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01.12.2014 | PHASE I STUDIES

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

verfasst von: Quincy S. Chu, Randeep Sangha, Sebastien J. Hotte, Gwen Sergenson, David Schnell, Vikram K. Chand, Hal W. Hirte

Erschienen in: Investigational New Drugs | Ausgabe 6/2014

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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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Titel: A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors
verfasst von: Quincy S. Chu
Randeep Sangha
Sebastien J. Hotte
Gwen Sergenson
David Schnell
Vikram K. Chand
Hal W. Hirte
Publikationsdatum: 01.12.2014
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 6/2014
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-014-0139-9

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24.04.2024 | DGIM 2024 | Nachrichten

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

Summary

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