Methods for treating relatively low-risk myelodysplastic syndromes

Abstract

The present disclosure relates to the use of pelabrasib and its pharmaceutically acceptable salts and hydrates for the treatment of relatively low-risk myelodysplastic syndromes (LR-MDS) and conditions associated therewith.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 433,833, filed December 20, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Myelodysplastic syndromes (MDS) are a heterogeneous collection of clonal bone marrow stem cell disorders characterized by ineffective hematopoiesis leading to cytopenias, and one-third of patients ultimately progress to acute myeloid leukemia (AML). More than 80% of MDS patients have two or more known recurrently mutated genes at the time of diagnosis (Haferlach et al., Leukemia. 2014;28:241-7). Most MDS cases are genomically complex, harboring one dominant clone and many other clones containing many cooperating mutations that may contribute to disease progression and / or relapse. In addition to acquired somatic mutations, cytokine abnormalities, immune dysregulation, and bone marrow microenvironment alterations also play important roles in pathogenesis.

[0003] Abnormalities in the microenvironment disrupt the integrity of normal hematopoiesis, resulting in increased apoptosis index, abnormal cell biology, and dysplasia of bone marrow progenitor cells. The abnormal microenvironment may also serve as a milieu for the selective proliferation of MDS clones, leading to disease progression. Dysregulation of key regulatory factors within bone marrow stem and progenitor cells leads to abnormal hematopoiesis, apoptosis, and cell proliferation, increasing the risk of infection, bleeding, and progression to AML (Ganan-Gomez et al., Leukemia. 2015;29:1458-69).

[0004] MDS is classified by risk according to the International Prognostic Scoring System (IPSS), original and revised (IPSS-R). See, for example, Greenberg et al., Blood 1997;89:2079-88 and Greenberg et al., Blood 2012;120:2454-65. Approximately 80% of patients with relatively low-risk MDS have anemia, and transfusion dependency in this population is associated with poor survival. In patients over 60 years of age, chronic anemia is associated with several comorbidities, including cardiovascular complications, increased risk of falls and fractures, and shortened survival. Even without transformation to AML, MDS is often a cause of death due to associated complications related to cytopenias and infections.

[0005] Limited treatment options are available for relatively low-risk MDS (LR-MDS), particularly for those who have anemia and are transfusion-dependent. Typically, the first-line treatment for relatively low-risk MDS is erythropoiesis-stimulating agents (ESAs), which aim to increase early red blood cell formation and proliferation. However, red blood cell (RBC) transfusion-dependent MDS patients often have a reduced response to ESAs. Luspatercept, an activin ligand trap that reduces abnormal Smad2 / 3 signaling, was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of anemia in adult patients with very low-risk to intermediate-risk MDS with ring sideroblasts or myelodysplastic / myeloproliferative neoplasms with ring sideroblasts and thrombocytosis who have failed ESA treatment and require two or more units of RBCs over an 8-week period. However, luspatercept is not indicated for other MDS subtypes, and it may not be suitable for patients with several common comorbidities, including thromboembolic disorders and hypertension. Furthermore, the majority of patients treated with luspatercept did not achieve the desired response. Lenalinomide is another treatment option for patients with relatively low-risk MDS. However, it is only approved for patients with del 5q cytogenic abnormality. Currently, the only known cure for MDS is bone marrow transplantation. However, this intensive treatment is reserved only for eligible patients and those with higher-risk MDS.

[0006] Thus, there is a need for additional therapeutic options for treating MDS and its related conditions. Summary of the Invention

[0007] LR-MDS is characterized by excessive apoptosis in the bone marrow and an autoimmune disease-like profile. Furthermore, multiple genetic abnormalities, such as TET2 and SF3B1 mutations, commonly seen in MDS, can induce NF-kB and proinflammatory signaling, which can impair erythropoiesis and lead to red blood cell death. A meta-analysis of multiple studies showed that levels of inflammatory cytokines, such as TNF-α, IL-6, and IL-8, were significantly higher in MDS patients compared with controls (Shi et al., Medicine (Baltimore). 2019;98:e15844). Furthermore, levels of these cytokines were higher in relatively low-risk patients compared with high-risk MDS patients (Shetty et al., Leuk Res. 1996;20:891-900). The NF-kB pathway is central to the regulation of these cytokines (Liu et al., Signal Transduct Target Ther. 2017;2). Mesenchymal activation of NF-κB signaling is common in LR-MDS, and NF-κB activation drives an inflammatory program that attenuates hematopoiesis in lower-risk myelodysplastic syndromes (Ping et al., Leukemia. 2019;33:536-41). BET proteins regulate gene expression of critical oncogenic pathways, such as NF-κB or TGF-beta signaling, which are important promoters of proinflammatory signaling and ineffective hematopoiesis in MDS.

[0008] Pelabrasib (CPI-0610) is a selective and potent small-molecule BET inhibitor that has demonstrated clinical activity in lymphoma and myelofibrosis (MF), where NF-κB signaling and inflammatory cytokine expression are relevant drivers of the disease process. In patients with lymphoma and MF, pelabrasib can reduce levels of inflammatory cytokines regulated by the NF-κB pathway (Blum et al., Annals of Oncology. 2018;29 and Talpaz et al., EHA Library. 2020;293580).

[0009] In addition to improving hematopoiesis by reducing the proinflammatory environment, pelabrasileid can also directly promote erythropoiesis. Among patients enrolled in a pelabrasileid clinical trial (arm 1 of the MANIFEST trial (NCT02158858)) investigating pelabrasileid monotherapy in patients with advanced MF who were refractory to or intolerant of JAK inhibitors, 57.9% (11 of 19) achieved a transfusion-free increase in Hgb levels of 1.5 g / dL or greater (Talpaz et al., EHA Library. 2020;293580). Consistent with this, an exploratory analysis of erythroid progenitors by immunohistochemical staining for CD71 was performed at a central site on all available paired bone marrow biopsies collected at baseline and week 24 in 37 patients. Semiquantitative analysis revealed an increase in erythroid progenitor cells in 59% (22 of 37) of patients (Mertz et al., American Society of Hematology 2020). Ex vivo proliferation / differentiation studies using CD34+ cells isolated from blood samples collected from healthy donors and MF patients and differentiated in the presence of a cytokine cocktail demonstrated that pelabrasin promotes erythroid maturation. Furthermore, pelabrasin treatment dose-dependently rescued the inhibitory effects of ruxolitinib on erythroid differentiation (Mertz et al., American Society of Hematology 2020).

[0010] Furthermore, in a phase 2 study using pelabrasib as monotherapy or in combination with ruxolitinib for patients with refractory, advanced MF, treatment with pelabrasib was able to induce an erythroid response. In arm 1 of the study, 21% of patients with transfusion-dependent relapsed / refractory MF achieved RBC-TI of 12 weeks or more over a median period of 44 weeks (Talpaz et al., EHA Library. 2020;293580). In arm 2 of the study, 36% of patients with transfusion-dependent MF who received pelabrasib in addition to ruxolitinib achieved RBC-TI of 12 weeks or more over a median period of 39 weeks (Verstovsek et al., Blood. 2020;136:51-52).

[0011] Thus, provided herein are methods of using pelabrasib or a pharmaceutically acceptable salt thereof to treat lower-risk MDS, including low-risk MDS and very low-risk MDS.

[0012] Also provided herein are methods of using pelabrasib or a pharmaceutically acceptable salt thereof to treat RBC transfusion-dependent, lower-risk MDS, including RBC transfusion-dependent low-risk MDS and very low-risk MDS.

[0013] Further provided herein are methods of using pelabusib or a pharmaceutically acceptable salt thereof to treat anemia associated with lower-risk MDS, including lower-risk MDS and very lower-risk MDS.

[0014] Further provided herein are methods of using pelabusib or a pharmaceutically acceptable salt thereof to improve hemoglobin levels (e.g., increase hemoglobin levels) in subjects with relatively low-risk MDS, including low-risk MDS and very low-risk MDS.

[0015] Further provided herein are methods of using pelabusib or a pharmaceutically acceptable salt thereof to treat cytopenias in subjects with lower-risk MDS, including lower-risk MDS and very lower-risk MDS.

[0016] Further provided herein are methods of using pelabusib or a pharmaceutically acceptable salt thereof to treat ineffective erythropoiesis in subjects with lower-risk MDS, including lower-risk MDS and very lower-risk MDS.

[0017] Further provided herein are methods of using pelabrasib or a pharmaceutically acceptable salt thereof to ameliorate myelofibrosis in subjects with lower-risk MDS, including lower-risk and very lower-risk MDS.

[0018] Further provided herein are methods of using pelabrasib or a pharmaceutically acceptable salt thereof to normalize platelets in subjects with lower-risk MDS, including lower-risk and very lower-risk MDS.

[0019] Further provided herein are methods of using pelabusib or a pharmaceutically acceptable salt thereof to reduce spleen size in subjects with lower-risk MDS, including lower-risk MDS and very lower-risk MDS.

[0020] Further provided herein are methods of using pelabusib or a pharmaceutically acceptable salt thereof to reduce transfusion burden in subjects with lower-risk MDS, including low-risk and very low-risk MDS, who are transfusion-dependent prior to treatment. [Brief explanation of the drawings]

[0021] [Figure 1] 1 shows IL-6 protein release from primary MDS patient PBMCs stimulated with LPS in parallel with perabresive treatment, as determined by electrochemiluminescence-based immunoassay. [Figure 2]Percentage of megakaryocyte-erythroid CD34+ progenitors (left) and percentage of CD34- proerythroblasts / erythroblasts (right) in isolated hematopoietic stem cell samples treated with erythroid growth supplement only (DMSO only) or erythroid growth supplement and 250 nM perabresib, n=2 donors. [Figure 3] Cytokine release from primary MDS patient PBMCs stimulated with LPS in parallel with perabresib treatment, as determined by electrochemiluminescence-based immunoassay. Values ​​normalized to "DMSO only" control, n=7-10 donors, mean ± SEM. DETAILED DESCRIPTION OF THE INVENTION

[0022] In a first embodiment, provided herein is a method of treating relatively low-risk MDS, including low-risk MDS and very low-risk MDS, in a subject in need thereof, the method comprising administering to the subject an effective amount of pelabrasib or a pharmaceutically acceptable salt thereof. Alternatively, as part of the first embodiment, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for treating relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In another alternative, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In yet another alternative, provided herein is a pharmaceutical composition comprising pelabrasib or a pharmaceutically acceptable salt thereof for treating relatively low-risk MDS, including low-risk MDS and very low-risk MDS.

[0023] In a second embodiment, provided herein is a method of treating RBC transfusion-dependent, relatively low-risk MDS, including RBC transfusion-dependent low-risk MDS and very low-risk MDS, in a subject in need thereof, the method comprising administering to the subject an effective amount of pelabrasib or a pharmaceutically acceptable salt thereof. Alternatively, as part of the second embodiment, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for treating RBC transfusion-dependent, relatively low-risk MDS, including RBC transfusion-dependent low-risk MDS and very low-risk MDS. In another alternative, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating RBC transfusion-dependent, relatively low-risk MDS, including RBC transfusion-dependent low-risk MDS and very low-risk MDS. In yet another alternative, as part of a second embodiment, provided herein is a pharmaceutical composition comprising pelabrasib or a pharmaceutically acceptable salt thereof for treating RBC transfusion-dependent, lower-risk MDS, including RBC transfusion-dependent, lower-risk MDS and very-low-risk MDS.

[0024] In a third embodiment, provided herein is a method of treating anemia associated with relatively low-risk MDS, including low-risk MDS and very low-risk MDS, in a subject in need thereof, the method comprising administering to the subject an effective amount of pelabrasib or a pharmaceutically acceptable salt thereof. Alternatively, as part of the third embodiment, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for treating anemia associated with relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In another alternative, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating anemia associated with relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In yet another alternative, provided herein is a pharmaceutical composition comprising pelabrasib or a pharmaceutically acceptable salt thereof for treating anemia associated with relatively low-risk MDS, including low-risk MDS and very low-risk MDS.

[0025] In a fourth embodiment, provided herein is a method of improving (e.g., increasing) hemoglobin levels in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS, comprising administering to the subject an effective amount of pelabrasib or a pharmaceutically acceptable salt thereof. Alternatively, as part of the fourth embodiment, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for improving (e.g., increasing) hemoglobin levels in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. Alternatively, as part of the fourth embodiment, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving (e.g., increasing) hemoglobin levels in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In yet another alternative, as part of a fourth embodiment, provided herein is a pharmaceutical composition comprising pelabrasib or a pharmaceutically acceptable salt thereof for improving (e.g., increasing) hemoglobin levels in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS.

[0026] In a fifth embodiment, provided herein is a method for treating cytopenias in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS, comprising administering to the subject an effective amount of pelavresib or a pharmaceutically acceptable salt thereof. Alternatively, as part of the fifth embodiment, provided herein is the use of pelavresib or a pharmaceutically acceptable salt thereof for treating cytopenias in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In another alternative, provided herein is the use of pelavresib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cytopenias in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In yet another alternative, provided herein is a pharmaceutical composition comprising pelavresib or a pharmaceutically acceptable salt thereof for treating cytopenias in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS.

[0027] In a sixth embodiment, provided herein is a method of treating ineffective erythropoiesis in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS, comprising administering to the subject an effective amount of pelabrasib or a pharmaceutically acceptable salt thereof. Alternatively, as part of the sixth embodiment, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for treating ineffective erythropoiesis in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In another alternative, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating ineffective erythropoiesis in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In yet another alternative, as part of a sixth embodiment, provided herein is a pharmaceutical composition comprising pelabusib or a pharmaceutically acceptable salt thereof for treating ineffective erythropoiesis in a subject suffering from lower-risk MDS, including lower-risk and very lower-risk MDS.

[0028] In a seventh embodiment, provided herein is a method for improving myelofibrosis in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS, comprising administering to the subject an effective amount of pelabresib or a pharmaceutically acceptable salt thereof. Alternatively, as part of the seventh embodiment, provided herein is the use of pelabresib or a pharmaceutically acceptable salt thereof for improving myelofibrosis in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In another alternative, provided herein is the use of pelabresib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving myelofibrosis in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In yet another alternative, provided herein is a pharmaceutical composition comprising pelabresib or a pharmaceutically acceptable salt thereof for improving myelofibrosis in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS.

[0029] In an eighth embodiment, provided herein is a method for normalizing platelets in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS, comprising administering to the subject an effective amount of pelabresib or a pharmaceutically acceptable salt thereof. Alternatively, as part of the eighth embodiment, provided herein is the use of pelabresib or a pharmaceutically acceptable salt thereof for normalizing platelets in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In another alternative, provided herein is the use of pelabresib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for normalizing platelets in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In yet another alternative, provided herein is a pharmaceutical composition comprising pelabresib or a pharmaceutically acceptable salt thereof for normalizing platelets in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS.

[0030] In a ninth embodiment, provided herein is a method for reducing spleen size in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS, comprising administering to the subject an effective amount of pelabrasib or a pharmaceutically acceptable salt thereof. Alternatively, as part of the ninth embodiment, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for reducing spleen size in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In another alternative, provided herein is the use of pelabrasib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing spleen size in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS. In yet another alternative, provided herein is a pharmaceutical composition comprising pelabrasib or a pharmaceutically acceptable salt thereof for reducing spleen size in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS.

[0031] In a tenth embodiment, provided herein is a method of reducing transfusion burden in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS, who is transfusion-dependent prior to treatment, comprising administering to the subject an effective amount of pelabrasib or a pharmaceutically acceptable salt thereof. Alternatively, provided herein as part of the tenth embodiment is the use of pelabrasib or a pharmaceutically acceptable salt thereof for reducing transfusion burden in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS, who is transfusion-dependent prior to treatment. In another alternative, provided herein as part of the tenth embodiment is the use of pelabrasib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing transfusion burden in a subject suffering from relatively low-risk MDS, including low-risk MDS and very low-risk MDS, who is transfusion-dependent prior to treatment. In yet another alternative, provided herein as part of a tenth embodiment is a pharmaceutical composition comprising pelabrasib or a pharmaceutically acceptable salt thereof for reducing transfusion burden in a subject with relatively low-risk MDS, including low-risk MDS and very low-risk MDS, who is transfusion-dependent prior to treatment.

[0032] Perabresib (CPI-0610), or 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, is exemplified as compound 144 in U.S. Pat. No. 8,796,261 and has the following structural formula: [ka] The term pelablescent as used herein includes crystalline and / or hydrated forms of pelablescent, such as the monohydrate and crystalline Form A monohydrate disclosed in U.S. Pat. No. 9,969,747, and in one embodiment, is included as part of the present invention.

[0033] The pelabrasib or pharmaceutically acceptable salts described herein can be formulated as pharmaceutical compositions and administered to a subject, such as a human, in a variety of forms adapted to the selected route of administration. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, buccal, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral, as used herein, includes subcutaneous injection, intravenous, intramuscular, intrathecal, and intrasternal injection or infusion techniques. Methods for formulating pharmaceutical compositions are well known in the art and are disclosed, for example, in "Remington: The Science and Practice of Pharmacy," University of the Sciences in Philadelphia, ed., 21st edition, 2005, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0034] As used herein, the term "relatively low-risk MDS" refers to MDS characterized as low-risk or very low-risk according to the IPSS-R prognostic risk category / score. See Greenberg PL, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454-65.

[0035] As used herein, the term " low-risk MDS " refers to the low-risk MDS defined by IPSS-R prognostic risk category / score.See Greenberg PL, et al.Revised international prognostic scoring system for myelodysplastic syndromes.Blood.2012;120:2454-65.For example, low-risk MDS is the MDS that the subject has IPSS-R prognostic risk score of more than 1.5 to 3.

[0036] As used herein, the term " very low-risk MDS " refers to the very low-risk MDS defined by IPSS-R prognostic risk category / score.See Greenberg PL, et al.Revised international prognostic scoring system for myelodysplastic syndromes.Blood.2012;120:2454-65.For example, very low-risk MDS is the MDS that the subject has an IPSS-R prognostic risk score of 1.5 or less.

[0037] The terms "relatively low-risk MDS-related anemia," "anemia associated with relatively low-risk MDS," and "anemia due to relatively low-risk MDS" are synonymous and refer to anemia that develops or is acquired in a subject as a result of having or suffering from relatively low-risk MDS.

[0038] The terms "subject" and "patient" are synonymous and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Unless stated to the contrary, a subject is a human in need of treatment.

[0039] The terms "administer," "administering," or "administration" refer to providing, implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing pelabrasib or a pharmaceutically acceptable salt or composition thereof to, into, or onto a subject.

[0040] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or one or more symptoms of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have occurred or have been observed (i.e., therapeutic treatment). In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (i.e., prophylactic treatment). Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence. In certain embodiments, treatment includes delaying the onset of at least one symptom of a disease for a period of time.

