Treatment methods for myeloproliferative disorders

Abstract

The present disclosure provides methods for alleviating thiamine deficiency. [Selection diagram] None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Application No. 62 / 736,369, filed on September 25, 2018, and U.S. Provisional Application No. 62 / 783,076, filed on December 20, 2018, the entireties of which are hereby incorporated by reference herein.

[0002] The present invention provides a method for treating, stabilizing, or reducing the severity or progression of myeloproliferative diseases.

Background Art

[0003] The search for new therapeutic agents has been greatly accelerated in recent years by the increasing understanding of the structures of enzymes and other biomolecules related to diseases. One important class of enzymes that has been the subject of extensive research is protein kinases.

[0004] Protein kinases constitute a large family of structurally related enzymes that are responsible for controlling various signal transduction processes within cells. Protein kinases are thought to have evolved from a common ancestral gene because their structures and catalytic functions are conserved. Almost all kinases have similar 250 - 300 amino acid catalytic domains. Kinases can be classified into several families based on the substrates they phosphorylate (e.g., protein tyrosine, protein serine / threonine, lipids, etc.).

[0005] Generally, protein kinases mediate intracellular signaling by inducing phosphoryl transfer from nucleoside triphosphates to protein acceptors involved in signaling pathways. These phosphorylation events act as molecular on / off switches capable of regulating or controlling the biological function of target proteins. These phosphorylation events are ultimately triggered in response to various extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet irradiation, bacterial endotoxins, and H2O2), cytokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α)), and growth factors (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell proliferation, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis regulation, and cell cycle regulation.

[0006] Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events, as described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related disorders. Therefore, the discovery of useful protein kinase inhibitors as therapeutic agents remains crucial. [Overview of the Initiative]

[0007] This disclosure provides methods for treating, stabilizing, or reducing the severity or progression of one or more myeloproliferative disorders. In certain embodiments, the methods provided include mitigating one or more adverse events associated with the treatment of myeloproliferative disorders. In some such embodiments, one or more adverse events are thiamine deficiency.

[0008] Depending on the aspect, this disclosure provides a method for treating, stabilizing, or reducing the severity or progression of one or more myeloproliferative disorders, wherein the method involves administering a compound of formula I to the patient: [ka] Alternatively, the method includes administering a pharmaceutically acceptable composition comprising a pharmaceutically acceptable salt or hydrate thereof. The compound of formula I is also referred to herein as "compound I." In some embodiments, compound I is in the dihydrochloride form. Compound I or a pharmaceutically acceptable salt thereof may also exist in hydrate form. In some such embodiments, compound I is in the dihydrochloride monohydrate form. Therefore, in some embodiments, the method provided includes administering compound II to a patient requiring compound II: [ka]

[0009] Depending on the embodiment, this disclosure provides a treatment for myeloproliferative disorders, and the method is as follows: (i) administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) to patients in need of treatment, (ii) Monitor the patient's thiamine levels, If thiamine levels are lower than the normal range, adjust the patient's thiamine levels. Includes.

[0010] In some embodiments, the patient's thiamine level is adjusted if it is approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more below the reference value. In some embodiments, the reference value is the patient's baseline thiamine level before administration of compound I. In some embodiments, the reference value is a thiamine level of approximately 74 nM / L to approximately 222 nM / L in whole blood.

[0011] Depending on the embodiment, patients may be at risk of developing Wernicke encephalopathy.

[0012] In some embodiments, a patient's thiamine levels are assessed by analyzing one or more biomarkers related to thiamine deficiency. In some embodiments, the biomarker related to thiamine deficiency is serum thiamine level.

[0013] In some embodiments, the patient's thiamine levels are adjusted by administering thiamine or a thiamine equivalent to the patient.

[0014] Depending on the embodiment, this disclosure provides a treatment for a patient that includes: (i) Administering the patient compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II), (ii) Analyze the patient's thiamine levels, and (iii) If the patient's thiamine level is lower than approximately 74 nM / L to approximately 222 nM / L of whole blood, but higher than approximately 30 nM / L of whole blood, administer thiamine or a thiamine equivalent to the patient.

[0015] In some embodiments, the patient is administered 100 mg of thiamine per day. In other embodiments, the patient is administered a thiamine equivalent sufficient to deliver approximately 100 mg of thiamine per day. In some of such embodiments, thiamine or a thiamine equivalent is administered orally.

[0016] Depending on the embodiment, this disclosure provides a treatment for a patient that includes: (i) Administering the patient compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II), (ii) Analyze the patient's thiamine levels, and (iii) If the patient's thiamine level is less than approximately 30 nM / L of whole blood, administer thiamine or a thiamine equivalent to the patient.

[0017] In some embodiments, thiamine or a thiamine equivalent is administered intravenously. In some embodiments, thiamine is administered to the patient in an amount of about 250 mg. In some embodiments, thiamine is administered to the patient in an amount of about 250 mg per day (QD). In some embodiments, the patient is administered a thiamine equivalent sufficient to deliver about 250 mg of thiamine per day.

[0018] In some embodiments, thiamine is administered to the patient in an amount of about 500 mg. In some embodiments, thiamine is administered to the patient in an amount of about 500 mg per day (QD). In some embodiments, the patient is administered a thiamine equivalent sufficient to deliver about 500 mg of thiamine QD. In some embodiments, thiamine is administered to the patient in an amount of about 500 mg three times a day (TID). In some embodiments, the patient is administered a thiamine equivalent sufficient to deliver about 500 mg of thiamine TID.

[0019] In some embodiments, thiamine is administered to the patient in an amount of about 500 mg TID for 2 or 3 days, followed by thiamine administration in an amount of about 250 mg to about 500 mg per day (QD) for 3 to 5 days, and then thiamine administration in an amount of about 100 mg QD for 90 days.

[0020] In some embodiments, the provided method further includes increasing the patient's magnesium level.

[0021] In some embodiments, the patient has a myeloproliferative disorder. In some such embodiments, the myeloproliferative disorder is myelofibrosis. In some embodiments, the myelofibrosis is primary myelofibrosis. In some embodiments, the primary myelofibrosis is intermediate- or high-risk primary myelofibrosis according to the Dynamic International Prognostic Scoring System (DIPSS). In some embodiments, the myelofibrosis is secondary myelofibrosis. In some embodiments, the myelofibrosis is post-essential thrombocythemia myelofibrosis. In some embodiments, the myelofibrosis is post-polycythemia vera myelofibrosis. In some embodiments, the myeloproliferative disorder is polycythemia vera. In some embodiments, the myeloproliferative disorder is essential thrombocythemia. In some embodiments, the myeloproliferative disorder is acute myeloid leukemia (AML).

[0022] In some embodiments, the present disclosure provides a method of treating a patient comprising: (i) administering Compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., Compound II), and (ii) performing a cognitive function assessment.

[0023] In some embodiments, the cognitive function assessment is performed during the second 28-day cycle. In some embodiments, the cognitive function assessment is performed during the third 28-day cycle. In some embodiments, the cognitive function assessment is performed during the third cycle each time at least three 28-day cycles are performed. In some embodiments, the cognitive function assessment includes a Mini-Mental State Examination. In some embodiments, the method further comprises analyzing the thiamine level of the patient.

