Phase I, pharmacokinetic study of temsirolimus in combination with nelfinavir in patients with solid tumors.

Abstract

2572 Background: Temsirolimus (CCI-779, TEM) is a selective inhibitor of mTOR with anticancer activity in a limited number of cancer types. A potential mechanism of drug resistance of TEM is feedback activation of the PI3k signaling pathway. Dual inhibition of PI3 kinase and mTOR may overcome this resistance. Nelfinavir (NFV), a human immunodeficiency protease inhibitor and a strong CYP3A4 inhibitor, has PI3kinase-inhibiting activity. In this phase I dose-escalation study TEM and NFV were combined (start dose of weekly 10 mg IV TEM infusion and daily 1,500 mg oral NFV in a 3-week cycle). Methods: Standard dose escalation was used in cohorts of 3-6 patients (pts). PK profiles of TEM, its active metabolite sirolimus (SIR), and NFV were obtained in each pt after the first administration and after combination of TEM and NFV (D1, D4, and D11of Cycle 1). Peripheral blood mononuclear cells and, where possible, tumor material of pts were obtained to determine the PD effects. Results: Pretreated pts received NFV at dose level 1 (1,500 mg, 7 pts) and dosel evel 0 (1,000 mg, 3 pts) in combination with 10mg TEM. Pts (6 females, 4 males, median age: 49 years [24-66], WHO 0-2, main tumor types: pancreas, glioblastoma, sarcoma, and galbladder) received up to 6 cycles. The most common reason for treatment discontinuation was disease progression. DLT was seen in 2 pts at dose level 1 (1,500 mg NFV and 10 mg TEM): grade 3 mucositis and nausea. Ulcerative mucositis was the most common toxicity (all grades) (7/10pts), then nausea (5/10 pts) and diarrhea (5/10pts). Neither CRs nor PRs were observed. TEM plasma exposure alone and in combination with NFV did not change (mean AUC0-24 1,435 vs. 1,250 nghr/mL, respectively), while SIR plasma exposure increased when TEM was combined with NFV (mean AUC0-24 678 vs. 1,050 respectively, p<0.05). NFV showed a high interpatient variability alone as well as in combination with TEM (CV= 55 and 71%, respectively). Pharmacodynamic investigations are ongoing. Conclusions: Nelfinavir 1,000 mg/day and temsirolimus 10 mg/wk can be safely combined. DLT was mucositis and nausea. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth