METHODS OF TREATING CHRONIC MYELOID LEUKEMIA USING

THE TYROSINE KINASE INHIBITOR VODOBATINIB

The present application claims the benefit of Indian Provisional Application No.

202221048373 and Indian Provisional Application No. 202221048415, filed on 25 Aug.

2022, the entire contents of which are hereby incorporated by reference.

FIELD OF INVENTION

The present invention relates to methods of treating leukemia. In one aspect, the present invention relates to methods of treating chronic myeloid leukemia (CML) using a compound of Formula I or a pharmaceutically acceptable salt thereof, as shown below.

BACKGROUND OF THE INVENTION

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder representing ~15-20% of adult leukemias [Apperley 2015; Deininger et al. 2003], The underlying cause of CML is the breakpoint cluster region-Abelson leukemia (BCR-ABL1) fusion oncoprotein, which results from a reciprocal t(9;22) chromosomal translocation in hematopoietic stem cells. This translocation leads to the fusion of 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. This translocation thus results in the activation of multiple downstream pathways that contribute to the growth and survival of leukemic cells [Hazlehurst et al. 2009], CML is characterized and classified by 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 of the CML patients are diagnosed in the chronic phase. In AP, the patient’s blood samples have 15% or more, but less than 30% blasts. In this phase, 20% of the blood cells consist of basophil, the platelet counts are low (100 x 1,000/mm3 or less) that are not caused by the treatment and there are chromosome changes in the leukemia cells with the Philadelphia chromosome. In the blast phase, bone marrow and/or blood samples have 20% or more blasts. Large clusters of blasts are seen in the bone marrow. The blast cells spread to tissues and organs beyond the bone marrow.

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

Dasatinib is approved for the treatment of adults with Ph+ CML in chronic phase, and adults with Ph+ acute lymphocytic leukemia (ALL) with resistance or intolerance to prior therapy. Nilotinib is approved for the treatment of Ph+ CML in the chronic phase in adult and pediatric patients at least 1 year of age. Bosutinib is approved for the treatment of chronic phase Ph+ CML. Second-generation tyrosine kinase inhibitors (TKIs) such as dasatinib, nilotinib, and bosutinib generally offer improved patient tolerance over the first-generation TKI, imatinib (Ferdinand, 2012). However, about 10% of patients do not tolerate their initial treatments with TKIs and many subjects develop long-term treatment-emergent adverse events (TEAEs) such as cardiovascular, pulmonary, gastrointestinal, and endocrine toxicities, and 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).

There is a need for improved TKIs, especially for patients who failed treatment with prior TKIs.

Documents

Siegel, R.L., Miller, K.D. and Jemal, A. (2019), Cancer statistics, 2019. CA A Cancer J Clin, 69: 7-34. https://doi.org/10.3322/caac.21551

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

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

Caldemeyer L, Dugan M, Edwards J, Akard L. Long-Term Side Effects of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia. Curr Hematol Malig Rep. 2016 Apr; 11(2): 71-9.

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

Buoen C, Bjerrum OJ, Thomsen MS. How First-time -in-human Studies are Being Performed: A survey of Phase I dose-escalation trials in healthy volunteers published between 1995 and 2004. J Clin Pharmacol. 2005 Oct;45(10): 1123-1136.

US Food and Drug Administration (FDA) Guidance for Industry (2005), Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Subjects.

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

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

BRIEF SUMMARY OF THE INVENTION

The use of a tyrosine kinase inhibitor (TKI) that targets BCR-ABL1 is a well-established and highly effective strategy for sustained disease control in CML, Ph+ CML and Ph+ ALL. A compound of Formula I is a novel BCR-ABL1 TKI under clinical development for the treatment of both refractory /intolerant chronic myeloid leukemia and newly diagnosed CML

The compound of Formula I has been studied in in-vitro and in-vivo studies and has specific and highly potent activity on wild-type BCR-ABL1 and several BCR-ABL1 mutations. The present disclosure relates to a method for the treatment of adult subjects with chronic phase (CP), accelerated phase (AP), or blast phase (BP) CML or Ph+ CML or Ph+ ALL.