[0024] Definitions When used herein, the term "about" refers to a measurable value such as a parameter, quantity, or length of time, and means that it includes a variation of no more than + / - 10%, preferably no more than + / - 5%, more preferably no more than + / - 1%, and even more preferably no more than + / - 0.1% from a given value, provided that such variation is reasonable in the inventions of this disclosure. For example, when the term "about" is used in conjunction with a specific number of days, it includes that specific number of days plus or minus one day, so for example, "about 6 days" includes any number of days between 5 and 7. Naturally, the value indicated by the modifier "about" is itself specific and preferably disclosed.

[0025] The term “biomarker” is used herein to describe entities, events, or characteristics whose presence, level, degree, type, and / or form correlate with a particular biological event or condition of interest, and are therefore considered to be a “marker” of that event or condition. To give a few examples, in some embodiments, a biomarker may be, or include, a marker of a particular disease condition, or a marker of the likelihood of a particular disease, disorder, or symptom developing, occurring, or recurring. In some embodiments, a biomarker may be, or include, a marker of a particular disease or treatment outcome, or the likelihood thereof. Thus, in some embodiments, a biomarker may be a predictive marker, in some embodiments, a prognostic marker, and in some embodiments, a diagnostic marker of the relevant biological event or condition of interest. A biomarker may be, or include, entities of any class of chemical substances, or a combination of entities. For example, in some embodiments, a biomarker may be, or include, nucleic acids, polypeptides, lipids, carbohydrates, small molecules, inorganic activators (e.g., metals or ions), or combinations thereof. In some embodiments, the biomarker is a cell surface marker. In some embodiments, the biomarker is an intracellular marker. In some embodiments, the biomarker is detected extracellularly (for example, the marker is secreted, otherwise produced, or present extracellularly, e.g., in bodily fluids such as blood, urine, tears, saliva, or cerebrospinal fluid). In some embodiments, the biomarker may be or include a gene signature or epigenetic signature. In some embodiments, the biomarker may be or include a gene expression signature.

[0026] As used herein, the term “combination therapy” refers to a situation in which a subject is administered two or more treatment regimens simultaneously (e.g., two or more therapeutic agents containing one or more of the compounds as described herein). The two or more regimens may be administered simultaneously or sequentially (e.g., all doses of the first regimen are administered before any dose of the second regimen is administered). In other embodiments, the compound is administered in a duplicate dosing regimen. “Administration” of combination therapy may involve administering one or more compounds to a subject receiving combination therapy with other compounds(s). For clarity, combination therapy may, depending on the embodiment, involve two or more compounds being administered together in a combination composition, or even as part of a combined compound (e.g., a single chemical complex or as part of a conjugated entity), but it is not necessary for the individual compounds to be administered together in a single composition (or even not simultaneously or via the same route of administration).

[0027] The term "thiamine equivalent" refers to an agent that delivers, or can deliver, a biological equivalent of thiamine. Examples of such thiamine equivalents include thiamine prodrugs, as well as thiamine derivatives, such as thiamine monophosphate, thiamine pyrophosphate (also known as thiamine diphosphate), and thiamine triphosphate. In some embodiments, the thiamine equivalent may be thiamine in food form, such as that found in vegetables or other food sources.

[0028] The terms “treat” or “treating,” as used herein, mean to partially or completely reduce, inhibit, delay the onset, prevent, induce remission, and / or alleviate a disorder or symptom, or one or more symptoms of a disorder or symptom. As used herein, the terms “treatment,” “treat,” and “treating,” as described herein, mean to partially or completely reduce, inhibit, delay the onset, prevent, induce remission, and / or alleviate a disorder or symptom, or one or more symptoms of a disorder or symptom. In some embodiments, treatment may be administered after the onset of one or more symptoms. In some embodiments, the term “treating” includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to an individual suspected of having a disorder before the onset of symptoms (e.g., in light of symptom history and / or genetic or other factors). Treatment may continue after symptoms have subsided, for example, to prevent or delay recurrence. Therefore, depending on the embodiment, the term “treating” may include preventing relapse or recurrence of the disease or disorder.

[0029] Where used herein, the term “unit dosage form” refers to a physically discrete unit of the present invention’s formulation that is appropriate for the subject being treated. However, naturally, the total daily dose of the present invention’s composition will be determined by the attending physician within the bounds of reasonable medical judgment. The specific effective dose level for a particular subject or organism, whatever it may be, will depend on a variety of factors, such as the disorder being treated and its severity; the activity of the specific activator used; the specific composition used; the subject’s age, weight, overall health, sex, and diet; the timing and elimination rate of the specific activator used; the duration of treatment; any drugs and / or additional therapies used in combination with or concurrently with the specific compound(s) used; and similar factors well known in the pharmaceutical field. [Modes for carrying out the invention]

[0030] Detailed description of specific embodiments Myelofibrosis Myeloproliferative neoplasms (MPNs)-associated myelofibrosis (MF) is a serious and life-threatening disease that may exist as de novo or primary myelofibrosis (PMF), or develop from previous polycythemia vera (PV) or essential thrombocythemia (ET) (Swerdlow SH, Campo E, Harris NL, Jafie ES, Pileri SA, Stein H, et al. World Health Organization classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press 2008). This disease is characterized by clonal myeloproliferation, ineffective erythropoiesis, bone marrow stromal changes, extramedullary hematopoiesis, and ectopic cytokine expression (Tefferi A, Pardanani A. JAK inhibitors in myeloproliferative neoplasms: rationale, current data and perspective. Blood Rev. 2011 Sep;25(5):229-37). Patients typically present with splenomegaly, systemic symptoms, moderate to severe anemia, thrombocytopenia, and leukocytosis.

[0031] Primary myelofibrosis (PMF) is a member of the Philadelphia chromosome (Ph1)-negative MPN group, which also includes PV and ET (Tefferi A. The recent advances in classic BCR-ABL-negative myeloproliferative disorders. Clin. Adv. Hematol. Oncol. 2007a;5:113-5). Nearly all PV patients and about half of ET and PMF patients have a JAK2 mutation, typically JAK2V617F. Other mutations in PMF patients include CALR and MPL. Approximately 20% of PMF patients do not have detectable mutations in JAK2, CALR, and MPL, and are referred to as triple-negative (Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-97; Werning G, Mercher T, Okabe R, Levine L, Lee BH, Gilliland GL. Expression of JAK2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood. 2006;107:4274-81). Mutations in JAK2, CALR, and MPL lead to activation of the JAK / STAT signaling pathway, resulting in cell proliferation and inhibition of cell death.The result is clonal proliferation (Ilhe JN, Gilliland DG. JAK2: normal function and role in hematopoietic disorders. Curr. Opin. Genet. Dev. 2007;17:8-14). In other words, JAK2 inhibitors that can downregulate the JAK / STAT pathway are expected to help reduce cell proliferation.

[0032] Polycythemia vera (PV) and essential thrombocythemia (ET) are characterized by elevated levels of red blood cells (RBCs) and platelets. However, approximately 10% of affected patients develop myelofibrosis that is morphologically distinguishable from PMF. These conditions are called post-PV MF and post-ET MF (Campbell PJ, Green AR. Management of polycythemia vera and essential thrombocythemia. Hematology Am. Soc. Hematol. Educ. Program. 2005;201-8), and are clinically known as MPN-associated myelofibrosis. Patients with MPN-associated myelofibrosis have a similar survival prognosis to those with PMF, and have approximately a 10% cumulative risk of developing acute myeloid leukemia (AML).

[0033] Several prognostic scoring systems exist to predict the survival time of patients with PMF (Progressive Morphology Factor). The International Prognostic Scoring System (IPSS) is used to predict survival at diagnosis, while the Dynamic International Prognostic Scoring System (DIPSS) is used at any point in the disease progression (Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;Mar 26;113(13):2895-901; Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010 Mar). 4;115(9):1703-8). Variable elements included in IPSS are age over 65 years, systemic symptoms, hemoglobin level less than 10 g / dL, and white blood cell (WBC) count. More recent prognostic scoring systems include the Dynamic International Prognostic Scoring System Plus (DIPSS Plus) and scoring systems that incorporate data from mutation analysis.A strong association exists between overall survival and DIPSS risk classification in MF patients, with median survival times of 15.4, 6.5, 2.9, and 1.3 years for low-risk, intermediate-risk 1, intermediate-risk 2, and high-risk patients, respectively (Tefferi A. Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 2016 Dec;91(12):1262-1271).

[0034] Approximately 70% of individuals with myelofibrosis (MF) fall into the intermediate-risk 2 or high-risk category (Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J. Clin. Oncol. 2011 Feb 1;29(4):392-7), representing the greatest unmet medical need. Symptomatic enlargement of the spleen and liver, the need for RBC transfusions, cachexia, and other MF-related symptoms significantly impair the quality of life for these patients ((Mesa RA, Camoriano JK, Geyer SM, Wu W, Kaufmann SH, Rivera CE, et al. A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia. Leukemia. 2007 Sep;21(9):1964-70).

[0035] Compound I The synthesis of compound I is disclosed in Example 90 of U.S. Patent No. 7,528,143, issued on May 5, 2009, which is incorporated herein by reference in its entirety. Compound I, also known as phedratinib, is a potent and selective inhibitor of JAK2 kinase activity, which inhibits JAK2 signaling, mutant JAK2, or mutant MPL-driven cell proliferation in cell assays and induces apoptosis in cells expressing constitutively active JAK2. Compound I also inhibits erythroblast colonization in hematopoietic progenitor cells isolated from myeloproliferative neoplasm (MPN) patients.

[0036] Myelofibrosis (MF) is a clonal disease caused by mutations that promote abnormal proliferation and myelodifferentiation in CD34+ hematopoietic stem cells (Mead AJ, 2017). In addition to JAK2V617F, several other mutations in JAK2 and other genes are found in MF patients, and these have been associated with prognosis, AML progression, and response to the JAK inhibitor ruxolitinib (Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017 Feb 9;129(6):667-679, Tefferi A, Guglielmelli P, Nicolosi M, Mannelli F, et al. GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia. 2018 Mar 23; Spiegel JY, McNamara C, Kennedy JA, Panzarella T, et al. Impact of genomic alterations on outcomes in myelofibrosis patients undergoing JAK1 / 2 inhibitor therapy. Blood. 2017 Sep 8;1(20):1729-1738;Newberry KJ, Patel K, Masarova L, Luthra R, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017 Aug 31;130(9):1125-1131;Patel KP, Newberry KJ, Luthra R, Jabbour E, et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib.Blood. 2015 Aug 6;126(6):790-7;Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-97;Werning G, Mercher T, Okabe R, Levine L, Lee BH, Gilliland GL. Expression of JAK2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood. 2006;107:4274-81;Mercher T, Wernig G, Moore SA, Levine RL, Gu TL, Frohling S, Cullen D, Polakiewicz RD, Bernard OA, Boggon TJ, Lee BH, Gilliland DG. JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model. Blood. 2006 Oct 15;108(8):2770-9;Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N. Engl. J. Med.2007 Feb 1;356(5):459-68;Pardanani A, Tefferi A, Jamieson C, Gabrail NY, et al. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J. 2015 Aug 7;5:e335)。.

[0037] Phosphorylated STAT3 (pSTAT3) is a downstream effector of activated JAK2. Tracking pSTAT3 levels in circulating cells has demonstrated it to be a useful pharmacodynamic (PD) biomarker of fedratinib JAK2 engagement in MF patients (Pardanani A, Tefferi A, Jamieson C, Gabrail NY, et al. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J. 2015 Aug 7;5:e335). Preclinical data have shown that fedratinib can also inhibit pSTAT5, and it has been reported that the response to fedratinib can be predicted from the baseline level of pSTAT5 in AML cells in an AML xenograft model (Chen WC, Yuan JS, Xing Y, Mitchell A, Mbong N, et al. An Integrated Analysis of Heterogeneous Drug Responses in Acute Myeloid Leukemia That Enables the Discovery of Predictive Biomarkers. Cancer Res. 2016 Mar 1;76(5):1214-24).Abnormal cytokine expression and myelofibrosis are unmistakable characteristics of MF (Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017 Feb 9;129(6):667-679; Mondet J, Hussein K, Mossuz P. Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest. Mediators Inflamm. 2015;2015:670580). High levels of pro-inflammatory and fibrinolytic cytokines have been reported to contribute to bone marrow (BM) stromal changes, ineffective erythropoiesis / extramedullary hematopoiesis, and systemic symptoms in MF (Mondet J, Hussein K, Mossuz P. Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest. Mediators Inflamm. 2015;2015:670580; Tefferi A, Pardanani A. JAK inhibitors in myeloproliferative neoplasms: rationale, current data and perspective. Blood Rev. 2011 Sep;25(5):229-37).Fedratinib was found to modulate circulating cytokines in MF patients who had not previously received treatment with a JAK inhibitor (Pardanani A, Tefferi A, Jamieson C, Gabrail NY, et al. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J. 2015 Aug 7;5:e335). Cytokine modulation correlated with improvements in persistent viral response (SVR) and systemic symptoms in these patients (Pardanani A, Tefferi A, Jamieson C, Gabrail NY, et al. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J. 2015 Aug 7;5:e335).

[0038] Recent research is beginning to reveal the immunomodulatory roles of JAK2V617F, as well as JAK inhibitors such as ruxolitinib. For example, JAK2V617F has been found to contribute to immune evasion in MPN myeloid cells by upregulating programmed cell death ligand 1 (PD-L1) (Prestipino A, Emhardt AJ, Aumann K, O'Sullivan D, et. al. Oncogenic JAK2V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci. Transl. Med. 2018 Feb 21;10(429)), and ruxolitinib has been reported to regulate PD-L1 expression in these cells (Prestipino A, Emhardt AJ, Aumann K, O'Sullivan D, et. al. Oncogenic JAK2V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci. Transl. Med. 2018 Feb 21;10(429)).However, preclinical and clinical data indicate that ruxolitinib is also a potent immunosuppressant and can suppress graft-versus-host disease (GVHD), reduce the frequency of T and NK cell appearance, and inhibit their activation in MF patients (Betts BC, Bastian D, Iamsawat S, Nguyen H, et al. Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation. Proc Natl Acad Sci US A. 2018 Feb 13;115(7):1582-1587. Epub 2018;Schonberg K, Rudolph J, Vonnahme M, Parampalli et al. Cancer JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms. Res. 2015 Jun 1;75(11):2187-99;Parampalli Yajnanarayana S, Stubig T, Cornez I, Alchalby H, et al. JAK1 / 2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms. Br. J. Haematol. 2015 Jun;169(6):824-33).Preclinical data suggest that fedratinib can regulate PD-L1 expression in lymphoma tumor cells (Hao Y, Chapuy B, Monti S, Sun HH, Rodig SJ, Shipp MA. Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo. Clin. Cancer Res. 2014 May 15;20(10):2674-83). However, fedratinib is not a potent inhibitor of GVHD, nor does it inhibit human T cell development in a xenograft mouse model (Betts BC, Veerapathran A, Pidala J, Yang H, et al. Targeting Aurora kinase A and JAK2 prevents GVHD while maintaining Treg and antitumor CTL function. Sci Transl Med. 2017 Jan 11;9(372)). The selective activity of fedratinib against JAK2 increases the likelihood that fedratinib exerts immunomodulatory effects in MF patients without impairing T cell or NK cell function.

