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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

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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 tmax 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.

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Acknowledgments

We wish to thank the patients who participated in this trial, and the study staff. We also wish to thank Quintiles Laboratories Europe, Livingston, Scotland for their analysis of biological samples.

This study was sponsored by AstraZeneca. We thank Zoё van Helmond PhD from Mudskipper Bioscience who provided medical writing support funded by AstraZeneca.

Conflict of interest disclosures

S Tjulandin has received honoraria from AstraZeneca as a lecturer. M Learoyd and M Stuart are employees of and stockholders of AstraZeneca. A Saunders is a paid consultant to AstraZeneca, as a project physician on AZD8931. All remaining authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. N. N. Blokhin Russian Cancer Research Centre of RAMS, Kashirskoe Shosse 24, 115478, Moscow, Russia

    S. Tjulandin

  2. Cancer Research Institute, St. Petersburg, Russia

    V. Moiseyenko & V. Semiglazov

  3. St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russia

    G. Manikhas

  4. AstraZeneca, Macclesfield, UK

    M. Learoyd, A. Saunders & M. Stuart

  5. Charité Comprehensive Cancer Center, Berlin, Germany

    U. Keilholz

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  1. S. Tjulandin
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Correspondence to S. Tjulandin.

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Tjulandin, S., Moiseyenko, V., Semiglazov, V. et al. Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors. Invest New Drugs 32, 145–153 (2014). https://doi.org/10.1007/s10637-013-9963-6

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