Methods of treating chronic myeloid leukemia using the tyrosine kinase inhibitor bodovatinib

Abstract

The present invention relates to methods for treating leukemia using tyrosine kinase inhibitors, and in particular to methods for treating CML and ALL using a compound of formula I or a pharmaceutically acceptable salt thereof. The compound of formula I has been found to be effective, safe, and well tolerated at doses between 10 mg and 210 mg.

Description

[Technical Field]

[0001] This application claims the benefit of Indian Provisional Patent Application No. 202221048373 filed on August 25, 2022, and Indian Provisional Patent Application No. 202221048415, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to methods of treating leukemia. In one aspect, the present invention relates to a method of treating chronic myeloid leukemia (CML) using a compound of formula I, or a pharmaceutically acceptable salt thereof, as shown below: [Background technology]

[0003] Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that accounts for approximately 15-20% of adult leukemias [Apperley 2015; Deininger et al. 2003]. The underlying cause of CML is a fusion oncoprotein between the breakpoint cluster region gene and the Abelson leukemia gene (BCR-ABL1) resulting from a t(9;22) reciprocal chromosomal translocation in hematopoietic stem cells. This translocation leads to the fusion of the breakpoint cluster region gene (BCR) coding sequence with the tyrosine kinase coding region of the Abelson leukemia gene (ABL1), resulting in constitutive activation of ABL1 kinase activity. This translocation therefore results in the activation of multiple downstream pathways that contribute to the growth and survival of leukemic cells [Hazlehurst et al. 2009]. CML is characterized and classified as chronic phase (CP), accelerated phase (AP), or blastic phase (BP). Patients with CP typically have fewer than 10% blasts in their blood or bone marrow samples. The symptoms these patients have are usually fairly mild. The majority of CML patients are diagnosed in the chronic phase. In AP, a patient's blood sample will have more than 15% but fewer than 30% blasts. At this stage, 20% of the blood cells consist of basophils, and the platelet count is low (100 × 1,000 / mm 3(See below), which is not caused by treatment and has chromosomal changes in leukemia cells that carry the Philadelphia chromosome. In the blastic phase, bone marrow and / or blood samples have 20% or more blasts. Large clusters of blasts are seen in the bone marrow. Blasts spread beyond the bone marrow to tissues and organs.

[0004] Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a rare and aggressive form of ALL characterized by the presence of the BCR-ABL1 fusion. It accounts for 25% of all ALL patients (Nicholas J. Short, 2020).

[0005] Dasatinib is approved for the treatment of adults with chronic-phase Ph+ CML and adults with Ph+ acute lymphoblastic leukemia (ALL) who are resistant or intolerant to previous therapy. Nilotinib is approved for the treatment of chronic-phase Ph+ CML in adult patients and pediatric patients at least 1 year of age. Bosutinib is approved for the treatment of chronic-phase Ph+ CML. Second-generation tyrosine kinase inhibitors (TKIs), such as dasatinib, nilotinib, and bosutinib, generally offer improved patient tolerability over the first-generation TKI, imatinib (Ferdinand, 2012). However, approximately 10% of patients cannot tolerate initial TKI treatment, and many develop long-term treatment-emergent adverse events (TEAEs), including cardiovascular, pulmonary, gastrointestinal, and endocrine toxicity, as well as secondary malignancies (Caldemeyer, 2016). Furthermore, point mutations occurring in the BCR-ABL1 kinase domain impair TKI binding and lead to the development of TKI resistance ( Deininger, 2015 ).

[0006] There is a need for improved TKIs, especially for patients who have failed previous TKI treatments.

[0007] document Siegel,R.L.,Miller,K.D.and Jemal,A.(2019),Cancer statistics,2019。CA A Cancer J Clin,69:7-34。https: / / doi.org / 10.3322 / caac.21551 Hazlehurst L,Bewry N,Nair R,Pinilla-Ibarz J.Signaling networks associated with BCR-ABL1-dependent transformation。Cancer control 2009;16(2):100-107。 Ferdinand R,Mitchell SA,Batson S,Tumur I.Treatments for chronic myeloid leukemia:a qualitative systematic review。J Blood Med.2012;3:51-76。 Caldemeyer L,Dugan M,Edwards J,Akard L.Long-Term Side Effects of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia。Curr Hematol Malig Rep.2016 Apr;11(2):71-9。 Deininger MW。Diagnosing and Managing Advanced Chronic Myeloid Leukemia。American Society of Clinical Oncology Educational Book 2015:35,e381-e388。 Buoen C, Bjerrum OJ, Thomsen MS. How First-time-in-human Studies are Being Performed: A survey of Phase I dose-escalation trials in healthy volunteers published between 1995 and 2004. J Clin Pharmacol.2005 Oct;45(10):1123-1136. US Food and Drug Administration (FDA) Guidance for Industry (2005), Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Subjects. Di Gion, P., Kanefendt, F., Lindauer, A. et al. Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors. Clin Pharmacokinet.2011;50:551-603. Nicholas J. Short, Poor Ph+ ALL outcomes require a re-examination of treatment standard, Hematology / Oncology News August 17,2020. Summary of the Invention

[0008] The use of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 is a well-established and highly effective strategy for durable disease control in CML, Ph+ CML, and Ph+ ALL. The compound of Formula I is a novel BCR-ABL1 TKI in clinical development for the treatment of both patients with treatment-resistant / intolerant chronic myeloid leukemia and newly diagnosed CML. [ka]

[0009] The compounds of Formula I have been studied in in vitro and in vivo tests and have specific and highly potent activity against wild-type BCR-ABL1 and several mutant BCR-ABL1.The present disclosure relates to methods for the treatment of adult subjects with chronic phase (CP), accelerated phase (AP), or blast crisis phase (BP) CML or Ph+ CML or Ph+ ALL.

[0010] Accordingly, provided herein is a method for treating a patient (such as an adult patient) with chronic myeloid leukemia (CML), comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to: [ka] Methods are disclosed that include oral administration of an initial daily dose and gradually increasing or decreasing the dose to achieve or maintain a complete hematologic response without severe adverse reactions.

[0011] Accordingly, provided herein is a method for the treatment of an adult patient with CML, comprising orally administering an initial daily dose of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and gradually escalating or tapering the dose to achieve or maintain a complete hematologic response without severe adverse reactions, and wherein the daily dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, in the patient is 6226±5827 mg / kg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0012] Accordingly, provided herein is a method for the treatment of adult patients with CML, comprising orally administering an initial daily dose of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and gradually escalating or tapering the dose to achieve or maintain a complete hematologic response without severe adverse reactions, and wherein the daily dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0013] Accordingly, disclosed herein is a method for the treatment of adult patients with CML, comprising orally administering an initial daily dose of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, with the dose gradually increased or decreased to achieve or maintain a disease response without severe adverse reactions.

[0014] Accordingly, provided herein is a method for the treatment of an adult patient with CML, comprising orally administering an initial daily dose of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and gradually increasing or decreasing the dose to achieve or maintain a disease response without severe adverse reactions, and wherein the daily dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, in the patient is 6226±5827 mg / kg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0015] Accordingly, provided herein is a method for the treatment of adult patients with CML, comprising orally administering an initial daily dose of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and gradually increasing or decreasing the dose to achieve or maintain a disease response without severe adverse reactions, and wherein the daily dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0016] Accordingly, disclosed herein is a method for treating adult patients with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 10 mg to 200 mg, and gradually escalating the dose by 20 mg to 210 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0017] Accordingly, provided herein is a method for treating an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 10 mg to 200 mg, with the dose gradually increasing by 20 mg to 210 mg, to achieve or maintain, without severe adverse reactions, at least one of: (a) complete hematological response; (b) complete hematological response and partial cytogenetic response; (c) complete hematological response and complete cytogenetic response; or (d) complete hematological response, complete cytogenetic response, and major molecular response; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0018] Accordingly, provided herein is a method for the treatment of adult patients with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 10 mg to 200 mg, with the dose gradually increasing by 20 mg to 210 mg, to achieve or maintain, without severe adverse reactions, at least one of: (a) complete hematologic response; (b) complete hematologic response and partial cytogenetic response; (c) complete hematologic response and complete cytogenetic response; or (d) complete hematologic response, complete cytogenetic response, and major molecular response; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0019] Accordingly, disclosed herein is a method for treating adult patients with CML, comprising orally administering a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 20 mg to 210 mg, and gradually tapering the dose by 10 mg to 200 mg upon the occurrence of severe adverse reactions, wherein the dose is tapered such that the patient achieves or maintains at least one of: (a) complete hematologic response; (b) complete hematologic response and partial cytogenetic response; (c) complete hematologic response and complete cytogenetic response; or (d) complete hematologic response, complete cytogenetic response, and major molecular response.

[0020] Accordingly, provided herein is a method for treating an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 20 mg to 210 mg, and tapering the dose by 10 mg to 200 mg upon the occurrence of severe adverse reactions, wherein the dose is tapered such that the patient achieves or maintains at least one of: (a) a complete hematologic response; (b) a complete hematologic response and a partial cytogenetic response; (c) a complete hematologic response and a complete cytogenetic response; or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0021] Accordingly, provided herein is a method for treating adult patients with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 20 mg to 210 mg, and tapering the dose by 10 mg to 200 mg upon the occurrence of severe adverse reactions, wherein the dose is tapered such that the patient achieves or maintains at least one of: (a) a complete hematologic response; (b) a complete hematologic response and a partial cytogenetic response; (c) a complete hematologic response and a complete cytogenetic response; or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0022] Accordingly, disclosed herein is a method for the treatment of adult patients with treatment-resistant CML, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions.

[0023] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which initial dose is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0024] Accordingly, provided herein is a method for the treatment of adult patients with treatment-resistant CML, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which initial dose is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0025] Accordingly, disclosed herein is a method for treating adult patients with treatment-resistant CML, comprising orally administering a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which is titrated to 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0026] Accordingly, provided herein is a method for treating an adult patient with treatment-resistant CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which is titrated to 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0027] Accordingly, provided herein is a method for the treatment of adult patients with treatment-resistant CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which initial dose is titrated to 204 mg to achieve or maintain, without severe adverse reactions, at least one of: (a) complete hematological response; (b) complete hematological response and partial cytogenetic response; (c) complete hematological response and complete cytogenetic response; or (d) complete hematological response, complete cytogenetic response, and major molecular response; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0028] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of the toxicity.

[0029] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0030] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0031] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; Also disclosed is a method in which the reduced dose is optionally readjusted to any one of doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0032] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The reduced dose may be optionally re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain, without severe adverse reactions, at least one of (a) a complete hematological response, (b) a complete hematological response and a partial cytogenetic response, (c) a complete hematological response and a complete cytogenetic response, or (d) a complete hematological response, a complete cytogenetic response, and a major molecular response, and the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24A method is disclosed that results in an average value of

[0033] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The reduced dose may be optionally re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response without severe adverse reactions, and the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0034] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of the toxicity.

[0035] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0036] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0037] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; Also disclosed is a method in which the reduced dose is optionally readjusted to any one of doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0038] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The reduced dose may be optionally re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain, without severe adverse reactions, at least one of (a) a complete hematological response, (b) a complete hematological response and a partial cytogenetic response, (c) a complete hematological response and a complete cytogenetic response, or (d) a complete hematological response, a complete cytogenetic response, and a major molecular response, and the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0039] Accordingly, provided herein is a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The reduced dose may be optionally re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response without severe adverse reactions, and the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. maxA method is disclosed that results in an average value of

[0040] Accordingly, disclosed herein is a method for treating adult patients with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg; if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from such toxicity; and treatment is continued at a reduced dose of 126 mg for index cases, and at 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity.

[0041] Accordingly, provided herein is a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg; if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity; and treatment is continued at a reduced dose of 126 mg for index cases, and at 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of said toxicity; and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0042] Accordingly, provided herein is a method for treating adult patients with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, with an initial daily dose of 174 mg; if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from such toxicity; and treatment is continued at a reduced dose of 126 mg for index cases, and at 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a Cmax in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0043] Also provided herein is a method for treating adult patients with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, with an initial daily dose of 174 mg; if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity; and treatment is continued at a reduced dose of 126 mg for index cases and at 90 mg, 66 mg, and 40 mg for recurrent cases that are a recurrence of the toxicity. and continuing the reduced dose at 8 mg, and optionally readjusting the dose to any one selected from 66 mg, 90 mg, 126 mg, and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0044] Also provided herein is a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, with an initial daily dose of 174 mg, and if the patient develops hematologic toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from such toxicity, and treatment is continued at a reduced dose of 126 mg for index cases and at 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity. and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain, without severe adverse reactions, at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, and the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0045] Also provided herein is a method for treating adult patients with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, with an initial daily dose of 174 mg, and if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a tapered dose of 126 mg for index cases and 90 mg for recurrent cases that are a recurrence of said toxicity, and and continuing the treatment at 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg, and optionally re-escalating the reduced dose to any one of doses selected from 66 mg, 90 mg, 126 mg, and 174 mg, until the patient achieves or maintains, without severe adverse reactions, at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0046] According to another embodiment, disclosed herein is a method for the treatment of newly diagnosed adult CML patients, comprising administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions.

[0047] According to one embodiment, provided herein is a method for the treatment of newly diagnosed adult CML patients, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which initial dose is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0048] According to another embodiment, provided herein is a method for the treatment of newly diagnosed adult CML patients, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which initial dose is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0049] Accordingly, disclosed herein is a method for treating newly diagnosed adult CML patients, comprising orally administering a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which is titrated to 204 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0050] Accordingly, provided herein is a method for the treatment of newly diagnosed adult CML patients, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is replaced for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) the initial daily dose is replaced for at least 7 days and restarted at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are a recurrence of the toxicity.

[0051] Accordingly, provided herein is a method for the treatment of newly diagnosed adult CML patients, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are a recurrence of such toxicity; Also disclosed are methods wherein the reduced dose is optionally re-escalated to any one of doses selected from 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0052] Accordingly, provided herein is a method for the treatment of newly diagnosed adult CML patients, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are a recurrence of the toxicity.