[0039] In some embodiments, the Disclosure provides a method for preventing and / or mitigating thiamine deficiency in a patient administered compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II). In some embodiments, the Disclosure provides a treatment method for a patient, which includes administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) and monitoring the patient's thiamine levels.

[0040] Depending on the embodiment, this disclosure provides a treatment for myeloproliferative disorders, the method including the following: (i) administering JAK1 and / or JAK2 inhibitors to patients in need of treatment, (ii) Monitor the patient's thiamine levels.

[0041] In some such embodiments, the method further includes adjusting the patient's thiamine level if it is below a reference value (e.g., baseline level). In some embodiments, the JAK1 and / or JAK2 inhibitor is compound I or a pharmaceutically acceptable salt thereof (e.g., compound II).

[0042] Therefore, depending on the embodiment, this disclosure provides a treatment for myeloproliferative disorders, and the method is as follows: (i) administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) to patients in need of treatment, (ii) Monitor the patient's thiamine levels. If thiamine levels are lower than the normal range, adjust the patient's thiamine levels. Includes.

[0043] In some embodiments, a patient's thiamine levels are assessed by analyzing one or more biomarkers for thiamine deficiency. In some embodiments, the biomarker for thiamine deficiency is serum thiamine level.

[0044] In some embodiments, the level of the biomarker is compared to a reference value. In some embodiments, the reference value is the baseline level of the biomarker (e.g., the biomarker level before administration of compound I or compound II). In some embodiments, the reference value is a biomarker level considered to be within the range typically observed in a healthy population (e.g., a population not suffering from the target disease or disorder). In some embodiments, the reference value is a biomarker level considered to be within the range typically observed in a population diagnosed with the target disease or disorder.

[0045] In some embodiments, the biomarker level after administration of compound I or compound II is lower than the reference value (for example, lower than the baseline level of the biomarker).

[0046] In some embodiments, the patient's thiamine level is adjusted if it is approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more below the reference value. In some embodiments, the reference value is the baseline thiamine level of the patient before administration of compound I or compound II. In some embodiments, the reference value is a thiamine level of approximately 74 nM / L to approximately 222 nM / L in whole blood.

[0047] Depending on the embodiment, patients may be at risk of developing Wernicke encephalopathy.

[0048] In some embodiments, the patient's thiamine levels are adjusted by administering thiamine or a thiamine equivalent to the patient.

[0049] Depending on the embodiment, this disclosure provides a treatment for a patient that includes: (i) Administering the patient compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II), (ii) Analyze the patient's thiamine levels, and (iii) If the patient's thiamine level is less than approximately 30 nM / L of whole blood, administer thiamine or a thiamine equivalent to the patient.

[0050] Depending on the embodiment, the present disclosure provides a method for mitigating thiamine deficiency, which comprises administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) to a patient at risk of developing thiamine deficiency, in which case the patient is also simultaneously exposed to thiamine or a thiamine equivalent.

[0051] In some of these embodiments, the patient is administered approximately 100 mg of thiamine per day. In other embodiments, the patient is administered a thiamine equivalent sufficient to deliver approximately 100 mg of thiamine per day. In other embodiments, thiamine or a thiamine equivalent is administered orally.

[0052] In some embodiments, the patient is administered a thiamine equivalent that delivers approximately 100 mg of thiamine per day.

[0053] Depending on the embodiment, the present disclosure provides a combination therapy comprising (i) compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II), and (ii) thiamine or a thiamine equivalent.

[0054] In some embodiments, this disclosure provides a treatment for myelofibrosis, the method comprising administering to a patient in need of treatment a combination therapy comprising compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) and thiamine or a thiamine equivalent. In some such embodiments, thiamine is administered in a dose of about 100 mg (QD) per day. In some embodiments, the patient is administered a thiamine equivalent sufficient to deliver about 100 mg of thiamine per day. In some embodiments, thiamine or a thiamine equivalent is administered orally.

[0055] In some of these embodiments, thiamine is administered in a dose of approximately 500 mg TID. In some of these embodiments, the patient is administered thiamine in doses of approximately 250 mg or approximately 500 mg QD. In some embodiments, the patient is administered a thiamine equivalent sufficient to deliver approximately 250 mg or approximately 500 mg (QD) of thiamine per day. In some embodiments, approximately 250 mg or approximately 500 mg of thiamine is administered orally. In some embodiments, the thiamine equivalent is administered orally.

[0056] In some embodiments, the thiamine equivalent is thiamine pyrophosphate ester.

[0057] In some embodiments, the method provided further includes increasing the patient's magnesium levels. In some embodiments, the patient's magnesium levels are increased by administering a magnesium supplement.

[0058] In some embodiments, the patient suffers from a myeloproliferative disorder.

[0059] In some embodiments, the myeloproliferative disorder is myelofibrosis. In some embodiments, myelofibrosis is primary myelofibrosis. In some embodiments, myelofibrosis is secondary myelofibrosis. In some embodiments, myelofibrosis is post-essential thrombocythemia myelofibrosis. In some embodiments, myelofibrosis is post-polycythemia myelofibrosis.

[0060] In some embodiments, the myeloproliferative disorder is polycythemia vera. In some embodiments, the myeloproliferative disorder is essential thrombocythemia. In some embodiments, the myeloproliferative disorder is acute myeloid leukemia.

[0061] In some embodiments, compound I is administered in the form of a dihydrochloride monohydrate (e.g., compound II).

[0062] In some embodiments, compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) is administered to the patient in unit dosage forms. In some embodiments, the unit dosage form of compound I or compound II is based on the free base weight of the compound. For example, a 100 mg dose of compound I in its free base form is equal to about 117.30 mg of compound I when it is in its dihydrochloride monohydrate form (i.e., compound II). In some embodiments, the unit dosage form of compound I or compound II is about 50 mg, about 100 mg, about 150 mg, or about 200 mg, based on the free base weight of the compound. In some embodiments, the unit dosage form of compound I or compound II is 100 mg, based on the free base weight of the mixture.

[0063] In some embodiments, compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) is administered in oral dosage form. In some such embodiments, the oral dosage form is a capsule. In other embodiments, the oral dosage form is a tablet.

[0064] Depending on the embodiment, compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) is administered once daily (QD). Depending on the embodiment, compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) is administered in a total daily dose of approximately 200 mg, approximately 300 mg, or approximately 400 mg. Depending on the embodiment, compound I or compound II is administered to the patient in a total daily dose of approximately 400 mg. Depending on the embodiment, compound I or compound II is administered to the patient in a total daily dose of approximately 300 mg. Depending on the embodiment, compound I or compound II is administered to the patient in a total daily dose of approximately 200 mg. Depending on the embodiment, the total daily dose of compound I or compound II is adjusted due to adverse events. Depending on the embodiment, the total daily dose of compound I or compound II is reduced. Depending on the embodiment, the total daily dose of compound I or compound II is reduced from approximately 400 mg to approximately 300 mg. Depending on the embodiment, the total daily dose of compound I or compound II may be reduced to approximately 200 mg.

