Cancer Treatment Methods

Abstract

The present invention relates to a heterotandem bicyclic peptide complex, BT7480, or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition thereof, and uses thereof.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 264,132, filed November 16, 2021, which is incorporated by reference in its entirety.

[0002] FIELD OF THEINVENTION The present invention relates to a heterotandem bicyclic peptide complex BT7480 or a pharma- ceutical acceptable salt thereof or a pharmaceutical composition thereof. The present invention provides the use of a heterotandem bicyclic peptide complex BT7480 or a pharma- ceutical acceptable salt thereof or a pharmaceutical composition thereof for preventing or treating Nectin-4-associated progressive malignant tumors. [Background technology]

[0003] Cyclic peptides are an attractive class of molecules for the development of therapeutic drugs, as they can bind with high affinity and target specificity to protein targets. Indeed, several cyclic peptides have already been successfully used in the clinic, such as the antimicrobial peptide vancomycin, the immunosuppressant cyclosporine, and the anticancer drug octreotide (Driggers et al. (2008), Nat Rev Drug Discov 7 (7), 608-24). The good binding properties arise from the relatively large interaction surface formed between the peptide and the target and the reduced conformational flexibility of the cyclic structure. Typically, macrocycles are used in a wide range of applications, e.g., the cyclic peptide CXCR4 antagonist CVX15 (400 Å 2 (Wu et al. (2007), Science 330, 1066-71), a cyclic peptide with an Arg-Gly-Asp motif that binds to integrin αVb3 (355 Å 2 (2002), Science 296 (5565), 151-5) or the cyclic peptide inhibitor upain-1 (603 Å) that binds to urokinase-type plasminogen activator. 2;Zhao et al. (2007), J Struct Biol 160 (1), 1-10), which bind to surfaces measuring several hundred square angstroms.

[0004] Due to their cyclic structure, peptide macrocycles are less flexible than linear peptides, which results in less entropy loss when binding to targets and higher binding affinity. The reduced flexibility also locks target-specific conformations, enhancing binding specificity compared to linear peptides. This effect is exemplified by potent and selective inhibitors of matrix metalloproteinase 8 (MMP-8), which lose selectivity over other MMPs upon ring opening (Cherney et al. (1998), J Med Chem 41 (11), 1749-51). The favorable binding properties achieved by macrocyclization are even more pronounced in polycyclic peptides with multiple peptide rings, such as vancomycin, nisin, and actinomycin.

[0005] Previously, various research teams have attached polypeptides with cysteine ​​residues to synthetic molecular structures (Kemp and McNamara (1985), J. Org. Chem; Timmerman et al. (2005), ChemBioChem). Meloen et al. have used tris(bromomethyl)benzene and related molecules to rapidly and quantitatively cyclize multiple peptide loops on synthetic scaffolds for structural mimicry of protein surfaces (Timmerman et al. (2005), ChemBioChem). Candidate drug compounds are generated by methods that attach cysteine-containing polypeptides to molecular scaffolds, such as TATA (1,1',1''-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one, Heinis et al. Angew Chem, Int Ed. 2014; 53:1602-1606).

[0006] A combinatorial approach based on phage display has been developed to generate and screen large libraries of bicyclic peptides against targets of interest (Heinis et al. (2009), Nat Chem Biol 5 (7), 502-7 and WO 2009 / 098450). Briefly, a combinatorial library of linear peptides containing three cysteine ​​residues and two regions with six random amino acids (Cys-(Xaa)6-Cys-(Xaa)6-Cys) was displayed on phage and cyclized by covalently linking the cysteine ​​side chains to a small molecule scaffold. Summary of the Invention

[0007] According to one aspect, the present invention provides a solid pharmaceutical composition comprising BT7480 or a pharma- ceutical acceptable salt thereof, Tris base, mannitol, and sodium hydroxide. According to another aspect, the present invention provides an aqueous pharmaceutical composition comprising BT7480 or a pharma- ceutical acceptable salt thereof, Tris base, mannitol, sodium hydroxide, and water.

[0008] In another aspect, there is provided a method for treating Nectin-4-associated progressive malignant tumors in a patient, comprising administering to the patient the pharmaceutical composition described herein.In some embodiments, there is provided a method for treating Nectin-4-associated progressive malignant tumors in a patient, comprising administering to the patient an aqueous pharmaceutical composition comprising BT7480 or a pharma-ceutical acceptable salt thereof, Tris base, mannitol, sodium hydroxide, sodium chloride and water by IV infusion. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] 1. General Description of Certain Embodiments of the Invention In one embodiment, the present invention provides a method of using the pharmaceutical compositions described herein for treating Nectin-4-associated advanced malignancies.

[0010] In some embodiments, the method for treating Nectin-4-associated progressive malignant tumors in patients is provided, comprising administering to the patient once a week an aqueous pharmaceutical composition comprising BT7480 or its pharma- ceutical acceptable salt, Tris base, mannitol, sodium hydroxide, sodium chloride and water by IV infusion.In some embodiments, the aqueous pharmaceutical composition described herein is administered in combination with Nivolumab.

[0011] In some embodiments, the Nectin-4-associated progressive malignant tumor is selected from the group consisting of bladder cancer, esophageal cancer, non-small cell lung cancer (NSCLC), head and neck cancer, ovarian cancer, breast cancer, e.g., triple-negative breast cancer (TNBC), gastric / upper gastrointestinal (GI) cancer, melanoma, pancreatic cancer and urothelial cancer.

[0012] In some embodiments, the Nectin-4-associated advanced malignant tumor is non-small cell lung cancer (NSCLC). In some embodiments, the Nectin-4-associated advanced malignant tumor is ovarian cancer. In some embodiments, the Nectin-4-associated advanced malignant tumor is breast cancer, such as triple-negative breast cancer (TNBC). In some embodiments, the Nectin-4-associated advanced malignant tumor is gastric / upper gastrointestinal (GI). In some embodiments, the Nectin-4-associated advanced malignant tumor is pancreatic cancer. In some embodiments, the Nectin-4-associated advanced malignant tumor is urothelial carcinoma. In some embodiments, the Nectin-4-associated advanced malignant tumor is bladder cancer. In some embodiments, the Nectin-4-associated advanced malignant tumor is head and neck cancer. In some embodiments, the Nectin-4-associated advanced malignant tumor is esophageal cancer. In some embodiments, the Nectin-4-associated advanced malignant tumor is melanoma.

[0013] 2. Compounds and definitions: The term "BT7480" as used herein is a heterotandem bicyclic peptide complex consisting of a Nectin-4 specific peptide linked to two CD137 specific peptides by N-(acid-PEG3)-N-bis(PEG3-azide) linkers and has the structure shown below. [ka]

[0014] The term "pharmaceutical acceptable salts" as used herein refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the contents of which are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutical acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0015] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations, formed where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates. It is to be understood that salt forms are within the scope of the present invention and that reference to a peptide ligand includes the salt form of that ligand.

[0016] The salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods, for example, methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or an organic solvent, or a mixture of the two.

[0017] As used herein, the term "about" refers to within 10% of a given value or range. In some embodiments, the term "about" refers to within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0018] Unless otherwise indicated, structures depicted herein are intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise indicated, all tautomers of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise indicated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or the replacement of C 13 or 14 Compounds having this structure including the replacement of a carbon with a C-rich carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0019] 3. Pharmaceutical Compositions According to one aspect, the present invention provides a solid pharmaceutical composition comprising BT7480 or a pharma- ceutical acceptable salt thereof, Tris base, mannitol, and sodium hydroxide. In some embodiments, the solid pharmaceutical composition of the present invention comprises about 66 mg of BT7480 or a pharma- ceutical acceptable salt thereof.

[0020] In some embodiments, the solid pharmaceutical composition of the present invention is in powder form. In some embodiments, the solid pharmaceutical composition of the present invention is a lyophilized powder. In some embodiments, the solid pharmaceutical composition of the present invention is a sterile lyophilized powder.

[0021] In some embodiments, the present invention provides a 4R injection vial containing a solid pharmaceutical composition described herein. In some embodiments, the present invention provides a 4R injection vial containing 66 mg of BT7480 or a pharma- ceutical acceptable salt thereof, Tris base, mannitol, and sodium hydroxide.

[0022] According to one aspect, the present invention provides an aqueous pharmaceutical composition comprising BT7480 or a pharma- ceutically acceptable salt thereof, Tris base, mannitol, sodium hydroxide, and water. In some embodiments, the aqueous pharmaceutical composition comprises BT7480 at a concentration of 60 mg / mL, Tris base, mannitol, sodium hydroxide, and water. In some embodiments, the present invention provides a 4R injection vial containing an aqueous pharmaceutical composition described herein. In some embodiments, the present invention provides a 4R injection vial containing 1.1 mL of an aqueous pharmaceutical composition comprising BT7480 at a concentration of 60 mg / mL, Tris base, mannitol, sodium hydroxide, and water.

[0023] In some embodiments, the present invention provides an aqueous pharmaceutical composition comprising BT7480 or a pharma- ceutical acceptable salt thereof, Tris base, mannitol, sodium hydroxide, sodium chloride, and water. In some embodiments, the aqueous pharmaceutical composition is prepared by diluting an aqueous pharmaceutical composition comprising BT7480 at a concentration of 60 mg / mL, Tris base, mannitol, sodium hydroxide, and water, into 0.9% saline. In some embodiments, the present invention provides an infusion bag containing BT7480 or a pharma-ceutical acceptable salt thereof, Tris base, mannitol, sodium hydroxide, sodium chloride, and water.

[0024] In some embodiments, the aqueous pharmaceutical composition of the present invention comprises an acceptable vehicle or solvent. In some embodiments, the acceptable vehicle or solvent is selected from sterile water, Ringer's solution, USP and isotonic sodium chloride solution. In some embodiments, the acceptable vehicle or solvent is sterile water. In some embodiments, the acceptable vehicle or solvent is a sterile injection medium.

[0025] In some embodiments, the pharma- ceutically acceptable additive or carrier comprises a buffer. In some embodiments, the buffer is selected from phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and wool fat. In some embodiments, the buffer is histidine. In some embodiments, the buffer is sodium hydroxide. In some embodiments, the buffer is hydrochloric acid.

[0026] In some embodiments, the pH of the aqueous pharmaceutical composition of the present invention is about 6 to 8. In some embodiments, the pH of the aqueous pharmaceutical composition of the present invention is about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, 7.9 or about 8.0. In some embodiments, the pH of the aqueous pharmaceutical composition of the present invention is about 7.0 or about 7.5. In some embodiments, the pH of the aqueous pharmaceutical composition of the present invention is about 7.0 to 7.5.

[0027] In some embodiments, the pharma- ceutically acceptable additive or carrier comprises a stabilizing agent or cryoprotectant. In some embodiments, the stabilizing agent or cryoprotectant is dimethylsulfoxide (DMSO). In some embodiments, the stabilizing agent or cryoprotectant is ethylene glycol. In some embodiments, the stabilizing agent or cryoprotectant is glycerol. In some embodiments, the stabilizing agent or cryoprotectant is propylene glycol. In some embodiments, the stabilizing agent or cryoprotectant is 2-methyl-2,4-pentanediol (MPD). In some embodiments, the stabilizing agent or cryoprotectant is trehalose. In some embodiments, the stabilizing agent or cryoprotectant is formamide. In some embodiments, the stabilizing agent or cryoprotectant is proline. In some embodiments, the stabilizing agent or cryoprotectant is glycerol 3-phosphate. In some embodiments, the stabilizing agent or cryoprotectant is sorbitol. In some embodiments, the stabilizing agent or cryoprotectant is diethyl glycol. In some embodiments, the stabilizing agent or cryoprotectant is sucrose.

[0028] In some embodiments, the pharma- ceutically acceptable excipient or carrier comprises a osmolality modifier. In some embodiments, the osmolality modifier is sodium chloride, dextrose, calcium chloride, or a combination thereof. In some embodiments, the osmolality modifier is dextrose. In some embodiments, the osmolality modifier is sodium chloride. In some embodiments, the osmolality modifier is a combination of sodium chloride and dextrose.

[0029] In some embodiments, the present invention provides BT7480 or a pharma- ceutical acceptable salt thereof; about 0.1 mg of Tris base per 1 mg of BT7480 or a pharma- ceutical acceptable salt thereof; About 0.4 mg of mannitol per mg of BT7480 or a pharma- ceutical acceptable salt thereof; and Sodium hydroxide in an amount that results in a pH of about 7.0 to 7.5 when the solid pharmaceutical composition is reconstituted in water. The present invention provides a solid pharmaceutical composition comprising:

[0030] In some embodiments, the present invention provides a solid pharmaceutical composition which is a lyophilized powder, comprising: about 66 mg of BT7480 or a pharma- ceutical acceptable salt thereof; Approximately 6.6 mg of Tris base; Approximately 26.4 mg of mannitol; and Sodium hydroxide in an amount that results in a pH of about 7.0 to 7.5 when the solid pharmaceutical composition is reconstituted in water. The present invention provides a solid pharmaceutical composition comprising:

[0031] In some embodiments, the present invention provides about 60 mg / mL BT7480 or a pharma- ceutical acceptable salt thereof; Approximately 6 mg / mL Tris base; Approximately 24 mg / mL mannitol; Sodium hydroxide; and water The present invention provides an aqueous pharmaceutical composition comprising the above, wherein the aqueous pharmaceutical composition has a pH of about 7.0 to 7.5.

[0032] In some embodiments, the present invention provides an aqueous pharmaceutical composition having a volume of about 1.1 mL, comprising: about 60 mg / mL BT7480 or a pharma- ceutical acceptable salt thereof; Approximately 6 mg / mL Tris base; Approximately 24 mg / mL mannitol; Sodium hydroxide; and water and the pH of the aqueous pharmaceutical composition is about 7.0 to 7.5.

[0033] In some embodiments, the present invention provides an aqueous pharmaceutical composition prepared by reconstituting the solid pharmaceutical composition of the present invention in water. In some embodiments, the present invention provides an aqueous pharmaceutical composition prepared by dissolving the solid pharmaceutical composition of the present invention in an injection medium (e.g., 0.9% w / v saline). In some embodiments, the present invention provides an aqueous pharmaceutical composition prepared by reconstituting the solid pharmaceutical composition of the present invention in water, followed by dilution in 0.9% w / v saline. In some embodiments, the aqueous pharmaceutical composition is diluted in a 0.9% w / v saline IV bag for IV infusion.

[0034] 4. Use of the pharmaceutical composition In one embodiment, the present invention provides a method or use for treating Nectin-4-associated progressive malignant tumors in a patient, comprising administering to the patient a pharmaceutical composition of the present invention. In some embodiments, the present invention provides a method or use for treating Nectin-4-associated progressive malignant tumors, comprising administering to a patient a pharmaceutical composition of the present invention. In some embodiments, renal failure refers to CLcr>30-59mL / min according to the MDRD formula or local equivalent. In some embodiments, the method or use described herein further comprises administering to the patient Nivolumab.

[0035] In some embodiments, nivolumab is administered by infusion over about 30 minutes once every two weeks at a dose level of 240 mg. In some embodiments, nivolumab is diluted in 0.9% sodium chloride. In some embodiments, nivolumab is diluted in 5% dextrose. In some embodiments, nivolumab is diluted to a final concentration of about 1 mg / mL to about 10 mg / ml prior to infusion. In some embodiments, the aqueous pharmaceutical composition described herein is administered in combination with nivolumab by continuous infusion of BT7480 first, followed by nivolumab. In some embodiments, the aqueous pharmaceutical composition described herein is administered about 1 hour before nivolumab is administered. In some embodiments, the aqueous pharmaceutical composition described herein is administered about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, or about 50 minutes before nivolumab is administered.

[0036] In some embodiments, the method of the present invention comprises administering intravenously to a patient a pharmaceutical composition as described herein. In some embodiments, the pharmaceutical composition of the present invention is administered by IV injection. In some embodiments, the pharmaceutical composition of the present invention is administered by IV infusion. In some embodiments, the IV infusion of the pharmaceutical composition of the present invention lasts for about 5 to 30 minutes. In some embodiments, the IV infusion of the pharmaceutical composition of the present invention lasts for about 30 to 60 minutes. In some embodiments, the IV infusion of the pharmaceutical composition of the present invention lasts for about 55 to 75 minutes. In some embodiments, the IV infusion of the pharmaceutical composition of the present invention lasts for about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, or about 90 minutes. In some embodiments, the IV infusion of the pharmaceutical composition of the present invention lasts for about 60 minutes. In some embodiments, the IV infusion of the pharmaceutical composition of the present invention lasts for about 2 hours, about 2.5 hours, about 3 hours, about 3 hours, about 3.5 hours, or about 4 hours.

[0037] In some embodiments, the pharmaceutical composition of the present invention is administered to a patient once every 1, 2, 3, 4, 5, 6 or 7 days. In some embodiments, the interval between two administrations of the pharmaceutical composition of the present invention to a patient is about 6 hours. In some embodiments, the interval between two administrations of the pharmaceutical composition of the present invention to a patient is about 12 hours, about 18 hours or about 24 hours. In some embodiments, the interval between two administrations of the pharmaceutical composition of the present invention to a patient is about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours or about 108 hours. In some embodiments, the pharmaceutical composition of the present invention is administered to a patient once every week. In some embodiments, the pharmaceutical composition of the present invention is administered to a patient once every two weeks. In some embodiments, the pharmaceutical composition of the present invention is administered to a patient once every three weeks. In some embodiments, the pharmaceutical composition of the present invention is administered to a patient once every four weeks. In some embodiments, the pharmaceutical composition of the present invention is administered to a patient once every month.

