title: Clinical Trial of Oral Nelfinavir before and during Radiation Therapy for Advanced Rectal Cancer.
abstract: OBJECTIVE
  Nelfinavir, a PI3K pathway inhibitor, is a radiosensitizer that increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach.
  
  
  METHODS
  Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1,250 mg b.i.d.) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pretreatment, after 7 days of nelfinavir and prior to the last fraction of RT. Biopsies taken pretreatment and 7 days after the last fraction of RT were analyzed for tumor cell density (TCD).
  
  
  RESULTS
  There were 3 drug-related grade 3 adverse events: diarrhea, rash, and lymphopenia. On DCE-MRI, there was a mean 42% increase in medianKtrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P= 0.01). Overall, 5 of 9 evaluable patients exhibited good tumor regression on MRI assessed by tumor regression grade (mrTRG).
  
  
  CONCLUSIONS
  This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow.
authors: Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors: Esme J
authors: EJ
authors: Hill
authors: Centre for Statistics in Medicine, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
authors: Corran
authors: C
authors: Roberts
authors: Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors: Jamie M
authors: JM
authors: Franklin
authors: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, United Kingdom.
authors: Monica
authors: M
authors: Enescu
authors: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
authors: Nicholas
authors: N
authors: West
authors: Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors: Thomas P
authors: TP
authors: MacGregor
authors: Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors: Kwun-Ye
authors: KY
authors: Chu
authors: Oncology Clinical Trials Office (OCTO), Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors: Lucy
authors: L
authors: Boyle
authors: Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, United Kingdom.
authors: Claire
authors: C
authors: Blesing
authors: Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, United Kingdom.
authors: Lai-Mun
authors: LM
authors: Wang
authors: Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors: Somnath
authors: S
authors: Mukherjee
authors: Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, United Kingdom.
authors: Ewan M
authors: EM
authors: Anderson
authors: Radiology Department, Royal Marsden Hospital, Sutton, Surrey, United Kingdom.
authors: Gina
authors: G
authors: Brown
authors: Centre for Statistics in Medicine, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
authors: Susan
authors: S
authors: Dutton
authors: Centre for Statistics in Medicine, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
authors: Sharon B
authors: SB
authors: Love
authors: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, United Kingdom.
authors: Julia A
authors: JA
authors: Schnabel
authors: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
authors: Phil
authors: P
authors: Quirke
authors: Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors: Ruth
authors: R
authors: Muschel
authors: Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors: William G
authors: WG
authors: McKenna
authors: Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors: Michael
authors: M
authors: Partridge
authors: Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom. ricky.sharma@oncology.ox.ac.uk.
authors: Ricky A
authors: RA
authors: Sharma
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000008:administration & dosage*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D012004:Rectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000532:radiotherapy*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D011838:Radiation-Sensitizing Agents; D019888:Nelfinavir