Phase 1 and pharmacokinetic study of everolimus, a mammalian target of rapamycin inhibitor, in combination with docetaxel for recurrent/refractory nonsmall cell lung cancer

Abstract

Background: Everolimus is a novel inhibitor of the mammalian target of rapamycin pathway, which is aberrantly activated in nonsmall cell lung cancer (NSCLC). The authors conducted a phase 1 and pharmacokinetic study of everolimus and docetaxel for recurrent NSCLC.

Methods: Patients with advanced stage NSCLC and progression after prior platinum-based chemotherapy were eligible. Sequential cohorts were treated with escalating doses of docetaxel (Day 1) and everolimus (orally daily, Days 1-19) every 3 weeks. Pharmacokinetic sampling of everolimus and docetaxel was done in Cycle 1. The primary endpoint was determination of the recommended phase 2 doses of the combination.

Results: Twenty-four patients were enrolled (median age, 62 years; women, 11; number of prior regimens, 1 [n=13], 2 [n=6], >or=3 [n=5]; Eastern Cooperative Oncology Group performance status, 0 [n=6], 1 [n=17]). The dose-limiting toxicities (DLTs) were fever with grade 3/4 neutropenia, grade 3 fatigue, and grade 3 mucositis. None of the 7 patients treated at the recommended phase 2 dose (docetaxel 60 mg/m2 and everolimus 5 mg daily) experienced DLT. Everolimus area under the concentration time curve (AUC) was not different with 60 or 75 mg/m2 docetaxel. Mean+/-standard deviation AUC-based accumulation factors for everolimus on Days 8 and 15 were 1.16+/-0.37 and 1.42+/-0.42, respectively. Docetaxel Day 1 half-life was 9.4+/-3.4 hours. Among 21 patients evaluable, 1 had a partial response, and 10 had disease stabilization.

Conclusions: The recommended phase 2 doses of docetaxel and everolimus for combination therapy are 60 mg/m2 and 5 mg orally daily, respectively. Promising anticancer activity has been noted.

Figure 1

Everolimus accumulation ratios in 7 subjects receiving 5 mg daily = Predicted R = Day 8 R = Day 15 R Predicted accumulation factor (R) = (1/1−e^−keτ), where ke is the elimination rate constant and τ is the dosing interval. Actual accumulation = AUC Dx/AUC D1(AUC = area under the concentration-time curve). For day 1, AUC_0-∞, days 8 and 15 AUC_0-24