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Phase I study of the oral mammalian target of rapamycin inhibitor everolimus (RAD001) in Japanese patients with relapsed or refractory non-Hodgkin lymphoma

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Abstract

Phase I study was conducted to evaluate the safety, pharmacokinetics (PK) and efficacy of the oral mammalian target of rapamycin inhibitor, everolimus (RAD001), in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Patients received everolimus 5 or 10 mg orally once daily. Dose escalation was based on the safety assessment and the probability of dose-limiting toxicities (DLTs) using a Bayesian logistic model. DLTs were evaluated in six patients at each dose level during the initial 28 days of study treatment. A total of 13 patients were enrolled; 5 mg (seven) and 10 mg (six). No DLTs were observed at either dose level. Frequently observed potentially drug-related adverse events included leukopenia (8/13), thrombocytopenia (8/13), elevated hepatic transaminase (9/13), stomatitis (7/13), anemia (6/13), and nasopharyngitis (6/13). All adverse events were reversible. Non-infectious pneumonitis (grade 1) in one patient resolved following discontinuation of everolimus. Two patients with diffuse large B cell lymphoma and two patients with follicular lymphomas achieved objective responses with an overall response rate of 31% (4/13). The pharmacokinetic profiles were not different from those in non-Japanese patients. Everolimus was well tolerated at doses up to 10 mg/day and showed potential efficacy in relapsed or refractory NHL, warranting further investigation.

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Acknowledgments

The authors thank the patients, doctors, nurses, and staff members who participated in this clinical trial for their excellent cooperation. They also thank K. Hatake, MD (Cancer Institute Hospital of Japanese Foundation for Cancer Research), H. Minami, MD (Kobe University), and N. Usui, MD (Jikei University) as members of the Independent Data Safety and Monitoring Committee, and M. Itoh and K. Kurei (Novartis Pharma K.K.). This study was supported by Novartis Pharmaceuticals Corporation. We thank Scientific Connexions for providing assistance with medical writing and editing. These services were funded by Novartis Pharmaceutical Corporation.

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Authors and Affiliations

  1. Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Kensei Tobinai & Dai Maruyama

  2. Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan

    Michinori Ogura & Toshiki Uchida

  3. Department of Hematology and Oncology, National Kyushu Cancer Center, Fukuoka, Japan

    Naokuni Uike & Ilseung Choi

  4. Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan

    Kenichi Ishizawa

  5. Division of Oncology and Hematology, National Cancer Center Hospital East, Kashiwa, Japan

    Kuniaki Itoh

  6. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan

    Kiyoshi Ando

  7. Department of Molecular Hematology and Oncology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan

    Masafumi Taniwaki

  8. Oncology Translational Medicine Department, Novartis Pharma K.K. Japan, Minato-ku, Tokyo, Japan

    Naomi Shimada & Ken Kobayashi

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  1. Kensei Tobinai
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  2. Michinori Ogura
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  11. Naomi Shimada
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  12. Ken Kobayashi
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Correspondence to Kensei Tobinai.

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Tobinai, K., Ogura, M., Maruyama, D. et al. Phase I study of the oral mammalian target of rapamycin inhibitor everolimus (RAD001) in Japanese patients with relapsed or refractory non-Hodgkin lymphoma. Int J Hematol 92, 563–570 (2010). https://doi.org/10.1007/s12185-010-0707-5

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  • DOI: https://doi.org/10.1007/s12185-010-0707-5

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