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01.12.2014 | PHASE I STUDIES | Ausgabe 6/2014

Investigational New Drugs 6/2014

A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors

Zeitschrift:
Investigational New Drugs > Ausgabe 6/2014
Autoren:
Quincy S. Chu, Randeep Sangha, Sebastien J. Hotte, Gwen Sergenson, David Schnell, Vikram K. Chand, Hal W. Hirte
Wichtige Hinweise

Previous Publication

This study has been presented, in part, at: the Annual Meeting of the American Society of Clinical Oncology; May 31–June 4, 2013; Chicago, IL; J Clin Oncol 31, 2013; abstract 2523 (poster discussion)

Trial Registration

NCT01169675 (ClinicalTrials.gov).

Summary

Introduction Afatinib, an irreversible ErbB family blocker, demonstrated synergistic inhibition of epidermal growth factor receptor-mutant cell growth with pemetrexed. This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of afatinib plus pemetrexed in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design, patients were given intravenous pemetrexed (500 mg/m2) on day 1 of a 21-day cycle (maximum 6 cycles), combined with continuous daily oral afatinib (schedule A [SA]; starting dose 30 mg, escalation to 50 mg) or pulsed-dose daily oral afatinib (schedule B [SB]; starting dose 50 mg, escalation to 70 mg) on days 1–6 of each 21-day cycle. Primary endpoint was determination of MTD based on dose-limiting toxicities (DLTs) in cycle 1. Results Fifty-three patients were treated (SA: n = 23; SB: n = 30). Eight patients had DLTs in SA, 11 patients in SB; diarrhea and fatigue were the most common. MTD of afatinib was 30 mg in SA and 50 mg in SB. Six patients in SA and eight in SB completed 6 treatment cycles. One patient in each schedule had confirmed objective response; 18/53 patients had disease control (SA: n = 7; SB: n = 11). Most frequent drug-related adverse events were diarrhea, rash, fatigue, and stomatitis. No relevant pharmacokinetic interactions were observed. Conclusions Continuous- or pulsed-dose afatinib combined with pemetrexed exhibited a manageable safety profile. Pulsed dosing conferred no apparent safety or dose advantage. Continuous-dose afatinib 30 mg/day with pemetrexed is recommended for phase II studies.

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