[0041] The term "effective amount" or "therapeutically effective amount" of pelabrasib or a pharmaceutically acceptable salt thereof, as described herein, refers to the amount of pelabrasib or a pharmaceutically acceptable salt thereof that is sufficient to provide a therapeutic effect in treating a condition described herein. In one embodiment, the effective amount is about 0.01 to about 100 mg / kg body weight / day of pelabrasib or a pharmaceutically acceptable salt thereof, e.g., about 0.1 to about 100 mg / kg body weight / day.

[0042] The specific dosage and treatment regimen for a particular patient will depend on a variety of factors, including the activity of the specific compound utilized, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. In one embodiment, perabresib or a pharmaceutically acceptable salt thereof may be formulated in a dosage of, for example, about 50 mg to about 500 mg for administration once, twice, or three times daily. In another embodiment, 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide or a pharmaceutically acceptable salt thereof may be formulated in a dosage of, for example, about 50 mg to about 500 mg for administration once, twice, or three times daily. In another embodiment, 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide or a pharmaceutically acceptable salt thereof can be formulated, for example, in a dosage of about 50 mg to about 500 mg for administration once, twice, or three times daily, wherein the 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide is a monohydrate or crystalline Form A monohydrate. For example, pelabrasib may be administered at a dose of about 50 mg to about 300 mg / day, about 50 mg to about 175 mg / day, about 50 mg to about 150 mg / day, about 75 mg to about 300 mg / day, about 75 mg to about 200 mg / day, about 75 mg to about 175 mg / day, about 75 mg to about 150 mg / day, about 70 mg to about 160 mg / day, about 100 mg to about 300 mg / day, about 150 mg to about 250 mg / day, or at about 50 mg / day, about 75 mg / day, or about 125 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, or about 250 mg / day. In one embodiment, perabresib monohydrate can be formulated in a dosage of about 50 mg to about 500 mg, for example, for administration once, twice, or three times daily.For example, perabresib monohydrate can be administered at a dose of about 50 mg to about 300 mg / day, about 50 mg to about 175 mg / day, about 50 mg to about 150 mg / day, about 75 mg to about 300 mg / day, about 75 mg to about 175 mg / day, about 75 mg to about 150 mg / day, about 70 mg to about 160 mg / day, about 100 (about 100) mg to about 300 mg / day, about 150 mg to about 250 mg / day, or at about 50 mg / day, about 75 mg / day, about 125 (about 25) mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, or about 250 mg / day. In one aspect, the monohydrate crystalline Form A of pelabusib described herein can be formulated in dosages of about 50 mg to about 500 mg, for example, for administration once, twice, or three times daily. For example, the monohydrate crystalline Form A of pelabresib described herein can be administered at a dose of about 50 mg to about 300 mg / day, about 50 mg to about 175 mg / day, about 50 mg to about 150 mg / day, about 75 mg to about 300 mg / day, about 75 mg to about 175 mg / day, about 75 mg to about 150 mg / day, about 70 mg to about 160 mg / day, about 100 mg to about 300 mg / day, about 150 mg to about 250 mg / day, or at about 50 mg / day, about 75 mg / day, about 125 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, or about 250 mg / day. In one embodiment, pelabrasib or a pharmaceutically acceptable salt thereof can be formulated in a dosage of 50 mg to 500 mg, for example, for administration once, twice, or three times daily. For example, pelabrasib can be administered at a dose of 50 mg to 300 mg / day, 50 mg to 175 mg / day, 50 mg to 150 mg / day, 75 mg to 300 mg / day, 75 mg to 175 mg / day, 75 mg to 150 mg / day, 70 mg to 160 mg / day, 100 mg to 300 mg / day, 150 mg to 250 mg / day, or 50 mg / day, 75 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, 200 mg / day, 225 mg / day, or 250 mg / day. In one embodiment, pelabusib, Form A monohydrate, can be formulated in dosages of 50 mg to 500 mg, for example, for administration once, twice, or three times daily.For example, pelabresib Form A monohydrate can be administered at doses of 50 mg to 300 mg / day, 50 mg to 175 mg / day, 50 mg to 150 mg / day, 75 mg to 300 mg / day, 75 mg to 200 mg / day, 75 mg to 175 mg / day, 75 mg to 150 mg / day, 70 mg to 160 mg / day, 100 mg to 300 mg / day, 150 mg to 250 mg / day, or 50 mg / day, 75 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, 200 mg / day, 225 mg / day, or 250 mg / day. In one embodiment, pelabresib monohydrate crystalline Form A described herein can be formulated in a dosage of 50 mg to 500 mg, for example, for administration once, twice, or three times daily. For example, the monohydrate crystalline Form A of pelabresib described herein can be administered at doses of 50 mg to 300 mg / day, 50 mg to 175 mg / day, 50 mg to 150 mg / day, 75 mg to 300 mg / day, 75 mg to 200 mg / day, 75 mg to 175 mg / day, 75 mg to 150 mg / day, 70 mg to 160 mg / day, 100 mg to 300 mg / day, 150 mg to 250 mg / day, or 50 mg / day, 75 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, 200 mg / day, 225 mg / day, or 250 mg / day.

[0043] As used herein, the recitation of ranges of values ​​is intended to serve as a shorthand method of referring individually to each separate value within the range, as well as the highest and lowest values ​​defining the range, and each value is incorporated herein as if it were individually recited herein unless expressly stated otherwise. For example, a range of values ​​from X to Y includes both X and Y and all values ​​between X and Y.

[0044] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended to better describe the present disclosure and is not a limitation on the scope of the disclosure, unless otherwise specified. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[0045] In an eleventh embodiment, the perabresive used in the described methods (e.g., as in any one of the first through tenth embodiments) is crystalline. Alternatively, as part of the eleventh embodiment, the perabresive used in the described methods is a hydrate. Alternatively, as part of the eleventh embodiment, the perabresive used in the described methods is a monohydrate. Alternatively, as part of the eleventh embodiment, the perabresive used in the described methods (e.g., as in any one of the first through tenth embodiments) is crystalline Form A (e.g., monohydrate crystalline Form A) characterized by at least three, at least four, at least five, or six X-ray powder diffraction peaks at 2θ angles selected from 4.73°, 18.09°, 18.48°, 18.80°, 19.70°, and 25.17°. Alternatively, as part of the eleventh embodiment, the perabresive used in the described methods (e.g., as in any one of the first through tenth embodiments) is crystalline Form A (e.g., monohydrate crystalline Form A) characterized by X-ray powder diffraction peaks at 2θ angles of 4.73°, 9.42°, 12.91°, 18.09°, 18.48°, 18.80°, 19.70°, 21.42°, and 25.17°. In yet another alternative, as part of the eleventh embodiment, the perabresist used in the described method (e.g., as in any one of the first through tenth embodiments) is crystalline Form A (e.g., monohydrate crystalline Form A) characterized by X-ray powder diffraction peaks at 2θ angles of 4.73°, 8.11°, 9.42°, 12.91°, 14.10°, 14.97°, 18.09°, 18.48°, 18.80°, 19.70°, 21.42°, and 25.17°, 26.07°, and 26.53°. Additional details on the characterization of crystalline Form A (e.g., monohydrate crystalline Form A) and hydrated forms of perabresist can be found in U.S. Pat. No. 9,969,747, the contents of which are incorporated herein by reference.

[0046] It will be understood that the 2-theta values ​​of the X-ray powder diffraction pattern of monohydrate crystalline Form A may vary slightly depending on the instrument, sample preparation variations, and batch-to-batch variations. For example, without wishing to be bound by theory, it is believed that some variation in 2-theta values ​​is due to the amount of water contained in the crystal lattice, for example, in the case of hydrated forms (such as the monohydrate) and anhydrous forms. Thus, the XRPD pattern / assignments of crystalline Form A (e.g., monohydrate crystalline Form A) are not to be construed as absolute and may vary by ±0.2 degrees, with the exception of the following 2-theta angles of crystalline Form A (e.g., monohydrate crystalline Form A), which may vary by ±0.3 degrees: 8.11°, 14.10°, 14.97°, 26.07°, and 26.53°.

[0047] In a twelfth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through eleventh embodiments) is classified as a transfusion-dependent (TD) subject. Alternatively, as part of the twelfth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through eleventh embodiments) is classified as a transfusion-dependent (TD) subject prior to treatment. As used herein, the term transfusion-dependent (TD) refers to a subject who requires regular transfusions. The term "red blood cell (RBC) transfusion-dependent LR-MDS" refers to LR-MDS in which the patient is also transfusion-dependent (TD).

