A CD47-SIRPα blocking agent for the treatment of cancer

Abstract

The present present disclosure relates to a CD47-SIRPα blocking agent of formula (I) stereoisomers thereof, and pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomer thereof for use in a method of treating or delaying progression of a disease or a disorder mediated by CD47-SIRPα pathway in a human subject suffering from said disease, such as cancer.

Description

[0001] A CD47-SIRPa BLOCKING AGENT FOR THE TREATMENT OF CANCER

[0002] TECHNICAL FIELD

[0003] The present disclosure relates to a method of treating or delaying progression of a disease or a disorder mediated by CD47-SIRPa pathway in a human subject suffering from said disease. More particularly, the disclosure relates to use in treatment of cancer, such as a haematological cancer.

[0004] BACKGROUND

[0005] Cluster of differentiation 47 (CD47) is a key immune checkpoint for macrophage mediated phagocytosis. CD47 is an immunoglobulin that is overexpressed on the surface of many types of cancer cells, including hematologic cancers such as Acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). AML is genetically heterogeneous hematologic malignancy characterized by multiple mutations and epigenetic dysregulation. While MDS is a heterogeneous group of myeloid disorders defined by a common set of features, of which the most prominent is morphologic bone marrow and peripheral blood dysplasia associated with inefficient haematopoiesis, the development of peripheral cytopenia and an increased risk of transformation to AML.

[0006] CD47 interacts with signalling complex with signal-regulatory protein a (SIRPa) to form CD47-SIRPa axis, which enables the escape of these cancer cells from macrophage- mediated phagocytosis and thus protects the cancer cells.

[0007] Targeting CD47-SIRPa axis using CD47-SIRPa blocking agents has emerged as one of the promising new immunotherapy approaches that target innate immune response. However, given the ubiquitous expression of CD47 on cancer cells as well as healthy cells, particularly hematopoietic cells, this approach has an inherent risk of safety, often resulting in cytotoxicity, more particularly anemia, thrombocytopenia, hyperbilirubinemia, leukopenia, and neutropenia. The use of CD47-SIRPa blocking agents may also affect solid tissues rich in macrophages such as liver, lung, and brain.

[0008] For solid tumors, there have been attempts to control or mitigate such side effects by using novel drug delivery systems for tumor specific delivery of CD47-SIRPa blocking agents, such as, tumor-targeting nanoparticles, or the use of antibody-drug conjugates for targeted delivery. For solid tumors as well as hematological cancers, monoclonal antibodies targeting CD47-SIRPa axis have also been tested in clinical setting (Zhao H, Song SS, Ma J, Yan ZY, Xie HW, Feng Y and Che SS (2022) CD47 as a promising therapeutic target in oncology. Front. Immunol. 13:757480).

[0009] Although approaches that block the CD47-SIRPa signalling axis have yielded promising preclinical results, with prominent induction of phagocytosis in various cancer types, reports of successful (experimental) clinical use of small molecule CD47 signalling pathways inhibitors for treatment of cancer, in particular hematological cancer, are extremely scarce. Treatment with CD47-SIRPa blocking therapeutics in patients is invariably associated with a lack of therapeutic effect at the maximum tolerated dose (MTD) and significant dose-limiting toxicity (DLT), most notably due to anaemia and thrombocytopenia.

[0010] It is an object of the present invention to provide methods that are efficacious in treating or delaying the progression of a disease or a disorder mediated by CD47-SIRPa pathway, with an acceptable safety profile.

[0011] SUMMARY

[0012] The present disclosure provides a safe and effective treatment of diseases or disorders mediated by CD47-SIRPa pathway, using a CD47-SIRPa blocking agent according to formula

[0013] Formula (I), stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof.

[0014] More in particular, the present disclosure is based, in one part, on the surprising finding that the CD47-SIRPa blocking agent of formula (I), as depicted below, is safe and well- tolerated up to a dose of 400 mg per oral BID, a total daily dose of 600 mg, or a total daily dose of 800 mg, with PD biomarker analysis indicating favorable modulation of cytokines and chemokines, which is indicative of the efficacy of the compound of formula (I) against cancer. Most surprisingly, the hematological safety of the compound of formula (I) was exceptionally high, with no grade 3 or grade 4 adverse events, and no hemolytic anemia in any of the tested subjects. The experimental findings underlying the present disclosure, provide strong support for the use of the CD47-SIRPa blocking agent in treating or delaying the progression of hematological cancers such as Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) in human subjects.

[0015] The compound of formula (I) has been disclosed in PCT publication WO2019 / 138367, which is directed to a larger group of 1,2,4-oxadiazole compounds as small molecule CD47 signalling pathways inhibitors. In the field of cancer treatment in particular, selecting the best compound and the most appropriate dose to provide a positive balance of efficacy and safety has been a challenge because of toxicities, compatibility issues, etc. The risk with small molecule therapeutics is particularly high when the small molecule anticancer agents target a ubiquitously expressed protein such as CD-47 as it can lead to serious hematological toxicities.

[0016] In a first aspect, a method of treating or delaying progression of a disease or a disorder mediated by CD47-SIRPa pathway in a human subject is provided, comprising the oral administration of a CD47-SIRPa blocking agent selected from the group consisting of a compound of formula (I), stereoisomers thereof, and pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomers thereof, wherein the method comprises the oral administration of the compound of formula (I) or stereoisomer thereof to the subject in a total oral daily dosage not exceeding 800 mg, preferably not exceeding 600, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or a molar equivalent amount or equipotent amount of a pharmaceutically acceptable salt, solvate, amide or esters of the compound of formula (I) or stereoisomer thereof.

[0017] A second aspect provides a CD47-SIRPa blocking agent selected from the group consisting of a compound of formula (I), stereoisomers thereof, and pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomers thereof; for use in a method of treating or delaying progression of a disease or a disorder mediated by CD47-SIRPa pathway in a human subject suffering from said disease or disorder, wherein the method comprises oral administration of the compound of formula (I) or stereoisomer thereof, to the subject, in a total oral daily dosage not exceeding 800 mg, preferably not exceeding 600, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or a molar equivalent amount or equipotent amount of a pharmaceutically acceptable salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof.

[0018] Yet a further aspect provides the use of a CD47-SIRPa blocking agent selected from the group consisting of a compound of formula (I), stereoisomers thereof, and a pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomers thereof; in the manufacture of a pharmaceutical composition or medicament for use in a method of treating or delaying progression of a disease or a disorder mediated by CD47-SIRPa pathway in a human subject suffering from said disease or disorder, wherein the method comprises oral administration of the compound of formula (I), or stereoisomer thereof, to the human subject in a total oral daily dosage not exceeding 800 mg, preferably not exceeding 600, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or a molar equivalent amount or equipotent amount of a pharmaceutically acceptable salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof.

[0019] In still a further aspect, a kit is provided comprising:

[0020] (i) A plurality of pharmaceutical composition, preferably in unit dosage form, comprising a CD47-SIRPa blocking agent selected from the group consisting of a compound of formula (I), stereoisomers thereof, and a pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomers thereof; and

[0021] (ii) a package and / or package insert, said package and / or insert having instructions printed thereon, to use said pharmaceutical compositions in a method of treating or delaying progression of a disease or a disorder mediated by CD47-SIRPa pathway in a human subject, wherein the instructions provide that the method comprises oral administration of the compound of formula (I) or stereoisomers thereof, to the subject in a total oral daily dosage not exceeding 800 mg, preferably not exceeding 600, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or a molar equivalent amount or equipotent amount of a pharmaceutically acceptable salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof.

[0022] In particularly preferred embodiments, the disease or a disorder mediated by CD47- SIRPa pathway is Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS).

[0023] Yet further aspects of the present disclosure provide, amongst others, pharmaceutical compositions, especially in unit dosage form, comprising a CD47-SIRPa blocking agent, selected from the group consisting of the compound of formula (I), stereoisomers thereof, and pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomer thereof. Typically, such pharmaceutical compositions are specifically adapted and / or suited for use in the methods of the present disclosure.

[0024] Specific details and preferred embodiments of the afore mentioned methods as well as of the compositions and pharmaceutical kits used therein will become evident to those skilled in the art on the basis of the following detailed description and experimental information. DEFINITIONS

[0025] The term “stereoisomer” as used herein refers to the field of stereochemistry, stereoisomerism or spatial isomerism. Stereoisomer is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution) but differ in the three-dimensional orientations of their atoms in space. Broadly, the stereoisomer includes enantiomers and diastereomers along with the sub-types thereof, including but not limited to meso compounds, cis-trans isomers, E-Z isomers, non-enantiomeric optical isomers etc.

[0026] The term “amide ” or “amide derivative(s) ” or “carboxamide ” as used herein refers to a functional group of general formula R-C(=O)-NR'R", where R, R, and R" represent any group including hydrogen atoms. Amides can be viewed as a derivative of a carboxylic acid R-C(=O)-OH wherein the hydroxyl group (-OH) is replaced by an amine group (-NR'R").

[0027] The term “ester” as used herein refers to a functional group of general formula R-C(=O)-OR’, where R and R’ represents any group and R’ cannot be hydrogen. Esters can be viewed as a derivative of a carboxylic acid R-C(=O)-OH wherein the hydrogen of hydroxyl group (-OH) is replaced by R’ .

[0028] The term “pharmaceutical composition” as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.

[0029] The term “pharmaceutically acceptable” as used herein has its conventional meaning and refers to compounds, material, compositions and / or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.

[0030] The term “salt” as used herein has its conventional meaning and includes the acid addition and base salts of a pharmaceutically active compound.

[0031] The term “solvate” as used herein has its conventional meaning and refers to a compound formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute. Well known solvent molecules include water, alcohols, nitriles and polar organic solvents.

[0032] The term “subject” as used herein refers to humans suffering from or at risk for a certain disease or disorder. The term “subject” and “patient” herein are used interchangeably.

[0033] The terms "treat", "treating" or "treatment", when used in conjunction with a specific disease or symptom (for example: “method of treating disease ... ”) refer to and / or encompass curing, alleviating or abrogating said disease and / or accompanying symptoms, diminishing extent of disease, stabilizing (i.e. not worsening) the state of disease, delaying or slowing of disease progression, ameliorating the disease state, prolonging survival (as compared to expected survival without treatment), etc. Treatment need not mean that the disease, disorder, or condition is totally cured. To be an effective treatment, a useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of one or more symptoms associated therewith, or provide improvement to a patient or subject’s quality of life. The terms “treat”, “treating” or “treatment”, when used in relation to a patient or subject (for example: “method of treating a subject”), typically refers to the act of administering a therapeutic compound to said patient or subject for whatever therapeutic and / or prophylactic purpose.

[0034] The terms "prevent", "preventing" or "prevention", as used herein, refer to and / or encompass the delay, prevention, suppression, or inhibition of the onset of a disease, disorder, or condition. As used in accordance with the presently described subject matter, the term “prevention ” relates to a process of prophylaxis in which a subject is given the presently described compositions or formulations prior to the induction or onset of the disease / disorder process. The term “suppression” is used to describe a condition wherein the disease / disorder process has already begun but obvious symptoms of the condition have yet to manifest. Thus, an individual may have the disease / disorder, but no outside signs of the disease / disorder have yet been clinically recognized. In either case, the term prophylaxis can be applied to encompass both prevention and suppression.

[0035] The term “molar equivalent” or “equimolar” in the context of a salt, solvate, amide and ester, or stereoisomers of the compound of formula (I) refers to the moles or molar concentration equivalent to corresponding free acid or base of the compound of formula (I), or stereoisomer thereof.

[0036] The term “equipotent” in the context of a salt, solvate, amide and ester, or stereoisomers of the compound of formula (I) refers to a dose or dosage that has an equivalent potency as the corresponding free acid or base of the compound of formula (I), or stereoisomer thereof. It is also common in the art to refer to amounts of a given compound ‘equivalent’ to a specified amount of a reference compound. In expressing dose amounts in the label and / or product information of authorized medicinal products comprising a salt form of an active compound that can also be used in free base form, it is customary practice to specify the dose of the free base to which the dose of the salt as used is equivalent. In this context, the term ‘equipotent’ is deemed synonymous to the term ‘equivalent’. DETAILED DESCRIPTION OF THE INVENTION

[0037] Compounds and Pharmaceutical Compositions

[0038] As defined herein before, the methods of the present disclosure comprise the administration of the CD47-SIRPa blocking agent, typically in the form of a pharmaceutical composition or in unit dosage form, wherein said CD47-SIRPa blocking agents, selected from the group consisting of the compound of formula (I):

[0039] Formula (I), stereoisomers thereof, and pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomer thereof.

