Nelfinavir, a Phase I/Phase II Rectal Cancer Study (Nelfinavir)

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 aim is to study safety and activity of nelfinavir , added to standard chemoradiotherapy in patients with locally advanced rectal cancer. Furthermore analysis of the effect of nelfinavir combined with chemoradiation on tumour tissue will be studied

Objective of the study: The aim is to study safety and activity of nelfinavir, added to standard chemoradiotherapy (28x1.8 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. Study design: 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, phosphorylation 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. Study population: Patients with locally advanced rectal cancer, who are candidates for chemoradiotherapy. In phase I, 6 patients will be included. In case of the occurrence of dose limiting toxicity, extra patients will be included, according to the rules described in the protocol. In phase II, 55 patients will be included.

Phase I: take nelfinavir tablets (minimum 6, maximum 10) starting 7 days before start of chemoradiotherapy, for 45 days day 0 and day 7 and week 2-3-4-5-6-7 weekly blood sample day 0: PET-CT Phase II: take nelfinavir tablets (MTD from phase 1) starting 7 days before start of chemoradiotherapy, for 45 days day 0 and day 7 and week 2-3-4-5-6-7 weekly blood sample day 7 biopsy day 7, 21 and week 15 :PET-CT + perfusion CT

phase I: Incidence of any grade 3 or higher non-hematological or grade 4 or higher hematological toxicity (CTCAE v3.0) and of grade 4 or higher postoperative toxicity within 30 days post-surgery phase II:rate of pathological complete remission

Inclusion Criteria: Histologically proven adenocarcinoma of the rectum (tumor <15cm from anal verge) Age >= 18 years UICC T3-4 N0-2 M0 WHO performance status 0-2 Less than 10 % weight loss the last 6 months No recent (< 3 months) severe cardiac disease (arrhythmia, congestive heart failure, infarction) Serum bilirubin = or < 3x normal ASAT and ALAT = or < 2,5x normal Creatinin clearance >50 ml/min Willing and able to comply with the study prescriptions No history of prior pelvic radiotherapy No known HIV infection No hemophilia No concurrent medication that is metabolized by the CYP3A4 isoenzyme (calcium channel blockers, antifungal agents, macrolide antibiotics, gastrointestinal prokinetics, terfenadin, midazolam) Statins should be stopped (except pravastatin and fluvastatin), No concurrent use of St. John's Wort (Hypericum perforatum) Women should not be pregnant or lactating Being willing and able to undergo one extra biopsy Have given written informed consent before patient registration Exclusion Criteria: the opposite of the above