Combination CBL-BI and antihistamine for cancer therapy

Abstract

Disclosed herein are methods of administering a Casitas B-lineage lymphoma proto-oncogene B inhibitor (CBL-Bi) for treating a cancer in a subject. Additionally disclosed herein are methods of administering a pre-treatment in combination with the CBL-Bi for treating a cancer in a subject.

Description

Attorney Docket No.: HOT-023WOCOMBINATION CBL-BI AND ANTIHISTAMINE FOR CANCER THERAPYCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 691 ,825 filed September 6, 2024, and U.S. Provisional Application No. 63 / 718, 1 15 filed November 8, 2024, which is hereby incorporated by reference in its entirety for all purposes.FIELD

[0002] The present field involves methods of administering a Casitas B -lineage lymphoma proto-oncogene B inhibitor (CBL-Bi) for treating a cancer in a subject and methods of administering a CBL-Bi in combination with a pre-treatment to counteract the side effects of the CBL-Bi in the subject.BACKGROUND

[0003] Novel cancer immunotherapeutics have been developed in the past decade, showing promise as new candidates for treating cancer. Several therapies, such as immune checkpoint inhibitors, are being investigated across a range of different cancer types. Not all patients respond to or have durable responses to currently available agents. In addition, many cancer treatment options, such as chemotherapies and radiotherapies, lead to severe side effects that make the treatments difficult to withstand for patients. The side effects of these therapeutics further limit the options available for the cancer patients. Thus, there is a need to identify new drug candidates for treating patients with cancers which do not respond to or are not as effective against currently available drugs. Furthermore, there is an unmet need for methods of treating cancer in patients with reduced side effects from the therapies.SUMMARY

[0004] The disclosure provides, in one aspect, a method of treating cancer in a patient in need thereof, the method comprising administering to the subject a CBL-Bi and an antihistamine.

[0005] In some embodiments, the CBL-B inhibitor is administered at a dose of about 2 mg to about 200 mg.11PTS / 200114525.1Attorney Docket No.: HOT-023WO

[0006] In some embodiments, the CBL-B inhibitor is administered at a dose of about 5 mg to about 150 mg.

[0007] In some embodiments, the CBL-B inhibitor is administered at a dose of about 5 mg to 40 mg.

[0008] In some embodiments, the CBL-B inhibitor is administered at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

[0009] In some embodiments, the antihistamine comprises either a second-generation Hl blocker or a H2 blocker.

[0010] In some embodiments, the antihistamine is one of cetirizine, fexofenadine, levocetirizine, or loratadine.

[0011] In some embodiments, the antihistamine is one of cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, and sufotidine.

[0012] In some embodiments, the antihistamine is cetirizine.

[0013] In some embodiments, the antihistamine is administered at a dose of about 1 mg to about 20 mg.

[0014] In some embodiments, the antihistamine is administered at a dose of about 5 mg to about 15 mg.

[0015] In some embodiments, the antihistamine is administered at about 10 mg.

[0016] In some embodiments, the antihistamine is administered at least once weekly.

[0017] In some embodiments, the antihistamine is administered at least twice weekly.

[0018] In some embodiments, the antihistamine is administered daily.

[0019] In some embodiments, the antihistamine is administered on the same day as the CBL-B inhibitor.

[0020] In some embodiments, the antihistamine is administered in the morning.

[0021] In some embodiments, methods further comprise administering one or more additional doses of the antihistamine.

[0022] In some embodiments, the one or more additional doses of the antihistamine are administered twice weekly.

[0023] In some embodiments, the method further comprising administering one or more additional doses of the CBL-B inhibitor.

[0024] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered once monthly.21PTS / 200114525.1Attorney Docket No.: HOT-023WO

[0025] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administer every two weeks.

[0026] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered once weekly.

[0027] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered twice weekly.

[0028] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered daily.

[0029] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered in the morning.

[0030] In some embodiments, the CBL-B inhibitor is administered orally.

[0031] In some embodiments, the antihistamine is administered orally.

[0032] In some embodiments, the method further comprises administering a steroid.

[0033] In some embodiments, the steroid is a glucocorticoid.

[0034] In some embodiments, the steroid is selected from: dexamethasone, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, betamethasone, triamcinolone, deflazacort, and beclomethasone.

[0035] In some embodiments, the steroid is dexamethasone.

[0036] In some embodiments, the glucocorticoid is administered at a dose of about 0.5 mg to about 6 mg.

[0037] In some embodiments, the glucocorticoid is administered at a dose of about 1 mg to about 5 mg.

[0038] In some embodiments, the glucocorticoid is administered at a dose of about 2 mg or about 4 mg.

[0039] In some embodiments, the glucocorticoid is administered at a dose of about 2 mg.

[0040] In some embodiments, the glucocorticoid is administered at a dose of about 4 mg.

[0041] In some embodiments, the glucocorticoid is administered at least once weekly.

[0042] In some embodiments, the glucocorticoid is administered at least twice weekly.

[0043] In some embodiments, the glucocorticoid is administered on the same day as the CBL-B inhibitor.

[0044] In some embodiments, the glucocorticoid is administered about 1 hour to about 4 hours before the CBL-B inhibitor.31PTS / 200114525.1Attorney Docket No.: HOT-023WO

[0045] In some embodiments, the glucocorticoid is administered about 2 hours before the CBL-B inhibitor.

[0046] In some embodiments, the method further comprising administering one or more additional doses of the steroid.

[0047] In some embodiments, the one or more additional doses of the steroid are administered twice weekly.

[0048] In some embodiments, the steroid is administered orally.

[0049] In some embodiments, the method further comprising administering an anti-nausea medication.

[0050] In some embodiments, the anti-nausea medication is a 5-HT3 serotonin receptor antagonist.

[0051] In some embodiments, the anti-nausea medication is selected from: ondansetron, granisetron, olanzapine, lorazepam, dolasetron, palonosetron, ramosetron, tropisetron, vortioxetine, bismuth subsalicylate, dimenhydrinate, meclizine, scopolamine, prochlorperazine, promethazine, and metoclopramide.

[0052] In some embodiments, the anti-nausea medication is ondansetron or granisetron.

[0053] In some embodiments, the anti-nausea medication is administered at a dose of about 2 mg to about 10 mg.

[0054] In some embodiments, the anti-nausea medication is administered at dose of about 3 mg to about 9 mg.

[0055] In some embodiments, the anti-nausea medication is administered at a dose of about 4 mg or about 8 mg.

[0056] In some embodiments, the anti-nausea medication is administered at a dose of about 4 mg.

[0057] In some embodiments, the anti-nausea medication is administered at a dose of about 8 mg.

[0058] In some embodiments, the anti-nausea medication is administered at least once weekly.

[0059] In some embodiments, the anti-nausea medication is administered at least twice weekly.

[0060] In some embodiments, the anti-nausea medication is administered on the same day as the CBL-B inhibitor.41PTS / 200114525.1Attorney Docket No.: HOT-023WO

[0061] In some embodiments, the anti-nausea medication is administered about 1 hour to about 4 hours before the CBL-B inhibitor.

[0062] In some embodiments, the anti-nausea medication is administered about 2 hours before the CBL-B inhibitor.

[0063] In some embodiments, the method further comprising administering one or more additional doses of the anti-nausea medication.

[0064] In some embodiments, the one or more additional doses of the anti-nausea medication are administered twice weekly.

[0065] In some embodiments, the anti-nausea medication is administered orally.

[0066] In some embodiments, the method further comprising administering a histamine H2 blocker.

[0067] In some embodiments, the histamine H2 blocker is selected from: famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, and sufotidine.

[0068] In some embodiments, the histamine H2 blocker is famotidine.

[0069] In some embodiments, the histamine H2 blocker is administered at a dose of about 10 mg to about 30 mg.

[0070] In some embodiments, the histamine H2 blocker is administered at a dose of about 20 mg.

[0071] In some embodiments, the H2 blocker is administered at least once weekly.

[0072] In some embodiments, the H2 blocker is administered at least twice weekly.

[0073] In some embodiments, the H2 blocker is administered daily.

[0074] In some embodiments, the H2 blocker is administered on the same day as the CBL-B inhibitor.

[0075] In some embodiments, the H2 blocker is administered in the morning.

[0076] In some embodiments, the method further comprising administering one or more additional doses of the H2 blocker.

[0077] In some embodiments, the one of more additional doses of the H2 blocker are administered twice weekly.

[0078] In some embodiments, the antihistamine is administered orally.

[0079] In some embodiments, the CBL-B inhibitor comprises one of the following compounds:51PTS / 200114525.1Attorney Docket No.: HOT-023WOp .

[0080] The disclosure provides, in another aspect, a method of treating cancer in a patient in need thereof comprising administering to the subject: a CBL proto-oncogene B (CBL-B) inhibitor at a dose of about 5 mg to 40 mg; and a pre-treatment regimen, wherein the pre-treatment regimen is administered to the patient prior to the CBL-B inhibitor, the pre-treatment regimen comprising: a histamine Hl blocker at a dose of about 10 mg; a glucocorticoid at a dose between about 2 mg to about 4 mg an anti-nausea medication at a dose between about 4 mg to about 8 mg; and a histamine H2 blocker at a dose of about 20 mg.

[0081] In some embodiments, the method further comprising administering one or more additional doses of the CBL-B inhibitor.

[0082] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered twice weekly.

[0083] In some embodiments, the CBL-B inhibitor is administered in the morning.

[0084] In some embodiments, the method further comprising administering the pretreatment regimen on a same day prior to an additional dose of the CBL-B inhibitor.

[0085] In some embodiments, the method further comprising administering the antihistamine and / or the H2 blocker daily.

[0086] In some embodiments, the antihistamine and / or the H2 blocker are administered in the morning.

[0087] In some embodiments, the CBL-B inhibitor and the pre-treatment regimen are administered orally.IPTS / 200114525.1Attorney Docket No.: HOT-023WO

[0088] In some embodiments, the treatment further comprises administering anti-diarrheal medication.

[0089] In some embodiments, the anti-diarrheal medication is selected from loperamide, bismuth subsalicylate, alosetron, eluxadoline, and rifaximin.

[0090] In some embodiments, the anti-diarrheal medication is administered at a dose of about 2 mg to 16 mg.

[0091] The disclosure provides, in another aspect, a method of treating cancer in a patient in need thereof, the method comprising administering to the subject a CBL proto-oncogene B (CBL-B) inhibitor at a dose of about 2 mg to about 200 mg.

[0092] In some embodiments, the CBL-B inhibitor comprises one of the following compounds:p .

[0093] In some embodiments, the CBL-B inhibitor comprises Compound 2:(Compound 2).

[0094] In some embodiments, the CBL-B inhibitor is administered at a dose of about 5 mg to about 150 mg.

[0095] In some embodiments, the CBL-B inhibitor is administered at a dose of about 5 mg to 40 mg.

[0096] In some embodiments, the CBL-B inhibitor is administered at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.IPTS / 200114525.1Attorney Docket No.: HOT-023WO

[0097] In some embodiments, the method further comprising administering one or more additional doses of the CBL-B inhibitor.

[0098] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered once monthly.

[0099] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered once every two weeks.

[0100] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered once weekly.

[0101] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered twice weekly.

[0102] In some embodiments, the one or more additional doses of the CBL-B inhibitor are administered daily.

[0103] In some embodiments, the CBL-B inhibitor is administered orally.

[0104] In some embodiments, the CBL-B inhibitor is administered in the morning.

[0105] In some embodiments, the cancer is selected from ovarian cancer, anal cancer, rectal cancer, prostate cancer, non-small cell lung cancer, small-cell lung cancer, malignant pleural mesothelioma, cutaneous squamous cell carcinoma, melanoma, merkel cell carcinoma, head and neck squamous cell cancer, and acral melanoma, esophageal carcinoma, gastric carcinoma, gastroesophageal junction cancer, renal cell carcinoma, urothelial cell carcinoma, cervical cancer, endometrial cancer, hepatocellular carcinoma, triple-negative breast cancer, biliary tract cancer, microsatellite instability-high (MSI-H), mismatch repair deficient colorectal cancer, tumor mutational burden-high (TMB-H) cancer. In some embodiments, the cancer comprises a tumor type that is treatable with an anti-PD-1 and / or and anti-PD-Ll antibody.