[0040] As already explained before, the compound of formula (I) has been disclosed in PCT publication WO2019 / 138367, which also teaches methods for preparing this compound.

[0041] In one embodiment, the pharmaceutically acceptable salts of compound of formula (I) is selected from a Calcium, Magnesium, Potassium and Sodium salts of the compound of formula (I). In another embodiment, the compound of formula (I) is a Calcium salt of the compound of formula (I). In yet another embodiment, the compound of formula (I) is a Sodium salt of the compound of formula (I).

[0042] In a particularly preferred embodiment, the CD47-SIRPa blocking agent is selected from the group consisting of the compound of formula (I) pharmaceutically acceptable salts thereof, solvates and hydrates thereof, more preferably from the group consisting of the compound of formula (I), the calcium salt thereof and solvates and hydrates thereof.

[0043] The present disclosure provides the CD47-SIRPa blocking agent in the form of a pharmaceutical composition. As used herein, the term “pharmaceutical composition” has its conventional meaning and refers to a composition which is pharmaceutically acceptable. The term ‘pharmaceutically acceptable’ as used herein has its conventional meaning and refers to compounds, materials, compositions and / or dosage forms, which are, within the scope of sound medical judgment can be administered to a human and / or placed in contact with the tissues of humans, without excessive toxicity, irritation, allergic response and other complications, commensurate with a reasonable benefit / risk ratio. The pharmaceutical composition of the present disclosure comprises, besides the CD47-SIRPa blocking agent, one or more additional ingredients. In a preferred embodiment, the composition comprises one or more additional ingredients that render the composition suitable for administration to subjects in need thereof, such as one or more carriers and / or excipients. As is known by those of average skill in the art, the appropriate choice of excipients is largely dependent on the pharmaceutical form and route of administration preferred. The compositions of the disclosure can be formulated for a variety of routes of administration, oral administration being particularly preferred. It is within the purview of those of average skill in the art to conceive and develop suitable formulations, relying on the common general knowledge as reflected in text books such as Remington's Pharmaceutical Sciences (Meade Publishing Co., Easton, Pa., 20thEd., 2000), the entire disclosure of which is herein incorporated by reference, and routine development efforts.

[0044] In accordance with the various aspects of the present disclosure, the pharmaceutical composition is preferably provided in a unit dosage form. Hence, the present disclosure also provides the CD47-SIRPa blocking agent in unit dosage form. The term 'unit dosage form' refers to a physically discrete unit suitable as a unitary dosage for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with any suitable pharmaceutical carrier(s) and / or excipient(s). Exemplary, non-limiting unit dosage forms include a tablet (e.g., a chewable tablet), caplet, capsule (e.g., a hard capsule or a soft capsule), lozenge, film, strip, gelcap as well as any metered volume of a solution, suspension, syrup or elixir or the like, which may be contained, for instance in a vial, syringe, applicator device, sachet, spray, micropump etc. In accordance with particularly preferred embodiments of the present disclosure, the unit dosage form, is a unit dosage form that is suitable for oral administration, preferably a tablet or capsule.

[0045] In one embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the CD47-SIRPa blocking agent at an amount not exceeding 800 mg, preferably not exceeding 600 mg, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg. In one embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the CD47-SIRPa blocking agent at an amount of 50 mg to 800 mg. In another embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the CD47-SIRPa blocking agent at an amount of 50 mg to 100 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 50 mg to 200 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 50 mg to 400 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 50 mg to 800 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 100 mg to 200 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 100 mg to 400 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 100 mg to 800 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 200 mg to 400 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 300 mg to 600 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 200 mg to 800 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 400 mg to 800 mg. In another embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the CD47-SIRPa blocking agent at an amount of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg or 800 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 50 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 100 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 200 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 400 mg. In another embodiment, the amount of the CD47-SIRPa blocking agent is 600 mg In another embodiment, the amount of the CD47-SIRPa blocking agent is 800 mg.

[0046] In one embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount not exceeding 800 mg, preferably not exceeding 600 mg, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the molar equivalent amount. In one embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount of 50 mg to 800 mg, or a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the molar equivalent amount. In another embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount of 50 mg to 100 mg; 50 mg to 200 mg; 50 mg to 400 mg; 50 mg to 800 mg; 100 mg to 200 mg; 100 mg to 400 mg; 100 mg to 800 mg; 200 mg to 400 mg; 200 mg to 800 mg; 300 mg to 600 mg, or 400 mg to 800 mg, or a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the molar equivalent amount. In another embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg or 800 mg, or a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the molar equivalent amount. In other embodiments, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg, or a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the molar equivalent amount.

[0047] In one embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount not exceeding 800 mg, preferably not exceeding 600 mg, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the equipotent amount. In one embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount of 50 mg to 800 mg, or a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the equipotent amount. In another embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount of 50 mg to 100 mg; 50 mg to 200 mg; 50 mg to 400 mg; 50 mg to 800 mg; 100 mg to 200 mg; 100 mg to 400 mg; 100 mg to 800 mg; 200 mg to 400 mg; 200 mg to 800 mg; or 400 mg to 800 mg, or a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the equipotent amount. In another embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg or 800 mg, or a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the equipotent amount. In other embodiments, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg, or a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the equipotent amount.

[0048] In one embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount not exceeding 800 mg, preferably not exceeding 600 mg, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg. In one embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount of 50 mg to 800 mg. In another embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount of 50 mg to 100 mg; 50 mg to 200 mg; 50 mg to 400 mg; 50 mg to 800 mg; 100 mg to 200 mg; 100 mg to 400 mg; 100 mg to 800 mg; 200 mg to 400 mg; 200 mg to 800 mg; 300 mg to 600 mg, or 400 mg to 800 mg. In another embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) at an amount of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg or 800 mg. In other embodiments, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the compound of formula (I) is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg.

[0049] In one embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the calcium salt of the compound of formula (I) at an amount not exceeding 800 mg, preferably not exceeding 600 mg, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg. In one embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the calcium salt of the compound of formula (I) at an amount of 50 mg to 800 mg. In another embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the calcium salt of the compound of formula (I) at an amount of 50 mg to 100 mg; 50 mg to 200 mg; 50 mg to 400 mg; 50 mg to 800 mg; 100 mg to 200 mg; 100 mg to 400 mg; 100 mg to 800 mg; 200 mg to 400 mg; 200 mg to 800 mg; 300 mg to 600 mg, or 400 mg to 800 mg. In another embodiment, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the calcium salt of the compound of formula (I) at an amount of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg or 800 mg. In other embodiments, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the calcium salt of the compound of formula (I) is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg.

[0050] In accordance with certain embodiments of the present disclosure, the pharmaceutical composition as defined herein, further comprises azacitidine or a pharmaceutically acceptable salt thereof as a further active pharmaceutical ingredient. Azacitidine is the international nonproprietary name (INN) of the compound having the IUPAC name 4-Amino-l-P-D- ribofuranosyl-s-triazin-2(lH)-one and the following structural formula (II)

[0051] Formula (II),

[0052] In accordance with the present disclosure, Azacitidine may be used in free base form as well as in the form of a pharmaceutically acceptable salt. Salts suitable for the purposes of the present disclosure include acid addition salts, such as salts formed with an acid having a pKaof about 5 or less, preferably an acid selected from the group consisting of hydrochloric, L-lactic, acetic, phosphoric, (+)-L-tartaric, citric, propionic, butyric, hexanoic, L-aspartic, L-glutamic, succinic, EDTA, maleic, methanesulfonic acid, HBr, HF, HI, nitric, nitrous, sulfuric, sulfurous, phosphorous, perchloric, chloric, chlorous acid, carboxylic acid, sulfonic acid, ascorbic, carbonic, and fumaric acid.

[0053] Medicinal products comprising Azacitidine as the sole active pharmaceutical ingredient have received regulatory approval for the treatment of (adult) patients with acute myeloid leukaemia (AML), higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), via oral administration as well as via subcutaneous injection. It will be understood by those skilled in the art, based on the present teachings, that it may be beneficial, in certain embodiments, to provide the CD47-SIRPa blocking agent and azacitidine, or a pharmaceutically acceptable salt of Azacitidine, in the form of an oral fixed dose combination (FDC) product, in particular in the form of a unit dosage form, such as a tablet or capsule, as described herein, comprising azacitidine or a pharmaceutically acceptable salt thereof, in addition to the CD47-SIRPa blocking agent.

[0054] In accordance with preferred embodiments of the present disclosure, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the Azacitidine or a pharmaceutically acceptable salt thereof in an amount of at least about 25 mg, more preferably at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg or at least about 200 mg. In accordance with the various aspects of the present disclosure, the composition is provided in a unit dosage form comprising Azacitidine or a pharmaceutically acceptable salt thereof in an amount of about 500 mg or less, more preferably about 450 mg or less, about 400 mg or less, about 350 mg or less, about 325 mg or less or about 300 mg or less. In accordance with embodiments of the present disclosure, the pharmaceutical composition is provided in a unit dosage form comprising Azacitidine or a pharmaceutically acceptable salt thereof in an amount of about 100-400 mg, more preferably in an amount of about 150-350 mg, most preferably in an amount of about 200-300 mg, e.g. in an amount of about 200 mg or in an amount of about 300 mg of Azacitidine or a pharmaceutically acceptable salt thereof.

[0055] In accordance with preferred embodiments of the present disclosure, the pharmaceutical composition is provided in a unit dosage form as defined herein, which unit dosage form comprises the Azacitidine in an amount of at least about 25 mg, more preferably at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg or at least about 200 mg, or a pharmaceutically acceptable salt of Azacitidine in the equimolar or equipotent amount. In accordance with the various aspects of the present disclosure, the composition is provided in a unit dosage form comprising Azacitidine in an amount of about 500 mg or less, more preferably about 450 mg or less, about 400 mg or less, about 350 mg or less, about 325 mg or less or about 300 mg or less, or a pharmaceutically acceptable salt of Azacitidine in the equimolar or equipotent amount. In present disclosure accordance with embodiments of the, the pharmaceutical composition is provided in a unit dosage form comprising Azacitidine in an amount of about 100-400 mg, more preferably in an amount of about 150-350 mg, most preferably in an amount of about 200- 300 mg, e.g. in an amount of about 200 mg or in an amount of about 300 mg or a pharmaceutically acceptable salt of Azacitidine in the equimolar or equipotent amount. Therapeutic indications

[0056] The methods of the present disclosure, comprising the administration of the CD47- SIRPa blocking agent, typically in the form of a pharmaceutical composition or unit dosage form as defined herein before, are intended to, directed at and / or effective in treating or delaying the progression of a disease or a disorder mediated by CD47-SIRPa pathway.

[0057] In one embodiment, the disease or disorder mediated by CD47-SIRPa pathway is a cancer.

[0058] In one embodiment, the disease or disorder mediated by CD47-SIRPa pathway is a solid cancer.

[0059] In one embodiment, the disease or disorder mediated by CD47-SIRPa pathway is selected from the group consisting of breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, oropharyngeal cancer, nasopharyngeal cancer, cervical cancer, stomach cancer, pancreatic cancer and liver cancer.

[0060] In one embodiment, the disease or disorder mediated by CD47-SIRPa pathway is a hematological cancer.

[0061] In one embodiment, the disease or disorder mediated by CD47-SIRPa pathway is leukemia.

[0062] In one embodiment, the disease or disorder mediated by CD47-SIRPa pathway is Acute Myeloid Leukemia (AML) or Myelodysplastic syndrome (MDS).

[0063] In yet another embodiment, AML is a newly diagnosed AML or a relapsed and / or refractory AML.