Accordingly, disclosed herein is a method for the treatment of a patient (such as an adult patient) with chronic myeloid leukemia (CML), comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof

Formula I

at an initial daily dose, and escalating or de-escalating the dose to achieve or maintain a complete hematologic response with no severe adverse reaction.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose, and escalating or de-escalating the dose to achieve or maintain complete hematologic response with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in a patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose, and escalating or de-escalating the dose to achieve or maintain complete hematologic response with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose, and escalating or de-escalating the dose to achieve or maintain disease response, with no severe adverse reaction.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose, and escalating or de-escalating the dose to achieve or maintain disease response, with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose, and escalating or de-escalating the dose to achieve or maintain disease response, with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of between 10 mg and 200 mg and escalating the dose between 20 mg and 210 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of between 10 mg and 200 mg and escalating the dose between 20 mg and 210 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of between 10 mg and 200 mg and escalating the dose between 20 mg and 210 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of between 20 mg and 210 mg and de-escalating to the dose between 10 mg and 200 mg on the occurrence of severe adverse reaction, wherein the dose is de-escalated such that with the de-escalated dose patient achieves or maintains at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of between 20 mg and 210 mg and de-escalating to the dose between 10 mg and 200 mg on the occurrence of severe adverse reaction, wherein the dose is de-escalated such that with the de-escalated dose patient achieves or maintains at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at an initial daily dose of between 20 mg and 210 mg and de-escalating to the dose between 10 mg and 200 mg on the occurrence of severe adverse reaction, wherein the dose is de-escalated such that with the de-escalated dose patient achieves or maintains at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with refractory CML comprising, administering a therapeutically effective amount of 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 complete hematologic response (CHR) with no severe adverse reaction.

Accordingly, disclosed herein is a method for the treatment of an adult patient with refractory CML comprising, administering a therapeutically effective amount of 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 complete hematologic response (CHR) with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with refractory CML comprising, administering a therapeutically effective amount of 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 complete hematologic response (CHR) with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with refractory 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 (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response; with no severe adverse reaction.

Accordingly, disclosed herein is a method for the treatment of an adult patient with refractory 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 (a) complete hematological response, (b) complete hematological response and

partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response; with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with refractory 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 (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response; with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of 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:

a) an initial daily dose is withheld for at least 7 days and resumed after recovery of patient from said toxicity at 174 mg; or

b) an initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrences of said toxicity.

Accordingly, disclosed herein is a method for the treatment of 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:

a) an initial daily dose is withheld for at least 7 days and resumed after recovery of patient from said toxicity at 174 mg; or

b) an initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrences of said toxicity;

and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of 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:

a) an initial daily dose is withheld for at least 7 days and resumed after recovery of patient from said toxicity at 174 mg; or

b) an initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrences of said toxicity;

and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with refractory CML, wherein the method comprises administering to said 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-hematologic toxicity:

a) the initial daily dose is withheld for at least 7 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrences of said toxicity;

and wherein, the reduced dose is optionally re-escalated to any one of the dose selected from 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic

response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction.

Accordingly, disclosed herein is a method for the treatment of an adult patient with refractory CML, wherein the method comprises administering to said 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-hematologic toxicity:

a) the initial daily dose is withheld for at least 7 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrences of said toxicity;

and wherein, the reduced dose is optionally re-escalated to any one of the dose selected from 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUCo-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with refractory CML, wherein the method comprises administering to said 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-hematologic toxicity:

a) the initial daily dose is withheld for at least 7 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrences of said toxicity;

and wherein, the reduced dose is optionally re-escalated to any one of the dose selected from 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of 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:

a) the initial daily dose is withheld for at least 14 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity.

Accordingly, disclosed herein is a method for the treatment of 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:

a) the initial daily dose is withheld for at least 14 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity;

and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of 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:

a) the initial daily dose is withheld for at least 14 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity;

and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of 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:

a) the initial daily dose is withheld for at least 14 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity;

and wherein, the reduced dose is optionally re-escalated to any one of the doses selected from 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction.

Accordingly, disclosed herein is a method for the treatment of 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:

a) the initial daily dose is withheld for at least 14 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity;

and wherein, the reduced dose is optionally re-escalated to any one of the dose selected from 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUCo-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of 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:

a) the initial daily dose is withheld for at least 14 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity;

and wherein, the reduced dose is optionally re-escalated to any one of the dose selected from 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of 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 recovery of patient from said toxicity and the treatment is continued at a reduced dose of 126 mg on first instance and at 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity.

Accordingly, disclosed herein is a method for the treatment of 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 recovery of patient from said toxicity and the treatment is continued at a reduced dose of 126 mg on first instance and at 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Accordingly, disclosed herein is a method for the treatment of 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 recovery of patient from said toxicity and the treatment is continued at a reduced dose of 126 mg on first instance and at 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity; and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Also disclosed herein is a method for the treatment of 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 that is 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 recovery of patient from said toxicity and the treatment is continued at a reduced dose of 126 mg on first instance and at 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity, and wherein the reduced dose is optionally re-escalated to any one of the dose selected from 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction.

