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Phase I and pharmacologic study of weekly amrubicin in patients with refractory or relapsed lung cancer: Central Japan Lung Study Group (CJLSG) 0601 trial

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Abstract

Purpose

To evaluate the safety and tolerability of amrubicin (AMR), determine its maximum tolerated dose (MTD), its dose-limiting toxicities (DLTs), and its recommended dose (RD), and to conduct a pharmacokinetic study of weekly AMR administrations in patients with chemotherapy-refractory or recurrent small cell or non–small cell lung cancer.

Patients and methods

Patients with refractory or relapsed non–small cell and small cell lung cancer after 1 or 2 regimens of chemotherapy were eligible. AMR was initiated at 45 mg/m2 weekly (repetition of dose on 1st and 8th day with a rest on day 15). The dose level was increased by 5 mg/m2 by modified Fibonacci dose escalation scheme.

Results

Seven patients had small cell lung cancer and 9 had non–small cell lung cancer. Fifty-four courses (median: 3, range: 1–6) were administered at 5 dose levels. At 65 mg/m2, 3 patients had DLTs as follows: 1 was grade 3 (CTCAE v3.0) in AST/ALT, 1 was grade 3 febrile neutropenia, and 1 was grade 4 neutropenia. Leukocytopenia and neutropenia were correlated with amrubicinol (AMR-OH) C max (P = 0.042, P = 0.047, respectively). The AUC (area under the curve of plasma concentration versus time extrapolated to concentration zero) of AMR and AMR-OH did not depend on the dose levels.

Conclusion

In the present phase I study of AMR administered weekly to previously treated lung cancer patients, the maximum tolerated dose and RD were 65 and 60 mg/m2, respectively. The best response rate was 15.4%, and adverse events with this schedule were tolerable.

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Author information

Authors and Affiliations

  1. Department of Medical Oncology, National Hospital Organization Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi, 460-0001, Japan

    Chiyoe Kitagawa & Hideo Saka

  2. Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi, 460-0001, Japan

    Chiyoe Kitagawa, Hideo Saka & Masahide Oki

  3. Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan

    Shigehisa Kajikawa

  4. Department of Respiratory Medicine, Anjo Kosei Hospital, 28 Higashihirokute, Anjo-cho, Anjo, 446-8602, Japan

    Kouki Mori

  5. Department of Allergy and Respiratory Medicine, Toyohashi Municipal Hospital, 50 Hachiken Nishi, Aotake–Cho, Toyohashi, 441-8570, Japan

    Ryujiro Suzuki

Authors
  1. Chiyoe Kitagawa
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  2. Hideo Saka
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  3. Shigehisa Kajikawa
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  4. Kouki Mori
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  5. Masahide Oki
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  6. Ryujiro Suzuki
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Corresponding author

Correspondence to Chiyoe Kitagawa.

Additional information

Translational relevance

Amrubicin (AMR) is classified as an anthracycline agent and a potent topoisomerase II inhibitor. AMR was recently approved for the treatment of NSCLC and SCLC in Japan. AMR 45 mg/m2 administered by intravenous infusion on days 1–3 of a 21-day course is an approved single-agent treatment schedule. A Japanese phase II study with intravenous infusion of AMR administered according to this schedule in previously untreated extensive-stage SCLC showed a high overall response rate (75.8%) and a long MST (11.7 months). Because of its substantial antitumor activity, the clinical development of AMR has also been focused on the treatment of refractory or recurrent lung cancer. However, severe, occasionally fatal myelotoxicity was found to predominate when AMR was administered to previously treated patients, even at the recommended dose of 45 mg/m2. Furthermore, previous trials revealed that a weekly schedule of chemotherapy had a higher dose intensity, less severe adverse effects, and antitumor activity as effective as other treatments.

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Kitagawa, C., Saka, H., Kajikawa, S. et al. Phase I and pharmacologic study of weekly amrubicin in patients with refractory or relapsed lung cancer: Central Japan Lung Study Group (CJLSG) 0601 trial. Cancer Chemother Pharmacol 69, 1379–1385 (2012). https://doi.org/10.1007/s00280-011-1812-8

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  • DOI: https://doi.org/10.1007/s00280-011-1812-8

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