[0038] In some embodiments, the pharmaceutical composition of the present invention is administered at a dose of up to about 10 mg / kg. In some embodiments, the pharmaceutical composition of the present invention is administered at a dose of about 0.002 mg / kg to about 7.5 mg / kg. In some embodiments, the pharmaceutical composition of the present invention is administered at a dose of about 0.02 mg / kg to about 7.5 mg / kg. In some embodiments, the pharmaceutical composition of the present invention is administered at a dose of about 0.05 mg / kg to about 7.5 mg / kg. In some embodiments, the pharmaceutical composition of the present invention is administered at a dose of about 0.15 mg / kg to about 7.5 mg / kg. In some embodiments, the pharmaceutical composition of the present invention is administered at a dose of about 0.02 to 6 mg / kg, about 0.05 to 6 mg / kg, about 0.15 to 6 mg / kg, about 0.3 to 6 mg / kg, about 0.6 to 6 mg / kg, about 1.3 to 6 mg / kg, or about 2.6 to 6 mg / kg. In some embodiments, the pharmaceutical compositions of the invention are administered at a dose of about 0.002 mg / kg, about 0.006 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.15 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.3 mg / kg, about 2.0 mg / kg, about 2.6 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg, about 3.9 mg / kg, about 4.25 mg / kg, about 5.0 mg / kg, about 5.75 mg / kg, about 6.0 mg / kg, about 6.5 mg / kg, about 7.0 mg / kg or about 7.5 mg / kg.

[0039] In some embodiments, the methods of the invention are for treating patients with locally advanced or metastatic disease that is unresponsive to standard therapy.

[0040] In some embodiments, the method of the present invention is for treating patients with histologically or cytologically confirmed malignant solid tumors associated with Nectin-4 expression, including, for example, urothelial (transitional cell) carcinoma; head and neck squamous cell carcinoma; non-small cell lung cancer; ovarian cancer; breast cancer; gastric cancer; or esophageal cancer. In some embodiments, the method of the present invention is for treating patients with urothelial (transitional cell) carcinoma. In some embodiments, the method of the present invention is for treating patients with head and neck squamous cell carcinoma. In some embodiments, the method of the present invention is for treating patients with non-small cell lung cancer. In some embodiments, the method of the present invention is for treating patients with ovarian cancer. In some embodiments, the method of the present invention is for treating patients with breast cancer. In some embodiments, the method of the present invention is for treating patients with gastric cancer. In some embodiments, the method of the present invention is for treating patients with esophageal cancer.

[0041] In some embodiments, the methods of the invention are for treating patients with radiographically confirmed metastatic or locally advanced disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

[0042] In some embodiments, the methods of the invention are for treating patients with non-measurable disease. In some embodiments, the methods of the invention are for treating patients with measurable disease.

[0043] In some embodiments, the methods of the invention are for treating a patient who is at least 18 years of age.

[0044] In some embodiments, the methods of the invention are for treating patients with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (score 0: fully active and able to perform all pre-onset performance without limitation; score 1: limited physically strenuous activity but ambulatory and able to perform light housework, clerical work, and other light or sedentary tasks).

[0045] In some embodiments, the patient has acceptable organ function and one or more of the following conditions: renal function with creatinine clearance (CLcr) ≥ 60 mL / min according to the Cockcroft-Gault formula or local equivalent formula; total bilirubin ≤ 1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) ≤2.5×ULN, or ≤5×ULN if liver metastases present; Alanine aminotransferase (ALT) ≤2.5×ULN, or ≤5×ULN if liver metastases are present; and International normalized ratio <1.5 or ≤ institutional ULN.

[0046] In some embodiments, the methods of the invention are for treating patients with impaired renal function who have a CLcr of >30-59 mL / min by the Modification of Diet in Renal Disease (MDRD) formula at screening.

[0047] In some embodiments, the patient has acceptable hematological function and one or more of the following conditions: hemoglobin ≥ 9 g / dL; Absolute neutrophil count (ANC) ≥ 1500 cells / mm 3 ; and Platelet count ≥75,000 cells / mm 3 .

[0048] In some embodiments, the methods of the invention are for treating female patients who are not lactating at the time of screening or who are not pregnant as confirmed by a negative serum pregnancy (β-human chorionic gonadotropin) test and a negative urine pregnancy test within 72 hours prior to the first administration of a pharmaceutical composition of the invention.

[0049] In some embodiments, the methods of the invention are for treating patients who have not been or have not received any cytotoxic, small molecule or other systemic chemotherapy within 14 days prior to the first administration of a pharmaceutical composition of the invention.

[0050] In some embodiments, the methods of the invention are for treating patients who have not been administered or have not been administered any immunotherapy, including monoclonal antibodies, within 28 days or 5 half-lives of the first administration of the pharmaceutical composition of the invention.

[0051] In some embodiments, the methods of the present invention are for treating a patient who has not been administered or has not been administered any cell-based therapy, including chimeric antigen receptor T cell therapy, within 60 days of the first administration of the pharmaceutical composition of the present invention.

[0052] In some embodiments, the methods of the present invention are for treating patients who have not been or have not been administered any experimental treatment other than systemic anti-cancer therapy within 28 days or 5 half-lives of the first administration of the pharmaceutical composition of the present invention.

[0053] In some embodiments, the methods of the present invention are for treating patients who have not been or have not been administered any radiation therapy within 28 days of the first administration of the pharmaceutical composition of the present invention.

[0054] In some embodiments, the methods of the invention are for treating patients who have not undergone invasive surgery, except for placement of vascular access, within 28 days of the first administration of the pharmaceutical composition of the invention. In some embodiments, the methods of the invention are for treating patients who have not undergone minimally invasive (laparoscopic, interventional radiology, or robotic) surgery within 14 days of the first administration of the pharmaceutical composition of the invention.

[0055] In some embodiments, the methods of the present invention are for treating patients who have not been or have never been administered any CD137 targeted therapy prior to the first administration of the pharmaceutical composition of the present invention.

[0056] In some embodiments, the methods of the invention are for treating patients who do not receive or have not received any red blood cell transfusions, platelet transfusions or growth factors within 14 days of the first administration of the pharmaceutical composition of the invention.

[0057] In some embodiments, the methods of the invention are for treating a patient with impaired renal function who has not been administered an erythroid growth factor within 4 weeks of the first administration of a pharmaceutical composition of the invention.

[0058] In some embodiments, the patient has no prior treatment-related toxicity that has not resolved to Grade 2 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 prior to the first administration of the pharmaceutical composition of the invention.

[0059] In some embodiments, the methods of the present invention are directed to patients with a body mass index of <35 kg / m 2 The present invention is intended to treat patients who are

[0060] In some embodiments, the patient does not have any serious medical condition, such as a condition that affects the skin (including an autoimmune condition, such as moderate / severe active eczema or psoriasis). In some embodiments, the patient does not have an active uncontrolled systemic infection. In some embodiments, the patient does not have organ system dysfunction (including, for example, severe ascites, coagulation disorder or encephalopathy). In some embodiments, the patient does not have any gastrointestinal, skin or pulmonary complications.

[0061] In some embodiments, the patient has no confirmed history of cerebrovascular events, including, for example, stroke or transient ischemic attack, unstable angina, myocardial infarction, or signs or symptoms of New York Heart Association class III to IV heart failure within six months prior to the first administration of a pharmaceutical composition of the invention.

[0062] In some embodiments, the patient does not have a mean resting QTc (eg, QTcF) >470 milliseconds on triplicate electrocardiograms (ECGs).

[0063] In some embodiments, the patient does not have any factors that increase the risk of QTc prolongation or the risk of arrhythmic events, including, for example, severe heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, sudden unexplained death before age 40, or use of any concomitant medications known to prolong the QT interval and / or cause torsades de pointes.

[0064] In some embodiments, the patient has no clinically significant abnormalities in resting electrocardiogram rhythm, conduction, or morphology, including, for example, complete left bundle branch block or third degree heart block not controlled, such as by a pacemaker.

[0065] In some embodiments, the patient does not have uncontrolled diabetes mellitus with glycated hemoglobin > 8%.

[0066] In some embodiments, the patient does not have uncontrolled symptomatic brain metastases.

[0067] In some embodiments, the methods of the invention are for treating patients who have been treated for brain metastases and who have been progression-free for at least 4 weeks following treatment targeted to the central nervous system.

[0068] In some embodiments, the patient does not have uncontrolled hypertension (unresponsive to intervention, repeatedly measured systolic blood pressure (BP) > 160 mmHg or diastolic BP > 100 mmHg).

[0069] In some embodiments, patients do not have HIV infection or acquired immune deficiency syndrome.In some embodiments, HIV-infected patients are admitted if they meet all of the following criteria at the time of enrollment: a. CD4+ T cell (CD4+) count ≧350 cells / μL; b. At least 4 weeks of established antiretroviral therapy (ART); and c. HIV viral load <400 copies / mL.