Also disclosed herein is a method for the treatment of 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 that is 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 recovery of patient from said toxicity and the treatment is continued at a reduced dose of 126 mg on first instance and at 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity, and wherein the reduced dose is optionally re-escalated to any one of the dose selected from 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

Also disclosed herein is a method for the treatment of 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 that is 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 recovery of patient from said toxicity and the treatment is continued at a reduced dose of 126 mg on first instance and at 90 mg, 66 mg and 48 mg on subsequent instances of recurrence of said toxicity, and wherein the reduced dose is optionally re-escalated to any one of the dose selected from 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction,

and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

According to another embodiment, disclosed herein is a method for the treatment of newly diagnosed adult CML patient comprising, administering a therapeutically effective amount of 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 complete hematologic response (CHR) with no severe adverse reaction.

According to one embodiment, disclosed herein is a method for the treatment of newly diagnosed adult CML patient comprising, administering a therapeutically effective amount of 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 complete hematologic response (CHR) with no severe adverse reaction, and wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof in the patient results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

According to another embodiment, disclosed herein is a method for the treatment of newly diagnosed adult CML patient comprising, administering a therapeutically effective amount of 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 complete hematologic response (CHR) with no severe adverse reaction, and wherein the

daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of newly diagnosed adult CML patient 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 (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction.

Accordingly, disclosed herein is a method for the treatment of a newly diagnosed adult CML patient, 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:

a) an initial daily dose is withheld for at least 7 days and resumed after recovery of patient from said toxicity 174 mg; or

b) an initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg, 48 mg, 24 mg and 12 mg on subsequent instances of recurrences of said toxicity.

Accordingly, disclosed herein is a method for the treatment of a newly diagnosed adult CML patient, 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-hematologic toxicity:

a) the initial daily dose is withheld for at least 7 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg 48 mg, 24 mg and 12 mg on subsequent instances of recurrences of said toxicity;

and wherein, the reduced dose is optionally re-escalated to any one of the dose selected from 24 mg, 48 mg, 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction.

Accordingly, disclosed herein is a method for the treatment of a newly diagnosed adult CML patient, 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:

a) the initial daily dose is withheld for at least 14 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg, 48 mg, 24 mg and 12 mg on subsequent instances of recurrence of said toxicity.

Accordingly, disclosed herein is a method for the treatment of a newly diagnosed adult CML patient, 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:

a) the initial daily dose is withheld for at least 14 days and resumed after recovery of patient from said toxicity; or

b) the initial daily dose is withheld for at least 14 days and resumed at a reduced daily dose of 126 mg on first instance and to 90 mg, 66 mg, 48 mg, 24 mg and 12 mg on subsequent instances of recurrence of said toxicity;

and wherein, the reduced dose is optionally re-escalated to any one of the dose selected from 24mg, 48 mg, 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction.

Accordingly, disclosed herein is a method for the treatment of a newly diagnosed adult CML patient, 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 recovery of patient from said toxicity and the treatment is continued at a reduced dose of 126 mg on first instance and at 90 mg, 66 mg, 48 mg, 24 mg and 12 mg on subsequent instances of recurrence of said toxicity.

Also disclosed herein is a method for the treatment of a newly diagnosed adult CML patient, 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 that is 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 recovery of patient from said toxicity and the treatment is continued at a reduced dose of 126 mg on first instance and at 90 mg, 66 mg, 48 mg, 24 mg and 12 mg on subsequent instances of recurrence of the toxicity, and wherein

the reduced dose is optionally re-escalated to any one of the dose selected from 24 mg, 48 mg, 66 mg, 90 mg, 126 mg and 174 mg, to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no hematologic toxicity.

According to an embodiment, disclosed herein is a method for the treatment of an adult patient with chronic myeloid leukemia (CML), comprising orally administering a pharmaceutical composition comprising a therapeutic effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, at an initial daily dose, and escalating or de-escalating the dose to achieve or maintain complete hematologic response, with no severe adverse reaction.

According to another embodiment, disclosed herein is a method for the treatment of an adult patient with chronic myeloid leukemia (CML), comprising orally administering a pharmaceutical composition comprising a therapeutic effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, at an initial daily dose, and escalating or de-escalating the dose to achieve or maintain complete hematologic response, with no severe adverse reaction, wherein the composition is administered under fasting condition and wherein the composition results in a mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL.

