Abstract
In this ongoing Phase 1/2 study (NCT01667133), we evaluated ponatinib and assessed its recommended dose in Japanese patients with chronic myeloid leukemia (CML) resistant/intolerant to dasatinib or nilotinib, or with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) resistant/intolerant to ≥1 tyrosine kinase inhibitor (TKI). The primary endpoints were safety of the recommended dose (Phase 1) and major cytogenetic response (MCyR) by 12 months in chronic-phase CML (CP-CML) patients or major hematologic response (MaHR) by 6 months in patients with advanced phase disease (Phase 2). MCyR was achieved/maintained by 12 months in 65% of CP-CML patients; MaHR was achieved by 6 months in 61% of patients with advanced phase disease. The most common nonhematologic grade 3/4 treatment-emergent adverse event (AE) was hypertension (37%); common hematologic grade 3/4 AEs were thrombocytopenia (57%), neutropenia (34%), and leukopenia (26%). Overall, five (14%) patients experienced arterial occlusive events (AOEs); no grade 5 AOEs were reported. The steady-state accumulation ratio of ponatinib (based on area under the curve) ranged from 2.6 (15 mg/day) to 1.3 (45 mg/day). In summary, ponatinib demonstrated efficacy in Japanese patients with CML and Ph+ALL resistant/intolerant to prior TKI treatment; safety data support a recommended starting dose of 45 mg/day in these patients.
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References
Au WY, Caguioa PB, Chuah C, Hsu SC, Jootar S, Kim DW, et al. Chronic myeloid leukemia in Asia. Int J Hematol. 2009;89:14–23.
Kantar Health. Treatment Architecture: Japan-Leukemia, Chronic Myelogenous. CancerMPact® Japan, V1.4; 2013 (October 2014).
Deininger M, O’Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes TP, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood. 2009;114:1126 (abstract).
Hochhaus A, Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, For the IRIS Investigators, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054–61 (erratum, Leukemia. 2010; 24:1102).
An X, Tiwari AK, Sun Y, Ding PR, Ashby CR Jr, Chen ZS. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk Res. 2010;34:1255–68.
Cortes JE, Kantarjian HM, Brümmendorf 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 (erratum, Blood. 2013; 122:524).
O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401–12.
Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory Philadelphia chromosome–positive leukemias. N Engl J Med. 2012;367:2075–88.
Gozgit JM, Wong MJ, Wardwell S, Tyner JW, Loriaux MM, Mohemmad QK, et al. Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther. 2011;10:1028–35.
Lierman E, Smits S, Cools J, Dewaele B, Debiec-Rychter M, Vandenberghe P. Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases. Leukemia. 2012;26:1693–5.
Iclusig® (ponatinib) tablets, for oral use [prescribing Information]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2016. http://www.iclusigrems.com/packaged/pdf/PI.pdf. Accessed on 19 February 2016.
Iclusig [summary of product characteristics]. Leatherhead, UK: ARIAD Pharma Ltd.; 2016. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002695/WC500145646.pdf. Accessed on 8 February 2016.
Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, For the PACE Investigators, et al. A phase 2 trial of ponatinib in Philadelphia chromosome–positive leukemias. N Engl J Med. 2013;369:1783–96.
Otsuka Pharmaceutical Co. L. Iclusig® Tablets 15 mg [prescribing information]; 2016. http://www.info.pmda.go.jp/downfiles/ph/PDF/180078_4291048F1020_1_01.pdf. Accessed on 1 December 2016.
Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N Engl J Med. 2006;354:2531–41.
O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. for the IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.
Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–70.
Narasimhan NI, Dorer DJ, Davis J, Turner CD, Marbury TC, Sonnichsen D. Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects. Cancer Chemother Pharmacol. 2014;74:341–8.
Narasimhan NI, Dorer DJ, Davis J, Turner CD, Sonnichsen D. Evaluation of the effect of multiple doses of lansoprazole on the pharmacokinetics and safety of ponatinib in healthy subjects. Clin Drug Investig. 2014;34:723–9.
Narasimhan NI, Dorer DJ, Niland K, Haluska F, Sonnichsen D. Effects of ketoconazole on the pharmacokinetics of ponatinib in healthy subjects. J Clin Pharmacol. 2013;53:974–81.
