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Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies

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Abstract

In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton’s tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42–78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (≥ 20 % patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose-dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3 % (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL. Clinical trial registration: NCT01704963.

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References

  1. Boffetta P. Epidemiology of adult non-Hodgkin lymphoma. Ann Oncol. 2011;22:iv27–iv31.

  2. Ravandi F, O’Brien S. Chronic lymphoid leukemias other than chronic lymphocytic leukemia: diagnosis and treatment. Mayo Clin Proc. 2005;80:1660–74.

    Article  PubMed  Google Scholar 

  3. The World Health Organization classification of malignant lymphomas in Japan: incidence of recently recognized entities. Lymphoma Study Group of Japanese Pathologists. Pathol Int. 2000;50:696–702.

  4. Tobinai K, Kobayashi Y, Narabayashi M, Ogura M, Kagami Y, Morishima Y, et al. Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma. The IDEC-C2B8 Study Group. Ann Oncol. 1998;9:527–34.

    Article  PubMed  CAS  Google Scholar 

  5. Ohmachi K, Ando K, Ogura M, Uchida T, Itoh K, Kubota N, et al. Multicenter phase II study of bendamustine for relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Cancer Sci. 2010;101:2059–64.

    Article  PubMed  CAS  Google Scholar 

  6. Ogura M, Morishima Y, Kobayashi Y, Uike N, Sugai S, Chou T, et al. Durable response but prolonged cytopenia after cladribine treatment in relapsed patients with indolent non-Hodgkin’s lymphomas: results of a Japanese phase II study. Int J Hematol. 2004;80:267–77.

    Article  PubMed  CAS  Google Scholar 

  7. Tobinai K, Watanabe T, Ogura M, Morishima Y, Ogawa Y, Ishizawa K, et al. Phase II study of oral fludarabine phosphate in relapsed indolent B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2006;24:174–80.

    Article  PubMed  CAS  Google Scholar 

  8. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–23.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507–16.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Joshi M, Sheikh H, Abbi K, Long S, Sharma K, Tulchinsky M, et al. Marginal zone lymphoma: old, new, targeted, and epigenetic therapies. Ther Adv Hematol. 2012;3:275–90.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. US Food and Drug Administration. Hematology/oncology (cancer) approvals & safety notifications. Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm (Accessed on 11 June 2015).

  13. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA. 2010;107:13075–80.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88–94.

    Article  PubMed  CAS  Google Scholar 

  15. de Jong J, Sukbuntherng J, Skee D, Murphy J, O’Brien S, Byrd JC, et al. The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia. Cancer Chemother Pharmacol. 2015;75:907–16.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Marostica E, Sukbuntherng J, Loury D, de Jong J, de Trixhe XW, Vermeulen A, et al. Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Cancer Chemother Pharmacol. 2015;75:111–21.

    Article  PubMed  CAS  Google Scholar 

  17. McDermott J, Jimeno A. Ibrutinib for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma. Drugs Today (Barc). 2014;50:291–300.

    Article  CAS  Google Scholar 

  18. O’Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15:48–58.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–86.

    Article  PubMed  Google Scholar 

  20. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–56.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank the Safety Monitoring Committee members for their participation in this study: Koji Izutsu (Toranomon Hospital, Tokyo), Norio Komatsu (Juntendo University School of Medicine, Tokyo), and Noriko Usui (The Jikei University School of Medicine, Dai-San Hospital, Tokyo). The authors thank all the patients, their families, investigators, review committee members, medical experts, nurses, and clinical research coordinators who participated in this clinical trial. The authors also thank Pravin Bolshete & Rishabh Pandey (SIRO Clinpharm Pvt. Ltd.) for writing assistance and Takamitsu Inami (Janssen Pharmaceutical K.K.) for additional editorial support for the development of this manuscript. This study was funded by Janssen Pharmaceutical K.K. Japan.

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Authors and Affiliations

  1. Department of Hematology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan

    Kensei Tobinai, Tatsuya Suzuki & Wataru Munakata

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

    Michinori Ogura, Tatsuya Suzuki, Toshiki Uchida, Tomohiro Aoki, Takanobu Morishita & Yoko Ushijima

  3. Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Kenichi Ishizawa

  4. Janssen Pharmaceutical K.K., Tokyo, Japan

    Satoko Takahara

Authors
  1. Kensei Tobinai
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  2. Michinori Ogura
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  3. Kenichi Ishizawa
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  4. Tatsuya Suzuki
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  5. Wataru Munakata
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  6. Toshiki Uchida
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  7. Tomohiro Aoki
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  8. Takanobu Morishita
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  9. Yoko Ushijima
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  10. Satoko Takahara
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Corresponding author

Correspondence to Kensei Tobinai.

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Conflict of interest

Dr. Tobinai received research funding from Janssen Pharmaceutical K.K., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Celgene K.K., GSK, Servier, Abbvie; received honoraria from Zenyaku Kogyo, and Spectrum Pharmaceuticals. Dr. Ishizawa received honoraria from Takeda Pharmaceutical Company Ltd., Kyowa Hakko Kirin Co. Ltd., and Sanofi; received research funding from Kyowa Hakko Kirin Co. Ltd. Drs. Suzuki, and Munakata received research funding from Janssen Pharmaceutical K.K. Drs. Ogura, Uchida, Aoki, Morishita, and Ushijima have no conflict of interest to declare. Dr. Takahara is an employee of Janssen Pharmaceutical K.K.

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Tobinai, K., Ogura, M., Ishizawa, K. et al. Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies. Int J Hematol 103, 86–94 (2016). https://doi.org/10.1007/s12185-015-1900-3

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  • DOI: https://doi.org/10.1007/s12185-015-1900-3

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