[0065] Depending on the embodiment, compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) is administered once daily during one 28-day cycle. Depending on the embodiment, compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) is administered once daily during two 28-day cycles. Depending on the embodiment, compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) is administered once daily during three, four, five, or more 28-day cycles. Depending on the embodiment, compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) is administered once daily during six, seven, eight, nine, ten, eleven, twelve, or more 28-day cycles. In some embodiments, compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) is administered once daily until the symptoms of the disease are no longer measurable. In some embodiments, compound I or compound II is administered for the lifetime of the patient. In some embodiments, compound I or compound II is administered once daily during one or more 28-day cycles, followed by a drug-free day. "Drug-free day," as used herein, refers to a period of time during which compound I or compound II is not administered to the patient. In some embodiments, the drug-free day is one day, one week, or one 28-day cycle. In some embodiments, compound I or compound II is administered once daily during one or more 28-day cycles, followed by a drug-free day, after which once-daily administration of compound I or compound II is resumed at the same dose level as before the drug-free day. In some embodiments, compound I or compound II is administered once daily during one or more 28-day cycles, followed by a rest day, after which once-daily administration of compound I or compound II is resumed at a dose level 100 mg lower than the dose level of compound I or compound II prior to the rest day. In some embodiments, the total daily dose of compound I or compound II is increased by 100 mg after the preceding dose reduction.

[0066] In some embodiments, the provided method involves administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) once daily for two or more 28-day cycles. In some such embodiments, the patient's thiamine levels are assessed at the beginning of the second 28-day cycle.

[0067] In some embodiments, the method provided involves administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) to a patient once daily for two or more 28-day cycles, with the patient's thiamine level being assessed at the beginning of each 28-day cycle. In some embodiments, the method provided involves administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) to a patient once daily for two or more 28-day cycles, with the patient's thiamine level being assessed at the end of each 28-day cycle. In some embodiments, the method provided involves administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) to a patient once daily for two or more 28-day cycles, with the patient's thiamine level being assessed at the beginning of the second 28-day cycle and at the beginning of the third 28-day cycle. In some such embodiments, the patient's thiamine level is subsequently assessed at the beginning of each subsequent three 28-day cycles. For example, if a patient is treated for 12 28-day cycles, thiamine levels are assessed on day 1 (±3 days) of each of the 2nd, 3rd, 6th, 9th, and 12th cycles. In some embodiments, the provided method involves administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) once daily to a patient for six or more 28-day cycles, and the patient's thiamine levels are assessed at the beginning of each of the 1st, 2nd, 3rd, 4th, 5th, and 6th cycles.

[0068] In some embodiments, the provided method involves administering thiamine or a thiamine equivalent to a patient when the patient's thiamine level is lower than normal (e.g., 74–222 nM / L in whole blood) but greater than or equal to 30 nM / L in whole blood. In some such embodiments, thiamine or a thiamine equivalent is administered orally. In some embodiments, thiamine is administered to the patient in a dose of approximately 100 mg per day. In some embodiments, the patient is administered a thiamine equivalent sufficient to deliver approximately 100 mg of thiamine per day.

[0069] In some embodiments, the provided method involves administering thiamine or a thiamine equivalent when a patient's thiamine level is 30 nM / L or less in whole blood. In some such embodiments, thiamine is administered to the patient according to the following schedule: (i) Approximately 500 mg (TID) three times a day for 2 or 3 days. (ii) For 3 to 5 days, approximately 250 mg to approximately 500 mg (QD) daily, and (iii) Approximately 100 mg (QD) daily for at least 90 days.

[0070] In some embodiments, patients with thiamine levels below 30 nM / L in whole blood are administered a thiamine equivalent sufficient to deliver a certain amount of thiamine according to the following schedule: (i) Approximately 500 mg (TID) three times a day for 2 or 3 days. (ii) For 3 to 5 days, approximately 250 mg to approximately 500 mg (QD) daily, and (iii) Approximately 100 mg (QD) daily for at least 90 days.

[0071] Depending on the embodiment, thiamine or a thiamine equivalent may be administered intravenously.

[0072] In some embodiments, the method provided further includes monitoring the patient's magnesium levels. In some such embodiments, the method provided includes increasing the patient's magnesium levels.

[0073] In some embodiments, the patient has a myeloproliferative disorder or condition. In some embodiments, the myeloproliferative disorder or condition is selected from primary myelofibrosis, secondary myelofibrosis, polycythemia vera, essential thrombocythemia, post-polycythemia vera, and post-essential thrombocythemia. In some embodiments, the myeloproliferative disorder is acute myeloid leukemia (AML). In some embodiments, the primary myelofibrosis is intermediate-risk or high-risk primary myelofibrosis according to the Dynamic International Prognostic Scoring System (DIPSS). In some embodiments, the method includes administering a composition according to the present invention to a patient in need of treatment.

[0074] Depending on the embodiment, this disclosure provides a treatment for a patient that includes: (i) administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II), (ii) Conduct a cognitive function assessment.

[0075] In some embodiments, cognitive function assessment is performed during the second 28-day cycle. In some embodiments, cognitive function assessment is performed during the third 28-day cycle. In some embodiments, cognitive function assessment is performed during the third cycle for every three 28-day cycles performed. In some embodiments, cognitive function assessment includes a Mini-Mental State Examination. In some embodiments, the method further includes analyzing the patient's thiamine levels. [Examples]

[0076] Summary of the study protocol: A multicenter, single-arm, open-label efficacy and safety study of fedratinib in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PV-MF), or post-essential thrombocythemia myelofibrosis (ET-MF) who have previously received ruxolitinib treatment and are classified as intermediate-risk or high-risk according to the DIPSS (Dynamic International Prognostic Scoring System).

[0077] Objective. The primary objective of this study is to evaluate the percentage of subjects with at least 35% splenic volume reduction using fedratinib. Secondary objectives are as follows: • Evaluate the safety of fedratinib. • Evaluate the decrease in spleen size by palpation. • Evaluate myelofibrosis (MF)-related symptoms as measured by the Myelofibrosis Symptom Assessment Form (MFSAF). • Evaluate the duration of the splenic reaction using MRI (magnetic resonance imaging) / CT (computed tomography) and palpation. • Evaluate the duration of the symptomatic reaction. • To evaluate the effectiveness of risk mitigation strategies for gastrointestinal (GI) events. • To evaluate the effectiveness of risk reduction strategies for Wernicke encephalopathy (WE).

[0078] The exploratory investigation is as follows: • Evaluate overall survival (OS) • Evaluate the effectiveness of the study treatment for selected treatment-related symptoms (diarrhea, nausea, vomiting, dizziness, headache) from the subject's perspective. The evaluation will be based on the patient-reported outcome version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). • To explore prognostic markers (e.g., gene mutations) at baseline and in relation to efficacy parameters. • To explore biomarkers related to the mechanism of action of fedratinib (e.g., circulating cytokines).

[0079] Study population. This study is expected to enroll approximately 110 patients with intermediate- or high-risk primary myelofibrosis (PMF), post-polycythemia myelofibrosis (PV-MF), or post-essential thrombocythemia myelofibrosis (ET-MF).

