Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer.

Abstract Purpose To investigate the toxicity of nelfinavir, administered during preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer. Material and methods Twelve patients were treated with chemoradiotherapy to 50.4Gy combined with capecitabine 825mg/m 2 BID. Three dose levels (DL) of nelfinavir were tested: 750mg BID (DL1), 1250mg BID (DL2) and an intermediate level of 1000mg BID (DL3). Surgery was performed between 8 and 10weeks after completion of CRT. Primary endpoint was dose-limiting toxicity (DLT), defined as any grade 3 or higher non-hematological or grade 4 or higher hematological toxicity. Results Eleven patients could be analyzed: 5 were treated in DL1, 3 in DL2 and 3 in DL3. The first 3 patients in DL1 did not develop a DLT. In DL2 one patient developed gr 3 diarrhea, 1 patient had gr 3 transaminase elevation and 1 patient had a gr 3 cholangitis with unknown cause. An intermediate dose level was tested in DL3. In this group 2 patients developed gr 3 diarrhea and 1 patient gr 3 transaminase elevation and gr 4 post-operative wound complication. Three patients achieved a pathological complete response (pCR). Conclusions Nelfinavir 750mg BID was defined as the recommended phase II dose in combination with capecitabine and 50.4Gy pre-operative radiotherapy in rectal cancer. First tumor response evaluations are promising, but a further phase II study is needed to get more information about efficacy of this treatment regimen.