M Martín1, A Chan2, L Dirix3, J O'Shaughnessy4, R Hegg5, A Manikhas6, M Shtivelband7, P Krivorotko8, N Batista López9, M Campone10, M Ruiz Borrego11, Q J Khan12, J T Beck13, M Ramos Vázquez14, P Urban15, S Goteti16, E Di Tomaso17, C Massacesi18, S Delaloge19. 1. Medical Oncology Service, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain. 2. Curtin University and Breast Cancer Research Centre, Perth, Australia. 3. Department of Oncological Research, Sint-Augustinus Hospital, Antwerp, Belgium. 4. Baylor-Charles A. Sammons Cancer Center, Dallas, USA Texas Oncology, US Oncology, Dallas, USA. 5. Centro de Oncologia Clínica, Hospital Pérola Byington and FMUSP, Paulo São, Brazil. 6. City Clinical Oncological Dispensary, Saint Petersburg, Russian Federation. 7. Hematology and Medical Oncology, Ironwood Cancer and Research Centers, Chandler, USA. 8. Department of Breast Tumors, Petrov Research Institute of Oncology, Saint Petersburg, Russian Federation. 9. Medical Oncology Service, Hospital Universitario de Canarias, Tenerife, Spain. 10. Institut de Cancérologie de l'Ouest, Nantes René Gauducheau Centrede Recherche en Cancérologie, France. 11. Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Seville, Spain. 12. University of Kansas Medical Center, University of Kansas, Kansas City. 13. Highlands Oncology Group, Fayetteville, USA. 14. Centro Oncológico de Galicia, La Coruña, Spain. 15. Novartis Pharma AG, Basel, Switzerland. 16. Novartis Pharmaceuticals Corporation, East Hanover. 17. Novartis Institutes for BioMedical Research, Cambridge, USA. 18. Novartis Oncology, Paris, France. 19. Breast Cancer Group, Gustave Roussy Cancer Campus, Villejuif, France.
Abstract
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-ClassI 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.
RCT Entities:
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 humanepidermal 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.
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