[0064] In a preferred embodiment of the present disclosure, the disease or disorder mediated by CD47-SIRPa pathway is Acute Myeloid Leukemia (AML), wherein the treatment is characterized by the treated subject achieving at least one of the following response criteria according to European Leukemia Net (ELN-2017) after at least one treatment cycle comprising 28 days of treatment: a. Complete remission; b. Complete remission with incomplete hematologic recovery; c. Morphologic leukemia free state; d. Partial remission; or, e. Stable Disease lasting 3 months or more.

[0065] In one embodiment, the disease or disorder mediated by CD47-SIRPa pathway is Myelodysplastic syndrome (MDS), and wherein the treatment is characterized by the treated subject achieving at least one of the following response criteria according to International Working Group (IWG) 2006: a. Complete remission; b. Partial remission; c. Stable disease; or d. Hematological Improvement.

[0066] In certain embodiments of the present disclosure, the administration of the CD47-SIRPa blocking agent achieves a steady state plasma level of the CD47-SIRPa blocking agent with a very beneficial safety and efficacy profile.

[0067] In one embodiment, at steady state plasma levels of the CD47-SIRPa blocking agent, the subject does not display a grade 4 thrombocytopenia with clinically significant bleeding and / or a grade 4 anemia that cannot be attributed to the underlying disease or disorder.

[0068] In one embodiment, the method does not result in thrombocytopenia or anemia. Preferably, the administration to a subject suffering from a disease or a disorder mediated by CD47-SIRPa pathway, does not result in grade 4 thrombocytopenia with clinically significant bleeding or grade 4 anemia that cannot be attributed to the underlying disease or disorder.

[0069] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 50 mg to 800 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0070] (a) a mean plasma Cmax of about 345 ng / ml to about 7000 ng / mL;

[0071] (b) a mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;

[0072] (c) a mean plasma retention time (MRT) of about 6 to 8 hours; and

[0073] (d) a mean plasma AUC0-12 of about 3200 hr x ng / mL to 68000 hr x ng / mL.

[0074] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 50 mg to 800 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a the steady state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0075] (a) a mean plasma Cmax of about 354 ± 5.67 ng / ml to about 4711 ± 2288 ng / mL;

[0076] (b) a mean plasma Tmax of about 4.67 ± 1. 15 to 6.67 ± 1.15 hours; (c) a mean plasma retention time (MRT) of about 5.99 ± 0.13 to 6.38 ± 0.25 hours; or

[0077] (d) a mean plasma AUC0-12 of about 3465 ± 169 hr x ng / mL to 45152 ± 22832 hr x ng / mL.

[0078] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 50 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a steady state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0079] (a) a steady state mean plasma Cmax of about 345 to about 355 ng / ml;

[0080] (b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;

[0081] (c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; and

[0082] (d) a steady state mean plasma AUC0-12 of about 3200 to about 3600 hr x ng / mL.

[0083] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 50 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a steady state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0084] (a) a steady state mean plasma Cmax of about 354 ± 5.67 ng / ml;

[0085] (b) a steady state mean plasma Tmax of about 6.67 ± 1.15 hours;

[0086] (c) a steady state mean plasma retention time (MRT) of about 6.38 ± 0.25 hours; and

[0087] (d) a steady state mean plasma AUC0-12 of about 3200 to about 3465 ± 169 hr x ng / mL.

[0088] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 100 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a steady state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0089] (a) a steady state mean plasma Cmax of about 410 to about 950 ng / ml;

[0090] (b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;

[0091] (c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; and

[0092] (d) a steady state mean plasma AUC0-12 of about 4200 to about 9200 hr x ng / mL.

[0093] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 100 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a steady state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0094] (a) a steady state mean plasma Cmax of about 678 ± 268 ng / ml;

[0095] (b) a steady state mean plasma Tmax of about 6.67 ± 4.62 hours;

[0096] (c) a steady state mean plasma retention time (MRT) of about 6.05 ± 0.34 hours; and

[0097] (d) a steady state mean plasma AUC0-12 of about 6669 ± 2479 hr x ng / mL.

[0098] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 200 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a steady state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0099] (a) a steady state mean plasma Cmax of about 500 to about 1250 ng / ml;

[0100] (b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;

[0101] (c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; and

[0102] (d) a steady state mean plasma AUC0-12 of about 5100 to about 12700 hr x ng / mL.

[0103] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 200 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a steady state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0104] (a) a steady state mean plasma Cmax of about 873 + 372 ng / ml;

[0105] (b) a steady state mean plasma Tmax of about 4.75 + 1.50 hours;

[0106] (c) a steady state mean plasma retention time (MRT) of about 6.06 + 0.29 hours; and

[0107] (d) a steady state mean plasma AUC0-12 of about 8890 + 3807 hr x ng / mL.

[0108] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 400 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, wherein the method achieves a steady state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of: (a) a steady state mean plasma Cmax of about 1170 to about 1920 ng / ml;

[0109] (b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;

[0110] (c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; and

[0111] (d) a steady state mean plasma AUC0-12 of about 11000 to about 20000 hr x ng / mL.

[0112] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 400 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a steady state plasma level of the compound of formula (I), characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0113] (a) a steady state mean plasma Cmax of about 1545 ± 374 ng / ml;

[0114] (b) a steady state mean plasma Tmax of about 6 hours;

[0115] (c) a steady state mean plasma retention time (MRT) of about 6.24 ± 0.24 hours; and

[0116] (d) a steady state mean plasma AUC0-12 of about 15584 ± 4532 hr x ng / mL.

[0117] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 800 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a steady state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0118] (a) a steady state mean plasma Cmax of about 2400 to about 7000 ng / ml;

[0119] (b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;

[0120] (c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; and

[0121] (d) a steady state mean plasma AUC0-12 of about 22000 to about 68000 hr x ng / mL.

[0122] In one embodiment, the method comprises oral administration to the human subject in a total daily dosage of 800 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and the method achieves a steady state plasma level of the compound of formula (I), characterized by one or more of the following properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:

[0123] (a) a steady state mean plasma Cmax of about 4711 ± 2288 ng / ml;

[0124] (b) a steady state mean plasma Tmax of about 4.67 ± 1.15 hours;

[0125] (c) a steady state mean plasma retention time (MRT) of about 5.99 ± 0.13 hours; and

[0126] (d) a steady state mean plasma AUC0-12 of about 45152 ± 22832 hr x ng / mL. Subjects to be treated

[0127] The methods of the present disclosure treat or delay the progression of a disease, or a disorder mediated by CD47-SIRPa pathway in a human subject. Hence, in preferred embodiments of the present disclosure, the human subject is a subject suffering from a disease or disorder mediated by CD47-SIRPa pathway. In one embodiment, the human subject is a subject suffering from a relapsing or refractory form of a disease or disorder mediated by CD47-SIRPa pathway. In one embodiment, the human subject is a subject at risk of suffering from a disease or disorder mediated by CD47-SIRPa pathway, especially a subject at risk of suffering from a relapse of a disease or disorder mediated by CD47-SIRPa pathway. Diseases or disorders mediated by CD47-SIRPa pathway can in principle occur and / or manifest at any stage in life but are most common in older adults. Hence, the subject to be treated in accordance with the present disclosure can typically have any age above 12 years, such an age ranging from 12-99 years. However, in preferred embodiments of the present disclosure the subject has an age of 40 years or older, such as 50 years or older, 55 years or older, 60 years or older or 65 years or older. In one embodiment of the present disclosure, the subject is human male. In another embodiment of the present disclosure, the subject is human female.

[0128] In one embodiment, the subject is a subject suffering from Acute myeloid leukemia (AML). In one embodiment, the subject is a subject diagnosed with AML. In one embodiment of the present disclosure, the subject has a positive diagnosis of AML according to the World Health Organization (WHO 2016) criteria. The WHO 2016 criteria categorizes AML into several groups. These include AML with certain genetic abnormalities, AML with myelodysplasia-related changes, AML related to previous chemotherapy or radiation, AML with minimal differentiation, AML without maturation, AML with maturation, acute myelomonocytic leukemia, acute monoblastic / monocytic leukemia, pure erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with fibrosis, myeloid sarcoma (also known as granulocytic sarcoma or chloroma), myeloid proliferations related to down syndrome [Arber DA, Orazi A, Hasseijian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405],

[0129] In one embodiment, the subject is a subject newly diagnosed with AML. In one embodiment, the human subject is a subject suffering from a relapsed and / or refractory AML. In one embodiment, the human subject is a subject suffering from a relapsed and / or refractory AML has received at least one line of previous therapy. In one embodiment, the human subject is a subject suffering from a relapsed and / or refractory AML has received at least one line of previous therapy and is eligible for one or more second or later line(s) of treatment. In one embodiment, wherein at least one line of previous therapy does not comprise a hypomethylating agent. In one embodiment, one of the second or later line of treatments is a therapeutically effective dose of Azacitidine, or a pharmaceutically acceptable salt thereof. In one embodiment, the subject is a subject diagnosed with relapsed / refractory AML who has received at least one line of previous therapy other than hypomethylating agents, and is eligible for receiving Azacitidine. In one embodiment, the subject is a newly diagnosed subject suffering from AML that is not eligible for intensive chemotherapy.

[0130] In one embodiment, the subject is a subject suffering from Myelodysplastic syndrome (MDS). In one embodiment, the subject is a subject diagnosed with MDS. In one embodiment of the present disclosure, the subject has a positive diagnosis of MDS according to the World Health Organization (WHO 2016) criteria. The WHO 2016 criteria divide MDS into several groups. These include, MDS with single lineage dysplasia, MDS with multilineage dysplasia MDS with ring sideroblasts (MDS-RS), MDS with excess blasts, MDS with isolated del(5q), MDS, unclassifiable (MDS-U) [Arber DA, Orazi A, Hasseijian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405],

[0131] The IWG criteria 2006 define 4 aspects of responses based on treatment goals: (1) altering the natural history of the disease, (2) cytogenetic response, (3) hematologic improvement (HI), and (4) QOL as provided in the below:

[0132] International Working Group (IWG) response criteria 2006 for altering natural history of MDS

[0133] To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.

[0134] MDS indicates myelodysplastic syndromes; Hgb, hemoglobin; CR, complete remission; HI, hematologic improvement; PR, partial remission; FAB, French-American-British; AML, acute myeloid leukemia; PFS, progression-free survival; DFS, disease-free survival.

[0135] * Dysplastic changes should consider the normal range of dysplastic changes (modification), t Modification to IWG response criteria.

[0136] { In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, maintenance) before the 4-week period. Such patients can be included in the response category into which they fit at the time the therapy is started. Transient cytopenias during repeated chemotherapy courses should not be considered as interrupting durability of response, as long as they recover to the improved counts of the previous course.

[0137] [Bruce D. Cheson et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia Blood (2006) 108 (2): 419-425],

[0138] In one embodiment, the subject is a subject newly diagnosed with MDS. In one embodiment, the human subject is a subject suffering from a relapsed and / or refractory MDS. In one embodiment, the human subject is a subject suffering from a relapsed and / or refractory MDS has received at least one line of previous therapy. In one embodiment, the subject suffering from MDS is an intermediate risk, high risk, or a very high-risk MDS subject. In one embodiment, the subject suffering from MDS is an intermediate risk, high risk, or a very high- risk MDS subject who is eligible to receive Azacitidine. In an embodiment, the subject suffering from MDS has a Revised International Prognostic Scoring System (IPSS-R) > 3.5. IPSS-R is a prognostic score values, and is determined by combining the scores of five disease factors: BM Blasts, Cytogenetics, Hemoglobin, Platelet count and Absolute neutrophil count (ANC) [Peter L. Greenberg et al. Revised International Prognostic Scoring System for Myelodysplastic Syndromes. Blood. 2012 Sep 20; 120(12): 2454-2465] ,

[0139] In an embodiment, the subject has not been previously treated with a hypomethylating agent. In an embodiment, the subject suffering from MDS is eligible for one or more second or later line(s) of treatment. In an embodiment, the one of the second or later line of treatments is a therapeutically effective dose of Azacitidine, or a pharmaceutically acceptable salt thereof.