According to another embodiment, disclosed herein is a method for the treatment of an adult patient with chronic myeloid leukemia (CML), comprising orally administering a pharmaceutical composition comprising a therapeutic effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, at an initial daily dose, and escalating or de-escalating the dose to achieve or maintain complete hematologic response, with no severe adverse reaction, wherein the composition is administered under fasting condition and wherein the composition results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a pharmaceutical composition comprising a therapeutic 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 to the dose between 20 mg and 210 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction due to the composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.

Accordingly, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a pharmaceutical composition comprising a therapeutic 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 to the dose between 20 mg and 210 mg to achieve or maintain at least one of (a) complete hematological response, (b) complete hematological response and partial cytogenetic response, (c) complete hematological response and complete cytogenetic response, or (d) complete

hematological response, complete cytogenetic response, and major molecular response, with no severe adverse reaction due to the composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the composition when administered under fasting condition results in a mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL and mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

According to another embodiment, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the patient at a daily dose wherein such daily dose does not result in patient's QT interval of more than about 500 ms.

According to another embodiment, disclosed herein is a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the patient at a daily dose wherein such daily dose results in a mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL and mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL and wherein the daily dose does not result in patient's QT interval of more than about 500 ms.

In another embodiment, disclosed herein is a method for the prevention of recurrence of CML in a patient that has previously undergone treatment using 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.

In yet another embodiment, disclosed herein is a method for the prevention of recurrence of CML in a patient that has previously undergone treatment using 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 AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL and mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.

According to an embodiment, there is provided a method of treating an adult patient with CML by orally administering a therapeutically effective amount of a compound of

Formula I or a pharmaceutically acceptable salt thereof under fasting conditions such that, a mean AUC0-24 achieved in patient by administering the compound of Formula I or a pharmaceutically acceptable salt thereof under fasting conditions is 15% higher as compared to the mean AUC0-24 obtained by administering the compound of Formula I or a pharmaceutically acceptable salt thereof under fed conditions.

Accordingly to an embodiment, there is provided a method of treating an adult patient with CML by orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at a daily dose ranging from 10 mg to 210 mg, wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL, when administered under fasting conditions.

According to another embodiment, there is provided a method of treating an adult patient with CML by orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof under fasting conditions such that, a mean Cmax achieved in patient by administering the compound of Formula I or a pharmaceutically acceptable salt thereof under fasting conditions is 20% higher as compared to the mean Cmax achieved by administering the compound of Formula I or a pharmaceutically acceptable salt thereof under fed conditions.

Accordingly, to an embodiment, there is provided a method of treating an adult patient with CML by orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at a daily dose ranging from 10 mg to 210 mg, wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof results in a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL, when administered under fasting conditions.

According to another embodiment, there is provided a method for the treatment of an adult patient with CML, wherein the method comprises administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the patient 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.

According to yet another embodiment, there is provided a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at a

predetermined daily dose, wherein said daily dose, (a) results in not less than 50 ng/mL of the compound of Formula I or a pharmaceutically acceptable salt thereof in the plasma; (b) results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL; (c) achieves a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL; (d) achieves 15% higher AUC0-24 and 20% higher Cmax when administered under fasting conditions as compared to when administered under fed conditions; and/or (e) results in patient's QT interval of less than about 500 ms.

According to yet another embodiment, there is provided a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at a predetermined daily dose, wherein said daily dose, (a) results in not less than 25 ng/mL of the compound of Formula I or a pharmaceutically acceptable salt thereof in the plasma; (b) results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL; (c) achieves a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL; (d) achieves 15% higher AUC0-24 and 20% higher Cmax when administered under fasting conditions as compared to when administered under fed conditions; and/or (e) results in patient's QT interval of less than about 500 ms.

According to an embodiment, there is provided a method for the treatment of an adult patient with CML, comprising orally administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof at a predetermined daily dose, wherein the daily dose is escalated to achieve or maintain complete hematologic response or the daily dose is reduced when the patient experiences severe adverse reaction, and wherein the predetermined, escalated or reduced daily dose; (a) results in not less than 50 ng/mL of the compound of Formula I or a pharmaceutically acceptable salt thereof in the plasma; (b) results in mean AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL; (c) achieves a mean Cmax ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL; (d) achieves 15% higher AUC0-24 and 20% higher Cmax when administered under fasting conditions as compared to when administered under fed conditions; and/or (e) results in patient's QT interval of less than about 500 ms.