[0070] In some embodiments, the patient does not have an active Hepatitis B (HBV) infection.

[0071] In some embodiments, the patient has a controlled (treated) Hepatitis B (HBV) infection and HBV antiviral therapy is administered at least one month prior to the first administration of a pharmaceutical composition of the invention.

[0072] In some embodiments, the patient has a controlled (treated) Hepatitis B (HBV) infection and an HBV viral load of <2000 IU / mL (104 copies / mL) prior to the first administration of a pharmaceutical composition of the invention.

[0073] In some embodiments, patients have a controlled (treated) Hepatitis B virus (HBV) infection with a viral load of <2000 IU / mL (104 copies / mL) and continue to receive the same anti-viral HBV therapy throughout the study treatment.

[0074] In some embodiments, the patient does not have an active Hepatitis C (HCV) infection.

[0075] In some embodiments, the patient is undergoing HCV treatment and has sustained virological negativity at week 12 (SVR12) or week 24 (SVR24) in the four weeks prior to the first administration of a pharmaceutical composition of the invention.

[0076] In some embodiments, the patient does not have any prior or concurrent malignancies within three years prior to the first administration of the pharmaceutical composition of the present invention. In some embodiments, the patient does not have any evidence of residual disease from a previously diagnosed malignancy prior to the first administration of the pharmaceutical composition of the present invention.

[0077] In some embodiments, the patient has had a prior or concurrent malignancy adequately controlled with curative intent treatment for basal cell carcinoma, squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, cervical intraepithelial carcinoma, melanoma in situ, or ductal carcinoma in situ of the breast.

[0078] In some embodiments, the patient has not received any live or attenuated vaccines within 30 days of the first administration of the pharmaceutical composition of the invention.

[0079] In some embodiments, the patient has not been diagnosed with or does not have a clinically relevant immune deficiency.

[0080] In some embodiments, the patient is not using 10 mg or more of prednisone or equivalent daily or another strong systemic immunosuppressant (including, for example, calcineurin inhibitors, antiproliferative drugs, mTOR (mammalian target of rapamycin) inhibitors).

[0081] In some embodiments, the patient has not received intravenous anti-infective treatment within 14 days prior to the first administration of the pharmaceutical composition of the present invention.

[0082] In some embodiments, the patient does not have a fever not due to an underlying disease within 14 days prior to the first administration of the pharmaceutical composition of the invention.

[0083] In some embodiments, the patient has not had any previous organ or hematopoietic cell transplant, including an allogeneic hematopoietic cell transplant.

[0084] In some embodiments, the patient does not have an autoimmune disease.

[0085] In some embodiments, the patient has well-controlled diabetes, alopecia, well-controlled thyroid disease or vitiligo.

[0086] In some embodiments, the patient does not have interstitial lung disease.

[0087] Exemplary Cancers In another aspect, the present invention provides a method for treating cancer in a patient, comprising administering to the patient the pharmaceutical composition described herein.In some embodiments, the present invention provides a method for treating cancer in a patient, comprising administering to the patient an aqueous pharmaceutical composition comprising BT7480 or its pharma-ceutical acceptable salt, Tris base, mannitol, sodium hydroxide, sodium chloride and water by IV infusion.

[0088] In some embodiments, the cancer is associated with Nectin-4. In some embodiments, the cancer is high Nectin-4 expression.

[0089] In some embodiments, the cancer is a solid tumor.

[0090] In some embodiments, the cancer is bladder cancer. In some embodiments, the bladder cancer is selected from the group consisting of basal cancer, p53-like cancer, and luminal cancer.

[0091] In some embodiments, the cancer is endometrial cancer. In some embodiments, the endometrial cancer is selected from the group consisting of MMR-D, POLE EDM, p53 WT, p53 or higher, type I, type II, carcinosarcoma, endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, mixed or undifferentiated carcinoma, mixed serous carcinoma and endometrioid carcinoma, mixed serous carcinoma and low-grade endometrioid carcinoma, and undifferentiated carcinoma.

[0092] In some embodiments, the cancer is esophageal cancer. In some embodiments, the esophageal cancer is selected from the group consisting of adenocarcinoma (EAC), squamous cell carcinoma (ESCC), chromosomally unstable cancer (CIN), Epstein-Barr virus cancer (EBV), genomically stable cancer (GS) and microsatellite unstable cancer (MSI).

[0093] In some embodiments, the cancer is glioblastoma. In some embodiments, the glioblastoma is selected from the group consisting of proneural, neurogenic, classical and mesenchymal.

[0094] In some embodiments, the cancer is mesothelioma. In some embodiments, the mesothelioma is selected from the group consisting of pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, epithelioid mesothelioma, sarcomatoid mesothelioma, biphasic mesothelioma, and malignant mesothelioma.

[0095] In some embodiments, the cancer is multiple myeloma.In some embodiments, the multiple myeloma is selected from the group consisting of hyperdiploid, non-hyperdiploid, cyclin D translocation, MMSET translocation, MAF translocation and unclassified.

[0096] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is selected from the group consisting of clear cell, endometrioid, mucinous, high grade serous and low grade serous ovarian cancer.

[0097] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is selected from the group consisting of squamous cell carcinoma, pancreatic precursor carcinoma, immunogenic carcinoma and ADEX (aberrant differentiated endocrine exocrine) pancreatic cancer.

[0098] In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is selected from the group consisting of AZGP1 (subtype I), MUC1 (subtype II) and MUC1 (subtype III) prostate cancer.

[0099] In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is met-amplified squamous NSCLC, squamous cell NSCLC with wild-type EGFR, or T790M EGFR-expressing lung adenocarcinoma.

[0100] In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the breast cancer is basaloid triple-negative breast cancer.

[0101] In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is colon adenocarcinoma. In some embodiments, the colon adenocarcinoma is high pgp expressing colon adenocarcinoma.

[0102] In some embodiments, the cancer is gastric cancer. In some embodiments, the gastric cancer is FGFR amplified gastric cancer.

[0103] In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is nasal septum squamous cell carcinoma.

[0104] In some embodiments, the cancer is a sarcoma. In some embodiments, the sarcoma is a fibrosarcoma. In some embodiments, the fibrosarcoma is an N-ras mutant / IDH1 mutant soft tissue sarcoma (STS).

[0105] In one embodiment, the cancer is selected from the group consisting of, but not limited to, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors, such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovium, mesothelioma, uterine sarcoma ... cancer, leiomyosarcoma, rhabdomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung carcinoma, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0106] In some embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0107] In some embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I for pilocytic astrocytoma, grade II for low grade astrocytoma, grade III for anaplastic astrocytoma, or grade IV for glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal tumor (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type that is more commonly seen in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or pediatric patient.

[0108] In another embodiment, the cancer is, but is not limited to, mesothelioma, hepatobiliary system (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, colorectal cancer, cancer of the anal region, stomach cancer, digestive system (stomach, colorectum and duodenum), uterine cancer, cancer of the fallopian tubes, cancer of the endometrium, cancer of the cervix, cancer of the vagina, cancer of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, adenocarcinoma, thyroid cancer, and adenocarcinoma. Cancer of the thyroid gland, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, cancer of the renal pelvis, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0109] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatic cholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid cancer; adrenal cortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0110] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, colorectal cancer, ovarian cancer, ovarian epithelial carcinoma, fallopian tube carcinoma, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatic cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenal cortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0111] In some embodiments, the cancer is a solid tumor, such as sarcoma, carcinoma or lymphoma.Solid tumors generally include an abnormal mass of tissue that typically does not include cysts or liquid areas.In some embodiments, the cancer is renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer; melanoma; breast cancer; colorectal cancer or colorectal cancer; colon cancer; colon cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian cancer or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatobiliary cancer. Selected from: ductal carcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid carcinoma; adrenal cortical carcinoma; pancreatic cancer; pancreatic ductal or adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0112] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal cancer, colon cancer, colon cancer, colorectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatic cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenal cortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0113] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, colorectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatic cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenal cortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0114] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is ovarian cancer or ovarian cancer. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatic cholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid carcinoma. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0115] In some embodiments, the cancer is a virus-associated cancer, including human immunodeficiency virus (HIV)-associated solid tumors, human papillomavirus (HPV)-16 positive untreatable solid tumors, and adult T-cell leukemia, a highly aggressive form of CD4+ T-cell leukemia caused by human T-cell leukemia virus type I (HTLV-I) and characterized by clonal integration of HTLV-I in leukemic cells (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746); and virus-associated tumors in gastric cancer, nasopharyngeal cancer, cervical cancer, vaginal cancer, vulvar cancer, head and neck squamous cell carcinoma, and Merkel cell carcinoma (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886; https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886; https: / / clinicaltrials.gov / ct2 / show / (See NCT02426892).