[0140] In one embodiment, the human subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status Scale of 0 - 2. ECOG performance status scale assesses a patient’s disease progression, daily living abilities, and guides treatment decisions based on a 5 -point scale ranging from grade 0 to grade 5 as defined below:

[0141] In another embodiment, the human subject meets at least one of the criteria a) and b), preferably the human subject meets both criteria a) and b): a) bone marrow assessment characterized by: i. WBC < 20,000 / pL, wherein hydroxyurea can be given to bring WBC count to < 20,000 / pl; ii. Platelet count > 50,000 / pL without transfusion support; and / or iii. Hemoglobin > 9 g / dL, wherein transfusion is allowed to achieve this Hb; and / or, b) organ function characterized by: i. Total Bilirubin < 1.5 x Upper Limit Normal (ULN); or < 2.5 x ULN if the subject has Gilbert’s syndrome; ii. AST (SGOT) < 3 x ULN (< 5 x ULN if the subject has liver metastases); iii. ALT (SGPT) < 3 x ULN (< 5 x ULN if the subject liver metastases); iv. Creatinine clearance (CrCl) > 60 mL / min; and / or v . Albumin > 3.0 g / dL .

[0142] Treatment Regimens

[0143] The methods of the present disclosure, treating or delaying the progression of a disease or a disorder mediated by CD47-SIRPa pathway in a human subject, comprise the administration of the CD47-SIRPa blocking agent, typically in the form of any of the pharmaceutical compositions or unit dosage forms defined herein elsewhere.

[0144] In one embodiment, the method comprises the oral administration of the CD47- SIRPa blocking agent at a total daily dose not exceeding 800 mg, preferably not exceeding 600 mg, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg.

[0145] In one embodiment, the method comprises the oral administration of the CD47-SIRPa blocking agent at a total daily dose of 50 mg to 800 mg. In another embodiment, the method comprises the oral administration of the CD47-SIRPa blocking agent at an amount of 50 mg to 100 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 50 mg to 200 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 50 mg to 400 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 50 mg to 800 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 100 mg to 200 mg. In another embodiment, the total daily dose of the CD47- SIRPa blocking agent is 100 mg to 400 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 100 mg to 800 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 200 mg to 400 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 200 mg to 800 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 400 mg to 800 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 300 mg to 600 mg. In a preferred embodiment, the total daily dose of the CD47-SIRPa blocking agent is 600 mg. In another embodiment, the method comprises the oral administration of the CD47-SIRPa blocking agent at a total daily dose of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg or 800 mg. In another embodiment, the total daily dose of the CD47- SIRPa blocking agent is 50 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 100 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 200 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 300 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 400 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 600 mg. In another embodiment, the total daily dose of the CD47-SIRPa blocking agent is 800 mg.

[0146] In one embodiment, the method comprises the oral administration of the compound of formula (I) at a total daily dose not exceeding 800 mg, preferably not exceeding 600 mg, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or the oral administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the molar equivalent dose. In one embodiment, the method comprises the oral administration of a compound of formula (I) at a total daily dose of 50 mg to 800 mg, or the oral administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the molar equivalent dose. In another embodiment, the method comprises the oral administration of a compound of formula (I) at a total daily dose of 50 mg to 100 mg; 50 mg to 200 mg; 50 mg to 400 mg; 50 mg to 800 mg; 100 mg to 200 mg; 100 mg to 400 mg; 100 mg to 800 mg; 200 mg to 400 mg; 200 mg to 800 mg; or 400 mg to 800 mg, or the oral administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the molar equivalent dose. In another embodiment, the method comprises the oral administration of a compound of formula (I) at an total daily dose of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg or 800 mg, or the oral administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the molar equivalent dose. In other embodiments, the method comprises the oral administration of the compound of formula (I) at a total daily dose of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg, or the oral administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the molar equivalent dose.

[0147] In one embodiment, the method comprises the oral administration of the compound of formula (I) at a total daily dose not exceeding 800 mg, preferably not exceeding 600 mg, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or the oral administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the equipotent dose. In one embodiment, the method comprises the oral administration of the compound of formula (I) at a total daily dose of 50 mg to 800 mg, or the oral administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the equipotent dose. In another embodiment, the method comprises the oral administration of the compound of formula (I) at a total daily dose of 50 mg to 100 mg; 50 mg to 200 mg; 50 mg to 400 mg; 50 mg to 800 mg; 100 mg to 200 mg; 100 mg to 400 mg; 100 mg to 800 mg; 200 mg to 400 mg; 200 mg to 800 mg; 300 mg to 600 mg, or 400 mg to 800 mg, or the oral administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the equipotent dose. In another embodiment, the method comprises the oral administration of the compound of formula (I) at a total daily dose of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg or 800 mg, or the oral administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the equipotent dose. In other embodiments, the method comprises the oral administration of the compound of formula (I) at a total daily dose of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg, or the oral administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof, at the equipotent dose.

[0148] In one embodiment, the method comprises the oral administration of the compound of formula (I) at a total daily dose not exceeding 800 mg, preferably not exceeding 600 mg, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg. In one embodiment, the method comprises the oral administration of the compound of formula (I) at a total daily dose of 50 mg to 800 mg. In another embodiment, the method comprises the oral administration of the compound of formula (I) at a total daily dose of 50 mg to 100 mg; 50 mg to 200 mg; 50 mg to 400 mg; 50 mg to 800 mg; 100 mg to 200 mg; 100 mg to 400 mg; 100 mg to 800 mg; 200 mg to 400 mg; 200 mg to 800 mg; 300 mg to 600 mg, or 400 mg to 800 mg. In another embodiment, the method comprises the oral administration of the compound of formula (I) at a total daily dose of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg or 800 mg. In other embodiments, the method comprises the oral administration of the compound of formula (I) at a total daily dose of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg.

[0149] In one embodiment, the method comprises the oral administration of the calcium salt of the compound of formula (I) at a total daily dose not exceeding 800 mg, preferably not exceeding 600 mg, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg. In one embodiment, the method comprises the oral administration of the calcium salt of the compound of formula (I) at a total daily dose of 50 mg to 800 mg. In another embodiment, the method comprises the oral administration of the calcium salt of the compound of formula (I) at a total daily dose of 50 mg to 100 mg; 50 mg to 200 mg; 50 mg to 400 mg; 50 mg to 800 mg; 100 mg to 200 mg; 100 mg to 400 mg; 100 mg to 800 mg; 200 mg to 400 mg; 200 mg to 800 mg; 300 mg to 600 mg, or 400 mg to 800 mg. In another embodiment, the method comprises the oral administration of the calcium salt of the compound of formula (I) at a total daily dose of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg or 800 mg. In other embodiments, the method comprises the oral administration of the calcium salt of the compound of formula (I) at a total daily dose of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg.

[0150] In accordance with preferred embodiments of the present disclosure, the CD47-SIRPa blocking agent is administered to the subject, typically at the total daily doses and / or in the form of the unit dosage for as defined herein before, once or twice daily. Typically, in case the method comprises the administration of the CD47-SIRPa blocking agent twice daily, then the total daily dose as defined herein above is administered in two equal portions, i.e. in such embodiments, half of the total daily dose is administered each time.

[0151] In accordance with certain embodiments of the present disclosure, the method comprises the twice daily administration of the CD47-SIRPa blocking agent at a dose of 100 to 400 mg, preferably 100 mg, 200 mg, 300 mg, or 400 mg. In accordance with preferred embodiments of the present disclosure, the method comprises the twice daily administration of the compound of formula (I) at a dose of 100 to 400 mg, preferably 100 mg, 200 mg, 300 mg, or 400 mg; or the twice daily administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof at the molar equivalent dose or at the equipotent dose.

[0152] In accordance with some embodiments of the present disclosure, the method comprises the once daily administration of the CD47-SIRPa blocking agent at a dose of 200 to 800 mg, preferably 200 mg, 400 mg, 600 mg, or 800 mg. In accordance with preferred embodiments of the present disclosure, the method comprises the once daily administration of the compound of formula (I) at a dose of 200 to 800 mg, preferably 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg; or the once daily administration of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof at the molar equivalent dose or at the equipotent dose. In accordance with certain embodiments, the method comprises oral administration of the CD47-SIRPa blocking agent to the human subject, in an amount sufficient to achieve a steady state plasma level of the compound of formula (I) characterized by one or more of the properties as specified herein before.

[0153] In one embodiment, the method comprises oral administration of the CD47-SIRPa blocking agent, in an amount sufficient to achieve the steady state plasma level of the compound of formula (I), wherein the steady state plasma level is characterized by one or more of the following properties:

[0154] (a) a steady state mean plasma C max^

[0155] (b) a steady state mean plasma T max^

[0156] (c) a steady state mean plasma retention time (MRT); and

[0157] (d) a steady state mean plasma AUC0-12; falling within a range of about 80% of the lower limit to about 120% of the upper limit of any of the ranges and values for these properties specified herein before.

[0158] In accordance with preferred embodiments of the present disclosure, methods comprise the administration of the CD47-SIRPa blocking agent to the subject, typically at the total daily doses and frequencies as defined herein before, for a period of at least 1 week, preferably at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks of at least 10 weeks, such as for a period of 1 week to 6 months, a period of 2 weeks to 4 months or a period of 3 to 8 weeks. In accordance with certain embodiments of the present disclosure, the method comprises the twice daily administration of the CD47-SIRPa blocking agent at a dose of 200 mg to 400 mg, preferably 200 mg, 300 mg or 400 mg, for at least 15 days, preferably for at least 28 days. In accordance with certain preferred embodiments of the present disclosure, the method comprises the twice daily administration of the compound of formula (I) at a dose of 200 mg to 400 mg, preferably 200 mg, 300 mg or 400 mg, for at least 15 days, preferably for at least 28 days; or the twice daily administration, for at least 15 days, preferably for at least 28 days, of a stereoisomer of the compound of formula (I) or a salt, solvate, amide or ester of the compound of formula (I) or stereoisomer thereof at the molar equivalent dose or at the equipotent dose.

[0159] In some embodiments of the present disclosure, the method comprises a multitude of treatment cycles, e.g. two or more treatment cycles, such as 2, 3, 4, 5 or 6 treatment cycles, wherein each cycle comprises the administration to the subject, typically at the regimens as defined herein before, for a period of at least 1 week, preferably at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks of at least 10 weeks, such as for a period of 1 week to 6 months, a period of 2 weeks to 4 months or a period of 3 to 8 weeks. The period of time elapsing between consecutive cycles may range from e.g. a period of 1 week to 6 months, a period of 2 weeks to 4 months or a period of 3 to 8 weeks.

[0160] In some embodiments, the method comprises administration of the CD47-SIRPa blocking agent to the human subject before food intake, on an empty stomach and / or at least two hours after food intake. Preferably, the method comprises administration of the CD47- SIRPa blocking agent to the human subject within one hour after food intake.

[0161] In one embodiment, the method results in the treated subject achieving at least one of the following response criteria according to European Leukemia Net (ELN-2017): a. Complete remission; b. Complete remission with incomplete hematologic recovery; c. Morphologic leukemia free state; d. Partial remission; or e. Stable Disease lasting 3 months or more.

[0162] In one embodiment, the method results in the treated subject achieving at least one of the following response criteria according to International Working Group (IWG) 2006: a. Complete remission; b. Partial remission; c. Stable disease; or d. Hematological Improvement.

[0163] In one embodiment, the method comprises escalating, optionally stepwise, such as in one, two, three, four or five steps, the total daily dose and / or dosing frequency of the compound of formula (I). In one embodiment, the escalated total daily dose is up to 1.5 times of the total daily dose at which the disease progression is displayed. In another embodiment, the escalated total daily dose is up to 2-times of the total daily dose at which the disease progression is displayed. In one embodiment, the escalated total daily dose is up to 3-times of the total daily dose at which the disease progression is displayed. In one embodiment, the escalated total daily dose is up to 4-times of the total daily dose at which the disease progression is displayed. In one embodiment, the escalation of the total daily dose and / or dosing frequency is done up to 3 times before the treatment is terminated.