According to another embodiment, there is provided a method of treating a CML patient having a relapsed or refractory CML condition, wherein the relapsed or refractory condition arises due to mutations in the kinase domain of BCR-ABL1 fusion oncoprotein, the method comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to said patient at a daily dose of 48 to 204 mg.

According to another embodiment, there is provided a method of treating a CML patient having a relapsed or refractory CML condition, wherein the relapsed or refractory condition arises due to mutations in the kinase domain of BCR-ABL1 fusion oncoprotein, the method comprising administration of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in an amorphous form and a pharmaceutically acceptable excipient.

According to another embodiment of the present invention, there is a method of increasing a survival likelihood of a CML patient, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to said patient, wherein prior to said administering, said CML patient failed at least 1 TKIs.

According to an embodiment of the present invention, there is provided a method for the treatment of an adult patient who had previously undergone treatment for T3151-positive CML and has a relapsed or refractory CML condition, 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 escalating or de-escalating the dose to achieve or maintain disease response, with no severe adverse reaction.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1: SAD: individual, Mean, Median AUC 25% of doses over 28 days due to toxicity in Cycle 1; and

c) Any grade of toxicity requiring dose reduction or discontinuation of IMP within the 28-days DLT assessment period (Cycle 1).

Hematological DLTs for subjects in CML-Chronic Phase are grade 3 neutropenia and/or thrombocytopenia for > 28 days off the study drug treatment or grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5 x 109/L in peripheral blood) > 7 days off the study drug (i.e.: after treatment interruption).

Hematological DLTs for subjects in CML-Accelerated Phase are grade 3 neutropenia and/or thrombocytopenia for > 28 days off the study drug treatment or grade 4 neutropenia (ANC < 0.5 x 109/L in peripheral blood) > 7 days off the treatment (i.e.: after treatment interruption) in the absence of features of an accelerated phase (except cytogenetic changes) such as a persistent increase in blasts or basophils.

Hematological DLTs for subjects in CML-Blast Phase are Grade 3 neutropenia and/or thrombocytopenia in the absence of persistent leukemia or ANC <500/mm3 or

thrombocytopenia < 50,000/mm3 for > 6 weeks with a bone marrow cellularity showing 5% blasts.

It would be appreciated by a skilled person in the art that the hematological DLT can be confirmed only after distinguishing between toxicity due to the compound of Formula I or a pharmaceutically acceptable salt thereof and anti-leukemic effect. This can be done by the methods known to the skilled person. For example, if the subject has neutropenia with clearance of leukemic cells or blasts, a bone marrow examination can be performed to distinguish between toxicity due to Formula I and the anti-leukemic effect, if the subject shows a normocellular marrow or persistence of the disease, can be said to be an antileukemic effect and the treatment can be continued, however, if there is evidence of drug toxicity such as hypocellular marrow, then the treatment is halted for a predetermined period.

The term ‘disease response’ or simply ‘response’ due to the compound of Formula I or a pharmaceutically acceptable salt thereof is understood as an effect of the compound of Formula I or a pharmaceutically acceptable salt thereof on the progression of the disease in the patient. The disease response is determined by screening the patient before and after initiation of the treatment.

The disease response is determined by screening the patient before and after initiation of the treatment. The screening may include both clinical and laboratory investigations such as physical examination, blood analysis, vital signs analysis for example temperature, heart rate, respiratory rate, and diastolic and systolic blood pressure, ECG, bone marrow aspiration, BCR-ABL mutational analysis, and BCR-ABL transcript analysis. From the screening results if it is evident that the compound of Formula I or a pharmaceutically acceptable salt thereof reduces or ameliorates or alleviates the disease or its symptoms, the patient is said to have a disease response. Particularly, in the case of leukemia, the disease response is confirmed when the patient exhibits hematological response (CHR), cytogenetic response, and molecular response, sequentially in the given order. For example, a CP CML patient is expected to initially exhibit a major or complete hematologic response and then show signs of cytogenetic response followed by molecular response. The patient with AP CML and BP CML is expected to initially exhibit complete hematologic response and then optionally exhibit partial or complete cytogenetic response. It is beneficial if the AP CML and BP CML patients show molecular responses as well.

For the purpose of the present invention, the hematological response assessment was performed on the 1st, 2nd, 3rd, 8th day and every 8th day thereafter, wherein the 1st day is the day when the subject had 1st dose of the compound of Formula I or a pharmaceutically acceptable salt thereof.

