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 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.

Figure 1

CONSORT diagram showing the flow of participants through each stage of the SONATINA study * one patient stopped taking Nelfinavir after 4 days due to vomiting † one patient stopped taking Nelfinavir after 4^th fraction of RT due to an allergic rash Abbreviations used: MRI, magnetic resonance imaging; CT CAP, computed tomography chest abdomen and pelvis; p-CT, perfusion CT; DCE-MRI, dynamic contrast enhanced magnetic resonance imaging; RT, radiation therapy; N/n, number of patients; ITT, intention to treat

Figure 2

Changes detected on perfusion imaging and biopsies taken before and after protocol therapy. Figure 2A: Percentage change in mean Blood Flow (BF), Blood Volume (BV) and Mean Transit Time (MTT) for each patient between p-CT scans 2 and 3 (as shown in Figure 1). Patient 7 was excluded from the perfusion-CT analysis for technical reasons Figure 2B: Percentage change in mean K_trans for each patient between DCE-MRI scans 2 and 3. Patient 1 did not undergo the second DCE-MRI scan because of vertigo. One scan each of patients 5 and 8 were excluded because of inadequate contrast enhancement. Figure 2C: Comparison of Tumour Cell Density (TCD) values for individual patients in biopsies taken before (blue bars) and 7 days after (orange bars) protocol therapy (nelfinavir and RT).