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).
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.



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.



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.



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.
Medical Oncology Service, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain.
M
M
Martín
Curtin University and Breast Cancer Research Centre, Perth, Australia.
A
A
Chan
Department of Oncological Research, Sint-Augustinus Hospital, Antwerp, Belgium.
L
L
Dirix
Baylor-Charles A. Sammons Cancer Center, Dallas, USA Texas Oncology, US Oncology, Dallas, USA.
J
J
O'Shaughnessy
Centro de Oncologia Clínica, Hospital Pérola Byington and FMUSP, Paulo São, Brazil.
R
R
Hegg
City Clinical Oncological Dispensary, Saint Petersburg, Russian Federation.
A
A
Manikhas
Hematology and Medical Oncology, Ironwood Cancer and Research Centers, Chandler, USA.
M
M
Shtivelband
Department of Breast Tumors, Petrov Research Institute of Oncology, Saint Petersburg, Russian Federation.
P
P
Krivorotko
Medical Oncology Service, Hospital Universitario de Canarias, Tenerife, Spain.
N
N
Batista López
Institut de Cancérologie de l'Ouest, Nantes René Gauducheau Centrede Recherche en Cancérologie, France.
M
M
Campone
Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Seville, Spain.
M
M
Ruiz Borrego
University of Kansas Medical Center, University of Kansas, Kansas City.
Q J
QJ
Khan
Highlands Oncology Group, Fayetteville, USA.
J T
JT
Beck
Centro Oncológico de Galicia, La Coruña, Spain.
M
M
Ramos Vázquez
Novartis Pharma AG, Basel, Switzerland.
P
P
Urban
Novartis Pharmaceuticals Corporation, East Hanover.
S
S
Goteti
Novartis Institutes for BioMedical Research, Cambridge, USA.
E
E
Di Tomaso
Novartis Oncology, Paris, France.
C
C
Massacesi
Breast Cancer Group, Gustave Roussy Cancer Campus, Villejuif, France.
S
S
Delaloge
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage; D017239:Paclitaxel / Q000008:administration & dosage; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
D000631:Aminopyridines; D009025:Morpholines; D017239:Paclitaxel; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C571178:NVP-BKM120; C508053:ERBB2 protein, human
HER2−; PI3K pathway; advanced breast cancer; breast cancer; buparlisib (BKM120); paclitaxel