[0048] In a thirteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through twelfth embodiments) becomes transfusion independent during treatment. In some aspects, as part of the thirteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through twelfth embodiments) becomes transfusion independent for a period of time during treatment. As used herein, the term transfusion independence (TI) refers to a subject who does not require regular transfusions. In one aspect, as part of the thirteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through eleventh embodiments) becomes transfusion independent, wherein transfusion independence is characterized by an absence of RBC transfusions for a period of at least about 4 consecutive weeks, at least about 6 consecutive weeks, at least about 8 consecutive weeks, at least about 10 consecutive weeks, or at least about 12 consecutive weeks during treatment. In one aspect, as part of the thirteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through eleventh embodiments) becomes transfusion independent, wherein transfusion independence is characterized by the absence of RBC transfusions for a period of about 8 consecutive weeks during treatment. In one aspect, as part of the thirteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through eleventh embodiments) becomes transfusion independent, wherein transfusion independence is characterized by the absence of RBC transfusions for a period of at least 10 consecutive days, at least about 15 consecutive days, at least about 20 consecutive days, at least about 25 consecutive days, at least about 30 consecutive days, at least about 35 consecutive days, at least about 40 consecutive days, at least about 45 consecutive days, at least about 50 consecutive days, at least about 55 consecutive days, at least about 60 consecutive days, at least about 70 consecutive days, at least about 75 consecutive days, at least about 80 consecutive days, or at least about 85 consecutive days during treatment.In one aspect, as part of a thirteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through eleventh embodiments) becomes transfusion independent, wherein transfusion independence is characterized by the absence of RBC transfusions for a period of about 10 to about 90 consecutive days, about 20 to about 90 consecutive days, about 30 to about 90 consecutive days, about 40 to about 90 consecutive days, about 50 to about 90 consecutive days, about 50 to about 60 consecutive days, about 55 to about 58 consecutive days, about 80 to about 90 consecutive days, or about 82 to about 56 consecutive days during treatment. In one aspect, as part of a thirteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through eleventh embodiments) becomes transfusion independent, wherein transfusion independence is characterized by the absence of RBC transfusions for any 56-day period following the initiation of treatment. In one aspect, as part of the thirteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through eleventh embodiments) becomes transfusion independent, wherein transfusion independence is characterized by the absence of RBC transfusions during any 84-day consecutive period following the initiation of treatment.

[0049] In a fourteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through thirteenth embodiments) experiences an improvement (e.g., an increase) in hemoglobin levels following treatment. In one aspect, as part of the fourteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through thirteenth embodiments) experiences an improvement in hemoglobin levels characterized as an increase in mean hemoglobin of 0.5 g / dL or more, 1.0 g / dL or more, or 1.5 g / dL or more during treatment. In one aspect, as part of the fourteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through thirteenth embodiments) experiences an improvement in hemoglobin levels characterized as an increase in mean hemoglobin of 0.5 g / dL or more, 1.0 g / dL or more, or 1.5 g / dL or more during treatment for a period of at least about four consecutive weeks, at least about six consecutive weeks, at least about eight consecutive weeks, at least about ten consecutive weeks, or at least about twelve consecutive weeks, or during a period otherwise described above in the twelfth embodiment in which the subject is also transfusion independent. In one aspect, as part of the fourteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through thirteenth embodiments) experiences an improvement in hemoglobin levels characterized as an increase in mean hemoglobin of 1.0 g / dL or more during a period of at least about eight consecutive weeks in which the subject is also transfusion independent.

[0050] In a fifteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through fourteenth embodiments) experiences an erythroid reaction (mHI-E). In one aspect, as part of the fifteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through fourteenth embodiments) experiences an erythroid reaction (mHI-E) defined as a reduction in RBC transfusion of 2 or more units, 3 or more units, 4 or more units, 5 or more units, or 6 or more units during treatment. In one aspect, as part of the fifteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through fourteenth embodiments) experiences an red blood cell response (mHI-E) defined as a reduction in RBC transfusions of 2 or more units, 3 or more units, 4 or more units, 5 or more units, or 6 or more units during treatment for a period of at least about 4 consecutive weeks, at least about 6 consecutive weeks, at least about 8 consecutive weeks, at least about 10 consecutive weeks, or at least about 12 consecutive weeks, or as otherwise described above in the thirteenth embodiment where the subject is also transfusion independent (for patients with a baseline RBC transfusion burden of 4 units / 8 weeks or greater). In one aspect, as part of a fifteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through fourteenth embodiments) experiences a red blood cell response (mHI-E) defined as a reduction in RBC transfusions of 4 units or more for a period of at least about 8 consecutive weeks in which the subject is also transfusion independent (for patients with a baseline RBC transfusion burden of 4 units / 8 weeks or more).In one aspect, as part of the fifteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through fourteenth embodiments) experiences an erythroid response (mHI-E) defined as a mean hemoglobin increase of 0.5 g / dL or more, 1.0 g / dL or more, 1.5 g / dL or more, or 2.0 g / dL or more during treatment for a period of at least about 4 consecutive weeks, at least about 6 consecutive weeks, at least about 8 consecutive weeks, at least about 10 consecutive weeks, or at least about 12 consecutive weeks, or as otherwise described above in the thirteenth embodiment where the subject is also transfusion independent (for patients with a baseline RBC transfusion burden of less than 4 units / 8 weeks). In one aspect, as part of a fifteenth embodiment, a subject being treated with pelabus or a pharmaceutically acceptable salt or composition thereof (including any one of the first through fourteenth embodiments) experiences an erythroid response (mHI-E) defined as a mean hemoglobin increase of 1.5 g / dL or greater over a period of at least about 8 consecutive weeks, where the subject is also transfusion independent (for patients with a baseline RBC transfusion burden of less than 4 units / 8 weeks).

[0051] In a sixteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through fifteenth embodiments) experiences a neutrophil response (HI-N). In one aspect, as part of the sixteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through fifteenth embodiments) experiences a neutrophil response of 1.0 x 10 9 For patients with a baseline neutrophil count of less than / L, a 100% or greater relative increase in neutrophil count from baseline and a 0.5 × 10 9 experience a neutrophil response (HI-N), defined as an absolute increase of >1 / L.

[0052] In a seventeenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through sixteenth embodiments) receives 75×10 9 Alternatively, as part of the seventeenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through sixteenth embodiments) has a platelet count of 75×10 / L or greater prior to treatment. 9 have a platelet count less than / L.

[0053] In an eighteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through seventeenth embodiments) experiences a platelet response (HI-P) during treatment. In one aspect, as part of the eighteenth embodiment, a subject being treated with pelabrasib or a pharmaceutically acceptable salt or composition thereof (including any one of the first through seventeenth embodiments) experiences a platelet response of 30 x 10 from baseline at all assessments during any consecutive eight-week period after baseline. 9 / L or greater absolute increase (baseline platelet count ≥ 20 × 10 9 / L~100×10 9 / L), or 20 × 10 9 / L and a relative increase of 100% or more from baseline (baseline platelet count of 20 × 10 9 Patients who experience a platelet response (HI-P) are defined as having a platelet count <1 / L.

[0054] In a nineteenth embodiment, a subject being treated by a method described herein (including any one of the first through eighteenth embodiments) is administered pelabrasib (e.g., pelabrasib monohydrate or pelabrasib monohydrate crystalline Form A) at a dosage ranging from about 50 mg / day to about 200 mg / day. Alternatively, as part of the nineteenth embodiment, a subject being treated by a method described herein (including any one of the first through eighteenth embodiments) is administered pelabrasib (e.g., pelabrasib monohydrate or pelabrasib monohydrate crystalline Form A) at a dosage ranging from about 100 mg / day to about 150 mg / day. In another alternative, as part of the nineteenth embodiment, a subject being treated by the methods described herein (including any one of the first through eighteenth embodiments) is administered pelabrasib (e.g., pelabrasib monohydrate or pelabrasib monohydrate crystalline Form A) at a dosage ranging from about 150 mg / day to about 200 mg / day. In yet another alternative, as part of the nineteenth embodiment, a subject being treated by the methods described herein (including any one of the first through eighteenth embodiments) is administered pelabrasib (e.g., pelabrasib monohydrate or pelabrasib monohydrate crystalline Form A) at a dosage ranging from about 50 mg / day to about 100 mg / day. In yet another alternative, as part of the nineteenth embodiment, a subject being treated by the methods described herein (including any one of the first through eighteenth embodiments) is administered pelabrasib (e.g., pelabrasib monohydrate or pelabrasib monohydrate crystalline Form A) at a dosage of about 75 mg / day, about 100 mg / day, about 125 mg / day, about 150 mg / day, or about 175 mg / day. In yet another alternative, as part of the nineteenth embodiment, a subject being treated by the methods described herein (including any one of the first through eighteenth embodiments) is administered pelabrasib (e.g., pelabrasib monohydrate or pelabrasib monohydrate crystalline Form A) at a dosage of about 75 mg / day.In yet another alternative, as part of the 19th embodiment, a subject being treated by the methods described herein (including any one of the first through eighteenth embodiments) is administered pelabrasib (e.g., pelabrasib monohydrate or pelabrasib monohydrate crystalline Form A) at a dosage of about 125 mg / day. In yet another alternative, as part of the 19th embodiment, a subject being treated by the methods described herein (including any one of the first through eighteenth embodiments) is administered pelabrasib (e.g., pelabrasib monohydrate or pelabrasib monohydrate crystalline Form A) at a dosage of about 175 mg / day. In yet another alternative, as part of the 19th embodiment, a subject being treated by the methods described herein (including any one of the first through eighteenth embodiments) is administered pelabrasib (e.g., pelabrasib monohydrate or pelabrasib monohydrate crystalline Form A) at a dosage of about 75×10 prior to treatment. 9 / L or greater, the subject is administered pelavresib (e.g., pelavresib monohydrate or pelavresib monohydrate crystalline Form A) at a dosage of about 125 mg / day. In yet another alternative, as part of a nineteenth embodiment, the subject being treated by the methods described herein (including any one of the first through eighteenth embodiments) is administered pelavresib monohydrate at a dosage of about 125 mg / day if the subject has a baseline platelet count of 75×10 / L or greater. 9 If the subject has a baseline platelet count of less than 1 / L, the subject is administered pelavresib (e.g., pelavresib monohydrate or pelavresib monohydrate crystalline Form A) at a dosage of about 75 mg / day. In another alternative, as part of a nineteenth embodiment, a subject being treated by the methods described herein (including any one of the first through eighteenth embodiments) is [Example]

[0055] To investigate the effect of pelabrasib on cytokine secretion in primary MDS patient cells This study was conducted to evaluate the anti-inflammatory activity of pelabrasib on MDS patient cells from different donors. The NF-kB pathway is central to the regulation of cytokines such as TNF-α, IL-6, and IL-8, which are elevated in MDS patients and play a role in the pathogenesis of myelodysplastic syndromes (see, e.g., doi:10.1097 / MD.0000000000015844).

