Methods of treating chronic myeloid leukemia using tyrosine kinase inhibitor vodopatinib

Abstract

The present invention relates to methods of treating leukemia using tyrosine kinase inhibitors. The present invention specifically relates to methods of treating CML and ALL using a compound of Formula I or a pharmaceutically acceptable salt thereof. The compounds of Formula 1 have been shown to be effectively safe and tolerable at doses of 10 mg to 210 mg.

Description

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

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

[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 root cause of CML is the breakpoint cluster region-Abelson leukemia (BCR-ABL1) fusion oncoprotein, caused by a reciprocal t(9;22) chromosomal translocation in hematopoietic stem cells. This translocation fuses the breakpoint cluster region (BCR) coding sequence with the tyrosine kinase coding region of Abelson leukemia (ABL1), resulting in constitutive activation of ABL1 kinase activity. Consequently, this translocation activates multiple downstream pathways that contribute to the growth and survival of leukemic cells [Hazlehurst et al. 2009]. CML is characterized by and classified into the following phases: chronic phase (CP), accelerated phase (AP), or blast phase (BP). Patients in CP typically have less than 10% blasts in their blood or bone marrow samples. These patients usually have fairly mild symptoms. Most CML patients are diagnosed in the chronic phase. In the AP phase, a patient's blood sample has 15% or more but less than 30% blasts. In this phase, 20% of the blood cells are composed of basophils, and the platelet count is low (100 x 1,000 / mm 3 or lower), which is not caused by treatment and involves chromosomal changes in leukemia cells with the Philadelphia chromosome. During blast crisis, bone marrow and / or blood samples may contain 20% or more blasts. Large clusters of blasts may be seen in the bone marrow. Blasts may spread to tissues and organs outside the bone marrow.

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

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

[0006] Improved TKIs are needed, particularly for patients who have failed prior TKI therapy.

[0007] References

[0008] Siegel, RL, Miller, KD, and Jemal, A. (2019). Cancer statistics. CA A Cancer J Clin, 69: 7-34. https: / / doi.org / 10.3322 / caac.21551

[0009] Hazlehurst L, Bewry N, Nair R, Pinilla-Ibarz J. Signaling networks associated with BCR-ABL1-dependent transformation. Cancer control 2009;16(2):100-107.

[0010] Ferdinand R, Mitchell SA, Batson S, Tumur I. Treatments for chronic myeloid leukemia: a qualitative systematic review. J Blood Med. 2012;3:51-76.

[0011] 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.

[0012] Deininger MW. Diagnosing and Managing Advanced Chronic Myeloid Leukemia. American Society of Clinical Oncology Educational Book 2015:35,e381-e388.

[0013] 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 1995and 2004. J Clin Pharmacol. 2005 Oct;45(10):1123-1136.

[0014] 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.

[0015] Di Gion, P., Kanefendt, F., Lindauer, A., et al. Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors. Clin Pharmacokinet. 2011; 50: 551-603.

[0016] Nicholas J. Short, Poor Ph+ ALL outcomes require a re-examination of treatment standard, Hematology / Oncology News, August 17, 2020. Summary of the Invention

[0017] The use of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 is a well-established and highly effective strategy for sustained 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 refractory / intolerant chronic myeloid leukemia and newly diagnosed CML patients.

[0018]

[0019] The compounds of Formula I have been studied in in vitro and in vivo studies and have specific and potent activity against wild-type BCR-ABL1 and several BCR-ABL1 mutations. The present disclosure relates to a method for treating adult subjects with chronic phase (CP), accelerated phase (AP) or blast phase (BP) CML or Ph+ CML or Ph+ ALL.

[0020] Thus, disclosed herein is a method for treating a patient (e.g., an adult patient) suffering from chronic myeloid leukemia (CML), comprising

[0021]

[0022] A therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is orally administered at an initial daily dose and increasing or decreasing doses to achieve or maintain a complete hematologic response without serious adverse effects.

[0023] Thus, disclosed herein is a method for treating an adult patient with CML, said method comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a complete hematologic response without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in an average AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0024] Thus, disclosed herein is a method for treating adult patients with CML, said method comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a complete hematologic response without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0025] Thus, 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 and increasing or decreasing doses to achieve or maintain a disease response without serious adverse effects.

[0026] Thus, disclosed herein is a method for treating an adult patient with CML, said method comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a disease response without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0027] Thus, disclosed herein is a method for treating adult patients with CML, said method comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a disease response without serious adverse effects, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0028] Thus, disclosed herein is a method for treating adult patients with CML, the method 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 between 10 mg and 200 mg and escalating doses of between 20 mg and 210 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0029] Thus, disclosed herein is a method for treating an adult patient with CML, the method 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 between 10 mg and 200 mg and escalating doses of between 20 mg and 210 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0030] Thus, disclosed herein is a method for treating adult patients with CML, the method 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 between 10 mg and 200 mg and escalating doses of between 20 mg and 210 mg to achieve or maintain at least one of the following without serious adverse reactions: (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, results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0031] Accordingly, disclosed herein is a method for treating adult patients with CML, the method 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 between 20 mg and 210 mg and a decreasing dose of between 10 mg and 200 mg upon the occurrence of a serious adverse reaction, wherein the dose is decreased such that, with the decreased dose, 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.

[0032] Thus, disclosed herein is a method for treating an adult patient with CML, the method 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 between 20 mg and 210 mg and decreasing doses of between 10 mg and 200 mg upon the occurrence of a serious adverse reaction, wherein the dose is decreased such that, with the decreasing dose, 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 results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0033] Thus, disclosed herein is a method for treating adult patients with CML, the method 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 between 20 mg and 210 mg and decreasing doses of between 10 mg and 200 mg upon the occurrence of a serious adverse reaction, wherein the dose is decreased such that, with the decreasing dose, 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, results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0034] Thus, disclosed herein is a method for treating adult patients with refractory 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, wherein the initial dose is escalated to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions.

[0035] Thus, disclosed herein is a method for treating an adult patient with refractory 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, wherein the initial dose is escalated to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0036] Thus, disclosed herein is a method for treating adult patients with refractory 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, wherein the initial dose is escalated to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean CHR of max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0037] Thus, disclosed herein is a method for treating adult patients with refractory CML, the method 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 dose is escalated to 204 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0038] Thus, disclosed herein is a method for treating adult patients with refractory CML, the method 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 dose is escalated to 204 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0039] Thus, disclosed herein is a method for treating adult patients with refractory CML, the method 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 dose is escalated to 204 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0040] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0041] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0042] b) The initial daily dose was withheld for at least 7 days and restarted at a reduced daily dose of 126 mg on the first occasion of recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg on subsequent occasions of recurrence of toxicity.

[0043] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0044] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0045] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of said toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of said toxicity;

[0046] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0047] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0048] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0049] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of said toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of said toxicity;

[0050] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C maxThe range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0051] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0052] a) the initial daily dose is withheld for at least 7 days and restarted after the patient recovers from the toxicity; or

[0053] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0054] and wherein the reduced dose is optionally further escalated to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0055] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0056] a) the initial daily dose is withheld for at least 7 days and restarted after the patient recovers from the toxicity; or

[0057] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0058] and wherein the reduced dose is optionally further increased to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 results in an average AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0059] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0060] a) the initial daily dose is withheld for at least 7 days and restarted after the patient recovers from the toxicity; or

[0061] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0062] and wherein the reduced dose is optionally further increased to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious 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, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0063] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0064] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0065] b) The initial daily dose was withheld for at least 14 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity.

[0066] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0067] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0068] b) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0069] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0070] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0071] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0072] b) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0073] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0074] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0075] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0076] b) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0077] and wherein the reduced dose is optionally further escalated to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0078] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0079] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0080] b) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0081] and wherein the reduced dose is optionally further increased to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 results in an average AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0082] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0083] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0084] b) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0085] and wherein the reduced dose is optionally further increased to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious 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, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0086] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced dose of 126 mg upon the first recurrence of the toxicity and at reduced doses of 90 mg, 66 mg, and 48 mg upon subsequent recurrence of the toxicity.

[0087] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity, and at reduced doses of 90 mg, 66 mg, and 48 mg on subsequent occasions of recurrence of the toxicity; and wherein the daily dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the patient results in a mean AUC of 174 mg. 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0088] Thus, disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity, and at reduced doses of 90 mg, 66 mg, and 48 mg on subsequent occasions of recurrence of the toxicity; and wherein the daily dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0089] Also disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity, and at reduced doses of 90 mg, 66 mg, and 48 mg on subsequent occasions of recurrence of the toxicity; and wherein the reduced dose is optionally further increased to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0090] Also disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced dose of 126 mg upon the first recurrence of the toxicity and at 90 mg, 66 mg, and 40 mg upon subsequent recurrences of the toxicity. wherein the reduced dose is optionally further escalated to any one of the following: 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0091] Also disclosed herein is a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity, and at reduced doses of 90 mg, 66 mg, and 48 mg on subsequent occasions of recurrence of the toxicity; and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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,

[0092] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0093] According to another embodiment, disclosed herein is a method for treating 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, wherein the initial dose is escalated to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions.

[0094] According to one embodiment, disclosed herein is a method for treating newly diagnosed adult CML patients, the method 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, wherein the initial dose is increased to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in an average AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0095] According to another embodiment, disclosed herein is a method for treating newly diagnosed adult CML patients, the method 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, wherein the initial dose is escalated to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean CHR of max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0096] Thus, disclosed herein is a method for treating newly diagnosed adult CML patients, the method 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 dose is escalated to 204 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0097] Thus, disclosed herein is a method for treating newly diagnosed adult CML patients, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0098] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0099] b) The initial daily dose was withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg upon subsequent recurrence of toxicity.

[0100] Thus, disclosed herein is a method for treating newly diagnosed adult CML patients, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0101] a) the initial daily dose is withheld for at least 7 days and restarted after the patient recovers from the toxicity; or

[0102] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg upon subsequent recurrences of toxicity;

[0103] and wherein the reduced dose is optionally further escalated to any one dose selected from the group consisting of 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0104] Thus, disclosed herein is a method for treating newly diagnosed adult CML patients, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0105] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0106] b) The initial daily dose was withheld for at least 14 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg upon subsequent recurrence of toxicity.

[0107] Thus, disclosed herein is a method for treating newly diagnosed adult CML patients, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0108] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0109] b) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg upon subsequent recurrences of toxicity;

[0110] and wherein the reduced dose is optionally further escalated to any one dose selected from the group consisting of 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0111] Thus, disclosed herein is a method for treating newly diagnosed adult CML patients, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is suspended for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity, and at reduced doses of 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg on subsequent occasions of recurrence of the toxicity.

[0112] Also disclosed herein is a method for treating newly diagnosed adult CML patients, wherein the method comprises administering to the patient a therapeutically effective amount of 174 mg of an initial daily dose of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0113] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity and at reduced doses of 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg on subsequent occasions of recurrence of the toxicity, and wherein

[0114] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without hematologic toxicity: (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.

[0115] According to one embodiment, disclosed herein is a method for treating adult patients with chronic myeloid leukemia (CML), comprising orally administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a complete hematologic response without serious adverse reactions.

[0116] According to another embodiment, disclosed herein is a method for treating an adult patient with chronic myeloid leukemia (CML), the method comprising orally administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a complete hematologic response without serious adverse reactions, wherein the composition is administered under fasting conditions, and wherein the composition results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0117] According to another embodiment, disclosed herein is a method for treating adult patients with chronic myeloid leukemia (CML), comprising orally administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a complete hematologic response without serious adverse reactions, wherein the composition is administered under fasting conditions, and wherein the composition results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0118] Accordingly, disclosed herein is a method for treating adult patients with CML, the method comprising orally administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of between 10 mg and 200 mg and escalating doses of between 20 mg and 210 mg to achieve or maintain at least one of the following without serious adverse reactions attributable to the composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof: (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.

[0119] Thus, disclosed herein is a method for treating adult patients with CML, the method comprising orally administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of between 10 mg and 200 mg and escalating doses of between 20 mg and 210 mg to achieve or maintain at least one of the following without serious adverse reactions attributable to the composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof: (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, wherein when administered under fasting conditions the composition results in a mean AUC of 0-24 The range was 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL, and the average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0120] 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 such daily dose does not result in the patient's QT interval being greater than about 500 milliseconds.

[0121] According to another embodiment, disclosed herein is a method for treating an adult patient with CML, comprising orally administering to said patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in a daily dose, wherein such daily dose results in an average AUC 0-24 The range was 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL, and the average C max The range of 664 ng / mL ± 450 ng / mL to 5054 ng / mL ± 3051 ng / mL, and wherein the daily dose does not result in a QT interval greater than about 500 milliseconds in the patient.

[0122] In another embodiment, disclosed herein is a method for preventing relapse of CML in a patient who has been previously treated with a tyrosine kinase inhibitor, wherein the method comprises 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.

[0123] In yet another embodiment, disclosed herein is a method for preventing relapse of CML in a patient who has been previously treated with a tyrosine kinase inhibitor, wherein the method comprises 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 results in a mean AUC of 0-24 The range was 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL, and the average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0124] According to one embodiment, a method for treating adult patients with CML by orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof under fasting conditions is provided, such that the average AUC obtained by administering the compound of Formula I or a pharmaceutically acceptable salt thereof under fed conditions is greater than that obtained by administering the compound of Formula I or a pharmaceutically acceptable salt thereof under fed conditions. 0-24 Compared to the mean AUC achieved by administering the compound of Formula I or a pharmaceutically acceptable salt thereof under fasting conditions, 0-24 15% higher.

[0125] According to one embodiment, 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 at a daily dose ranging from 10 mg to 210 mg is provided, wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in an average AUC of 0.001% when administered under fasting conditions. 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0126] According to another embodiment, a method of treating adult patients with CML by orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof under fasting conditions is provided, such that the average C is greater than that obtained by administering the compound of Formula I or a pharmaceutically acceptable salt thereof under fed conditions. max Compared to the patients' average C max 20% higher.

[0127] According to one embodiment, a method of treating adult patients with CML by orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at a daily dose ranging from 10 mg to 210 mg is provided, wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0128] According to another embodiment, a method for treating an adult patient with CML is provided, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at a daily dose such that the plasma concentration of the compound of Formula I or a pharmaceutically acceptable salt thereof is not less than 50 ng / mL.

[0129] According to yet another embodiment, a method for treating an adult patient with CML is provided, comprising 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 (a) results in a plasma level of the compound of Formula I or a pharmaceutically acceptable salt thereof of not less than 50 ng / mL; (b) results in a mean AUC of 0-24 The range was 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL; (c) the average C max ranged from 664 ng / mL ± 450 ng / mL to 5054 ng / mL ± 3051 ng / mL; (d) AUC was achieved when administered under fasting conditions compared to when administered under fed conditions. 0-24 15% higher and C max and / or (e) results in a QT interval of less than about 500 milliseconds in the patient.

[0130] According to yet another embodiment, a method for treating an adult patient with CML is provided, comprising 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 (a) results in a plasma level of the compound of Formula I or a pharmaceutically acceptable salt thereof of not less than 25 ng / mL; (b) results in a mean AUC of 0-24 The range was 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL; (c) the average C max ranged from 664 ng / mL ± 450 ng / mL to 5054 ng / mL ± 3051 ng / mL; (d) AUC was achieved when administered under fasting conditions compared to when administered under fed conditions. 0-24 15% higher and C max and / or (e) results in a QT interval of less than about 500 milliseconds in the patient.

[0131] According to one embodiment, a method for treating an adult patient with CML is provided, the method comprising 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 increased 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, increased, or reduced daily dose: (a) results in a plasma level of the compound of Formula I or a pharmaceutically acceptable salt thereof of not less than 50 ng / mL; (b) results in a mean AUC of 0-24 The range was 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL; (c) the average C max ranged from 664 ng / mL ± 450 ng / mL to 5054 ng / mL ± 3051 ng / mL; (d) AUC was achieved when administered under fasting conditions compared to when administered under fed conditions. 0-24 15% higher and C max and / or (e) results in a QT interval of less than about 500 milliseconds in the patient.

[0132] According to another embodiment, a method of treating a CML patient suffering from relapsed or refractory CML condition is provided, wherein the relapsed or refractory condition arises due to 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 at a daily dose of 48 mg to 204 mg.

[0133] According to another embodiment, a method of treating a CML patient suffering from relapsed or refractory CML condition is provided, wherein the relapsed or refractory condition arises due to 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.

[0134] According to another embodiment of the present invention, there is a method for increasing the likelihood of survival of a CML patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein prior to said administration, the CML patient has failed at least one TKI.

[0135] According to one embodiment of the present invention, a method for treating adult patients who have previously undergone T315I-positive CML treatment and have relapsed or refractory CML symptoms is provided, wherein the method comprises orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a disease response without serious adverse reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0136] Figure 1 : SAD: individual, mean, median AUC (0-24) relative to the dose administered;

[0137] Figure 2 : Schematic diagram of the study overview and timing of clinical visits for assessments.

[0138] definition

[0139] As used herein, the term "baseline" is the same as understood by a person with knowledge about clinical trials and the processes involved therein. It refers to the condition of the patient who needs treatment before starting the treatment. The condition includes, but is not limited to, physical condition, disease status, vital signs, mental ability, and the patient's performance status in daily activities. In the case of cancer patients, performance status is graded according to the criteria listed by the Eastern Cooperative Oncology Group (ECOG). For the purposes of this study, patients are ECOG grade 0 or 1 patients, who are fully active and can perform all daily activities without restriction, or are restricted in physical strenuous activities and can perform work of a light or sedentary nature. For the present invention, ECOG grade 2 patients who are ambulatory and can take care of themselves but cannot perform any work activities are also considered. Baseline analysis is necessary to compare the effects of treatment on patients.

[0140] The terms "adverse event (AE)", "serious adverse reaction", "serious adverse event", "adverse reaction", "adverse effect", "toxicity", "treatment-emergent adverse event (TEAE)", "side effect" are used interchangeably and mean an event that was not present or was present at a lower intensity at baseline before treatment and that appeared or worsened after treatment was started in a patient. Such events are undesirable, unacceptable, unfavorable and unintended signs, symptoms or diseases that can be attributed to the use of the drug or treatment. Based on the intensity and impact of the adverse event, the technician may have to modify the treatment conditions. The daily dose can be administered continuously until the disease progresses. According to the CTCAE, toxicity can resolve when there is less than or equal to Grade 1 and / or Grade 2 toxicity.

[0141] For the purposes of the present invention, adverse events are graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 and version 5.0 (https: / / evs.nci.nih.gov / ftp1 / CTCAE / About.html). It is a descriptive term that can be used for adverse event (AE) reporting. CTCAE displays a grade of 1 to 5, with a unique clinical description of the severity of each AE based on the following general guidelines:

[0142] a) Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observation only; no intervention indicated;

[0143] b) Level 2: Moderate; minimal, local, or non-invasive intervention is indicated; limitations include age-appropriate instrumental activities of daily living (ADLs), such as preparing meals, shopping for groceries or clothing, using the telephone, and managing money;

[0144] c) Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization is indicated; disabling; limits self-care ADLs, such as bathing, dressing and undressing, feeding oneself, toileting, and taking medications, and is not bedridden;

[0145] d) Level 4: Life-threatening consequences; urgent intervention indicated; and

[0146] e) Grade 5: Death related to AE.

[0147] For purposes of the present invention, adverse events (AE) are assessed in the whole study until study drug stops after 30 days. AE is graded according to NCI-CTCAE 5.0 versions. In this study, other most common AEs of the monitored patient are thrombocytopenia, neutropenia and anemia, and any AE reported by the patient after the AE collection period is completed and thought to be relevant to study drug is reported. AE is followed up to find a satisfactory solution, until it becomes stable, or until it can be explained by another known reason (that is, concurrent symptom or medicine), and clinical judgment indication does not need further evaluation.

[0148] Unless clearly and uncontroversially related to the underlying disease, dose-limiting toxicity (DLT) was defined as the occurrence of any of the following. Hematologic DLT was defined according to CML stage:

[0149] 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;

[0150] b) missed ≥25% of doses within 28 days due to toxicity in cycle 1; and

[0151] c) Any toxicity grade requiring IMP dose reduction or discontinuation during the 28-day DLT assessment period (Cycle 1).

[0152] Hematologic DLTs for subjects in the chronic phase of CML were Grade 3 neutropenia and / or thrombocytopenia for ≥28 days after study drug treatment, or Grade 4 neutropenia (absolute neutrophil count (ANC) <0.5 × 10 in peripheral blood) for ≥7 days after study drug treatment (i.e., after treatment interruption). 9 / L).

[0153] A hematologic DLT for subjects in the accelerated phase of CML was grade 3 neutropenia and / or thrombocytopenia for ≥28 days after study drug treatment, or grade 4 neutropenia (ANC <0.5 × 10 in peripheral blood) for ≥7 days after treatment (i.e., after treatment interruption), in the absence of features of the accelerated phase (other than cytogenetic changes), such as a persistent increase in blasts or basophils. 9 / L).

[0154] Hematologic DLTs in subjects in blast crisis of CML were defined as those in the absence of persistent leukemia lasting >6 weeks or ANC ≤500 / mm 3 or thrombocytopenia <50,000 / mm 3 In cases of Grade 3 neutropenia and / or thrombocytopenia, bone marrow cellularity showed <5% blasts.

[0155] Those skilled in the art will understand that only after distinguishing the toxicity due to the compound of Formula I or its pharmaceutically acceptable salt from the anti-leukemic effect, can hematological DLT be confirmed. This can be accomplished by methods known to those skilled in the art. For example, if the subject suffers from neutropenia with clearance of leukemic cells or blasts, a bone marrow examination can be performed to distinguish the toxicity due to Formula I from the anti-leukemic effect. If the subject shows normal cell bone marrow or persistence of the disease, it can be considered an anti-leukemic effect and treatment can be continued. However, if there is evidence of drug toxicity, such as cytopenic bone marrow, treatment can be suspended for a predetermined period of time.

[0156] The term 'disease response' or simply 'response' due to a compound of formula I or a pharmaceutically acceptable salt thereof is understood to mean the effect of a 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 patients before and after initiation of treatment.

[0157] Disease response is determined by screening patients before and after treatment begins. Screening can include both clinical and laboratory studies, such as physical examination, blood analysis, vital signs analysis (e.g., temperature, heart rate, respiratory rate, and diastolic and systolic blood pressure), ECG, bone marrow aspiration, BCR-ABL mutation analysis, and BCR-ABL transcript analysis. Based on the screening results, if it is apparent that the compound of Formula I or a pharmaceutically acceptable salt thereof reduces or alleviates or alleviates the disease or its symptoms, the patient is referred to as having a disease response. Specifically, in the case of leukemia, the disease response is confirmed when the patient shows a hematological response (CHR), a cytogenetic response, and a molecular response in a given order. For example, CP CML patients are expected to initially show a major or complete hematological response, and then show signs of a cytogenetic response, followed by a molecular response. Patients with AP CML and BP CML are expected to initially show a complete hematological response, and then optionally show a partial or complete cytogenetic response. If AP CML and BP CML patients also show a molecular response, this is beneficial.

[0158] For purposes of the present invention, hematological response assessments are performed on Day 1, Day 2, Day 3, Day 8, and every 8th day thereafter, where Day 1 is the day the subject takes the first dose of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0159] Bone marrow aspirates were used to determine cytogenetic response assessments. Aspirates were obtained after completion of every 3 cycles (Example: After cycle 3, the next aspirate was scheduled at the completion of cycle 6, and the next aspirate was scheduled at the completion of cycle 9), with each cycle consisting of 28 days of treatment. For patients who demonstrated a complete cytogenetic response (CCyR) on 2 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.

[0160] Molecular response assessments were performed at the end of cycle 3 and every three cycles thereafter (e.g., after cycle 3, the next sample collection was scheduled at the completion of cycle 6), with each cycle consisting of 28 days of treatment. Samples were collected at the end of every three cycles until a major molecular response (MMR) was achieved in two subsequent assessments and thereafter only if the MMR increased 10-fold until disease progression or the subject withdrew consent or the subject discontinued the study.

[0161] For subjects who achieve CCyR and MMR at 2 repeat assessments during the study: a bone marrow aspirate is required only if a 10-fold increase in BCR-ABL levels is detected. Additional bone marrow aspirates may be performed at the investigator's discretion during unscheduled visits.

[0162] Those skilled in the art will understand that in cases where bone marrow samples are insufficient, a BCR-ABL FISH assay for identification of Ph+ should be performed instead of conventional bone marrow cytogenetics, and the percentage of cells with Ph+ chromosome positivity should be reported. A BCR-ABL FISH assay can also be performed on subjects with minimal residual disease.

[0163] The term 'hematologic response' (HR) or 'hematologic response' is a normalization of blood counts, particularly WBC counts resulting from treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof. This is the first significant indicator that treatment begins to work (although not necessarily in the bone marrow). The response can be a partial hematologic response (PHR) in which WBC is reduced but not reduced to a normal range, or a complete hematologic response (CHR) in which all blood counts are normalized. CHR typically reaches expectations within one month of treatment, however, some subjects may even take up to 2 months to reach this level. It was surprisingly observed that patients who have undergone several previous treatments using other known TKIs and have stopped responding to such previous treatments can easily achieve CHR at or before the 2-month mark when treated with a compound of Formula I or a pharmaceutically acceptable salt thereof. Major hematologic response (MaHR) includes complete hematologic response (CHR) and / or no evidence of leukemia (NEL). For the purposes of the present invention, the criteria for hematologic response are given in Table 01.

[0164] Table 01: Hematological response criteria:

[0165]

[0166] 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, rather than solely in the blood. It is a Philadelphia positive (Ph+) chromosome reading obtained after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, as explained below:

[0167] There are 3 levels of cytogenetic response:

[0168] a) Partial cytogenetic response (PCyR): This indicates that only 1% to 35% of the samples contain Ph+ metaphases;

[0169] b) Complete cytogenetic response (CCyR): This indicates that no Ph+ cells can be measured by conventional or fluorescence in situ hybridization cytogenetic testing (although the PCR test may still be positive); and

[0170] c) Major cytogenetic response (MCyR) is a cytogenetic response that includes both PCyR and CCyR.

[0171] For the purposes of the present invention, cytogenetic responses are determined using bone marrow aspirate evaluation, Giemsa staining (karyotyping), or fluorescence in situ hybridization (FISH) assays. As will be appreciated by those skilled in the art, at least 20 metaphases are evaluated to confirm a cytogenetic response. If fewer metaphases are reported, absolute percentage values ​​are reported. Furthermore, peripheral blood cells are not considered for bone marrow aspirate evaluation. In cases where limited bone marrow or aspirate availability prevents cytogenetic evaluation by Giemsa staining, FISH assays are performed to evaluate Ph+ cells. A complete cytogenetic response (CCyR) by FISH is reported when no Ph+ cells are observed or when fewer than 1 of 200 nuclei are BCR / ABL1-positive.

[0172] Table 02: Cytogenetic response criteria:

[0173]

[0174] Major molecular response (MMR): A molecular response is a response to a treatment that affects the number of BCR-ABL transcripts in the blood cells of a patient with CML or ALL. It is measured as the ratio of reverse transcribed transcripts of BCR-ABL to ABL. For a major molecular response, the ratio is ≤ 0.1% on the International Scale (IS) (equivalent to a 3-log reduction in transcripts). It can be determined by polymerase chain reaction (PCR) or any other molecular test known to those skilled in the art.

[0175] Major molecular response (MMR) is used to select and monitor patients who are eligible to discontinue 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.

[0176] For the purposes of the present invention, molecular responses are determined using PCR. Patients are considered to have a major molecular response when the amount of BCR-ABL protein in the blood is very low, i.e., if the BCR-ABL transcript is 0.1% by quantitative PCR (International Scale (IS)), or if quantitative PCR (IS) is not available, the BCR-ABL mRNA is reduced by greater than or equal to 3 logs from the normalized baseline. A complete molecular response is considered to be achieved if BCR-ABL mRNA is not detectable by quantitative PCR (IS) using an assay with a sensitivity of at least 4.5 logs below the normalized baseline.

[0177] The phrase 'optimal management' is used herein in relation to adverse events or toxicities and refers to steps taken to reduce or eliminate the adverse event. Management is based on the CTCAE grade. For example, a Grade 1 adverse event may be managed by withholding treatment for several days, while a CTCAE Grade 2 adverse event may require the relevant medication plus withholding treatment. The skilled artisan is aware of methods for treating adverse events, including any medications used for such purposes.

[0178] As used herein, the term "subject" or "person 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 leukemias, such as hairy cell leukemia, myelodysplastic syndrome or myeloproliferative disorders or a combination thereof. More preferably, the subject is diagnosed with ALL or CML and needs such treatment to reduce or alleviate or mitigate the disease or its symptoms or to cure the subject and exempt the subject from the disease or its symptoms. The subject may have a newly diagnosed, refractory or relapsed leukemia, wherein newly diagnosed and relapse have meanings known to those skilled in the art. When the subject has been treated with a known therapy, preferably a tyrosine kinase inhibitor (TKI), and has resistance or intolerance to such therapy, the subject or patient is said to have a refractory leukemia.

[0179] For the purposes of the present invention, a refractory leukemia patient is a patient who has been previously treated with at least one TKI or at least two TKIs or at least three TKIs. In a specific embodiment, when a patient has undergone prior treatment with at least three TKIs, one of the TKIs is ponatinib. In a specific embodiment, when a patient has undergone prior treatment with at least three TKIs, one of the TKIs is bosutinib. In yet another embodiment, when a patient has undergone prior treatment with at least three TKIs, one of the TKIs is ponatinib or asciminib. In yet another embodiment, when a patient has undergone prior treatment with at least three TKIs, treatment includes treatment with ponatinib and asciminib.

[0180] A subject is considered 'resistant' to prior treatment with a known TKI if their disease does not respond and improve. For the purposes of this invention, a subject is considered resistant to prior treatment or therapy if any of the following incidences occur as given in Table 03:

[0181] Table: 03

[0182]

[0183]

[0184] In addition, when a subject develops one or more toxicities that persist and are unresponsive to optimal management, they are considered 'intolerant to the previous treatment'. Intolerance is categorized as hematologic or non-hematologic. Patients are considered to have developed non-hematologic intolerance to the previous treatment with a TKI if they develop grade 3 or 4 toxicity during therapy, or have persistent grade 2 toxicity that is unresponsive to optimal management (including dose adjustments to the manufacturer's lowest recommended dose), unless dose reduction is not considered in the patient's best interest if they have responded in the absence of CCyR for CP CML subjects or in the absence of MaHR for AP and BP subjects.

[0185] Patients were considered to have developed 'hematologic intolerance' to the previous treatment if they developed grade 3 or 4 toxicity during therapy that recurred after dose reduction to the lowest dose recommended by the manufacturer, unless dose reduction was not considered to be in the patient's best interest in the absence of CCyR for subjects with CP CML or MaHR for subjects with AP CML and BP CML.

[0186] As used herein, treatment failure may be defined based on the following criteria as given in Table 04:

[0187] Table 04:

[0188]

[0189]

[0190] In patients who failed treatment, patient compliance, drug interactions, and mutation analysis were evaluated. Bone marrow cytogenetic analysis was considered CCyR at 15 months if BCR-ABL1 transcripts were >1%-10%.

[0191] Disease progression: The date of disease progression is defined as the date of any of the disease progression criteria given in Table 05 below:

[0192] Table 05:

[0193]

[0194] Therapeutic Switch: Therapeutic Switch 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:

[0195] a) CHR was not achieved 3 months after the start of treatment;

[0196] b) No cytogenetic response (>95% Ph+ cells) within three months of starting therapy;

[0197] c) less than a minor cytogenetic response (>65% Ph+) within six months of starting therapy;

[0198] d) less than PCyR (>35% Ph+) within twelve months after the start of therapy;

[0199] e) loss of cytogenetic response at any time after the start of therapy (i.e., cytogenetic response converts to at least 1 grade worse from the patient's most recent bone marrow cytogenetics);

[0200] f) BCR-ABL1 ratio >10% within six months after starting therapy;

[0201] g) BCR-ABL1 ratio >1% within twelve months after the start of therapy;

[0202] h) confirmed MMR loss in 2 consecutive tests at any time during therapy;

[0203] i) loss of CHR, CCyR, or PCyR at any time after initiation of therapy; and

[0204] j) Development of novel clonal chromosomal abnormalities in Ph+ cells or development of novel BCR-ABL1 mutations that may result in resistance to study treatment or loss of previously achieved response to TKIs (i.e., hematologic response, cytogenetic response, or molecular response) at any time after the start of therapy.

[0205] As used herein, when preceding a range, the term "about" should be understood to refer to both endpoints of the range. In such cases, the range should also be understood to include the range bounded by the specific endpoints listed, and also include subranges within the listed endpoints. When "about" precedes a number, it should be understood that the number includes a range of ±5%.

[0206] As used herein, the term "between" when preceding a range should be understood to refer to the two endpoints of the range. In such cases, the range should also be understood to include the range defined by the specific endpoints listed, and also include the sub-ranges within the listed endpoints.

[0207] As used herein, the term "therapeutically effective amount" means the amount of a drug (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof) that has the desired effect of reducing, curing, or alleviating a disease or its symptoms when administered to a subject in need thereof. For 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 for treating 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 preparation. Specifically, a compound of formula I or a pharmaceutically acceptable salt thereof is administered as a solid oral dosage form. The terms "incremental" or "re-incremental" may be interchangeable.

[0208] Pharmacokinetic (PK) evaluation is one of the endpoints of clinical trials. As known to those skilled in the art, PK evaluation includes, for example, determining C 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 (AUC 0-tau ), oral clearance (CL / F), apparent volume of distribution (V / F), and normalized dose [AUC (0-tau) / dose or (C max / dose)].

[0209] As used herein, AUC 0-24It refers to the steady-state area under the plasma concentration versus time curve from time zero to twenty-four hours after administration of the drug (in the present case, a compound of Formula I or a pharmaceutically acceptable salt thereof). min and C max The plasma concentration of the drug is the minimum and maximum steady-state effective concentration of the drug in the plasma during a specific dosing interval. The time to reach the maximum plasma concentration after administration of a dose is called T max . DETAILED DESCRIPTION

[0210] The present invention relates to a method for treating leukemia. Specifically, the present invention relates to a method for treating CML and ALL. In a specific embodiment, the method comprises treating CP CML, AP CML, BP CML, Ph+ CML, and Ph+ ALL. The present invention also relates to methods for treating: Ph+ CML in chronic phase (CP) previously treated with two or more tyrosine kinase inhibitors; T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL; newly diagnosed chronic phase (CP) Ph+ CML; chronic phase, accelerated phase (AP), or blast phase (BP) Ph+ CML that is resistant or intolerant to previous therapy.

[0211] In one embodiment, the invention relates to a method of treating an adult patient with refractory CML.

[0212] In another embodiment, the invention is directed to a method of treating an adult patient with newly diagnosed CML.

[0213] According to one embodiment of the present invention, the method comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof.

[0214] The compound of formula I has the following chemical name and formula:

[0215] Chemical name: N'-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolinyl)ethynyl]-benzohydrazide

[0216]

[0217] International Publication No. WO2012098416A1, which is hereby incorporated by reference, discloses compounds of Formula I and processes for their preparation.

[0218] The compound of formula I or a pharmaceutically acceptable salt thereof can be administered to a leukemia patient in the form of an oral dosage form. In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof can be administered to a leukemia patient in the form of an oral dosage form comprising a compound of formula I or a pharmaceutically acceptable salt thereof in an amorphous form and a pharmaceutically acceptable excipient. According to another embodiment, the method comprises orally administering the compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a disease response.

[0219] The oral dosage form may include a compound of Formula I or a pharmaceutically acceptable salt thereof in its amorphous form and may further include one or more pharmaceutically acceptable excipients. In some embodiments, the oral dosage form may be a hard gelatin capsule.

[0220] Pharmaceutically acceptable excipients that can be included in oral dosage forms of the present invention include, for example, one or more of polyvinyl caprolactam, polyvinyl acetate, polyethylene glycol graft copolymers, silicon dioxide, sodium lauryl sulfate, silicified microcrystalline cellulose, crospovidone, and / or gelatin.

[0221] The desired dosage form of the compound of formula I or its pharmaceutically acceptable salt is an oral dosage form containing 10mg to 300mg of the compound of formula I or its pharmaceutically acceptable salt, as measured according to the daily dose. The daily dose can be applied in the process of once a day to four times a day. In certain embodiments, the amount of the compound of formula I or its pharmaceutically acceptable salt in the dosage form is between 10mg and 210mg, as measured by the amount of the compound of formula I or its pharmaceutically acceptable salt applied every day. The dosage can be applied as a single daily dose. The dosage can be applied as multiple daily doses.

[0222] The total daily dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, administered to a subject may be between 10 mg and 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. The inventors found that, based on their studies, the highest effective and tolerable daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 204 mg, present at a daily dose of 240 mg in patients with prior TKI exposure, mutations and ACAs, and dose-limiting toxicities.

[0223] In one embodiment, for newly diagnosed CML patients, the effective dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 240 mg. More specifically, the effective dose is 10 mg to 210 mg.

[0224] In one embodiment, a daily dose of between 10 mg and 210 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, when administered to a subject, can result in a mean AUC of 0-24 The range is 1000 ng*h / mL to 120,000 ng*h / mL.

[0225] In one embodiment, a daily dose of between 10 mg and 210 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, when administered to a subject, can result in a mean C max The range is 100 ng / mL to 9000 ng / mL.

[0226] According to one embodiment, the method of the present invention comprises orally administering a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a disease response without severe adverse effects.

[0227] In one embodiment, the initial daily dose is selected from a dose between 10 mg and 210 mg. In another embodiment, the initial daily dose is selected from a dose between 12 mg and 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.

[0228] In one aspect of the invention, the initial daily dose is escalated to achieve or maintain a disease response.

[0229] According to one embodiment, the initial daily dose is escalated to subsequent higher daily doses. In some embodiments, an initial daily dose of 12 mg is escalated to a daily dose selected from the group consisting of 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 escalated to a daily dose selected from the group consisting of 48 mg, 66 mg, 90 mg, 126 mg, 174 mg, and 204 mg. In some embodiments, an initial daily dose of 48 mg is escalated to a daily dose selected from the group consisting of 66 mg, 90 mg, 126 mg, 174 mg, and 204 mg. In some embodiments, an initial daily dose of 66 mg is escalated to a daily dose selected from the group consisting of 90 mg, 126 mg, 174 mg, and 204 mg. In some embodiments, an initial daily dose of 90 mg is escalated to a daily dose selected from the group consisting of 126 mg, 174 mg, and 204 mg. In some embodiments, an initial daily dose of 126 mg is escalated to a daily dose selected from the group consisting of 174 mg and 204 mg. In some embodiments, an initial daily dose of 174 mg is escalated to a daily dose of 204 mg.

[0230] According to one embodiment, the initial dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is increased to maintain or achieve a disease response, wherein the disease response includes a hematological response, a cytogenetic response, and a molecular response. It will be understood by those skilled in the art that the disease response is gradual, wherein the first response in the subject is a hematological response that may be a partial or complete hematological response. The subject with a complete hematological response is then tested for a cytogenetic response, which may again be partial or complete, and it is expected that patients who show a cytogenetic response have a molecular response, particularly a major molecular response.

