Advertisement

International Journal of Hematology

, Volume 101, Issue 2, pp 154–164 | Cite as

A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia

  • Chiaki NakasekoEmail author
  • Naoto Takahashi
  • Kenichi Ishizawa
  • Yukio Kobayashi
  • Kazuteru Ohashi
  • Yasunori Nakagawa
  • Kazuhito Yamamoto
  • Koichi Miyamura
  • Masafumi Taniwaki
  • Masaya Okada
  • Tatsuya Kawaguchi
  • Atsushi Shibata
  • Yosuke Fujii
  • Chiho Ono
  • Kazunori Ohnishi
Original Article

Abstract

This phase 1/2 study evaluated the safety and pharmacokinetics (part 1) and efficacy and safety (part 2) of bosutinib in Japanese Philadelphia chromosome-positive (Ph+) chronic-phase (CP) or advanced-phase chronic myeloid leukemia (CML) patients resistant/intolerant to previous imatinib (2L) or imatinib+dasatinib/nilotinib (3L). Based on dose-limiting toxicities and previous studies, the part 2 bosutinib starting dose was 500 mg/day (n = 63). For CP CML 2L (n = 28), the cumulative major cytogenetic response (MCyR) rate by week 24 was 36 % (primary endpoint); the cumulative major molecular response (MMR) rate through the study was 43 %. Transformation to accelerated/blast phase (AP/BP) was observed in one patient. Progression-free survival (PFS) and overall survival (OS) rates at 96 weeks were 94 and 96 %, respectively. Of seven advanced-phase 2L patients, one had confirmed complete hematologic response at week 84, and one had AP/BP transformation. PFS and OS rates at week 96 were 21 and 43 %. For 3L (n = 11), cumulative MCyR rate by week 24 was 18 %; cumulative MMR rate was 18 %; no transformations occurred. Common non-hematologic adverse events (AEs) were diarrhea (95 %), rash (57 %), and nasopharyngitis (51 %). Sixteen patients discontinued due to adverse events; no deaths occurred within 30 days of the last dose. Bosutinib 500 mg/day demonstrated efficacy and manageable toxicity in Japanese Ph+ CML patients resistant/intolerant to imatinib.

Keywords

Phase 1/2 Bosutinib Tyrosine kinase inhibitor Chronic myeloid leukemia Japan 

Notes

Acknowledgments

Editorial and medical writing support was provided by Simon J. Slater, PhD, of Complete Healthcare Communications, Inc., and was funded by Pfizer Inc. This study was sponsored by Wyeth Research, which was acquired by Pfizer Inc in October 2009.

Conflict of interest

Dr. Nakaseko reports Grants and scholarship support from Pfizer Inc. Dr. Takahashi reports Grants, personal fees and non-financial support from Pfizer Inc during the conduct of the study; Grants and personal fees from Novartis, Bristol-Myers Squibb, Kyowa Hakko Kirin, Chugai Pharma, Dainippon Sumitomo Pharma, Celgene, Janssen Pharma; Grants from Takeda Pharma; and personal fees from Asahikasei Pharma outside the submitted work. Dr. Kobayashi reports Grants from Pfizer Inc during the conduct of the study; Grants from ARIAD Pharmaceuticals, Inc., Boehringer Ingelheim, Novartis Pharma K·K., Otsuka Pharmaceuticals Co., Ltd., and Onconova Therapeutics, Inc., outside the submitted work. Dr. Yamamoto reports Grants and non-financial support from Pfizer Inc during the conduct of the study; Grants and non-financial support from Novartis Pharma K·K and Grants from ARIAD Pharmaceuticals, Inc, outside the submitted work. Dr. Kawaguchi reports Grants from Pfizer Inc during the conduct of the study. Dr. Ishizawa reports personal fees from Chugai Pharma, Takeda Pharma, Celgene, Janssen Pharma, and Sanofi, outside the submitted work. Dr. Taniwaki reports Grants from Pfizer Inc during the conduct of the study; Grants and/or personal fees from Bristol-Myers Squibb, Novartis, Kyowa Hakko Kirin, Chugai Pharma, Dainippon Sumitomo Pharma, Celgene, Janssen Pharma, Takeda Pharma, and Asahikasei Pharma, outside the submitted work. Drs. Ono, Fujii, and Shibata are employees of Pfizer Japan and contributed to this clinical trial as follows: protocol development (pharmacokinetics components) and data analysis (Dr. Ono; clinical pharmacologist); protocol development (statistical components) and data analysis (Dr. Fujii; study statistician); protocol development (clinical components), trial management, and data analysis (Dr. Shibata; study clinician). Drs. Ohashi, Nakagawa, Ohnishi, Miyamura, and Okada have nothing to disclose.