[0056] Primary MDS patient samples (cryopreserved peripheral blood mononuclear cells (PBMCs)) were purchased from Discovery Life Sciences. For sample selection, we selected patients with low blast counts (ideally less than 5%) to select patients exhibiting LR-MDS characteristics, excluded patients with multilineage dysplasia, and reviewed blood parameters such as white blood cell counts and disease staging notes (if available). Freshly thawed PBMCs were seeded at 50,000 cells / well in 96-well flat-bottom plates. IL-6 production was induced by adding 0.001 μg / mL lipopolysaccharide (LPS-B5, Invivogen). Additionally, a nine-point dose-escalation series of pelabusib (CPI-0610) at concentrations ranging from 5 μM to 3.3 nM was added in duplicate. The absolute amount of DMSO in each well was kept constant. "DMSO alone" served as a control for maximal IL-6 secretion. The assay plate was incubated for approximately 18 hours at 37°C and 5% CO2. After centrifugation, the cell supernatant was collected, and IL-6 protein in the supernatant was quantified using a Human IL-6 Kit (V-PLEX, Meso Scale Discovery). The assay plate was read on a Meso Sector S600. Data analysis: In Microsoft Excel, the average background signal (0 pg / mL of a calibrator brand served as the background control) was subtracted from the raw data of all wells. Values ​​for compound-treated wells were normalized to the "DMSO only" control, which was set to 100% IL-6 release. The average normalized values ​​for each experiment were plotted using GraphPad Prism 8. The half-maximal inhibitory concentration (IC50) was calculated by logarithmic transformation of compound concentration and applying the "log(inhibitor) vs. response - variable slope (4 parameters)" function. The mean ± SD and fitted curves were displayed graphically.

[0057] As shown in Figure 1, pelabusib dose-dependently inhibited IL-6 release in donor PBMCs. Values ​​were normalized to the "DMSO only" control, n=2 donors, mean±SD, IC50=248 nM.

[0058] Additional studies were performed following the same procedure outlined above, using an eight-point dose-escalation series of pelabusib (CPI-0610) in triplicate at concentrations ranging from 5 μM to 8.2 nM. After centrifugation, cell supernatants were collected, and IFNγ, TNFα, IL-6, IL-8, or IL-10 protein in the supernatants was quantified using the Proinflammatory Panel 1 Human Kit (IFNγ, TNFα, IL-6, and IL-10) or Human IL-8 Kit (both V-PLEX, Meso Scale Discovery). Assay plates were read on a Meso Sector S600. Data analysis: In Microsoft Excel, the average background signal (a 0 pg / mL calibrator brand served as the background control) was subtracted from the raw data for all wells. Values ​​for compound-treated wells were normalized to the "DMSO only" control, which was set to 100% cytokine release. The average normalized values ​​for all experiments per cytokine were plotted using GraphPad Prism 8. Half maximal inhibitory concentration (IC 50 ) was calculated using a logarithmic transformation of compound concentrations and a "log(inhibitor) vs. response - variable slope (4 parameters)" function. Mean ± SEM and fitted curves are displayed graphically. The results are shown in Figure 3. Pelabus inhibited the release of IFNγ, TNFα, IL-6, IL-8, and IL-10.

[0059] To investigate the effect of pelabus on erythropoiesis of hematopoietic stem cells isolated from bone marrow of MDS patients Primary MDS patient samples (cryopreserved bone marrow mononuclear cells (BMMCs)) were purchased from Discovery Life Sciences. For sample selection, we selected patients with low blast counts (ideally less than 5%), excluded patients with multilineage dysplasia, and reviewed blood parameters such as white blood cell counts (if available) and disease staging notes to select patients exhibiting LR-MDS characteristics.

[0060] Hematopoietic stem cells (CD34+) were isolated using freshly thawed cells using the EasySep Human CD34+ Selection Kit II (StemCell Technologies). Cells were seeded into 96-flat-well plates at 1,000 cells / well (for erythropoiesis) or 2,500 cells / well (for CC100 differentiation mix). The differentiation cocktail StemSpan™ Erythroid Expansion Supplement (for erythropoiesis) or StemSpan™ CC100 (differentiation mix) was added according to the manufacturer's instructions. A five-point titration series of perabresib monohydrate was tested in duplicate, ranging in concentration from 500 nM to 31.25 nM. "DMSO-only"-treated wells served as controls and were also used to prepare flow cytometry controls (e.g., FMO). A feeding step was performed for erythropoiesis on days 3 or 4 after seeding. On day 7, cells were analyzed by flow cytometry. Cell staining was performed according to the manufacturer's instructions using the following antibodies: BV421 anti-human CD34 [clone: ​​561] (BioLegend), AF700 anti-human CD71 [clone: ​​M-A712] (BD Biosciences), FITC anti-human CD235a [clone: ​​GA-R2 (HIR2)] (BD Biosciences), and Dye eFluor506 Invitrogen (Live / Dead) (Invitrogen / ThermoFisher) to distinguish live from dead cells. Cells were acquired on a BD FACS LSR x20 Fortessa. Gating was performed as follows: debris removal → single cells → live cells. Among live cells, the percentage of CD34+CD71+ (megakaryocyte-erythroid progenitors (MEP)) and the percentage of CD34-CD71+ (pro-erythroblasts / erythroblasts (pro-EB / EB)) were determined and depicted in GraphPad Prism 8 for each donor.

[0061] As shown in Figure 2, perabresib enhanced the differentiation of CD34+ stem cells from LR-MDS donors towards erythropoiesis.

[0062] A phase 2 study of pelabrasib in transfusion-dependent patients with lower-risk myelodysplastic syndromes (MDS) A Phase 2b trial will be conducted to evaluate the efficacy and safety of pelabrasib in transfusion-dependent patients with relatively low-risk MDS.

[0063] Test Design This Phase 2 part of the study is a multicenter, open-label study of pelabrasib treatment in patients with lower-risk MDS. Pelabrasib monohydrate will be administered orally once daily (QD) for 14 consecutive days, followed by a 7-day break, considered one cycle of treatment (1 cycle = 21 days), until unacceptable toxicity, disease progression, or other discontinuation criteria (i.e., need for intervention / therapy excluded by eligibility criteria, patient noncompliance, pregnancy, or other medical condition preventing study participation).

[0064] Baseline platelet count 75 × 10 9 Patients with a baseline platelet count of 75 x 10 / L or higher will receive a starting dose of 125 mg QD or 150 mg QD of pelabresib monohydrate. 9 Patients with a baseline platelet count of < 50 × 10 should be started at a dose of 75 mg QD. 9 / L or more is 75 x 10 9 Patients with platelet counts less than 75 x 10 / L should start at a dose of 75 mg QD. The pelabresib monohydrate dose may be increased in 25 mg QD increments no more frequently than once every two cycles, up to a maximum of 175 mg QD or 200 mg QD, provided that: 1) the platelet count is 75 x 10 9 / L or more, 2) absolute neutrophil count (ANC) of 750 × 10 in the absence of growth factors. 6 / L or greater, 3) no bleeding episodes were experienced, and 4) no adverse events (AEs) of grade 3 or greater attributable to pelabrasib were observed. Clinical evaluation was performed on a baseline platelet count of 50 x 10 9 / L or more is 75 x 10 9 This is done in patients with a blood glucose level of less than 1 / L using a single starting dose level of 75 mg.

[0065] Inclusion criteria Subjects are eligible for inclusion in the Phase 2 study if they meet all of the following criteria: 1. Male or female, aged 18 or over. 2. A confirmed diagnosis of MDS according to the 2016 World Health Organization (WHO) criteria (Arber et al., Blood. 2016;127:2391-405) is required, except for patients with a diagnosis of treatment-related MDS or disease with del 5q aberration. Patients with secondary MDS or MDS with isolated del(5q) are not eligible. Patients with MDS / MPN overlap are not eligible, but patients with MDS / MPN with ring sideroblasts and thrombocytosis [MDS / MPN-RS-T] are eligible. 3. IPSS-R classification of very low, low, or moderate risk disease (Greenberg et al., Blood. 2012;120:2454-65). 4. Patients with ≥15% ring sideroblasts or >5% ring sideroblasts of erythroid precursors in the bone marrow and the presence of an SF3B1 mutation must have been previously treated with luspatercept. 5. Patients with ringed sideroblasts in less than 15% of erythroid precursors in the bone marrow and no SF3B1 mutations should be refractory or intolerant to previous ESA treatment or unlikely to benefit from ESA therapy (endogenous erythropoietin level >200 U / L). 6. Patients must be transfusion-dependent, requiring an average of 2-6 packed red blood cell (pRBC) units per 8 weeks during the 16 weeks prior to enrollment, with no 8 consecutive weeks without RBC transfusions during those 16 weeks. 7. Acceptable clinical laboratory assessments within 28 days prior to the first dose of study drug: a. Absolute neutrophil count (ANC) ≥ 750 x 10 within the last 14 days without growth factors 6 / L. b. Platelet count ≥ 50 x 10 without platelet transfusion or platelet stimulating agents 9 / L. c. Peripheral blood and bone marrow blast count <5% d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN). e. Serum direct bilirubin <2.0 × ULN. f. Calculated or measured creatinine clearance (CrCl) ≥ 30 mL / min. 8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 9. Patients must be able to swallow medication in solid form. 10. Both male and female patients and their partners of reproductive potential must agree to use at least one highly effective method of contraception (preferably one with a low risk of user dependence, particularly if contraception is being introduced as a result of clinical trial participation) while receiving study treatment and for 94 days after the last dose of study drug for male patients and male partners of female patients, and for 184 days after the last dose of study drug for female patients and female partners of male patients. Note: Patients may consider seeking information from the investigator regarding germ cell donation and cryopreservation prior to treatment. Male patients must be informed of the risk of testicular toxicity and given appropriate counseling regarding sperm banking.

[0066] Alternative inclusion criteria Subjects are eligible for inclusion in the Phase 2 study if they meet all of the following criteria: 1. Patients must be 18 years of age or older and of legal age of consent in the jurisdiction in which the study is conducted at the time of signing the Informed Consent Form (ICF). 2. Patients have a confirmed diagnosis of MDS with very low, low, or intermediate risk disease according to the World Health Organization (WHO) 2022 classification (Arber et al., Blood. 2016; 127:2391-405) that meets the IPSS-R classification (Greenberg et al., Blood. 2012; 120:2454-65) with a score of 3.5 or less and have less than 5% blasts in the bone marrow. 3. Patient requires RBC transfusion as documented by the following criteria: 3a. Average transfusion requirement of 2-6 units / 8 weeks of RBCs established over a minimum of 16 weeks immediately prior to the start of treatment; 3b. The Hgb level must have been 9.5 g / dL or less at the time of administration of the RBC transfusion or within the 7 days prior to it in order for the transfusion to count toward meeting the eligibility criteria; and Note: RBC transfusions administered for elective surgery, infection, or bleeding events are not eligible for transfusions required for purposes that meet the eligibility criteria. 3c. No consecutive 56-day period without RBC transfusion required during the 16 weeks immediately preceding the start of treatment. 4. Acceptable clinical laboratory assessments obtained within 28 days prior to the first dose of study drug: 4a. Absolute neutrophil count (ANC) ≥ 750 x 10 in the absence of growth factors within 14 days prior to the start of study treatment 9 / L, 4b. Platelet count ≥ 75 x 10 without PLT transfusion or PLT stimulating agent within 14 days prior to the start of study treatment 9 / L. Platelet count is 75 × 10 9 Patients with a ≥100% CI of 0.01-0.15 or ... 4c. Platelet count of 50 x 10 in the absence of PLT transfusion or PLT stimulating agents within 14 days prior to the start of study treatment 9 / L or more is 75 x 10 9 / L. Platelet count is less than 50 × 10 9 / L or more is 75 x 10 9 Patients with <1 / L are only eligible for the safety cohort (Stage 2 pelabrasin monotherapy). 4d. Calculated or measured creatinine clearance ≥ 45 mL / min (using Cockroft and Gault (Nephron 1976;16(1):31-41. doi:10.1159 / 000180580) 4e. Bilirubin ≤ 1.5 x upper limit of normal (ULN), and 4f. Isolated elevation of aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) ≦3× ULN of local reference range (≦5× if elevation may be due to hepatic involvement, e.g., in the presence of MDS with cirrhosis). 5. Patient has an Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2. 6. Intention to avoid conceiving or fathering a child based on the following criteria: Male patients and their female partners of childbearing potential must agree to take appropriate measures (with at least 99% certainty) to avoid fathering a child from screening until 94 days after the last dose of pelabrasib. In addition, male patients must refrain from donating sperm during this period. Patients must be informed of and their understanding of approved methods that are at least 99% effective in preventing pregnancy. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and agree to take appropriate measures to prevent pregnancy (with at least 99% certainty) from screening through the end of relevant systemic exposure (i.e., 184 days after the last dose of pelabrasib). They must also agree to undergo regular urine pregnancy tests during the study treatment period and monthly pregnancy tests until 184 days after the last dose of pelabrasib. They must also cease breastfeeding and oocyte donation during the course of the study and for 184 days after the last dose of pelabrasib. Patients must be informed of, and their understanding of, permitted methods that are at least 99% effective in preventing pregnancy. Women of non-childbearing potential (i.e., postmenopausal with 12 months or more of amenorrhea without surgical sterilization by hysterectomy and / or bilateral oophorectomy, or another medical cause) are eligible.

[0067] Exemplary cohort of pelabus monotherapy treatment Patients in the monotherapy cohort were eligible for study inclusion only if they met all of the criteria in the alternative exclusion criteria stated above, plus the following additional criteria: 7. Patient is refractory to, intolerant to, or unlikely to benefit from at least one prior therapy, excluding RBC transfusion, as assessed by the investigator. 8. Ringed sideroblast (RS) status at baseline (RS+ defined as RS in ≥ 15% of erythroid progenitors in the bone marrow or ≥ 5% (but < 15%) if SF3B1 mutation is present). Up to 40% of randomized patients will be RS+. Enrollment of a total of 60 patients randomized across two dose stages in Stages 1 and 2 will be capped according to RS status. Note: This is a platelet count of 50 x 10 9 / L or more is 75 x 10 9 This does not apply to patients enrolled in pelabrasib monotherapy with a CI < 10 / L (safety cohort; n=10).

[0068] Exclusion criteria Subjects will be excluded from the Phase 2 study if they meet all of the following criteria:

[0069] A. Medical Condition 1. Patients with secondary MDS or del 5q aberration are not eligible. Patients with MDS / myeloproliferative neoplasms (MPN) overlap are not eligible, with the exception of MDS / MPN with ringed sideroblasts and thrombocytosis [MDS / MPN-RS-T]. 2. Known clinically significant anemia due to iron, vitamin B12, or folate deficiency, or autoimmune or hereditary hemolytic anemia. 3. Have current, known active or chronic HIV, hepatitis B, or hepatitis C infection. Screening of patients with serology for these viruses is not required. However, patients with a past history of viral hepatitis or current suspected viral hepatitis should have hepatitis B and hepatitis C serology performed to determine whether there is current evidence of ongoing infection with these viruses. 4. Active, clinically uncontrolled infection with significant worsening of chronic infection. Patients are not eligible for enrollment until they have recovered to Grade 1 or less for at least 2 weeks prior to the first dose of study drug. COVID-19 testing is not mandatory during screening for this study. However, based on the local epidemiological situation and each patient's individual COVID-19 exposure risk and / or vaccination status, investigators should consider testing and, if COVID-19 positive, delaying the initiation of study treatment until the infection has resolved. 5. Patients with certain gastrointestinal (GI) conditions that, in the investigator's judgment, may interfere with the patient's ability to swallow solid forms of medication and absorption of oral medication (e.g., inflammatory bowel disease [i.e., ulcerative colitis, Crohn's disease, or celiac disease] are not eligible to participate in the study). 6.Has impaired cardiac function or clinically significant cardiac disease, including any of the following: - Acute myocardial infarction or unstable angina within 6 months prior to initiation of study drug. - QTcF>500msec on screening ECG. - New York Heart Association Class III or IV congestive heart failure. - Uncontrolled clinically significant cardiac arrhythmias (patients with rate-controlled atrial fibrillation are not excluded). Note that patients with coronary artery disease and a history of revascularization are not excluded. 7. Patients have ongoing inadequately controlled hypertension (resting systolic blood pressure >160mmHg and resting diastolic blood pressure >100mmHg) despite maximal treatment with at least two antihypertensive drugs. 8. Has ongoing uncontrolled diabetes (HbA1c ≥ 9%) despite maximal treatment with oral and / or injectable antihyperglycemic agents. 9. History of concurrent or second malignancies, except for adequately treated localized basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and requiring no therapy or only hormonal therapy and with normal prostate-specific antigen for ≥1 year prior to randomization, adequately treated stage 1 or 2 cancer currently in complete remission, or any other cancer in complete remission for ≥3 years. 10. Patients with any other concurrent severe and / or poorly controlled concomitant medical condition that, in the opinion of the investigator, may impair study participation or analysis of study data, including, but not limited to, clinically significant pulmonary or neurological disorders.

[0070] B. Previous Therapy / Concomitant Therapy 11. Prior treatment with hypomethylating agents (HMA) (azacitadine, decitabine) 12. Prior treatment with lenalidomide 13. Prior treatment with an investigational drug for MDS. 14. Previous immunosuppressive therapy for MDS (e.g., antithymocyte globulin [ATG], cyclosporine-based regimen, etc.) 15. Prior treatment with a BET inhibitor 16. Treatment with strong CYP3A4 inhibitors or inducers, including St. John's wort, within 7 days prior to the first dose of study drug. Initiation or concomitant treatment with strong CYP3A4 inhibitors or inducers during study treatment is prohibited. 17. Previous hematopoietic stem cell transplant 18. Patients who initiated iron chelation therapy within 56 days prior to Cycle 1, Day 1 (C1D1) were not eligible to participate in the study, with the exception of patients who had been on a stable or tapering dose for 8 weeks or more prior to enrollment.

[0071] C. Other Exclusions 19. Lactating or pregnant women, as evidenced by a highly sensitive serum β-hCG pregnancy test consistent with pregnancy obtained within 72 hours prior to the first dose of study drug. A serum pregnancy test is not required for female patients who are not of childbearing potential (postmenopausal for more than 1 year; permanently sterilized by hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). 20. Unwilling or unable to comply with this Study Protocol or Study Requirements.