[0116] In some embodiments, the cancer is melanoma cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). EXAMPLES

[0117] Example 1: A Phase 1 / 2 Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT7480 in Patients with Nectin-4-Associated Advanced Malignancies Main purpose Phase 1 To evaluate the safety and tolerability of BT7480, as monotherapy and in combination with nivolumab, in patients with advanced solid tumors associated with Nectin-4 expression; and To evaluate the safety and tolerability of BT7480 as a monotherapy in patients with renal failure and advanced solid tumors.

[0118] Phase 2 To evaluate the clinical activity of BT7480 as monotherapy and in combination with nivolumab in patients with advanced solid tumors associated with Nectin-4 expression.

[0119] Secondary Objectives Phase 1 To evaluate the clinical activity of BT7480, as a monotherapy and in combination with nivolumab, in patients with advanced solid tumors associated with Nectin-4 expression; and To evaluate the clinical activity of BT7480 as a monotherapy in patients with renal failure and advanced solid tumors.

[0120] Phase 2 To evaluate the safety and tolerability of BT7480 as monotherapy and in combination with nivolumab in patients with advanced solid tumors associated with Nectin-4 expression.

[0121] Phase 1 and 2 To evaluate additional indicators of antitumor efficacy of BT7480 as monotherapy and in combination with nivolumab; To evaluate the pharmacokinetic (PK) parameters of BT7480, as monotherapy and in combination with nivolumab, in patients with advanced solid tumors associated with Nectin-4 expression; To evaluate the PK parameters of BT7480 as monotherapy in patients with renal failure and advanced solid tumors; To evaluate the occurrence of anti-drug antibodies (ADA) in patients treated with BT7480; and To evaluate cluster of differentiation (CD)137 target engagement in peripheral blood of patients treated with BT7480 as monotherapy and in combination with nivolumab.

[0122] Purpose of exploration Phase 1 and 2 To evaluate potential pharmacodynamic (transcriptomic and proteomic) activity related to PK / target engagement in blood and tumors of patients treated with BT7480; To evaluate biomarkers associated with pharmacological activity in patients treated with BT7480; To evaluate pharmacogenomics (PGx) in patients treated with BT7480; To evaluate circulating tumor deoxyribonucleic acid (ctDNA) in patients treated with BT7480.

[0123] Inclusion criteria Patients who meet the following criteria are eligible to participate in the study: 1. Patients must have locally advanced or metastatic disease that is unresponsive to standard therapy or for which standard therapy is not appropriate or does not provide clinical benefit as determined by the investigator; 2. Must have histologically or cytologically confirmed malignant solid tumors associated with Nectin-4 expression (including urothelial (transitional cell) carcinoma; head and neck squamous cell carcinoma; non-small cell lung carcinoma; and ovarian, breast, gastric, or esophageal cancer); NOTE: Renal cell carcinoma and glioblastoma multiforme are considered to have little to no Nectin-4 expression. 3. Must have radiographically confirmed metastatic or locally advanced disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; NOTE: In monotherapy dose escalation, patients with non-measurable disease may also be enrolled in cohorts 1-3, and only patients with measurable disease are enrolled in cohorts 4 and beyond. 4. Fresh or archived tumor tissue must be submitted; 5. Written informed consent, signed and dated by the patient or legal guardian, must be provided in accordance with local guidelines before any study-specific procedures, sampling or analyses are performed; 6. You must be at least 18 years of age; 7. Eastern Cooperative Oncology Group (ECOG) performance status score must be 0 or 1 (score 0: fully active and able to perform all pre-onset performance without limitation; score 1: physically strenuous activity is limited, but ambulatory and light housework, clerical work, and other light or sedentary tasks); 8. Must have acceptable organ function as evidenced by all of the following laboratory data: Creatinine clearance (CLcr) ≥ 60mL / min by Cockcroft-Gault formula or local equivalent renal function; NOTE: Patients enrolled in the optional renal impairment cohort must have impaired renal function with CLcr >30–59 mL / min by the Modification of Diet in Renal Disease (MDRD) equation at screening. b. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); NOTE: Patients with Gilbert's syndrome are eligible if their direct bilirubin is ≤1.5 × ULN. c. Aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN if liver metastases are present; d. Alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN if liver metastases are present; and e. International normalized ratio <1.5 or ≤ institutional ULN. 9. Must have acceptable hematological function as evidenced by all of the following laboratory data: f. Hemoglobin ≥ 9 g / dL; g. Absolute neutrophil count (ANC) ≥ 1500 cells / mm 3 ; and h. Platelet count ≥75,000 cells / mm 3 . 10. Female patients must not be lactating or pregnant at screening, as confirmed by a negative serum pregnancy (β-human chorionic gonadotropin) test and a negative urine pregnancy test within 72 hours prior to the first dose of study drug. All women are considered of childbearing potential unless they are postmenopausal (have had at least 12 months of amenorrhea and have follicle-stimulating hormone in the postmenopausal range at screening) or surgically sterile; 11. Male patients of reproductive potential and female patients of reproductive potential who are at risk of pregnancy must agree to use a highly effective (failure rate <1%) protocol-recommended method of contraception in combination with an acceptable but less effective method (failure rate ≥1%) during study participation and until 3 months after the last dose of BT7480 and, if applicable, until 5 months after the last dose of nivolumab; 12. Male patients of reproductive potential must agree to refrain from sperm donation from day 1 until at least 3 months after the last dose of BT7480 and, if applicable, until 5 months after the last dose of nivolumab; 13. Life expectancy must be ≥ 12 weeks after initiation of study drug, as determined by the investigator; and 14. Willing and able to comply with the protocol, scheduled visits, treatment plan, study restrictions, clinical testing, contraception guidelines, and other study procedures.

[0124] Exclusion criteria Patients who meet any of the following criteria will be excluded from participating in the study: 1. Prior treatment with any of the following: i. Cytotoxic, small molecule or other systemic chemotherapy within 14 days of the first dose of study drug; j. Immunotherapy containing a monoclonal antibody within 28 days or 5 half-lives of the first dose of study drug, whichever is shorter; k. Cell-based therapy, including chimeric antigen receptor T-cell therapy, within 60 days of the first dose of study drug; l. Experimental treatment other than systemic anticancer therapy within 28 days or 5 half-lives of the first dose of study drug, whichever is shorter; m. Radiation therapy within 28 days of the first dose of study drug; n. Major surgery, excluding vascular access placement, within 28 days of first administration of study drug if invasive surgery, or within 14 days of first administration of study drug if minimally invasive (laparoscopy, interventional radiology, or robotic); NOTE: Patients must be adequately recovered after surgery before starting study medication. o. CD137 targeted therapy; or p. Red blood cell transfusion, platelet transfusion, or growth factors within 14 days of the first dose of BT7480. NOTE: Patients in the optional renal impairment cohort may have received erythroid growth factor within 4 weeks of the first dose of BT7480, if clinically indicated. 2. Prior treatment-related toxicity that has not resolved to grade 2 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0; 3. Body mass index ≥ 35 kg / m 2 ; 4. Known hypersensitivity to any component of the study drug; 5. Any serious medical condition that, in the opinion of the investigator, may compromise or interfere with patient safety or the integrity of the study results, such as conditions affecting the skin (including moderate / severe and autoimmune diseases such as active eczema or psoriasis, diseases related to or that may interfere with rash monitoring), immediately life-threatening diseases (other than cancer), active and uncontrolled systemic infection, organ system dysfunction (e.g. severe ascites, coagulopathy or encephalopathy), or other gastrointestinal, skin or pulmonary (following screening chest computed tomography (CT) scan, if clinically indicated) complications; 6. A confirmed history of cerebrovascular events (e.g., stroke or transient ischemic attack), unstable angina, myocardial infarction, or signs or symptoms of New York Heart Association class III to IV heart failure within 6 months prior to the first dose of study drug; 7. Mean resting QTc (e.g., QTcF) >470 ms on triplicate electrocardiograms (ECGs) obtained at screening; 8. Any factor that increases the risk of QTc prolongation or the risk of arrhythmic events, such as severe heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, sudden unexplained death before age 40 years, or use of any concomitant medications known to prolong the QT interval and / or cause torsades de pointes; 9. Any clinically significant abnormality in resting electrocardiogram rhythm, conduction, or morphology as assessed by the investigator, such as complete left bundle branch block or third-degree heart block not controlled by a pacemaker or similar; 10. Uncontrolled diabetes mellitus with glycated hemoglobin ≥8%; 11. Uncontrolled symptomatic brain metastases; NOTE: Patients with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after central nervous system-targeted treatment. 12. Uncontrolled hypertension (not responding to intervention, with repeated measurements of systolic blood pressure (BP) ≥ 160 mmHg or diastolic BP ≥ 100 mmHg) at screening or before initiation of study drug; 13. Known HIV infection or acquired immune deficiency syndrome; Note: Patients are considered to have well-controlled HIV if they meet all of the following criteria at the time of enrollment: a. CD4+ T cell (CD4+) count ≥350 cells / μL; b. At least 4 weeks of established antiretroviral therapy (ART) c. HIV viral load <400 copies / mL 14. Active hepatitis B (HBV) infection; NOTE: Hepatitis is considered controlled (treated) if the patient meets all of the following criteria: q. HBV antiviral treatment must be administered for at least 1 month prior to the first dose of study drug; r. HBV viral load must be <2000 IU / mL (104 copies / mL) prior to the first dose of study drug; and s. Individuals on active HBV therapy with viral loads <2000 IU / mL (104 copies / mL) should continue on the same antiviral HBV therapy throughout study treatment. 15. Active hepatitis C (HCV) infection; NOTE: Patients with successfully treated chronic HCV infection, defined as sustained virologic response at week 12 (SVR12) or week 24 (SVR24), are allowed if there are 4 weeks between achievement of sustained virologic response (SVR12 or SVR24) and initiation of study drug. 16. Prior or concurrent malignancies whose natural history or treatment may interfere with the evaluation of the safety or effectiveness of the investigational regimen, particularly patients with a history of another malignancy within 3 years prior to the first dose of study drug, or patients with evidence of residual disease from a previously diagnosed malignancy (except those adequately controlled with curative-intent treatment for basal cell carcinoma, squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, cervical intraepithelial carcinoma, melanoma in situ, or ductal carcinoma in situ of the breast). 17. Receipt of a live or attenuated vaccine within 30 days of the first dose of study drug; Note: Patients who have received the COVID-19 vaccine will be considered on an individual basis after consultation with the medical monitor. 18. Diagnosis of clinically relevant immunodeficiency; 19. Use of 10 mg or more of prednisone or equivalent daily or another potent systemic immunosuppressant (e.g., calcineurin inhibitors, antiproliferative agents, mTOR (mammalian target of rapamycin) inhibitors); 20. Received intravenous anti-infective treatment or had fever not attributable to an underlying disease within 14 days prior to the first dose of study drug; 21. Psychological, familial, social or geographical conditions that make it difficult to comply with the protocol and / or the follow-up procedures outlined in the protocol; 22. Clinically significant safety concerns associated with prior checkpoint inhibitor therapy; 23. Previous organ or hematopoietic cell transplant, including allogeneic hematopoietic cell transplant; 24. History of autoimmune disease (excluding well-controlled diabetes, alopecia, well-controlled thyroid disease, or vitiligo); 25. History of interstitial lung disease; or 26. Previous or current evidence of any condition, treatment or laboratory abnormality that may confound the results of the study, prevent the patient's participation, or where, in the investigator's opinion, it would not be in the patient's best interest to participate in the study.