[0106] In some embodiments, the cancer comprises a solid tumor.

[0107] In some embodiments, the solid tumor is an advanced solid tumor.

[0108] In some embodiments, the solid tumor is metastatic, recurrent, and / or unresectable.

[0109] The disclosure provides, in another aspect, a method of treating cancer in a patient in need thereof, the method comprising administering to the subject one or more doses of a CBL proto-oncogene B (CBL-B) inhibitor of Compound 2 having the following formula:81PTS / 200114525.1Attorney Docket No.: HOT-023WO(Compound 2), wherein each of the one or more doses comprise about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg of the CBL-Bi.BRIEF DESCRIPTION OF THE FIGURES

[0110] FIGs. 1A-1D are graphs showing the changes in cell scores, derived from NanoString gene expression analysis, of different cell populations within the tumors treated with either vehicle control or Compound 1 at 60 milligrams per kilogram (mpk) twice daily (BID) in murine tumor models EMT6 (FIG. 1A), Pan02 (FIG. IB), H22 (FIG. 1C), and CT26 (FIG. ID).

[0111] FIG. 2 is a graph showing the cell score of mast cells in different murine tumor models (EMT6, Pan02, H22, and CT26) treated with vehicle or Compound 1 at 60 mpk twice a day (BID). Data represents at least 3 animals per group and are expressed as mean ± SD. Tumor growth inhibition (TGI) observed in each tumor model is also shown.

[0112] FIG. 3 A is a graph showing the cell score of mast cells present in the tumors of CT26 mouse models administered with vehicle, different dosing frequencies of Compound 1 alone, an anti-PD-1 inhibitor alone (aPDl), or different frequencies of Compound 1 in combination with the anti-PD-1 inhibitor. FIGs. 3B and 3C are graphs showing mRNA levels (normalized log2 nCounter data with housekeeping gene normalization) of mast cell markers Cmal (FIG. 3B) and Tpsabl (FIG. 3C) for the same treatment groups evaluated in the data shown in FIG. 3A. Data represents 3 animals per group and are expressed as mean ± SD.

[0113] FIG. 4A is a graph showing the cell score of mast cells present in the tumors of CT26 mouse models administered with vehicle, Compound 1 alone, an IL- 15 agonist alone (at 0.2 mpk once a week (QW)), or Compound 1 in combination with the IL- 15 agonist. FIGs. 4B and 4C are graphs showing normalized mRNA levels (normalized log2 nCounter data with housekeeping gene normalization) of mast cell markers Cmal (FIG. 4B) and Tpsabl (FIG. 4C) for the same treatment groups evaluated in the data shown in FIG. 4A. Data represents 3 animals per group and are expressed as mean ± SD.9IPTS / 200114525.1Attorney Docket No.: HOT-023WO

[0114] FIGs. 5A and 5B are graphs showing mRNA levels (normalized nCounter data with housekeeping gene normalization) of mast cell markers Cmal (FIG. 5A) and Tpsabl (FIG. 5B) in the tumors of CT26 mouse models administered with vehicle, with Compound 2 at 3 mpk, 10 mpk, or 30 mpk twice a day (BID), or with Compound 2at 6 rnpk, 20 mpk, or 60 mpk once a day (QD). Data represents at least 2 animals per group and are expressed as mean ± SD.

[0115] FIGs. 6A-6C are graphs showing tumor volume (in mm3) over 13 days in CT26 mouse models administered with Compound 2 at 6 mpk (FIG. 6A), 12 mpk (FIG. 6B), or 20 mpk (FIG. 6C) once day (QD), once a week (QW), or twice per week (BIW), or with vehicle. Data represents ten animals per group and are expressed as mean ± SEM.

[0116] FIG. 7 is a graph showing tumor volume (in mm3) at day 13 after treatment with Compound 2 at 6 mpk, 12 mpk, or 20 mpk once a day (QD), once a week (QW), or twice per week (BIW), or with vehicle in CT26 mouse models. Data represents 10 animals per group and are expressed as mean + SEM.

[0117] FIG. 8 is a graph showing tumor volume (in mm3) over 18 days in EG7 mouse models administered with Compound 2 at 20 mpk once a day (QD), 20 mpk twice per week (BIW), or 60 mpk twice per week (BIW) or with vehicle. Data represents ten animals per group and are expressed as mean ± SEM.

[0118] FIG. 9 is a graph showing tumor volume (in mm3) after 18 days from treatment in CT26 mouse models administered with Compound 2at 20 mpk once a day (QD), 20 mpk twice per week (BIW), or 60 mpk twice per week (BIW) or with vehicle. Data represents 20 animals per group and are expressed as mean ± SEM.

[0119] FIGs. 10A and 10B are diagrams showing exemplary dosing regimens for Compound 2 administered twice per week (FIG. 10A) or once per week (FIG. 10B), including exemplary dosing for the pre-treatment medications (anti-nausea medication and steroids) and daily administration of anti-histamines and H2 receptor antagonists.

[0120] FIG. 11 is a diagram describing the phase I clinical trial evaluating Compound 2 alone (Part A) and in combination with cemiplimab (Part B) in patients with advanced solid tumors.

[0121] FIGs. 12A and 12B are graphs showing pharmacokinetics of Compound 2 in subjects administered with 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg by measuring Compound 2 plasma concentration (in ng / mL) over 24 hours after administration on day 1 (FIG. 12A) and day 22 (FIG. 12B) from beginning of treatment. Dotted lines represent the EC50 of101PTS / 200114525.1Attorney Docket No.: HOT-023WOCompound 2 for activating T cell proliferation and induce IFNy secretion. Data are expressed as mean ± SD.

[0122] FIG. 13 is a graph showing percent change in the expression of Notch 1 relative to CD8 in peripheral T-cells after 4 hours and 24 hours from administration of Compound 2 at 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg. Data represents 2-8 subjects per group (as specified in the x-axis of the graph) and are expressed as mean ± SEM

[0123] FIGs. 14A-14C are box-and-whisker graphs showing changes in overall cytokine expression (FIG. 14A) at day 1 of Compound 2 administration, and IFNy secretion at day 1 (FIG. 14B) and day 22 (FIG. 14C) of Compound 2 administration at doses of 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg. Data represents 2-6 subjects per group (as specified in the x-axis of the graph) and are expressed as median ± SEM.

[0124] FIG. 15 is a graph showing the IFNy levels at days 1 and 22 at pre-dosing and 2, 4, and 8 hours after administration of Compound 2 in a subject with non-small cell lung cancer.

[0125] FIG. 16 depicts a dose dependent modulation of immune related transcriptional pathways in peripheral blood samples following administration of Compound 2.

[0126] FIGs. 17A-17D depicts induced changes in different TCR and BCR repertoire metrics following administration of Compound 2.

[0127] FIG. 18 depicts a tumor microenvironment (TME) RNA signature testing to predict clinical benefit.DETAILED DESCRIPTIONDefinitions

[0128] As used herein, the term “about” refers to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 nM to 5.5 nM.

[0129] As used herein, the singular forms “a,” “an” and “the” include plural referents unless context clearly dictates otherwise. For instance, in some embodiments, reference to “compounds” includes a plurality of compounds, a single compound, etc.

[0130] As used herein, the expression “and / or” in connection with two or more recited objects includes individually each of the recited objects and the various combinations of two or more of the recited objects, unless otherwise understood from the context and use.111PTS / 200114525.1Attorney Docket No.: HOT-023WO

[0131] As used herein, the term “administration” refers providing a composition to a subject or system. Administration to a subject may be by any appropriate route, dose and / or dose schedule.

[0132] As used herein, the term “pre-treatment” refers to a combination of at least one or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication for counteracting the side effects of the CBL-Bi.

[0133] As used herein, the terms “subject” and “patient” refer to an organism, such as a human, that receives treatment for a particular disease or condition as described herein. In some embodiments, a patient, such as a human patient, that is in need of a cancer treatment may receive a treatment that includes a CBL-Bi so as to treat a cancer.

[0134] As used herein, the terms “treat” or “treatment” refer to therapeutic treatment, in which the object is to prevent or slow down (lessen) an undesired physiological change or disorder or to promote a beneficial phenotype in the patient being treated. Beneficial or desired clinical results include, but are not limited to: reducing the volume / size of tumors, preventing proliferation of cancer cells, and preventing development of new lesions / tumors. In some embodiments, the benefits include preventing side effects of the therapeutic treatment in the subject, including but not limited to: allergic reactions, nausea, vomiting, diarrhea, stomach ulcers, and acid reflux.

[0135] “Preventing” includes delaying the onset of clinical symptoms, complications, or biochemical indicia of the state, disorder, disease, or condition developing in a subject that may be afflicted with or predisposed to the state, disorder, disease, or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder, disease, or condition. “Preventing” includes prophylactically treating a state, disorder, disease, or condition in or developing in a subject, including prophylactically treating clinical symptoms, complications, or biochemical indicia of the state, disorder, disease, or condition in or developing in a subject.

[0136] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein interchangeably refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.121PTS / 200114525.1Attorney Docket No.: HOT-023WOOverview

[0137] The present disclosure provides methods of administering a CBL-Bi for treating a cancer in a subject. The present disclosure also provides methods of administering a pretreatment in combination with the CBL-Bi for treating a cancer in a subject. Administration of the CBL-Bi can result in an innate immune response. An innate immune response can be as observed by an increase in global mast cells and / or an increase in mast cell activation e.g., relative to other immune cell types in the subject, which can cause side effects in the subject. Therefore, the pre-treatment can be provided to the subject to counteract the side effects of the CBL-Bi treatment. In various embodiments, the pre-treatment comprises one or more anti-histamines e.g., an Hi blocker and / or and H2 blocker), a steroid (e.g., a glucocorticoid), an anti-nausea medication, and / or an anti-diarrheal medication.

[0138] The present disclosure also describes further co- administration of medications with the CBL-Bi for treating said cancer in the subject. Co- administrating said medications can counteract additional side effects of the pre-treatment and / or the CBL-Bi treatment in the subject. In various embodiments, the co-treatment comprises at least one anti-histamine (e.g., an Hi blocker and / or an H2 blocker).Methods of Treatment

[0139] The present disclosure provides methods of administering a pre-treatment with a CBL-Bi for treating a cancer in a subject. In some embodiments, the method comprises administering the CBL-Bi with an antihistamine. In certain embodiments, the antihistamine can be an Hi blocker or an H2 blocker. In certain embodiments, the method comprises administering at least one antihistamine (e.g., an Hi blocker and / or an H2 blocker). In certain embodiments, the method comprises administering two antihistamines (e.g., an Hi blocker and an H2 blocker). In some embodiments, the method comprises administering the CBL-Bi with a steroid. In certain embodiments, the steroid can be a glucocorticoid. In some embodiments, the method comprises administering the CBL-Bi with an anti-nausea medication. In some embodiments, the method comprises administering the CBL-Bi with an anti-diarrheal medication.

[0140] In some embodiments, the method comprises administering the CBL-Bi with a combination of any one of the following: an Hi blocker, an H2 blocker, a steroid, an antinausea medication, and an anti-diarrheal medication. For example, in certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker. In certain embodiments,131PTS / 200114525.1Attorney Docket No.: HOT-023WO the method comprises administering the CBL-Bi with an H2 blocker. In certain embodiments, the method comprises administering the CBL-Bi with a steroid. In certain embodiments, the method comprises administering the CBL-Bi with an anti-nausea medication. In certain embodiments, the method comprises administering the CBL-Bi with an anti-diarrheal medication.

[0141] In some embodiments, the method comprises administering the CBL-Bi with a combination of any two of the following: an Hi blocker, an H2 blocker, a steroid, an antinausea medication, and an anti-diarrheal medication. For example, in certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker and an H2 blocker. In certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker and a steroid. In certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker and an anti-nausea medication. In certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker and an anti-diarrheal medication. In certain embodiments, the method comprises administering the CBL-Bi with an H2 blocker and a steroid. In certain embodiments, the method comprises administering the CBL-Bi with an H2 blocker and an anti-nausea medication. In certain embodiments, the method comprises administering the CBL-Bi with an H2 blocker and an anti-diarrheal medication. In certain embodiments, the method comprises administering the CBL-Bi with a steroid and an antinausea medication. In certain embodiments, the method comprises administering the CBL-Bi with a steroid and an anti-diarrheal medication. In certain embodiments, the method comprises administering the CBL-Bi with an anti-nausea medication and an anti -diarrheal medication.

[0142] In some embodiments, the method comprises administering the CBL-Bi with a combination of any three of the following: an Hi blocker, an H2 blocker, a steroid, an antinausea medication, and an anti-diarrheal medication. For example, in certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker, an H2 blocker, and a steroid. In certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker, an H2 blocker, and an anti-nausea medication. In certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker, an H2 blocker, and an anti-diarrheal medication. In certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker, a steroid, and an anti-nausea medication. In certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker, a steroid, and an anti-diarrheal medication. In certain embodiments, the method comprises administering the CBL-Bi with an141PTS / 200114525.1Attorney Docket No.: HOT-023WOHi blocker, an anti-nausea medication, and an anti-diarrheal medication. In certain embodiments, the method comprises administering the CBL-Bi with an H2 blocker, a steroid, and an anti-nausea medication. In certain embodiments, the method comprises administering the CBL-Bi with an H2 blocker, a steroid, and an anti-diarrheal medication. In certain embodiments, the method comprises administering the CBL-Bi with a steroid, an anti-nausea medication, and an anti-diarrheal medication.

[0143] In some embodiments, the method comprises administering the CBL-Bi with a combination of any four of the following: an Hi blocker, an H2 blocker, a steroid, an antinausea medication, and an anti-diarrheal medication. For example, in certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker, an H2 blocker, a steroid, and an anti-nausea medication. In certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker, an H2 blocker, a steroid, and an anti-diarrheal medication. In certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker, an H2 blocker, an anti-nausea medication, and an anti-diarrheal medication. In certain embodiments, the method comprises administering the CBL-Bi with an Hi blocker, a steroid, an anti-nausea medication, and an anti-diarrheal medication. In certain embodiments, the method comprises administering the CBL-Bi with an H2 blocker, a steroid, an anti-nausea medication, and an anti-diarrheal medication.

[0144] In some embodiments, the method comprises administering the CBL-Bi with a combination of the following: an Hi blocker, an H2 blocker, a steroid, an anti-nausea medication, and an anti -diarrheal medication.

[0145] The present disclosure also provides methods of co-administering a medication with a CBL-Bi for treating a cancer in a subject. In some embodiments, the method comprises coadministering an Hi blocker and / or and an H2 blocker with the CBL-Bi. In some embodiments, the method comprises co-administering an Hi blocker and an H2 blocker with the CBL-Bi.Administration and Dosing of CBL-B Inhibitors

[0146] The present disclosure provides a method of administering and dosing a CBL-Bi for treating a cancer in a subject. Example CBL-Bi are disclosed herein as e.g., Compound 1 and Compound 2 (as shown in Table 1). In particular embodiments, the present disclosure provides a method of treating cancer in a patient in need thereof, the method comprising administering to the subject a CBL-Bi of Compound 1. In particular embodiments, the151PTS / 200114525.1Attorney Docket No.: HOT-023WO present disclosure provides a method of treating cancer in a patient in need thereof, the method comprising administering to the subject a CBL-Bi of Compound 2.

[0147] In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 3 mg / kg to about 60 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 3 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 5 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 10 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 20 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 30 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 40 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 50 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 60 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 70 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 80 mg / kg to about 90 mg / kg.

[0148] In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 90 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 80 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 70 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 60 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 50 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 40 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 30 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 20 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 10 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a161PTS / 200114525.1Attorney Docket No.: HOT-023WO dose of about 1 mg / kg to about 5 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg to about 3 mg / kg.

[0149] In some embodiments, the method comprises administering the CBL-Bi at a dose of about 1 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 3 mg / kg. In some embodiments, the method comprises administering the CBL- Bi at a dose of about 6 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 10 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 12 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 20 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 30 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 40 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 50 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 60 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 70 mg / kg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 90 mg / kg.

[0150] In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 200 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 150 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 100 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 50 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 40 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 30 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 25 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 20 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 15 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 10 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 5 mg.

[0151] In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 200 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 5 mg to about 200 mg. In some embodiments, the method171PTS / 200114525.1Attorney Docket No.: HOT-023WO comprises administering the CBL-Bi at a dose of about 10 mg to about 200 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 15 mg to about 200 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 20 mg to about 200 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 25 mg to about 200 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 30 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 40 mg to about 200 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg to about 50 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 100 mg to about 200 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 150 mg to about 200 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 5 mg to about 150 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 5 mg to about 40 mg.

[0152] In some embodiments, the method comprises administering the CBL-Bi at a dose of about 2 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 5 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 10 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 15 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 20 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 25 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 30 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 35 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 40 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 50 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 100 mg. In some embodiments, the method comprises administering the CBL-Bi at a dose of about 150 mg. In some embodiments, the method comprises administering the CBL- Bi at a dose of about 200 mg.

[0153] In some embodiments, the method comprises administering the CBL-Bi once monthly. In some embodiments, the method comprises administering the CBL-Bi every two weeks. In some embodiments, the method comprises administering the CBL-Bi once weekly.181PTS / 200114525.1Attorney Docket No.: HOT-023WOIn some embodiments, the method comprises administering the CBL-Bi twice weekly. In some embodiments, the method comprises administering the CBL-Bi daily.

[0154] In some embodiments, the method comprises administering the CBL-Bi twice weekly, e.g. the method comprises a first dose and a second dose of the CBL-Bi in a week. In various embodiments, the first dose of the CBL-Bi is on day 0 and the second dose of the CBL-Bi is on day 3. In various embodiments, the first dose of the CBL-Bi is on day 0 and the second dose of the CBL-Bi is on day 4. In various embodiments, the first dose of the CBL-Bi is on day 0 and the second dose of the CBL-Bi is on day 5. In various embodiments, the first dose of the CBL-Bi is on day 0 and the second dose of the CBL-Bi is on day 6. In various embodiments, the first dose and the second dose are taken 3 days apart. In various embodiments, the first dose and the second dose are taken 4 days apart. In various embodiments, the first dose and the second dose are taken 5 days apart. In various embodiments, the first dose and the second dose are taken 6 days apart.Administration and Dosing of Pre-Treatment

[0155] In various embodiments, the pre-treatment includes administering one or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication. In various embodiments, the pre-treatment includes administering two or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication. In various embodiments, the pre-treatment includes administering three or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication. In various embodiments, the pre-treatment includes administering three or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication. In various embodiments, the pre-treatment includes administering four or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication. In various embodiments, the pre-treatment includes administering five or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication.

[0156] In various embodiments, the pre-treatment is administered on the same day the CBL- Bi is administered. In various embodiments, the pre-treatment is administered about 1 hour to about 4 hours before the CBL-Bi is administered. In various embodiments, the pre-treatment is administered about 1 hour to about 3 hours before the CBL-Bi is administered. In various embodiments, the pre-treatment is administered about 1 hour to about 2 hours before the CBL-Bi is administered. In various embodiments, the pre-treatment is administered about 2 hours to about 4 hours before the CBL-Bi is administered. In various embodiments, the pre- 191PTS / 200114525.1Attorney Docket No.: HOT-023WO treatment is administered about 3 hours to about 4 hours before the CBL-Bi is administered. In various embodiments, the pre-treatment is administered about 1 hour before the CBL-Bi is administered. In various embodiments, the pre-treatment is administered about 2 hours before the CBL-Bi is administered. In various embodiments, the pre-treatment is administered about 3 hours before the CBL-Bi is administered. In various embodiments, the pre-treatment is administered about 4 hours before the CBL-Bi is administered.

[0157] In some embodiments, the method comprises administering an anti-histamine as a pre-treatment. In some embodiments, the method comprises administering the anti-histamine at a dose of about 1 mg to about 30 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 5 mg to about 30 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 10 mg to about 30 mg. In some embodiments, the method comprises administering the antihistamine at a dose of about 15 mg to about 30 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 20 mg to about 30 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 25 mg to about 30 mg. In some embodiments, the method comprises administering the antihistamine at a dose of about 1 mg to about 25 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 1 mg to about 20 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 1 mg to about 15 mg. In some embodiments, the method comprises administering the antihistamine at a dose of about 1 mg to about 10 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 1 mg to about 5 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 5 mg to about 10 mg. In some embodiments, the method comprises administering the antihistamine at a dose of about 10 mg to about 30 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 10 mg to about 25 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 10 mg to about 20 mg. In some embodiments, the method comprises administering the antihistamine at a dose of about 10 mg to about 15 mg

[0158] In some embodiments, the method comprises administering the anti-histamine at a dose of about 1 mg. In some embodiments, the method comprises administering the antihistamine at a dose of about 5 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 10 mg. In some embodiments, the method201PTS / 200114525.1Attorney Docket No.: HOT-023WO comprises administering the anti-histamine at a dose of about 15 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 20 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 25 mg. In some embodiments, the method comprises administering the anti-histamine at a dose of about 30 mg.

[0159] In some embodiments, the method comprises administering the anti-histamine at least once weekly. In some embodiments, the method comprises administering the antihistamine at least twice weekly. In some embodiments, the method comprises administering the anti-histamine daily. In some embodiments, the method comprises administering the antihistamine on the same day as the CBL-Bi. In some embodiments, the method comprises administering the anti-histamine in the morning the CBL-Bi is administered. In some embodiments, the method comprises administering the anti-histamine about 1 hour to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-histamine about 1 hour to about 3 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-histamine about 1 hour to about 2 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-histamine about 2 hours to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-histamine about 3 hours to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-histamine about 1 hour before the CBL-Bi. In some embodiments, the method comprises administering the anti-histamine about 2 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-histamine about 3 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-histamine about 4 hours before the CBL-Bi.

[0160] In various embodiments, the anti-histamine is an Hi blocker or an H2 blocker.

[0161] In some embodiments, the method comprises administering the Hi blocker at a dose of about 1 mg to about 20 mg. In some embodiments, the method comprises administering the Hi blocker at a dose of about 1 mg to about 20 mg. In some embodiments, the method comprises administering the Hi blocker at a dose of about 5 mg to about 20 mg. In some embodiments, the method comprises administering the Hi blocker at a dose of about 10 mg to about 20 mg. In some embodiments, the method comprises administering the Hi blocker at a dose of about 15 mg to about 20 mg. In some embodiments, the method comprises administering the Hi blocker at a dose of about 1 mg to about 15 mg. In some embodiments, the method comprises administering the Hi blocker at a dose of about 1 mg to about 10 mg.211PTS / 200114525.1Attorney Docket No.: HOT-023WOIn some embodiments, the method comprises administering the Hi blocker at a dose of about 1 mg to about 5 mg. In some embodiments, the method comprises administering the Hi blocker at a dose of about 5 mg to about 15 mg. In some embodiments, the method comprises administering the Hi blocker at a dose of about 10 mg.

[0162] In some embodiments, the method comprises administering the Hi blocker at a dose and dosing regimen as described in an approved label indication.

[0163] In some embodiments, the method comprises administering the H2 blocker at a dose of about 1 mg to about 40 mg. In some embodiments, the method comprises administering the Hr blocker at a dose of about 5 mg to about 40 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 10 mg to about 40 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 15 mg to about 40 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 20 mg to about 40 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 25 mg to about 40 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 30 mg to about 40 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 35 mg to about 40 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 1 mg to about 35 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 1 mg to about 30 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 1 mg to about 25 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 1 mg to about 20 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 1 mg to about 15 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 1 mg to about 10 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 1 mg to about 5 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 5 mg to about 35 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 10 mg to about 30 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 15 mg to about 25 mg. In some embodiments, the method comprises administering the H2 blocker at a dose of about 20 mg.

[0164] In some embodiments, the method comprises administering the H2 blocker at a dose and dosing regimen as described in an approved label indication.221PTS / 200114525.1Attorney Docket No.: HOT-023WO

[0165] In some embodiments, the method comprises administering a steroid as a pretreatment. In some embodiments, the method comprises administering the steroid at a dose of about 0.5 mg to about 6 mg. In some embodiments, the method comprises administering the steroid at a dose of about 1 mg to about 6 mg. In some embodiments, the method comprises administering the steroid at a dose of about 2 mg to about 6 mg. In some embodiments, the method comprises administering the steroid at a dose of about 4 mg to about 6 mg. In some embodiments, the method comprises administering the steroid at a dose of about 5 mg to about 6 mg. In some embodiments, the method comprises administering the steroid at a dose of about 0.5 mg to about 5 mg. In some embodiments, the method comprises administering the steroid at a dose of about 0.5 mg to about 4 mg. In some embodiments, the method comprises administering the steroid at a dose of about 0.5 mg to about 2 mg. In some embodiments, the method comprises administering the steroid at a dose of about 0.5 mg to about 1 mg.

[0166] In some embodiments, the method comprises administering the steroid at a dose of about 0.5 mg. In some embodiments, the method comprises administering the steroid at a dose of about 1 mg. In some embodiments, the method comprises administering the steroid at a dose of about 2 mg. In some embodiments, the method comprises administering the steroid at a dose of about 4 mg. In some embodiments, the method comprises administering the steroid at a dose of about 5 mg. In some embodiments, the method comprises administering the steroid at a dose of about 6 mg.

[0167] In some embodiments, the method comprises administering the steroid at least once weekly. In some embodiments, the method comprises administering the steroid at least twice weekly. In some embodiments, the method comprises administering the steroid on the same day as the CBL-Bi. In some embodiments, the method comprises administering the steroid about 1 hour to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the steroid about 1 hour to about 3 hours before the CBL-Bi. In some embodiments, the method comprises administering the steroid about 1 hour to about 2 hours before the CBL-Bi. In some embodiments, the method comprises administering the steroid about 2 hours to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the steroid about 3 hours to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the steroid about 1 hour before the CBL-Bi. In some embodiments, the method comprises administering the steroid about 2 hours before the CBL-Bi. In some embodiments, the method comprises administering the231PTS / 200114525.1Attorney Docket No.: HOT-023WO steroid about 3 hours before the CBL-Bi. In some embodiments, the method comprises administering the steroid about 4 hours before the CBL-Bi.

[0168] In some embodiments, the method comprises administering an anti-nausea medication as a pre-treatment. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 2 mg to about 10 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 2 mg to about 9 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 2 mg to about 8 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 2 mg to about 6 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 2 mg to about 4 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 4 mg to about 10 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 6 mg to about 10 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 8 mg to about 10 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 9 mg to about 10 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 3 mg to about 9 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 4 mg to about 8 mg.

[0169] In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 2 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 3 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 4 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 6 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 8 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 9 mg. In some embodiments, the method comprises administering the anti-nausea medication at a dose of about 10 mg.

[0170] In some embodiments, the method comprises administering the anti-nausea medication at least once weekly. In some embodiments, the method comprises administering the anti-nausea medication at least twice weekly. In some embodiments, the method comprises administering the anti-nausea medication on the same day as the CBL-Bi. In some embodiments, the method comprises administering the anti-nausea medication about 1 hour241PTS / 200114525.1Attorney Docket No.: HOT-023WO to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-nausea medication about 1 hour to about 3 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-nausea medication about 1 hour to about 2 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-nausea medication about 2 hours to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-nausea medication about 3 hours to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-nausea medication about 1 hour before the CBL-Bi. In some embodiments, the method comprises administering the anti-nausea medication about 2 hours before the CBL-Bi. In some embodiments, the method comprises administering the antinausea medication about 3 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-nausea medication about 4 hours before the CBL-Bi.

[0171] In some embodiments, the method comprises administering the anti-nausea medication about 24 hours to about 48 hours after the CBL-Bi. In some embodiments, the method comprises administering the anti-nausea medication about 24 hours after the CBL-Bi. In some embodiments, the method comprises administering the anti-nausea medication about 48 hours after the CBL-Bi.

[0172] In some embodiments, the method comprises administering an anti-diarrheal medication as a pre-treatment. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 2 mg to about 16 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 4 mg to about 16 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 6 mg to about 16 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 8 mg to about 16 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 10 mg to about 16 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 12 mg to about 16 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 14 mg to about 16 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 2 mg to about 14 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 2 mg to about 12 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 2 mg to about 10 mg. In some embodiments, the method251PTS / 200114525.1Attorney Docket No.: HOT-023WO comprises administering the anti-diarrheal medication at a dose of about 2 mg to about 8 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 2 mg to about 6 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 2 mg to about 4 mg.

[0173] In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 2 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 4 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 8 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 10 mg. In some embodiments, the method comprises administering the anti- diarrheal medication at a dose of about 12 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 14 mg. In some embodiments, the method comprises administering the anti-diarrheal medication at a dose of about 16 mg.

[0174] In some embodiments, the method comprises administering the anti-diarrheal medication at least once weekly. In some embodiments, the method comprises administering the anti-diarrheal medication at least twice weekly. In some embodiments, the method comprises administering the anti-diarrheal medication on the same day as the CBL-Bi. In some embodiments, the method comprises administering the anti-diarrheal medication about 1 hour to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-diarrheal medication about 1 hour to about 3 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-diarrheal medication about 1 hour to about 2 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-diarrheal medication about 2 hours to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-diarrheal medication about 3 hours to about 4 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-diarrheal medication about 1 hour before the CBL- Bi. In some embodiments, the method comprises administering the anti-diarrheal medication about 2 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-diarrheal medication about 3 hours before the CBL-Bi. In some embodiments, the method comprises administering the anti-diarrheal medication about 4 hours before the CBL- Bi.

[0175] In various embodiments, the method comprises administering a pre-treatment and a CBL-Bi, wherein the pre-treatment includes at least an anti-histamine. In various261PTS / 200114525.1Attorney Docket No.: HOT-023WO embodiments, the pre-treatment further includes one or more of a steroid, an anti-nausea medication, and an anti-diarrheal medication. In particular embodiments, the pre-treatment includes each of an anti-histamine, a steroid, an anti-nausea medication, and an antidiarrheal medication. In further particular embodiments, the anti-histamine is either an Hi blocker an H2 blocker, or both.

[0176] In various embodiments, the method comprises administering each of an antihistamine, a steroid, an anti-nausea medication, and an anti-diarrheal medication prior to administering the CBL-Bi. In particular embodiments, the method comprises administering each of an anti-histamine, a steroid, an anti-nausea medication, and an anti-diarrheal medication about 2 hours before administering the CBL-Bi.

[0177] In particular embodiments, the method comprises administering the anti-histamine at a dose of about 10 mg to about 20 mg, a steroid at a dose of about 2 mg to about 4 mg, an anti-nausea medication at a dose of about 4 mg to about 8 mg, and an anti-diarrheal medication at a dose of about 2 mg to 16 mg. In particular embodiments, the method comprises administering the anti-histamine at a dose of about 10 mg if an Hi blocker or about 20 mg if an H2 blocker, a steroid at a dose of about 2 mg, an anti-nausea medication at a dose of about 4 mg, and an anti-diarrheal medication at a dose of about 4 mg. In particular embodiments, the method comprises administering the anti-histamine at a dose of about 10 mg if an Hi blocker or about 20 mg if an H2 blocker, a steroid at a dose of about 2 mg, an anti-nausea medication at a dose of about 4 mg, and an anti-diarrheal medication at a dose of about 4 mg about 2 hours before administering the CBL-Bi. In particular embodiments, the method comprises administering the anti-histamine at a dose of about 10 mg if an Hi blocker or about 20 mg if an H2 blocker, a steroid at a dose of about 2 mg, an anti-nausea medication at a dose of about 4 mg, and an anti-diarrheal medication at a dose of about 4 mg about 2 hours before administering the CBL-Bi, wherein the CBL-Bi is administered at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 40 mg.CBL-B Inhibitors

[0178] Casitas B-lineage Lymphoma Proto-oncogene B (CBL-B) is a protein in the CBL gene family. CBL-B is an E3 ubiquitin-protein ligase and is considered a master negative regulator of the immune system as it controls the activation of T-cells and NK cells.271PTS / 200114525.1Attorney Docket No.: HOT-023WO

[0179] The present disclosure provides methods of administering a CBL-B inhibitor (CBL- Bi) for treating a cancer in a subject. Examples of CBL-Bi include Compound 1 or Compound 2, as shown in Table 1. Further example CBL-Bi are disclosed in W020220221704, which is incorporated by reference in its entirety.Table 1. Exemplary CBL-Bi compoundsAnti-histamines

[0180] Anti-histamines are a class of medication that inhibit the release or block the function of histamines. Anti-histamines are administered for treating symptoms associated with allergy, common cold, influenza, and digestive conditions, among others. Antihistamines are categorized by their ability to block either the histamine- 1 (Hi) or histamine-2 (H2) receptors. In some embodiments, the anti-histamine is an Hi blocker or an H2 blocker.

[0181] The present disclosure provides methods of administering anti-histamines as a pretreatment to administering a CBL-Bi for the treatment of a cancer. In some embodiments, the anti-histamine is selected from at least one of Hi blocker and H2 blocker. In some embodiments, the pre-treatment comprises both Hi blockers and H2 blockers.Hl blockers

[0182] Hi blockers, also known as Hi antagonists or Hi receptor antagonists, are a class of anti-histamines that specifically target the function of Hi receptors. Hi are administered for the treatment of histamine-related allergies, such as rhinitis, conjunctivitis, urticaria, as well as nausea and vomiting, where an immune response is observed. In some embodiments , the 28IPTS / 200114525.1Attorney Docket No.: HOT-023WOHi blocker is a first-generation Hi blocker or a second-generation Hi blocker. In some embodiments, the Hi blocker is selected from one of cetirizine, fexofenadine, levocetirizine, and loratadine.H2 blockers

[0183] H2 blockers, also known as H2Ras, Hi receptor antagonists, or Hi antagonists, are a type of anti-histamines which block Hi receptors in the stomach. Blockade of Hi receptors by Hi blockers reduces stomach acid production. Hi blockers are used for the treatment of acid- related gastrointestinal conditions, including ulcers, gastroesophageal reflux disease, and dyspepsia. In some embodiments, the Hi blocker is selected from famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, and sufotidine.Steroids

[0184] Steroids, or steroid hormones, are a large group of organic compounds with various physiological functions, including but not limited to regulation of metabolism and inflammation. The present disclosure provides methods of administering steroids as a pretreatment to administering a CBL-Bi for the treatment of a cancer. In some embodiments, the steroid is selected from one of corticosteroids and sex steroids. In some embodiments, the corticosteroid is selected from one of glucocorticoids and mineralocorticoids. In particular embodiments, the steroid is a glucocorticoid.Glucocorticoids

[0185] Glucocorticoids, or glucocorticosteroids, are a subclass of steroids that bind to the glucocorticoid receptor of cells. Glucocorticoids are naturally produced by the adrenal glands and are involved in regulating glucose and fat metabolism, and immune system regulation. In some embodiments, the glucocorticoid is selected from dexamethasone, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, betamethasone, triamcinolone, deflazacort, beclomethasone.Anti-nausea Medication

[0186] Nausea and vomiting are symptoms in subjects administered with cancer therapies. The present disclosure provides methods of administering an anti-nausea medication as a pretreatment to administering a CBL-Bi for the treatment of a cancer in order to prevent and 291PTS / 200114525.1Attorney Docket No.: HOT-023WO treat nausea and vomiting. In some embodiments, the anti-nausea medication is selected from a 5-HT3 serotonin receptor antagonist, a dopamine receptor antagonist, an anti-histamine, an NK- 1 receptor antagonist, and a cannabinoid.5-HT3 serotonin receptor antagonists

[0187] 5 -HT3 serotonin receptor antagonists are a class of compounds that block the serotonin receptor 5-HT3. In some embodiments, the 5-HT3 serotonin receptor antagonist is selected from one of ondansetron, granisetron, olanzapine, lorazepam, dolasetron, palonosetron, ramosetron, tropisetron, vortioxetine, bismuth subsalicylate, dimenhydrinate, meclizine, scopolamine, prochlorperazine, promethazine, and metoclopramide.Anti-diarrheal medication

[0188] Diarrhea is a symptom observed in subjects administered with cancer therapies. The present disclosure provides methods of administering anti-diarrheal medication as a pretreatment to administering a CBL-Bi for the treatment of a cancer. In some embodiments, the anti-diarrheal medication is selected from one of loperamide, bismuth subsalicylate, alosetron, eluxadoline, and rifaximin.Anti-PD-1 and Anti-PD-Ll Inhibitors

[0189] The term "PD-1" or "PD-1 receptor" refers to the programmed death- 1 protein, a T- cell co-inhibitor, also known as CD279. The amino acid sequence of the human full-length PD-1 protein is set forth, for example, in GenBank Accession Number NP 005009.2. PD-1 is a 288 amino acid protein with an extracellular N-terminal domain which is IgV-like, a transmembrane domain and an intracellular domain containing an immunoreceptor tyrosinebased inhibitory (ITIM) motif and an immunoreceptor tyrosine-based switch (ITSM) motif (Chattopadhyay et al, Immunol Rev, 2009, 229(l):356-386). The term "PD-1" includes recombinant PD-1 or a fragment thereof, or variants thereof. The PD-1 receptor has two ligands, PD-ligand-1 (PD-L1) and PD-ligand-2 (PD-L2).

[0190] The term "PD-L1" or "programmed death ligand 1" refers to a ligand of the PD-1 receptor, also known as CD274 and B7H1. The amino acid sequence of the human full-length PD-L1 protein is set forth, for example, in GenBank Accession Number NP 054862.1 PD-L1 is a 290 amino acid protein with an extracellular IgV-like domain, a transmembrane domain301PTS / 200114525.1Attorney Docket No.: HOT-023WO and a highly conserved intracellular domain of approximately 30 amino acids. PD-L1 is constitutively expressed on many cells such as antigen presenting cells (e.g., dendritic cells, macrophages, and B-cells) and on hematopoietic and non-hematopoietic cells (e.g., vascular endothelial cells, pancreatic islets, and sites of immune privilege). PD-L1 is also expressed on a wide variety of tumors, virally -infected cells and autoimmune tissue.

[0191] In some embodiments, the PD-1 and / or PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, pembrolizumab, nivolumab, AP-106, AP-105, MSB- 2311, CBT-501, avelumab, AK-105, 10-102, 10-103, PDR-001, CX-072, SHR-1316, JTX-4014, GNS-1480, recombinant humanized anti-PDl mAh (Shanghai Junshi Biosciences), REGN-2810, pelareorep, SHR-1210, PD-1 / PD-L1 inhibitor vaccine (THERAVECTYS), BGB-A317, recombinant humanized anti-PD-1 mAh (Bio- Thera Solutions), Probody targeting PD-1 (CytomX), XmAb-20717, FS-118, PSI-001, SN-PDL01, SN-PD07, PD-1 modified TILs (Sangamo Therapeutics), PRS-332, FPT-155, jienuo mAb (Genor Biopharma), TSR-042, REGN-1979, REGN-2810, resminostat, FAZ-053, PD- l / CTLA-4 bispecific antibody (MacroGenics), MGA-012, MGD-013, M-7824, PD-1 based bispecific antibody (Beijing Hanmi Pharmaceutical), AK-112, AK-106, AK-104, AK-103, BI-754091, ENUM-244C8, MCLA-145, MCLA-134, anti-PD-1 oncolytic monoclonal antibody (Transgene SA), AGEN-2034, IBI-308, WBP-3155, JNJ-63723283, MEDI-0680, SSI-361, CBT-502, anti-PD-1 bispecific antibody, dual targeting anti-PD-1 / LAG-3 mAbs (TESARO), dual targeting anti-PD-1 / TIM-3 mAbs (TESARO), PF-06801591, LY-3300054, BCD- 100, STI-1 110, pembrolizumab biosimilar, nivolumab hiosimilar, PD-L1 -TGF-beta therapy, KY-1003, STI-1014, GLS-010, AM-0001, GX- P2, KD-033, PD-L1 / BCMA bispecific antibody (Immune Pharmaceuticals), PD-1 / Ox40 targeting bispecific antibody (Immune Pharmaceuticals), BMS-936559, anti-PD-l / VEGF-A DARPins (Molecular Partners), mDX-400, ALN-PDL, PD-1 inhibitor peptide (Aurigene), siRNA loaded dendritic cell vaccine (Alnylam Pharmaceuticals), GB-226, PD-L1 targeting CAR-TNK-based immunotherapy (TNK Therapeutics / NantKwest), INSIX RA, INDUS-903, AMP-224, anti- CTLA-4 / anti-PD-l bispecific humanized antibody (Akeso Biopharma), B7-H1 vaccine (State Key Laboratory of Cancer Biology / Fourth Military Medical University), and GX-D1.

[0192] In some embodiments, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF- 06801591, PDR-001, GB-226, STI-1110, biosimilars thereof, biobetters thereof, and bioequivalents thereof.311PTS / 200114525.1Attorney Docket No.: HOT-023WO

[0193] In some embodiments, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF- 06801591, PDR-001, GB-226, and STI-1110.

[0194] In some embodiments, the PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA- 170, CA-327, STI-1014, KY-1003, biosimilars thereof, biobetters thereof, and bioequivalents thereof.

[0195] In some embodiments, the PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA- 170, STI-1014, and KY-1003.Example Cancers

[0196] The present disclosure provides methods of treating cancer using a CBL-Bi. In some embodiments, the cancer is selected from ovarian cancer, anal cancer, rectal cancer, prostate cancer, non-small cell lung cancer, small-cell lung cancer, malignant pleural mesothelioma, cutaneous squamous cell carcinoma, melanoma, merkel cell carcinoma, head and neck squamous cell cancer, and acral melanoma, esophageal carcinoma, gastric carcinoma, gastroesophageal junction cancer, renal cell carcinoma, urothelial cell carcinoma, cervical cancer, endometrial cancer, hepatocellular carcinoma, triple-negative breast cancer, biliary tract cancer, microsatellite instability-high (MSI-H), mismatch repair deficient colorectal cancer, tumor mutational burden-high (TMB-H) cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the solid tumor is an advanced solid tumor. In some embodiments, the solid tumor is a metastatic, recurrent, and / or resectable tumor.

[0197] The present disclosure also provides methods of treating cancer using a CBL-Bi in combination with an anti-PD-1 or an anti-PD-Ll therapy in subjects with cancer. In various embodiments, an anti-PD-1 or an anti-PD-Ll therapy has been previously approved for the cancer and therefore, methods can include administering CBL-Bi in addition to the approved anti-PD-1 or anti-PD-Ll therapy. In some embodiments, the cancer is selected from ovarian cancer, anal cancer, rectal cancer, prostate cancer, non-small cell lung cancer, small-cell lung cancer, malignant pleural mesothelioma, cutaneous squamous cell carcinoma, melanoma, merkel cell carcinoma, head and neck squamous cell cancer, and acral melanoma, esophageal carcinoma, gastric carcinoma, gastroesophageal junction cancer, renal cell carcinoma, urothelial cell carcinoma, cervical cancer, endometrial cancer, hepatocellular carcinoma,321PTS / 200114525.1Attorney Docket No.: HOT-023WO triple- negative breast cancer, biliary tract cancer, microsatellite instability -high (MSI-H), mismatch repair deficient colorectal cancer, tumor mutational burden-high (TMB-H) cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the solid tumor is an advanced solid tumor. In some embodiments, the cancer is relapsed or refractory to an anti-PD-1 or an anti-PD-Ll therapy and / or other standard of care therapies. In some embodiments, the method comprises treating the cancer using a CBL-Bi in combination with an anti-PD-1 or an anti-PD-Ll therapy before relapse or refractory to other standard of care therapies.Methods of Administration

[0198] In various embodiments, a disclosed CBL-Bi or a disclosed component of the pretreatment (e.g., one or more of anti-histamines, steroids, anti-nausea medication, and anti- diarrheal medication) may be administered by one or several routes, including topically, intrathecally, intrathalamically, intracistemally, intracerebroventricularly, parenterally, orally, rectally, buccally, sublingually, vaginally, pulmonarily, intratracheally, intranasally, transdermally, or intraduodenally. The term parenteral as used herein includes subcutaneous injections, intrapancreatic administration, intravenous, intracistemal, intracerebroventricular, intralesional, intrathecal, intrathalamic, intramuscular, intraperitoneal, intrasternal injection or infusion techniques. In particular embodiments, a disclosed CBL-Bi is administered orally. In particular embodiments, a disclosed component of the pre-treatment (e.g., one or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication) is administered orally.

[0199] In various embodiments, a pharmaceutical composition comprising a disclosed CBL- Bi or a pharmaceutical composition comprising a disclosed component of the pre-treatment (e.g., one or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication) may be administered by one or several routes, including topically, intrathecally, intrathalamically, intracistemally, intracerebroventricularly, parenterally, orally, rectally, buccally, sublingually, vaginally, pulmonarily, intratracheally, intranasally, transdermally, or intraduodenally. In particular embodiments, a pharmaceutical composition comprising a disclosed CBL-Bi is administered orally. In particular embodiments, a pharmaceutical composition comprising a disclosed component of the pre-treatment (e.g., one or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication) is administered orally.331PTS / 200114525.1Attorney Docket No.: HOT-023WOPharmaceutical Compositions

[0200] The present disclosure provides methods of treating cancer using a CBL-Bi, examples of which are described in Table 1. In various embodiments, a CBL-Bi disclosed herein may be formulated into a pharmaceutical composition for administration to a subject, such as a mammalian subject (e.g., a human subject). For instance, contemplated herein are pharmaceutical compositions comprising a CBL-Bi, in admixture with one or more suitable diluents, carriers, and / or excipients. Pharmaceutical compositions may include sterile aqueous suspensions. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy (2012, 22nded.) and in The United States Pharmacopeia: The National Formulary (2015, USP 38 NF 33), the disclosure of which is incorporated herein by reference in its entirety. The preparation of an aqueous composition, such as an aqueous pharmaceutical composition containing a disclosed CBL-Bi, will be known to those of skill in the art in light of the present disclosure. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including normal saline, artificial cerebrospinal fluid, sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0201] The present disclosure further provides methods of treating cancer using a CBL-Bi in combination with a pre-treatment (e.g., one or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication). In various embodiments, one or more of antihistamines, steroids, anti-nausea medication, and anti-diarrheal medication disclosed herein may be formulated into a pharmaceutical composition for administration to a subject, such as a mammalian subject (e.g., a human subject). In various embodiments, anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication may be separately formulated into distinct pharmaceutical compositions for administration to the subject. In various embodiments, two or more, three or more, or each of anti-histamines, steroids, anti-nausea341PTS / 200114525.1Attorney Docket No.: HOT-023WO medication, and anti-diarrheal medication are formulated together into a pharmaceutical composition for administration to the subject.

[0202] For instance, contemplated herein are pharmaceutical compositions comprising one or more of anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication, in admixture with one or more suitable diluents, carriers, and / or excipients. Pharmaceutical compositions may include sterile aqueous suspensions. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy (2012, 22nded.) and in The United States Pharmacopeia: The National Formulary (2015, USP 38 NF 33), the disclosure of which is incorporated herein by reference in its entirety. The preparation of an aqueous composition, such as an aqueous pharmaceutical composition containing disclosed antihistamines, steroids, anti-nausea medication, and / or anti-diarrheal medication, will be known to those of skill in the art in light of the present disclosure.

[0203] A pharmaceutical composition may be administered to a subject, such as a human subject, alone or in combination with pharmaceutically acceptable carriers, the proportion of which may be determined by the quantity of active pharmaceutical ingredient (i.e., a CBL-Bi described in Table 1 or anti-histamines, steroids, anti-nausea medication, and anti-diarrheal medication), chosen route of administration, and standard pharmaceutical practice.EXAMPLES

[0204] The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of the disclosure.Example 1: CBL-B inhibitor increases the presence of mast cells in tumors

[0205] Female C57BL / 6 mice, aged 6-8 weeks, were inoculated subcutaneously into the right flank with Pan02 (pancreatic cancer) cells. Female BALB / c mice of the same age range received subcutaneous injections of H22 (hepatoma), CT-26 (colon carcinoma), and EMT-6 (mammary carcinoma) cells in the flank. Tumor growth was monitored by caliper measurements, and tumor volume was determined using the formula (length x width2) / 2. Upon tumors reaching an average volume of 80-100 mm3, mice were randomly allocated to351PTS / 200114525.1Attorney Docket No.: HOT-023WO treatment and control groups (n=10 per group). Treatment groups received Compound 1 at 60 mpk orally twice daily. Control groups were administered the vehicle solution following the same schedule. Tumor volumes and body weights were recorded biweekly throughout the study. Mice were euthanized if tumor volumes reached 2000 mm3or if signs of distress were noted. At the endpoint, 3-5 tumors from each group were excised and processed to analyze gene expression using NanoString™ mouse PanCancer immune profiling panel. NanoString analysis calculated cell type scores using the arithmetic mean of the log2-transformed normalized expression of all selected marker genes for the cell type, which correlates with the abundance of that cell population.

[0206] FIGs. 1A-1D show the change in cell scores of different cell populations in murine tumor models EMT6 (FIG. 1A; colon cancer model), Pan02 (FIG. IB; pancreatic cancer model), H22 (FIG. 1C; hepatoma model), and CT26 (FIG. ID; colon cancer model) treated with vehicle or Compound 1 at 60 mpk. Increased mast cell numbers were observed in all four cancer tumor models when treated with Compound 1 compared to the vehicle group, indicating that Compound 1 treatment enhances innate immune response.

[0207] FIG. 2 shows the cell score of mast cells in different murine tumor models (EMT6, Pan02, H22, and CT26) treated with vehicle or Compound 1 at 60 mpk twice a day (BID). Increased mast cell numbers were observed in all four cancer tumor models, and the magnitude of the effect is different in the different tumor models. These results indicate that Compound 1 treatment increases mast cell number in tumors.

[0208] FIG. 3A shows the cell score of mast cells present in the tumors of CT26 mouse models administered with vehicle, different doses and frequencies of Compound 1 alone, an anti-PD-1 inhibitor alone, or different frequencies of Compound 1 in combination with the anti-PD-1 inhibitor. FIGs. 3B and 3C show normalized mRNA levels of mast cell markers Cmal (FIG. 3B) and Tpsabl (FIG. 3C) for the same treatment groups evaluated in the data shown in FIG. 3A. Cmal and Tpsabl are genes specifically expressed by mast cells.Increased cell score and increased expression of Cmal and Tpsabl were observed in all tumors from groups treated with Compound 1. Tumors from animals treated only with the anti-PD-1 inhibitor were found to have similar mast cell scores, and Cmal and Tpsabl expression levels as the vehicle groups. These results suggest that Compound 1 but not the anti-PD-1 inhibitor increase the presence of mast cells in the tumor.

[0209] FIG. 4A shows the cell score of mast cells present in the tumors of CT26 mouse models administered with vehicle, Compound 1 alone, an IL- 15 agonist alone, or Compound361PTS / 200114525.1Attorney Docket No.: HOT-023WO1 in combination with the IL- 15 agonist. FIGs. 4B and 4C show normalized mRNA levels of mast cell markers Cmal (FIG. 4B) and Tpsabl (FIG. 4C) for the same treatment groups evaluated in the data shown in FIG. 4A. Increased cell score and increased expression of Cmal and Tpsabl were observed in all tumors from groups treated with Compound 1. Tumors from animals treated only with the IL- 15 agonist were found to have similar mast cell scores, and Cmal and Tpsabl expression levels as the vehicle groups. These results suggest that Compound 1 but not the IL- 15 agonist increase the presence of mast cells in the tumor.

[0210] These results indicate that administration of Compound 1 increases the number of mast cells in tumors, and that this feature is not observed with other cancer immunotherapeutic drugs, such as anti-PD-1 and IL- 15 agonists.Example 2: CBL-B inhibitor increases the presence of mast cells in tumors in a dosedependent manner

[0211] Female BALB / c mice, aged 6-8 weeks, were inoculated subcutaneously into the right flank with CT-26 (colon carcinoma) cells. Tumor growth was monitored by caliper measurements, and tumor volume was determined using the formula (length x width2) / 2. Upon tumors reaching an average volume of 80-100 mm3, mice were randomly allocated to treatment and control groups (n=10 per group). Treatment groups received Compound 2 at 3 mpk, 10 mpk, or 30 mpk orally twice a day (BID), or with Compound 2 at 6 mpk, 20 mpk, or 60 mpk once a day (QD). Control groups were administered the vehicle solution following the same schedule. Tumor volumes and body weights were recorded biweekly throughout the study. Mice were euthanized if tumor volumes reached 2000 mm3or if signs of distress were noted. At the day 18, three tumors from each group were excised and processed to analyze gene expression using NanoString™ mouse PanCancer immune profiling panel. NanoString analysis calculated cell type scores using the arithmetic mean of the log2-transformed normalized expression of all selected marker genes for the cell type, which correlates with the abundance of that cell population.

[0212] FIGs. 5A and SB show normalized mRNA levels of mast cell markers Cmal (FIG. 5A) and Tpsabl (FIG. 5B) in the tumors of CT26 mouse models administered with vehicle, with Compound 2 at 3 mpk, 10 mpk, or 30 mpk twice a day (BID), or with Compound 2at 6 mpk, 20 mpk, or 60 mpk once a day (QD). Increased mast cell recruitment to the tumors (as measured by the expression of both Cmal and Tpsabl) was observed in a dose-dependent371PTS / 200114525.1Attorney Docket No.: HOT-023WO manner in groups administered with Compound 2at 10 mpk, or 30 mpk twice a day (BID), or with Compound 2at 6 mpk, 20 mpk, or 60 mpk once a day (QD). These results indicate that increased doses of Compound 2 increase the amount of mast cells recruited to the tumors.Example 3: CBL-Bi successfully inhibits tumor growth across different dosing schedules

[0213] BALB / C mice were inoculated in the right front flank with CT26 cancer cells. Compound 2 was administered when the tumor reached about 80mm3in volume.

[0214] FIGs. 6A-6C show tumor volume (in mm3) over 13 days in CT26 mouse models administered with Compound 2at 6 mpk (FIG. 6A), 12 mpk (FIG. 6B), or 20 mpk (FIG. 6C) once day (QD), once a week (QW), or twice per week (BIW), or with vehicle. FIG. 7 shows tumor volume (in mm3) after 13 days from treatment in CT26 mouse models administered with Compound 2at 6 mpk, 12 mpk, or 20 mpk once a day (QD), once a week (QW), or twice per week (BIW), or with vehicle. Table 2 shows the mean percent difference of tumor volume between the vehicle group and the different treatment groups.Table 2. Mean percentage of tumor growth inhibition in CT26 tumor mouse models after 13 days of Compound 2 administration

[0215] Tumors from CT26 mouse model treated with Compound 2 at doses of either 6 mpk, 12 mpk, or 20 mpk once a day showed delayed increase in volume compared to the vehicle group. Administration of Compound 2 at doses of either 6 mpk, 12 mpk, or 20 mpk twice per week consistently demonstrated tumor growth inhibition compared to the vehicle group. Comparable tumor growth was observed between the vehicle group and the group administered with weekly doses of Compound 2 at 6 mpk. Interestingly, administration of Compound 2 at any dose once a day showed preferred efficacy in tumor growth inhibition.381PTS / 200114525.1Attorney Docket No.: HOT-023WOThese results indicate that different dosing schedules are efficacious in tumor growth inhibition, with a preference for a daily dosing schedule. A dosing window of less than 2 weeks poses a challenge in observing the effects of intermittent dosing.Example 4: CBL-Bi slows tumor growth when administered as a prophylactic treatment across different dosing schedules

[0216] BALB / C mice were inoculated with EG7 cancer cells. Compound 2 was administered as a pre-treatment 3 days before inoculation with cancer cells.

[0217] FIG. 8 shows tumor volume (in mm3) over 18 days in EG7 mouse models administered with Compound 2 at 20 mpk once a day (QD), 20 mpk twice per week (BIW), or 60 mpk twice per week (BIW) or with vehicle. FIG. 9 shows tumor volume (in mm3) after 18 days from treatment in EG7 mouse models administered with Compound 2 at 20 mpk once a day (QD), 20 mpk twice per week (BIW), or 60 mpk twice per week (BIW) or with vehicle. Tumor growth inhibition was observed through the 18 days, when animals were administered Compound 2 at 20 mpk once day (QD) or twice per week (BIW) or 60 mpk twice per week (BIW) as a prophylactic. Consistent with these observations, the tumor volume of animals treated with Compound 2 was significantly lower compared to the vehicle group. These results indicate that administering Compound 2 prophylactically once per day or twice per week are equally efficacious in inhibiting tumor growth.Example 5: Exemplary Dosing Regimens involving CBL-Bi and pre-treatment medications

[0218] FIGs. 10A and 10B show exemplary dosing regimens for Compound 2 administered twice per week (FIG. 10A) or once per week (FIG. 10B), including exemplary dosing for the pre-treatment medications (anti-nausea medication and steroids) and daily administration of anti-histamines and H2 receptor antagonists.

[0219] Phase 1 is a multipart study in which patients will receive Compound 2 as either monotherapy or in combination with the anti-PD-1 antibody cemiplimab. FIG. 11 is a diagram describing the phase I clinical trial evaluating Compound 2 alone (Part A) and in combination with cemiplimab (Part B) in patients with advanced solid tumors.

[0220] The monotherapy will consist of two parts: (a) dose escalation and (b) dose optimization. In the monotherapy dose escalation, cohorts of patients receive increasing doses of Compound 2. In the monotherapy dose optimization, several cohorts of patients with pre- 391PTS / 200114525.1Attorney Docket No.: HOT-023WO specified tumor types will be evaluated utilizing a dose and schedule of Compound 2 deemed safe in part (a).