[0072] Alternative exclusion criteria Patients will be excluded from the study if they meet any of the following criteria:

[0073] A. Medical Condition 1. Patients with secondary MDS, MDS / MPN overlap excluding RS and MDS / MPN with thrombocytosis). 2. Patients with known clinically significant anemia due to iron, vitamin B12, or folate deficiency, known autoimmune or hereditary hemolytic anemia, clinically significant bleeding, drug-induced anemia, or known hypothyroidism 3. Patients with currently known active or chronic infection with HIV, hepatitis B, or hepatitis C. Screening of patients with serology for these viruses is not required. However, patients with a past history of viral hepatitis or current suspicion of viral hepatitis should have hepatitis B and hepatitis C serology performed to determine whether there is current evidence of ongoing infection with these viruses. 4. Patients with active, clinically uncontrolled infection with a significant worsening of their chronic infection. Patients are not eligible for enrollment until they have recovered to Grade 1 or less for at least 2 weeks prior to the first dose of study drug. COVID-19 testing is not mandatory during screening for this study. However, based on the local epidemiological situation and each patient's individual COVID-19 exposure risk and / or vaccination status, investigators should consider testing and, if COVID-19 positive, delaying the initiation of study treatment until the infection has resolved. 5. Patients with certain gastrointestinal conditions (e.g., inflammatory bowel disease or celiac disease) that, in the judgment of the investigator, may interfere with the patient's ability to swallow solid forms of medication and absorption of oral medication. 6.Patients with impaired cardiac function or clinically significant cardiac disease, including any of the following: 6a. Acute myocardial infarction or unstable angina within 6 months prior to the start of study treatment; 6b. Fridericia-corrected QT interval (QTcF) of more than 470 msec on the screening electrocardiogram (ECG) (QTcF interval is not relevant for patients with pacemaker-controlled arrhythmias), 6c. New York Heart Association Class III or IV congestive heart failure, or 6d. Uncontrolled clinically significant cardiac arrhythmias (patients with rate-controlled atrial fibrillation are not excluded). Note: Patients with a history of coronary artery disease or revascularization are not excluded. 7. Patients with ongoing insufficiently controlled hypertension (resting systolic blood pressure >160mmHg and resting diastolic blood pressure >100mmHg). 8. Patients with ongoing, poorly controlled diabetes (glycosylated hemoglobin [HbA1c] ≥ 9%). 9. Patients with a history of concurrent or second malignancies, except for adequately treated localized basal cell or squamous cell carcinoma of the skin, cervical intraepithelial carcinoma, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and requiring no therapy or only hormonal therapy and with normal prostate-specific antigen for at least one year prior to the start of treatment, adequately treated stage 1 or 2 cancer currently in complete remission, or any other cancer in complete remission for at least three years. 10. Patients with any other concurrent severe and / or poorly controlled concomitant medical condition that, in the opinion of the investigator, may impair study participation or analysis of study data, including, but not limited to, clinically significant pulmonary disease or neurological disorders.

[0074] B. Combination Therapy 11. Prior treatment with a hypomethylating agent (HMA) (azacytidine, decitabine) with the last dose administered less than 8 weeks prior to the first dose of study treatment. Patients may be enrolled at the investigator's discretion. (The last dose must be administered at least 8 weeks prior to the first dose of study treatment.) 12. Prior treatment with an immunomodulatory drug (e.g., lenalidomide [IMiD]) for a condition other than del(5q) abnormality. Patients may be enrolled at the investigator's discretion. (The last dose of an IMiD must be ≥ 8 weeks before the first dose of study treatment.) 13. Concomitant treatment with an investigational drug within 28 days (or within 5 half-lives, whichever is longer) prior to the first dose of study treatment. 14. Previous immunosuppressive therapy for MDS (e.g., antithymocyte globulin, cyclosporine-based regimens, etc.). 15. Prior treatment with a BET inhibitor. 16. Treatment with strong CYP3A4 inhibitors or inducers, including St. John's wort, within 7 days prior to the first dose of study treatment. Initiation or concomitant treatment with strong CYP3A4 inhibitors or inducers during study treatment is prohibited. 17. Previous hematopoietic stem cell transplant. 18. Patients who have initiated iron chelation therapy within 56 days prior to the first dose of study treatment are not eligible to participate in the study, with the exception of patients who have been on a stable or decreasing dose for 8 weeks or more prior to the first dose of study treatment. 19. Prior treatment with androgens within 8 weeks of the first dose of study treatment, with the exception of treatment for hypogonadism. 20. Concomitant treatment with RBC hematopoietic growth factors within 28 days of the first dose of study treatment.

[0075] C. Other Exclusions 21. Unable to give signed informed consent, including compliance with the requirements and limitations listed in the ICF and this protocol. 22. Patient is unwilling or unable to comply with the study visit schedule and other protocol requirements. Patients who are legally detained or in judicial custody. 23. Concurrent enrollment in another interventional clinical trial. 24. History of hypersensitivity to the study treatment or any of its excipients, or to drugs of a similar chemical class. 25.Female patients who are breastfeeding or pregnant, or who are not using adequate contraception as specified in the inclusion criteria. 26. Any male patient who does not agree to use contraception during the treatment period and for at least 94 hours after the last dose of study treatment (if they have a heterosexual partner who is a female of childbearing potential) and who does not discontinue sperm donation during this period. 27. Patient has a history of stroke (including ischemic, embolic, and hemorrhagic stroke), transient ischemic attack, deep vein thrombosis (including proximal and distal), pulmonary or arterial embolism, arterial thrombosis, or other venous thrombosis within 6 months prior to randomization. Note: Previous superficial thrombophlebitis is not an exclusion criterion.

[0076] Primary endpoint The primary endpoint of the study includes 8-week RBC transfusion independence (TI), defined as the absence of RBC transfusions during any consecutive 56-day period after initiation of treatment.

[0077] Secondary endpoints Secondary endpoints include: - 12-week RBC TI, defined as no RBC transfusions during any consecutive 84-day period after initiation of treatment; - Time to 8-week RBC TI, defined as the time from first dose of study drug to first initiation of 56-day RBC TI; - duration of 8-week RBC-TI, defined as the time between the last RBC transfusion before the achievement of 8-week RBC TI and the first RBC transfusion after the achievement (if there are multiple achievements, the one associated with the longest duration will be recognized); - Hbg response, defined as a mean Hgb increase of ≥ 1.0 g / dL from baseline through any 8-week RBC transfusion-free period after baseline; - Red blood cell response (mHI-E), defined as a decrease in RBC transfusions of ≥4 units from baseline to any 8-week period after baseline (for patients with a baseline RBC transfusion burden of ≥4 units / 8 weeks) or a mean Hgb increase of ≥1.5 g / dL from baseline to any 56-day RBC transfusion-free period after baseline (for patients with a baseline RBC transfusion burden of <4 units / 8 weeks); and -Safety and tolerability will be assessed by the incidence of AEs and SAEs, and by evaluating changes in vital signs, physical examination, and clinical laboratory values.

[0078] Exploratory endpoints Exploratory endpoints include: - Time to 12-week RBC TI, defined as the time from first dose of study drug to first start of 84-day RBC TI. Duration of 12-week RBC TI, defined as the time between the last RBC transfusion before and the first RBC transfusion after achieving 12-week RBC TI (if multiple achievements occur, the one associated with the longest duration will be recognized) Baseline neutrophil count 1.0 x 10 9 For patients with neutrophil counts less than 100% relative increase from baseline at all assessments during any 8-week period after baseline and 0.5 × 10 9 Neutrophil response (HI-N), defined as an absolute increase of >1 / L. - Platelet counts from baseline of 30 x 10 at any assessment during any 8-week period after baseline 9 / L or greater absolute increase (baseline platelet count ≥ 20 × 10 9 / L~100×10 9 / L), or 20 × 10 9 / L and a relative increase of 100% or more from baseline (baseline platelet count of 20 × 10 9 Platelet response (HI-P), defined as <100 / L (for patients with <100 / L). -PK of pelabusib assessed by Cmax. -Target engagement is defined as the change in gene expression in peripheral blood before and after treatment. -PD effects on blood and bone marrow cells assessed by including but not limited to effects on RBC and Mk progenitor populations, genes regulating RBC and Mk lineage differentiation. - Changes in inflammatory cytokines in blood samples before and after treatment and cytokine transcript levels in bone marrow aspirates. - Changes in cytogenetic and mutational profiles in blood and / or bone marrow samples before, during, and at the end of treatment. QoL assessed by EORTC-QLC-30 and FACT-An questionnaires. Change in HRQoL at 24 weeks compared to baseline.

[0079] Dose adjustment Alternatively, pleabresib monohydrate is available at two starting dose levels (i.e., 75 mg and 150 mg) to treat patients with a baseline platelet (PLT) count of 75 x 10 9 / L or greater. Further clinical evaluation is required if the baseline platelet count is 50 × 10 9 / L or more is 75 x 10 9 A single starting dose level of 75 mg will be administered to patients with a blood glucose level of less than 1 / L. Pelabresib monohydrate will be administered QD for 14 consecutive days, followed by a 7-day break, until unacceptable toxicity or disease progression, which is considered one cycle of treatment (1 cycle = 21 days).

[0080] The pelabusib monohydrate dose may be increased in 25 mg QD increments no more frequently than once every two cycles, up to a maximum of 175 mg QD or 200 mg QD, provided that the following is observed: - Platelet count 75 x 10 9 / L or more - Absolute neutrophil count (ANC) of 750 x 10 in the absence of growth factors 6 / L or more -No bleeding episodes No grade ≥ 3 AEs attributable to pelabrasin

[0081] Guidelines for dose adjustments during successive treatment periods, including dose reductions and / or withholding of pelabrasib treatment due to platelet count decline, are provided in Table 2 and due to other toxicities in Table 1.

