title: A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer.
abstract: BACKGROUND
  Novel, effective therapies are warranted in the management of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Perifosine is an oral alkylphospholipid that inhibits AKT phosphorylation and has shown preclinical antitumor activity in head and neck cancer cell lines and xenografts.
  
  
  METHODS
  We conducted a phase II trial of perifosine in patients with incurable, recurrent or metastatic SCCHN. Previous therapy for recurrent or metastatic disease was limited to no more than one prior chemotherapy and one prior targeted/biologic agent regimen. Patients had to have measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate laboratory parameters. Perifosine was given as a loading dose of 150 mg every 6 hours x 6 doses orally in the first two days, with antiemetic prophylaxis, followed by 100 mg/day orally without interruption. Administration via gastrostomy tube was allowed. Tumor response was assessed every two cycles (eight weeks). Biomarkers in pathways potentially affected by perifosine, including AKT, P-AKT, P38, p53 and p21 were measured on tumor tissue by immunohistochemistry by manual and automated methods.
  
  
  RESULTS
  Nineteen patients were enrolled. No objective responses were observed. One patient had stable disease as best response and 18 patients progressed at first evaluation. The median overall survival time was 5.5 months and the median progression-free survival time was 1.7 months. The most frequent toxicities were gastrointestinal (constipation, nausea, vomiting) and fatigue. One patient developed grade 4 anorexia. Although the sample size was small, a significant correlation was detected between high expression of P38 and AKT in baseline tumor tissue and better survival.
  
  
  CONCLUSIONS
  Perifosine in the doses and schedule used lacks single-agent activity in SCCHN. Our data do not justify further investigation of perifosine as a single agent in SCCHN.
authors.affiliation: Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania 15232, USA. argirisae@upmc.edu
authors.forename: Athanassios
authors.initials: A
authors.lastname: Argiris
authors.forename: Ezra
authors.initials: E
authors.lastname: Cohen
authors.forename: Theodore
authors.initials: T
authors.lastname: Karrison
authors.forename: Benjamin
authors.initials: B
authors.lastname: Esparaz
authors.forename: Ann
authors.initials: A
authors.lastname: Mauer
authors.forename: Rafat
authors.initials: R
authors.lastname: Ansari
authors.forename: Stuart
authors.initials: S
authors.lastname: Wong
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Michael
authors.initials: M
authors.lastname: Pins
authors.forename: Janet
authors.initials: J
authors.lastname: Dancey
authors.forename: Everett
authors.initials: E
authors.lastname: Vokes
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000556:secondary*; D005260:Female; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy*; D010743:Phospholipids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010743:Phospholipids; D010767:Phosphorylcholine; C105905:perifosine; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases