Combination therapies with cbl-b inhibitor compounds and antiemetic agents
OwnerRobert BROWNinventor
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Abstract
The present disclosure relates to combination therapies with Cbl inhibitor compounds, and compositions and kits comprising combinations with the Cbl compounds. Also provided are methods of using the combinations with Cbl compounds and compositions thereof, such as in therapeutic methods. Therapies include Cbl inhibitor compounds in combination with a serotonin receptor antagonist.
Claims59
A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject:
- (a) an effective amount of Cbl inhibitor compound;
- and
- (b) a serotonin receptor antagonist.
The method of any of claims 2-3, wherein the dose of the serotonin receptor antagonist is reduced after 2-4 weeks. The method of any of claims 2-4, wherein the dose of the serotonin receptor antagonist is eliminated after 2-4 weeks.
The method of any of the previous claims, wherein the serotonin receptor antagonist is ondansetron, optionally wherein the dose of the ondansetron is 8 mg, 16 mg or 24 mg.
The method of any of the previous claims, wherein the serotonin receptor antagonist is granisetron, optionally wherein the dose of the granisetron is 1 mg or 2 mg.
The method of any of the previous claims, wherein the serotonin receptor antagonist is palonosetron, optionally wherein the dose of the palonosetron is 0.25 mg, 0.5 mg or mg.
The method of any of the previous claims, wherein the serotonin receptor antagonist is dolasetron, optionally wherein the dose of the dolasetron is 100 mg or 200 mg.
A method of treating or preventing nausea or vomiting, or both, in a patient undergoing Cbl treatment comprising administering to the subject:
- an effective amount of a serotonin receptor antagonist.
The method of any of the previous claims, wherein the Cbl inhibitor is a Cbl-b inhibitor.
The method of any of the previous claims, wherein the Cbl inhibitor is a c-Cbl inhibitor.
The method of any of the previous claims, wherein the Cbl inhibitor is a Cbl-b inhibitor and a c-Cbl inhibitor.
The method of any of the previous claims, wherein the Cbl-b inhibitor compound is according to Formula (I), or a pharmaceutically acceptable stereoisomer, tautomer, salt, or solvate thereof
- or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein
- Z1 is CH or nitrogen;
- Z2 is CH or nitrogen;
- R1 is —CF3 or cyclopropyl;
- R2 is —CF3 or cyclopropyl;
- R3 is hydrogen, C1-C2 alkyl, or C1-C2 haloalkyl;
- R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 4- to 8-membered heterocyclyl, or C3-C6 cycloalkyl, wherein the heterocyclyl or cycloalkyl groups are optionally substituted by one to five R6 groups;
- or R3 and R4 are taken together with the carbon atom to which they are attached to form a C3-C5 cycloalkyl or 4- to 6-membered heterocyclyl, each of which is optionally substituted by one to five R6 groups;
- R5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;
- each R6 is independently C1-C6 alkyl, halo, hydroxy, —O(C1-C6 alkyl), —CN, C1-C6 alkyl—CN, C1-C6 alkyl-OH, or C1-C6 haloalkyl;
- or two R6 groups attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a spiro C3-C6 cycloalkyl or spiro 4- to 6-membered heterocyclyl;
- X is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl—CN, C3-C6 cycloalkyl optionally substituted by one to five R8 groups, or
- is a 4- to 7-membered heterocyclyl or 5- to 8- membered heteroaryl, wherein each heterocyclyl or heteroaryl optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein each heterocyclyl or heteroaryl is optionally substituted by one to five R8 groups;
- each R7 is independently hydrogen, C1-C6 alkyl, C1-C6 alkyl-OH, or C1-C6 haloalkyl;
- or two R7 groups are taken together with the carbon atom to which they are attached to form a C3-cycloalkyl or 3- to 5- membered heterocyclyl;
- and
- each R8 is independently halo, C1-C6 alkyl, C1-C6 alkyl—CN, C1-C6 alkyl-OH, C1-C6 haloalkyl, —CN, oxo, or —O(C1-C6 alkyl);
- or two R8 groups are taken together with the carbon atom or atoms to which they are attached to form a spiro or fused C3-C5 cycloalkyl or 3- to 5-membered heterocyclyl.
The method of any of the previous claims, wherein the Cbl inhibitor compound is selected from the compounds in Table 1 or Table 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.
The method of any of the previous claims, wherein the Cbl inhibitor compound is according to Formula (II), or a pharmaceutically acceptable stereoisomer, tautomer, salt, or solvate thereof
The method of any of the previous claims, wherein the disease or condition is a cancer.
The method of any of the previous claims, wherein the disease or condition is a solid tumor.
The method of any of the previous claims, wherein the disease or condition is a hematological cancer.
The method of any of the previous claims, where the dose of the Cbl inhibitor compound is periodically increased.
A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a Cbl inhibitor compound at a dose of 15 mg and subsequently administering the Cbl inhibitor compound at a dose of 25 mg.
A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a Cbl inhibitor compound at a dose of 15 mg, subsequently administering the Cbl inhibitor compound at a dose of 25 mg, and subsequently administering the Cbl inhibitor compound at a dose of 50 mg.
A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a Cbl inhibitor compound at a dose of 25 mg and subsequently administering the Cbl inhibitor compound at a dose of 50 mg.
A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a Cbl inhibitor compound at an increasing dose of mg daily for one week to 20 mg daily for one week to 25 mg daily for 3 weeks.
A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a Cbl inhibitor compound at an increasing dose of mg daily after the 25 mg daily for 3 weeks dose.
A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a Cbl inhibitor compound at an increasing dose of mg daily for 3 weeks to 30 mg daily for 3 weeks to 25 mg thereafter.
A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a Cbl inhibitor compound at an increasing dose of mg daily for one week to 25 mg daily for one week to 30 mg daily.
A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a Cbl inhibitor compound at an increasing dose of mg daily to 35 mg daily over several weeks by increments of 5 mg each week.
A pharmaceutical composition comprising a Cbl inhibitor compound and a serotonin receptor antagonist.
Dependencies are inferred from the claim text.