[0221] The combination therapy will consist of a dose escalation of Compound 2 given in combination with the standard dose / regimen of cemiplimab. Dosing may commence prior to the completion of the monotherapy part (a) of the study, but the starting dose of Compound 2 in the combination therapy will be at least 2 dose levels lower than the cleared Compound 2 dose in the monotherapy part (a) of the study. The combination therapy dose escalation study will be followed by a combination dose optimization study in which several cohorts of patients with pre-specified tumor types will be evaluated utilizing a dose and schedule of Compound 2 deemed safe in the combination dose escalation study.Example 6: Treatment using Compound 2 demonstrates safety, tolerability, and acceptable pharmacokinetics

[0222] Table 3 shows the demographics of the patients of a phase I clinical trial. Patients were generally older, with a diversity between sexes. Most patients had an ECOG status of 1, a median of almost 4 years since diagnosis and were heavily pretreated with a median of 4 prior lines of therapy, with most having had at least 1 prior experience on anti-PD- 1 and anti- PD-L1 containing regimen. There was also a diversity of tumor types indicative of the significant heterogeneity that are often observed in early clinical trials.Table 3. Overview of Compound 2 monotherapy patient demographics401PTS / 200114525.1Attorney Docket No.: HOT-023WO

[0223] Table 4 shows the safety and tolerability results of Compound 2 monotherapy from phase I clinical trial. Single agent use of Compound 2 demonstrated an acceptable safety profile across the dose range tested. There have been no dose-limiting toxicities and most treatment related adverse events have been Grade 1 or 2. The predominant adverse events have been related to gastrointestinal effects, particularly nausea, vomiting and diarrhea, which occurred on days of dosing and have generally been mitigated or minimized with a prophylactic pre-treatment regimen. These effects show no similarities to colitis associated with other immune-oncology agents but they are believed to be related to local effects on the immune system. Even in the small number of cases of Grade 3 toxicity, there was no discontinuation of Compound 2 treatment. These data demonstrated that Compound 2 could be safely administered to patients despite a wide range of co-morbidities and concomitant treatments.Table 4. Safety and tolerability results of Compound 2 monotherapy from phase I clinical trial411PTS / 200114525.1Attorney Docket No.: HOT-023WO

[0224] FIGs 12A and 12B are graphs showing pharmacokinetics of Compound 2 in subjects administered with 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg by measuring Compound 2 plasma concentration (in ng / mL) over 24 hours after administration on day 1 (FIG. 12A) and day 22 (FIG. 12B) from beginning of treatment. Pharmacokinetic analyses demonstrated a concentration vs. time profile that is typical of an oral drug. Plasma half life was about 3-5 hours with acceptable patient to patient variability. Plasma concentrations of Compound 2, particularly at 20 mg and higher, were clearly above key benchmarks of immune activation that were associated with robust anti-tumor activity in preclinical models. These PK data suggest that systemic exposures were well within a pharmacologically active range, which is further supported by initial target engagement observationsExample 7: Compound 2 increases Notch 1 levels in peripheral T-cells

[0225] Flow cytometry was performed on peripheral T-cells from subjects treated with Compound 2 to measure levels of surface Notch 1 in the cells as an indicator of CBL-B inhibition.

[0226] FIG. 13 is a graph showing percent change in the expression of Notchl relative to CD8 in peripheral T-cells after 4 hours and 24 hours from administration of Compound 2 at 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg.

[0227] Two indicators of dose-related CBL-B inhibition by Compound 2 were observed. First, at the time of near maximal plasma concentrations (4 hours), a significant increase in Notchl expression was observed from 5 mg to 10 mg and then a plateau thereafter. Second, at 24 hours post-dose, when plasma concentrations of Compound 2 were low to below detection, sustained Notchl was observed at 20 mg and higher. The prolonged effect on target engagement, as observed by increased Notchl levels, aligns with the very slow off rate of Compound 2.42IPTS / 200114525.1Attorney Docket No.: HOT-023WOExample 8: Compound 2 activates the immune system

[0228] FIGs. 14A-14C are box-and-whisker graphs showing changes in overall cytokine expression (FIG. 14A) at day 1 of Compound 2 administration, and IFNy secretion at day 1 (FIG. 14B) and day 22 (FIG. 14C) of Compound 2 administration at doses of 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg.

[0229] As shown in FIG. 14A, Compound 2 caused a dose-dependent increase in inflammatory cytokines and chemokines also found increased in subjects with loss-of- function mutations in their CBL-B gene (IL-6, TNF-a, IL-10, CXCL9, and CXCL10; Janssen et al. (2022). J. Clin. Invest, 132(20): el54487.). These data show that Compound 2 can phenocopy what has been reported with CBL-B loss-of-function mutations in humans.

[0230] Changes in systemic levels of IFNy were also assessed (FIGs. 14B and 14C). Both on days 1 and 22, a dose-related increase in IFNy levels were observed, with generally more substantial and sustained levels observed over time with administration of Compound 2 at 30 and 40 mg. Taken together, these data suggest that pharmacologically active exposures to Compound 2 were achieved, as observed by the downstream immune activation in the periphery.Example 9: Compound 2 treatment showed signs of clinical benefit

[0231] Table 5 shows the clinical effects observed in subjects treated with Compound 2 during phase I of clinical trial. Indications of some clinical benefit were observed in 10 out of the 28 subjects administered with Compound 2 monotherapy. The clinical effects were observed in the tumor status of anal and rectal cancer patients, and short-term reductions or mixed responses in subjects with cutaneous squamous cell and melanoma. A very significant decrease in one target lesion was observed in a subject with melanoma, but an appearance of a new lesion was also observed. There were also decreases in well known peripheral markers of disease like CAI 25 or PSA levels in subjects with ovarian and prostate cancer, respectively. These were interesting examples because the benefits to these two patients were only observed following intra-patient dose escalation to higher doses where more consistent evidence of pharmacologic activity were observed. The range of patients with some evidence of benefit included tumor types where immunotherapy is not standard of care, as well as those like non-small cell lung carcinoma (NSCLC), a type of cancer broadly considered to be immunoresponsive.431PTS / 200114525.1Attorney Docket No.: HOT-023WOTable 5. Clinical effects observed in subjects treated with Compound 2 during phase I of clinical trials* Days of stable disease were calculated from the first dosing day as a baseline until cancer progression.** Scan for clinical assessment, not tumor evaluation per protocol

[0232] FIG. 15 is a graph showing the IFNy levels at days 1 and 22 at pre-dosing and 2, 4, and 8 hours after administration of Compound 2 in a subject with non-small cell lung cancer subject. Table 6 shows the tumor response outcomes of the patient based on clinical and radiographic observations and measurements of peripheral biomarkers.Table 6. Summary of tumor response outcomes in subject with non-small cell lung cancer treated with Compound 244IPTS / 200114525.1Attorney Docket No.: HOT-023WO* “SD” refers to “stable disease” and “PD” refers to “progressive disease.”

[0233] Compound 2 administration induced significant increases in IFNy levels, which were sustained over time (FIG. 15). Clinical improvements were observed in the subject throughout the treatment duration. Furthermore, radiographic data showed stable disease up to week 36, as determined by the size of the lesion in the subject. Lastly, a decrease in circulating tumor DNA (ctDNA) was observed during the treatment. Overall, this patient was on study with a monotherapy of Compound 2 for nearly 9 months. These data are illustrative of the phase I monotherapy dose escalation outcomes.Example 10: Compound 2 treatment modulates different immune related pathways

[0234] FIG. 16 depicts a dose dependent modulation of immune related transcriptional pathways in peripheral blood samples following administration of Compound 2. Patient peripheral blood samples were analyzed. Here RNA was extracted from patient samples (at various timepoints during the first cycle of treatment with Compound 2) and tested on a Nanostring Immunology V2 chip for expression analysis. Gene expression was categorized into different pathways. These different pathways were annotated by Nanostring and these pathways were applied to the RNA expression data from patients in the dose escalation cohorts. FIG. 16 shows 6 different pathways identified as being modulated by, and also showing a dose dependent increase to, Compound 2. The 6 different pathways included 1) chemokine signaling, 2) cytokine signaling, 3) host pathogen interaction, 4) innate immune system, 5) lymphocyte tracking, and 6) type II interferon signaling.Example 11: Compound 2 treatment impacts TCR and BCR repertoire metrics from peripheral samples

[0235] TCR and BCR repertoire metrics were developed at iRepertoire (Huntsville, AL) using their 7-chain assay (Hou, X. et al., Complete all-in-one immune repertoire profiling of newborn babies via novel dimer-avoided multiplex PCR (dam-PCR). J Immunol 1 May 2019;451PTS / 200114525.1Attorney Docket No.: HOT-023WO202 (1 -Supplement): 131.28, which is incorporated by reference in its entirety). Samples used for this testing were derived from peripheral blood RNA obtained across 2 time points. This included Cycle 1 Day 1 pre-dose and Cycle 2 Day 1 pre-dose from the same patients. Data shows different TCR and BCR metrics being modulated by 1 cycle of therapy with Compound 2.

[0236] FIGs. 17A-17D depict induced changes in different TCR and BCR repertoire metrics following administration of Compound 2. Specifically, FIG. 17A shows that a decrease in TCR diversity index (beta and alpha) D50 was observed in patients who benefitted from therapy suggesting a focused T-cell response. FIG. 17B shows that patients with clinical benefit showed an increase in naive B-cells undergoing mutations, and the class switch ratio (CSR) indicating an adaptive immune response. FIG. 17C shows Uniform Manifold Approximation and Projection (UMAP) analysis, which separated patients according to clinical benefit / no benefit. FIG. 17D shows key TCR and BRR indexes used in UMAP analysis.Example 12: Impact of Compound 2 treatment measured by tumor microenvironment RNA signature

[0237] FIG. 18 depicts a tumor microenvironment (TME) RNA signature testing to predict clinical benefit. Several patients with clinical benefit were found with tumor signature call near IS (top right corner) or IA (bottom right comer) suggesting those with high immune signature scores tend to benefit from Compound 2 treatment. Alternatively, the other dots shown in FIG. 18 correspond to limited benefit or no benefit.

[0238] A tumor microenvironment (TME) RNA signature was derived according to the previously published articles (Uhlik M, et al., Xerna™ TME Panel is a machine learningbased transcriptomic biomarker designed to predict therapeutic response in multiple cancers. (2023) Front. Oncol. 13:1158345, which is incorporated by reference in its entirety). The signature is made up of 124 genes across two main biological axes including angiogenesis and immune.

[0239] Samples were obtained from patients following administration of Compound 2. The RNA sequencing data was generated and then further analyzed. The data in FIG. 18 shows those patients who benefitted clinically from Compound 2 (“Clinical benefit”) had tumors that fell in the high immune signature quadrants (IS and IA) for the signature calling.461PTS / 200114525.1Attorney Docket No.: HOT-023WOOTHER EMBODIMENTS

[0240] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

[0241] While the disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the disclosure that come within known or customary practice within the art to which the disclosure pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[0242] Other embodiments are within the claims.1PTS / 200114525.1

Claims

Attorney Docket No.: HOT-023WOCLAIMS1. A method of treating cancer in a patient in need thereof, the method comprising administering to the subject a CBL proto-oncogene B (CBL-B) inhibitor and an antihistamine.

2. The method of claim 1, wherein the CBL-B inhibitor is administered at a dose of about 2 mg to about 200 mg.

3. The method of claim 1 or 2, wherein the CBL-B inhibitor is administered at a dose of about 5 mg to about 150 mg.

4. The method of any one of claims 1-3, wherein the CBL-B inhibitor is administered at a dose of about 5 mg to 40 mg.

5. The method of any one of claims 1-4, wherein the CBL-B inhibitor is administered at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

6. The method of any one of claims 1-5, wherein the antihistamine comprises either a second-generation Hl blocker or a H2 blocker.

7. The method of any one of claims 1-6, wherein the antihistamine is one of cetirizine, fexofenadine, levocetirizine, or loratadine.

8. The method of any one of claims 1-6, wherein the antihistamine is one of cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, and sufotidine.

9. The method of any one of claims 1-7, wherein the antihistamine is cetirizine.

10. The method of claim 9, wherein the antihistamine is administered at a dose of about 1 mg to about 20 mg.

11. The method of claim 9 or claim 10, wherein the antihistamine is administered at a dose of about 5 mg to about 15 mg.

12. The method of any one of claims 9-11, wherein the antihistamine is administered at about 10 mg.

13. The method of any one of claims 1-12, wherein the antihistamine is administered at least once weekly.

14. The method of any one of claims 1-13, wherein the antihistamine is administered at least twice weekly.

15. The method of any one of claims 1-14, wherein the antihistamine is administered daily.

16. The method of any one of claims 1-14, wherein the antihistamine is administered on the same day as the CBL-B inhibitor.481PTS / 200114525.1Attorney Docket No.: HOT-023WO17. The method of any one of claims 1-16 wherein the antihistamine is administered in the morning.