[0080] All subjects who discontinue treatment as defined in the study protocol for any reason will be followed up every three months until death, or up to 12 months after end of treatment (EOT), until they become unfollowed, withdraw consent for further data collection, or end of the clinical trial, until any of these first occurs, and their survival, subsequent treatment, and progression from myelofibrosis to acute myeloid leukemia (AML) are monitored.

[0081] Test plan. This test is planned to consist of the following three stages: • 28-day screening period • Fedratinib treatment duration, including a 30-day follow-up after the last medication visit. • 12-month survival follow-up period

[0082] Trial duration. The expected trial period is approximately 4 years, which includes approximately 18 months for full enrollment, as well as 24 months for treatment and follow-up.

[0083] The end of a clinical trial is defined as the later of the following two dates: the date the last subject made their final visit and completed the survival follow-up, or the date the last data point required for primary, secondary, and / or exploratory analysis was received from the last subject, as specified in the trial protocol.

[0084] Screening Period. All enrolled subjects will undergo a screening procedure during the screening period, which must be completed within 28 days prior to the start of the study treatment. This serves to determine the eligibility of subjects based on all inclusion and exclusion criteria defined in the study protocol. For subjects who will receive ruxolitinib during the screening period, or for subjects whose abnormal laboratory values ​​(or other criteria for exclusion) detected during screening may reverse, the screening period may be extended up to 35 days (with an additional 7 days).

[0085] Treatment duration. Upon confirmation of eligibility, subjects will be enrolled and will receive continuous treatment with fedratinib at a dose of 400 mg once daily orally. Fedratinib will be administered in dihydrochloride monohydrate form (i.e., compound II). A cycle is defined as a 4-week (28-day) period for treatment purposes. Unless otherwise specified, the visit window is ±3 days, with the exception of MRI / CT scan procedures, which have a visit window of ±7 days. During the first three cycles, facility visits are scheduled for days 1 and 15, and for subsequent cycles, they are scheduled for day 1. On day 8 of cycle 1, the facility will contact the subject by telephone to assess the occurrence of nausea, vomiting, and diarrhea and discuss their management. Subjects may continue treatment with fedratinib until unacceptable toxicity, lack of therapeutic effect, or withdrawal of consent occurs. All subjects will be monitored for adverse events throughout the study. All participants who discontinue treatment as defined in the study protocol for any reason will be followed up for 30 days after their last dose of fedratinib.

[0086] Fedratinib is administered orally once daily at the same time each day, preferably with dinner, as an outpatient. If a dose is missed, the next dose should be taken the following day at the same time as the previous dose.

[0087] During the first three cycles, facility visits are scheduled for days 1 and 15, and for subsequent cycles, they will be scheduled for day 1. On day 8 of cycle 1, the facility will contact the patient by telephone to assess the occurrence of nausea, vomiting, and diarrhea and discuss their management.

[0088] Patients may continue treatment with fedratinib until they experience unacceptable toxicity, lack of therapeutic effect, disease progression, or withdrawal of consent.

[0089] All participants will be monitored for adverse events throughout the trial.

[0090] All participants who discontinue treatment as defined in the study protocol for any reason will be followed up for 30 days after their last dose of fedratinib.

[0091] The most common adverse events associated with fedratinib are hematological and gastrointestinal adverse events. Hematological adverse events associated with JAK inhibitors are dose-dependent and mechanism-based, and are managed through dose reduction, discontinuation of medication, and blood transfusion.

[0092] The fedratinib dose in this study is 400 mg / day. If a patient experiences drug toxicity as specified in the dose change schedule (Table 1), medication should be discontinued, and a dose change may be necessary.

[0093] If a patient remains intolerant to fedratinib treatment after a dose reduction of two steps from the starting dose, they must be discontinued from the study. If toxicity does not resolve within the period specified in the dose change schedule (Table 1), the patient must be discontinued from the study. Dose increases are permitted only in specific cases as defined in the dose change schedule (Table 1). The daily dose of fedratinib cannot exceed 400 mg / day.

[0094] The patient may continue treatment with fedratinib until there is unacceptable toxicity, lack of therapeutic effect, or the patient fails to comply with treatment or withdraws consent.

[0095] Dosage change schedule

[0096] Flexible dose-modification regimens can be used to minimize drug toxicity for individual patients, with possible daily doses being 200 mg, 300 mg, or 400 mg.

[0097] The most common adverse events associated with fedratinib are hematological and gastrointestinal adverse events. Hematological adverse events associated with JAK inhibitors are dose-dependent and mechanism-based, and are managed through dose reduction, discontinuation of medication, and blood transfusion.

[0098] If a patient experiences any of the drug toxicity listed in Table 1 below, the medication must be discontinued. In some cases (i.e., when liver function tests (LFT) are not abnormal), the dose may be reduced to a minimum of 200 mg / day during the study, at the discretion of the principal investigator, by a decrease of 100 mg / day. The fedratinib dose will be adjusted for patients with severe renal impairment and those receiving co-administration of potent or moderate CYP3A4 inhibitors.

[0099] If a patient remains intolerant to fedratinib after the dose level has been reduced two steps from the starting dose, the patient must discontinue participation in the study treatment. If toxicity does not resolve within the period specified in Table 1, the patient must discontinue participation in the study treatment. Dose increases are permitted in specific cases. The daily dose of fedratinib cannot exceed 400 mg / day (based on free base weight). [Table 1] [Table 2]

[0100] Dose adjustment for co-administration of potent or moderate CYP3A4 inhibitors.

[0101] Concomitant administration of fedratinib with potent or moderate CYP3A4 inhibitors may increase fedratinib exposure. Increased fedratinib exposure may increase the risk of exposure-related adverse events and should be carefully considered.

[0102] For patients receiving concomitant treatment with a potent CYP3A4 inhibitor, it is recommended to reduce the starting dose of fedratinib from 400 mg to 200 mg. If the introduction of a potent CYP3A4 inhibitor is required during fedratinib treatment, consider reducing the dose level by two steps (e.g., from 300 mg to 100 mg). Potent CYP3A4 inhibitors include, but are not limited to, boceprevir, cobicistat, conivaptan, danoprevir / ritonavir combination, elvitegravir / ritonavir combination, grapefruit juice, indinavir / ritonavir combination, itraconazole, ketoconazole, lopinavir / ritonavir combination, paritaprevir / ritonavir / (ombitasvir and / or dasabuvir) combination, posaconazole, ritonavir, saquinavir / ritonavir combination, telaprevir, tipranavir / ritonavir combination, troleandmycin, and voriconazole.

[0103] For patients receiving concomitant treatment with a moderate CYP3A4 inhibitor, it is recommended to reduce the starting dose of fedratinib from 400 mg to 300 mg. If the introduction of a moderate CYP3A4 inhibitor is required during fedratinib treatment, consider lowering the dose level by one step (e.g., from 300 mg to 200 mg). Examples of moderate CYP3A4 inhibitors include, but are not limited to, aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, and verapamil.

[0104] If it is necessary to reduce the fedratinib dose to less than 100 mg per day due to any fedratinib-related adverse event (AE) caused by a potential increase in plasma concentrations of fedratinib, consider further lowering the average daily dose by, for example, administering 100 mg of fedratinib every other day. Administering 100 mg of fedratinib every other day is equivalent to an average daily dose of 50 mg.

[0105] If adverse events (AEs) persist after dose reduction of fedratinib, consider discontinuing either fedratinib or a potent CYP3A4 inhibitor based on the overall benefit / risk for the patient.