[0053] Accordingly, provided herein is a method for the treatment of newly diagnosed adult CML patients, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are a recurrence of such toxicity; Also disclosed are methods wherein the reduced dose is optionally re-escalated to any one of doses selected from 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0054] Accordingly, disclosed herein is a method for treating newly diagnosed adult CML patients, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg; if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from such toxicity; and treatment is continued at a reduced dose of 126 mg for index cases, and at 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are a recurrence of such toxicity.

[0055] Also provided herein is a method for treating newly diagnosed adult CML patients, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced dose of 126 mg for index cases and 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are a recurrence of the toxicity; and Disclosed are methods wherein the reduced dose is optionally re-escalated to any one of doses selected from 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without hematological toxicity.

[0056] According to certain embodiments, disclosed herein is a method for the treatment of adult patients with chronic myeloid leukemia (CML), comprising orally administering an initial daily dose of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and gradually escalating or tapering the dose to achieve or maintain a complete hematologic response without severe adverse reactions.

[0057] According to another embodiment, provided herein is a method for the treatment of adult patients with chronic myeloid leukemia (CML), comprising orally administering an initial daily dose of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and gradually escalating or tapering the dose to achieve or maintain a complete hematologic response without severe adverse reactions, wherein the pharmaceutical composition is administered under fasting conditions, and wherein the pharmaceutical composition comprises 6226±5827 mg of leukemia or a pharmaceutically acceptable salt thereof. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is disclosed that results in an average value of

[0058] According to another embodiment, provided herein is a method for the treatment of adult patients with chronic myeloid leukemia (CML), comprising orally administering an initial daily dose of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and gradually escalating or tapering the dose to achieve or maintain a complete hematological response without severe adverse reactions, wherein the pharmaceutical composition is administered under fasting conditions, and wherein the pharmaceutical composition has a Cmax ranging from 664±450 ng / mL to 5054±3051 ng / mL. max A method is disclosed that results in an average value of

[0059] Accordingly, disclosed herein is a method for treating adult patients with CML, comprising orally administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, at an initial daily dose of 10 mg to 200 mg, and gradually escalating the dose by 20 mg to 210 mg, until at least one of (a) a complete hematological response, (b) a complete hematological response and a partial cytogenetic response, (c) a complete hematological response and a complete cytogenetic response, or (d) a complete hematological response, a complete cytogenetic response, and a major molecular response is achieved or maintained without severe adverse reactions attributable to the pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0060] Accordingly, provided herein is a method for treating an adult patient with CML, comprising orally administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 10 mg to 200 mg, with the dose gradually increasing by 20 mg to 210 mg, to achieve or maintain at least one of (a) a complete hematological response, (b) a complete hematological response and a partial cytogenetic response, (c) a complete hematological response and a complete cytogenetic response, or (d) a complete hematological response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions attributable to the pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition has a cytogenetic activity of 6226±5827 mg / mL when administered under fasting conditions. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 and C, which ranged from 664±450ng / mL to 5054±3051ng / mL. max A method is disclosed that results in an average value of

[0061] According to another embodiment, disclosed herein is a method for treating an adult patient with CML, comprising orally administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in a daily dose, wherein the daily dose does not result in a QT interval in the patient of greater than about 500 ms.

[0062] According to another embodiment, provided herein is a method for the treatment of an adult patient with CML, comprising orally administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in a daily dose, wherein the daily dose is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 and C, which ranged from 664±450ng / mL to 5054±3051ng / mL. max and the daily dose does not result in a patient's QT interval exceeding about 500 ms.

[0063] In another embodiment, disclosed herein is a method for preventing recurrence of CML in a patient who has previously been treated with a tyrosine kinase inhibitor, comprising orally administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg.

[0064] In yet another embodiment, provided herein is a method for preventing recurrence of CML in a patient who has previously undergone treatment with a tyrosine kinase inhibitor, comprising orally administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, wherein the initial daily dose is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 and C, which ranged from 664±450ng / mL to 5054±3051ng / mL. max A method is disclosed that results in an average value of

[0065] According to certain embodiments, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is orally administered under fasting conditions, whereby the AUC 0-24is the mean AUC obtained by administering a compound of formula I or a pharmaceutically acceptable salt thereof under fed conditions. 0-24 The present invention provides a method for treating adult patients with CML by orally administering under fasting conditions a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof results in a mean serum serotonin concentration (SSC) of 15% higher than the mean serum SSC ...

[0066] According to one embodiment, there is provided a method of treating an adult patient with CML by orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in a daily dose ranging from 10 mg to 210 mg, wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof provides a daily dose of 6226±5827 mg when administered under fasting conditions. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 A method is provided which results in an average value of

[0067] According to another embodiment, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof is orally administered under fasting conditions, whereby the C achieved in a patient by administering a compound of formula I or a pharmaceutically acceptable salt thereof under fasting conditions is max is achieved by administering a compound of formula I or a pharmaceutically acceptable salt thereof under fed conditions. max The present invention provides a method for treating adult patients with CML by orally administering under fasting conditions a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof results in a mean serum serotonin concentration (SSC) of 20% higher than the mean serum SSC ...

[0068] Thus, according to certain embodiments, there is provided a method of treating an adult patient with CML by orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in a daily dose ranging from 10 mg to 210 mg, wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof provides a CML in the range of 664±450 ng / mL to 5054±3051 ng / mL when administered under fasting conditions. maxA method is provided which results in an average value of

[0069] According to another embodiment, there is provided a method for treating an adult patient with CML, comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a daily dose such that the plasma concentration of the compound of formula I, or a pharmaceutically acceptable salt thereof, is 50 ng / mL or greater.

[0070] According to yet another embodiment, there is provided a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a predetermined daily dose, wherein the daily dose (a) results in a plasma concentration of the compound of formula I, or a pharmaceutically acceptable salt thereof, of 50 ng / mL or more, and (b) a plasma concentration of 6226±5827 ng / mL or more. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 (c) C ranged from 664 ± 450 ng / mL to 5054 ± 3051 ng / mL max and (d) achieved a 15% higher AUC when administered under fasted conditions compared to when administered under fed conditions. 0-24 and 20% higher C max and / or (e) resulting in a QT interval in the patient of less than about 500 ms.

[0071] According to yet another embodiment, there is provided a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a predetermined daily dose, wherein the daily dose (a) results in a plasma concentration of the compound of formula I, or a pharmaceutically acceptable salt thereof, of greater than or equal to 25 ng / mL, and (b) results in a plasma concentration of 6226±5827 ng / mL. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 (c) C ranged from 664 ± 450 ng / mL to 5054 ± 3051 ng / mL maxand (d) achieved a 15% higher AUC when administered under fasted conditions compared to when administered under fed conditions. 0-24 and 20% higher C max and / or (e) resulting in a QT interval in the patient of less than about 500 ms.

[0072] According to certain embodiments, a method for the treatment of an adult patient with CML comprises orally administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof at a predetermined daily dose, wherein the daily dose is titrated up to achieve or maintain a complete hematologic response, or the daily dose is reduced if the patient experiences a severe adverse reaction, and wherein the predetermined, escalated, or reduced daily dose (a) results in a plasma concentration of the compound of formula I or a pharmaceutically acceptable salt thereof of 50 ng / mL or more, and (b) results in a plasma concentration of 6226±5827 ng / mL or more. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 (c) C ranged from 664 ± 450 ng / mL to 5054 ± 3051 ng / mL max and (d) achieved a 15% higher AUC when administered under fasted conditions compared to when administered under fed conditions. 0-24 and 20% higher C max and / or (e) resulting in a QT interval in the patient of less than about 500 ms.

[0073] According to another embodiment, there is provided a method of treating a CML patient having a relapsed or treatment-resistant CML condition, wherein the relapsed or treatment-resistant condition results from a mutation in the kinase domain of the BCR-ABL1 fusion oncoprotein, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in a daily dose of 48 to 204 mg.

[0074] According to another embodiment, there is provided a method of treating a CML patient having a relapsed or treatment-resistant CML condition, wherein the relapsed or treatment-resistant condition results from a mutation in the kinase domain of the BCR-ABL1 fusion oncoprotein, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in amorphous form, and a pharmaceutically acceptable excipient.

[0075] According to another embodiment of the present invention, there is provided a method of increasing the survival chances of a CML patient, comprising administering to said patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein said CML patient has failed at least one TKI prior to said administration.

[0076] According to one embodiment of the present invention, there is provided a method for treating an adult patient who has received prior treatment for T315I-positive CML and has a relapsed or treatment-refractory CML condition, comprising orally administering an initial daily dose of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, with the dose gradually increased or decreased to achieve or maintain a disease response without severe adverse reactions. [Brief explanation of the drawings]

[0077] [Figure 1] Figure 1 shows the individual, mean, and median AUC(0-24) versus administered dose for the SAD (single ascending dose study). [Figure 2] Figure 2 provides a schematic overview of the study and timing of assessment visits.

[0078] definition As used herein, the term "baseline" is understood by those knowledgeable about clinical trials and the processes involved. It refers to the condition of a patient in need of treatment before the start of said treatment. Conditions include, but are not limited to, physical condition, pathology, vital signs, mental function, and performance status of the patient's daily activities. For cancer patients, performance status is categorized according to the criteria outlined by the Eastern Cooperative Oncology Group (ECOG). For the purposes of this study, patients were ECOG grade 0 or grade 1 patients, who were either fully active and able to perform all daily activities without limitation, or who were limited in physically strenuous activity and could perform light or sedentary tasks. ECOG grade 2 patients, who were ambulatory and capable of all self-care but unable to perform any work activities, may also be considered for this invention. Baseline analysis is necessary to compare the effects of treatment on patients.

[0079] The terms "adverse event (AE)," "serious adverse reaction," "serious adverse event," "adverse reaction," "adverse effect," "toxicity," "treatment-emergent adverse event (TEAE)," and "side effect" are used interchangeably and refer to events that were not present or were present at a lower intensity at baseline before treatment and that occur or worsen after treatment is initiated in a patient. Such events are undesirable, unacceptable, unfavorable, and unintended signs, symptoms, or diseases that may result from the use of a drug or treatment. Based on the intensity and impact of the adverse event, those skilled in the art may need to modify the treatment conditions. The daily dose may be administered continuously until disease progression. Resolution of toxicity may occur when there is toxicity of grade 1 and / or 2 or less according to CTCAE.

[0080] For purposes of this invention, adverse events were graded according to the National Cancer Institute's Common Toxicity Criteria (NCI-CTCAE) version 4.03 and version 5.0 (https: / / evs.nci.nih.gov / ftp1 / CTCAE / About.html), a descriptive terminology available for reporting adverse events (AEs). The CTCAE designates grades 1-5 with specific clinical descriptions of the severity of each AE based on the following general guidelines: a) Grade 1: Mild; asymptomatic or mildly symptomatic; clinical or laboratory findings only; no intervention required; b) Grade 2, moderate; requiring minimal, localized, or non-invasive intervention; limitations in activities of daily living (ADL) other than age-appropriate self-care such as meal preparation, grocery or clothing shopping, telephone use, and money management; c) Grade 3: Severe or medically significant, but not immediately life-threatening; requiring hospitalization or prolonged hospitalization; interfering with activities of daily living; limitation of self-care ADLs such as bathing, dressing, self-feeding, using the toilet, taking medication, and not being bedridden; d) Grade 4: Life-threatening consequences; requiring urgent intervention; and e) Death related to grade 5 AE.

[0081] For the purposes of this invention, adverse events (AEs) were evaluated throughout the trial until 30 days after discontinuation of study drug. AEs were categorized according to NCI-CTCAE version 5.0. In this study, the most common AEs observed during patient monitoring were thrombocytopenia, neutropenia, and anemia, among others. Any AE reported by patients after the completion of the AE collection period and deemed related to study drug was reported. AEs continued to resolve satisfactorily until they stabilized or could be explained by another known cause (i.e., concomitant symptoms or medication), and clinical judgment indicated that further evaluation was not warranted.

[0082] Dose-limiting toxicity (DLT) is defined as the occurrence of any of the following, unless clearly and irreversibly related to the underlying disease. Hematological DLTs are defined according to the stage of CML: a) Grade 3 or higher or other non-hematologic toxicities, including nausea, vomiting, and diarrhea, refractory to standard antiemetic therapy, except for alopecia and nail disorders; b) ≥25% of the dose is not taken for more than 28 days due to toxicity in Cycle 1, and c) Any grade toxicity requiring dose reduction or interruption of IMP within the 28-day DLT evaluation period (Cycle 1).

[0083] Hematologic DLTs for subjects in chronic phase of CML were grade 3 neutropenia and / or thrombocytopenia during a ≥ 28-day interruption of study drug treatment, or grade 4 neutropenia (absolute peripheral blood neutrophil count (ANC) < 0.5 x 10) with a ≥ 7-day interruption of study drug (i.e., after treatment interruption). 9 / L).

[0084] Hematologic DLTs in subjects with accelerated-phase CML were grade 3 neutropenia and / or thrombocytopenia during a ≥28-day interruption of study drug treatment, in the absence of accelerated-phase features such as a persistent increase in blasts or basophils (excluding cytogenetic changes), or grade 4 neutropenia (peripheral blood ANC <0.5 × 10) with a ≥7-day interruption of treatment (i.e., after treatment interruption). 9 / L).

[0085] Hematologic DLTs for subjects in blast crisis with CML were persistent leukemia for more than 6 weeks or 500 / mm3 with bone marrow cellularity <5% blasts. 3 ANC below 50,000 / mm 3 Grade 3 neutropenia and / or thrombocytopenia in the absence of <100 mg / kg / day thrombocytopenia.