Cortes JE, Pinilla Ibarz J, Le Coutre PD, Paquette R, Chuah C, Nicolini FE, et al. 4-year results of the ponatinib phase 2 PACE trial in heavily pretreated leukemia patients [abstract 7013]. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 3-7. Chicago, IL; 2016.
Nakaseko C, Takahashi N, Ishizawa K, Kobayashi Y, Ohashi K, Nakagawa Y, et al. A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia. Int J Hematol. 2015;101:154–64.
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.
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.
Dorer DJ, Knickerbocker RK, Baccarani M, Cortes JE, Hochhaus A, Talpaz M, et al. Impact of dose intensity of ponatinib on selected adverse events: multivariate analyses from a pooled population of clinical trial patients. Leuk Res. 2016;48:84–91.
Acknowledgements
The authors thank Kumiko Yanase, MD, PhD for contributions to this work. Medical writing assistance was provided by Carolyn S. Schober, Ph.D., Evidence Scientific Solutions, Philadelphia, PA, USA, and supported by ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA.
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Dr. Tojo reports grants from Daiichi Sankyo, Pfizer, BMS, and Chugai Pharma and personal fees from Sysmex, Taiho Pharma, Novartis, Pfizer, BMS, Otsuka, and Takara Bio outside the submitted work; Dr. Yamamoto reports Grants from ARIAD/CMIC, and personal fees from ARIAD/CMIC and Otsuka, during the conduct of the study, and Grants from AbbVie, MSD, Pfizer, Novartis, Celgene, Takeda, Chugai Pharma, and Ono Pharmaceutical and personal fees from Pfizer, Novartis, Celgene, Takeda, Chugai Pharma, Ono Pharmaceutical, Kowa Hakko Kirin, Janssen, BMS, and Sumitomo Dainippon Pharma outside the submitted work; Dr. Nakamae reports Grants from ARIAD, during the conduct of the study, and Grants and other from Otsuka outside the submitted work; Dr. Takahashi reports personal fees and non-financial support from Otsuka, during the conduct of the study, and Grants from Pfizer, Novartis, Chugai Pharma, Kyowa Hakko Kirin, and Fujimoto Pharma and personal fees Pfizer and Novartis outside the submitted work; Dr. Kobayashi reports Grants from ARIAD, Astellas, Pfizer, Otsuka, and Boehringer Ingelheim outside the submitted work; Dr. Okamoto reports Grants from BMS, Novartis, and Otsuka and other from BMS, Novartis, Otsuka, and Pfizer outside the submitted work; Dr. Miyamura reports personal fees from Nippon Shinyaku, Pfizer, Novartis, and Alexion outside the submitted work; Dr. Iwasaki reports personal fees from Novartis, BMS, Kyowa Hakko Kirin, and Otsuka and Grants from BMS, Novartis, Kyowa Hakko Kirin, and Chugai Pharma outside the submitted work; Dr. Matsumura reports personal fees and non-financial support from Otsuka, during the conduct of the study; Dr. Usui reports personal fees and non-financial support from Otsuka during the conduct of the study, and Grants from BMS, Celgene, Fujimoto Pharma, Kyowa Hakko Kirin, Nippon Shinyaku, Novartis, Pfizer and personal fees from Astellas, BMS, Celgene, Chugai Pharma, CIMIC, Eli Lilly Japan, Janssen, Kyowa Hakko Kirin, Otsuka, Pfizer, SymBio, Sysmex, Takada Bio Development Center, and Zenyaku Kogyo outside the submitted work; Dr. Naoe reports Grants from Fuji film outside the submitted work; Dr. Tugnait, Dr. Narasimhan, Dr. Lustgarten, and Dr. Farin report personal fees (employment) from ARIAD and other (stock and other ownership interests) from ARIAD during the conduct of the study; Dr. Haluska reports personal fees (previous employment) from ARIAD and other (stock and other ownership interests) from ARIAD during the conduct of the study; Dr. Kyo, Dr. Tauchi, Dr. Hatake, and Dr. Ohyashiki have nothing to disclose.
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Tojo, A., Kyo, T., Yamamoto, K. et al. Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study. Int J Hematol 106, 385–397 (2017). https://doi.org/10.1007/s12185-017-2238-9
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DOI: https://doi.org/10.1007/s12185-017-2238-9