References

  1. 1.
    Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, Shen ZX, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118:4567–76.PubMedCrossRefGoogle Scholar
  2. 2.
    Cortes JE, Kim DW, Kantarjian HM, Brummendorf TH, Dyagil I, Griskevicius L, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30:3486–92.PubMedCrossRefGoogle Scholar
  3. 3.
    Gambacorti-Passerini C, Cortes J, Khoury H, Baccarani M, Kantarjian H, Chandy M, et al. Safety and efficacy of bosutinib in patients with AP and BP CML and ph+ ALL following resistance/intolerance to imatinib and other TKIs: update from study SKI-200. J Clin Oncol. 2010;28:6509.CrossRefGoogle Scholar
  4. 4.
    Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119:3403–12.PubMedCrossRefGoogle Scholar
  5. 5.
    Daud AI, Krishnamurthi SS, Saleh MN, Gitlitz BJ, Borad MJ, Gold PJ, et al. Phase I study of bosutinib, a src/abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors. Clin Cancer Res. 2012;18:1092–100.PubMedCrossRefGoogle Scholar
  6. 6.
    Gambacorti-Passerini C, Cortes JE, Khoury HJ, Baccarani M, Kantarjian H, Chandy M, et al. Safety and efficacy of bosutinib in patients with AP and BP CML and ph+ ALL following resistance/intolerance to imatinib and other TKIs: update from study SKI-200. J Clin Oncol. 2010;28:6509.CrossRefGoogle Scholar
  7. 7.
    Sakamaki H, Ishizawa K, Taniwaki M, Fujisawa S, Morishima Y, Tobinai K, et al. Phase 1/2 clinical study of dasatinib in Japanese patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol. 2009;89:332–41.PubMedCrossRefGoogle Scholar
  8. 8.
    Tojo A, Usuki K, Urabe A, Maeda Y, Kobayashi Y, Jinnai I, et al. A Phase I/II study of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL. Int J Hematol. 2009;89:679–88.PubMedCrossRefGoogle Scholar
  9. 9.
    Usuki K, Tojo A, Maeda Y, Kobayashi Y, Matsuda A, Ohyashiki K, et al. Efficacy and safety of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL: a 36-month analysis of a phase I and II study. Int J Hematol. 2012;95:409–19.PubMedCrossRefGoogle Scholar
  10. 10.
    Nakamae H, Shibayama H, Kurokawa M, Fukuda T, Nakaseko C, et al. Nilotinib as frontline therapy for patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase: results from the Japanese subgroup of ENESTnd. Int J Hematol. 2011;93:624–32PubMedCrossRefGoogle Scholar
  11. 11.
    Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A, et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 2006;66:11314–22.PubMedCrossRefGoogle Scholar
  12. 12.
    Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, Lee FY, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res. 2006;66:473–81.PubMedCrossRefGoogle Scholar
  13. 13.
    Chen Z, Lee FY, Bhalla KN, Wu J. Potent inhibition of platelet-derived growth factor-induced responses in vascular smooth muscle cells by BMS-354825 (dasatinib). Mol Pharmacol. 2006;69:1527–33.PubMedCrossRefGoogle Scholar
  14. 14.
    Gleixner KV, Mayerhofer M, Aichberger KJ, Derdak S, Sonneck K, Bohm A, et al. PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816 V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood. 2006;107:752–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009;23:477–85.PubMedCrossRefGoogle Scholar
  16. 16.
    Irvine E, Williams C. Treatment-, patient-, and disease-related factors and the emergence of adverse events with tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. Pharmacotherapy. 2013;33:868–81.PubMedCrossRefGoogle Scholar
  17. 17.
    Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G, et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta. 2010;1804:445–53.PubMedCrossRefGoogle Scholar
  18. 18.
    Cervantes F, Hernandez-Boluda JC, Steegmann JL, Conde E, Alvarez-Larran A, Lopez-Jimenez J, et al. Imatinib mesylate therapy of chronic phase chronic myeloid leukemia resistant or intolerant to interferon: results and prognostic factors for response and progression-free survival in 150 patients. Haematologica. 2003;88:1117–22.PubMedGoogle Scholar
  19. 19.
    Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109:5143–50.PubMedCrossRefGoogle Scholar
  20. 20.
    Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110:3540–6.PubMedCrossRefGoogle Scholar
  21. 21.
    SPRYCEL® dasatinib Princeton. NJ: Bristol-Myers Squibb; 2014.Google Scholar
  22. 22.
    BOSULIF® bosutinib New York. NY: Pfizer Labs; 2013.Google Scholar
  23. 23.
    Tasigna® nilotinib East Hanover. NJ: Novartis Pharmaceuticals Corporation; 2014.Google Scholar