[0086] It will be understood by those skilled in the art that hematological DLT can only be confirmed after distinguishing between toxicity caused by the compound of Formula I or its pharmaceutically acceptable salt and anti-leukemia effect. This can be done by methods known to those skilled in the art. For example, if a subject has neutropenia accompanied by clearance of leukemia cells or blasts, a bone marrow examination can be performed to distinguish between toxicity caused by Formula I and anti-leukemia effect. If the subject shows normoplastic bone marrow or residual disease, this can be considered an anti-leukemia effect, and treatment can be continued. However, if there is evidence of drug toxicity, such as hypoplastic bone marrow, treatment is stopped for a predetermined period of time.

[0087] The term "disease response" or simply "response" as used herein with reference to a compound of Formula I or a pharmaceutically acceptable salt thereof is understood as the effect of the compound of Formula I or a pharmaceutically acceptable salt thereof on the progression of the disease in a patient. Disease response is determined by screening the patient before and after initiation of treatment.

[0088] Disease response is determined by screening patients before and after the start of treatment. Screening may include both clinical and laboratory tests, such as physical examination, blood analysis, vital signs analysis, such as body temperature, heart rate, respiratory rate, and diastolic and systolic blood pressure, ECG, bone marrow aspiration, BCR-ABL mutation analysis, and BCR-ABL transcription analysis. If the screening results clearly show that the compound of Formula I or its pharmaceutically acceptable salt reduces, improves, or alleviates the disease or its symptoms, the patient is considered to have disease response. In particular, in the case of leukemia, disease response is confirmed when the patient sequentially shows hematological response (CHR), cytogenetic response, and molecular genetic response in a given order. For example, it is expected that CP CML patients will first show hematological major response or hematological complete response, and then show signs of cytogenetic response, followed by molecular genetic response. Patients with AP CML and BP CML are expected to initially experience a complete hematologic response, followed optionally by a partial or complete cytogenetic response. It would be beneficial if patients with AP CML and BP CML also experienced a molecular response.

[0089] For purposes of this invention, assessments of hematological response are performed on days 1, 2, 3, 8, and every 8 days thereafter, where day 1 is the day the subject receives the first dose of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0090] Bone marrow aspirates were used to determine cytogenetic response assessment. Aspirates were obtained after the completion of every three cycles (e.g., after cycle 3, the next aspirate was scheduled at the completion of cycle 6, and the next at the completion of cycle 9, where each cycle consisted of 28 days of treatment). For patients who demonstrated complete cytogenetic response (CCyR) on two repeat assessments, bone marrow aspirate samples were collected at 6-month intervals thereafter until disease progression, subject withdrawal of consent, or subject discontinuation from the study.

[0091] Molecular response assessments were performed at the end of the third cycle and every three cycles thereafter (e.g., after cycle 3, the next sample collection was scheduled at the completion of cycle 6), where each cycle consisted of 28 days of treatment. Samples were collected at the end of every three cycles until major molecular response (MMR) was achieved at two outcome assessments, and then repeated only if there was a 10-fold increase in MMR until disease progression or subject withdrawal or consent or discontinuation from the study.

[0092] For subjects who achieve CCyR and MMR on two repeat assessments, a bone marrow aspirate should be performed only if a 10-fold increase in BCR-ABL levels is detected. Additional bone marrow aspirates may be performed at unscheduled visits at the investigator's discretion.

[0093] Those skilled in the art will understand that in situations where bone marrow samples are insufficient, a BCR-ABL FISH assay for identification of Ph+ should be performed in place of conventional bone marrow cytogenetics and should report the percentage of cells that are Ph+ chromosome positive. The BCR-ABL FISH assay can also be performed on subjects with minimal residual disease.

[0094] The term "hematologic response" (HR) or "hematological response" refers to the normalization of blood cell counts, particularly WBC counts, resulting from treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof. This is the first noticeable indicator that treatment is beginning to work, although not necessarily in the bone marrow. This response can be a partial hematological response (PHR), in which there is a decrease in WBC counts but not down to the normal range, or a complete hematological response (CHR), in which all blood cell counts are normalized. A CHR is usually expected within one month of treatment, although some subjects may take up to two months to achieve this level. Surprisingly, it has been observed that patients who have received several previous treatments with other known TKIs and have stopped responding to the previous treatments can easily achieve a CHR at or before the two-month mark with treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof. A major hematologic response (MaHR) includes a complete hematological response (CHR), and / or no evidence of leukemia (NEL). For purposes of this invention, the criteria for hematological response are shown in Table 01. [Table 1]

[0095] As used herein, the term "cytogenetic response" means a response to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof that occurs in the bone marrow and not just in the blood, which is a Philadelphia positive (Ph+) chromosome reading obtained after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, interpreted as described below.

[0096] There are three levels of cytogenetic response: a) partial cytogenetic response (PCyR), which indicates that only 1-35% of the sample contains Ph+ metaphase cells; b) Complete cytogenetic response (CCyR), which indicates that no Ph+ cells can be measured by either conventional or fluorescent in situ hybridization cytogenetic testing (although PCR testing may still be positive); c) Major cytogenetic response (MCyR) is a cytogenetic response that includes PCyR and CCyR.

[0097] For the purposes of this invention, cytogenetic response was determined using bone marrow aspirate evaluation by Giemsa staining (karyotyping) or fluorescence in situ hybridization (FISH) assay. As will be understood by those skilled in the art, at least 20 metaphases are evaluated to confirm cytogenetic response. If fewer metaphases are reported, absolute percentage values ​​are reported. Also, peripheral blood cells are not considered in bone marrow aspirate evaluation. Because limited bone marrow and aspirate availability precludes cytogenetic evaluation by Giemsa staining, FISH assay is performed to evaluate Ph+ cells. For FISH, a complete cytogenetic response (CCyR) is reported if no Ph+ cells are observed or if fewer than 1 in 200 nuclei are BCR / ABL1 positive. [Table 2]

[0098] Major molecular response (MMR): A molecular response is a response to treatment that affects the number of BCR-ABL transcripts in the blood cells of patients with CML or ALL. This is measured as the ratio of BCR-ABL reverse transcripts to ABL. In the case of a major molecular response, this ratio is ≦0.1% International Standard (IS) (equivalent to a 3-log reduction in transcripts). This can be determined by polymerase chain reaction (PCR) or any other molecular test known to those skilled in the art.

[0099] Major molecular response (MMR) is used to select and monitor patients eligible for discontinuation of tyrosine kinase therapy. In another embodiment, the major molecular response rate is determined at 12 weeks of treatment. In another embodiment, the major molecular response rate is determined at 24 weeks of treatment. In another embodiment, the major molecular response rate is determined at 96 weeks of treatment.

[0100] For the purposes of this invention, molecular response was determined using PCR. Patients were considered to have a major molecular response if the amount of BCR-ABL protein in the blood was very low, i.e., if the BCR-ABL transcript was 0.1% (international standard interval (IS)) by quantitative PCR, or if quantitative PCR (IS) was unavailable, if there was a 3-log reduction or greater in BCR-ABL mRNA from a standardized baseline. A complete molecular response was considered to be when no BCR-ABL mRNA was detected by quantitative PCR (IS) using an assay with a sensitivity of at least 4.5 logs below the standardized baseline.

[0101] The phrase "optimal management" is used herein in connection with an adverse event or toxicity and refers to steps taken to reduce or eliminate the adverse event. Optimal management is based on CTCAE grade. For example, a grade 1 adverse event may be managed by withholding treatment for several days, while a CTCAE grade 2 AE may require withholding treatment in conjunction with concomitant drug therapy. Those skilled in the art will recognize methods used to treat adverse events, including any drug therapy used for such purposes.

[0102] As used herein, the term "subject" or "human in need thereof" or "patient" refers to a human subject diagnosed with a disease such as leukemia and in need of treatment. These terms may be interchangeable. Preferably, the subject is diagnosed with acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), Ph+ CML, or other leukemia such as hairy cell leukemia, myelodysplastic syndrome, or myeloproliferative disorder, or a combination thereof. More preferably, the subject is diagnosed with ALL or CML and is in need of treatment to reduce, ameliorate, or alleviate the disease or its symptoms, or to treat the disease or its symptoms so that the subject is free from the disease or its symptoms. The subject may have newly diagnosed, treatment-resistant, or relapsed leukemia, where newly diagnosed and relapsed have meanings known to those skilled in the art. A subject or patient is said to have refractory leukemia when the subject has been treated with known therapies, preferably with tyrosine kinase inhibitors (TKIs), and is resistant or intolerant to the therapy.

[0103] For the purposes of the present invention, a resistant leukemia patient is a patient who has previously been treated with at least one TKI, or at least two TKIs, or at least three TKIs. In a specific embodiment, if a patient has previously been treated with at least three TKIs, one of the TKIs is ponatinib. In a specific embodiment, if a patient has previously been treated with at least three TKIs, one of the TKIs is bosutinib. In yet another embodiment, if a patient has previously been treated with at least three TKIs, one of the TKIs is ponatinib or asciminib. In yet another embodiment, if a patient has previously been treated with at least three TKIs, the treatment includes treatment with ponatinib and asciminib.

[0104] A subject is considered to be "resistant" to previous treatment with a known TKI if the subject experiences no response or improvement in disease. For purposes of this invention, a subject is considered to be resistant to previous treatment or therapy if any of the following occur: [Table 3] TIFF2025527620000006.tif123162

[0105] Additionally, a subject is considered "intolerant to prior therapy" if they develop toxicity that persists and does not respond to optimal management. Intolerance is classified as hematologic or nonhematologic intolerance. A patient is considered to have developed nonhematologic intolerance to prior therapy with a TKI if they develop grade 3 or 4 toxicity during treatment or have persistent grade 2 toxicity that does not respond to optimal management, including dose adjustment to the lowest dose recommended by the manufacturer, unless dose reduction is deemed in the patient's best interest in the absence of a response that is CCyR in CP CML subjects or MaHR in AP and BP subjects.

[0106] Patients are considered to have developed "hematologic intolerance" to previous treatment if they develop grade 3 or 4 toxicity during treatment that recurs after dose reduction to the lowest dose recommended by the manufacturer, unless dose reduction is deemed to be in the patient's best interest in the absence of CCyR in CP CML subjects or MaHR in AP CML and BP CML subjects.

[0107] As used herein, treatment failure may be defined based on the following criteria shown in Table 04. [Table 4]

[0108] In compliant patients with treatment failure, drug interactions and mutation analysis are evaluated. Bone marrow cytogenetic analysis may be considered to assess CCyR at 15 months if BCR-ABL1 transcripts are >1%-10%.

[0109] Disease Progression: The date of disease progression will be determined as the date of any of the criteria for disease progression as shown in Table 05 below. [Table 5]

[0110] Treatment Switch: Therapy switching refers to switching a patient from a previous tyrosine kinase inhibitor to a compound of Formula I, or a pharmaceutically acceptable salt thereof. The following are the criteria for switching a patient from a previous tyrosine kinase inhibitor to a compound of Formula I, or a pharmaceutically acceptable salt thereof: a) Failure to achieve CHR after 3 months of treatment b) cytogenetic failure (>95% Ph+ cells) three months after initiation of treatment; c) Less than minor cytogenetic response (>65% Ph+) six months after initiation of treatment d) less than PCyR (>35% Ph+) 12 months after starting treatment; e) Loss of cytogenetic response at any time after initiation of treatment (i.e., a shift in cytogenetic response to at least one grade worsening from the patient's most recent bone marrow cytogenetic study), f) BCR-ABL1 ratio >10% six months after starting treatment; g) BCR-ABL1 ratio >1% 12 months after starting treatment; h) loss of MMR confirmed by two consecutive tests at any time during treatment; i) Loss of CHR, CCyR, or PcyR at any time after initiation of treatment, and j) Development of new clonal chromosomal abnormalities in Ph+ cells, or development of new BCR-ABL1 mutations that may cause resistance to the study treatment, or loss of a previous response to a TKI (i.e., either hematologic, cytogenetic, or molecular response) at any time after initiation of treatment.

[0111] As used herein, the term "about" when appearing before a range should be understood to refer to both endpoints of the range. In such instances, the range should also be understood to include the range defined by the particular endpoints recited, as well as any subranges within the recited endpoints. When "about" appears before a number, the number should be understood to include a range of ±5%.

[0112] As used herein, the term "between," when appearing before a range, should be understood to refer to both endpoints of the range. In such instances, the range should also be understood as including the range defined by the particular endpoints recited, as well as any sub-ranges within the recited endpoints.

[0113] As used herein, the term "therapeutically effective amount" refers to the amount of a drug, such as a compound of Formula I or a pharmaceutically acceptable salt thereof in the present case, which, when administered to a subject in need thereof, has the desired effect of reducing, curing, or alleviating a disease or its symptoms. For the purposes of the present invention, a therapeutically effective amount is an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof used in the treatment of CML or ALL. Such a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered to a patient in need thereof as is or in the form of a pharmaceutical formulation. In particular, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as a solid oral dosage form. The terms "titration" and "reatitration" can be interchangeable.

[0114] Pharmacokinetic (PK) evaluation is one of the endpoints of clinical trials. As known to those skilled in the art, PK evaluation includes, for example, min , C max , T max , half-life, C avg , C trough , terminal rate constant (Kel), AUC 0-12 , AUC 0-24 , the area under the concentration-time curve from time 0 to the last quantifiable time point (AUC 0-tau ), oral clearance (CL / F), apparent volume of distribution (V / F), and dose-normalized [AUC (0-tau) / dose or (C max This includes determining the dose / dose.

