Premium
Phase 1 and pharmacokinetic study of everolimus, a mammalian target of rapamycin inhibitor, in combination with docetaxel for recurrent/refractory nonsmall cell lung cancer
Author(s) -
Ramalingam Suresh S.,
Harvey R. Donald,
Saba Nabil,
Owonikoko Taofeek K.,
Kauh John,
Shin Dong M.,
Sun ShiYong,
Strychor Sandra,
Tighiouart Mourad,
Egorin Merrill J.,
Fu Haian,
Khuri Fadlo R.
Publication year - 2010
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.25264
Subject(s) - docetaxel , everolimus , medicine , pharmacokinetics , mucositis , lung cancer , oncology , neutropenia , febrile neutropenia , clinical endpoint , phases of clinical research , response evaluation criteria in solid tumors , progressive disease , urology , chemotherapy , pharmacology , clinical trial
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], ≥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/m 2 and everolimus 5 mg daily) experienced DLT. Everolimus area under the concentration time curve (AUC) was not different with 60 or 75 mg/m 2 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/m 2 and 5 mg orally daily, respectively. Promising anticancer activity has been noted. Cancer 2010. © 2010 American Cancer Society.