Clinical trial of oral nelfinavir before and during radiation therapy for advanced rectal cancer

Hill EJ, Roberts C, Franklin JM, Enescu M, West N, Macgregor TP, Chu KY, Boyle L, Blesing C, Wang LM, Mukherjee S, Anderson EM, Brown G, Dutton S, Love SB, Schnabel JA, Quirke P, Muschel R, Mckenna WG, Partridge M, Sharma RA (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Clinical Cancer Research American Association for Cancer Research

Book Volume: 22

Pages Range: 1922-1931

Journal Issue: 8

DOI: 10.1158/1078-0432.CCR-15-1489

Abstract

Purpose: 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. Experimental Design: 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 median Ktrans, 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.

Involved external institutions

University of Oxford GB United Kingdom (GB) University of Leeds GB United Kingdom (GB) Oxford University Hospitals NHS Foundation Trust GB United Kingdom (GB) Royal Marsden Hospital / The Royal Marsden NHS Foundation Trust GB United Kingdom (GB)

How to cite

APA:

Hill, E.J., Roberts, C., Franklin, J.M., Enescu, M., West, N., Macgregor, T.P.,... Sharma, R.A. (2016). Clinical trial of oral nelfinavir before and during radiation therapy for advanced rectal cancer. Clinical Cancer Research, 22(8), 1922-1931. https://doi.org/10.1158/1078-0432.CCR-15-1489

MLA:

Hill, Esme J., et al. "Clinical trial of oral nelfinavir before and during radiation therapy for advanced rectal cancer." Clinical Cancer Research 22.8 (2016): 1922-1931.

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