Inhibition of EGFR, HER2 and HER3 signaling with AZD8931 alone and in combination with paclitaxel: phase i study in Japanese patients with advanced solid malignancies and advanced breast cancer.

Abstract

BACKGROUND:

AZD8931 is an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), human EGFR 2 (HER2) and HER3. This two-part Japanese study (NCT01003158) assessed the safety/tolerability of AZD8931 monotherapy in patients with advanced solid tumors and in combination with paclitaxel in female patients with advanced breast cancer.

METHODS:

Monotherapy part: ascending doses of AZD8931 (40/60/80 mg twice daily [bid]) for 21 consecutive days. Combination part: AZD8931 40 mg bid and paclitaxel 90 mg/m(2) (on days 1, 8 and 15 of a 28-day cycle).

RESULTS:

Seventeen patients received AZD8931: 11 received AZD8931 monotherapy (40/60/80 mg [n = 3/4/4]) and six AZD8931 40 mg bid plus paclitaxel. No dose-limiting toxicities were observed for AZD8931 alone or combined with paclitaxel. The most frequent adverse events (AEs) were diarrhea, paronychia, pustular rash and dry skin (each n = 8) with AZD8931 monotherapy and diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n = 4) with combination therapy. Grade ≥3 AEs were reported for one, two and four patients in the 40 mg, 60 mg and combination groups, respectively. AZD8931 was rapidly absorbed with a half-life of 12 h. There was no evidence of pharmacokinetic interaction between AZD8931 and paclitaxel. Two patients (one in each part) had unconfirmed and confirmed partial responses, with a duration of 42 and 172 days, respectively.

CONCLUSION:

Although maximum tolerated dose was not confirmed for AZD8931, based on overall incidence of rash and diarrhea AEs in the 80 mg group, doses up to 60 mg bid as monotherapy and 40 mg bid combined with paclitaxel are the feasible AZD8931 doses in Japanese patients.

• Authors: Takayasu Kurata, Junji Tsurutani, Yasuhito Fujisaka, Wataru Okamoto, Hidetoshi Hayashi, Hisato Kawakami, Eisei Shin, Nobuya Hayashi, Kazuhiko Nakagawa
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 5 Pg. 946-54 (Oct 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24875132 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AZD 8931
• Quinazolines
• ERBB2 protein, human
• ERBB3 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Receptor, ErbB-3
• Paclitaxel

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, blood, pharmacokinetics, therapeutic use)
• Asian People
• ErbB Receptors (antagonists & inhibitors)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (blood, drug therapy)
• Paclitaxel (administration & dosage, adverse effects)
• Quinazolines (administration & dosage, adverse effects, blood, pharmacokinetics)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Receptor, ErbB-3 (antagonists & inhibitors)