[0115] As used herein, AUC 0-24 C refers to the area under the steady-state plasma concentration versus time curve from time zero to 24 hours after administration of the drug (in this case, a compound of Formula I or a pharmaceutically acceptable salt thereof). min and C max The plasma concentrations, called T, are the steady-state minimum and maximum effective concentrations of the drug in plasma during a specific dosing interval, respectively. The time to reach the maximum plasma concentration after administration of a dose is called the T max It is called. DETAILED DESCRIPTION OF THE INVENTION

[0116] The present invention relates to methods for treating leukemia. In particular, the present invention relates to methods for treating CML and ALL. In certain embodiments, the methods include treating CP CML, AP CML, BP CML, Ph+ CML, and Ph+ ALL. The present invention also relates to methods for treating chronic phase (CP) Ph+ CML, T315I-positive CML (chronic phase, accelerated phase, or blast crisis phase) or T315I-positive Ph+ ALL previously treated with two or more tyrosine kinase inhibitors, newly diagnosed chronic phase (CP) Ph+ CML, and chronic phase, accelerated phase (AP), or blast crisis phase (BP) Ph+ CML that is resistant or intolerant to previous treatment.

[0117] In one embodiment, the present invention relates to a method of treating an adult patient with treatment-resistant CML.

[0118] In another embodiment, the invention relates to a method for treating an adult patient with newly diagnosed CML.

[0119] According to one embodiment of the invention, the method comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof.

[0120] The compounds of formula I have the following chemical names and formulas: N'-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide [ka] WO2012098416A1, incorporated herein by reference, discloses compounds of formula I and processes for their preparation.

[0121] The compound of Formula I or a pharmaceutically acceptable salt thereof can be administered to a patient with leukemia as an oral dosage form. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered to a patient with leukemia as an oral dosage form comprising the compound of Formula I or a pharmaceutically acceptable salt thereof in amorphous form and a pharmaceutically acceptable excipient. According to another embodiment, a method comprises orally administering an initial daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof, and gradually increasing or decreasing the dose to achieve or maintain a disease response.

[0122] The oral dosage form may comprise the compound of Formula I or a pharmaceutically acceptable salt thereof in its amorphous form and may further comprise one or more pharmaceutically acceptable excipients. In some embodiments, the oral dosage form may be a hard gelatin capsule.

[0123] Pharmaceutically acceptable excipients that can be included in oral dosage forms of the invention include, for example, one or more of polyvinyl caprolactam, polyvinyl acetate, polyethylene glycol graft copolymer, silicon dioxide, sodium lauryl sulfate, silicified microcrystalline cellulose, crospovidone, and / or gelatin.

[0124] A desirable dosage form of the compound of Formula I or a pharmaceutically acceptable salt thereof is an oral dosage form containing 10 mg to 300 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, as measured according to the daily dose. The daily dose may be administered in a series of one to four doses per day. In certain embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the dosage form is about 10 mg to about 210 mg, as measured by the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof administered daily. The dose may be administered as a single daily dose. The dose may be administered as multiple daily doses.

[0125] The total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof administered to a subject can be from about 10 mg to about 210 mg. In some embodiments, the total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg. In some embodiments, the total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 12 mg. In some embodiments, the total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 24 mg. In some embodiments, the total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 48 mg. In other embodiments, the total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 66 mg. In other embodiments, the total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 90 mg. In other embodiments, the total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 126 mg. In other embodiments, the total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 174 mg. In other embodiments, the total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 204 mg. In some embodiments, the total daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 210 mg. In their studies, the inventors found that the most effective and tolerable daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof was 204 mg in patients with previous TKI exposure, mutations, and ACA, and that dose-limiting toxicity was present at a daily dose of 240 mg.

[0126] In one embodiment, for newly diagnosed CML patients, the effective dose of the compound of Formula I or a pharmaceutically acceptable salt thereof can be 10 mg to 240 mg. More specifically, the effective dose is 10 mg to 210 mg.

[0127] In one embodiment, a daily dose of 10 mg to 210 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, when administered to a subject, provides an AUC 0-24 This can result in an average value of

[0128] In one embodiment, a daily dose of 10 mg to 210 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, when administered to a subject, provides a C in the range of 100 ng / mL to 9000 ng / mL. max This can result in an average value of

[0129] According to one embodiment, the method of the present invention comprises orally administering an initial daily dose of a compound of formula I or a pharmaceutically acceptable salt thereof, and gradually increasing or decreasing the dose to achieve or maintain a disease response without severe adverse reactions.

[0130] In one embodiment, the initial daily dose is selected from a dose of 10 mg to 210 mg. In another embodiment, the initial daily dose is selected from a dose of 12 mg to 210 mg. In a specific embodiment, the initial daily dose is selected from 12 mg, 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, 174 mg, and 204 mg. In a more specific embodiment, the initial daily dose is 174 mg.

[0131] In one aspect of the invention, the initial daily dose is titrated up to achieve or maintain a disease response.

[0132] According to certain embodiments, the initial daily dose is titrated to subsequent higher daily doses. In some embodiments, an initial daily dose of 12 mg is titrated to a daily dose selected from 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, 174 mg, and 204 mg. In some embodiments, an initial daily dose of 24 mg is titrated to a daily dose selected from 48 mg, 66 mg, 90 mg, 126 mg, 174 mg, and 204 mg. In some embodiments, an initial daily dose of 48 mg is titrated to a daily dose selected from 66 mg, 90 mg, 126 mg, 174 mg, and 204 mg. In some embodiments, an initial daily dose of 66 mg is titrated to a daily dose selected from 90 mg, 126 mg, 174 mg, and 204 mg. In some embodiments, an initial daily dose of 90 mg is titrated to a daily dose selected from 126 mg, 174 mg, and 204 mg. In some embodiments, an initial daily dose of 126 mg is titrated to a daily dose selected from 174 mg and 204 mg. In some embodiments, an initial daily dose of 174 mg is titrated to a daily dose of 204 mg.

[0133] According to one embodiment, the initial dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is gradually increased to maintain or achieve a disease response, including a hematological response, a cytogenetic response, and a molecular response. Those skilled in the art will understand that disease response is gradual, and that the initial response in a subject is a hematological response, which may be a partial hematological response or a complete hematological response. Subjects with a complete hematological response are then tested for a cytogenetic response, which may also be partial or complete, and patients who show a cytogenetic response are expected to have a molecular response, particularly a major molecular response.

[0134] In some embodiments, treatment-resistant subjects can maintain the same disease response achieved during previous treatment.For example, if a subject has achieved a hematological complete response in previous treatment but has to discontinue treatment due to adverse events, this patient may eventually achieve the same response using the compound of formula I or its pharmaceutically acceptable salt.In some embodiments, treatment-resistant subjects can achieve a hematological complete response, a cytogenetic complete response, and a major molecular genetic response, even if they have not achieved this with any of the previous treatments.Newly diagnosed subjects are expected to sequentially achieve a hematological complete response, a cytogenetic complete response, and a major molecular genetic response using the method of the present invention.

[0135] It has been found that subjects who have failed to respond to previous TKIs surprisingly exhibit favorable disease responses when treated with the compound of Formula I or a pharmaceutically acceptable salt thereof. For example, in treatment-resistant patients who had previously been treated with two or more tyrosine kinase inhibitors (TKIs), an open-label, dose-ranging, single-agent, multicenter, multiple-dose, dose-escalation study using the compound of Formula I or a pharmaceutically acceptable salt thereof demonstrated complete hematologic responses in 29 of 41 enrolled subjects (70.7%) and complete cytogenetic responses in 23 of 41 enrolled subjects (56.1%), while major molecular responses were reported in 18 of 41 enrolled subjects (43.9%).

[0136] In some embodiments, a subject may achieve a disease response with a particular daily dose over 7 days of treatment. In some embodiments, a subject may achieve a disease response with a particular daily dose over 14 days of treatment. In some embodiments, a subject may achieve a disease response with a particular daily dose over 21 days of treatment. In some embodiments, a subject may achieve a disease response with a particular daily dose over 28 days of treatment. In some embodiments, a subject may achieve a disease response with a particular dose over 3 months of treatment. In some embodiments, a subject may achieve a disease response with a particular dose over 6 months of treatment.

[0137] In certain embodiments, a subject may achieve a complete hematological response with a particular daily dose over 21 days of treatment. In certain embodiments, a subject may achieve a complete hematological response and a partial cytogenetic response with a particular daily dose over 28 days of treatment. In certain embodiments, a subject may achieve a complete hematological response and a complete cytogenetic response with a particular daily dose over 28 days of treatment. In certain embodiments, a subject may achieve a complete hematological response, a complete cytogenetic response, and a major molecular response with a particular daily dose over 3 months of treatment.

[0138] Those skilled in the art will understand that disease response may vary in different patients based on, for example, the patient's age, medical history, previous treatment, physical and vital sign status, and the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof. While the majority of patients tested in this invention experienced at least a hematological response (partial or complete) within the first cycle (28 days) of treatment, it can be expected that some patients may experience a disease response after two or three months of treatment. In certain embodiments, treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof at a specific daily dose may be continued for at least 28 days before escalating the daily dose to a subsequent dose, even in the absence of a disease response. In certain embodiments, treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof at a specific daily dose may be continued for at least three months before escalating the daily dose to a subsequent dose, even in the absence of a disease response. In certain embodiments, treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof at a specific daily dose may be continued for at least six months before escalating the daily dose to a subsequent dose, even in the absence of a disease response.

[0139] In one embodiment, the initial daily dose is titrated to subsequent higher daily doses, and the titrated doses range from 1000 ng*h / mL to 120,000 ng*h / mL. * AUC in the range of h / mL 0-24 This gives the average value of

[0140] According to one embodiment, the initial daily dose is titrated to subsequent higher daily doses, the titrated doses being in the range of 100 ng / mL to 9000 ng / mL of C. max This gives the average value of

[0141] According to certain embodiments, the initial daily dose is titrated to achieve or maintain a disease response without severe adverse reactions.

[0142] Adverse reactions or adverse events (AEs) are classified according to NCI-CTCAE version 5.0 (https: / / evs.nci.nih.gov / ftp1 / CTCAE / About.html). For AEs without an assigned CTCAE grade, the recommendations in the CTCAE criteria for converting mild, moderate, and severe events into CTCAE grades may be considered. AEs in patients may be considered "unrelated" if they are attributable to external causes, such as medical history, demographic details, disease, and environment, or "unlikely" if they do not follow a reasonable timeline or can be explained by the patient's comorbidities, environmental factors, medical history, and other concomitant medications or chemicals, including food-drug interactions. Those skilled in the art will understand that dose modifications, particularly dose reductions, are necessary only if the adverse event is attributable to the drug (the compound of Formula I or its pharmaceutically acceptable salt). Adverse events considered unrelated and unlikely may not lead to dose modifications.

[0143] Methods for determining whether an AE is due to the compound of Formula I or a pharmaceutically acceptable salt thereof, the underlying disease, or external causes are within the knowledge of those skilled in the art. For example, in AP CML and BP CML, patients with grade 3 or grade 4 bone marrow suppression may be due to the disease rather than the compound of Formula I or a pharmaceutically acceptable salt thereof. In such cases, a bone marrow biopsy was performed to distinguish between toxicity and antileukemic effects. If the patient had normoplastic bone marrow or persistent disease, treatment continued with maintenance medication. If there was evidence of toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof, such as hypoplastic bone marrow, treatment was suspended for up to four weeks, allowing the event to resolve to Grade 1 or less or to baseline, and then reinstated at a reduced dose. While a bone marrow biopsy is one method for distinguishing between toxicity due to the drug or symptoms of the underlying disease, embodiments of the present application include all methods known to those skilled in the art for this purpose. Those skilled in the art may practice other known methods to distinguish between toxicity due to a compound of Formula I or a pharmaceutically acceptable salt thereof, or an underlying disease condition.

[0144] In some embodiments of the present invention, if a patient experiences an adverse event due to the compound of Formula I or a pharmaceutically acceptable salt thereof, the daily dose is withheld. In some embodiments, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof may be withheld until the patient recovers from the adverse event. In other embodiments, the initial daily dose may be withheld for at least 7 days. In some embodiments, the initial daily dose is withheld for at least 14 days. In some embodiments, the initial daily dose is withheld for at least 28 days. In some embodiments, the initial daily dose is withheld for at least 48 days. In some embodiments, the initial daily dose is withheld for at least 56 days.

[0145] If a patient experiences an AE due to the compound of Formula I or a pharmaceutically acceptable salt thereof at a given daily dose, the dose is withheld for a specific period, and then the daily dose is resumed at the given dose or at a tapered daily dose. In particular, the daily dose is resumed after the patient has recovered from the AE. A subject was considered to have recovered from an adverse event when the toxicity level of the AE decreased to Grade 1 according to NCI-CTCAE version 5.0, or when the patient had fully recovered or returned to baseline. Those skilled in the art will understand that a patient is considered to have recovered from an AE based on a comparison of the patient's assessment reports before and after the start of treatment with the compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the patient may be treated for the AE. In some embodiments, the patient may receive optimal management of the AE. In some embodiments, the AE may resolve without treatment. Treatment of AEs and their optimal management are within the skill of those skilled in the art.

[0146] According to another embodiment, the initial daily dose is tapered to subsequent doses if the patient experiences severe adverse reactions.

[0147] According to certain embodiments, the initial daily dose is tapered to a subsequent lower daily dose. In some embodiments, an initial daily dose of 24 mg is tapered to a daily dose of 12 mg. In some embodiments, an initial daily dose of 48 mg is tapered to a daily dose selected from 12 mg and 24 mg. In some embodiments, an initial daily dose of 66 mg is tapered to a daily dose selected from 12 mg, 24 mg, and 48 mg. In some embodiments, an initial daily dose of 90 mg is tapered to a daily dose selected from 12 mg, 24 mg, 48 mg, and 66 mg. In some embodiments, an initial daily dose of 126 mg is tapered to a daily dose selected from 12 mg, 24 mg, 48 mg, 66 mg, and 90 mg. In some embodiments, an initial daily dose of 174 mg is tapered to a daily dose of 12 mg, 24 mg, 48 mg, 66 mg, 90 mg, or 126 mg. In some embodiments, an initial daily dose of 204 mg is tapered to a daily dose of 12 mg, 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, or 174 mg. In some embodiments, an initial daily dose of 180 mg is tapered to a daily dose of 45 mg, 90 mg, or 135 mg. In some embodiments, an initial daily dose of 174 mg is tapered to a daily dose of 43.5 mg, 87 mg, or 130.5 mg. In some embodiments, an initial daily dose of 135 mg is tapered to a daily dose of 45 mg or 90 mg. In some embodiments, an initial daily dose of 130.5 mg is tapered to a daily dose of 43.5 mg or 87 mg.

