A phase I study of mTOR inhibitor everolimus in association with cisplatin and radiotherapy for the treatment of locally advanced cervix cancer: PHOENIX I

Abstract

Cervix cancer (CC) represents the fourth most common cancer in women. Treatment involving cis platin and radiotherapy has been the standard for locally advanced disease. Everolimus inhibits the aberrant activ ity of mTOR that is part of carcinogenesis in CC. Further everolimus inactivates the HPV E7 oncoprotein and inhib its its proliferation. Preclinical models have suggested that everolimus sensitizes tumoral cells and vasculature to cis platin and radiotherapy. Methods In a 3 + 3 design, the trial aimed to treat three dose levels of at least three patients with daily doses of everolimus (2.5, 5 and 10 mg/day), cisplatin and radiother apy delivered in a 9-week interval in CC patients, stage IIB, IIIA or IIIB. Patients received everolimus from day −7 up to the last day of brachytherapy. Primary objective was to evaluate safety, toxicity and the maximum-tolerated dose (MTD) of everolimus in association with cisplatin and radi otherapy. Pharmacokinetic (PK) parameters and response rates were analyzed as secondary objectives. Results Thirteen patients were enrolled, 6 at 2.5 mg, 3 at 5 mg and 4 at 10 mg. Four patients did not complete the planned schedule, 1 at 2.5 mg presented grade 4 acute renal failure interpreted as dose-limiting toxicity (DLT) and 3 at 10 mg: 1 with disease progression, and 2 with DLTs—1 grade 3 rash and 1 grade 4 neutropenia. PK results were characterized by dose-dependent increases in AUC and Cmax. Conclusions The MTD of everolimus in combination with cisplatin and radiotherapy has been defined as 5 mg/day. The data regarding safety and response rates support fur ther studies.