. Batista López, N. Campone, M. Ruiz Borrego, M. Khan, Q. Beck, J. Ramos Vázquez, M. Urban, P. Goteti, S. Di Tomaso, E. Massacesi, C. Delaloge, S. |
| author_sort | Martín, M. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | © The Author 2016.Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2- negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after = 125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. Results: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (= 40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Conclusions: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II. |
| first_indexed | 2025-11-14T10:11:46Z |
| format | Journal Article |
| id | curtin-20.500.11937-57649 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T10:11:46Z |
| publishDate | 2017 |
| publisher | Oxford University Press |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-576492017-11-24T05:45:58Z A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4) Martín, M. Chan, Arlene Dirix, L. O'Shaughnessy, J. Hegg, R. Manikhas, A. Shtivelband, M. Krivorotko, P. Batista López, N. Campone, M. Ruiz Borrego, M. Khan, Q. Beck, J. Ramos Vázquez, M. Urban, P. Goteti, S. Di Tomaso, E. Massacesi, C. Delaloge, S. © The Author 2016.Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2- negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after = 125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. Results: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (= 40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Conclusions: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II. 2017 Journal Article http://hdl.handle.net/20.500.11937/57649 10.1093/annonc/mdw562 Oxford University Press restricted |
| spellingShingle | Martín, M. Chan, Arlene Dirix, L. O'Shaughnessy, J. Hegg, R. Manikhas, A. Shtivelband, M. Krivorotko, P. Batista López, N. Campone, M. Ruiz Borrego, M. Khan, Q. Beck, J. Ramos Vázquez, M. Urban, P. Goteti, S. Di Tomaso, E. Massacesi, C. Delaloge, S. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4) |
| title | A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4) |
| title_full | A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4) |
| title_fullStr | A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4) |
| title_full_unstemmed | A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4) |
| title_short | A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4) |
| title_sort | randomized adaptive phase ii/iii study of buparlisib, a pan-class i pi3k inhibitor, combined with paclitaxel for the treatment of her2- advanced breast cancer (belle-4) |
| url | http://hdl.handle.net/20.500.11937/57649 |