Phase 0-I clinical trial of nelfinavir with hypofractionated radiotherapy for rectal cancer: Clinical safety and changes in tumour perfusion observed


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Esme Hill1,2, Jamie Franklin2, Monica Enescu3, Thinn Pwint2, Julia Schnabel3, Ewan Anderson2, Gina Brown4, W Gillies McKenna1, Tim Maughan1, Ricky Sharma1,2
1Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford, UK, 2The Churchill Hospital, Oxford, UK, 3Department of Engineering Science, University of Oxford, Oxford, UK, 4The Royal Marsden Hospital, Sutton, UK


In preclinical models, nelfinavir, an inhibitor of the PI3-kinase signalling pathway, is an intrinsic radiosensitiser, which increases blood flow to tumours and reduces tumour hypoxia. The aims of the trial were to evaluate the safety and effectiveness of nelfinavir when administered in combination with hypofractionated pelvic radiotherapy (RT) and to explore changes in tumour perfusion.


Eight patients with metastatic rectal cancer received 25 Gy in 5 fractions in 7 days to the pelvis and nelfinavir 1250 mg bd PO for 7 days before and for 7 days during RT. Treatment toxicity was assessed by CTCAE version 4. Tumour Regression Grade (TRG) was assessed on MRI scans performed 8 weeks post therapy¹.Dynamic Contrast Enhanced Magnetic Resonance (dce-MRI) and Perfusion Computed Tomography (pCT) scans of the pelvis were performed pre-treatment, after 7 days of nelfinavir treatment alone and on the last day of nelfinavir plus radiotherapy.


Three patients developed ≥Grade 3 toxicity (rash, lymphopenia and diarrhoea). No grade 4 toxicities were observed. Theprimary tumour(T)stage at baseline was T3/T4 for all patients. On MRI at 8 weeks from last fraction of RT, 4 patients had good (0-3) ymrTRG scores and 4 patients had poor (4-5) ymrTRG scores. All eight patients had three pCT scans, from which perfusion parameters could be derived for 7 out of 8 patients. Seven out of 8 patients had three DCE-MRI scans, of which 5 were suitable for analysis at all of the timepoints. Analysis of changes in tumour perfusion are ongoing to determine their predictive value.


The combination of nelfinavir and hypofractionated pelvic radiotherapy was well tolerated and resulted in good tumour regression in 50% of patients treated. The feasibility of evaluating changes in tumour perfusion in patients treated with nelfinavir and radiotherapy was demonstrated.