[0125] Study design and duration This is a Phase 1 / 2 first-in-human (FIH), open-label, dose escalation, dose confirmation and dose expansion multicenter study to evaluate the safety, PK and clinical activity of BT7480 in patients with advanced solid tumors associated with Nectin-4 expression. Dose escalation and dose expansion of BT7480 monotherapy with potential renal impairment cohorts will be the focus of the Phase 1 portion of the study. Subsequent dose escalation and dose expansion cohorts evaluating BT7480 in combination with nivolumab may also be evaluated as part of Phase 1. Enrollment in the optional renal impairment cohort may be concurrent with enrollment in the monotherapy dose expansion / combination therapy dose escalation cohorts. Phase 2 of the study is planned to evaluate the efficacy of BT7480, either as a monotherapy or in combination with nivolumab, administered at the phase 2 recommended dose (RP2D) determined in Phase 1. The study is planned to be conducted at up to 20 clinical sites worldwide.

[0126] Patients with histologically or cytologically confirmed malignant solid tumors associated with Nectin-4 expression will be enrolled in the study. Patients must have locally advanced or metastatic disease that has not responded to standard therapy or for which, in the investigator's judgment, standard therapy is not appropriate or will not provide clinical benefit.

[0127] Patients must submit fresh or archived tumor tissue at baseline, have an ECOG performance status score of 0 or 1, acceptable protocol-defined organ and hematologic function, and a life expectancy of ≥12 weeks. Tumor-associated Nectin-4 expression levels will be determined retrospectively for all patients using archived tumor tissue or fresh tumor biopsies taken during screening.

[0128] During Phase 1 monotherapy (dose escalation (cohort 3 onwards), expansion and renal impairment cohorts) and during Phase 1 combination therapy (dose escalation and expansion cohorts), patients may provide optional paired (pre- and on-treatment) tumor biopsies. If the patient consents to an optional paired tumor biopsy, both a pre-treatment baseline tumor biopsy and archived tumor tissue will be requested. On-treatment biopsy sample collection is permitted any time after Cycle 1 Day 1 and also at the time of recurrence, if applicable and possible.

[0129] Safety and tolerability will be assessed from the time of informed consent through safety follow-up visits with vital signs, physical examination, 12-lead ECG, routine laboratory evaluation (chemistry, hematology, coagulation and urinalysis), ADAs and adverse events (AEs). For the cohort receiving combination treatment with nivolumab, further monitoring for autoimmune and endocrine disorders is planned.

[0130] CT or magnetic resonance imaging scans or manual measurements of visual lesions or other types of imaging for investigator assessment of disease per RECIST 1.1 should be performed at screening; every 8 weeks (± 7 days) for the first 12 months; and every 12 weeks (± 28 days) thereafter until disease progression, death, or another stopping criterion is met. From cycle 3 onwards, investigator assessment of disease per RECIST 1.1 should be performed at the start of odd-numbered cycles (± 7 days) for 12 months, and every 12 weeks (± 28 days) thereafter until disease progression, death, or another stopping criterion is met. It is also acknowledged that disease progression may require further evaluation for possible pseudoprogression in certain circumstances.

[0131] PK of BT7480 will be assessed using serial blood and urine samples taken at pre-specified time points. Tumor concentrations, when available, will also be analyzed in a similar manner. Pharmacodynamic response to treatment will be assessed by biomarker analysis (e.g., CD137 target engagement (circulating mechanistic protein and flow cytometry-based receptor occupancy), exploratory transcriptomic and proteomic immune profiling in blood and tumor (inflammatory cytokines, neutralizing antibodies, flow cytometric immunophenotyping, multiplex immunofluorescence, RNA immune profiling)). A single blood sample for germline genomics will be taken pre-dose on day 1 of cycle 1, and blood samples for ctDNA PGx will be taken at pre-specified time points.

[0132] The trial duration will be approximately 36 months, with approximately 24 months of dose escalation and approximately 12 months of dose expansion.

[0133] Patients who meet the inclusion criteria during the screening period (weeks -4 to 0) will be enrolled in the study.

[0134] Phase 1 dose escalation – BT7480 monotherapy

[0135] The starting dose of BT7480 monotherapy dose escalation cohorts is planned to be 0.002 mg / kg. Patients will be assigned to sequentially increasing doses of BT7480 (see Table 1). The dose of BT7480 will be escalated in subsequent cohorts after patients enrolled in each cohort have completed both the planned dose and the dose-limiting toxicity (DLT) period (28 days after first dose). Patients who do not receive the planned dose within the DLT period but experience a DLT will be considered DLT-evaluable. Monitoring for hepatic dysfunction will continue for the entire duration of patients' participation in the study.

[0136] Patients with nonmeasurable disease may be enrolled in cohorts 1-3, and only patients with measurable disease will be enrolled in cohorts 4-13. At least one evaluable patient will be enrolled in each of the first four cohorts, unless a subject in one of the first four cohorts experiences a grade 2 or higher adverse event that may be related to the study drug. If such an event occurs, the next subsequent cohort will contain at least three evaluable patients; if a subject experiences a DLT, it will need to be further expanded by adding three subjects. If a subject experiences grade 3 or higher toxicity in any of the single patient expansion cohorts, the current cohort will be expanded to at least three patients. [Table 1]

[0137] Subsequent dose escalation cohorts (cohort 5 onwards, or prior cohorts if a 3 patient expansion occurs in that cohort) will enroll patients based on a 3+3 design with 3 patients initially enrolled and treated at each dose level. The 3+3 design, and the plan of action in case of DLT, are shown in Table 2. In all 3+3 cohorts, there will be at least 48 hours between a patient's first dose and any subsequent patient doses. Treatment cycles will be sequential according to the schedule of assessments (SOA) in Table S1. [Table 2]

[0138] In a 3+3 design, if one patient experiences a DLT, three more patients are treated at the same dose. Evaluation of a cohort of at least three patients who complete the DLT period (28 days after first dose) is required before proceeding to the next dose level. If two or more patients out of up to six at a dose level experience a DLT, the maximum tolerated dose (MTD) is exceeded. If two or more patients out of up to six at a dose level experience a DLT and only three patients were evaluated at the previous (next lower) dose, three more patients are evaluated at the previous (next lower) dose; if zero or one patient has a DLT, the Safety Review Committee (SRC) will consider enrolling patients at intermediate dose levels, identified in Table 1, that are lower than the later dose levels. If there are no DLTs during escalation of the intermediate dose levels, the SRC will meet to determine the MTD.