[0148] In one embodiment, the initial daily dose is tapered to a lower daily dose, the tapered dose being 1000 ng * h / mL~120,000ng * AUC in the range of h / mL 0-24 This gives the average value of

[0149] In one embodiment, the initial daily dose is tapered to a lower daily dose, the tapered dose being in the range of 100 ng / mL to 9000 ng / mL of C max This gives the average value of

[0150] According to certain embodiments, patients who experience an adverse drug reaction due to administration of a compound of Formula I or a pharmaceutically acceptable salt thereof are subjected to a dose delay (withholding) or a dose reduction, or both.

[0151] In some embodiments, patients who experience Grade 1 or 2 hematologic or non-hematologic toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof may continue treatment without any dose delays or tapering. In some embodiments, patients who experience Grade 1 or 2 hematologic or non-hematologic toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof may continue treatment without any dose delays or tapering while receiving supportive care and management of the AE.

[0152] In some embodiments, patients experiencing Grade 1 or 2 non-hematological toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof may undergo a dose delay of at least 7 days. In some embodiments, patients experiencing Grade 1 or 2 non-hematological toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof may undergo a dose delay of at least 14 days. In some embodiments, patients experiencing Grade 1 or 2 non-hematological toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof may undergo a dose delay of at least 28 days. In some embodiments, patients experiencing Grade 1 or 2 non-hematological toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof may undergo a dose delay for a period of 28 days or less. Patients may need to delay (or withhold) dosing if Grade 1 or 2 non-hematological toxicity is intolerable due to either clinical symptoms or interference with daily activities, and if such toxicity is not controlled by optimal supportive care or optimal management.

[0153] In some embodiments, treatment may be withheld for at least 14 days for patients experiencing grade 3 hematological or non-hematological toxicity or grade 4 asymptomatic hematological toxicity. In some embodiments, treatment may be withheld for at least 28 days for patients experiencing grade 3 hematological or non-hematological toxicity or grade 4 asymptomatic hematological toxicity. In some embodiments, treatment may be withheld for at least 56 days for patients experiencing grade 3 hematological or non-hematological toxicity or grade 4 asymptomatic hematological toxicity. In some embodiments, treatment may be withheld for 28 days or less for patients experiencing grade 3 hematological or non-hematological toxicity or grade 4 asymptomatic hematological toxicity. In some embodiments, treatment may be withheld for 56 days or less for patients experiencing grade 3 hematological or non-hematological toxicity or grade 4 asymptomatic hematological toxicity.

[0154] In some embodiments, the daily dose may be resumed at the same daily dose. In some embodiments, the daily dose may be resumed at a tapered dose. In certain embodiments, patients who experience a recurrence of an AE may be treated with a tapered daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0155] According to one embodiment of the present invention, the tapered daily dose may optionally be re-escalated to a dose selected from 24 mg to 210 mg, provided that the patient does not experience an AE. Dose escalation may be performed as described above.

[0156] The treatment method according to the present invention may be discontinued if the subject does not experience any disease response after 3 to 6 months of treatment using the maximum tolerated dose. Treatment may also be discontinued for subjects who are intolerant to the minimum dose. Subjects experiencing uncontrollable adverse events due to the daily dose of 12 mg in newly diagnosed patients or 48 mg in treatment-resistant patients may discontinue treatment. Discontinuation may also occur if the subject voluntarily discontinues or dies.

[0157] In certain embodiments, the present invention relates to a method for the treatment of adult patients with CML, comprising administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions.

[0158] In another specific embodiment, the invention relates to a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which is titrated to 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0159] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of said toxicity.

[0160] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity.

[0161] In certain embodiments, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity, a) The initial daily dose is withheld for at least 7 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and at reduced doses of 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are a recurrence of said toxicity.

[0162] In certain embodiments, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity.

[0163] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 28598 mg. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0164] In one particular embodiment, the present invention provides a method for the treatment of a human patient with chronic myeloid leukemia (CML), such as newly diagnosed or refractory chronic myeloid leukemia (CML), comprising administering to a subject a therapeutically effective amount of a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof to a patient, Methods are provided wherein the chronic myeloid leukemia (CML) is Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase, accelerated phase, or blast crisis phase.

[0165] According to any one of the embodiments described herein, a therapeutically effective amount of a compound of Formula I or a pharmaceutical salt thereof is 6226±5827 mg * h / mL~60373±55659ng *AUC in the range of h / mL 0-24 or a range of 664±450ng / mL to 5054±3051ng / mL C max is sufficient to achieve an average value of

[0166] According to any one of the embodiments described herein, the compound of formula I or a pharmaceutical salt thereof is administered at an initial daily dosage of 10 mg to 204 mg.

[0167] According to any one of the embodiments described herein, the compound of formula I or a pharmaceutical salt thereof is administered at an initial daily dose selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, and 180 mg.

[0168] According to any one of the embodiments described herein, the initial daily dose is titrated up or down to achieve or maintain at least one of: (a) complete hematological response; (b) complete hematological response and partial cytogenetic response; (c) complete hematological response and complete cytogenetic response; or (d) complete hematological response, complete cytogenetic response, and major molecular response.

[0169] According to any one of the embodiments described herein, the initial daily dose may be gradually increased or decreased without serious adverse reactions.

[0170] According to any one of the embodiments described herein, the patient is resistant or intolerant to at least one tyrosine kinase inhibitor.

[0171] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

[0172] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is selected from dasatinib, nilotinib, radotinib, and bosutinib.

[0173] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

[0174] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is selected from ponatinib and asciminib.

[0175] According to any one of the embodiments described herein, the patient has one or more of the following mutations in the BCR-ABL1 kinase domain: M244V, L248V, E499E, Q252H, P223S, A337T, F359C, E255V, Y253F, F317L, Y253H, V299L, E255V, F317L, E255V, F359V, G250E, E255K, F359V, M351T, G250E, H369R, H396R, and V359I.

[0176] According to any one of the embodiments described herein, the patient has one or more of the following characteristics: a) 15% blasts in peripheral blood and bone marrow; b) <30% blasts + promyelocytes in peripheral blood and bone marrow; c) <20% basophils in peripheral blood; d) ≥ 50 × 10 9 / L(≧50,000 / mm 3 ) platelets, e) Transient prior treatment-related thrombocytopenia (<50,000 / mm for ≤30 days prior to screening) 3 ), f) No evidence of extramedullary leukemia except for hepatosplenomegaly; g) ≥15 to <30% blasts in peripheral blood or bone marrow; h) ≥20% basophils in peripheral blood or bone marrow; i) ≥30% (blasts + promyelocytes) in peripheral blood or bone marrow (but <30% blasts); j) ≤100 × 109 platelets / L in peripheral blood, regardless of treatment; k) additional clonal cytogenetic abnormalities in Ph+ cells; l) ≥30% blasts in peripheral blood, bone marrow, or both, and m) Extramedullary disease.

[0177] According to any one of the embodiments described herein, the patient does not have T315I-positive CML.

[0178] According to any one of the embodiments described herein, treatment is withheld for at least 7 days and then resumed if the patient experiences a Grade 1 or Grade 2 non-hematologic adverse event.

[0179] According to any one of the embodiments described herein, treatment is withheld for a period of up to 56 days (e.g., 14 to 56 days, or 28 to 56 days) and then resumed if the patient experiences a Grade 3 hematologic or non-hematologic adverse event or a Grade 4 asymptomatic hematologic adverse event.

[0180] According to any one of the embodiments described herein, treatment is discontinued if the patient does not recover to grade 1 or less adverse events after a 56-day withholding period.

[0181] In one particular embodiment, the present invention provides a method of treating a treatment-resistant human patient with chronic myeloid leukemia (CML), comprising administering to a patient a therapeutically effective amount of a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof to a patient; i. the method comprises orally administering 174 to 200 mg of a compound of formula I daily; ii. The patient is resistant or intolerant to at least one tyrosine kinase inhibitor prior to administration of the compound of Formula I.

[0182] According to any one of the embodiments described herein, the patient has Ph+ CML.

[0183] According to any one of the embodiments described herein, the patient has chronic phase CML.

[0184] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

[0185] According to any one of the embodiments described herein, the second generation tyrosine kinase inhibitor is selected from dasatinib, nilotinib, radotinib, and bosutinib.

[0186] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

[0187] According to any one of the embodiments described herein, the third-generation tyrosine kinase inhibitor is selected from ponatinib and asciminib.

[0188] According to any one of the embodiments described herein, the patient has one or more of the following mutations in the BCR-ABL1 kinase domain: M244V, L248V, E499E, Q252H, P223S, A337T, F359C, E255V, Y253F, F317L, Y253H, V299L, E255V, F317L, E255V, F359V, G250E, E255K, F359V, M351T, G250E, H369R, H396R, and V359I.

[0189] According to any one of the embodiments described herein, the patient does not have T315I-positive CML.

[0190] According to any one of the embodiments described herein, the compound of formula I is orally administered in the form of an oral capsule.

[0191] According to any one of the embodiments described herein, each capsule contains 43.5 mg, 45 mg, 48 mg, or 50 mg of the compound of formula I.

[0192] According to any one of the embodiments described herein, the compound of formula I is administered every morning, and optionally with a two-hour fast before and after administration of the compound of formula I.

[0193] According to any one of the embodiments described herein, if a patient experiences a Grade 1 or Grade 2 non-hematological adverse event that is intolerable due to clinical symptoms or interference with daily activities, treatment is withheld for a period of time and then resumed.

[0194] According to any one of the embodiments described herein, the period of withholding treatment is 7 days.

[0195] According to any one of the embodiments described herein, the period of withholding treatment is 14 days.

[0196] According to any one of the embodiments described herein, if a patient experiences a Grade 3 hematological or non-hematological adverse event or a Grade 4 asymptomatic hematological adverse event, treatment is withheld for a period of time and then resumed.

[0197] According to any one of the embodiments described herein, treatment is withheld for up to 56 days (e.g., 14 to 56 days, or 28 to 56 days) for recovery to Grade 1 or less adverse events, and if the patient does not recover to Grade 1 or less adverse events, treatment with the compound of Formula I is discontinued.

[0198] According to any one of the embodiments described herein, the method comprises the daily oral administration of one or more oral capsules, (i) each capsule containing the same amount of the compound of formula I, (ii) the amount selected from 43.5 mg, 45 mg, 48 mg, and 50 mg of the compound of formula I, and (iii) in the event of the occurrence of a specific adverse event that does not require discontinuation or temporary withholding of treatment, the daily dosage is reduced by administering a smaller number of identical oral capsules daily.

[0199] According to any one of the embodiments described herein, prior to dose reduction, four oral capsules are administered daily.

[0200] In one particular embodiment, the present invention provides a method for the treatment of a human patient with chronic myeloid leukemia (CML), such as newly diagnosed or refractory chronic myeloid leukemia (CML), comprising administering to a subject a therapeutically effective amount of a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof is administered to a patient at an initial daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg), and if the patient develops hematologic and / or non-hematologic toxicity, a) the initial daily dose is withheld for at least 7 days and then resumed at an initial daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg); or b) the initial daily dose is withheld for less than 7 days, and once toxicity has resolved, treatment is resumed at an initial daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg); or c) the initial daily dose is withheld for at least 7 days and then resumed at a reduced daily dose of 43.5 mg to 192 mg (e.g., any one selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, and 192 mg); The reduced daily dose may also be re-escalated to a daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg), or d) the initial daily dose is withheld for at least 7 days and then resumed at a reduced daily dose of 43.5 mg to 192 mg (e.g., any one of doses selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, and 192 mg); In addition, the reduced daily dose is further reduced to a subsequent reduced daily dose of 43.5 mg to 180 mg for recurrent cases of toxicity (e.g., any one of doses selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, and 180 mg), Also provided is a method wherein the reduced daily dose or subsequent reduced daily dose may be re-escalated to a re-escalated daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

[0201] In another specific embodiment, the present invention provides a method for the treatment of a human patient with chronic myeloid leukemia (CML), such as newly diagnosed or refractory chronic myeloid leukemia (CML), comprising administering to a patient a therapeutically effective amount of a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof is administered to a patient at an initial daily dose of 174 mg, and if the patient develops hematologic and / or non-hematologic toxicity, a) The initial daily dose is withheld for at least 7 days and then resumed at an initial daily dose of 174 mg; or b) the initial daily dose is withheld for less than 7 days, and once toxicity has resolved, treatment is resumed at an initial daily dose of 174 mg; or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 135 mg (e.g., any one of doses selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, and 135 mg), preferably such that the reduced daily dose is 87 mg; The reduced daily dose may also be re-escalated to a maximum re-escalated daily dose of 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg), preferably the re-escalated daily dose is 200 mg; or d) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 135 mg (e.g., any one of doses selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, and 135 mg), preferably the reduced daily dose is 130.5 mg; or The reduced daily dose may be further reduced to a subsequent reduced daily dose of 43.5 mg to 130.5 mg (e.g., any one of doses selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, and 130.5 mg) for recurrent cases of toxicity, preferably 87 mg; Also provided is a method wherein the reduced daily dose or subsequent reduced daily dose may be retitrated to a maximum re-escalated daily dose of 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg), preferably the re-escalated daily dose is 200 mg.