[0164] In one embodiment, the method further comprises administration of one or more other anticancer agents to the human subject. In accordance with the present disclosure, the method typically comprises the administration of Azacitidine or a pharmaceutically acceptable salt thereof via the oral or the parenteral route. In preferred embodiments, Azacitidine is administered to the subject via the parenteral route, preferably via a subcutaneous injection or an intravenous infusion.

[0165] In accordance with preferred embodiments of the present disclosure, the method comprises the oral administration of azacitidine or a pharmaceutically acceptable salt thereof in a total daily dose of at least about 25 mg, more preferably at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg or at least about 200 mg. In accordance with certain embodiments, the method comprises the oral administration of azacitidine or a pharmaceutically acceptable salt thereof in a total daily dose of about 500 mg or less, more preferably about 450 mg or less, about 400 mg or less, about 350 mg or less, about 325 mg or less or about 300 mg or less. In accordance with embodiments of the present disclosure, the method comprises the oral administration of azacitidine or a pharmaceutically acceptable salt thereof in a total daily dose of about 100-400 mg, more preferably about 150-350 mg, most preferably in about 200-300 mg, e.g. in a total daily dose of about 200 mg or in a total daily dose of about 300 mg. In accordance with other embodiments of the present disclosure, the method comprises the oral administration of azacitidine in a total daily dose of at least about 25 mg, more preferably at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg or at least about 200 mg or the oral administration of a pharmaceutically acceptable salt of azacitidine in the equimolar or equipotent dose. In accordance with certain embodiments, the method comprises the oral administration of azacitidine in a total daily dose of about 500 mg or less, more preferably about 450 mg or less, about 400 mg or less, about 350 mg or less, about 325 mg or less or about 300 mg or less, or the oral administration of a pharmaceutically acceptable salt of Azacitidine in the equimolar or equipotent dose. In accordance with embodiments of the present disclosure, the method comprises the oral administration of azacitidine in a total daily dose of about 100-400 mg, more preferably about 150-350 mg, most preferably in about 200-300 mg, e.g. in a total daily dose of about 200 mg or in a total daily dose of about 300 mg, or the oral administration of a pharmaceutically acceptable salt of Azacitidine in the equimolar or equipotent dose.

[0166] In one embodiment, the azacitidine or its pharmaceutically acceptable salt is administered orally, preferably at the daily doses defined herein above, once daily, for 14 days in a 28 days of treatment cycle for a minimum of 3 to 4 treatment cycles. In some embodiments, Azacitidine is administered at a dose of 300 mg orally once daily, for 14 days in a 28 days of treatment cycle for a minimum of 3 to 4 treatment cycles.

[0167] In preferred embodiments of the present disclosure, azacitidine or a pharmaceutically acceptable salt is orally administered to the subject daily, typically at the total daily doses defined here above, for 7 days, followed by a 21 day rest period, during which rest period the subject is not administered azacitidine or a pharmaceutically acceptable salt thereof. In preferred embodiments of the present disclosure, the method comprises a number of such 28- day treatment cycles, e.g. at least 4 treatment cycles, such as 4 treatment cycles, 5 treatment cycles or 6 treatment cycles.

[0168] In preferred embodiments of the present disclosure, a therapeutically effective dose of Azacitidine is administered orally once daily, for 14 days in a 28 days of treatment cycle for a minimum of 3 to 4 treatment cycles.

[0169] In other preferred embodiments of the present disclosure, the method comprises the parenteral administration, preferably the administration by subcutaneous injection or intravenous infusion, of azacitidine or a pharmaceutically acceptable salt thereof in a total daily dose of at least about 10 mg / m2of body surface area, more preferably at least about 25 mg / m2, at least about 40 mg / m2, at least about 45 mg / m2, at least about 50 mg / m2, at least about 55 mg / m2, at least about 60 mg / mg2, at least about 65 mg / mg2or at least about 70 mg / mg2e.g. about 75 mg / m2. In accordance with certain embodiments, the method comprises the parenteral administration, preferably the administration by subcutaneous injection or intravenous infusion, of azacitidine or a pharmaceutically acceptable salt thereof in a total daily dose of about 200 mg / m2of body surface area or less, more preferably about 150 mg / m2or less, about 125 mg / m2or less, about 100 mg / m2or less, about 90 mg / m2or less, or about 80 mg / m2or less. In accordance with embodiments of the present disclosure, the method comprises the parenteral administration, preferably the administration by subcutaneous injection or intravenous infusion, of azacitidine or a pharmaceutically acceptable salt thereof in a total daily dose of about 25-150 mg / m2of body surface area, more preferably about 50-100 mg / m2, most preferably about 70- 80 mg / m2, e.g. in a total daily dose of about 75 mg / m2. In accordance with other embodiments of the present disclosure, the method comprises the parenteral administration, preferably the administration by subcutaneous injection or intravenous infusion, of azacitidine in a total daily dose of at least about 10 mg / m2of body surface area, more preferably at least about 25 mg / m2, at least about 40 mg / m2, at least about 45 mg / m2, at least about 50 mg / m2, at least about 55 mg / m2, at least about 60 mg / mg2, at least about 65 mg / mg2or at least about 70 mg / mg2e.g. about 75 mg / m2or the parenteral administration of a pharmaceutically acceptable salt of azacitidine in the equimolar or equipotent dose. In accordance with certain embodiments, the method comprises the parenteral administration, preferably the administration by subcutaneous injection or intravenous infusion, of azacitidine in a total daily dose of about 200 mg / m2of body surface area or less, more preferably about 150 mg / m2or less, about 125 mg / m2or less, about 100 mg / m2or less, about 90 mg / m2or less, or about 80 mg / m2or less, or the parenteral administration of a pharmaceutically acceptable salt of azacitidine in the equimolar or equipotent dose. In accordance with embodiments of the present disclosure, the method comprises the parenteral administration, preferably the administration by subcutaneous injection or intravenous infusion, of azacitidine in a total daily dose of about 25-150 mg / m2of body surface area, more preferably about 50-100 mg / m2, most preferably about 70-80 mg / m2, e.g. in a total daily dose of about 75 mg / m2, or the parenteral administration of a pharmaceutically acceptable salt of azacitidine in the equimolar or equipotent dose.

[0170] In preferred embodiments of the present disclosure, azacitidine or a pharmaceutically acceptable salt thereof is parenterally administered to the subject, preferably as a subcutaneous injection or intravenous infusion, daily, typically at the total daily doses defined here above, for 7 days, followed by a 21 day rest period, during which the subject is not administered azacitidine or a pharmaceutically acceptable salt thereof. In other embodiments of the present disclosure, azacitidine or a pharmaceutically acceptable salt is parenterally administered to the subject, preferably as a subcutaneous injection or intravenous infusion, daily, typically at the total daily doses defined here above, only on days 1-5 and on day 8 and 9 of the 28 days of treatment cycle. In one embodiment, azacitidine or a pharmaceutically acceptable salt thereof is subcutaneously (SC) administered on days 1-5 followed by 2 days rest period, and then two days again in a 28 days of treatment cycle. In another embodiment, azacitidine or a pharmaceutically acceptable salt thereof is intravenously (IV) administered on days 1-5 followed by 2 days off, and then two days again in a 28 days of treatment cycle.

[0171] In certain preferred embodiments of the present disclosure, azacitidine or a pharmaceutically acceptable salt thereof is administered as subcutaneous injection or intravenous infusion, daily for 7 days in a 28 days of treatment cycle for a minimum of 4 to 6 treatment cycles. In certain preferred embodiments of the present disclosure, azacitidine or a pharmaceutically acceptable salt thereof is subcutaneously (SC) or intravenously (IV) administered on days 1-5 followed by 2 days off, and then two days again in a 28 days of treatment cycle. In preferred embodiments of the present disclosure, the method comprises a number of such 28-day treatment cycles, e.g. at least 4 of such 28-day treatment cycles, such as 4 of said treatment cycles, 5 of said treatment cycles or 6 of said treatment cycles.

[0172] In one embodiment, the CD47-SIRPa blocking agent and azacitidine are administered simultaneously or sequentially. In certain embodiment of the present disclosure, the treatment with the CD47-SIRPa blocking agent and the treatment with azacitidine or a pharmaceutically acceptable salt thereof, are both started on the same day. In certain embodiment of the present disclosure, the treatment with the CD47-SIRPa blocking agent is started on the day a new 28- day treatment cycle with azacitidine pharmaceutically acceptable salt thereof is started.

[0173] Kits of parts

[0174] Another aspect of the present disclosure is directed to a pharmaceutical kit comprising a package containing a plurality of unit dosage forms and a package and / or package insert, wherein said unit dosage form is a unit dosage form comprising a CD47-SIRPa blocking agent selected from the group consisting of the compound of formula (I), stereoisomers thereof, and pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomer thereof, such as the unit dosage forms described herein elsewhere, and wherein said package and / or package insert contains printed instructions to repeatedly administer or self-administer, typically via the oral route, said unit dosage forms in order to accomplish any of the therapeutic objectives as defined herein, such as to treat and / or delay the progression of a disease or a disorder mediated by CD47-SIRPa pathway in a human subject.

[0175] In accordance with embodiments of the present disclosure, the pharmaceutical kit preferably comprises a container, such as a cardboard box, holding one or more blister packs, said one or more blister packs containing a plurality of solid unit dosage forms comprising the CD47-SIRPa blocking agent, such as the unit dosage forms described herein elsewhere, preferably a plurality of tablets as defined herein before. In particularly preferred embodiments of the present disclosure, the pharmaceutical kit comprises at least 5, at least 8, at least 10, at least 12 of at least 15 of said unit dosage forms, e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of said unit dosage forms. In one embodiment of the present disclosure, the pharmaceutical kit only comprises unit dosage forms as defined herein that contain the CD47- SIRPa blocking agent as the sole active ingredient. In one embodiment of the present disclosure, the pharmaceutical kit only comprises a plurality of unit dosage forms as defined herein that contain CD47-SIRPa blocking agent as the sole active ingredient and a plurality of unit dosage forms that contain azacitidine or a pharmaceutically acceptable salt thereof as the sole active ingredient, preferably a solid unit dosage form suitable for oral administration or a unit dosage form adapted for parenteral administration, such as a vial containing a powder for reconstitution, typically in the dose amounts recited herein elsewhere. In one embodiment of the present disclosure, the pharmaceutical kit can comprise a plurality of unit dosage forms as defined herein, comprising a CD47-SIRPa blocking agent as well as azacitidine or a pharmaceutically acceptable salt thereof.

[0176] In accordance with preferred embodiments of the present disclosure, the pharmaceutical kit comprises a package insert, such as a leaflet inserted into the container, typically a patient information leaflet, containing instructions printed thereon, which information may include a description of the form and composition of the unit dosage forms contained in the kit, an indication of the therapeutic indications for which the product is intended, instructions as to how the product is to be used and information and warnings concerning adverse effects and contraindications associated with the use. It will be understood by those of average skill in the art, based on the information presented herein, that the package insert, such as the leaflet, that is part of the kit according to the present disclosure, will typically contain instructions providing for the therapeutic indications, uses, target subjects, and treatment regimens, as described here above in relation to the methods of treatment of the present disclosure.

[0177] In accordance with one or more embodiments of the present disclosure, the pharmaceutical kit optionally further contains a plurality of pharmaceutical composition, preferably in unit dosage form, comprising one or more other anticancer agents. In a preferred embodiment, the pharmaceutical kit may optionally contain a plurality of pharmaceutical composition, preferably in unit dosage form, comprising azacitidine, or a pharmaceutically acceptable salt thereof.

[0178] Miscellaneous

[0179] As used herein, the term "comprise" and variations of the term, such as "comprising" and "comprises," are not intended to exclude other additives, components, integers or steps.

[0180] The terms "a," "an," and "the" and similar referents used herein are to be construed to cover both the singular and the plural unless their usage in context indicates otherwise. Furthermore, to the extent that the term "include," "have," or the like is used in the description or the claims, such term is intended to be inclusive in a manner similar to the term "comprise" as "comprise" is interpreted when employed as a transitional word in a claim. As used herein, the phrase "at least one of preceding a series of items, with the term "and" or "or" to separate any of the items, modifies the list as a whole, rather than each member of the list (i.e., each item).

