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A phase I study of tasisulam sodium using an albumin-tailored dose in Japanese patients with advanced solid tumors

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Abstract

Purpose

This phase I study was designed to determine the maximum tolerated dose (MTD) and the dose to be recommended for a future phase II study of tasisulam sodium in Japanese patients with advanced, refractory solid tumors. Safety, pharmacokinetics and preliminary anti-tumor activities were assessed. Due to high-affinity albumin binding, an albumin-tailored dose to reduce the variability in tasisulam exposure was also studied.

Methods

A dose escalation scheme of tasisulam was used over 4 dose levels. Dose levels 1-3 targeted the maximum plasma concentration (C max) of 300, 340, and 360 μg/mL. Dose level 4 used an albumin-tailored range of C max-targeted doses to achieve an albumin-corrected exposure (AUCalb) of 1,200–6,400 μg h/mL, the range chosen for global tasisulam studies. Tasisulam was administered intravenously on day 1 of each 21-day (dose levels 1 and 2) or 28-day (dose levels 3 and 4) cycle.

Results

The major adverse events were related to bone marrow suppression, particularly neutropenia and thrombocytopenia. Dose-limiting toxicities (DLTs) were not observed until dose level 4, where 3 out of 6 patients experienced DLT, despite a tendency toward lower AUCalb variability (CV %) in the albumin-tailored dose group (38 %) compared with the targeted C max groups (50–236 %).

Conclusions

Tasisulam in doses up to dose level 3 (target C max 360 μg/mL) was well tolerated. Although albumin-tailored dosing provided less AUCalb variability, a MTD that aligns with other global tasisulam studies was not identified. A lower AUCalb range may be required for the Japan population.

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Acknowledgments

We thank all patients who participated in this study, their families, and all the study site personnel. This study was funded by Eli Lilly Japan K.K. Gregory H. Smith, Communication Consultant to Eli Lilly Japan, assisted in writing the manuscript.

Conflict of interest

The following authors disclose relationships with Eli Lilly and Company: RI, PKT, JF, and KM are employed by Eli Lilly and HM contributed in an advisory role. The other authors declare no conflict of interests.

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Authors and Affiliations

  1. Division of Medical Oncology/Hematology, Department of Medicine, Graduate School of Medicine, Kobe University Hospital, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Yutaka Fujiwara, Toru Mukohara, Naomi Kiyota, Naoko Chayahara & Hironobu Minami

  2. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, 466-8560, Japan

    Yuichi Ando, Ayako Mitsuma, Megumi Inada-Inoue & Masataka Sawaki

  3. Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan

    Yutaka Fujiwara

  4. Eli Lilly and Company, Indianapolis, IN, 46285, USA

    Robert Ilaria Jr.

  5. Eli Lilly UK, Surrey, GU20 6PH, UK

    P. Kellie Turner

  6. Eli Lilly Japan KK, Kobe, 651-0086, Japan

    Jumpei Funai & Kaijiro Maeda

Authors
  1. Yutaka Fujiwara
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  2. Yuichi Ando
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  3. Toru Mukohara
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  4. Naomi Kiyota
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  5. Naoko Chayahara
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  6. Ayako Mitsuma
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  7. Megumi Inada-Inoue
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  8. Masataka Sawaki
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  9. Robert Ilaria Jr.
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  10. P. Kellie Turner
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  11. Jumpei Funai
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  12. Kaijiro Maeda
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  13. Hironobu Minami
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Corresponding author

Correspondence to Hironobu Minami.

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Fujiwara, Y., Ando, Y., Mukohara, T. et al. A phase I study of tasisulam sodium using an albumin-tailored dose in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 71, 991–998 (2013). https://doi.org/10.1007/s00280-013-2092-2

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  • DOI: https://doi.org/10.1007/s00280-013-2092-2

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