[0202] In another specific embodiment, the present invention provides a method for the treatment of a human patient with chronic myeloid leukemia (CML), such as newly diagnosed or refractory chronic myeloid leukemia (CML), comprising administering to a patient a therapeutically effective amount of a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof is administered to a patient at an initial daily dose of 87 mg, and if the patient develops hematologic and / or non-hematologic toxicity, a) The initial daily dose is withheld for at least 7 days and then resumed at an initial daily dose of 87 mg; or b) the initial daily dose is withheld for less than 7 days, and once toxicity has resolved, treatment is resumed at an initial daily dose of 87 mg; or c) the initial daily dose is withheld for at least 7 days and then resumed at a reduced daily dose of 43.5 mg or 50 mg, preferably such that the reduced daily dose is 43.5 mg; Also provided is a method wherein the reduced daily dose may be re-escalated to a maximum re-escalated daily dose of 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg), preferably the re-escalated daily dose is 174 mg.

[0203] In one aspect, the present invention provides a method for the treatment of a human patient with chronic myeloid leukemia (CML), such as newly diagnosed or refractory chronic myeloid leukemia (CML), comprising administering to a patient a therapeutically effective amount of a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof to a patient in an initial daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

[0204] In some embodiments, the initial daily dose is any one of doses selected from 87 mg, 130.5 mg, and 174 mg. In a preferred embodiment, the initial daily dose is 130.5 mg. In a more preferred embodiment, the initial daily dose is 87 mg.

[0205] In some embodiments, patients are monitored for any hematological and / or non-hematological toxicity, which is commonly known to those skilled in the art, for example, as discussed in accordance with the National Cancer Institute's Common Toxicity Criteria (NCI-CTCAE) version 4.03 and version 5.0 (https: / / evs.nci.nih.gov / ftp1 / CTCAE / About.html).

[0206] In one embodiment, if a patient develops hematologic and / or non-hematologic toxicity at the initial daily dose, the initial daily dose is withheld for at least 7 days and resumed at an initial daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

[0207] In one embodiment, if a patient is on an initial daily dose of 174 mg and develops any hematologic and / or non-hematologic toxicity, treatment is withheld for at least 7 days (e.g., 14, 21, 28 days, etc.), after which treatment is resumed again at the initial dose of 174 mg. Similarly, if a patient is treated with an initial daily dose of 130.5 mg and develops any hematologic and / or non-hematologic toxicity, treatment is withheld for at least 7 days (e.g., 14, 21, 28 days, etc.), after which treatment is resumed again at the initial dose of 130.5 mg.

[0208] In another embodiment, if a patient is on an initial daily dose of 87 mg and develops any hematologic and / or non-hematologic toxicity, treatment is withheld for at least 7 days (14 days, 21 days, 28 days, etc.), after which treatment is resumed again at the initial dose of 87 mg.

[0209] In one embodiment, if a patient develops hematologic and / or non-hematologic toxicity at the initial daily dose, the initial daily dose is withheld for less than 7 days (e.g., 4 days), and once the toxicity resolves, treatment is resumed at an initial daily dose of 50 mg to 200 mg (e.g., selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

[0210] In one embodiment, if a patient is treated with an initial daily dose of 174 mg and develops any hematologic and / or non-hematologic toxicity, treatment is withheld for less than 7 days (such as 4 days), after which treatment is resumed again at the initial dose of 174 mg. Similarly, if a patient is treated with an initial daily dose of 130.5 mg and develops any hematologic and / or non-hematologic toxicity, treatment is withheld for less than 7 days (such as 4 days), after which treatment is resumed again at the initial dose of 130.5 mg.

[0211] In a preferred embodiment, if a patient is treated with an initial daily dose of 87 mg and develops any hematological and / or non-hematological toxicity, treatment is withheld for less than 7 days (such as 4 days), after which treatment is resumed again at the initial dose of 87 mg.

[0212] In one embodiment, if a patient develops hematologic and / or non-hematologic toxicity at the initial daily dose, the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 192 mg (e.g., selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, and 192 mg), and the reduced daily dose may be re-escalated to a daily dose of 50 mg to 200 mg (e.g., 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

[0213] In one embodiment, if a patient develops hematologic and / or non-hematologic toxicity at an initial daily dose of 174 mg, the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 130.5 mg (e.g., selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, and 192 mg), preferably a reduced daily dose of 130.5 mg. Furthermore, the reduced daily dose may optionally be titrated or re-titrated to a daily dose of 50 mg to 200 mg (e.g., selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg), preferably the titrated or re-titrated daily dose is 200 mg.

[0214] In another embodiment, if a patient develops hematologic and / or non-hematologic toxicity at an initial daily dose of 130.5 mg, the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 130.5 mg (e.g., selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, and 130.5 mg), preferably the reduced daily dose is 87 mg. Furthermore, the reduced daily dose may be optionally titrated or re-escalated to a daily dose of 50 mg to 130.5 mg (e.g., selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, and 130.5 mg), preferably the titrated or re-escalated daily dose is 174 mg or 200 mg, more preferably the titrated or re-escalated daily dose is 174 mg.

[0215] In another embodiment, if a patient develops hematologic and / or non-hematologic toxicity at an initial daily dose of 87 mg, the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 126 mg (e.g., selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, and 126), preferably the reduced daily dose is 43.5 mg. Furthermore, the reduced daily dose may optionally be titrated or re-titrated to a daily dose of 50 mg to 200 mg (e.g., selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, and 200 mg), preferably the titrated or re-titrated daily dose is any one of doses selected from 130.5 mg, 174 mg, and 200 mg, more preferably the titrated or re-titrated daily dose is 174 mg.

[0216] In one embodiment, if a patient develops hematologic and / or non-hematologic toxicity at the initial daily dose, the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 192 mg (e.g., selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, and 192 mg). The reduced daily dose may optionally be further reduced to a subsequent reduced daily dose of 43.5 mg to 180 mg (e.g., selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, and 180 mg) for recurrent cases of toxicity. The reduced daily dose or subsequent reduced daily doses may optionally be titrated or re-titrated to a dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

[0217] In one embodiment, if a patient develops hematologic and / or non-hematologic toxicity at an initial daily dose of 174 mg, the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 135 mg (e.g., selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, and 135 mg), preferably 130.5 mg. The reduced daily dose may optionally be further reduced to a subsequent reduced daily dose of 43.5 mg to 126 mg (e.g., selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, and 126 mg) for recurrent cases of toxicity, preferably 87 mg. The reduced daily dose or subsequent reduced daily doses may optionally be titrated or re-titrated to a dose of up to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

[0218] In one embodiment, if a patient develops hematologic and / or non-hematologic toxicity at an initial daily dose of 130.5 mg, the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 126 mg (e.g., selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, and 126 mg), preferably the reduced daily dose is 87 mg. The reduced daily dose may optionally be further reduced to a subsequent reduced daily dose of 43.5 mg to 66 mg (e.g., selected from 43.5 mg, 45 mg, 48 mg, 50 mg, and 66 mg) for recurrent cases of toxicity, preferably the subsequent reduced dose is 43.5 mg. The reduced daily dose or subsequent reduced daily doses may optionally be titrated or re-titrated to a dose of up to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg), preferably the titrated or re-titrated daily dose is 174 mg.

[0219] In one embodiment, if a patient develops hematologic and / or non-hematologic toxicity at an initial daily dose of 87 mg, the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg. The reduced daily dose or subsequent reduced daily doses may optionally be titrated or re-escalated to a dose of up to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg), preferably the titrated or re-escalated dose is 130.5 mg. More preferably, the titrated or re-escalated daily dose is 174 mg.

[0220] According to any one of the embodiments described herein, the initial daily dose may be gradually increased or decreased without serious adverse reactions.

[0221] According to any one of the embodiments described herein, the patient is resistant or intolerant to at least one tyrosine kinase inhibitor.

[0222] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

[0223] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is selected from rodatinib, dasatinib, nilotinib, and bosutinib.

[0224] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

[0225] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is selected from ponatinib and asciminib.

[0226] According to any one of the embodiments described herein, the patient has one or more of the following mutations in the BCR-ABL1 kinase domain: M244V, L248V, E499E, Q252H, P223S, A337T, F359C, E255V, Y253F, F317L, Y253H, V299L, E255V, F317L, E255V, F359V, G250E, E255K, F359V, M351T, G250E, H369R, H396R, and V359I.

[0227] According to any one of the embodiments described herein, the chronic myeloid leukemia (CML) is Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase, accelerated phase, or blast crisis phase.

[0228] According to any one of the embodiments described herein, the initial daily dose may be gradually increased or decreased without serious adverse reactions.

[0229] According to any one of the embodiments described herein, the patient is resistant or intolerant to at least one tyrosine kinase inhibitor.

[0230] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

[0231] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is selected from dasatinib, nilotinib, radotinib, and bosutinib.

[0232] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

[0233] According to any one of the embodiments described herein, the at least one tyrosine kinase inhibitor is selected from ponatinib and asciminib.

[0234] According to any one of the embodiments described herein, the patient has one or more of the following mutations in the BCR-ABL1 kinase domain: M244V, L248V, E499E, Q252H, P223S, A337T, F359C, E255V, Y253F, F317L, Y253H, V299L, E255V, F317L, E255V, F359V, G250E, E255K, F359V, M351T, G250E, H369R, H396R, and V359I.

[0235] According to any one of the embodiments described herein, the chronic myeloid leukemia (CML) is Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase, accelerated phase, or blast crisis phase.

[0236] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0237] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0238] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0239] In certain embodiments, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity, a) The initial daily dose is withheld for at least 7 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are recurrences of toxicity; The reduced dose is optionally re-escalated to any one of doses selected from 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0240] In another embodiment, the invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0241] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 28598 mg. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0242] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 28598 mg. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0243] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0244] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of the toxicity.

[0245] In one embodiment, the invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity.

[0246] In certain embodiments, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are a recurrence of the toxicity.

[0247] In certain embodiments, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity.

[0248] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 28598 mg. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0249] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0250] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 28598 mg. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0251] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0252] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are recurrences of toxicity; The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0253] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0254] In certain embodiments, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are recurrences of toxicity; The reduced dose is optionally re-escalated to any one of doses selected from 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0255] In certain embodiments, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0256] In certain embodiments, the invention relates to a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg; if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from such toxicity; and treatment is continued at a reduced dose of 126 mg for index cases, and at 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity.

[0257] In certain embodiments, the invention relates to a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg; if the patient develops hematologic toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity; and treatment is continued at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity.

[0258] In certain embodiments, the invention relates to a method for treating an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced dose of 126 mg for index cases, and at 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are a recurrence of toxicity.

[0259] In one embodiment, the invention relates to a method for treating an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg; if the patient develops hematologic toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from such toxicity; and treatment is continued at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity.

[0260] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0261] In a particular embodiment, the present invention provides a method for the treatment of adult patients with treatment-resistant CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, with an initial daily dose of 174 mg; if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity; and treatment is continued at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity. and optionally re-escalating the reduced dose to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0262] In certain embodiments, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced dose of 126 mg for index cases and 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response without hematological toxicity.

[0263] In certain embodiments, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 130.5 mg for index cases and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0264] In another specific embodiment, the present invention provides a method for treating an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg; if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity; and treatment is continued at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 28598 mg. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0265] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed chronic myeloid leukemia (CML), comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof: The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 130.5 mg for index cases and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity, and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0266] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 130.5 mg for index cases and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose may optionally be re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain, without severe adverse reactions, at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 28598 mg or less. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0267] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of 174 mg, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 130.5 mg for index cases and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose may optionally be re-escalated to any one of the doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg until at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response is achieved or maintained without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0268] In certain embodiments, the present invention provides a method for the treatment of an adult patient with CML, comprising orally administering an initial daily dose of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and gradually escalating or tapering the dose to achieve or maintain a complete hematologic response without severe adverse reactions, and wherein the daily dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, in the patient is 6226±5827 mg / kg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0269] In another specific embodiment, the present invention provides a method for the treatment of adult patients with CML, comprising orally administering an initial daily dose of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and gradually escalating or tapering the dose to achieve or maintain a complete hematologic response without severe adverse reactions, and wherein the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0270] In yet another specific embodiment, the present invention provides a method for the treatment of an adult patient with CML, comprising orally administering an initial daily dose of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and gradually increasing or decreasing the dose to achieve or maintain a disease response without severe adverse reactions, and wherein the daily dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, in the patient is 6226±5827 mg / kg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0271] In another specific embodiment, the present invention provides a method for the treatment of adult patients with CML, comprising orally administering an initial daily dose of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, with escalating or tapering the dose to achieve or maintain a disease response without severe adverse reactions, and wherein the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention provides a method for producing an average value of

[0272] In a particular embodiment, the invention provides a method for treating an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 10 mg to 200 mg, with the dose gradually increasing by 20 mg to 210 mg to achieve or maintain, without severe adverse reactions, at least one of: (a) complete hematological response; (b) complete hematological response and partial cytogenetic response; (c) complete hematological response and complete cytogenetic response; or (d) complete hematological response, complete cytogenetic response, and major molecular response; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention provides a method for producing an average value of

[0273] In another specific embodiment, the present invention provides a method for the treatment of adult patients with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 10 mg to 200 mg, and gradually escalating the dose by 20 mg to 210 mg to achieve or maintain, without severe adverse reactions, at least one of: (a) complete hematological response; (b) complete hematological response and partial cytogenetic response; (c) complete hematological response and complete cytogenetic response; or (d) complete hematological response, complete cytogenetic response, and major molecular response; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0274] In yet another specific embodiment, the present invention provides a method for treating an adult patient with CML, comprising orally administering a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 20 mg to 210 mg, and tapering the dose by 10 mg to 200 mg upon the occurrence of severe adverse reactions, wherein the dose is tapered such that the patient achieves or maintains at least one of: (a) a complete hematologic response; (b) a complete hematologic response and a partial cytogenetic response; (c) a complete hematologic response and a complete cytogenetic response; or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0275] In yet another specific embodiment, the present invention provides a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 20 mg to 210 mg, and tapering the dose by 10 mg to 200 mg upon the occurrence of severe adverse reactions, wherein the dose is tapered such that the patient achieves or maintains at least one of: (a) a complete hematologic response; (b) a complete hematologic response and a partial cytogenetic response; (c) a complete hematologic response and a complete cytogenetic response; or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0276] In yet another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which initial dose is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions, and wherein the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0277] In certain embodiments, the present invention provides a method for the treatment of adult patients with treatment-resistant CML, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which initial dose is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL.max The present invention relates to a method for producing an average value of

