Phase I and pharmacokinetic study of everolimus, an mTOR inhibitor, in combination with docetaxel for recurrent/refractory non-small cell lung cancer

• Type of Material: Article
• Authors: Suresh S. Ramalingam, Emory University; R Donald Harvey, Emory University; Nabil F Saba, Emory University; Taofeek K Owonikoko, Emory University; John Kauh, Emory University; Dong M Shin, Emory University; Shi-Yong Sun, Emory University; Sandra Strychor, University of Pittsburgh; Mourad Tighiouart, Emory University; Merrill J. Egorin, University of Pittsburgh; Haian Fu, Emory University; Fadlo Khuri, Emory University
• Language: English
• Date: 2010-08-15
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 American Cancer Society
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/cncr.25264/abstract
• Title of Journal or Parent Work: Cancer
• ISSN: 0008-543X
• Volume: 116
• Issue: 16
• Start Page: 3903
• End Page: 3909
• Grant/Funding Information: Supported by NCI 5 P01 CA116676-03and, in part, by Novartis pharmaceuticals.
• Keywords: pharmacokinetics; phase I; Everolimus; non-small cell lung cancer; docetaxel
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

Purpose Everolimus is a novel inhibitor of the mammalian target of rapamycin (mTOR) pathway, which is aberrantly activated in non-small cell lung cancer (NSCLC). We conducted a phase I and pharmacokinetic study of everolimus and docetaxel for recurrent NSCLC. Methods Patients with advanced stage NSCLC and progression following prior platinum-based chemotherapy were eligible. Sequential cohorts were treated with escalating doses of docetaxel (day 1) and everolimus (PO daily, days 1–19), every 3 weeks. Pharmacokinetic (PK) sampling of everolimus and docetaxel were done in cycle 1. The primary endpoint was determination of the recommended phase II doses (RP2D) of the combination. Results Twenty-four patients were enrolled. Median age, 62 yrs; Females, 11; number of prior regimens, 1(n=13), 2 (n=6), ≥3 (n=5) ECOG PS 0(n=6), 1(n=17). The dose-limiting toxicities (DLT) were fever with grade 3/4 neutropenia, grade 3 fatigue and grade 3 mucositis. None of the 7 patients treated at the RP2D (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 ±SD AUC-based accumulation factors (R) 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 RP2D of docetaxel and everolimus for combination therapy are 60 mg/m2 and 5 mg PO daily, respectively. Promising anti-cancer activity has been noted.