[0231] In one embodiment, a refractory subject can maintain the same disease response achieved during the previous treatment. For example, if a subject has achieved a complete hematological response in a previous treatment, but has to stop treatment due to an adverse event, the patient may ultimately achieve the same response using the compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, a refractory subject can achieve a complete hematological response, a complete cytogenetic response, and a major molecular response, even if they were not achieved by any of the previous treatments. Using the methods of the present invention, newly diagnosed subjects are expected to achieve a complete hematological response, a complete cytogenetic response, and a major molecular response, in that order.

[0232] It was found that when treated with the compound of formula I or a pharmaceutically acceptable salt thereof, subjects who had not responded to previous TKIs surprisingly showed good disease responses. For example, in refractory patients who had previously received two or more tyrosine kinase inhibitors (TKIs), complete hematologic responses were seen in 29 of 41 enrolled subjects (70.7%), and complete cytogenetic responses were seen in 23 of 41 enrolled subjects (56.1%), while major molecular responses were reported in 18 of 41 enrolled subjects (43.9%), in 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.

[0233] In one embodiment, a subject can achieve a disease response at a specific daily dose within 7 days of treatment. In one embodiment, a subject can achieve a disease response at a specific daily dose within 14 days of treatment. In one embodiment, a subject can achieve a disease response at a specific daily dose within 21 days of treatment. In one embodiment, a subject can achieve a disease response at a specific daily dose within 28 days of treatment. In one embodiment, a subject can achieve a disease response at a specific daily dose within 3 months of treatment. In one embodiment, a subject can achieve a disease response at a specific dose within 6 months of treatment.

[0234] In a specific embodiment, a subject can achieve a complete hematologic response at a specific daily dose within 21 days of treatment. In a specific embodiment, a subject can achieve a complete hematologic and partial cytogenetic response at a specific daily dose within 28 days of treatment. In a specific embodiment, a subject can achieve a complete hematologic and complete cytogenetic response at a specific daily dose within 28 days of treatment. In a specific embodiment, a subject can achieve a complete hematologic, complete cytogenetic, and major molecular response at a specific daily dose within 3 months of treatment.

[0235] It will be understood by those skilled in the art that disease response can vary in different patients based on, for example, the patient's age, medical history, previous treatment, physical and vital conditions, and the dosage of the compound of formula I or its pharmaceutically acceptable salt. Although most patients studied in the present invention develop at least a hematological response (partial or complete) within the first cycle (28 days) of treatment, it is expected that some patients may develop a disease response after 2 or 3 months of treatment. In one embodiment, even in the absence of a disease response, treatment with a compound of formula I or its pharmaceutically acceptable salt at a specific daily dose can continue for at least 28 days, and then the daily dose is increased to the subsequent dose. In one embodiment, even in the absence of a disease response, treatment with a compound of formula I or its pharmaceutically acceptable salt at a specific daily dose can continue for at least 3 months, and then the daily dose is increased to the subsequent dose. In one embodiment, even in the absence of a disease response, treatment with a compound of formula I or its pharmaceutically acceptable salt at a specific daily dose can continue for at least 6 months, and then the daily dose is increased to the subsequent dose.

[0236] According to one embodiment, an initial daily dose is escalated to a subsequent higher daily dose, wherein the increasing dose results in a mean AUC 0-24 The range is 1000 ng*h / mL to 120,000 ng*h / mL.

[0237] According to one embodiment, an initial daily dose is escalated to a subsequent higher daily dose, wherein the increasing dose results in a mean C max The range is 100 ng / mL to 9000 ng / mL.

[0238] According to one embodiment, the initial daily dose is escalated to achieve or maintain a disease response without severe adverse effects.

[0239] Adverse reactions or adverse events (AEs) are classified based on NCI-CTCAE v 5.0 (https: / / evs.nci.nih.gov / ftp1 / CTCAE / About.html). For those AEs that are not assigned a CTCAE grade, the recommendations in the CTCAE criteria for converting mild, moderate, and severe events to CTCAE grades can be considered. An AE in a patient may be 'unrelated' in that it develops due to external causes such as medical history, demographic details, disease, and environment; or 'atypical' in that it does not follow a reasonable time sequence; or it may also be explained by the patient's concurrent illness, environmental factors, medical history, and other concomitant medications or chemicals, including food-drug interactions. Those skilled in the art will understand that dose modification, in particular dose reduction, will only be required if the adverse event is due to the drug (a compound of Formula I or a pharmaceutically acceptable salt thereof). Unrelated and atypical adverse events may not lead to dose modifications.

[0240] Methods for determining whether an AE is due to the compound of formula I or a pharmaceutically acceptable salt thereof, due to an underlying disease or due to an external cause 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 attributable to the disease, rather than to the compound of formula I or a pharmaceutically acceptable salt thereof. In such cases, a bone marrow biopsy is performed to distinguish toxicity from anti-leukemic effects. If the patient has normal cell bone marrow or persistence of the disease, treatment with supportive medications is continued. If there is evidence of toxicity due to the compound of formula I or a pharmaceutically acceptable salt thereof (such as bone marrow with reduced cells), treatment is stopped for up to four weeks to allow the event to ease to ≤ grade 1 or baseline, and to start again with a reduced dose. Although bone marrow biopsy is one of the methods for distinguishing toxicity due to drugs or symptoms of underlying diseases, the embodiments of the present application include all methods known to technicians for this purpose. Technicians can implement other known methods to distinguish toxicity due to the compound of formula I or a pharmaceutically acceptable salt thereof or symptoms of underlying diseases.

[0241] In one embodiment of the present invention, when a patient experiences an adverse event due to the compound of Formula I or a pharmaceutically acceptable salt thereof, the daily dose is suspended. In one embodiment, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof can be suspended until the patient recovers from the adverse event. In another embodiment, the initial daily dose can be suspended for a period of at least 7 days. In one embodiment, the initial daily dose is suspended for a period of at least 14 days. In one embodiment, the initial daily dose is suspended for a period of at least 28 days. In one embodiment, the initial daily dose is suspended for a period of at least 48 days. In one embodiment, the initial daily dose is suspended for a period of at least 56 days.

[0242] When 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 suspended for a specific period of time, and then the daily dose is restarted at a given dose or at a decreasing daily dose. Specifically, the daily dose is restarted after the patient recovers from the AE. When the toxicity level of the AE is reduced to grade 1 or completely subsides or subsides to baseline according to NCI-CTCAE version 5.0, the subject is considered to have recovered from the adverse event. Technicians will understand that based on a comparison of patient assessment reports before and after treatment with the compound of Formula I or a pharmaceutically acceptable salt thereof, the patient is considered to have recovered from the AE. In certain embodiments, the patient can experience the treatment of the AE. In certain embodiments, the patient can experience the optimal management of the AE. In certain embodiments, the AE can be resolved without assistance. The treatment of the AE and its optimal management are within the scope of technicians.

[0243] According to another embodiment, the initial daily dose is tapered to subsequent doses when the patient develops a severe adverse reaction.

[0244] According to one embodiment, the initial daily dose is tapered to a subsequently 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, 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 selected from 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 and 90 mg. In some embodiments, an initial daily dose of 130.5 mg is tapered to a daily dose of 43.5 mg and 87 mg.

[0245] According to one embodiment, the initial daily dose is tapered to a lower daily dose, wherein the decreasing dose results in a mean AUC 0-24 The range is 1000 ng*h / mL to 120,000 ng*h / mL.

[0246] According to one embodiment, the initial daily dose is tapered to a lower daily dose, wherein the tapering dose results in a mean C max The range is 100 ng / mL to 9000 ng / mL.

[0247] According to one embodiment, a patient who experiences an adverse drug reaction due to administration of the compound of Formula I or a pharmaceutically acceptable salt thereof is subjected to a dose delay (dose suspension) or dose reduction, or both.

[0248] 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, can continue treatment without any dose delay or reduction. 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, can continue treatment without any dose delay or reduction while receiving supportive care and AE management.

[0249] In some embodiments, patients who experience grade 1 or grade 2 non-hematological toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof may experience a dose delay of at least 7 days. In some embodiments, patients who experience grade 1 or grade 2 non-hematological toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof may experience a dose delay of at least 14 days. In some embodiments, patients who experience grade 1 or grade 2 non-hematological toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof may experience a dose delay of at least 28 days. In some embodiments, patients who experience grade 1 or grade 2 non-hematological toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof may experience a dose delay of no more than 28 days. When grade 1 or grade 2 non-hematological toxicity is intolerable due to clinical symptoms or due to interference with daily activities, and if such toxicity is not controlled by best supportive care or best management, the patient may have to delay the dose (or pause).

[0250] In some embodiments, treatment may be withheld for at least 14 days for patients who experience Grade 3 hematologic or non-hematologic toxicity or Grade 4 asymptomatic hematologic toxicity. In some embodiments, treatment may be withheld for at least 28 days for patients who experience Grade 3 hematologic or non-hematologic toxicity or Grade 4 asymptomatic hematologic toxicity. In some embodiments, treatment may be withheld for at least 56 days for patients who experience Grade 3 hematologic or non-hematologic toxicity or Grade 4 asymptomatic hematologic toxicity. In some embodiments, treatment may be withheld for no more than 28 days for patients who experience Grade 3 hematologic or non-hematologic toxicity or Grade 4 asymptomatic hematologic toxicity. In some embodiments, treatment may be withheld for no more than 56 days for patients who experience Grade 3 hematologic or non-hematologic toxicity or Grade 4 asymptomatic hematologic toxicity.

[0251] In some embodiments, the daily dose can be restarted with the same daily dose. In some embodiments, the daily dose can be restarted with a decreasing dose. In a specific embodiment, patients experiencing recurrence of AEs can be treated with a decreasing daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0252] According to one embodiment of the present invention, if the patient does not develop an AE, the reduced daily dose can optionally be increased again to a dose selected from 24 mg to 210 mg. The dose increase can be performed as discussed above.

[0253] In the case where the subject does not have any disease response after 3 to 6 months of treatment with the maximum tolerated dose, the treatment method according to the present invention can be stopped. Treatment can also be stopped in subjects who are intolerant to the minimum dose amount. Subjects with unmanageable adverse events due to a daily dose of 12 mg in newly diagnosed patients or 48 mg in refractory patients can stop treatment. Stopping can also occur when the subject voluntarily does so or in the event of death.

[0254] In a specific embodiment, the present invention relates to a method for treating adult patients with 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, wherein the initial dose is escalated to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions.

[0255] In another specific embodiment, the present invention is directed to 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 174 mg, wherein the initial dose is escalated to 204 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0256] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises 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, such that when the patient develops non-hematological toxicity:

[0257] a) the initial daily dose is withheld for at least 7 days and restarted after the patient recovers from the toxicity; or

[0258] b) The initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg on the first occasion of recurrence of toxicity and then reduced to 90 mg, 66 mg, and 48 mg on subsequent occasions of recurrence of toxicity.

[0259] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0260] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0261] b) The initial daily dose was withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg on the first occasion of recurrence of toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of toxicity.

[0262] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises 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, such that when the patient develops non-hematological toxicity:

[0263] a) the initial daily dose is withheld for at least 7 days and restarted after the patient recovers from the toxicity; or

[0264] b) The initial daily dose is withheld for at least 7 days and then restarted at a reduced daily dose of 126 mg on the first occasion of recurrence of toxicity and reduced to 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg on subsequent occasions of recurrence of toxicity.

[0265] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0266] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0267] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0268] c) The initial daily dose was withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity.

[0269] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0270] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0271] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0272] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0273] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0274] In a specific embodiment, the present invention provides a method for treating a human patient with chronic myeloid leukemia (CML), such as newly diagnosed chronic myeloid leukemia (CML) or refractory chronic myeloid leukemia (CML), comprising administering to the patient a therapeutically effective amount of a compound of formula I:

[0275]

[0276] or a pharmaceutically acceptable salt thereof,

[0277] The chronic myeloid leukemia (CML) is chronic, accelerated or blast crisis Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML).

[0278] According to any of the embodiments described herein, the therapeutically effective amount of the compound of Formula I or a pharmaceutical salt thereof is sufficient to achieve an average AUC in the range of 6226 ng*h / mL ± 5827 ng*h / mL to 60373 ng*h / mL ± 55659 ng*h / mL 0-24 or a mean C ranging from 664 ng / mL ± 450 ng / mL to 5054 ng / mL ± 3051 ng / mL max .

[0279] According to any of the embodiments described herein, the compound of formula I or a pharmaceutical salt thereof is administered in an initial daily dose of 10 mg to 204 mg.

[0280] According to any 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.

[0281] According to any of the embodiments described herein, the initial daily dose is increased or decreased to achieve or maintain 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.

[0282] According to any of the embodiments described herein, the initial daily dose is escalated or decreased without severe adverse effects.

[0283] According to any of the embodiments described herein, the patient is resistant or intolerant to at least one tyrosine kinase inhibitor.

[0284] According to any of the embodiments described herein, the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

[0285] According to any of the embodiments described herein, the at least one tyrosine kinase inhibitor is selected from dasatinib, nilotinib, radotinib, and bosutinib.

[0286] According to any of the embodiments described herein, the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

[0287] According to any of the embodiments described herein, the at least one tyrosine kinase inhibitor is selected from ponatinib and aximinib.

[0288] According to any 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.