[0181] The phrase "at least one of does not require selection of at least one of each item listed; rather, the phrase allows a meaning that includes at least one of any one of the items, and / or at least one of any combination of the items, and / or at least one of each of the items. By way of example, the phrase "at least one of A, B, and C" refers to only A, only B, or only C; any combination of A, B, and C; and / or at least one of each of A, B, and C.

[0182] The term "about", whenever used in conjunction with a number or value, means within the tolerance range of the equipment used to determine the value, or in some examples, means plus or minus 10%, or plus or minus 5%, or plus or minus 1%, unless otherwise expressly specified. Further, herein the term "substantially" as used herein means a majority, or almost all, or all, or an amount with a range of about 51% to about 100%, for example.

[0183] Throughout this text, the use of words in brackets as part of a given term usually means that the wording within brackets specifies a possible option or a possible meaning and that each option or meaning is encompassed by the term.

[0184] All publications and patents cited in this disclosure are incorporated by reference in their entirety. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material. The citation of any references herein is not an admission that such references are prior art to the present invention.

[0185] The foregoing description is provided to enable a person skilled in the art to practice the various embodiments described herein. While the subject technology has been particularly described with reference to the various embodiments, it should be understood that these are for illustration purposes only and should not be taken as limiting the scope of the subject technology. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein.

[0186] The various aspects and embodiments as defined in the foregoing will be further illustrated by means of the following non-limiting examples. EXAMPLES

[0187] EXAMPLE 1: A Phase I, Open Label, Dose-Escalation, study evaluating the Safety and Pharmacokinetics of Compound of Formula (I) in subjects with relapsed advanced malignancies, and its effect on Pharmacodynamic Biomarkers

[0188] Study objective: To evaluate the overall safety and pharmacokinetic profile of the compound of formula (I) in human subjects with relapsed advanced malignancies.

[0189] The following table summarizes the (final) study protocol.

[0190] Table 1 : Study Design

[0191] Table 2: Schedule of Events a) After Cycle 1, clinical laboratory tests can be done two days prior to the scheduled visit b) Details of histopathological diagnosis of cancer, all previous treatments and any biomarkers done previously c) Complete physical examination d) Symptom -directed examination e) Cycle 1 Day 1 procedures before test drug administration f) Temperature, pulse rate, blood pressure (seated 5 minutes) pre-dose at all applicable visits; and at five additional times (15, 30 min, 1, 2, and 4 hours (± 5 minutes) post-dose) on Cycle 1 Day 1. g) Hematology: complete blood count with differential, platelet count. Reticulocyte count

[0192] • Serum Chemistry: sodium, potassium, chloride, bicarbonate, calcium, phosphorus, magnesium, blood urea nitrogen, creatinine, glucose, bilirubin (direct and total), AST, ALT, alkaline phosphatase, albumin, total protein, LDH, haptoglobin. CPK measurement during Screening and then Day 1 of each cycle. • Coagulation Parameters: partial thromboplastic time or activated partial thromboplastin time, and prothrombin time or international normalized ratio. PT / PTT (aPTT)

[0193] • Urinalysis: protein, glucose, ketones, urobilinogen, occult blood, and, when indicated by dipstick abnormality, microscopic sediment evaluation $) Monitoring for hemolytic anemia on Days 1, 2, 5 and 8 of cycle 1 by monitoring CBC, Reticulocyte Count, LDH, Bilirubin (Total, Direct and Indirect), Haptoglobin and urinalysis. h) ECG (after supine / reclined for 5 minutes) pre-dose and 1 hour (± 10 min) after the first dose of study drug on Cycle 1 Day 1; ECG pre-dose on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22 and Day 1 of all future Cycles; On Cycle 1 Day 15, ECG two hours post dose; On the ECG days, subjects to take the study drug only after coming to the site and after having the ECG; ECG’s also to be performed as clinically indicated i) Serum P-HCG at Screening; urine pregnancy test at subsequent visits. Only for Women with Childbearing Potential. Cycle 1 Day 1 procedures before test drug administration j) Calcium salt of compound of formula (I) on all days through all the cycles as capsules taken orally with water at approximately the same time on each dosing day; subjects not to eat (drink water) for one hour before and one hour after taking the capsules k) AEs assessment at every timepoint, when study staff interact with the subjects, treatment- related AEs / SAEs ongoing at the time of follow-up visit (28-day after last study drug administration) to be followed up until resolution or return to baseline or until < Grade 1 l) Pharmacokinetics sampling: In cycle 1, intensive PK on day 1 and day 15 (timepoints: predose and 0.5, 1, 2, 3, 4, 6, 8, 12 hours post morning dose). Sparse PK sampling (pre dose samples) on cycle 1 day 8, cycle 2 day 1 and cycle 3 day 1.

[0194] Food effect Evaluation: Food effect evaluation during the Cycle 1, Part 1 of the study in the first 3-4 cohorts (or at least 8 patients). Standard food just before the dosing on Day 15 of Cycle 1. Intensive PK sampling on Day 15 at the same time-points as on Day 1 (timepoints: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 hours post morning dose) to evaluate the effect of food on pharmacokinetics. m) Pharmacodynamic markers sampling: In cycle 1, PD samples on days 1, 8 and 15. On Cycle 1 Day 1, PD pre-dose and immediately before evening dose. On Days 8 and 15 of Cycle 1, PD only pre-dose; also, PD pre-dose on Cycle 2 Day 1 and Cycle 3 Day 1.

[0195] Results

[0196] Safety

[0197] In all subjects, across dose levels, the treatment was well tolerated without any DLT (Dose Limiting Toxicity) or any other safety concerns. No dose limiting toxicities or serious adverse effects, especially hemolytic anemia was reported in any of the subjects. These findings were quite surprising, given the ubiquitous expression of CD47 across cell types in the human body, especially hematopoietic cells, and its crucial role in multiple fundamental cellular functions, including determining lifespan of erythrocytes, cell migration, apoptosis, and axon development, which has impeded the development of small molecule CD47 antagonists so far.

[0198] Pharmacokinetics (PK)

[0199] There was minimal to moderate variability of PK in between subjects within any cohort. The compound of formula (I) Calcium showed dose dependent increase in exposure from 25 mg to 400 mg bid.

[0200] Table 3: Summary of the PK parameters (Mean + SD) on Day 15 from cohorts 1,2, 3, 4 and 5

[0201] Adverse events (AE)

[0202] All the reported non-serious adverse events were mild to moderate in nature and the causality of most of them was due to the underlying malignancy. There were no clear patterns in these AEs. Some of the Grade 1 adverse events were itching, body ache, pain in wrist, elbow or shoulder; nausea, vomiting, myalgia, constipation, abdominal pain, diarrhoea, fever and tingling. A few subjects experienced Grade 2 adverse events like dropping of an eye lid or constipation. All of the above lower grade AEs were either considered related to underlying cancer or discovered to have another cause (e.g. scabies for itching) or resolved while the trial continued. No patterns of relationship with dose or cohort were found. Hemolytic anemia was not reported in any subject.

[0203] Serious Adverse Events (SAE)

[0204] No Grade 3 or 4 toxicities were found in any of the cohorts that could be correlated with the treatment. Two serious adverse events were reported - one in cohort 2 and another in cohort 3, however, both were determined to be a manifestation of the underlying cancer of the subjects and were assessed as ‘Not Related’ by the respective principal investigators (PI) and the study sponsor. There were no dose reductions due to treatment-related AEs during the reporting period. No Serious Adverse Reactions (SAR’s) or Suspected Unexpected Serious Adverse Reactions (SUSAR’s) were reported during the reporting period.

[0205] Pharmacodynamics Biomarkers:

[0206] Despite certain variations / outliers among subjects and / or over time, at steady state, a trend towards downregulation of IL-6 and IL- la; and a trend towards upregulation of IL12p40, TNLa, MCP-1, MIP-la, MIP-1B, and MCP-3 as a result of treatment were observable in all cohorts.

[0207] Chemokines are known for their role in recruitment of macrophages to sites of infection, damage, or tumors for the purpose of phagocytosis and healing. An upregulation of chemokines followed by administration of the compound of formula (I) is indicative of the CD-47 inhibition mediated enhanced phagocytosis. Disruption of the IL-6-STAT3 axis is known to reduce the ability of tumor cells to escape phagocytosis (Jing Chen et al. Oncoimmunology 2019, VOL. 8, NO. 11, el652540). A drop in IL-6 level is also indicative of macrophage activation.

[0208] Overall, it was found that, at steady state, most of the pharmacodynamic biomarkers displayed modulation on the favourable direction indicating enhanced phagocytosis mediated via CD-47 inhibition.

[0209] Conclusion

[0210] Compound of formula (I) was shown to be safe and well-tolerated up to a dose of 400 mg per oral BID, or a total daily dose of 800 mg. PD biomarker analysis at steady state indicated favourable modulation of the cytokines and chemokines, supporting efficacy of the compound of formula (I) in cancer treatment. Surprisingly, the hematological safety of the compound of formula (I) was exceptionally high, with no grade 3 or grade 4 adverse events at steady state, and no signs of hemolytic anemia in any of the tested subjects.

[0211] EXAMPLE 2: A Phase Ila, two-part, open label, dose escalation study to evaluate the safety, efficacy and PK profile of a combination of the Compound of formula (I) and Azacitidine in human subjects with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

[0212] Main study objective: To evaluate the safety, tolerability, efficacy and PK profile of a combination of the compound of formula (I) and Azacitidine in human subjects diagnosed with AML or MDS. Objective of Part A of the study: to evaluate the safety, tolerability and pharmacokinetic profde of the orally administered compound of formula (I) at different dose levels, when administered along with Azacitidine (AZA) to human subjects diagnosed with AML or MDS.

[0213] Objective of Part B of the study: To evaluate the efficacy of the combination in human subjects diagnosed with AML or MDS.

[0214] The following table summarizes the (final) study protocol.

[0215] Table 4: Study Design:

[0216] Part A [Dose escalation - combination of Compound of formula (I) Calcium + Azacitidine] - Part B [Randomization - combination of Compound of formula (I) Calcium +

[0217] Azacitidine]

[0218] Table 5: Schedule of Events [Part A and B] a) All assessments prior to treatment, unless specified otherwise in the protocol. After Cycle 1, clinical laboratory tests can be done two days prior to the scheduled visit. b) Collect histopathological diagnosis of cancer, all previous treatments and any biomarkers done previously as part of “Medical History” c) Complete physical examination d) Symptom -directed examination e) All the pre-dose Cycle 1 Day 1 procedures before administration of compound of formula (I), except vital signs, ECG, pre-dose PK and pre-dose PD up to 2 days prior f) Temperature, pulse rate, blood pressure (seated 5 minutes) pre-dose at all applicable visits; 15, 30 min, 1, 2, and 4 hours (± 5 minutes) post-dose on Cycle 1 Day 1, vital signs measurement on the days of Azacitidine administration as per institutional practice g) Hematology: complete blood count with differential, platelet count. Reticulocyte count

[0219] • Serum Chemistry: sodium, potassium, chloride, bicarbonate, calcium, phosphorus, magnesium, blood urea nitrogen, creatinine, glucose, bilirubin (direct and total), AST, ALT, alkaline phosphatase, albumin, total protein, LDH, Haptoglobin. CPK measurement during Screening and end of treatment visit only

[0220] • Coagulation Parameters: partial thromboplastic time or activated partial thromboplastin time, and prothrombin time or international normalized ratio. PT / PTT (aPTT)

[0221] • Urinalysis: protein, glucose, ketones, urobilinogen, occult blood, and, when indicated by dipstick abnormality, microscopic sediment evaluation. Clinical laboratory tests within 48 hours prior to scheduled Day 1 or Day 15 of the respective cycles