[0278] In yet another specific embodiment, the present invention provides a method for treating an adult patient with treatment-resistant CML, comprising orally administering a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which is titrated to 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0279] In yet another specific embodiment, the present invention provides a method for the treatment of adult patients with treatment-resistant CML, comprising orally administering a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which is titrated to 204 mg to achieve or maintain, without severe adverse reactions, at least one of: (a) complete hematological response; (b) complete hematological response and partial cytogenetic response; (c) complete hematological response and complete cytogenetic response; or (d) complete hematological response, complete cytogenetic response, and major molecular response; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0280] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0281] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 28598 mg. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0282] According to certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0283] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0284] According to certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The reduced dose may be optionally re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain, without severe adverse reactions, at least one of (a) a complete hematological response, (b) a complete hematological response and a partial cytogenetic response, (c) a complete hematological response and a complete cytogenetic response, or (d) a complete hematological response, a complete cytogenetic response, and a major molecular response, and the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention provides a method for producing an average value of

[0285] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 28598 mg. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention provides a method for producing an average value of

[0286] According to another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The reduced dose may be optionally re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response without severe adverse reactions, and the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention provides a method for producing an average value of

[0287] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention provides a method for producing an average value of

[0288] According to another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention provides a method for producing an average value of

[0289] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 28598 mg. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0290] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention provides a method for producing an average value of

[0291] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0292] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg, and 174 mg, and at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response is achieved or maintained without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0293] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 28598 mg. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0294] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity: a) The initial daily dose is withheld for at least 14 days and resumed after the patient has recovered from the toxicity; or b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg, and 174 mg, and at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response is achieved or maintained without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0295] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 174 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 174 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 174 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of such toxicity; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0296] In certain embodiments, the invention provides a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a reduced dose of 126 mg for index cases and at 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of said toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0297] In another specific embodiment, the invention provides a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof; if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity; and treatment is continued at a reduced daily dose of 130.5 mg for index cases, and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 28598 mg. * h / mL~42898±33827ng * h / mL.

[0298] In another specific embodiment, the invention provides a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a reduced dose of 126 mg for index cases and at 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of said toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0299] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 130.5 mg for index cases and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 3370 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0300] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose may optionally be re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without severe adverse reactions: (a) complete hematologic response; (b) complete hematologic response and partial cytogenetic response; (c) complete hematologic response and complete cytogenetic response; or (d) complete hematologic response, complete cytogenetic response, and major molecular response; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0301] In certain embodiments, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, administering to the patient an initial daily dose of 174 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced dose of 126 mg for index cases and 90 mg, 66 mg, and 48 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose may optionally be re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without severe adverse reactions: (a) complete hematologic response; (b) complete hematologic response and partial cytogenetic response; (c) complete hematologic response and complete cytogenetic response; or (d) complete hematologic response, complete cytogenetic response, and major molecular response; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0302] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 130.5 mg for index cases and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0303] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 130.5 mg for index cases and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose may optionally be re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain, without severe adverse reactions, at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 28598 mg or less. * h / mL~42898±33827ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0304] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 174 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 130.5 mg for index cases and 87 mg and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose may optionally be re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain, without severe adverse reactions, at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 3370 ng / mL to 5054±3051 ng / mL. maxThe present invention relates to a method for producing an average value of

[0305] In a particular embodiment, the present invention provides a method for the treatment of newly diagnosed adult CML patients, comprising administering an initial daily dose of 174 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, which initial dose is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions, and wherein the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in the patient is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0306] In another specific embodiment, the present invention provides a method for the treatment of newly diagnosed adult CML patients, comprising administering the compound of formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, which initial dose is titrated to 204 mg to achieve or maintain a complete hematologic response (CHR) without severe adverse reactions, and wherein the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 664±450 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value.

[0307] In another specific embodiment, the present invention provides a method for the treatment of adult patients with chronic myeloid leukemia (CML), comprising orally administering an initial daily dose of a therapeutically effective amount of a pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof, and gradually escalating or tapering the dose to achieve or maintain a complete hematologic response without severe adverse reactions, wherein the pharmaceutical composition is administered under fasting conditions, and wherein the pharmaceutical composition comprises 6226±5827 mg of leukemia or a pharmaceutically acceptable salt thereof. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0308] In another specific embodiment, the present invention provides a method for the treatment of adult patients with chronic myeloid leukemia (CML), comprising orally administering an initial daily dose of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and gradually escalating or tapering the dose to achieve or maintain a complete hematological response without severe adverse reactions, wherein the pharmaceutical composition is administered under fasting conditions, and wherein the pharmaceutical composition achieves a Cmax ranging from 664±450 ng / mL to 5054±3051 ng / mL. max The present invention relates to a method for producing an average value of

[0309] In certain embodiments, the present invention provides a method for the treatment of adult patients with CML, comprising orally administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 10 mg to 200 mg, and gradually increasing the dose by 20 mg to 210 mg, to achieve or maintain at least one of (a) a complete hematological response, (b) a complete hematological response and a partial cytogenetic response, (c) a complete hematological response and a complete cytogenetic response, or (d) a complete hematological response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions attributable to the pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition has a cytogenetic activity of 6226±5827 mg / mL when administered under fasting conditions. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 and C, which ranged from 664±450ng / mL to 5054±3051ng / mL. max The present invention relates to a method for producing an average value of

[0310] In yet another specific embodiment, the present invention provides a method for the treatment of an adult patient with CML, comprising orally administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in a daily dose, wherein the daily dose is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24and C, which ranged from 664±450ng / mL to 5054±3051ng / mL. max and the daily dose does not result in a patient's QT interval exceeding about 500 ms.

[0311] In certain embodiments, the present invention provides a method for preventing relapse of CML in patients who have previously received treatment with a tyrosine kinase inhibitor, comprising orally administering an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the initial daily dose is 6226±5827 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 and C, which ranged from 664±450ng / mL to 5054±3051ng / mL. max The present invention relates to a method for producing an average value of

[0312] In one particular embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of said toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg.

[0313] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0314] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 18237 mg. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0315] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 2277 ng / mL to 3415±1566 ng / mL. max The present invention relates to a method for producing an average value of

[0316] In another embodiment, the invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 18237 mg. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0317] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 2277 ng / mL to 3415±1566 ng / mL. max The present invention relates to a method for producing an average value of

[0318] In one particular embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and, in the event of a recurrence of said toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg.

[0319] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and, in the event of a recurrence of such toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0320] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and, in the event of a recurrence of such toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 18237 mg. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0321] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and, in the event of a recurrence of such toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 2277 ng / mL to 3415±1566 ng / mL. max The present invention relates to a method for producing an average value of

[0322] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 18237 mg. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0323] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 2277 ng / mL to 3415±1566 ng / mL. max The present invention relates to a method for producing an average value of

[0324] In one particular embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, such that if the patient develops hematological toxicity attributable to the compound of formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for relapses that are a recurrence of said toxicity.

[0325] In another specific embodiment, the present invention provides a method for treating an adult patient with newly diagnosed chronic myeloid leukemia (CML), comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, such that if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for relapses that are a recurrence of said toxicity. and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0326] In another embodiment, the invention provides a method for treating an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for relapses that are a recurrence of said toxicity, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 18237 mg. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0327] In another embodiment, the present invention provides a method for treating an adult patient with newly diagnosed chronic myeloid leukemia (CML), comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for relapses that are a recurrence of the toxicity, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is in the range of 2277 ng / mL to 3415±1566 ng / mL. max The present invention relates to a method for producing an average value of

[0328] In another specific embodiment, the present invention provides a method for treating an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for relapses that are a recurrence of said toxicity, and the reduced dose is optionally selected from 66 mg. , 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and achieves or maintains, without severe adverse reactions, at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 18237 mg or less. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0329] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for recurrent cases of the toxicity; and The reduced dose may optionally be re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain, without severe adverse reactions, at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is in the range of 2277 ng / mL to 3415±1566 ng / mL. max The present invention relates to a method for producing an average value of

[0330] In one embodiment, the invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of said toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg.

[0331] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0332] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 18237 mg. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0333] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with refractory chronic myeloid leukemia (CML), comprising administering to the patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 2277 ng / mL to 3415±1566 ng / mL. max The present invention relates to a method for producing an average value of

[0334] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 18237 mg. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention provides a method for producing an average value of

[0335] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 2277 ng / mL to 3415±1566 ng / mL. max The present invention provides a method for producing an average value of

[0336] In one particular embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and, in the event of a recurrence of said toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg.

[0337] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and, in the event of a recurrence of the toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0338] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and, in the event of a recurrence of such toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 18237 mg. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0339] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and, in the event of a recurrence of such toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 2277 ng / mL to 3415±1566 ng / mL. max The present invention relates to a method for producing an average value of

[0340] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and, in the event of a recurrence of such toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 18237 mg. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0341] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 90 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 90 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and, in the event of a recurrence of such toxicity, is resumed at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg, and the patient achieves or maintains at least one of (a) a complete hematologic response, (b) a complete hematologic response and a partial cytogenetic response, (c) a complete hematologic response and a complete cytogenetic response, or (d) a complete hematologic response, a complete cytogenetic response, and a major molecular response, without severe adverse reactions; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is in the range of 2277 ng / mL to 3415±1566 ng / mL. max The present invention relates to a method for producing an average value of

[0342] In another specific embodiment, the invention relates to a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, such that if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for relapses that are a recurrence of said toxicity.

[0343] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for recurrent cases of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0344] In another specific embodiment, the present invention provides a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for relapses that are a recurrence of said toxicity, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 18237 mg. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0345] In another specific embodiment, the present invention provides a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for relapses that are a recurrence of the toxicity, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is in the range of 2277 ng / mL to 3415±1566 ng / mL.max The present invention relates to a method for producing an average value of

[0346] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for recurrent cases of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0347] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for recurrent cases of the toxicity; and The reduced dose may optionally be re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain, without severe adverse reactions, at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient is 18237 mg or less. * h / mL~27355±2782ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0348] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 90 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg for recurrent cases of the toxicity; and The reduced dose may optionally be re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain, without severe adverse reactions, at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, and the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is in the range of 2277 ng / mL to 3415±1566 ng / mL. maxThe present invention relates to a method for producing an average value of

[0349] In one particular embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 87 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 87 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 87 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg for such toxicity.

[0350] In another embodiment, the invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 87 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 87 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 87 mg once toxicity has resolved, or c) The initial daily dose should be withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg for the toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0351] In one particular embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 87 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 87 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 87 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 43.5 mg for such toxicity.

[0352] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 87 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 87 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 87 mg once toxicity has resolved, or c) The initial daily dose should be withheld for at least 14 days and resumed at a reduced daily dose of 43.5 mg for the toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0353] In one particular embodiment, the invention relates to a method for treating an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 87 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from such toxicity, and treatment is continued at a reduced daily dose of 43.5 mg for relapses that are a recurrence of such toxicity.

[0354] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 87 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 43.5 mg for recurrent cases of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0355] In one particular embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 87 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 87 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 87 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg for such toxicity.

[0356] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 87 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 87 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 87 mg once toxicity has resolved, or c) The initial daily dose should be withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg for the toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0357] In one particular embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 87 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 87 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 87 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 43.5 mg for such toxicity.

[0358] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 87 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 87 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 87 mg once toxicity has resolved, or c) The initial daily dose should be withheld for at least 14 days and resumed at a reduced daily dose of 43.5 mg for the toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0359] In one particular embodiment, the invention relates to a method for treating an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 87 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a reduced daily dose of 43.5 mg for relapses that are a recurrence of said toxicity.

[0360] In another specific embodiment, the invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 87 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and treatment is continued at a reduced daily dose of 43.5 mg for relapses that are a recurrence of said toxicity, and optionally, the reduced dose is the method of achieving or maintaining at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0361] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 87 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 43.5 mg for recurrent cases of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0362] In one embodiment, the invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 130.5 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 130.5 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 130.5 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity.

[0363] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 130.5 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 130.5 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 130.5 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0364] In one embodiment, the invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 130.5 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 130.5 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 130.5 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity.

[0365] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 130.5 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 130.5 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 130.5 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0366] In one embodiment, the invention relates to a method for treating an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 130.5 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from such toxicity, and treatment is continued at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of such toxicity.

[0367] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 130.5 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0368] In one embodiment, the invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 130.5 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 130.5 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 130.5 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity.

[0369] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 130.5 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 130.5 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 130.5 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0370] In one particular embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 130.5 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 130.5 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 130.5 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity.

[0371] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to said patient an initial daily dose of 130.5 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 14 days and resumed at 130.5 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 14 days and resumed at 130.5 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0372] In one embodiment, the invention relates to a method for treating adult patients with treatment-resistant chronic myeloid leukemia (CML), comprising administering to the patient an initial daily dose of 130.5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is withheld for up to four weeks to allow the patient to recover from such toxicity, and treatment is continued at a reduced daily dose of 87 mg for index cases and 43.5 mg for relapsed cases that are a recurrence of such toxicity.

[0373] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with refractory chronic myeloid leukemia (CML), comprising administering to the patient an initial daily dose of 130.5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof: the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0374] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with treatment-resistant CML, comprising administering to the patient an initial daily dose of 130.5 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, and if the patient develops hematological toxicity attributable to the compound of formula I or a pharmaceutically acceptable salt thereof: the initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment is continued at a reduced daily dose of 87 mg for index cases and 43.5 mg for recurrent cases that are a recurrence of the toxicity; and The reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0375] In one particular embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 126 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 126 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 126 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 90 mg for index cases, and 66 mg and 48 mg for recurrent cases that are a recurrence of the toxicity.