[0289] According to any of the embodiments described herein, the patient has one or more of the following characteristics:

[0290] a) blasts in peripheral blood and bone marrow are 15%;

[0291] b) blasts plus promyelocytes <30% in peripheral blood and bone marrow;

[0292] c) basophils in the peripheral blood are less than 20%;

[0293] d) Platelets ≥50 x 10 9 / L(≥50,000 / mm 3 );

[0294] e) Transient prior therapy-related thrombocytopenia (<50,000 / mm within ≤30 days before screening) 3 );

[0295] f) no evidence of extramedullary leukemic involvement other than hepatosplenomegaly;

[0296] g) blasts ≥15% to <30% in peripheral blood or bone marrow;

[0297] h) basophils ≥ 20% in peripheral blood or bone marrow;

[0298] i) (blasts + promyelocytes) ≥ 30% in peripheral blood or bone marrow (but blasts < 30%);

[0299] j) ≤100X 109 platelets / L in peripheral blood, regardless of therapy;

[0300] k) additional clonal cytogenetic abnormalities in Ph+ cells;

[0301] l) ≥30% blasts in peripheral blood, bone marrow, or both; and

[0302] m) Extramedullary disease.

[0303] According to any of the embodiments described herein, the patient does not have T315I-positive CML.

[0304] According to any of the embodiments described herein, when the patient exhibits a grade 1 or 2 non-hematological adverse event, the treatment is suspended for a period of at least 7 days and then restarted.

[0305] According to any of the embodiments described herein, when the patient exhibits a grade 3 hematologic or non-hematologic adverse event or a grade 4 asymptomatic hematologic adverse event, the treatment is suspended for a period of up to 56 days (e.g., 14 to 56 days or 28 to 56 days) and then restarted.

[0306] According to any of the embodiments described herein, the treatment is discontinued when the patient has not recovered to a Grade 1 adverse event or less after a 56-day hold period.

[0307] In a specific embodiment, the present invention provides a method of treating a treatment-resistant human patient suffering from chronic myeloid leukemia (CML), said method comprising administering to said patient a therapeutically effective amount of a compound of formula I:

[0308]

[0309] or a pharmaceutically acceptable salt thereof, wherein

[0310] i. The method comprises orally administering 174 mg to 200 mg of the compound of formula I per day, and

[0311] ii. Prior to said administering of said compound of formula I, said patient is resistant or intolerant to at least one tyrosine kinase inhibitor.

[0312] According to any of the embodiments described herein, the patient has Ph+ CML.

[0313] According to any of the embodiments described herein, the patient is in the chronic phase of CML.

[0314] According to any of the embodiments described herein, the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

[0315] According to any of the embodiments described herein, the second generation tyrosine kinase inhibitor is selected from dasatinib, nilotinib, radotinib and bosutinib.

[0316] According to any of the embodiments described herein, the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

[0317] According to any of the embodiments described herein, the third generation tyrosine kinase inhibitor is selected from ponatinib and aximinib.

[0318] According to any 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.

[0319] According to any of the embodiments described herein, the patient does not have T315I-positive CML.

[0320] According to any of the embodiments described herein, the compound of formula I is administered orally in the form of an oral capsule.

[0321] According to any of the embodiments described herein, each of the capsules contains 43.5 mg, 45 mg, 48 mg or 50 mg of the compound of formula I.

[0322] According to any of the embodiments described herein, the compound of formula I is administered each morning, and optionally, fasting is performed for two hours before and after administration of the compound of formula I.

[0323] According to any of the embodiments described herein, when the patient exhibits a grade 1 or 2 non-hematological adverse event that is not tolerable due to clinical symptoms or interference with daily activities, the treatment is suspended for a certain period of time and then restarted.

[0324] According to any of the embodiments described herein, the period of time during the treatment pause is 7 days.

[0325] According to any of the embodiments described herein, the period of time during the treatment pause is 14 days.

[0326] According to any of the embodiments described herein, when the patient exhibits a grade 3 hematological or non-hematological adverse event or a grade 4 asymptomatic hematological adverse event, the treatment is suspended for a period of time and then restarted.

[0327] According to any of the embodiments described herein, the treatment is suspended for up to 56 days (e.g., 14 to 56 days or 28 to 56 days) for recovery to Grade 1 adverse event or less; and if the patient has not recovered to Grade 1 adverse event or less, treatment with the compound of Formula I is discontinued.

[0328] According to any of the embodiments described herein, the method comprises orally administering one or more oral capsules per day, wherein (i) each capsule contains the same amount of the compound of Formula I, (ii) the amount is selected from 43.5 mg, 45 mg, 48 mg and 50 mg of the compound of Formula I, and (iii) upon the occurrence of certain adverse events that do not require cessation or temporary suspension of treatment, the daily dose is reduced by administering a smaller number of the same oral capsules per day.

[0329] According to any of the embodiments described herein, 4 oral capsules are administered daily prior to dose reduction.

[0330] In a specific embodiment, the present invention provides a method for treating a human patient suffering from chronic myeloid leukemia (CML), such as newly diagnosed chronic myeloid leukemia (CML) or refractory chronic myeloid leukemia (CML), comprising administering to the patient a therapeutically effective amount of a compound of formula I at an initial daily dose of:

[0331]

[0332] or a pharmaceutically acceptable salt thereof: 50 mg to 200 mg (e.g., any one dose selected from the group consisting of 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), such that when the patient develops hematological and / or non-hematological toxicity:

[0333] a) the initial daily dose is suspended for at least 7 days and restarted at the initial daily dose of 50 mg to 200 mg (e.g., any one dose selected from the group consisting of 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

[0334] b) the initial daily dose is withheld for less than 7 days, and if the toxicity resolves, the treatment is restarted at the initial daily dose of 50 mg to 200 mg (e.g., any one dose selected from the group consisting of 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

[0335] c) the initial daily dose is suspended for at least 7 days and restarted at a reduced daily dose of 43.5 mg to 192 mg (e.g., any one dose selected from the group consisting of 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);

[0336] and wherein the reduced daily dose is optionally re-escalated to a further increasing daily dose of 50 mg to 200 mg (e.g., any one dose selected from the group consisting of 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

[0337] d) the initial daily dose is suspended for at least 7 days and restarted at a reduced daily dose of 43.5 mg to 192 mg (e.g., any one dose selected from the group consisting of 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);

[0338] and wherein upon subsequent recurrence of said toxicity, said reduced daily dose is further reduced to a subsequent reduced daily dose of 43.5 mg to 180 mg (e.g., any one dose selected from the group consisting of 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);

[0339] and wherein the reduced daily dose or the subsequently reduced daily dose is optionally re-escalated to a further increasing daily dose of 50 mg to 200 mg (e.g., any one dose selected from the group consisting of 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

[0340] In another specific embodiment, the present invention provides a method for treating a human patient with chronic myeloid leukemia (CML), such as newly diagnosed chronic myeloid leukemia (CML) or refractory chronic myeloid leukemia (CML), comprising administering to the patient a therapeutically effective amount of a compound of formula I at an initial daily dose of 174 mg:

[0341]

[0342] or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological and / or non-hematological toxicity:

[0343] a) the initial daily dose is suspended for at least 7 days and restarted at the initial daily dose of 174 mg; or

[0344] b) the initial daily dose is withheld for less than 7 days, and if the toxicity resolves, the treatment is restarted at the initial daily dose of 174 mg; or

[0345] c) the initial daily dose is suspended for at least 7 days and restarted at a reduced daily dose of 43.5 mg to 135 mg (e.g., any one dose selected from the group consisting of 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 87 mg;

[0346] and wherein the reduced daily dose is optionally re-escalated to a further increasing daily dose of up to 200 mg (e.g., any one selected from the group consisting of 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 further increasing daily dose is 200 mg; or

[0347] d) the initial daily dose is suspended for at least 7 days and restarted at a reduced daily dose of 43.5 mg to 135 mg (e.g., any one dose selected from the group consisting of 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

[0348] and wherein in subsequent instances of recurrence of said toxicity, said reduced daily dose is optionally further reduced to a subsequent reduced daily dose of 43.5 mg to 130.5 mg (e.g., any one dose selected from the group consisting of 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, and 130.5 mg), preferably, said subsequent reduced daily dose is 87 mg;

[0349] and wherein the reduced daily dose or the subsequently reduced daily dose is optionally re-increased to a further increasing daily dose of up to 200 mg (e.g., any one selected from the group consisting of 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 further increasing daily dose is 200 mg.

[0350] In another specific embodiment, the present invention provides a method for treating a human patient with chronic myeloid leukemia (CML), such as newly diagnosed chronic myeloid leukemia (CML) or refractory chronic myeloid leukemia (CML), comprising administering to the patient a therapeutically effective amount of a compound of formula I at an initial daily dose of 87 mg:

[0351]

[0352] or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological and / or non-hematological toxicity:

[0353] a) the initial daily dose is suspended for at least 7 days and restarted at the initial daily dose of 87 mg; or

[0354] b) the initial daily dose is withheld for less than 7 days and, if the toxicity resolves, the treatment is restarted at the initial daily dose of 87 mg; or

[0355] c) the initial daily dose is suspended for at least 7 days and restarted at a reduced daily dose of 43.5 mg or 50 mg, preferably, the reduced daily dose is 43.5 mg;

[0356] And wherein the reduced daily dose is optionally re-increased to a further increasing daily dose of up to 200 mg (for example, any one dose selected from the following: 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 further increasing daily dose is 174 mg.

[0357] In one aspect, the present invention relates to a method for treating a human patient suffering from chronic myeloid leukemia (CML), such as newly diagnosed chronic myeloid leukemia (CML) or refractory chronic myeloid leukemia (CML), comprising administering to the patient a therapeutically effective amount of a compound of formula I at an initial daily dose of:

[0358]

[0359] or a pharmaceutically acceptable salt thereof: 50 mg to 200 mg (e.g., any one dose 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).

[0360] In one embodiment, the initial daily dose is any one of 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.

[0361] In one embodiment, patients are monitored for any hematologic and / or non-hematologic toxicities. The hematologic and / or non-hematologic toxicities are generally known to those skilled in the art, for example, as discussed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 and Version 5.0 (https: / / evs.nci.nih.gov / ftp1 / CTCAE / About.html).

[0362] In one embodiment, when the patient develops hematological and / or non-hematological toxicity at the initial daily dose, the initial daily dose is suspended for at least 7 days and restarted at the initial daily dose of 50 mg to 200 mg (e.g., any one dose selected from the group consisting of 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).

[0363] In one embodiment, when a patient's initial daily dose is 174 mg and develops any hematological and / or non-hematological toxicity, the treatment is suspended for at least 7 days (e.g., 14 days, 21 days, 28 days, etc.), and then the treatment is restarted at the initial dose of 174 mg. Similarly, when a patient is treated at an initial daily dose of 130.5 mg and develops any hematological and / or non-hematological toxicity, the treatment is suspended for at least 7 days (e.g., 14 days, 21 days, 28 days, etc.), and then the treatment is restarted at the initial dose of 130.5 mg.

[0364] In another embodiment, when a patient's initial daily dose is 87 mg and develops any hematological and / or non-hematological toxicity, the treatment is suspended for at least 7 days (e.g., 14 days, 21 days, 28 days, etc.), and then the treatment is restarted again at the initial dose of 87 mg.

[0365] In one aspect, when the patient develops hematologic and / or non-hematologic toxicity at the initial daily dose, the initial daily dose is suspended for less than 7 days (e.g., 4 days), and if the toxicity resolves, the treatment is resumed at the 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).

[0366] In one embodiment, when a patient is treated at an initial daily dose of 174 mg and develops any hematological and / or non-hematological toxicity, the treatment is suspended for less than 7 days (e.g., 4 days), and then the treatment is restarted at the initial dose of 174 mg. Similarly, when a patient is treated at an initial daily dose of 130.5 mg and develops any hematological and / or non-hematological toxicity, the treatment is suspended for less than 7 days (e.g., 4 days), and then the treatment is restarted at the initial dose of 130.5 mg.

[0367] In a preferred embodiment, when a patient is treated at an initial daily dose of 87 mg and develops any hematological and / or non-hematological toxicity, the treatment is suspended for less than 7 days (e.g., 4 days), and then the treatment is restarted again at the initial dose of 87 mg.

[0368] In one aspect, when the 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 restarted 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 wherein the reduced daily dose is optionally re-escalated 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).

[0369] In one embodiment, when a patient develops hematological and / or non-hematological toxicity at the initial daily dose of 174 mg, the initial daily dose is suspended for at least 7 days and restarted 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, the reduced daily dose is 130.5 mg. In addition, the reduced daily dose can be optionally increased or re-increased to a daily dose of 50 mg to 200 mg (for example, 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 increased or re-increased daily dose is 200 mg.

[0370] In another embodiment, when a patient develops hematologic and / or non-hematologic toxicity at the initial daily dose of 130.5 mg, the initial daily dose is suspended for at least 7 days and restarted 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. In addition, the reduced daily dose can be optionally increased or re-increased 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 increased or re-increased daily dose is 174 mg or 200 mg, more preferably, the increased or re-increased daily dose is 174 mg.

[0371] In another embodiment, when a patient develops hematologic and / or non-hematologic toxicity at the initial daily dose of 87 mg, the initial daily dose is suspended for at least 7 days and restarted 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. In addition, the reduced daily dose can be optionally increased or re-increased to a daily dose of 50 mg to 200 mg (for example, 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 increased or re-increased daily dose is any one dose selected from 130.5 mg, 174 mg and 200 mg, more preferably, the increased or re-increased daily dose is 174 mg.