[0139] The MTD is defined according to the above guidelines, but if further data become available after the SRC decision that may change the attribution of causality or severity of a given event (e.g., based on the subsequent evolution of the event, follow-up investigations or follow-up observations), the SRC may decide to resume dose escalation and the previous MTD may be revoked. The RP2D will be determined by the SRC based on the available safety, PK and pharmacodynamic data, including efficacy data, not exceeding the MTD.

[0140] The DLT observation period is designed to primarily evaluate acute events. Long-term and possibly immune-related AEs requiring special attention to liver function that may arise over several cycles of treatment will be considered in the evaluations performed during each SRC meeting.

[0141] After completion of the DLT period for each cohort, the SRC will review the available safety, PK, and pharmacodynamic data, including efficacy data, to determine the potential for dose escalation and the recommended dose level for the next cohort. The data must meet minimum criteria (specified in the SRC Charter) that are sufficient to satisfy the SRC for continued administration.

[0142] Intra-patient Dose Escalation: At the discretion of the Medical Monitor and Investigator, patients in the previous lower dose cohort may receive a higher dose that is one dose level below the highest dose level deemed safe by a formal dose escalation decision by the SRC. For example, if a patient tolerates 0.006 mg / kg and 0.05 mg / kg is deemed safe, the patient may be escalated to a dose of 0.02 mg / kg. The clinical experience of patients in the higher dose cohorts will be considered as part of the overall data by the SRC but will not contribute to any formal dose escalation decisions that may have been made.

[0143] Optional Backfill Cohorts: During dose escalation, selected dose levels may be further expanded (also known as backfill) to include up to 10 patients per given dose level to further evaluate the tolerability, PK, pharmacodynamics, and biological activity of BT7480. To ensure that patients are not unnecessarily enrolled at sub-therapeutic levels, these dose level expansions will only be initiated if evidence of therapeutic exposure, target engagement, or investigator-assessed response indicates that dose levels already declared safe by the SRC are not sufficient to support treatment.

[0144] Subsequent dose levels above this will also be eligible for expanded enrollment once declared safe by the SRC. If slots are simultaneously available in both the optional backfill cohort and the dose escalation cohort, priority will be given to enrollment in the dose escalation cohort.

[0145] Patients who discontinue or terminate treatment before study completion for reasons other than DLT and do not meet the minimum requirements for inclusion in the population in which the MTD is determined will be replaced as necessary to ensure adequate safety evaluation of each cohort.

[0146] Phase 1 dose confirmation - optional BT7480 monotherapy renal impairment cohort

[0147] After the SRC determines the dose of BT7480 monotherapy, two cohorts of six patients each with moderate renal insufficiency (CLcr >30-59 mL / min by MDRD formula or local equivalent) will be enrolled at a dose based on the overall PK, pharmacodynamics, safety and efficacy in patients with normal renal function and mild renal impairment (creatinine clearance ≥60 mL / min). If there are sufficient concerns regarding the therapeutic index during dose escalation, the SRC will prescribe a lower dose for the renal cohort. Six patients with CLcr 50-59 mL / min will be enrolled first, followed by six patients with CLcr >30-49 mL / min. Treatment cycles will be sequential as shown in Table S2.

[0148] If 2 or more patients in a renal impairment cohort with 6 or fewer patients experience a DLT during the DLT period (28 days after first dose), the MTD has been exceeded and enrollment will be halted pending review by the SRC. The SRC will review available safety, PK, and pharmacodynamic data, including efficacy data, to determine whether additional cohorts / patients are needed. Patients who discontinue or terminate treatment prior to study completion for reasons other than a DLT and do not meet the minimum requirements for inclusion in the population that determines the MTD will be replaced as necessary to ensure adequate safety evaluation of each cohort.

[0149] Phase 1 Dose Escalation – Optional Combination Treatments

[0150] After the SRC determines the dose of BT7480 monotherapy, dose escalation of the combination treatment (BT7480 + nivolumab) can be started. The starting dose of BT7480 in the combination treatment is one dose level lower than the BT7480 monotherapy RP2D. See Table 3. Patients will be enrolled based on a 3+3 design, with three patients initially enrolled and treated at each dose level. Treatment cycles will be sequential as shown in Table S3. [Table 3]

[0151] If one of these three patients experiences a DLT during the DLT period (28 days after first dose), the dose level will be expanded to six patients. The BT7480 dose will be increased in subsequent cohorts after patients enrolled in each cohort have completed the planned dose of BT7480 and nivolumab and the DLT period. Patients who do not receive the planned dose within the DLT period but experience a DLT will be considered evaluable for DLT.

[0152] If 2 or more patients experience a DLT in any cohort of 6 or fewer patients, the MSD is exceeded. After each cohort, the SRC will review the available safety, PK, and pharmacodynamic data, including efficacy data, to determine if additional cohorts / patients are required. Dose levels will not exceed the BT7480 monotherapy RP2D.

[0153] If a patient has an intercurrent event that is not considered related to BT7480, the patient may be considered evaluable for SRC consideration. If a patient has an event that is not a DLT but is related to BT7480 and is considered clinically significant by the SRC, the event will be evaluated for dose escalation decisions.

[0154] Patients who discontinue or terminate treatment before study completion for reasons other than DLT and do not meet the minimum requirements for inclusion in the population in which the MTD is determined will be replaced as necessary to ensure adequate safety evaluation of each cohort.

[0155] Phase 1 dose expansion – monotherapy and optional combination therapy

[0156] After determining the RP2D for either monotherapy (BT7480) or combination therapy (BT7480 + nivolumab), the study will be expanded and up to 20 patients in two cohorts will be exposed to the doses selected for monotherapy and combination therapy. Treatment cycles will be performed as shown in Table S1 for monotherapy and Table S3 for combination therapy.

[0157] Phase 2 Efficacy Evaluation - Monotherapy and Optional Combination Therapies

[0158] Based on clinical activity observed in Phase 1 dose escalation and dose expansion, up to two cohorts of patients may be enrolled in two tumor-defined cohorts during the Phase 2 study. BT7480 will be administered at the RP2D determined from the Phase 1 monotherapy or combination treatment cohorts. Treatment cycles will be performed as shown in Table S1 for monotherapy and Table S3 for combination treatment.

[0159] Dose-limiting toxicity Toxicity will be assessed using NCI CTCAE version 5.0 unless otherwise specified. Toxicity will be considered "dose limiting" if it meets the definition of DLT, occurs during the DLT period (28 days after first dose), and is related to BT7480. Note that these criteria apply when the first dose or combination is administered. The SRC will also consider if supportive care medications are administered thereafter. Continuing measurements of relevant parameters, including ALT, AST, total bilirubin, and alkaline phosphatase (ALP), will be performed beyond the DLT period and will be examined periodically by the SRC and individual investigators, noting history of CD137 agonist targeted medications.

[0160] In the combination cohort, toxicities known to be related to nivolumab will not necessarily be considered DLTs unless they are unusual or markedly increased in severity or duration as determined by the investigator. Patients in the combination cohort with toxicities known to be directly related to nivolumab and causing discontinuation of nivolumab treatment may receive single-agent BT7480 at the investigator's discretion and continue on the study. Patients in the combination cohort with toxicities suspected or known to be directly related to BT7480 may also discontinue nivolumab and continue on the study for safety follow-up at the investigator's discretion.

[0161] The DLT definition includes: 1. Hematological AEs: Grade 4 or greater neutropenia lasting for more than 5 days; b. Febrile neutropenia (ANC <1000 cells / mm 3 defined as a single temperature of 38.3°C (101°F) or a sustained temperature of 38°C (100.4°F) for more than one hour); c. Grade 4 or greater thrombocytopenia; d. Grade 3 thrombocytopenia accompanied by clinically significant bleeding; or e. Grade 3 or greater anemia not explained by underlying disease or pre-existing renal impairment (renal impairment cohort). 2. Non-hematological AEs: a. Grade 3 or greater fatigue lasting for 5 days or more; b. Any Grade ≥ 3 non-hematologic AE of any clinically significant duration occurring from the start of infusion on Day 1 of Cycle 1 through the end of the DLT period (excluding Grade ≥ 3 nausea, vomiting, or diarrhea that responded to supportive care and lasted ≤ 72 hours); c. Grade 3 or higher hypertension; d. Any relevant AE that leads to the inability to deliver at least 75% of the planned total dose during the DLT period, excluding circumstances other than toxicity (e.g., participant non-adherence, significant contribution of underlying disease states, or logistical issues with drug delivery); or e. Elevations in aminotransferases and total bilirubin meeting the criteria for drug-induced liver injury (Hy's Law), i.e., the co-occurrence of the following: ·ALT or AST >3×ULN (or >3×baseline for patients with liver metastases); · Total bilirubin >2×ULN (or >2×baseline for patients with liver metastases); ALP <2 × ULN; and No other reason could be identified to explain the combination of increases in aminotransferases and serum total bilirubin, such as viral hepatitis, alcohol abuse, ischemia, preexisting liver disease, or another drug capable of causing the observed injury.