[0106] If co-administration with a CYP3A4 inhibitor is discontinued, the fedratinib dose should be increased again as needed.

[0107] Dose adjustment in cases of renal impairment. Dose adjustment is not recommended for patients with mild to moderate renal impairment. In patients who develop severe renal impairment during clinical trials, the fedratinib dose must be adjusted by reducing the dose level by one step (e.g., from 400 mg once daily [QD] to 300 mg). Patients with a planned dose of 200 mg QD may be reduced to 100 mg.

[0108] Management of Latent Wernicke Encephalopathy (WE)

[0109] Potential cases of WE are medical emergencies. Screening for WE and management of potential cases of WE during treatment with fedratinib will be carried out according to the following procedures:

[0110] Clinical and cognitive function assessment. Intermediate medical history: including reviewing the subject's history of confusion, memory impairment, visual disturbances (e.g., double vision), signs and symptoms of malnutrition and malabsorption, and alcohol consumption. • Physical examination: Includes assessment of abnormal eye movements, cerebellar abnormalities, and weight (weight loss compared to previous examinations or patient history) during screening, and at follow-up visits on day 1, day 30, and day 1 of each treatment cycle. • Mini-Mental State Examination (MMSE): To objectively assess signs / symptoms of encephalopathy, it is performed during screening, on day 1 of cycles 2 and 3, then every three cycles thereafter, at end-of-cycle therapy (EOT), and more frequently if clinically necessary.

[0111] Management of potential WE. If there are signs or symptoms that may indicate WE: • Hold off on fedratinib until WE is ruled out. • Obtain a sample for thiamine levels. • Experimentally begin thiamine supplementation. • Report the event to the trial sponsor as an AESI (Analytics and Assistance Systems Initiative). • Obtain neurological advice • Perform a brain MRI. If WE is confirmed, fedratinib will be permanently discontinued.

[0112] Thiamine monitoring and correction. We plan to monitor thiamine levels (whole blood), and thiamine supplementation will be administered to all subjects whose thiamine levels are below the normal range. • Thiamine levels are assessed at screening and require correction and re-examination before initiating fedratinib treatment. During treatment with fedratinib, thiamine levels are assessed at the start of each cycle (cycles 2, 3, and every three subsequent cycles) or as clinically necessary: - If the subject receives thiamine supplementation, thiamine levels must be assessed in a starved state with respect to thiamine supplementation, and thiamine should be administered after blood collection. - If the thiamine level result is lower than normal, the implementing medical institution should contact the patient as soon as possible and start thiamine supplementation. - Thiamine levels are lower than normal but ≥30 nM / L, and there are no signs or symptoms of WE: • Oral supplementation with 100 mg of thiamine must be initiated. • If the results are obtained in a local laboratory, report the event to the trial sponsor as an adverse event of particular interest (AESI). -If thiamine levels are <30 nM / L, regardless of the presence or absence of signs or symptoms of WE: Immediately treat with thiamine (preferably intravenously (IV)) at a therapeutic dose (e.g., 500 mg infusion three times a day for 30 minutes each time for 2-3 days), or an equivalent dose intramuscularly (IM) according to local standard treatment; • Report the event to the trial sponsor as a particularly noteworthy adverse event (AESI). Next, administer 250mg-500mg of IV thiamine once daily for 3-5 days, or administer an equivalent amount of IM according to local standard treatment guidelines. Subsequently, continue administering 100 mg of thiamine orally per day for at least 90 days. • Fedratinib should be withheld until thiamine levels return to the normal range. - Thiamine supplementation must be administered as a thiamine-only formulation. - If thiamine levels are low, check that magnesium levels are normal, and correct them if they are low. * Adverse events of particular interest (AESIs) are those that are of scientific and medical interest specific to understanding investigational drugs, and may require close monitoring and prompt reporting from the principal investigator to the trial sponsor.

[0113] The following are considered adverse events of particular interest (AESI): • Cases of Wernicke encephalopathy (WE) or suspected WE accompanied by thiamine levels below the normal range. • Thiamine levels below the normal range, regardless of the presence or absence of signs or symptoms of WE. • New malignant tumors after the start of experimental treatment • Progression from myelofibrosis to acute myeloid leukemia (AML) • Heart failure or cardiac hypertrophy • Grade 3 and 4 hyperlipasemia or grade 3 and 4 hyperamylasemia or pancreatitis events according to CTCAE criteria v5.0 • Grade 3 or 4 elevated alanine transaminase (ALT), aspartate transaminase (AST), or total bilirubin levels, or hepatotoxic events.

[0114] Management of nausea and vomiting. The management of nausea and vomiting during treatment with fedratinib will be carried out according to the following procedure: • Before treatment begins, participants will be provided with a management instruction form (including when to contact the clinical trial site). • To reduce nausea and vomiting, it is recommended to take fedratinib with dinner. • For the first eight weeks of treatment, it is strongly recommended to use anti-nausea / emetic drugs (e.g., ondansetron) prophylactically, in accordance with local practice. When using dimenhydrinate or other muscarinic receptor antagonists for nausea and vomiting, these agents should be administered at night to minimize the possibility of drowsiness and other neurological adverse events. • Withhold / reduce the fedratinib dose according to Table 1. • Hospitalization may be required for nausea or vomiting of grade 3 or higher, or for persistent events. Regarding medications administered for prophylactic use against nausea and vomiting, if clinically significant nausea and vomiting do not occur during the first 8 weeks of fedratinib treatment, consider discontinuing these medications.

[0115] Management of diarrhea. The management of diarrhea during treatment with fedratinib will be carried out according to the following procedure: • Participants should have loperamide available for home use, and instructions for diarrhea management (including when to contact the clinical trial site) must be provided before starting treatment. • Loperamide should not be administered prophylactically if the patient is not experiencing diarrhea. When diarrhea occurs, treat it with loperamide as per local practice. Start with an initial dose of 4 mg of loperamide, and then consider increasing it to 2 mg each time diarrhea occurs, but do not exceed 16 mg / 24 hours. • Dietary adjustments, including adequate hydration, avoidance of lactose-containing foods and alcohol, and small meals using rice, bananas, bread, etc. • Withhold / reduce the fedratinib dose according to Table 1. • Hospitalization may be required for persistent diarrhea of ​​grade 3 or higher. Nausea, vomiting, and diarrhea will be assessed during the patient's visit on day 1 of each subsequent 28-day cycle, and through mandatory telephone contacts on day 15 of the first three cycles and day 8 of the first cycle.

[0116] Summary of key effectiveness evaluations. Unless otherwise specified, spleen volume response analysis will be performed in the efficacy-evaluable population, myelofibrosis symptom response analysis will be performed in the MFSAF population, and spleen size response analysis will be performed in the safety population.

[0117] Spleen volume response rate (RR) as determined by MRI / CT. The response rate for splenic volume reduction is defined as the proportion of subjects whose splenic volume reduction was ≥35% compared to baseline at the end of cycle 6. Response rates and 95% confidence intervals will be provided. Descriptive summary statistics for splenic volume measurements and percentage changes from baseline will also be provided. Subjects without MRI / CT splenic volume data at the end of cycle 6, including those who met the criteria for splenomegaly progression before the end of cycle 6, will be considered non-responders.

[0118] Sensitivity analysis will be performed on the response rate of subjects who showed a 25% or greater reduction in spleen volume compared to baseline at the end of cycle 6.