[0372] On the one hand, when the patient develops hematological and / or non-hematological toxicity under the initial daily dose, the initial daily dose is suspended for at least 7 days and restarted with a daily dose of 43.5mg to 192mg (e.g., selected from 43.5mg, 45mg, 48mg, 50mg, 66mg, 87mg, 90mg, 126mg, 130.5mg, 135mg, 174mg, 180mg and 192mg). In the subsequent case of the toxicity recurrence, the daily dose of the reduction can further optionally be reduced to a daily dose of 43.5mg to 180mg (e.g., selected from 43.5mg, 45mg, 48mg, 50mg, 66mg, 87mg, 90mg, 126mg, 130.5mg, 135mg, 174mg and 180mg). The reduced daily dose or the subsequently reduced daily dose can optionally be increased or re-increased to a dose of 50 mg to 200 mg (e.g., any one dose selected from the group consisting of 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

[0373] In one embodiment, when a patient develops hematologic and / or non-hematologic toxicity at the initial daily dose of 174 mg, the initial daily dose is suspended for at least 7 days and restarted 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, the reduced daily dose is 130.5 mg. In subsequent cases of recurrence of the toxicity, the reduced daily dose can be further optionally reduced to a subsequently 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 subsequently reduced dose is 87 mg. The reduced daily dose or the subsequently reduced daily dose can optionally be increased or re-increased to a dose of up to 200 mg (e.g., any one dose selected from the group consisting of 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192 mg, and 200 mg).

[0374] In one embodiment, when a patient develops hematologic and / or non-hematologic toxicity at the initial daily dose of 130.5 mg, the initial daily dose is suspended for at least 7 days and restarted 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. In subsequent cases of recurrence of the toxicity, the reduced daily dose can be further optionally reduced to a subsequently 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), preferably, the subsequently reduced dose is 43.5 mg. The reduced daily dose or the subsequently reduced daily dose can optionally be increased or re-increased to a dose of up to 200 mg (e.g., any one of the following doses: 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 increased or re-increased daily dose is 174 mg.

[0375] In one embodiment, when the patient develops hematology and / or non-hematology toxicity under the described initial daily dose of 87mg, the described initial daily dose is suspended for at least 7 days, and restarts with the daily dose of the reduction of 43.5mg. The daily dose of the described reduction or the described daily dose of subsequent reduction can optionally increase progressively or increase progressively to a dosage of 200mg at the most (for example, selected from any one of following dosage: 50mg, 66mg, 87mg, 90mg, 126mg, 130.5mg, 135mg, 174mg, 180mg, 192mg and 200mg), preferably, the dosage 130.5mg of the described increase progressively or increase progressively again is. More preferably, the daily dose of the described increase progressively or increase progressively again is 174mg.

[0376] According to any of the embodiments described herein, wherein the initial daily dose is escalated or decremented without severe adverse effects.

[0377] According to any of the embodiments described herein, wherein the patient is resistant or intolerant to at least one tyrosine kinase inhibitor.

[0378] According to any of the embodiments described herein, wherein the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

[0379] According to any of the embodiments described herein, wherein the at least one tyrosine kinase inhibitor is selected from radotinib, dasatinib, nilotinib, and bosutinib.

[0380] According to any of the embodiments described herein, wherein the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

[0381] According to any of the embodiments described herein, wherein the at least one tyrosine kinase inhibitor is selected from ponatinib and aximinib.

[0382] According to any 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.

[0383] According to any of the embodiments described herein, the chronic myeloid leukemia (CML) is chronic, accelerated, or blast phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML).

[0384] According to any of the embodiments described herein, the initial daily dose is escalated or decreased without severe adverse effects.

[0385] According to any of the embodiments described herein, the patient is resistant or intolerant to at least one tyrosine kinase inhibitor.

[0386] According to any of the embodiments described herein, the at least one tyrosine kinase inhibitor is a second generation tyrosine kinase inhibitor.

[0387] According to any of the embodiments described herein, the at least one tyrosine kinase inhibitor is selected from dasatinib, nilotinib, radotinib, and bosutinib.

[0388] According to any of the embodiments described herein, the at least one tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor.

[0389] According to any of the embodiments described herein, the at least one tyrosine kinase inhibitor is selected from ponatinib and aximinib.

[0390] According to any 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, H369RH396R, and V359I.

[0391] According to any of the embodiments described herein, the chronic myeloid leukemia (CML) is chronic, accelerated, or blast phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML).

[0392] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0393] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0394] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0395] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0396] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0397] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises 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, such that when the patient develops non-hematological toxicity:

[0398] a) the initial daily dose is withheld for at least 7 days and restarted after the patient recovers from the toxicity; or

[0399] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0400] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0401] and wherein the reduced dose is optionally further escalated to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0402] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0403] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0404] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0405] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0406] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0407] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises 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, such that when the patient develops non-hematological toxicity:

[0408] a) the initial daily dose is withheld for at least 7 days and restarted after the patient recovers from the toxicity; or

[0409] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg upon subsequent recurrences of toxicity;

[0410] and wherein the reduced dose is optionally further escalated to any one dose selected from the group consisting of 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0411] In another embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0412] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0413] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0414] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0415] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0416] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0417] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0418] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0419] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0420] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0421] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0422] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0423] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0424] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0425] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0426] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0427] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0428] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0429] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0430] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0431] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0432] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0433] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0434] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises 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, such that when the patient develops hematological toxicity:

[0435] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0436] b) The initial daily dose was withheld for at least 14 days and resumed at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity.

[0437] In one embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0438] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0439] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0440] c) The initial daily dose was withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg on the first occasion of recurrence of toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of toxicity.

[0441] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises 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, such that when the patient develops hematological toxicity:

[0442] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0443] b) The initial daily dose was withheld for at least 14 days and resumed at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg upon subsequent recurrences of toxicity.

[0444] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0445] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0446] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0447] c) The initial daily dose was withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg on the first occasion of recurrence of toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of toxicity.

[0448] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0449] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0450] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0451] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0452] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0453] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0454] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0455] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0456] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0457] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0458] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0459] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0460] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0461] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0462] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0463] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0464] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0465] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0466] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0467] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0468] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0469] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0470] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises 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, such that when the patient develops hematological toxicity:

[0471] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0472] b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0473] and wherein the reduced dose is optionally further escalated to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0474] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0475] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0476] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0477] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0478] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0479] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises 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, such that when the patient develops hematological toxicity:

[0480] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0481] b) The initial daily dose was withheld for at least 14 days and resumed at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg upon subsequent recurrences of toxicity.

[0482] and wherein the reduced dose is optionally further escalated to any one dose selected from the group consisting of 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0483] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0484] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0485] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0486] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0487] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0488] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises 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, such that when 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 the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity, and at reduced doses of 90 mg, 66 mg, and 48 mg on subsequent occasions of recurrence of the toxicity.

[0489] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced daily dose of 130.5 mg in the first instance of recurrence of the toxicity and is reduced to 87 mg and 43.5 mg in subsequent instances of recurrence of the toxicity.

[0490] In a specific embodiment, the present invention is directed to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises 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, such that when 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 the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity, and at reduced doses of 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg on subsequent occasions of recurrence of the toxicity.

[0491] In one embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is suspended for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 130.5 mg in the first instance of recurrence of the toxicity and is reduced to 87 mg and 43.5 mg in subsequent instances of recurrence of the toxicity.

[0492] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises 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, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0493] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity and at reduced doses of 90 mg, 66 mg, and 48 mg on subsequent occasions of recurrence of the toxicity, and wherein

[0494] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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.

[0495] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced daily dose of 130.5 mg on the first occasion of recurrence of the toxicity and on subsequent occasions of recurrence of the toxicity. and 43.5 mg; and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0496] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises 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, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0497] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity and at reduced doses of 90 mg, 66 mg, 48 mg, 24 mg, and 12 mg on subsequent occasions of recurrence of the toxicity, and wherein

[0498] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 24 mg, 48 mg, 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without hematologic toxicity: (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.

[0499] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0500] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 130.5 mg on the first occasion of recurrence of the toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of the toxicity, and wherein,

[0501] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0502] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced daily dose of 130.5 mg upon the first recurrence of the toxicity and is reduced to 87 mg and 43.5 mg upon subsequent recurrences of the toxicity; and wherein the daily dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the patient results in a mean AUC of 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0503] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed chronic myeloid leukemia (CML), wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0504] The initial daily dose is suspended for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 130.5 mg on the first occasion of recurrence of the toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of the toxicity, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in a mean C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0505] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0506] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 130.5 mg on the first occasion of recurrence of the toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of the toxicity, and wherein,

[0507] The reduced dose is optionally further escalated to any one of the following doses: 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 the following without serious adverse reactions: (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 results in a mean AUC 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0508] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient a therapeutically effective amount of an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0509] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 130.5 mg on the first occasion of recurrence of the toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of the toxicity, and wherein,

[0510] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0511] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0512] In a specific embodiment, the present invention relates to a method for treating an adult patient with CML, said method comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a complete hematologic response without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in an average AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0513] In another specific embodiment, the present invention relates to a method for treating adult patients with CML, said method comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a complete hematologic response without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0514] In yet another specific embodiment, the present invention relates to a method for treating an adult patient with CML, said method comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a disease response without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0515] In another specific embodiment, the present invention provides a method for treating adult patients with CML, said method comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a disease response without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0516] In a specific embodiment, the present invention provides a method for treating an adult patient with CML, the method 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 between 10 mg and 200 mg and escalating doses of between 20 mg and 210 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0517] In another specific embodiment, the present invention relates to a method for treating adult patients with CML, said method 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 between 10 mg and 200 mg and escalating doses of between 20 mg and 210 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 said daily dose of said compound of Formula I, or a pharmaceutically acceptable salt thereof, results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0518] In yet another specific embodiment, the present invention relates to a method for treating an adult patient with CML, said method 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 between 20 mg and 210 mg and decreasing doses of between 10 mg and 200 mg upon the occurrence of a serious adverse reaction, wherein the dose is decreased such that, with the decreasing dose, 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 results in a mean AUC of 1.00; ... 0-24The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0519] In yet another specific embodiment, the present invention relates to a method for treating adult patients with CML, said method 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 between 20 mg and 210 mg and decreasing doses of between 10 mg and 200 mg upon the occurrence of a serious adverse reaction, wherein said dose is decreased such that, with said decreasing dose, said 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 said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0520] In yet another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, said method 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, wherein said initial dose is escalated to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0521] In a specific embodiment, the present invention relates to a method for treating adult patients with refractory CML, said method 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, wherein said initial dose is escalated to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean CHR of max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0522] In yet another specific embodiment, the present invention relates to a method for treating adult patients with refractory CML, said method 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 said initial dose is escalated to 204 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0523] In yet another specific embodiment, the present invention relates to a method for treating adult patients with refractory CML, said method 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 said initial dose is escalated to 204 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0524] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0525] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0526] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of said toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of said toxicity;

[0527] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0528] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0529] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0530] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0531] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0532] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0533] According to a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0534] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0535] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of said toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of said toxicity;

[0536] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C maxThe range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0537] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0538] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0539] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0540] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0541] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0542] According to a specific embodiment, the present invention provides a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0543] a) the initial daily dose is withheld for at least 7 days and restarted after the patient recovers from the toxicity; or

[0544] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0545] and wherein the reduced dose is optionally further increased to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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 results in an average AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0546] In a specific embodiment, the present invention provides a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0547] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0548] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0549] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0550] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0551] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0552] According to another specific embodiment, the present invention provides a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0553] a) the initial daily dose is withheld for at least 7 days and restarted after the patient recovers from the toxicity; or

[0554] b) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0555] and wherein the reduced dose is optionally further increased to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious 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, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0556] In a specific embodiment, the present invention provides a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0557] a) the initial daily dose is withheld for at least 7 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0558] b) the initial daily dose is withheld for less than 7 days and restarted at 174 mg if the toxicity resolves; or

[0559] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0560] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0561] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0562] According to another specific embodiment, the present invention provides a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0563] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0564] b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0565] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0566] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0567] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0568] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0569] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0570] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0571] In another specific embodiment, the present invention provides a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0572] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0573] b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0574] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0575] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0576] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0577] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0578] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0579] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0580] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0581] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0582] b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0583] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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,

[0584] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0585] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0586] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0587] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0588] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0589] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0590] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0591] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity:

[0592] a) the initial daily dose is withheld for at least 14 days and restarted after the patient recovers from the toxicity; or

[0593] b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg upon the first recurrence of toxicity and reduced to 90 mg, 66 mg, and 48 mg upon subsequent recurrences of toxicity;

[0594] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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,

[0595] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0596] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0597] a) the initial daily dose is withheld for at least 14 days and restarted at 174 mg after the patient recovers from the toxicity; or

[0598] b) the initial daily dose is withheld for less than 14 days and restarted at 174 mg if the toxicity resolves; or

[0599] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 130.5 mg upon the first recurrence of toxicity and reduced to 87 mg and 43.5 mg upon subsequent recurrences of toxicity;

[0600] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0601] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0602] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced dose of 126 mg upon the first recurrence of the toxicity and at reduced doses of 90 mg, 66 mg, and 48 mg upon subsequent recurrences of the toxicity;

[0603] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0604] In another specific embodiment, the present invention relates to a method for treating adult patients with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced daily dose of 130.5 mg on the first occasion of recurrence of the toxicity and is reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of the toxicity; and wherein the daily dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the patient results in a mean AUC0-24 in the range of 28598 ng*h / mL to 42898 ng*h / mL±33827 ng*h / mL.

