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Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors

Tjulandin, S. ; Moiseyenko, V. ; Semiglazov, V. ; Manikhas, G. ; Learoyd, M. ; Saunders, A. ; Stuart, M. ; Keilholz, U.

Investigational new drugs, 2014-02, Vol.32 (1), p.145-153 [Periódico revisado por pares]

New York: Springer US

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Título:
Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors
Autor: Tjulandin, S. ; Moiseyenko, V. ; Semiglazov, V. ; Manikhas, G. ; Learoyd, M. ; Saunders, A. ; Stuart, M. ; Keilholz, U.
Assuntos: Adult ; Aged ; Angina pectoris ; Cancer therapies ; Cell growth ; Clinical trials ; Demography ; Diarrhea ; Dose-Response Relationship, Drug ; Drug dosages ; Epidermal growth factor ; Female ; Humans ; Inhibitor drugs ; Lung diseases ; Male ; Medical research ; Medicine ; Medicine & Public Health ; Metastasis ; Middle Aged ; Neoplasm Staging ; Neoplasms - drug therapy ; Neoplasms - metabolism ; Neoplasms - pathology ; Oncology ; Patients ; Pharmaceutical sciences ; Pharmacokinetics ; Pharmacology/Toxicology ; Phase I Studies ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - blood ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - therapeutic use ; Quinazolines - administration & dosage ; Quinazolines - blood ; Quinazolines - pharmacokinetics ; Quinazolines - therapeutic use ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Epidermal Growth Factor - metabolism ; Receptor, ErbB-2 - antagonists & inhibitors ; Receptor, ErbB-2 - metabolism ; Receptor, ErbB-3 - antagonists & inhibitors ; Receptor, ErbB-3 - metabolism ; Signal Transduction ; Studies ; Treatment Outcome ; Tumor Burden ; Tumors
É parte de: Investigational new drugs, 2014-02, Vol.32 (1), p.145-153
Descrição: Summary Aim AZD8931 is an oral equipotent inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling. This Phase I, open-label study evaluated the safety, tolerability, and pharmacokinetics of multiple ascending doses of AZD8931 in patients with advanced solid tumors ( NCT00637039 ). Methods Patients received AZD8931 as a single oral dose followed by 4 days of observation, then twice-daily dosing for 21 consecutive days. Using a standard 3 + 3 design, AZD8931 doses were escalated from 40 mg bid until the maximum tolerated dose (MTD) was established. Results Twenty-eight patients received AZD8931 (n = 5, 40 mg bid; n = 8, 80 mg bid; n = 6, 160 mg bid; n = 6, 240 mg bid; n = 3, 300 mg bid). Ovary ( n = 8) and breast ( n = 5) were the most common primary tumor types. The most frequent adverse events were treatment-emergent cutaneous ( n = 27) and diarrhea ( n = 21). Dose-limiting toxicities (DLTs) were identified in one patient in the 240 mg bid cohort (Grade 3 rash) and two patients in the 300 mg bid cohort (Grade 3 and 4 diarrhea). The pharmacokinetic profile of AZD8931 supported twice-daily dosing. AZD8931 was rapidly absorbed (median t max 1–3 h), was well distributed and had moderate to high clearance with an elimination half-life of approximately 11 h. Exposure appeared to increase approximately proportionally with dose up to 160 mg. Of 21 patients evaluable for response at day 21, 12 had stable disease and nine had disease progression. Conclusion The MTD of AZD8931 determined from the 21-day DLT period was 240 mg bid, although more long-term data are needed to confirm a dose of AZD8931 suitable for chronic treatment.
Editor: New York: Springer US
Idioma: Inglês;Russo

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Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors

Tjulandin, S. ; Moiseyenko, V. ; Semiglazov, V. ; Manikhas, G. ; Learoyd, M. ; Saunders, A. ; Stuart, M. ; Keilholz, U.

New York: Springer US

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