Copyright information

© The Japanese Society of Hematology 2014

Authors and Affiliations

  • Chiaki Nakaseko
    • 1
    Email author
  • Naoto Takahashi
    • 2
  • Kenichi Ishizawa
    • 3
  • Yukio Kobayashi
    • 4
  • Kazuteru Ohashi
    • 5
  • Yasunori Nakagawa
    • 6
  • Kazuhito Yamamoto
    • 7
  • Koichi Miyamura
    • 8
  • Masafumi Taniwaki
    • 9
  • Masaya Okada
    • 10
  • Tatsuya Kawaguchi
    • 11
  • Atsushi Shibata
    • 12
  • Yosuke Fujii
    • 13
  • Chiho Ono
    • 14
  • Kazunori Ohnishi
    • 15
  1. 1.Department of HematologyChiba University HospitalChibaJapan
  2. 2.Department of Hematology, Nephrology, and RheumatologyAkita University School of MedicineAkitaJapan
  3. 3.Department of Rheumatology and HematologyTohoku University HospitalMiyagiJapan
  4. 4.Department of Hematology and OncologyNational Cancer Center HospitalTokyoJapan
  5. 5.Hematology DepartmentTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalTokyoJapan
  6. 6.Department of ChemotherapyJapanese Red Cross Medical CenterTokyoJapan
  7. 7.Department of Hematology and Cell TherapyAichi Cancer Center HospitalAichiJapan
  8. 8.Hematology DivisionJapanese Red Cross Nagoya First HospitalAichiJapan
  9. 9.Department of Hematology and OncologyUniversity Hospital, Kyoto Prefectural University of MedicineKyoto CityJapan
  10. 10.Division of HematologyThe Hospital of Hyogo College of MedicineHyogoJapan
  11. 11.Department of Hematology and Infectious DiseasesKumamoto University HospitalKumamotoJapan
  12. 12.Oncology Clinical ResearchPfizer JapanTokyoJapan
  13. 13.Clinical StatisticsPfizer JapanTokyoJapan
  14. 14.Clinical PharmacologyPfizer JapanTokyoJapan
  15. 15.Oncology CenterHamamatsu University School of MedicineShizuokaJapan

Personalised recommendations