[0222] $) Monitoring for hemolytic anemia and tumor lysis syndrome (TLS) once daily on Days 1, 2, 4, 6 and 8 of cycle 1 by monitoring CBC, Reticulocyte Count, Haptoglobin, LDH, Bilirubin (Total, Indirect and Direct), Uric Acid, Serum Potassium, Serum Calcium, Serum Phosphate, Creatinine, Blood Urea Nitrogen and urinalysis parameters. h) ECG (after supine / reclined for 5 minutes) pre-dose and 1 hour (± 10 min) after the first dose of study drug on Cycle 1 Day 1; also pre-dose on Cycle 1 Day 8, day 15, day 22 and then day 1 of each subsequent cycle; on cycle 1 day 15, ECG two-hours post dose, or as clinically indicated i) Serum P-HCG at Screening; urine pregnancy test at subsequent visits. Only for Women with Childbearing Potential. j) Bone marrow assessment for disease evaluation for subjects of both AML and MDS by bone marrow aspirates and biopsy; Bone marrow assessment at screening (within 28 days of the first dose of study drug); If bone marrow assessment is already done prior to screening, (within 28 days of expected Cycle 1 Day 1), then same can be used for screening; Subsequent bone marrow aspirates collection on Cycle 3 DI (±7 days) and every 2 cycles afterwards, and as clinically indicated., such as when clinical progression is suspected. After C5D1 (±7 days) bone marrow evaluation, the frequency of bone marrow assessments can be decreased to every 3 cycles, as per the judgment of PI. However, for documentation of CR or PR or marrow CR, bone marrow assessment is required. k) Calcium salt of compound of formula (I) on all days through all the cycles taken as capsules orally with water at approximately the same time on each dosing day. Subjects not to eat (drink water) for one hour before and one hour after taking the capsules. l) Azacitidine dosing: Azacitidine administration subcutaneously (SC) or intravenously (IV) over 15 minutes on days 1-7 of the cycle. Local practice patterns (such as 5 days on followed by 2 days off and then 2 days on) can be considered by the PI. m) Pharmacodynamic markers sampling: In Part A, cycle 1, PD samples on Day 1 (Pre-dose, and 12 hours), i.e., before evening dose), Day 8 and Day 15. PD samples pre-dose in Cycle 2 Day 1 and Cycle 3 Day 1 . n) AEs were assessment at every timepoint, when study staff interacts with the subject. Treatment-related AEs / SAEs ongoing at the time of follow-up visit (28-day after last study drug administration) continue to be followed until resolution or return to baseline or until < Grade 1. o) Pharmacokinetics sampling: In Part 2 A, cycle 1, intensive PK on day 1 and day 15 (timepoints: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 hours post morning dose). Sparse PK sampling (pre dose samples) on cycle 1 day 8, cycle 2 day 1 and cycle 3 day 1. Results

[0223] Pharmacokinetics (PK)

[0224] There was minimal to moderate variability of PK in between subjects within any cohort. The compound of formula (I) Calcium showed dose dependent systemic exposure between the 200 mg and 300 mg dose (Table 6 and 7)

[0225] Table 6: Summary of the PK parameters of 200 mg BID (Mean + SD) on Day 1 and Day 15 from cohort 1

[0226] Table 7: Summary of the PK parameters of 300mg BID (Mean + SD) on Day 1 and Day 15 from cohort 2

Claims

Claims1. A CD47-SIRPa blocking agent selected from the group consisting of a compound of formula (I):Formula (I), stereoisomers thereof, and pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomer thereof; for use in a method of treating or delaying progression of a disease or a disorder mediated by CD47-SIRPa pathway in a human subject suffering from said disease or disorder, wherein the method comprises oral administration of the compound of formula (I) or stereoisomer thereof, to the subject, in a total oral daily dosage not exceeding 800 mg, preferably not exceeding 600, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof.

2. The CD47-SIRPa blocking agent for use according to claim 1, wherein the method does not result in thrombocytopenia or anemia.

3. The CD47-SIRPa blocking agent for use according to claim 1 , wherein the method does not result in grade 4 thrombocytopenia with clinically significant bleeding or grade 4 anemia that cannot be attributed to the underlying disease or disorder.4 The CD47-SIRPa blocking agent for use according to claim 1, wherein the subject, during treatment, does not display a grade 4 thrombocytopenia with clinically significant bleeding or a grade 4 anemia that cannot be attributed to the underlying disease or disorder.

5. The CD47-SIRPa blocking agent for use according to claim 1, wherein at steady state plasma levels of the CD47-SIRPa blocking agent, the subject does not display a grade 4 thrombocytopenia with clinically significant bleeding and / or a grade 4 anemia that cannot be attributed to the underlying disease or disorder.

6. The CD47-SIRPa blocking agent for use according to claim 5, wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a mean plasma Cmax of about 345 ng / ml to about 7000 ng / mL;(b) a mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a mean plasma AUC0-12 of about 3200 hr x ng / mL to 68000 hr x ng / mL.

7. The CD47-SIRPa blocking agent for use according to claim 1, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 50 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a steady state mean plasma Cmax of about 345 to about 355 ng / ml;(b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a steady state mean plasma AUC0-12 of about 3200 to about 3600 hr x ng / mL.

8. The CD47-SIRPa blocking agent for use according to claim 1, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 100 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a steady state mean plasma Cmax of about 410 to about 950 ng / ml;(b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a steady state mean plasma AUC0-12 of about 4200 to about 9200 hr x ng / mL.

9. The CD47-SIRPa blocking agent for use according to claim 1, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 200 mg of the compoundof formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a steady state mean plasma Cmax of about 500 to about 1250 ng / ml;(b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a steady state mean plasma AUC0-12 of about 5100 to about 12700 hr x ng / mL.

10. The CD47-SIRPa blocking agent for use according to claim 1, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 400 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a steady state mean plasma Cmax of about 1170 to about 1920 ng / ml;(b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a steady state mean plasma AUC0-12 of about 11000 to about 20000 hr x ng / mL.

11. The CD47-SIRPa blocking agent for use according to claim 1, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 600 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of: a) a steady state mean plasma Cmax of about 1000 to about 3100 ng / ml; b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 10 to 12 hours; c) a steady state mean plasma AUC0-12 of about 9000 to about 29000 hr x ng / mL.

12. The CD47-SIRPa blocking agent for use according to claim 1, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I)or stereoisomer thereof, to the human subject in a total daily dosage of 800 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a steady state mean plasma Cmax of about 2400 to about 7000 ng / ml;(b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a steady state mean plasma AUC0-12 of about 22000 to about 68000 hr x ng / mL.

13. The CD47-SIRPa blocking agent for use according to any one of the preceding claims, wherein the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof is administered to the human subject for a period of at least 15 days, preferably 28 days.

14. The CD47-SIRPa blocking agent for use according to any one of the preceding claims, wherein the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof is administered to the human subject before food intake; on an empty stomach; and / or at least two hour after food intake.

15. The CD47-SIRPa blocking agent for use according to any one of the preceding claims 1-13, wherein the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof is administered to the human subject within one hour after food intake.

16. The CD47-SIRPa blocking agent for use according to any one of the preceding claims, wherein the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof is administered to the human subject once daily or twice daily.

17. The CD47-SIRPa blocking agent for use according to any one of the preceding claims, wherein the salt of compound of formula (I) is selected from the group consisting of Calcium, Magnesium, Potassium and Sodium salts of the compound of formula (I), preferably a Calcium salt of compound of formula (I).

18. The CD47-SIRPa blocking agent for use according to any one of the preceding claims, wherein the disease or disorder mediated by CD47-SIRPa pathway is a cancer.

19. The CD47-SIRPa blocking agent for use according to claim 18, wherein the cancer is a solid cancer.

20. The CD47-SIRPa blocking agent for use according to claim 19, wherein the solid cancer is selected from the group consisting of breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, oropharyngeal cancer, nasopharyngeal cancer, cervical cancer, stomach cancer, pancreatic cancer and liver cancer.

21. The CD47-SIRPa blocking agent for use according to claim 19, wherein the cancer is a hematological cancer.

22. The CD47-SIRPa blocking agent for use according to claim 21, wherein the hematological cancer is a leukemia.

23. The CD47-SIRPa blocking agent for use according to claim 21, wherein the hematological cancer is Acute Myeloid Leukemia (AML) or Myelodysplastic syndrome (MDS).

24. The CD47-SIRPa blocking agent for use according to claim 23, wherein the subject is a newly diagnosed subject or a subject suffering from a relapsed and / or refractory AML.

25. The CD47-SIRPa blocking agent for use according to claim 24, wherein the subject suffering from a relapsed and / or refractory AML has received at least one line of previous therapy and is eligible for one or more second or later line(s) of treatment.

26. The CD47-SIRPa blocking agent for use according to claim 25, wherein the at least one line of previous therapy does not comprise a hypomethylating agent.

27. The CD47-SIRPa blocking agent for use according to any one of the claims 25-26, wherein the one of the second or later line of treatments is a therapeutically effective dose of Azacitidine, or a pharmaceutically acceptable salt thereof.

28. The CD47-SIRPa blocking agent for use according to claim 24, wherein the newly diagnosed subject suffering from AML is not eligible for intensive chemotherapy.

29. The CD47-SIRPa blocking agent for use according to any one of the preceding claims 23-28, wherein the treatment of AML is characterized by the treated subject achieving at least one of the following response criteria according to European Leukemia Net (ELN-2017) after at least one treatment cycle comprising 28 days of treatment: a. Complete remission; b. Complete remission with incomplete hematologic recovery; c . Morphologic leukemia free state . ; d. Partial remission; or e. Stable Disease lasting 3 months or more.

30. The CD47-SIRPa blocking agent for use according to claim 23, wherein the subject is an intermediate risk, high risk, or a very high-risk MDS subject who is eligible to receive Azacitidine.

31. The CD47-SIRPa blocking agent for use according to claim 30, wherein the subject suffering from MDS has a Revised International Prognostic Scoring System (IPSS-R) > 3.5.

32. The CD47-SIRPa blocking agent for use according to claims 26 or 27, wherein the subject has not been previously treated with a hypomethylating agent.

33. The CD47-SIRPa blocking agent for use according to any one of the preceding claims 30-32, wherein the subject suffering from MDS is eligible for one or more second or later line(s) of treatment.

34. The CD47-SIRPa blocking agent for use according to claim 33 wherein one of the second or later line of treatments is a therapeutically effective dose of Azacitidine, or a pharmaceutically acceptable salt thereof.

35. The CD47-SIRPa blocking agent for use according to any one of the preceding claims 26-30, and wherein the treatment of MDS is characterized by the treated subject achieving at least one of the following response criteria according to International Working Group (IWG) 2006: a. Complete remission; b. Partial remission; c. Stable disease; or d. Hematological Improvement.

36. The CD47-SIRPa blocking agent for use according to any one of the preceding claims, wherein the human subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status Scale of 0 - 2.

37. The CD47-SIRPa blocking agent for use according to any one of the preceding claims 21-35, wherein the human subject meets at least one of the criteria selected from: a) bone marrow assessment characterized by: i. WBC < 20,000 / pL, wherein hydroxyurea can be given to bring WBC count to < 20,000 / pl; ii. Platelet count > 50,000 / pL without transfusion support; and iii. Hemoglobin > 9 g / dL, wherein transfusion is allowed to achieve this Hb; and / or, b) organ function characterized by: i. Total Bilirubin < 1.5 x Upper Limit Normal (ULN); or < 2.5 xULN if the subject has Gilbert’s syndrome;ii. AST (SGOT) < 3 x ULN (< 5 x ULN if the subject has liver metastases); iii. ALT (SGPT) < 3 x ULN (< 5 x ULN if the subject liver metastases); iv. Creatinine clearance (CrCl) > 60 mL / min; and v. Albumin > 3.0 g / dL.

38. The CD47-SIRPa blocking agent for use according to any one of the preceding claims, wherein the use further comprises administration of one or more other anticancer agents to the human subject.

39. The CD47-SIRPa blocking agent for use according to claim 38, wherein the other anticancer agent is Azacitidine or a pharmaceutically acceptable salt thereof.

40. The CD47-SIRPa blocking agent for use according to any one of the claims 38 or 39, wherein the CD47-SIRPa blocking agent and Azacitidine are administered simultaneously or sequentially.

41. The CD47-SIRPa blocking agent for use according to any one of the claims 38 - 40, wherein Azacitidine is administered to the subject via an oral route or a parenteral route, preferably via a subcutaneous injection or an intravenous infusion.

