Phase II study of everolimus (E) in refractory germ cell tumors (GCTs).

Abstract

TPS4677 Background: GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients (pts) develop disease recurrence. Because of insufficient results in the treatment of relapsed GCTs, evaluation of new treatments is a priority. Loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog) marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive GCTs. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not in early event in GCTs development, but is associated with disease progression. PTEN inactivation is associated with dysregulation of PI3K/Akt pathway and increased mTOR signalling. We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN inactivation in GCTs suggests that these pts could have greater benefit from mTOR inhibition. Methods: In December 2011, National Cancer Institute of Slovakia launched an one arm, two-staged phase II study aimed to evaluate the efficacy and toxicity of E in pts with refractory GCTs. The primary objective is to determine the efficacy of E in patients with refractory GCTs. Secondary objectives includes favourable response rate, time to progression and safety. The pts with radiological and/or serological proof of relapsed GCTs, who were not amenable to be cured by chemotherapy or surgery and who failed at least two platinum-based regimens or one platinum regimen in case of platinum-refractory disease or primary mediastinal non-seminomatous GCTs were eligible. All other standard inclusion and exclusion criteria for study of salvage treatment in refractory GCTs pts were applied. E will be administered at a dose of 10mg daily until progression or unacceptable toxicity. Assuming a response rate of clinical interest of ≥40%, a minimal response rate of 20%, a probability of 5% for rejecting an active drug, and a probability of 20% to further evaluate an ineffective drug, 18 pts will be enrolled into the first cohort. If <4 responses will be observed, the study will be terminated, otherwise, it will be continued with a second cohort of 20 pts.