[0605] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein said method comprises administering to said patient an initial daily dose of 174 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when said patient develops hematologic toxicity attributable to said compound of Formula I, or a pharmaceutically acceptable salt thereof, said initial daily dose is withheld for up to four weeks to allow the patient to recover from said toxicity, and said treatment is continued at a reduced dose of 126 mg upon the first recurrence of said toxicity and at reduced doses of 90 mg, 66 mg, and 48 mg upon subsequent recurrence of said toxicity;

[0606] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0607] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0608] The initial daily dose was withheld for up to four weeks to allow the patient to recover from the toxicity, and treatment was continued at a reduced daily dose of 130.5 mg on the first occasion of recurrence of the toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of the toxicity.

[0609] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0610] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0611] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity and at reduced doses of 90 mg, 66 mg, and 48 mg on subsequent occasions of recurrence of the toxicity, and wherein

[0612] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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,

[0613] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0614] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0615] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced dose of 126 mg on the first occasion of recurrence of the toxicity and at reduced doses of 90 mg, 66 mg, and 48 mg on subsequent occasions of recurrence of the toxicity, and wherein

[0616] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 66 mg, 90 mg, 126 mg, and 174 mg to achieve or maintain at least one of the following without serious adverse reactions: (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,

[0617] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0618] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0619] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 130.5 mg on the first occasion of recurrence of the toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of the toxicity, and wherein,

[0620] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0621] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0622] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 130.5 mg on the first occasion of recurrence of the toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of the toxicity, and wherein,

[0623] The reduced dose is optionally further escalated to any one of the following doses: 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 the following without serious adverse reactions: (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 results in a mean AUC 0-24 The range was 28598 ng*h / mL to 42898 ng*h / mL ± 33827 ng*h / mL.

[0624] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 174 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0625] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 130.5 mg on the first occasion of recurrence of the toxicity and reduced to 87 mg and 43.5 mg on subsequent occasions of recurrence of the toxicity, and wherein,

[0626] The reduced dose is optionally further increased to any one of the following doses: 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 the following without serious 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, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean C max The range was 3370 ng / mL to 5054 ng / mL ± 3051 ng / mL.

[0627] In a specific embodiment, the present invention relates to a method for treating newly diagnosed adult CML patients, said method comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, wherein said initial dose is increased to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average AUC 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0628] In another specific embodiment, the present invention relates to a method for treating newly diagnosed adult CML patients, said method comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, wherein said initial dose is escalated to 204 mg to achieve or maintain a complete hematologic response (CHR) without serious adverse reactions, and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean CHR of max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0629] In another specific embodiment, the present invention relates to a method for treating adult patients with chronic myeloid leukemia (CML), said method comprising orally administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a complete hematologic response without serious adverse reactions, wherein said composition is administered under fasting conditions, and wherein said composition results in a mean AUC of 0-24 The range is 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL.

[0630] In another specific embodiment, the present invention relates to a method for treating adult patients with chronic myeloid leukemia (CML), comprising orally administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose and increasing or decreasing doses to achieve or maintain a complete hematologic response without serious adverse reactions, wherein the composition is administered under fasting conditions, and wherein the composition results in a mean C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0631] In a specific embodiment, the present invention relates to a method for treating adult patients with CML, said method comprising orally administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, at an initial daily dose of between 10 mg and 200 mg and escalating doses of between 20 mg and 210 mg to achieve or maintain at least one of the following without serious adverse reactions attributable to the composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof: (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, wherein when administered under fasting conditions, said composition results in a mean AUC of 0-24 The range was 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL, and the average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0632] In yet another specific embodiment, the present invention relates to a method for treating an adult patient suffering from CML, said method comprising orally administering to said patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in a daily dose, wherein such daily dose results in a mean AUC 0-24 The range was 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL, and the average C max The range of 664 ng / mL ± 450 ng / mL to 5054 ng / mL ± 3051 ng / mL, and wherein the daily dose does not result in a QT interval greater than about 500 milliseconds in the patient.

[0633] In a specific embodiment, the present invention relates to a method for preventing relapse of CML in a patient who has been previously treated with a tyrosine kinase inhibitor, wherein the method comprises orally administering a compound of formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg, wherein the initial daily dose results in a mean AUC of 0-24 The range was 6226ng*h / mL±5827ng*h / mL to 60373ng*h / mL±55659ng*h / mL, and the average C max The range was 664ng / mL±450ng / mL to 5054ng / mL±3051ng / mL.

[0634] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0635] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0636] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0637] c) said initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg and 66 mg on subsequent occasions of recurrence of said toxicity.

[0638] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0639] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0640] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0641] c) said initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg and 66 mg on subsequent occasions of recurrence of said toxicity.

[0642] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0643] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0644] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0645] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0646] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0647] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0648] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0649] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0650] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0651] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0652] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0653] In another embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0654] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0655] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0656] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0657] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0658] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0659] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0660] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0661] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0662] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0663] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0664] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0665] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0666] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0667] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0668] c) said initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose selected from 45 mg, 48 mg and 66 mg on subsequent occasions of recurrence of said toxicity.

[0669] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0670] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0671] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0672] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0673] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0674] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0675] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0676] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0677] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0678] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0679] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0680] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0681] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0682] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0683] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0684] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0685] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0686] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0687] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0688] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0689] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0690] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0691] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0692] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0693] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0694] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0695] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0696] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is suspended for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose selected from 45 mg, 48 mg and 66 mg on subsequent occasions when the toxicity recurs.

[0697] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed chronic myeloid leukemia (CML), wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is suspended for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced dose selected from 45 mg, 48 mg and 66 mg upon subsequent recurrence of the toxicity. The daily dose is continued; and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0698] In another embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued on subsequent occasions when the toxicity recurs at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and wherein the daily dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the patient results in a mean AUC of 0-24 The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0699] In another embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed chronic myeloid leukemia (CML), wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued on subsequent occasions when the toxicity recurs at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in a mean C max The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0700] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is suspended for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued on subsequent occasions when the toxicity recurs 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 dose selected from the group consisting of 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 the following without serious adverse reactions: (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 results in an average AUC of 0-24 The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0701] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0702] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued on subsequent occasions when the toxicity recurs at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg, and wherein

[0703] The reduced dose is optionally further increased to any one of the following doses: 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 the following without serious 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, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in a mean Cmax The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0704] In one embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0705] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0706] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0707] c) said initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg and 66 mg on subsequent occasions of recurrence of said toxicity.

[0708] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0709] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0710] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0711] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0712] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0713] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0714] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0715] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0716] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0717] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0718] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory chronic myeloid leukemia (CML), wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0719] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0720] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0721] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0722] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0723] In another specific embodiment, the present invention provides a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0724] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0725] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0726] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0727] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0728] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0729] In another specific embodiment, the present invention provides a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0730] a) the initial daily dose is withheld for at least 7 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0731] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0732] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0733] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0734] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0735] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0736] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0737] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0738] c) said initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose selected from 45 mg, 48 mg and 66 mg on subsequent occasions of recurrence of said toxicity.

[0739] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0740] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0741] b) the initial daily dose is withheld for less than 7 days and restarted at 90 mg if the toxicity resolves; or

[0742] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0743] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0744] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0745] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0746] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0747] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0748] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24 The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0749] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0750] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0751] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0752] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0753] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in an average C max The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0754] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0755] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0756] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0757] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0758] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0759] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof in said patient results in a mean AUC 0-24The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0760] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0761] a) the initial daily dose is withheld for at least 14 days and restarted at 90 mg after the patient recovers from the toxicity; or

[0762] b) the initial daily dose is withheld for less than 14 days and restarted at 90 mg if the toxicity resolves; or

[0763] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg upon subsequent recurrence of the toxicity;

[0764] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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,

[0765] and wherein said daily dose of said compound of Formula I or a pharmaceutically acceptable salt thereof results in an average C max The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0766] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg on subsequent occasions of recurrence of the toxicity.

[0767] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced daily dose selected from 45 mg, 48 mg and 66 mg on subsequent occasions when the toxicity recurs. , and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0768] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued on subsequent occasions when the toxicity recurs at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in a mean AUC of 0-24 The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0769] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued on subsequent occasions when the toxicity recurs at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in a mean C maxThe range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0770] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced daily dose selected from 45 mg, 48 mg and 66 mg on subsequent occasions when the toxicity recurs. , and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0771] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of formula I or a pharmaceutically acceptable salt thereof,

[0772] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued on subsequent occasions when the toxicity recurs at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg, and wherein

[0773] The reduced dose is optionally further escalated to any one of the following doses: 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 the following without serious adverse reactions: (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 results in a mean AUC 0-24The range was 18237 ng*h / mL to 27355 ng*h / mL ± 2782 ng*h / mL.

[0774] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 90 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of formula I or a pharmaceutically acceptable salt thereof,

[0775] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued on subsequent occasions when the toxicity recurs at a reduced daily dose selected from 45 mg, 48 mg, and 66 mg, and wherein

[0776] The reduced dose is optionally further increased to any one of the following doses: 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 the following without serious 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, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean C max The range was 2277 ng / mL to 3415 ng / mL ± 1566 ng / mL.

[0777] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0778] a) the initial daily dose is withheld for at least 7 days and restarted at 87 mg after the patient recovers from the toxicity; or

[0779] b) the initial daily dose is withheld for less than 7 days and restarted at 87 mg if the toxicity resolves; or

[0780] c) The initial daily dose was withheld for at least 7 days and restarted at a reduced daily dose of 43.5 mg due to the toxicity.

[0781] In another embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0782] a) the initial daily dose is withheld for at least 7 days and restarted at 87 mg after the patient recovers from the toxicity; or

[0783] b) the initial daily dose is withheld for less than 7 days and restarted at 87 mg if the toxicity resolves; or

[0784] c) the initial daily dose was withheld for at least 7 days and restarted at a reduced daily dose of 43.5 mg due to the toxicity;

[0785] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0786] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0787] a) the initial daily dose is withheld for at least 14 days and restarted at 87 mg after the patient recovers from the toxicity; or

[0788] b) the initial daily dose is withheld for less than 14 days and restarted at 87 mg if the toxicity resolves; or

[0789] c) The initial daily dose was withheld for at least 14 days and restarted at a reduced daily dose of 43.5 mg due to the toxicity.

[0790] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0791] a) the initial daily dose is withheld for at least 14 days and restarted at 87 mg after the patient recovers from the toxicity; or

[0792] b) the initial daily dose is withheld for less than 14 days and restarted at 87 mg if the toxicity resolves; or

[0793] c) the initial daily dose was withheld for at least 14 days and restarted at a reduced daily dose of 43.5 mg due to the toxicity;

[0794] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0795] In a specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is suspended for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 43.5 mg in subsequent instances of recurrence of the toxicity.

[0796] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0797] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 43.5 mg on subsequent occasions of recurrence of the toxicity, and wherein,

[0798] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0799] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0800] a) the initial daily dose is withheld for at least 7 days and restarted at 87 mg after the patient recovers from the toxicity; or

[0801] b) the initial daily dose is withheld for less than 7 days and restarted at 87 mg if the toxicity resolves; or

[0802] c) The initial daily dose was withheld for at least 7 days and restarted at a reduced daily dose of 43.5 mg due to the toxicity.

[0803] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0804] a) the initial daily dose is withheld for at least 7 days and restarted at 87 mg after the patient recovers from the toxicity; or

[0805] b) the initial daily dose is withheld for less than 7 days and restarted at 87 mg if the toxicity resolves; or

[0806] c) the initial daily dose was withheld for at least 7 days and restarted at a reduced daily dose of 43.5 mg due to the toxicity;

[0807] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0808] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0809] a) the initial daily dose is withheld for at least 14 days and restarted at 87 mg after the patient recovers from the toxicity; or

[0810] b) the initial daily dose is withheld for less than 14 days and restarted at 87 mg if the toxicity resolves; or

[0811] c) The initial daily dose was withheld for at least 14 days and restarted at a reduced daily dose of 43.5 mg due to the toxicity.

[0812] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0813] a) the initial daily dose is withheld for at least 14 days and restarted at 87 mg after the patient recovers from the toxicity; or

[0814] b) the initial daily dose is withheld for less than 14 days and restarted at 87 mg if the toxicity resolves; or

[0815] c) the initial daily dose was withheld for at least 14 days and restarted at a reduced daily dose of 43.5 mg due to the toxicity;

[0816] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0817] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when 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 the treatment is continued at a reduced daily dose of 43.5 mg in subsequent instances of recurrence of the toxicity.

[0818] In another specific embodiment, the invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, such that when the patient develops hematologic toxicity attributable to the compound of Formula I, or a pharmaceutically acceptable salt thereof, the initial daily dose is suspended for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 43.5 mg on subsequent occasions when the toxicity recurs; and wherein the reduced dose is optionally re-escalated to any one of the following doses: 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 the following without serious adverse reactions: (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.

