Clinical Trial of Oral Nelfinavir before and during Radiation Therapy for Advanced Rectal Cancer

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 K trans , 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 ¼ 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.

HIV‐protease inhibitors for the treatment of cancer: Repositioning HIV protease inhibitors while developing more potent NO‐hybridized derivatives?

“…In another phase II trial of 10 patients with advanced metastatic rectal cancer treated for 7 days with oral nelfinavir (1250 mg bid) and for further 7 days with nelfinavir during pelvic RT (25 Gy/5 fractions/7 days), median tumor cell density decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT. Overall, 5/9 evaluable patients exhibited good tumor regression on MRI assessed by Tumor Regression Grade …”

Clinical development of new drug–radiotherapy combinations

“…These opportunities include repurposing drugs to be used as radiosensitisers, for which extensive phase I to IV clinical experience of the drug might already exist from their use in other indications 39 . The development route for a new drug could include changes to the patent life of candidate .…”

“…However, this assumption is challenged by the concept of 'adjuvant' systemic therapy following the drug-radiotherapy combination, such as using temozolomide during and after radiotherapy to treat glioblastoma multiforme 108 , by the repurposing of non-cancer drugs for use as radiosensitisers 39 , and by immuno-radio-oncology…”

Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer

“…Emerging therapeutic concept attempting to target epigenetic regulatory mechanisms and act as a radiosensitizer in combination therapy. SAHA approved as a single agent for refractory cutaneous T-cell lymphoma Folkvord et al 106 Preclinical study of SAHA using 2 xenograft models In vitro: improved radiosensitivity (P ≤ 0⋅050) across cell lines at all radiation doses less than 6 h after exposure In vivo: pCR achieved in 1 model Saelen et al 107 Vorinostat assessed under hypoxic conditions in vitro Enhanced radiosensitivity across cell lines Warrants further research Small molecular inhibitors Low molecular weight; able to target both extracellular and intracellular proteins Kleiman et al 108 Preclinical Focus on radiosensitizers for KRAS mutant tumours 28 known radiosensitizers assessed 6 effective; AZD7762 most highly potent Suggested investigation into role of CHK2 inhibitors Nelfinavir HIV protease inhibitor; inhibits Akt at standard clinical doses and results in radiosensitivity Hill et al 109 Non-randomized SONATINA clinical trial focusing on safety in 10 patients with T3-4 N0-2 M1 rectal cancers recruited over 2 years 14 days total oral treatment (7 days preoperative) 2 discontinued owing to toxicity 5 grade 3 toxicity Warrants further research Buijsen et al 110 Phase I trial including 12 patients Escalating doses with capecitabine Primary endpoint: dose-limiting toxicity 4 of 6 experienced toxicity, precluding further dose escalation pCR 27% Further toxicity concerns…”