A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors.
Autor: | Chu, Quincy, Sangha, Randeep, Hotte, Sebastien, Sergenson, Gwen, Schnell, David, Chand, Vikram, Hirte, Hal |
---|---|
Předmět: |
ANTINEOPLASTIC agents
PEMETREXED ACADEMIC medical centers BLOOD testing COMBINATION drug therapy DOSE-response relationship in biochemistry DRUG side effects EPIDERMAL growth factor HIGH performance liquid chromatography LUNG cancer MEDICAL cooperation GENETIC mutation ONCOGENES PHARMACOKINETICS PHOSPHOTRANSFERASES RESEARCH RESEARCH funding SAFETY TUMORS DATA analysis software DESCRIPTIVE statistics INVESTIGATIONAL drugs CHEMICAL inhibitors PHARMACODYNAMICS THERAPEUTICS |
Zdroj: | Investigational New Drugs; Dec2014, Vol. 32 Issue 6, p1226-1235, 10p |
Abstrakt: | 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/m) 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. [ABSTRACT FROM AUTHOR] |
Databáze: | Complementary Index |
Externí odkaz: |