18. The method of any one of claims 1-17, further comprising administering one or more additional doses of the antihistamine.

19. The method of claim 18, wherein the one or more additional doses of the antihistamine are administered twice weekly.

20. The method of any one of claims 1-19, further comprising administering one or more additional doses of the CBL-B inhibitor.

21. The method of claim 20, wherein the one or more additional doses of the CBL-B inhibitor are administered once monthly.

22. The method of claim 20, wherein the one or more additional doses of the CBL-B inhibitor are administer every two weeks.

23. The method of claim 20, wherein the one or more additional doses of the CBL-B inhibitor are administered once weekly.

24. The method of claim 20, wherein the one or more additional doses of the CBL-B inhibitor are administered twice weekly.

25. The method of claim 20, wherein the one or more additional doses of the CBL-B inhibitor are administered daily.

26. The method of claim 20, wherein the one or more additional doses of the CBL-B inhibitor are administered in the morning.

27. The method of any one of claims 1-26, wherein the CBL-B inhibitor is administered orally.

28. The method of any one of claims 1-27, wherein the antihistamine is administered orally.

29. The method of any one of claims 1-28, further comprising administering a steroid.

30. The method of claim 29, wherein the steroid is a glucocorticoid.

31. The method of claim 29 or 30, wherein the steroid is selected from: dexamethasone, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, betamethasone, triamcinolone, deflazacort, and beclomethasone.

32. The method of any one of claims 29-31 , wherein the steroid is dexamethasone.

33. The method of claim 32, wherein the glucocorticoid is administered at a dose of about 0.5 mg to about 6 mg.

34. The method of claim 32 or claim 33, wherein the glucocorticoid is administered at a dose of about 1 mg to about 5 mg.491PTS / 200114525.1Attorney Docket No.: HOT-023WO35. The method of any one of claims 32-34, wherein the glucocorticoid is administered at a dose of about 2 mg or about 4 mg.

36. The method of any one of claims 32-35, wherein the glucocorticoid is administered at a dose of about 2 mg.

37. The method of any one of claims 32-35, wherein the glucocorticoid is administered at a dose of about 4 mg.

38. The method of any one of claims 29-37, wherein the glucocorticoid is administered at least once weekly.

39. The method of any one of claims 29-38, wherein the glucocorticoid is administered at least twice weekly.

40. The method of any one of claims 29-39, wherein the glucocorticoid is administered on the same day as the CBL-B inhibitor.

41. The method of any one of claims 29-40, wherein the glucocorticoid is administered about 1 hour to about 4 hours before the CBL-B inhibitor.

42. The method of any one of claims 29-41, wherein the glucocorticoid is administered about 2 hours before the CBL-B inhibitor.

43. The method of any one of claims 29-42, further comprising administering one or more additional doses of the steroid.

44. The method of claim 43, wherein the one or more additional doses of the steroid are administered twice weekly.

45. The method of any one of claims 29-44, wherein the steroid is administered orally.

46. The method of any one of claims 1-45, further comprising administering an antinausea medication.

47. The method of claim 46, wherein the anti-nausea medication is a 5-HTa serotonin receptor antagonist.

48. The method of claim 46 or claim 47, wherein the anti-nausea medication is selected from: ondansetron, granisetron, olanzapine, lorazepam, dolasetron, palonosetron, ramosetron, tropisetron, vortioxetine, bismuth subsalicylate, dimenhydrinate, meclizine, scopolamine, prochlorperazine, promethazine, and metoclopramide.

49. The method of any one of claims 46-48, wherein the anti-nausea medication is ondansetron or granisetron.

50. The method of claim 49, wherein the anti-nausea medication is administered at a dose of about 2 mg to about 10 mg.

51. The method of claim 49 or claim 50, wherein the anti-nausea medication is administered at dose of about 3 mg to about 9 mg.501PTS / 200114525.1Attorney Docket No.: HOT-023WO52. The method of any one of claims 49-51, wherein the anti-nausea medication is administered at a dose of about 4 mg or about 8 mg.

53. The method of any one of claims 49-52, wherein the anti-nausea medication is administered at a dose of about 4 mg.

54. The method of any one of claims 49-52, wherein the anti-nausea medication is administered at a dose of about 8 mg.

55. The method of any one of claims 46-54, wherein the anti-nausea medication is administered at least once weekly.

56. The method of any one of claims 46-55, wherein the anti-nausea medication is administered at least twice weekly.

57. The method of any one of claims 46-56, wherein the anti-nausea medication is administered on the same day as the CBL-B inhibitor.

58. The method of any one of claims 46-57, wherein the anti-nausea medication is administered about 1 hour to about 4 hours before the CBL-B inhibitor.

59. The method of any one of claims 46-58, wherein the anti-nausea medication is administered about 2 hours before the CBL-B inhibitor.

60. The method of any one of claims 46-59, further comprising administering one or more additional doses of the anti-nausea medication.

61. The method of claim 60, wherein the one or more additional doses of the anti-nausea medication are administered twice weekly.

62. The method of any one of claims 46-61, wherein the anti-nausea medication is administered orally.

63. The method of any one of claims 1-62, further comprising administering a histamine H2 blocker.

64. The method of claim 63, wherein the histamine H2 blocker is selected from: famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, and sufotidine.

65. The method of claim 63 or claim 64, wherein the histamine H2 blocker is famotidine.

66. The method of claim 65, wherein the histamine H2 blocker is administered at a dose of about 10 mg to about 30 mg.

67. The method of claim 65 or claim 66, wherein the histamine H2 blocker is administered at a dose of about 20 mg.

68. The method of any one of claims 63-67, wherein the H2 blocker is administered at least once weekly.511PTS / 200114525.1Attorney Docket No.: HOT-023WO69. The method of any one of claims 63-68, wherein the H2 blocker is administered at least twice weekly.

70. The method of any one of claims 63-69, wherein the H2 blocker is administered daily.

71. The method of any one of claims 63-69, wherein the H2 blocker is administered on the same day as the CBL-B inhibitor.

72. The method of any one of claims 63-71 , wherein the H2 blocker is administered in the morning.

73. The method of any one of claims 63-72, further comprising administering one or more additional doses of the H2 blocker.

74. The method of claim 73, wherein the one of more additional doses of the H2 blocker are administered twice weekly.

75. The method of any one of claims 63-74, wherein the antihistamine is administered orally.

76. The method of any one of claims 1-75, wherein the CBL-B inhibitor comprises one of the following compounds:ompoun .

77. A method of treating cancer in a patient in need thereof comprising administering to the subject: a CBL proto-oncogene B (CBL-B) inhibitor at a dose of about 5 mg to 40 mg; and a pre-treatment regimen, wherein the pre-treatment regimen is administered to the patient prior to the CBL-B inhibitor, the pre-treatment regimen comprising: a histamine Hi blocker at a dose of about 10 mg; a glucocorticoid at a dose between about 2 mg to about 4 mg an anti-nausea medication at a dose between about 4 mg to about 8 mg; and a histamine H2 blocker at a dose of about 20 mg.52IPTS / 200114525.1Attorney Docket No.: HOT-023WO78. The method of claim 77, further comprising administering one or more additional doses of the CBL-B inhibitor.

79. The method of claim 78, wherein the one or more additional doses of the CBL-B inhibitor are administered twice weekly.

80. The method of any one of claims 77-79, wherein the CBL-B inhibitor is administered in the morning.

81. The method of claim 78, further comprising administering the pre-treatment regimen on a same day prior to an additional dose of the CBL-B inhibitor.

82. The method of any one of claims 77-81, further comprising administering the antihistamine and / or the H blocker daily.

83. The method of claim 82, wherein the antihistamine and / or the Hi blocker are administered in the morning.

84. The method of any one of claims 77-83, wherein the CBL-B inhibitor and the pretreatment regimen are administered orally.

85. The method of any one of claims 1-84, wherein the treatment further comprises administering anti-diarrheal medication.

86. The method of claim 85, wherein the anti-diarrheal medication is selected from loperamide, bismuth subsalicylate, alosetron, eluxadoline, and rifaximin.

87. The method of claim 85 or claim 86, wherein the anti-diarrheal medication is administered at a dose of about 2 mg to 16 mg.

88. A method of treating cancer in a patient in need thereof, the method comprising administering to the subject a CBL proto-oncogene B (CBL-B) inhibitor at a dose of about 2 mg to about 200 mg.

89. The method of claim 88, wherein the CBL-B inhibitor comprises one of the following compounds:IPTS / 200114525.1Attorney Docket No.: HOT-023WO90. The method of claim 88, wherein the CBL-B inhibitor comprises Compound 2:(Compound 2).

91. The method of claim 88, wherein the CBL-B inhibitor is administered at a dose of about 5 mg to about 150 mg.

92. The method of claim 88 or 91, wherein the CBL-B inhibitor is administered at a dose of about 5 mg to 40 mg.

93. The method of any one of claims 88-92, wherein the CBL-B inhibitor is administered at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

94. The method of any one of claims 88-93, further comprising administering one or more additional doses of the CBL-B inhibitor.

95. The method of any one of claims 88-94, wherein the one or more additional doses of the CBL-B inhibitor are administered once monthly.

96. The method of any one of claims 88-94, wherein the one or more additional doses of the CBL-B inhibitor are administered once every two weeks.

97. The method of any one of claims 88-94, wherein the one or more additional doses of the CBL-B inhibitor are administered once weekly.

98. The method of any one of claims 88-94, wherein the one or more additional doses of the CBL-B inhibitor are administered twice weekly.

99. The method of any one of claims 88-98, wherein the one or more additional doses of the CBL-B inhibitor are administered daily.

100. The method of any one of claims 88-99, wherein the CBL-B inhibitor is administered orally.

101. The method of any one of claims 88-100, wherein the CBL-B inhibitor is administered in the morning.

102. The method of any one of 88-101, wherein the cancer is selected from ovarian cancer, anal cancer, rectal cancer, prostate cancer, non-small cell lung cancer, small-cell lung cancer, malignant pleural mesothelioma, cutaneous squamous cell carcinoma, melanoma, merkel cell carcinoma, head and neck squamous cell cancer, and acral melanoma, esophageal carcinoma, gastric carcinoma, gastroesophageal junction cancer, renal cell carcinoma, urothelial cell carcinoma, cervical cancer, endometrial cancer, hepatocellular carcinoma, triple-negative breast cancer, biliary tract cancer,54IPTS / 200114525.1Attorney Docket No.: HOT-023WO microsatellite instability-high (MSI-H), mismatch repair deficient colorectal cancer, and tumor mutational burden-high (TMB-H) cancer.

103. The method of any one of claims 88-102, wherein the cancer comprises a solid tumor.

104. The method of claim 103, wherein the solid tumor is an advanced solid tumor.

105. The method of claim 103 or 104, wherein the solid tumor is metastatic, recurrent, and / or unresectable.

106. A method of treating cancer in a patient in need thereof, the method comprising administering to the subject one or more doses of a CBL proto-oncogene B (CBL-B) inhibitor of Compound 2 having the following formula:(Compound 2), wherein each of the one or more doses comprise about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg of the CBL-Bi.

107. The method of any one of claims 88-106, wherein the method increases gene expression by at least 2-fold in one or more of chemokine signaling pathway, cytokine signaling pathway, host pathogen interaction pathway, innate immune system pathway, lymphocyte tracking pathway, and type II interferon signaling pathway.

108. The method of any one of claims 88-106, wherein the method induces an adaptive immune response in the patient as measured by one or more TCR and / or BCR repertoire metrics.

109. The method of any one of claims 88-108, wherein the method induces a change in immune tissue microenvironment of the patient as measured by a tumor microenvironment (TME) RNA signature.IPTS / 200114525.1

Images