Bone marrow aspirates were utilized to determine cytogenetic response assessments. Aspirates were obtained after the completion of every 3 cycles (Example: After Cycle 3, the next aspirate was scheduled on completion of Cycle 6, and the next aspirate was scheduled on completion of Cycle 9, wherein each cycle consisted of 28 days of treatment. For patients who demonstrated complete cytogenetic response (CCyR) on 2 repeated assessments: Bone marrow aspirate samples were collected at 6 monthly intervals thereafter until disease progression, subject withdrawal of consent or discontinuation of the subject from the study.

Molecular response assessments were performed at the end of 3rd cycle and thereafter every 3 cycles (e.g., after Cycle 3, the next sample collection was scheduled on completion of Cycle 6), wherein each cycle consisted of 28 days of treatment. Samples were collected at the end of every 3 cycles until major molecular response (MMR) was achieved in two consequent assessments and repeated thereafter only in case there was a 10 times increase in the MMR until disease progression or subject withdrawal or consent or discontinuation of the subject from the study.

For subjects who had achieved CCyR and MMR in the study on 2 repeated assessments: Bone marrow aspirate needs to be performed only when a 10-fold increase in BCR-ABL levels was detected. Additional bone marrow aspirations may be performed at unscheduled visits at Investigator’s discretion.

The skilled person in the art would appreciate that under circumstances, of bone marrow sample insufficiency, BCR-ABL FISH assay for identification of Ph + should be performed in lieu of conventional bone marrow cytogenetics and the percentage of cells with Ph+ Chromosome positivity should be reported. BCR-ABL FISH assay may also be performed for subjects with minimum residual disease.

The term ‘hematologic response’ (HR) or ‘hematological response’ is a normalization of the blood counts, particularly WBC counts due to the treatment using a compound of Formula I or a pharmaceutically acceptable salt thereof. This is the first noticeable indicator that treatment is beginning to work, though not necessarily in the bone marrow.

The response can be a partial hematological response (PHR) wherein there is a reduction in WBC, but not down to normal range or complete hematological response (CHR) with all the blood counts normalized. A CHR is usually anticipated within a month of treatment, however, some subjects may take even up to 2 months to achieve this level. It was surprisingly observed that the patients that had undergone several previous treatments using other known TKIs and had stopped responding to such prior treatments, could easily achieve CHR on or before the 2-month mark with treatment using a compound of Formula I or a pharmaceutically acceptable salt thereof. Major haematologic response (MaHR) is inclusive of complete hematological response (CHR) and/or no evidence of leukemia (NEL). For the purpose of the present invention, the criteria of hematologic response are given in Table 01.

Table 01 : Hematological response criteria:

The term ‘cytogenetic response’ as used herein 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 just in the blood. It is a Philadelphia-positive (Ph+) chromosome reading obtained after administration of the compound of Formula I or a pharmaceutically acceptable salt thereof interpreted as described below:

There are 3 levels of cytogenetic response:

a) Partial Cytogenetic Response (PCyR): This indicates that only 1 to 35% of the sample contains Ph+ metaphases;

b) Complete Cytogenetic Response (CCyR): This indicates no Ph+ cells can be measured by either conventional or fluorescence in situ hybridization cytogenetic testing (though the PCR test may still be positive); and

c) Major Cytogenetic Response (MCyR) is cytogenetic response inclusive of PCyR and CCyR.

For the purpose of the present invention, the cytogenetic response was determined using bone marrow aspirate evaluation by Giemsa staining method (karyotyping) or Fluorescence in situ hybridization, FISH assay. As understood by the skilled person for confirmation of cytogenetic response at least 20 metaphases are evaluated. If fewer metaphases are reported, absolute percentage values are reported. Also, the peripheral blood cells are not considered for bone marrow aspirate evaluation. Under limited bone marrow, aspirate availability precluding cytogenetic evaluation by Giemsa staining, a FISH assay for evaluation of Ph+ Cells is performed. A complete cytogenetic response (CCyR) is reported for FISH when No Ph+ cells are observed or fewer than 1 out of 200 nuclei are BCR/ABLl-positive.

Table 02: Cytogenetic Response Criteria:

Major Molecular Response (MMR): Molecular response is a response to the treatment that affects the number of BCR-ABL transcripts in blood cells of patients with CML or ALL. It is measured as the ratio of the reverse transcribed transcript of BCR-ABL to ABL. For major molecular response, the ratio is < 0.1% on the international scale (IS) (equivalent to 3 log reduction in the transcript). It may be determined by polymerase chain reaction (PCR) or any other molecular test as known to the skilled person.