[0119] Rate of splenic response by palpation (RRP). The rate of splenic response by palpation is the proportion of subjects with a splenic response according to IWG-MRT2013 at the end of cycle 6, compared to baseline. This will be calculated for subjects with splenomegaly (5 cm or more below the LCM) at baseline. Subjects without a splenic size assessment at the end of cycle 6, including those who met the criteria for splenomegaly progression before the end of cycle 6, will be considered non-responders. The response rate and 95% confidence interval will be provided.

[0120] Symptomatic response rate (SRR). The symptom response rate (SRR) is defined as the proportion of subjects whose total symptom score (TSS), measured by MFSAF version 4.0, decreased by ≥50% from baseline by the end of cycle 6. We plan to provide the SRR and 95% confidence interval. The TSS will be defined as the sum of the scores for each of the seven symptoms (Gwaltney C, Paty J, Kwitkowski VE, Mesa RA, Dueck AC, Papadopoulos EJ, et al. Development of a harmonized patient-reported outcome questionnaire to assess myelofibrosis symptoms in clinical trials. Leuk Res. 2017 Aug;59:26-31). To allow for indirect comparison with previous MF studies, a modified TSS (Mesa RA, Gotlib J, Gupta V, Catalano JV, Deininger MW, Shields AL, et al. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J. Clin. Oncol. 2013 Apr 1;31(10):1285-92) will also be calculated from the six symptoms being examined (night sweats, itching, abdominal discomfort, early satiety, left subcostal pain, bone or muscle pain), and SRR analysis will also be performed.

[0121] We plan to calculate the TSS (based on seven symptom categories) and modified TSS at each point in time. Descriptive summary statistics (dimensions, mean, standard deviation, median, and range) will be provided for baseline scores, post-baseline scores, and changes from baseline in TSS, modified TSS, and symptom scores.

[0122] Subjects whose baseline TSS is not > 0 will be considered unreviewable for SRR analysis (due to no room for symptom reduction). Subjects with no TSS at the end of cycle 6 or whose disease progressed before the end of cycle 6 will be considered non-responders.

[0123] The MRI / CT splenic volume response period (DR) is defined as the period from the first reported splenic response (i.e., a ≥35% decrease in splenic volume) to the first reported <35% decrease in splenic volume. If no events occur (i.e., splenic volume reduction remains <35% from before the analysis), the DR will be terminated on the date of the last valid assessment performed prior to the analysis date.

[0124] The duration of spleen volume response obtained from MRI / CT scans will be analyzed using the Kaplan-Meier method. We plan to provide KM estimates at the 25th, 50th, and 75th percentiles, as well as 95% confidence intervals for the median. We also plan to plot the KM curves.

[0125] Duration of palpable splenic reaction (DRP). The duration of palpable splenic reaction (DRP) is defined as the period from the first time a palpable splenic reaction is reported according to IWG-MRT2013 to the first time a decrease in the reaction is reported according to IWG-MRT2013. The duration of palpable splenic reaction according to IWG-MRT2013 criteria will be calculated for subjects with splenomegaly (5 cm or more below the LCM) at baseline and subjects with a palpable splenic reaction. If no events exist before the analysis (i.e., no decrease in palpable splenic reaction), the DRP will be terminated at the date of the last valid assessment performed before the analysis date.

[0126] Symptomatic Response Period (DSR). The symptomatic response period is defined as the period from the first reported TSS response (i.e., a ≥50% reduction in TSS) as measured by MFSAF version 4.0 to the first reported TSS reduction of <50%. If no <50% reduction in TSS exists before the analysis, the DSR will be censored at the date of the last valid assessment performed prior to the analysis date. The DSR will be analyzed using the KM method. KM estimates for the 25th, 50th, and 75th percentiles, as well as 95% confidence intervals for the median, will be provided. KM curves will be plotted.

[0127] [Table 3] [Table 4] [Table 5] AE = Adverse event; C1D1 = Day 1 of cycle 1; CTC = Common Terminology Criteria for Adverse Events; ICF = Informed Consent Form; MFSAF = Myelofibrosis Symptom Assessment Form; MRI = Magnetic Resonance Imaging; NCI = National Cancer Institute; PRO-CTCAE = Patient-Reported Outcome Version of Common Terminology Criteria for Adverse Events; SVR = Splenic volume reduction.

[0128] Survival follow-up period. All subjects who discontinue treatment as defined in the study protocol for any reason will be followed up every three months until death or up to 12 months after end of treatment (EOT), until they become unfollowed, withdraw consent for further data collection, or end of the clinical trial, until any of these first occurs, for survival, subsequent treatment, new malignancies, and progression from myelofibrosis to acute myeloid leukemia (AML).

Claims

1. Compound I 【Chemistry 1】 Alternatively, a pharmaceutical composition for use in a method for treating myeloproliferative disorders, comprising a pharmaceutically acceptable salt or hydrate thereof as an active ingredient, wherein the method is (i) Administer the compound or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient to a patient in need of treatment. (ii) Monitor the patient's thiamine level, then (iii) If the thiamine level is lower than the reference value, the patient is administered thiamine or a thiamine equivalent, wherein the reference value is approximately 74 to approximately 222 nM / L of whole blood, where, Thiamine will be administered according to the following schedule: Take approximately 500 mg for 2 or 3 days, TID. For 3 to 5 days, take approximately 250 mg to 500 mg daily (QD), and Approximately 100 mg for 90 days, QD It is administered according to the following: Alternatively, thiamine equivalents are available according to the following schedule: Take approximately 500 mg for 2 or 3 days, TID. For 3 to 5 days, take approximately 250 mg to 500 mg daily (QD), and Approximately 100 mg for 90 days, QD The pharmaceutical composition is administered in such a manner that it is sufficient to deliver an amount of thiamine according to [a certain condition].

2. The pharmaceutical composition according to claim 1, wherein the thiamine level of the patient is evaluated by analyzing one or more biomarkers related to thiamine deficiency.

3. The pharmaceutical composition according to claim 1, wherein thiamine is administered intravenously.

4. The pharmaceutical composition according to claim 1, wherein the thiamine equivalent is administered orally.

5. The pharmaceutical composition according to claim 1, further comprising increasing the magnesium level of the patient.

6. The pharmaceutical composition according to claim 1, wherein the patient suffers from a myeloproliferative disorder.

7. The pharmaceutical composition according to claim 6, wherein the myeloproliferative disorder is myelofibrosis.

8. The pharmaceutical composition according to claim 7, wherein the myelofibrosis is primary myelofibrosis.

9. The pharmaceutical composition according to claim 8, wherein the primary myelofibrosis is selected from intermediate-risk primary myelofibrosis and high-risk primary myelofibrosis.

10. The pharmaceutical composition according to claim 7, wherein the myelofibrosis is secondary myelofibrosis.

11. The pharmaceutical composition according to claim 7, wherein the myelofibrosis is post-essential thrombocythemia myelofibrosis.

12. The pharmaceutical composition according to claim 7, wherein the myelofibrosis is post-polycythemia vera myelofibrosis.

13. The pharmaceutical composition according to claim 1, wherein the myeloproliferative disorder is acute myeloid leukemia (AML).

14. The pharmaceutical composition according to claim 1, wherein the myeloproliferative disorder is polycythemia vera.

15. The pharmaceutical composition according to claim 1, wherein the myeloproliferative disorder is essential thrombocythemia.

16. The pharmaceutical composition according to claim 1, wherein the compound I is in the form of a dihydrochloride monohydrate.

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