[0376] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 126 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 126 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 126 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 90 mg for index cases, and 66 mg and 48 mg for recurrent cases that are a recurrence of the toxicity; and wherein the reduced dose is optionally re-escalated to any one of doses selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 200 mg, and 204 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, without severe adverse reactions.

[0377] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 126 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 126 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 126 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 90 mg for index cases, and 66 mg and 48 mg for recurrent cases that are a recurrence of the toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in patients is 40249 mg. * h / mL~60373±55659ng * AUC in the range of h / mL 0-24 The present invention relates to a method for producing an average value of

[0378] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to said patient an initial daily dose of 126 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patient develops non-hematologic toxicity: a) The initial daily dose is withheld for at least 7 days and resumed at 126 mg after the patient has recovered from the toxicity; or b) The initial daily dose is withheld for less than 7 days and resumed at 126 mg once toxicity has resolved, or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 90 mg for index cases, and 66 mg and 48 mg for recurrent cases that are a recurrence of the toxicity; The daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a patient is in the range of 3282 ng / mL to 4924±3289 ng / mL. max The present invention relates to a method for producing an average value of

[0379] In another specific embodiment, the present invention provides a method for the treatment of an adult patient with newly diagnosed CML, comprising administering to the patient an initial daily dose of 126 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, and if the patien...

Claims

1. 1. A method for the treatment of a human patient having chronic myeloid leukemia (CML), such as newly diagnosed or refractory chronic myeloid leukemia (CML), comprising administering to a patient a therapeutically effective amount of a compound of formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof to a patient, The method, wherein said chronic myeloid leukemia (CML) is Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase, accelerated phase, or blast crisis phase.

2. The therapeutically effective amount of the compound of formula I or a pharmaceutical salt thereof provides an AUC range of 6226±5827 ng*h / mL to 60373±55659 ng*h / mL. ０－２４ or a range of 664±450 ng / mL to 5054±3051 ng / mL C ｍａｘ 2. The method of claim 1, wherein the average value of

3. 10. The method of claim 1, wherein the compound of formula I or a pharmaceutical salt thereof is administered at an initial daily dosage of 10 mg to 204 mg.

4. 4. The method of any one of claims 1 to 3, wherein the compound of formula I or a pharmaceutical salt thereof is administered at an initial daily dose selected from 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, and 180 mg.

5. 5. The method of any one of claims 1 to 4, wherein the initial daily dose is titrated up or down to achieve or maintain at least one of: (a) complete hematological response; (b) complete hematological response and partial cytogenetic response; (c) complete hematological response and complete cytogenetic response; or (d) complete hematological response, complete cytogenetic response, and major molecular response.

6. 6. The method of any one of claims 1 to 5, wherein the initial daily dose is gradually increased or decreased without severe adverse reactions.

7. 7. The method of any one of claims 1 to 6, wherein the patient is resistant or intolerant to at least one tyrosine kinase inhibitor.

8. 8. The method of claim 7, wherein the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

9. 9. The method of claim 7, wherein the at least one tyrosine kinase inhibitor is selected from dasatinib, nilotinib, radotinib, and bosutinib.

10. 8. The method of claim 7, wherein the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

11. 11. The method of claim 7 or 10, wherein the at least one tyrosine kinase inhibitor is selected from ponatinib and asciminib.

12. 12. The method of any one of claims 1 to 11, wherein the patient has one or more of the following mutations in the BCR-ABL1 kinase domain: M244V, L248V, E499E, Q252H, P223S, A337T, F359C, E255V, Y253F, F317L, Y253H, V299L, E255V, F317L, E255V, F359V, G250E, E255K, F359V, M351T, G250E, H369R, H396R, and V359I.

13. The patient has the following characteristics: a) 15% blasts in peripheral blood and bone marrow; b) <30% blasts + promyelocytes in peripheral blood and bone marrow; c) <20% basophils in peripheral blood; d) ≧50×10 ９ / L (≧50,000 / mm ３ ) platelets, e) Transient prior treatment-related thrombocytopenia (<50,000 / mm for ≤30 days prior to screening) ３ ), f) No evidence of extramedullary leukemic involvement except for hepatosplenomegaly; g) ≥15 to <30% blasts in peripheral blood or bone marrow; h) ≥20% basophils in peripheral blood or bone marrow; i) ≥30% (blasts + promyelocytes) in peripheral blood or bone marrow (but <30% blasts); j) ≦100×109 platelets / L in peripheral blood, regardless of treatment; k) additional clonal cytogenetic abnormalities in Ph+ cells; l) ≥30% blasts in peripheral blood, bone marrow, or both; and m) extramedullary disease.

14. 14. The method of any one of claims 1 to 13, wherein the patient does not have T315I-positive CML.

15. 15. The method of any one of claims 1 to 14, wherein the treatment is withheld for a period of at least 7 days if the patient experiences a grade 1 or grade 2 non-hematological adverse event, and then resumed.

16. 16. The method of any one of claims 1 to 15, wherein the treatment is withheld for a period of up to 56 days (e.g., 14 to 56 days, or 28 to 56 days) and then resumed if the patient experiences a grade 3 hematological or non-hematological adverse event or a grade 4 asymptomatic hematological adverse event.

17. 17. The method of claim 16, wherein the treatment is discontinued if the patient does not recover to a Grade 1 or less adverse event after a withholding period of 56 days.

18. 1. A method of treating a treatment-resistant human patient with chronic myeloid leukemia (CML), comprising administering to a subject a therapeutically effective amount of a compound of formula I: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof to a patient; i. the method comprises orally administering 174 to 200 mg of a compound of formula I daily; ii. The method, wherein the patient is resistant or intolerant to at least one tyrosine kinase inhibitor prior to administration of the compound of formula I.

19. 19. The method of claim 18, wherein the patient has Ph+ CML.

20. 20. The method of claim 18 or 19, wherein the patient has chronic phase CML.

21. 21. The method of any one of claims 18 to 20, wherein the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

22. 22. The method of claim 21, wherein the second generation tyrosine kinase inhibitor is selected from dasatinib, nilotinib, radotinib, and bosutinib.

23. 23. The method of any one of claims 18 to 22, wherein the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

24. 24. The method of claim 23, wherein the third generation tyrosine kinase inhibitor is selected from ponatinib and asciminib.

25. 25. The method of any one of claims 18 to 24, wherein the patient has one or more of the following mutations in the BCR-ABL1 kinase domain: M244V, L248V, E499E, Q252H, P223S, A337T, F359C, E255V, Y253F, F317L, Y253H, V299L, E255V, F317L, E255V, F359V, G250E, E255K, F359V, M351T, G250E, H369R, H396R, and V359I.

26. 26. The method of any one of claims 18 to 25, wherein the patient does not have T315I-positive CML.

27. 27. The method of any one of claims 1 to 26, wherein the compound of formula I is orally administered in oral capsule form.

28. 28. The method of claim 27, wherein the capsules each contain 43.5 mg, 45 mg, or 50 mg of the compound of formula I.

29. 29. The method of claim 28, wherein the compound of formula I is administered every morning, and optionally with a two-hour fast before and after administration of the compound of formula I.

30. 30. The method of any one of claims 18 to 29, wherein if the patient experiences a Grade 1 or Grade 2 non-hematological adverse event that is intolerable due to clinical symptoms or interference with daily activities, the treatment is withheld for a period of time and then resumed.

31. 31. The method of claim 30, wherein the period of withholding treatment is 7 days.

32. 32. The method of claim 31, wherein the period of withholding treatment is 14 days.

33. 33. The method of any one of claims 18 to 32, wherein if the patient experiences a Grade 3 hematological or non-hematological adverse event or a Grade 4 asymptomatic hematological adverse event, the treatment is withheld for a period of time and then resumed.

34. 34. The method of claim 33, wherein the treatment is withheld for up to 56 days (e.g., 14 to 56 days, or 28 to 56 days) for recovery to Grade 1 or less adverse events, and if the patient does not recover to Grade 1 or less adverse events, treatment with the compound of Formula I is discontinued.

35. 35. The method of any one of claims 1 to 34, wherein the method comprises the daily oral administration of one or more oral capsules, (i) each capsule containing the same amount of the compound of formula I, (ii) the amount selected from 43.5 mg, 45 mg, and 50 mg of the compound of formula I, and (iii) in the event of the occurrence of a specific adverse event that does not require discontinuation or temporary withholding of treatment, the daily dosage is reduced by administering a smaller number of identical oral capsules daily.

36. 36. The method of claim 35, wherein prior to the dose reduction, four oral capsules are administered daily.

37. 1. A method for the treatment of a human patient having chronic myeloid leukemia (CML), such as newly diagnosed or refractory chronic myeloid leukemia (CML), comprising administering to a patient a therapeutically effective amount of a compound of formula I: 【Chemistry 3】 or a pharmaceutically acceptable salt thereof is administered to a patient at an initial daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg), and the patient develops hematologic and / or non-hematologic toxicity; a) the initial daily dose is withheld for at least 7 days and then resumed at an initial daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg); or b) the initial daily dose is withheld for less than 7 days, and once toxicity has resolved, treatment is resumed at an initial daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg); or c) the initial daily dose is withheld for at least 7 days and then resumed at a reduced daily dose of 43.5 mg to 192 mg (e.g., any one selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, and 192 mg); The reduced daily dose may also be re-escalated to a daily re-escalation dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg); or d) the initial daily dose is withheld for at least 7 days and then resumed at a reduced daily dose of 43.5 mg to 192 mg (e.g., any one of doses selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, and 192 mg); Furthermore, the reduced daily dose is further reduced to a subsequent reduced daily dose of 43.5 mg to 180 mg (e.g., any one of doses selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, and 180 mg) for recurrent cases, which are recurrences of the toxicity; The reduced daily dose or any subsequent reduced daily dose may also be re-escalated to a re-escalated daily dose of 50 mg to 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

38. 1. A method for the treatment of a human patient having chronic myeloid leukemia (CML), such as newly diagnosed or refractory chronic myeloid leukemia (CML), comprising administering to a patient a therapeutically effective amount of a compound of formula I: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof is administered to a patient at an initial daily dose of 174 mg, and if said patient develops hematological and / or non-hematological toxicity, a) the initial daily dose is withheld for at least 7 days and then resumed at an initial daily dose of 174 mg; or b) the initial daily dose is withheld for less than 7 days, and once toxicity has resolved, treatment is resumed at an initial daily dose of 174 mg; or c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 135 mg (e.g., any one of doses selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, and 135 mg), preferably such that the reduced daily dose is 87 mg; The reduced daily dose may also be re-escalated to a maximum re-escalated daily dose of 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg), preferably the re-escalated daily dose is 200 mg, or d) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 43.5 mg to 135 mg (e.g., any one of doses selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, and 135 mg), preferably the reduced daily dose is 130.5 mg; or The reduced daily dose may be further reduced to a subsequent reduced daily dose of 43.5 mg to 130.5 mg (e.g., any one of doses selected from 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, and 130.5 mg) for recurrent cases of toxicity, preferably 87 mg; and wherein the reduced daily dose or the subsequent reduced daily dose may be re-escalated to a maximum re-escalated daily dose of 200 mg (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg), preferably the re-escalated daily dose is 200 mg.

39. 1. A method for the treatment of a human patient having chronic myeloid leukemia (CML), such as newly diagnosed or refractory chronic myeloid leukemia (CML), comprising administering to a patient a therapeutically effective amount of a compound of formula I: 【Chemistry 5】 or a pharmaceutically acceptable salt thereof is administered to a patient at an initial daily dose of 87 mg, and if said patient develops hematological and / or non-hematological toxicity, a) the initial daily dose is withheld for at least 7 days and then resumed at an initial daily dose of 87 mg; or b) the initial daily dose is withheld for less than 7 days, and once toxicity has resolved, treatment is resumed at an initial daily dose of 87 mg; or c) the initial daily dose is withheld for at least 7 days and then resumed at a reduced daily dose of 43.5 mg or 50 mg, preferably such that the reduced daily dose is 43.5 mg; The reduced daily dose may also be retitrated to a maximum 200 mg re-escalated daily dose (e.g., any one of doses selected from 50 mg, 66 mg, 87 mg, 90 mg, 96 mg, 100 mg, 126 mg, 130.5 mg, 135 mg, 150 mg, 174 mg, 180 mg, 192 mg, and 200 mg), preferably wherein the re-escalated daily dose is 174 mg.

40. 40. The method of any one of claims 37-39, wherein the initial daily dose is gradually increased or decreased without severe adverse reactions.

41. 41. The method of any one of claims 37 to 40, wherein the patient is resistant or intolerant to at least one tyrosine kinase inhibitor.

42. 42. The method of any one of claims 37 to 41, wherein the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

43. 43. The method of any one of claims 37 to 42, wherein the at least one tyrosine kinase inhibitor is selected from dasatinib, nilotinib, radotinib, and bosutinib.

44. 44. The method of any one of claims 37 to 43, wherein the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

45. 45. The method of any one of claims 37 to 44, wherein the at least one tyrosine kinase inhibitor is selected from ponatinib and asciminib.

46. 46. ​​The method of any one of claims 37 to 45, wherein the patient has one or more of the following mutations in the BCR-ABL1 kinase domain: M244V, L248V, E499E, Q252H, P223S, A337T, F359C, E255V, Y253F, F317L, Y253H, V299L, E255V, F317L, E255V, F359V, G250E, E255K, F359V, M351T, G250E, H369R, H396R, and V359I.

47. 47. The method of any one of claims 37 to 46, wherein the chronic myelogenous leukemia (CML) is Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in chronic phase, accelerated phase, or blast crisis phase.

Images