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

For the purpose of the present invention, the molecular response was determined using PCR. The patient is said to have major molecular response when the amount of BCR-ABL protein in the blood is very low that is if BCR-ABL transcripts are 0.1% by quantitative PCR (International scale (IS)) or more than or equal to 3-log reduction on BCR-ABL mRNA from the standardized baseline if quantitative PCR (IS) is not available. If no BCR-ABL mRNA is detectable by quantitative PCR (IS) using an assay with a sensitivity of at least 4.5 logs below the standardized baseline, it is said to be complete molecular response.

298
We Claim:
1. A method for the treatment of a human patient with chronic myeloid leukemia (CML)
(such as a newly diagnosed chronic myeloid leukemia (CML) or a refractory chronic
myeloid leukemia (CML)), comprising administering to the patient a therapeutically
effective amount of compound of Formula I:
N
NH
O
NH
O
Cl
Formula I
or a pharmaceutically acceptable salt thereof,
wherein the chronic myeloid leukemia (CML) is chronic, accelerated, or blast phase
Philadelphia Chromosome Positive Chronic Myeloid Leukemia (Ph+ CML).
2. The method as claimed in claim 1, wherein the therapeutically effective amount of
compound of Formula I or its pharmaceutically salt is sufficient to achieve a mean
AUC0-24 ranging from 6226 ± 5827 ng*h/mL to 60373 ± 55659 ng*h/mL or a mean Cmax
ranging from 664 ± 450 ng/mL to 5054 ± 3051 ng/mL.
3. The method as claimed in claim 1, wherein the compound of Formula I or its
pharmaceutically salt is administered at an initial daily dose of 10 mg to 204 mg.
4. The method as claimed in any one of the preceding claims, wherein the initial daily dose
is escalated or de-escalated to achieve or maintain at least one of (a) complete
hematological response, (b) complete hematological response and partial cytogenetic
response, (c) complete hematological response and complete cytogenetic response, or
(d) complete hematological response, complete cytogenetic response, and major
molecular response.
5. The method as claimed in any one of the preceding claims, wherein the patient is
resistant or intolerant to at least one tyrosine kinase inhibitor.
6. The method as claimed in 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,
299
E255V, F317L, E255V, F359V, G250E, E255K, F359V, M351T, G250E, H369R,
H396R, and V359I.
7. The method as claimed in any one of the preceding claims, wherein the treatment is
withheld for a period of at least 7 days, when the patient exhibits a grade 1 or grade 2
non-hematological adverse event, and then reinitiated.
8. The method as claimed in any one of the preceding claims, wherein the treatment is
withheld for a period of up to 56 days (e.g., 14 days to 56 days, or 28 days to 56 days),
when the patient exhibits a grade 3 hematological or non-hematological adverse event
or grade 4 asymptomatic hematological adverse event, and then reinitiated.
9. The method as claimed in claim 8, wherein the treatment is discontinued when the
patient does not recover to a grade 1 adverse event or less after a withholding period of
56 days.
10. A method of treating a treatment-resistant human patient having chronic myeloid
leukemia (CML) comprising administering a therapeutically effective amount of a
compound of Formula I:
N
NH
O
NH
O
Cl
Formula I
or a pharmaceutically acceptable salt thereof to the patient, wherein
i. the method includes orally administering 174 to 200 mg of the compound of
Formula I daily, and
ii. the patient is resistant or intolerant to at least one tyrosine kinase inhibitor prior
to the administration of the compound of Formula I.
11. The method as claimed in claim 10, 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.
12. The method as claimed in any one of the preceding claims, wherein the compound of
Formula I is orally administered in the form of oral capsules.
300
13. The method as claimed in claim 12, wherein the capsules each contain 43.5 mg, 45 mg
or 50 mg of the compound of Formula I.
14. The method as claimed in claims 10-13, wherein upon the patient exhibiting a grade 1
or grade 2 non-hematological adverse event which was intolerable due to clinical
symptoms or interference with daily activities, the treatment is withheld for a period of
time and then reinitiated.
15. The method as claimed in claims 10-14, wherein upon the patient exhibiting a grade 3
hematological or non-hematological adverse event or grade 4 asymptomatic
hematological adverse event, the treatment is withheld for a period of time and then
reinitiated.
16. The method as claimed in any one of the preceding claims, wherein the method includes
orally administering one or more oral capsules daily, where (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 not requiring discontinuation or temporary withholding treatment, the
daily dosage is reduced by administering a fewer number of the same oral capsules daily.
17. The method as claimed in claim 16, wherein prior to a dose reduction, 4 oral capsules
are administered daily.
18. A method for the treatment of a human patient with chronic myeloid leukemia (CML)
