title: Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer.
abstract: OBJECTIVE
  To investigate the toxicity of nelfinavir, administered during preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer.
  
  
  METHODS
  Twelve patients were treated with chemoradiotherapy to 50.4 Gy combined with capecitabine 825 mg/m(2) BID. Three dose levels (DL) of nelfinavir were tested: 750 mg BID (DL1), 1250 mg BID (DL2) and an intermediate level of 1000 mg BID (DL3). Surgery was performed between 8 and 10 weeks after completion of CRT. Primary endpoint was dose-limiting toxicity (DLT), defined as any grade 3 or higher non-hematological or grade 4 or higher hematological toxicity.
  
  
  RESULTS
  Eleven patients could be analyzed: 5 were treated in DL1, 3 in DL2 and 3 in DL3. The first 3 patients in DL1 did not develop a DLT. In DL2 one patient developed gr 3 diarrhea, 1 patient had gr 3 transaminase elevation and 1 patient had a gr 3 cholangitis with unknown cause. An intermediate dose level was tested in DL3. In this group 2 patients developed gr 3 diarrhea and 1 patient gr 3 transaminase elevation and gr 4 post-operative wound complication. Three patients achieved a pathological complete response (pCR).
  
  
  CONCLUSIONS
  Nelfinavir 750 mg BID was defined as the recommended phase II dose in combination with capecitabine and 50.4 Gy pre-operative radiotherapy in rectal cancer. First tumor response evaluations are promising, but a further phase II study is needed to get more information about efficacy of this treatment regimen.
authors: Department of Radiation Oncology (MAASTRO Clinic), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands. jeroen.buijsen@maastro.nl
authors: Jeroen
authors: J
authors: Buijsen
authors: Guido
authors: G
authors: Lammering
authors: Rob L H
authors: RL
authors: Jansen
authors: Geerard L
authors: GL
authors: Beets
authors: Jaap
authors: J
authors: Wals
authors: Meindert
authors: M
authors: Sosef
authors: Marien O
authors: MO
authors: Den Boer
authors: Jeroen
authors: J
authors: Leijtens
authors: Robert G
authors: RG
authors: Riedl
authors: Jan
authors: J
authors: Theys
authors: Philippe
authors: P
authors: Lambin
mesh_terms: D000368:Aged; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D012004:Rectal Neoplasms / Q000628:therapy*
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D019888:Nelfinavir