title: Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial.
abstract: Phosphatidylinositol 3-kinase (PI3K) pathway activation in squamous cell carcinoma of the head and neck contributes to treatment resistance and disease progression. Buparlisib, a pan-PI3K inhibitor, has shown preclinical antitumour activity and objective responses in patients with epithelial malignancies. We assessed whether the addition of buparlisib to paclitaxel improves clinical outcomes compared with paclitaxel and placebo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
  
  
  
  In this multicentre, randomised, double-blind, placebo-controlled phase 2 study (BERIL-1), we recruited patients aged 18 years and older with histologically or cytologically confirmed recurrent and metastatic squamous cell carcinoma of the head and neck after disease progression on or after one previous platinum-based chemotherapy regimen in the metastatic setting. Eligible patients were enrolled from 58 centres across 18 countries and randomly assigned (1:1) to receive second-line oral buparlisib (100 mg once daily) or placebo, plus intravenous paclitaxel (80 mg/m2on days 1, 8, 15, and 22) in 28 day treatment cycles. Randomisation was done via a central patient screening and randomisation system with an interactive (voice and web) response system and stratification by number of previous lines of therapy in the recurrent and metastatic setting and study site. Patients and investigators (including local radiologists) were masked to treatment assignment from randomisation until the final overall survival analysis. The primary endpoint was progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in all randomly assigned patients. Efficacy analyses were done on the intention-to-treat population, whereas safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01852292, and is ongoing but no longer enrolling patients.
  
  
  
  Between Nov 5, 2013, and May 5, 2015, 158 patients were enrolled and randomly assigned to receive either buparlisib plus paclitaxel (n=79) or placebo plus paclitaxel (n=79). Median progression-free survival was 4·6 months (95% CI 3·5-5·3) in the buparlisib group and 3·5 months (2·2-3·7) in the placebo group (hazard ratio 0·65 [95% CI 0·45-0·95], nominal one-sided p=0·011). Grade 3-4 adverse events were reported in 62 (82%) of 76 patients in the buparlisib group and 56 (72%) of 78 patients in the placebo group. The most common grade 3-4 adverse events (occurring in ≥10% of patients in the buparlisib group vs the placebo group) were hyperglycaemia (17 [22%] of 76 vs two [3%] of 78), anaemia (14 [18%] vs nine [12%]), neutropenia (13 [17%] vs four [5%]), and fatigue (six [8%] vs eight [10%]). Serious adverse events (regardless of relation to study treatment) were reported for 43 (57%) of 76 patients in the buparlisib group and 37 (47%) of 78 in the placebo group. On-treatment deaths occurred in 15 (20%) of 76 patients in the buparlisib group and 17 (22%) of 78 patients in the placebo group; most were caused by disease progression and none were judged to be related to study treatment.
  
  
  
  On the basis of the improved clinical efficacy with a manageable safety profile, the results of this randomised phase 2 study suggest that buparlisib in combination with paclitaxel could be an effective second-line treatment for patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck. Further phase 3 studies are warranted to confirm this phase 2 finding.
  
  
  
  Novartis Pharmaceuticals Corporation.
authors.affiliation: Department of Medicine, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Soulières
authors.affiliation: Oncology Unit, Hôpitaux Universitaires Paris Nord Val de Seine, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.affiliation: Medical Oncology Department, Institut Català d'Oncologia L'Hospitalet, Barcelona, Spain.
authors.forename: Ricard
authors.initials: R
authors.lastname: Mesía
authors.affiliation: Head, Neck and Jaw, Reconstructive Plastic Surgery and Laser Surgery Department, Országos Onkológiai Intézet, Budapest, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Remenár
authors.affiliation: Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shau-Hsuan
authors.initials: SH
authors.lastname: Li
authors.affiliation: Department of Oncology, Leningrad Regional Oncology Dispensary, Saint Petersburg, Russian Federation.
authors.forename: Andrey
authors.initials: A
authors.lastname: Karpenko
authors.affiliation: Department of Medicine, Prince of Songkla University, Songkhla, Thailand.
authors.forename: Arunee
authors.initials: A
authors.lastname: Dechaphunkul
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité Comprehensive Cancer Center, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ochsenreither
authors.affiliation: Department of Otorhinolaryngology, Szent Imre University Teaching Hospital, Budapest, Hungary.
authors.forename: Laura Anna
authors.initials: LA
authors.lastname: Kiss
authors.affiliation: Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Jin-Ching
authors.initials: JC
authors.lastname: Lin
authors.affiliation: Department of Surgical Oncology, Curie Manavata Cancer Centre, Maharashtra, India.
authors.forename: Raj
authors.initials: R
authors.lastname: Nagarkar
authors.affiliation: Department of Otorhinolaryngology and Head and Neck Surgery, Semmelweis University, Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Tamás
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Sung-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Radiation Oncology Department, Jósa András Teaching Hospital, Nyíregyháza, Hungary.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Erfán
authors.affiliation: Department of Oncology, Prevoljskiy Region Medical Centre, Novgorod, Russia.
authors.forename: Anna
authors.initials: A
authors.lastname: Alyasova
authors.affiliation: West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Medical Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Barone
authors.affiliation: Oncology Global Development, Novartis Pharma SAS, Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Turri
authors.affiliation: Oncology Biostatistics, Novartis Healthcare Private Limited, Hyderabad, India.
authors.forename: Arunava
authors.initials: A
authors.lastname: Chakravartty
authors.affiliation: Oncology Precision Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Chol
authors.affiliation: Oncology Global Development, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Aimone
authors.affiliation: Novartis Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Samit
authors.initials: S
authors.lastname: Hirawat
authors.affiliation: Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; University of Milan, Milan, Italy. Electronic address: lisa.licitra@istitutotumori.mi.it.
authors.forename: Lisa
authors.initials: L
authors.lastname: Licitra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000556:secondary; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007390:International Agencies; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D010984:Platinum / Q000008:administration & dosage; D011379:Prognosis; D015996:Survival Rate
chemical_list: D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120; D010984:Platinum; D017239:Paclitaxel