Results of a phase 1 clinical trial investigating a combination of the oral mTOR-inhibitor Everolimus (E, RAD001) and Gemcitabine (GEM) in patients (pts) with advanced cancers

Abstract

3120 Background: Pre-clinical studies of E have shown dose-dependent inhibition of tumor growth, reduced tumor vascularity and potentiation of the activity of a number of cytotoxics, particularly GEM. This phase 1 study investigated E alone and then in combination with GEM. Initially, pts with advanced, refractory solid tumors were recruited to a dose-escalation study with E given weekly to investigate safety, pharmacokinetics (PK) and optimal biological dose (OBD) as shown by sustained inhibition of the mTOR downstream substrate, S6 kinase 1 in peripheral blood mononuclear cells, comparable to that associated with anti-tumor activity in preclinical models. The OBD was concluded to be 20mg and was well tolerated. Methods: In a new cohort, the OBD was combined with GEM 600mg/m2 given IV, weekly, for 3 weeks in 4-week cycles. Sequential cohorts were planned with incremental doses of 800, and 1,000 mg/m2 to identify the maximum tolerated dose. Results: 8 pts were recruited to an expanded first dose level for the combined schedule (5M:3F; median age 58y, range 46–71y). During the first 28 days, 2/8 pts experienced toxicities (grade 4 neutropenia, grade 3 thrombocytopenia), requiring interruption of GEM according to prescribing recommendations. A further 3/8 developed thrombocytopenia requiring dose reduction. No PK interaction between the drugs was observed in an additional cohort of pts studied at the same dose level. Conclusions: Treatment with GEM, in a standard 4-week cycle at 600mg/m2, a dose lower than usually administered, was not tolerated in a majority of pts receiving E at 20mg/week due to myelosuppression. In the absence of PK interaction it seems likely (in line with pre-clinical data) that the toxicity is the result of combined impact on haemopoiesis. Additional studies with this combination should consider alternative schedules for better tolerability. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis