title: A phase I trial of the HIV protease inhibitor nelfinavir with concurrent chemoradiotherapy for unresectable stage IIIA/IIIB non-small cell lung cancer: a report of toxicities and clinical response.
abstract: BACKGROUND
  The objective of this phase I trial was to determine dose-limiting toxicities (DLT) and the maximally tolerated dose of the radiosensitizer Nelfinavir in combination with concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Nelfinavir (dose level 1: 625 mg orally [PO] twice a day; dose level 2: 1250 mg PO twice a day) was administered for 7 to 14 days before and concurrently with concurrent chemoradiotherapy to patients with biopsy confirmed IIIA or IIIB unresectable NSCLC. Five patients were treated at dose level 1; eight patients were treated at dose level 2. Patients were treated with concurrent chemoradiotherapy to a dose of 66.6 Gy. DLTs were defined as any treatment-related grade 4 hematologic toxicity requiring a break in therapy or nonhematologic grade 3 or higher toxicity except esophagitis and pneumonitis.
  
  
  RESULTS
  Sixteen patients were enrolled and 13 patients received at least one dose of nelfinavir. Twelve patients were treated with nelfinavir and concurrent chemoradiotherapy. No DLTs have been observed at either dose level. The maximum tolerated dose of nelfinavir was therefore 1250 mg PO twice a day. Six patients experienced grade 4 leukopenia. One patient experienced grade 4 thromobcytopenia. Median follow-up for all 12 response-evaluable patients was 31.6 months and for survivors is 23.5 months. Nine of the 12 patients had evaluable posttreatment positron emission tomography/computed tomography with metabolic response as follows: overall response: 9/9 (100%); complete response: 5/9 (56%); and partial response: 4/9 (44%).
  
  
  CONCLUSIONS
  Nelfinavir administered with concurrent chemoradiotherapy is associated with acceptable toxicity in stage IIIA/IIIB NSCLC. The metabolic response and tumor response data suggest that nelfinavir has promising activity in this disease.
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. rengan@uphs.upenn.edu
authors.forename: Ramesh
authors.initials: R
authors.lastname: Rengan
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.forename: Daniel
authors.initials: D
authors.lastname: Pryma
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rosen
authors.forename: Lilie L
authors.initials: LL
authors.lastname: Lin
authors.forename: Amit M
authors.initials: AM
authors.lastname: Maity
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Evans
authors.forename: James P
authors.initials: JP
authors.lastname: Stevenson
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.forename: John
authors.initials: J
authors.lastname: Kucharczuk
authors.forename: Joseph
authors.initials: J
authors.lastname: Friedberg
authors.forename: Susan
authors.initials: S
authors.lastname: Prendergast
authors.forename: Tiffany
authors.initials: T
authors.lastname: Sharkoski
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hahn
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000009:adverse effects / Q000627:therapeutic use*; D009367:Neoplasm Staging; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014057:Tomography, X-Ray Computed
chemical_list: D017320:HIV Protease Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019888:Nelfinavir