Abstract CT403: A Phase I study of oral administration of mTOR inhibitor everolimus (E) in association with cisplatin (C) and radiotherapy (R) for the treatment of locally advanced cervix cancer (LACC) - PHOENIX I

Background: Cervical cancer (CC) represents the second most commonly diagnosed cancer in women. The combined treatment involving C and R has been the standard treatment for stages IIB-IIIB. However the results are still disappointing with 5-year survival rates lower than 50%. There is a great need to explore new strategies in order to improve the prognosis of these patients. E inhibits the mammalian target of rapamycin (mTOR). The high aberrant activity of mTOR complexes is part of the underlying cause of carcinogenesis in CC. Further E inactivates the oncoprotein E7 (essential in the carcinogenesis of HPV) and inhibits its proliferation. Preclinical models have suggested that mTOR inhibitors sensitize tumoral cells and vasculature to C and R effects. Therefore mTOR inhibition may represent a promising treatment approach in CC. Methods: The primary objective of this trial is to evaluate the safety, toxicity (according to NCI CTCAE 3.0) and the maximum tolerated dose (MTD) of E in association to C and R in the treatment of locally advanced CC. The secondary objectives are to quantify PK and PD parameters, and to evaluate the response rate (using RECIST 1.1). In a modified Fibonacci design the trial aims to evaluate three cohorts of at least three patients treated with daily escalating doses of E (2.5/5/10 mg) in association with C (40 mg/m2 of body surface per week, for 5 weeks during teletherapy) and R (teletherapy - 4.500 cGy in 25 fractions, followed by 4 fractions of 600 cGy weekly of brachytherapy - B) in squamous cell cervical carcinoma patients stage IIB to IIIB. Patients are treated with E from day -7 to day 0 (one week before the C+R starting) up to the last day of B. Results: As of December 01, 2013, 13 patients were enrolled, 6 in the cohort #1, 3 in the cohort #2 and 4 in the cohort #3. Two patients did not completed the planned schedule, one at dose level of 2,5 mg presented grade 4 acute renal failure interpreted as dose limiting toxicity (DLT) and one at dose level of 10 mg with disease progression. Grade 3 toxicity occurred in cohorts #1 and #2 as follows: lymphopenia in 6 patients, neutropenia in 3 patients and leukopenia in 1 patient. Three patients in the cohort #3 are still on treatment. PK and PD studies will be performed together, after collection of the entire set of samples. Conclusions: The end of treatment of the last cohort is due to February 2014, when the MTD will be established. To the best of our knowledge this is the first study of everolimus, cisplatin and pelvic radiotherapy combination. Citation Format: Carlos Gil Ferreira, Flávia V. Guerra Alves, Rachele Grazziotin, Felipe Erlich, Giulliana Moralez, Michel P. Carneiro, Mariane Fontes Dias, Andréia C. de Melo. A Phase I study of oral administration of mTOR inhibitor everolimus (E) in association with cisplatin (C) and radiotherapy (R) for the treatment of locally advanced cervix cancer (LACC) - PHOENIX I. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT403. doi:10.1158/1538-7445.AM2014-CT403