A phase I/II trial testing nelfinavir, an inhibitor of Akt signaling, in combination with preoperative chemoradiotherapy in patients with locally advanced rectal cancer

The incidence of colorectal cancer is high in The Netherlands. The treatment of
rectal cancer has changed importantly over the last decades. At the moment
preoperative radiotherapy is a cornerstone in rectal cancer treatment. In
patients with locally advanced tumors, combined treatment using capecitabine
and radiotherapy in 6 weeks, followed by surgical resection 6-8 weeks after
completion of chemoradiation. This combined modality treatment can cause
tumorregression, resulting in downsizing and downstaging. In 10-15% of cases
this treatment results in a pathological complete response (pCR). There is a
correlation between the degree of response and the chance to develop a local
recurrence. Therefore, it is important to develop new combined treatments
resulting in higher persentages of pCR, without an important increase of
toxicity. Preclinical work shows that nelfinavir, a protease inhibitor used in
the treatment of HIV, increases the radiosensitivity of tumor cells without
sensitization of normal tissues to radiation. For that reason, no extra
toxicity is expected by adding nelfinavir to the combined chemoradiation
treatment.

The aim is to study safety and activity of nelfinavir, added to standard
chemoradiotherapy (26x1.8 Gy and capecitabine 825 mg/m2 BID) in patients with
locally advanced rectal cancer. Furthermore analysis of the effect of
nelfinavir combined with chemoradiation on tumor tissue will be studied.

This is an open label, single-center phase I/II trial. During phase I the
toxicity of 2 dose levels will be studied (750 mg BID and 1250 mg BID). During
phase II the activity of nelfinavir in combination with capecitabine and
radiotherapy will be studied, using the MTD from phase I. With respect to
translational research, phosphporylation of Akt in monocytes and tumorcells
will be measured at different timepoints during treatment. Furthermore, dynamic
CT-PET scans will be obtained at different time points to get an impression of
changes in SUV and perfusion during treatment and to correlate these changes
with pathological response.

Phase I:
- take nelfinavir tablets (minimum 6, maximum 10) starting 7 days before start
of chemoradiotherapy, for 35 days
- day 7 and week 2-4-6 bloodsamples

Phase II:
- take XXXX ( to define ) nelfinavir tablets starting 7 days before start of
chemoradiotherapy, for 35 days
- day 7 and week 2-4-6 bloodsamples
- day 7 biopsy
- day 7-14-21 and week 13 PET-CT

No major toxicity is expected from the addition of nelfinavir to the standard
chemoradotherapy. The most common side effect of nelfinavir is diarrhoea. Extra
scans, blood samples and biopsy demands extra time. For the extra scans, the
injection of 18FDG and IV contrast is necessary. To take an extra biopsy, an
extra sigmoidoscopy must be performed.