[0819] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 87 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of formula I or a pharmaceutically acceptable salt thereof,

[0820] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 43.5 mg on subsequent occasions of recurrence of the toxicity, and wherein,

[0821] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0822] In one embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0823] a) the initial daily dose is withheld for at least 7 days and restarted at 130.5 mg after the patient recovers from the toxicity; or

[0824] b) the initial daily dose is withheld for less than 7 days and restarted at 130.5 mg if the toxicity resolves; or

[0825] c) The initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 87 mg upon the first recurrence of toxicity and reduced to 43.5 mg upon subsequent recurrence of toxicity.

[0826] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0827] a) the initial daily dose is withheld for at least 7 days and restarted at 130.5 mg after the patient recovers from the toxicity; or

[0828] b) the initial daily dose is withheld for less than 7 days and restarted at 130.5 mg if the toxicity resolves; or

[0829] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 87 mg upon the first recurrence of toxicity and reduced to 43.5 mg upon subsequent recurrence of toxicity;

[0830] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0831] In one embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0832] a) the initial daily dose is withheld for at least 14 days and restarted at 130.5 mg after the patient recovers from the toxicity; or

[0833] b) the initial daily dose is withheld for less than 14 days and restarted at 130.5 mg if the toxicity resolves; or

[0834] c) The initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 87 mg upon the first recurrence of toxicity and reduced to 43.5 mg upon subsequent recurrence of toxicity.

[0835] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0836] a) the initial daily dose is withheld for at least 14 days and restarted at 130.5 mg after the patient recovers from the toxicity; or

[0837] b) the initial daily dose is withheld for less than 14 days and restarted at 130.5 mg if the toxicity resolves; or

[0838] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 87 mg upon the first recurrence of toxicity and reduced to 43.5 mg upon subsequent recurrence of toxicity;

[0839] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0840] In one embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is suspended for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 87 mg on the first occasion of recurrence of the toxicity and is reduced to 43.5 mg on subsequent occasions of recurrence of the toxicity.

[0841] In another specific embodiment, the present invention relates to a method for treating an adult patient with newly diagnosed CML, wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0842] The initial daily dose is withheld for up to four weeks to allow the patient to recover from the toxicity, and the treatment is continued at a reduced daily dose of 87 mg on the first occasion of recurrence of the toxicity and reduced to 43.5 mg on subsequent occasions of recurrence of the toxicity, and wherein,

[0843] The reduced dose is optionally further escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0844] In one embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0845] a) the initial daily dose is withheld for at least 7 days and restarted at 130.5 mg after the patient recovers from the toxicity; or

[0846] b) the initial daily dose is withheld for less than 7 days and restarted at 130.5 mg if the toxicity resolves; or

[0847] c) The initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 87 mg upon the first recurrence of toxicity and reduced to 43.5 mg upon subsequent recurrence of toxicity.

[0848] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0849] a) the initial daily dose is withheld for at least 7 days and restarted at 130.5 mg after the patient recovers from the toxicity; or

[0850] b) the initial daily dose is withheld for less than 7 days and restarted at 130.5 mg if the toxicity resolves; or

[0851] c) the initial daily dose is withheld for at least 7 days and restarted at a reduced daily dose of 87 mg upon the first recurrence of toxicity and reduced to 43.5 mg upon subsequent recurrence of toxicity;

[0852] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0853] In a specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0854] a) the initial daily dose is withheld for at least 14 days and restarted at 130.5 mg after the patient recovers from the toxicity; or

[0855] b) the initial daily dose is withheld for less than 14 days and restarted at 130.5 mg if the toxicity resolves; or

[0856] c) The initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 87 mg upon the first recurrence of toxicity and reduced to 43.5 mg upon subsequent recurrence of toxicity.

[0857] In another specific embodiment, the present invention relates to a method for treating an adult patient with refractory CML, wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops non-hematological toxicity:

[0858] a) the initial daily dose is withheld for at least 14 days and restarted at 130.5 mg after the patient recovers from the toxicity; or

[0859] b) the initial daily dose is withheld for less than 14 days and restarted at 130.5 mg if the toxicity resolves; or

[0860] c) the initial daily dose is withheld for at least 14 days and restarted at a reduced daily dose of 87 mg upon the first recurrence of toxicity and reduced to 43.5 mg upon subsequent recurrence of toxicity;

[0861] and wherein the reduced dose is optionally re-escalated to any one dose selected from the group consisting of 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 the following without serious adverse reactions: (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.

[0862] In one embodiment, the present invention relates to a method for treating an adult patient with refractory chronic myeloid leukemia (CML), wherein the method comprises administering to the patient an initial daily dose of 130.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological toxicity attributable to the compound of Formula I or a pharmaceutically acceptable salt thereof, the initial daily dose is suspended for up to four weeks to allow the patient to recover from the toxicity, ...

Claims

1. A method for treating a human patient suffering from chronic myeloid leukemia (CML), such as newly diagnosed chronic myeloid leukemia (CML) or refractory chronic myeloid leukemia (CML), the method comprising administering to the patient a therapeutically effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof, The chronic myeloid leukemia (CML) is chronic, accelerated or blast crisis Philadelphia chromosome (PhiladelphiaChromosome) positive chronic myeloid leukemia (Ph+CML).

2. The method of claim 1, wherein the therapeutically effective amount of the compound of Formula I or a pharmaceutical salt thereof is sufficient to achieve an average AUC ranging from 6226 ng*h / mL ± 5827 ng*h / mL to 60373 ng*h / mL ± 55659 ng*h / mL 0-24 or a mean C ranging from 664 ng / mL ± 450 ng / mL to 5054 ng / mL ± 3051 ng / mL max .

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

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

5. The method of any of the preceding claims, wherein the initial daily dose is escalated or decreased to achieve or maintain 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.

6. The method according to any one of the preceding claims, wherein the initial daily dose is increased or decreased without serious adverse effects.

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

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

9. The method according to any one of claims 7 to 8, wherein the at least one tyrosine kinase inhibitor is selected from dasatinib, nilotinib, radotinib and bosutinib.

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

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

12. The method of any one of the preceding claims, 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 method according to any one of the preceding claims, wherein the patient has one or more of the following characteristics: a) blasts in peripheral blood and bone marrow are 15%; b) blasts plus promyelocytes in peripheral blood and bone marrow < 30%; c) basophils in the peripheral blood are <20%; d) Platelets ≥ 50 x 10 9 / L(≥50,000 / mm 3 ); e) Transient prior therapy-related thrombocytopenia (<50,000 / mm within ≤30 days before screening) 3 ); f) no evidence of extramedullary leukemic involvement other than hepatosplenomegaly; g) blasts ≥15% to <30% in peripheral blood or bone marrow; h) basophils ≥ 20% in peripheral blood or bone marrow; i) (blasts + promyelocytes) ≥ 30% in peripheral blood or bone marrow (but blasts < 30%); j) ≤100X 109 platelets / L in peripheral blood, regardless of therapy; k) Additional clonal cytogenetic abnormalities in Ph+ cells; l) ≥30% blasts in peripheral blood, bone marrow, or both; and m) Extramedullary disease.

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

15. The method according to any of the preceding claims, wherein when the patient exhibits a grade 1 or 2 non-hematological adverse event, the treatment is suspended for a period of at least 7 days and then restarted.

16. The method of any one of the preceding claims, wherein the treatment is suspended for a period of up to 56 days (e.g., 14 to 56 days or 28 to 56 days) and then restarted when the patient exhibits a Grade 3 hematological or non-hematological adverse event or a Grade 4 asymptomatic hematological adverse event.

17. The method of claim 16, wherein the treatment is stopped when the patient has not recovered to a Grade 1 adverse event or less after a 56-day pause period.

18. A method of treating a treatment-resistant human patient suffering from chronic myeloid leukemia (CML), the method comprising administering to the patient a therapeutically effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein i. The method comprises orally administering 174 mg to 200 mg of the compound of formula I per day, and ii. Prior to said administering of said compound of formula I, said patient is resistant or intolerant to at least one tyrosine kinase inhibitor.

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

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

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

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

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

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

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

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

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

29. The method of claim 28, wherein the compound of formula I is administered each morning, and optionally fasting for two hours before and after administration of the compound of formula I.

30. The method according to any one of claims 18 to 29, wherein when the patient exhibits a grade 1 or 2 non-hematological adverse event that is not tolerable due to clinical symptoms or interference with daily activities, the treatment is suspended for a certain period of time and then restarted.

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

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

33. The method according to any one of claims 18 to 32, wherein the treatment is suspended for a period of time and then restarted when the patient exhibits a grade 3 hematological or non-hematological adverse event or a grade 4 asymptomatic hematological adverse event.

34. The method of claim 33, wherein the treatment is suspended for up to 56 days (e.g., 14 to 56 days or 28 to 56 days) to recover to a Grade 1 adverse event or less; and if the patient has not recovered to a Grade 1 adverse event or less, treatment with the compound of Formula I is discontinued.

35. The method according to any one of the preceding claims, wherein the method comprises oral administration of one or more oral capsules per day, wherein (i) each capsule contains the same amount of the compound of Formula I, (ii) the amount is selected from 43.5 mg, 45 mg and 50 mg of the compound of Formula I, and (iii) upon the occurrence of certain adverse events that do not require cessation or temporary suspension of treatment, the daily dose is reduced by administering a smaller number of the same oral capsules per day.

36. The method of claim 35, wherein 4 oral capsules are administered daily prior to dose reduction.

37. A method for treating a human patient suffering from chronic myeloid leukemia (CML), such as newly diagnosed chronic myeloid leukemia (CML) or refractory chronic myeloid leukemia (CML), the method comprising administering to the patient a therapeutically effective amount of a compound of formula I at an initial daily dose of: or a pharmaceutically acceptable salt thereof: 50 mg to 200 mg (e.g., any one dose 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), such that when the patient develops hematological and / or non-hematological toxicity: a) the initial daily dose is suspended for at least 7 days and restarted at the initial daily dose of 50 mg to 200 mg (e.g., any one dose selected from the group consisting of 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 suspended for less than 7 days and if the toxicity resolves, the treatment is restarted at the initial daily dose of 50 mg to 200 mg (e.g., any one dose selected from the group consisting of 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 suspended for at least 7 days and restarted at a reduced daily dose of 43.5 mg to 192 mg (e.g., any one dose selected from the group consisting of 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 wherein the reduced daily dose is optionally re-escalated to a further increasing daily dose of 50 mg to 200 mg (e.g., any one dose 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 suspended for at least 7 days and restarted at a reduced daily dose of 43.5 mg to 192 mg (e.g., any one dose 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 wherein in subsequent instances of recurrence of said toxicity, said reduced daily dose is further reduced to a subsequent reduced daily dose of 43.5 mg to 180 mg (e.g., any one dose selected from the group consisting of 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); And wherein the reduced daily dose or the subsequently reduced daily dose is optionally increased again to a further increasing daily dose of 50 mg to 200 mg (e.g., any one dose selected from the following: 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. A method for treating a human patient suffering from chronic myeloid leukemia (CML), such as newly diagnosed chronic myeloid leukemia (CML) or refractory chronic myeloid leukemia (CML), the method comprising administering to the patient a therapeutically effective amount of a compound of formula I at an initial daily dose of 174 mg: or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological and / or non-hematological toxicity: a) the initial daily dose is suspended for at least 7 days and restarted at the initial daily dose of 174 mg; or b) the initial daily dose is withheld for less than 7 days and if the toxicity resolves, the treatment is restarted at the initial daily dose of 174 mg; or c) the initial daily dose is suspended for at least 7 days and restarted at a reduced daily dose of 43.5 mg to 135 mg (e.g., any one dose selected from the following: 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 87 mg; and wherein the reduced daily dose is optionally increased again to a further increasing daily dose of up to 200 mg (e.g., any one of the following doses: 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 further increasing daily dose is 200 mg; or d) the initial daily dose is suspended for at least 7 days and restarted at a reduced daily dose of 43.5 mg to 135 mg (e.g., any one dose 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 and wherein in subsequent instances of recurrence of said toxicity, said reduced daily dose is optionally further reduced to a subsequent reduced daily dose of 43.5 mg to 130.5 mg (e.g., any one dose selected from the group consisting of 43.5 mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg and 130.5 mg), preferably, said subsequent reduced daily dose is 87 mg; And wherein the reduced daily dose or the subsequently reduced daily dose is optionally increased again to a further increased daily dose of up to 200 mg (for example, any one dose selected from the following: 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 further increased daily dose is 200 mg.

39. A method for treating a human patient suffering from chronic myeloid leukemia (CML), such as newly diagnosed chronic myeloid leukemia (CML) or refractory chronic myeloid leukemia (CML), the method comprising administering to the patient a therapeutically effective amount of a compound of formula I at an initial daily dose of 87 mg: or a pharmaceutically acceptable salt thereof, such that when the patient develops hematological and / or non-hematological toxicity: a) the initial daily dose is suspended for at least 7 days and restarted at the initial daily dose of 87 mg; or b) the initial daily dose is withheld for less than 7 days and if the toxicity resolves, the treatment is restarted at the initial daily dose of 87 mg; or c) the initial daily dose is suspended for at least 7 days and restarted at a reduced daily dose of 43.5 mg or 50 mg, preferably, the reduced daily dose is 43.5 mg; And wherein the reduced daily dose is optionally increased again to a further increasing daily dose of up to 200 mg (for example, any one dose selected from the following: 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 further increasing daily dose is 174 mg.

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

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

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

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

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

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