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Author Notes:

Correspondence: Suresh S. Ramalingam, MD, Associate Professor, Emory University, Winship Cancer Institute, 1365 Clifton Road, C-3090, Atlanta, GA 30322. Email: ssramal@emory.edu. Phone: 404-778-5378. Fax: 404-778-5520

Disclosures: Suresh S. Ramalingam, Taofeek K. Owonikoko, Shi-Yong Sun, Dong M. Shin and Fadlo R. Khuri are Distinguished Cancer Scholars of the Georgia Cancer Coalition.

Merrill J. Egorin is an ASCO Cancer Foundation Translational Research Professor.

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Research Funding:

Supported by NCI 5 P01 CA116676-03and, in part, by Novartis pharmaceuticals.

Keywords:

  • Everolimus
  • docetaxel
  • phase I
  • pharmacokinetics
  • non-small cell lung cancer

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

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Journal Title:

Cancer

Volume:

Volume 116, Number 16

Publisher:

, Pages 3903-3909

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2010 American Cancer Society

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