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Building IP: CELG Patent Application re "COMBINATION THERAPY WITH 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)M- ETHYL)-2,2-DIFLUOROACETAMIDE"
COMBINATION THERAPY WITH 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)M- ETHYL)-2,2-DIFLUOROACETAMIDE Provided herein are methods of treating, preventing, managing, and/or ameliorating hypotension related to administration of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in a cancer patient, wherein the methods comprise administering a combination comprising 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof and a glucocorticoid receptor agonist, an interleukin-1 receptor antagonist, or an interleukin-1.beta. blocker.
1. A method of treating, preventing, managing, and/or ameliorating hypotension related to 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide, or a stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (Compound 1) in a cancer patient, wherein the method comprises administering to the patient a therapeutically effective amount of Compound 1 and a therapeutically effective amount of a glucocorticoid receptor agonist, an interleukin-1 receptor antagonist, or an interleukin-1.beta. blocker. 2. A method of suppressing interleukin-1.beta. induction related to 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide, or a stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (Compound 1) in a cancer patient, wherein the method comprises administering to the patient a therapeutically effective amount of Compound 1 and a therapeutically effective amount of a glucocorticoid receptor agonist, an interleukin-1 receptor antagonist, or an interleukin-1.beta. blocker. 3. The method of claim 1, wherein the glucocorticoid receptor agonist is prednisone, prednisolone, methylpredisolone, hydrocortisone, cortisone, cortisol, triamcinolone, betamethasone, or dexamethasone. 4. The method of claim 1, wherein the glucocorticoid receptor agonist is dexamethasone. 5. The method of claim 1, wherein the interleukin-1 receptor antagonist is anakinra. 6. The method of claim 1, wherein the interleukin-1.beta. blocker is canakinumab. 7. The method of claim 2, wherein the interleukin-1.beta. induction is suppressed by about 10% or more. 8. The method of claim 2, wherein the interleukin-1.beta. induction is suppressed by about 10% to 90%. 9. The method of claim 1, wherein the cancer is leukemia. 10. The method of claim 9, wherein the leukemia is acute myeloid leukemia. 11. The method of claim 10, wherein the acute myeloid leukemia is refractory or relapsed acute myeloid leukemia. 12. The method of claim 1, wherein the therapeutically effective amount of Compound 1 is about 0.1 mg to about 10 mg. 13. The method of claim 1, wherein the therapeutically effective amount of Compound 1 is about 0.3 mg, 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, 3 mg, 3.6 mg, 4.5 mg, 5.4 mg or 8.1 mg per day. 14. The method of claim 1, wherein Compound 1 is administered on days 1 to 5 of a 28 day treatment cycle. 15. The method of claim 14, wherein the treatment cycle comprises a rest period of 23 days. 16. The method of claim 1, wherein Compound 1 is administered on days 1 to 5 of a 42 day treatment cycle. 17. The method of claim 1, wherein Compound 1 is administered on days 1 to 3 of a 28 day treatment cycle. 18. The method of claim 1, wherein Compound 1 is administered on days 1 to 5 and days 15 to 19 of a 28 day treatment cycle. 19. The method of claim 14, wherein the treatment cycle is repeated at least once. 20. The method of claim 19, wherein the treatment cycle is repeated 2 to 4 times. 21. The method of claim 1, wherein the method comprises administering one or more of calcium, calcitriol, or vitamin D supplementation. 22. The method of claim 1, wherein the method comprises administering one or more of calcium, calcitriol, or vitamin D supplementation prior to Compound 1. 23. The method of claim 1, wherein the method comprises administering one or more of calcium, calcitriol, or vitamin D supplementation at least 3 days prior to Compound 1 on day 1 of the cycle. 24. The method of claim 21, wherein the patient does not have a disorder disrupting normal calcium homeostasis or preventing calcium supplementation. 25. The method of claim 1, further comprising administering a therapeutically effective amount of another additional active agent or a supportive care therapy. 26. The method of claim 25, wherein the additional active agent is selected from a hematopoietic growth factor, a cytokine, anti-cancer agent, an antibiotic, a cox-2 inhibitor, an immunomodulatory agent, an immunosuppressive agent, a corticosteroid or a pharmacologically active mutant or derivative thereof and a therapeutic antibody that specifically binds to a cancer antigen. RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/931,040, filed Nov. 5, 2019, the disclosure of which is incorporated herein by reference in its entirety. FIELD [0002] Provided herein are methods of treating, preventing, managing, and/or ameliorating hypotension related to administration of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in a cancer patient, wherein the methods comprise administering a therapeutically effective amount of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof and a therapeutically effective amount of a glucocorticoid receptor agonist, an interleukin-1 receptor antagonist, or an interleukin-1.beta. blocker. Also disclosed herein is 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide for use in such methods. BACKGROUND [0003] 2-(4-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-- 5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof has been shown to have anti-cancer activities. The compound, methods of use thereof and pharmaceutical compositions comprising the same are disclosed in U.S. Pat. Nos. 9,499,514; 9,808,451; 9,968,596; 10,189,808; 10,449,187; 10,052,315; and 10,245,258; and U.S. Publication Nos. US 2018/0221361 A1; US 2019/0106405 A1; US 2019/0175573 A1; and US 2019/003018 A1. [0004] There is a continuing to need for efficient methods of using 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide or a stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in treating cancer. BRIEF SUMMARY [0005] In one embodiment, provided herein are methods of treating, preventing, managing, and/or ameliorating hypotension related to administration of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (collectively Compound 1) in a cancer patient, wherein the methods comprise administering to the patient a therapeutically effective amount of Compound 1 and a therapeutically effective amount of a glucocorticoid receptor agonist, an interleukin-1 receptor antagonist, or an interleukin-1.beta. blocker. In one embodiment, the glucocorticoid receptor agonist is prednisone, prednisolone, methylprednisolone, hydrocortisone, cortisol, triamcinolone, betamethasone, or dexamethasone. In one embodiment, the glucocorticoid receptor agonist is prednisone, prednisolone, methylprednisolone, hydrocortisone, cortisone, cortisol, triamcinolone, betamethasone, or dexamethasone. In one embodiment, the glucocorticoid receptor agonist is dexamethasone. In one embodiment, the IL-1 receptor antagonist is anakinra. In one embodiment, the IL-1.beta. blocker is canakinumab. In one embodiment, the cancer is a hematological cancer. In one embodiment, the hematological cancer is leukemia. In one embodiment, the leukemia is acute myeloid leukemia (AML). In certain embodiments, the AML, is relapsed or refractory AML. [0006] In one embodiment, provided herein are methods suppressing Compound 1 related interleukin-1.beta. (IL-1.beta.) induction in a cancer patient, wherein the methods comprise administering to the patient a therapeutically effective amount of Compound 1 and a therapeutically effective amount of a glucocorticoid receptor agonist, an IL-1.beta. receptor antagonist or an IL-1.beta. blocker. In one embodiment, the glucocorticoid receptor agonist is prednisone, prednisolone, methylprednisolone, hydrocortisone, cortisol, triamcinolone, betamethasone, or dexamethasone. In one embodiment, the glucocorticoid receptor agonist is prednisone, prednisolone, methylprednisolone, hydrocortisone, cortisone, cortisol, triamcinolone, betamethasone, or dexamethasone. In one embodiment, the glucocorticoid receptor agonist is dexamethasone. In one embodiment, the IL-1 receptor antagonist is anakinra. In one embodiment, the IL-1.beta. blocker is canakinumab. In one embodiment, the cancer is a hematological cancer. In one embodiment, the hematological cancer is leukemia. In one embodiment, the leukemia is acute myeloid leukemia (AML). In certain embodiments, the AML is relapsed or refractory AML. [0007] In one embodiment, the methods provided herein further comprise administering to the patient a therapeutically effective amount of a vasopressor. In one embodiment, the methods further comprise administering to the patient a single low-dose vasopressor. In one embodiment, the methods further comprise administering to the patient one or more high-dose vasopressors. Non-limiting examples of vasopressors include epinephrine, isoproterenol, phenylephrine, norepinephrine, dobutamine, ephedrine, droxidopa, dopamine, and others known in the art. [0008] In certain embodiments, the methods provided herein further comprise administering to the patient an additional agent selected from JAK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors. [0009] Compound 1 and pharmaceutical compositions comprising the same used in the methods herein are described in U.S. Pat. Nos. 9,499,514; 9,808,451; 9,968,596; 10,189,808; 10,449,187; 10,052,315; and 10,245,258; and U.S. Publication Nos. US 2018/0221361 A1; US 2019/0106405 A1; US 2019/0175573 A1; and US 2019/003018 A1, the disclosures of each which are incorporated herein by reference in their entireties. [0010] In certain embodiments, provided herein are pharmaceutical compositions, single unit dosage forms, and kits comprising Compound 1 and a glucocorticoid receptor agonist, an interleukin-1 receptor antagonist, or an interleukin-1.beta. blocker, suitable for use in treating, preventing, ameliorating and/or managing hypotension. In certain embodiments, provided herein are pharmaceutical compositions, single unit dosage forms, and kits comprising Compound 1 and a glucocorticoid suitable for use in the methods suppressing Compound 1 related interleukin-1.beta. (IL-1.beta.) induction. In one embodiment, the glucocorticoid receptor agonist is prednisone, prednisolone, methylprednisolone, hydrocortisone, cortisol, triamcinolone, betamethasone, or dexamethasone. In one embodiment, the glucocorticoid receptor agonist is prednisone, prednisolone, methylprednisolone, hydrocortisone, cortisone, cortisol, triamcinolone, betamethasone, or dexamethasone. In one embodiment, the glucocorticoid receptor agonist is dexamethasone. In certain embodiments, such compositions include Compound 1 and dexamethasone optionally in combination with one or more additional therapeutic agents. In other embodiments, IL-1 receptor antagonist is anakinra. In certain embodiments, such compositions include Compound 1 and anakinra, optionally in combination with one or more additional therapeutic agents. In one embodiment, the IL-1.beta. blocker is canakinumab. In certain embodiments, such compositions include Compound 1 and canakinumab, optionally in combination with one or more additional therapeutic agents. [0011] Also provided herein is 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide, or a stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (Compound 1) for use in a method of treating, preventing, managing, and/or ameliorating hypotension in a cancer patient, wherein the method comprises administering to the patient a therapeutically effective amount of Compound 1 and a therapeutically effective amount of a glucocorticoid receptor agonist, an interleukin-1 receptor antagonist, or an interleukin-1.beta. blocker. [0012] Also provided herein is 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)m- ethyl)-2,2-difluoroacetamide, or a stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (Compound 1) for use in a method of suppressing interleukin-1.beta. induction in a cancer patient, wherein the method comprises administering to the patient a therapeutically effective amount of Compound 1 and a therapeutically effective amount of a glucocorticoid receptor agonist, an interleukin-1 receptor antagonist, or an interleukin-1.beta. blocker. [0013] These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description. |
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