[0082] [Table 1-1]

[0083] [Table 1-2]

[0084] [Table 1-3]

[0085] [Table 1-4]

[0086] If a patient becomes infected with COVID-19 during the study, the investigator, in consultation with the sponsor's medical monitor as appropriate, must use their clinical judgment regarding interruption of the study drug depending on the patient's symptoms, disease state, comorbidities, and concomitant medications. Pelabrasib should be withheld for Grade 3 or greater infections. In the case of Grade 1-2 COVID-19 infection and / or COVID-19-related illness, pelabrasib may be withheld, again at the investigator's clinical judgment and in accordance with local and institutional standard of care.

[0087] [Table 2-1]

[0088] [Table 2-2]

[0089] Treatment will be discontinued if withheld for more than 28 days due to treatment-related toxicity. Longer discontinuation times for mitigating reasons, such as clinical benefit, must be discussed with and approved by the Company Medical Monitor.

[0090] Dose adjustments due to toxicity Guidelines for dose adjustments during successive treatment periods, including dose reductions and / or withholding of pelabrasib due to other toxicities, are provided in Table 3 and due to platelet count decline in Table 4.

[0091] [Table 3-1]

[0092] [Table 3-2]

[0093] [Table 3-3]

[0094] [Table 3-4]

[0095] If a patient becomes infected with COVID-19 during the study, the investigator, in consultation with the sponsor's medical monitor as appropriate, must use their clinical judgment regarding suspending the study drug depending on the patient's symptoms, disease state, comorbidities, and concomitant medications. In the case of Grade 1-2 COVID-19 infection and / or COVID-19-related illness, pelabrasib may be withheld, again at the investigator's clinical judgment and in accordance with local and institutional standard of care.

[0096] [Table 4-1]

[0097] [Table 4-2]

[0098] Re-escalation of pelabrasib after dose reduction due to toxicity Patients who have had a pelabresib dose reduction or dose withholding due to an AE may have their pelabresib dose increased as follows: If the toxicities listed in Table 3 improve to the grades specified for at least one cycle (with exceptions noted below), the dose level may be escalated by one higher dose level (25 mg / day) per cycle. This may be repeated until the original dose level (defined as the dose level prior to the de-escalation) is reached. Patients experience grade 4 neutropenia with toxicity improvement for at least one cycle (ANC 0.75 x 10 9 / L), the dose escalation may be one dose escalation per cycle. If a patient experiences thrombocytopenia of any grade, all dose adjustments should be made according to Table 4. Decisions to re-escalate should be made according to the criteria defined for pelabus. If the dose is reduced for non-hematologic toxicity, dose escalation cannot be initiated until the toxicity has resolved to Grade 1 or less for at least one cycle. If the same toxicity recurs after dose re-escalation, further dose escalation is prohibited. If the dose is reduced due to Grade 4 non-hematologic toxicity, subsequent dose escalation is prohibited.

[0099] If these criteria are met, the pelabusib monohydrate dose may be increased in increments of 25 mg QD no more frequently than once every two cycles, up to a maximum dose of 125 mg QD.

[0100] While several embodiments of this have been described, it will be apparent that the inventors' basic examples can be modified to provide other embodiments that utilize the compounds and methods of the present disclosure. It will therefore be appreciated that the scope of the present disclosure is intended to be defined by the appended claims rather than by the specific embodiments that have been presented by way of example.

[0101] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all scientific and technical terms used herein are to be given the meaning commonly known to those of ordinary skill in the art.

Claims

1. 1. A method of treating relatively low-risk myelodysplastic syndrome (LR-MDS) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of pelabrasib or a pharmaceutically acceptable salt thereof.

2. 10. The method of claim 1, wherein the subject is administered a therapeutically effective amount of pelabus.

3. 3. The method of claim 1 or 2, wherein the perabresib is a hydrate.

4. 4. The method of claim 1 or 3, wherein the perabresib is a monohydrate.

5. 5. The method of any one of claims 1 to 4, wherein the perabresive is in crystalline form.

6. 6. The method of any one of claims 1 to 5, wherein the perabresive is crystalline form A characterized by at least three, at least four, at least five, or six X-ray powder diffraction peaks at 2θ angles selected from 4.73°, 18.09°, 18.48°, 18.80°, 19.70°, and 25.17°.

7. 7. The method of any one of claims 1 to 6, wherein the perabresive is crystalline form A characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 4.73°, 18.09°, 18.48°, 18.80°, 19.70°, and 25.17°.

8. 8. The method of any one of claims 1 to 7, wherein the perabresive is crystalline form A characterized by at least four X-ray powder diffraction peaks at 2θ angles selected from 4.73°, 18.09°, 18.48°, 18.80°, 19.70°, and 25.17°.

9. 9. The method of any one of claims 1 to 8, wherein the perabresive is crystalline form A characterized by at least five X-ray powder diffraction peaks at 2θ angles selected from 4.73°, 18.09°, 18.48°, 18.80°, 19.70°, and 25.17°.

10. 10. The method of any one of claims 1 to 9, wherein the perabresive is crystalline form A characterized by X-ray powder diffraction peaks at 2θ angles selected from 4.73°, 18.09°, 18.48°, 18.80°, 19.70°, and 25.17°.

11. The method of any one of claims 1 to 10, wherein the LR-MDS is low-risk MDS.

12. The method of any one of claims 1 to 11, wherein the LR-MDS is very low-risk MDS.

13. The method of any one of claims 1 to 12, wherein the subject is anemic.

14. The method of any one of claims 1 to 13, wherein the subject is red blood cell transfusion dependent prior to treatment.

15. 15. The method of claim 14, wherein the subject becomes transfusion independent during treatment.

16. 16. The method of claim 14 or 15, wherein transfusion independence is characterized by a period of about 8 consecutive weeks without RBC transfusions during treatment.

17. 16. The method of claim 15, wherein transfusion independence is characterized by the absence of RBC transfusions for any 56 consecutive day period after initiation of treatment.

18. 18. The method of any one of claims 1-17, wherein the subject experiences an improvement in hemoglobin levels during treatment.

19. 20. The method of claim 18, wherein the improvement in hemoglobin is characterized by an increase in hemoglobin levels of about 1.0 g / dL or greater during treatment.

20. 20. The method of any one of claims 1-16, 18, and 19, wherein the subject becomes transfusion independent, characterized by no RBC transfusions for a period of about 8 consecutive weeks during treatment, and the subject experiences an improvement in hemoglobin, characterized by a mean hemoglobin increase of 1.0 g / dL or greater during the period of about 8 consecutive weeks of transfusion independence.

21. 20. The method of any one of claims 1-16, 18, and 19, wherein the subject becomes transfusion independent, characterized by no RBC transfusions for a period of about 8 consecutive weeks during treatment, and the subject experiences an erythroid response (mHI-E) defined as a reduction in RBC transfusions of 4 or more units during the period of about 8 consecutive weeks of transfusion independence.

22. 20. The method of any one of claims 1-16, 18, and 19, wherein the subject becomes transfusion independent, characterized by a period of about 8 consecutive weeks without RBC transfusions during treatment, and the subject experiences an erythroid response (mHI-E) defined as a mean hemoglobin increase of 1.5 g / dL or greater during the period of about 8 consecutive weeks of transfusion independence.

23. The method of any one of claims 1 to 22, wherein the subject experiences a neutrophilic response (HI-N) during treatment.

24. The subject has a baseline neutrophil count of 1.0 x 10 ９ For patients with <100% neutrophil count and ≥0.5 x 10 neutrophil count at all assessments during any consecutive 8-week period after baseline, for patients with <100% neutrophil count and ≥0.5 x 10 neutrophil count at all assessments during any consecutive 8-week period after baseline, ９ 24. The method of any one of claims 1 to 23, wherein the patient experiences a neutrophil response during treatment characterized by an absolute increase of >1000 neutrophils / L (HI-N).

25. The subject has 75×10 ９ The method of any one of claims 1 to 24, wherein the patient has a platelet count of 1 / L or more.

26. The subject has 75×10 ９ 25. The method of any one of claims 1 to 24, wherein the patient has a platelet count of less than 1 / L.

27. The subject has 50×10 ９ / L or more: 75 x 10 ９ 25. The method of any one of claims 1 to 24, wherein the patient has a platelet count of less than 1 / L.

28. The method of any one of claims 1 to 27, wherein the subject experiences a platelet response (HI-P) during treatment.

29. The object is 20 x 10 ９ / L ~ 100 x 10 ９ / L and a 30 x 10 increase from baseline at all assessments during any consecutive 8-week period after baseline ９ 25. The method of any one of claims 1 to 24, wherein the patient experiences a platelet response (HI-P) during treatment characterized by an absolute increase of 1 / L or more.

30. The object is 20 x 10 ９ 25. The method of any one of claims 1-24, wherein the patient has a baseline platelet count of less than 100 / L and experiences a platelet response during treatment characterized by a 100% or greater relative increase from baseline (HI-P) at all assessments during any consecutive 8-week period after baseline.

31. 31. The method of any one of claims 1-30, wherein the subject is administered about 75 mg / day of pelabusib.

32. The subject has 75 x 10 ９ 32. The method of claim 31 , wherein the patient has a baseline platelet count of less than 1 / L.

33. 31. The method of any one of claims 1-30, wherein the subject is administered about 125 mg / day of perabresib.

34. 31. The method of any one of claims 1-30, wherein the subject is administered about 150 mg / day of perabresib.

35. The subject has 75×10 ９ 35. The method of any one of claims 31, 33, and 34, wherein the patient has a baseline platelet count of 100 / L or greater.

36. 31. The method of any one of claims 1-30, wherein the subject is administered about 175 mg / day of perabresib.

Images