title: A phase 1 study of everolimus plus docetaxel plus cisplatin as induction chemotherapy for patients with locally and/or regionally advanced head and neck cancer.
abstract: BACKGROUND
  Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in head and neck cancers, and it has been demonstrated that inhibition of mTOR complex 1 sensitizes cell lines to platinum and taxane chemotherapy. The authors conducted a phase 1 study to evaluate the addition of oral everolimus to cisplatin and docetaxel as induction chemotherapy for head and neck cancer.
  
  
  METHODS
  In this single-institution phase 1 study, 3 doses of daily everolimus were explored: 5 mg daily, 7.5 mg daily (administered as 5 mg daily alternating with 10 mg daily), and 10 mg daily of each 21-day cycle. Cisplatin and docetaxel doses were fixed (both were 75 mg/m(2) on day 1 of 21-day cycle) at each dose level with pegfilgrastim support. A standard 3 + 3 dose-escalation plan was used. After induction, patients were removed from protocol.
  
  
  RESULTS
  Eighteen patients were enrolled (15 men, 3 women), and their median Karnofsky performance status was 90. The most common toxicities were hyperglycemia, low hemoglobin, fatigue, and thrombocytopenia. Dose-limiting toxicities (DLTs) were neutropenic fever (1 event at dose level 2, 2 events at dose level 3), and all patients recovered fully from these DLTs. The maximum tolerated dose was exceeded at dose level 3. The progression-free survival rate at 1 year was 87.5% (95% confidence interval, 56.8%-96.7%); and, at 2 years, it was 76.6% (95% confidence interval, 41.2%-92.3%). Activating PI3K catalytic subunit α (PIK3CA) gene mutations were identified in 2 human papillomavirus-associated oropharyngeal cancers.
  
  
  CONCLUSIONS
  The phase 2 recommended dose was 7.5 mg daily for everolimus plus cisplatin and docetaxel (both at 75 mg/m(2) on day 1 of a 21-day cycle) given with pegfilgrastim support.
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
authors: Matthew G
authors: MG
authors: Fury
authors: Eric
authors: E
authors: Sherman
authors: Alan L
authors: AL
authors: Ho
authors: Han
authors: H
authors: Xiao
authors: Frank
authors: F
authors: Tsai
authors: Oby
authors: O
authors: Nwankwo
authors: Camelia
authors: C
authors: Sima
authors: Adrian
authors: A
authors: Heguy
authors: Nora
authors: N
authors: Katabi
authors: Sofia
authors: S
authors: Haque
authors: David G
authors: DG
authors: Pfister
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D060828:Induction Chemotherapy / Q000009:adverse effects / Q000379:methods*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D030361:Papillomavirus Infections / Q000150:complications; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D012907:Smoking / Q000009:adverse effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D002945:Cisplatin; D000077143:Docetaxel; D000068338:Everolimus; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D043823:Taxoids; C546842:MTOR protein, human