(such as a newly diagnosed chronic myeloid leukemia (CML) or a refractory chronic
myeloid leukemia (CML)) comprising administering to the patient a therapeutically
effective amount of compound of Formula I:
N
NH
O
NH
O
Cl
Formula I
or a pharmaceutically acceptable salt thereof at an initial daily dose of 50 mg to 200 mg
(e.g. any one of the 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 hematologic and/or non-hematologic toxicity:
301
a) the initial daily dose is withheld for at least 7 days and resumed at the initial daily
dose of 50 mg to 200 mg (e.g. any one of the 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
b) the initial daily dose is withheld for less than 7 days and if the toxicity is resolved,
then the treatment is resumed at the initial daily dose of 50 mg to 200 mg (e.g. any
one of the 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
c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily
dose of 43.5 mg to 192 mg (e.g. any one of the 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 re-escalated daily
dose of 50 mg to 200 mg (e.g. any one of the 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 withheld for at least 7 days and resumed at a reduced daily
dose of 43.5 mg to 192 mg (e.g. any one of the 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, the reduced daily dose is further reduced to a subsequent reduced daily
dose of 43.5 mg to 180 mg (e.g. any one of the 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 and 180 mg) on
subsequent instances of recurrences of the toxicity;
and wherein, the reduced daily dose or the subsequent reduced daily dose is optionally
re-escalated to a re-escalated daily dose of 50 mg to 200 mg (e.g. any one of the dose
selected from 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180
mg, 192 mg, and 200 mg).
19. A method for the treatment of a human patient with chronic myeloid leukemia (CML)
(such as a newly diagnosed chronic myeloid leukemia (CML) or a refractory chronic
myeloid leukemia (CML)) comprising administering to the patient a therapeutically
effective amount of compound of Formula I:
302
N
NH
O
NH
O
Cl
Formula I
or a pharmaceutically acceptable salt thereof at an initial daily dose of 174 mg such that
when the patient develops hematologic and/or non-hematologic toxicity:
a) the initial daily dose is withheld for at least 7 days and resumed 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 is resolved,
then the treatment is resumed at the initial daily dose of 174 mg; or
c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily
dose of 43.5 mg to 135 mg (e.g. any one of the 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 87 mg;
and wherein, the reduced daily dose is optionally re-escalated to a re-escalated daily
dose up to 200 mg (e.g. any one of the 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), preferably the re-escalated daily dose is 200 mg; or
d) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily
dose of 43.5 mg to 135 mg (e.g. any one of the 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, the 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 of the dose selected from 43.5
mg, 45 mg, 48 mg, 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, and 130.5 mg) on subsequent
instances of recurrences of the toxicity, preferably the subsequent reduced daily dose is
87 mg;
and wherein, the reduced daily dose or the subsequent reduced daily dose is optionally
re-escalated to a re-escalated daily dose up to 200 mg (e.g. any one of the dose selected
303
from 50 mg, 66 mg, 87 mg, 90 mg, 126 mg, 130.5 mg, 135 mg, 174 mg, 180 mg, 192
mg, and 200 mg), preferably the re-escalated daily dose is 200 mg.
20. A method for the treatment of a human patient with chronic myeloid leukemia (CML)
(such as a newly diagnosed chronic myeloid leukemia (CML) or a refractory chronic
myeloid leukemia (CML)) comprising administering to the patient a therapeutically
effective amount of compound of Formula I:
N
NH
O
NH
O
Cl
Formula I
or a pharmaceutically acceptable salt thereof at an initial daily dose of 87 mg such that
when the patient develops hematologic and/or non-hematologic toxicity:
a) the initial daily dose is withheld for at least 7 days and resumed 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 is resolved,
then the treatment is resumed at the initial daily dose of 87 mg; or
c) the initial daily dose is withheld for at least 7 days and resumed at a reduced daily
dose of 43.5 mg or 50 mg, preferably the reduced daily dose is 43.5 mg;
and wherein, the reduced daily dose is optionally re-escalated to a re-escalated daily
dose up to 200 mg (e.g. any one of the 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), preferably the re-escalated daily dose is 174 mg.
21. The method as claimed in claims 18-20, wherein the patient is resistant or intolerant to
at least one tyrosine kinase inhibitor.
22. The method as claimed in claims 18-21, 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.
304
23. The method as claimed in claims 18-22, wherein the chronic myeloid leukemia (CML)
is chronic, accelerated, or blast phase Philadelphia Chromosome Positive Chronic
Myeloid Leukemia (Ph+ CML).