42. The CD47-SIRPa blocking agent for use in according to claim 1, wherein the method comprises administering to the human subject a total daily dosage ranging from 400 to 800 mg, preferably 400 mg, 600 mg or 800 mg, of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and a therapeutically effective dose of Azacitidine, or its pharmaceutically acceptable salt, wherein the subject upon treatment for at least 15 days, preferably for 28 days, does not display a grade 4 thrombocytopenia with clinically significant bleeding or a grade 4 anemia that cannot be attributed to the underlying disease or disorder.

43. The CD47-SIRPa blocking agent for use in a method according to claim 42, wherein Azacitidine is administered as subcutaneous injection or intravenous infusion, daily for 7 days in a 28 days of treatment cycle for a minimum of 4 to 6 treatment cycles.

44. The CD47-SIRPa blocking agent for use in a method according to claim 42, wherein Azacitidine is administered orally once daily, for 14 days in a 28 days of treatment cycle for a minimum of 3 to 4 treatment cycles.

45. The CD47-SIRPa blocking agent for use according to claim 42, wherein Azacitidine is administered on days 1-5 of the treatment, followed by 2 days off, and then two days again in a 28 days of treatment cycle.

46. A method of treating or delaying progression of a disease or a disorder mediated by CD47-SIRPa pathway in a human subject suffering from said disease or disorder, wherein themethod comprises oral administration of a CD47-SIRPa blocking agent selected from the group consisting of a compound of formula (I):Formula (I), stereoisomers thereof, and pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomers thereof, wherein the method comprises oral administration of the compound of formula (I) or stereoisomer thereof, to the subject, in a total oral daily dosage not exceeding 800 mg, preferably not exceeding 600, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof.

47. The method according to claim 46, wherein the method does not result in thrombocytopenia or anemia.

48. The method according to claim 46, wherein the method does not result in a grade 4 thrombocytopenia with clinically significant bleeding or a grade 4 anemia that cannot be attributed to the underlying disease or disorder.

49. The method according to claim 46, wherein the subject, during treatment, does not display a grade 4 thrombocytopenia with clinically significant bleeding or a grade 4 anemia that cannot be attributed to the underlying disease or disorder.

50. The method according to claim 46, wherein at steady state plasma levels of the CD47- SIRPa blocking agent, the subject does not display a grade 4 thrombocytopenia with clinically significant bleeding or a grade 4 anemia that cannot be attributed to the underlying disease or disorder.

51. The method according to claim 46, wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a mean plasma Cmax of about 345 ng / ml to about 7000 ng / mL;(b) a mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a mean plasma AUC0-12 of about 3200 hr x ng / mL to 68000 hr x ng / mL.

52. The method according to claim 46, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 50 mg, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a steady state mean plasma Cmax of about 345 to about 355 ng / ml;(b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a steady state mean plasma AUC0-12 of about 3200 to about 3600 hr x ng / mL.

53. The method according to claim 46, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 100 mg, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a steady state mean plasma Cmax of about 410 to about 950 ng / ml;(b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a steady state mean plasma AUC0-12 of about 4200 to about 9200 hr x ng / mL.

54. The method according to claim 46, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 200 mg, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a steady state mean plasma Cmax of about 500 to about 1250 ng / ml;(b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a steady state mean plasma AUC0-12 of about 5100 to about 12700 hr x ng / mL.

55. The method according to claim 46, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 400 mg, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a steady state mean plasma Cmax of about 1545 + 375 ng / ml;(b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a steady state mean plasma AUC0-12 of about 15500 + 4500 hr x ng / mL.

56. The method according to claim 46, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 600 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of: a) a steady state mean plasma Cmax of about 1000 to about 3100 ng / ml; b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 10 to 12 hours; c) a steady state mean plasma AUC0-12 of about 9000 to about 29000 hr x ng / mL.

57. The method according to claim 46, wherein the method comprises oral administration of the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof, to the human subject in a total daily dosage of 800 mg, and wherein the steady state plasma level of the compound of formula (I) is characterized by one or more of the properties falling within a range of about 80% of the lower limit to about 120% of the upper limit of:(a) a steady state mean plasma Cmax of about 1170 to about 1920 ng / ml;(b) a steady state mean plasma Tmax of about 4 to 12 hours, preferably about 4 to 8 hours;(c) a steady state mean plasma retention time (MRT) of about 6 to 8 hours; or(d) a steady state mean plasma AUCO-12 of about 11000 to about 20000 hr x ng / mL.

58. The method according to any one of the claims 46-57, wherein the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof is administered to the human subject for a period of at least 15 days, preferably 28 days.

59. The method according to any one of the claims 46-58, wherein the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof is administered to the human subject before food intake; on an empty stomach; and / or at least two hour after food intake.

60. The method according to any one of the claims 46-58, wherein the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof is administered to the human subject within one hour after food intake.

61. The method according to any one of the preceding claims 46-60, wherein the compound of formula (I), stereoisomers thereof, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof is administered to the human subject once daily or twice daily.

62. The method according to any one of the preceding claims 46-61, wherein the salt of compound of formula (I) is selected from the group consisting of Calcium, Magnesium, Potassium and Sodium salts of the compound of formula (I), preferably a Calcium salt of compound of formula (I).

63. The method according to any one of the preceding claims 46-62, wherein the disease or disorder mediated by CD47-SIRPa pathway is a cancer.

64. The method according to claim 63, wherein the cancer is a solid cancer.

65. The method according to claim 64, wherein the solid cancer is selected from breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, oropharyngeal cancer, nasopharyngeal cancer, cervical cancer, stomach cancer, pancreatic cancer, liver cancer.

66. The method according to claim 63, wherein the cancer is a hematological cancer.

67. The method according to claim 66, wherein the hematological cancer is a leukemia.

68. The method according to claim 67, wherein the hematological cancer is Acute Myeloid Leukemia (AML) or Myelodysplastic syndrome (MDS).

69. The method according to claim 68, wherein the subject is a newly diagnosed subject or a subject suffering from a relapsed and / or refractory AML.

70. The method according to claim 69, wherein the subject suffering from a relapsed and / or refractory AML has received at least one line of previous therapy and is eligible for one or more second or later line(s) of treatment.

71. The method according to claim 70, wherein the at least one line of previous therapy does not comprise a hypomethylating agent.

72. The method according to any one of the claims 70, wherein the one of the second or later line of treatments is a therapeutically effective dose of Azacitidine, or a pharmaceutically acceptable salt thereof.

73. The method according to claim 69, wherein the newly diagnosed subject suffering from AML is not eligible for intensive chemotherapy.

74. The method according to any one of the preceding claims 68-73, wherein the treatment of AML is characterized by the treated subject achieving at least one of the following response criteria according to European Leukemia Net (ELN-2017) after at least one treatment cycle comprising 28 days of treatment: a. Complete remission; b. Complete remission with incomplete hematologic recovery; c. Morphologic leukemia free state.; d. Partial remission; or e. Stable Disease lasting 3 months or more.

75. The method according to claim 68, wherein the subject is an intermediate risk, high risk, or a very high-risk MDS subject who is eligible to receive Azacitidine.

76. The method according to claim 75, wherein the subject suffering from MDS has a Revised International Prognostic Scoring System (IPSS-R) > 3.5.

77. The method according to any one of the claims 75 or 76, wherein the subject has not been previously treated with a hypomethylating agent.

78. The method according to any one of the preceding claims 75-77, wherein the subject suffering from MDS is eligible for one or more second or later line(s) of treatment.

79. The method according to claim 78, wherein the one of the second or later line of treatments is a therapeutically effective dose of Azacitidine, or a pharmaceutically acceptable salt thereof.

80. The method according to any one of the preceding claims 75-79, wherein the treatment of MDS is characterized by the treated subject achieving at least one of the following response criteria according to International Working Group (IWG) 2006: a. Complete remission;b. Partial remission; c. Stable disease; or d. Hematological Improvement.

81. The method according to any one of the preceding claims 46-80, wherein the human subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status Scale of 0 - 2.

82. The method according to any one of the preceding claims 66-81, wherein the human subject meets at least one of the criteria selected from: a. bone marrow assessment characterized by: i.WBC < 20,000 / pL, wherein hydroxyurea can be given to bring WBC count to < 20,000 / pl; ii.Platelet count > 50,000 / pL without transfusion support; and iii.Hemoglobin > 9 g / dL, wherein transfusion is allowed to achieve this Hb; and / or, b. organ function characterized by: i.Total Bilirubin < 1.5 x Upper Limit Normal (ULN); or < 2.5 x ULN if the subject has Gilbert’s syndrome; ii.AST (SGOT) < 3 x ULN (< 5 x ULN if the subject has liver metastases); iii.ALT (SGPT) < 3 x ULN (< 5 x ULN if the subject liver metastases); iv. Creatinine clearance (CrCl) > 60 mL / min; and v. Albumin > 3.0 g / dL.

83. The method according to any one of the preceding claims 46-82, wherein the method further comprises administration of one or more other anticancer agents to the human subject.

84. The method according to claim 81, wherein the other anticancer agent is Azacitidine or a pharmaceutically acceptable salt thereof.

85. The method according to any one of the preceding claims 46-84, wherein the CD47- SIRPa blocking agent and Azacitidine are administered simultaneously or sequentially.

86. The method according to any one of the preceding claims 46-84, wherein Azacitidine is administered to the subject via an oral or a parenteral route, preferably via a subcutaneous injection or an intravenous infusion.

87. The method according to any one of the preceding claims 46-86, wherein the method comprises administering to the human subject a total daily dosage ranging from 400 to 800 mg, preferably 400 mg, 600 mg or 800 mg of the compound of formula (I) or stereoisomer thereof, or a molar equivalent amount of a pharmaceutically acceptable salt, solvate, amide or ester thereof, and a therapeutically effective dose of Azacitidine, or its pharmaceutically acceptablesalt, wherein the subject upon treatment for at least 15 days, preferably for 28 days, does not display a grade 4 thrombocytopenia with clinically significant bleeding or a grade 4 anemia that cannot be attributed to the underlying disease or disorder.

88. The method according to claim 87, wherein Azacitidine is administered as subcutaneous injection or intravenous infusion, daily for 7 days in a 28 days of treatment cycle for a minimum of 4 to 6 treatment cycles.

89. The CD47-SIRPa blocking agent for use in a method according to claim 87, wherein Azacitidine is administered orally once daily, for 14 days in a 28 days of treatment cycle for a minimum of 3 to 4 treatment cycles.

90. The method according to claim 87, wherein Azacitidine is administered on days 1-5 of the treatment, followed by 2 days off, and then two days again in a 28 days of treatment cycle.

91. Use of a CD47-SIRPa blocking agent selected from the group consisting of a compound of formula (I):Formula (I), stereoisomers thereof, and a pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof; in the manufacture of a pharmaceutical composition or medicament for use in a method of treating or delaying progression of a disease or a disorder mediated by CD47-SIRPa pathway in a human subject suffering from said disease or disorder, wherein the method comprises oral administration of the compound of formula (I), or stereoisomer thereof, to the human subject in a total oral daily dosage not exceeding 800 mg, preferably not exceeding 600, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof.

92. A kit comprising:(i) a plurality of pharmaceutical composition, preferably in unit dosage form, comprising a CD47-SIRPa blocking agent selected from the group consisting of a compound of formula (I):Formula (I), stereoisomers thereof, and a pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof; and (ii) a package and / or package insert, said package and / or insert having instructions printed thereon, to use said pharmaceutical compositions in a method of treating or delaying progression of Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) in a subject suffering from AML or MDS, wherein the instructions provide that the method comprises oral administration of the compound of formula (I) or stereoisomers thereof, to the subject in a total oral daily dosage not exceeding 800 mg, preferably not exceeding 600, more preferably not exceeding 500 mg, most preferably not exceeding 400 mg, or a molar equivalent amount of pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) or stereoisomer thereof.

93. The kit for use according to claim 92, wherein the package and / or package insert further provide that the compound of formula (I) and Azacitidine are administered to the subject in need thereof in a simultaneous or sequential manner.

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