[0162] Events that are not automatically considered DLT include: · Grade 3 or less nausea, vomiting, or diarrhea lasting 72 hours or less; Grade 3 or greater electrolyte abnormalities that persist for 72 hours or less, are clinically uncomplicated, and resolve spontaneously or respond to conventional medical intervention; amylase or lipase grade 3 or higher without clinical signs of pancreatitis; and AEs clearly related to the disease, pre-existing conditions, nivolumab or environmental factors.

[0163] Patients who discontinue treatment early due to disease progression or treatment discontinuation will be asked to complete all end-of-treatment safety assessments. Patients who discontinue, or who terminate treatment before study completion for reasons other than DLT and do not meet the minimum requirements for inclusion in the population defining the MTD, will be replaced as necessary to ensure adequate safety assessment of each dose escalation and optional renal impairment cohort.

[0164] Dosage form and route of administration BT7480 BT7480 is provided in 4R injection vials containing 66 mg of BT7480 per vial. The formulation is reconstituted with 1 mL of water for injection (total reconstituted volume is 1.1 mL) to obtain a target concentration of 60 mg / mL BT7480 and is diluted into a 0.9% saline infusion bag prior to intravenous administration (infusion).

[0165] Dose will be calculated based on dose cohort assignment and patient weight (kg). No dose readjustments will be performed during a cycle unless body weight changes by ≥10% from day 1 of the cycle.

[0166] If manageable infusion-related reactions are observed, premedication (e.g., diphenhydramine, acetaminophen) is recommended for subsequent doses, if necessary. Steroids should be avoided as premedication / prophylaxis.

[0167] BT7480 will be administered QW as an intravenous infusion over 60 (-5 / +15) minutes (i.e., allowing an infusion time of 55 to 75 minutes).

[0168] Nivolumab Nivolumab is available in vials of 40 mg / 4 mL, 100 mg / 10 mL, and 240 mg / 24 mL. The dose administered during the study will be 240 mg Q2W.

[0169] Nivolumab should be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration ranging from 1 mg / mL to 10 mg / mL. The total volume of the infusion should not exceed 160 mL.

[0170] Premedication for nivolumab should follow local standard of care (e.g., acetaminophen, diphenhydramine). Steroids should be avoided as premedication / prophylaxis.

[0171] Nivolumab 240 mg will be administered as an intravenous infusion over 30 (-5 / +15) minutes QW as part of the combination treatment. The total duration of nivolumab administration will be based on the patient's response to treatment and the investigator's discretion.

[0172] On days of concomitant nivolumab administration, BT7480 should be administered first, followed by observation for at least 1 hour, and then nivolumab should be administered as an intravenous infusion after appropriate flushing of the first line or via a separate line.

[0173] Evaluation items Primary endpoint Phase 1 Incidence and severity of treatment-related adverse events (TEAEs), potentially including abnormalities in clinical laboratory results, ECG findings, and vital signs, using NCI CTCAE version 5.0.

[0174] Phase 2 Overall response rate (ORR), defined as complete response (CR) and partial response (PR) by RECIST 1.1 based on investigator assessment; and Clinical benefit rate (CBR), defined as the proportion of patients with CR, PR or stable disease (SD) for ≥8 weeks per RECIST 1.1 based on investigator assessment.

[0175] Secondary endpoints Phase 1 ORR by RECIST 1.1 based on investigator assessment; and CBR, defined as the proportion of patients with CR, PR or SD for ≥8 weeks by RECIST 1.1 based on investigator assessment.

[0176] Phase 2 Incidence and severity of TEAEs, including laboratory test results, ECG findings, and vital sign abnormalities, using NCI CTCAE version 5.0.

[0177] Phase 1 and 2 · Duration of response (DoR), defined as the time between first response to treatment (CR or PR) and subsequent disease progression according to RECIST 1.1; -6-month and overall progression-free survival, time to progression, duration of response, overall survival at 12 months and time to response in patients treated with BT7480 as monotherapy or in combination with nivolumab; ·PK parameters of BT7480 in patients with normal and reduced renal function treated with BT7480 as monotherapy or in combination with nivolumab; The incidence of ADAs in patients treated with BT7480 as monotherapy or in combination with nivolumab; and · Determination of CD137 target engagement in peripheral blood of patients treated with BT7480, either as monotherapy or in combination with nivolumab.

[0178] Exploratory endpoints Phase 1 and 2 ·Evaluation of potential changes in immune cell activation in blood and tumors of patients treated with BT7480 (transcriptomic and proteomic profiling); ·Evaluation of potential changes in spatial proteomic profiles between immune and tumor cells in patients treated with BT7480; ·Evaluation of potential changes from baseline in soluble targets and inflammatory cytokines in plasma of patients treated with BT7480; Assessment of biomarkers from baseline tumor and peripheral blood samples (including but not limited to Nectin-4, CD137, and programmed cell death protein 1 / PD-L1); Assessment of germline PGx in patients treated with BT7480; and Quantification of ctDNA in patients treated with BT7480.

[0179] Pharmacokinetic evaluation PK characterization of BT7480 as monotherapy and in combination with nivolumab will be performed with validated bioanalytical methods and will include calculation of the following parameters using non-compartmental analysis: ·Maximum plasma concentration (C max ); C max Time to; · Terminal half-life; · area under the plasma concentration-time curve from time 0 to time t; · Area under the plasma concentration-time curve from time 0 to infinity; · Apparent total body clearance of the drug from plasma; Apparent volume of distribution. When available, urinary concentrations of BT7480 will be used to calculate the following PK parameters: · the cumulative amount of BT7480 excreted in urine; Renal clearance; and -Proportion of a dose excreted by the kidney.

[0180] Correlation Test: Patients must submit fresh or archived tumor tissue at baseline for histological or cytological confirmation, assessment of Nectin-4 expression levels, and further molecular or genetic specific evaluation including, but not limited to, markers of immune status (e.g., programmed death-ligand 1 (PD-L1) expression and immune cell infiltration), proliferation (e.g., Ki-67) and / or immunogenic cell death.

[0181] Paired (pre- and intra-treatment) tumor biopsies may be taken to investigate the intratumoral PK and pharmacodynamic effects of BT7480.

[0182] Pre- and post-dose blood samples will be collected to assess pharmacodynamic response, biomarkers associated with BT7480 response and treatment resistance biomarkers.

[0183] Statistical analysis: The following analysis populations will be defined: Analysis populations will be defined separately for each study phase.

[0184] The full analysis set included all enrolled patients.

[0185] The safety analysis set included all patients who received at least one dose of BT7480.

[0186] The response-evaluable analysis set included all patients who received at least one dose of BT7480 and were evaluable for at least one post-baseline RECIST 1.1 assessment.

[0187] The PK analysis set included all patients who received at least one dose of BT7480 and had at least three post-dose plasma concentrations available.

[0188] Other analysis sets may be defined as necessary and will be described in the statistical analysis plan, if applicable.

[0189] No formal hypothesis testing is planned and summaries will generally be descriptive. Appropriate summaries will be provided for each assessment based on the type of data (continuous or categorical).

[0190] Unless otherwise stated, analyses are generally presented separately by study phase and BT7480 dose level (Phase 1) and cohort (Phase 2). Where appropriate for Phase 1 summaries, renal impairment cohort patients and patients treated with concomitant therapy may be presented separately, depending on the analysis.

[0191] In phase 2, the primary efficacy analysis will present point estimates of ORR and CBR with associated 95% exact confidence intervals for the safety analysis set. To be included in the calculation of ORR, a response had to be confirmed by the next RECIST 1.1 assessment. If a patient had a SD (or better) response before 8 weeks and no subsequent assessments, the patient was considered a failure for the calculation of CBR. If the safety analysis set and the response-evaluable analysis set are different, a sensitivity analysis may be performed using the response-evaluable analysis set.

[0192] For secondary efficacy analyses, time-to-event endpoints (progression-free survival, time to progression, duration of response, overall survival, and time to response) will be summarized using the Kaplan-Meier method. Further details regarding censoring rules are described in the statistical analysis plan. Levels of CD137 target engagement in peripheral blood will be summarized descriptively.

[0193] Safety analyses will be performed using the safety analysis set. Safety assessments will be summarized narratively for continuous variables as actual values ​​and changes from baseline. TEAEs, serious AEs and DLTs will be summarized by system organ class and preferred term. Further summaries of AEs by severity, seriousness and relationship to study drug will be presented. The incidence of ADAs will also be summarized. Further details will be provided in the statistical analysis plan.

[0194] BT7480 PK parameters will be calculated using standard non-compartmental analytical methods and summarized using descriptive statistics. PK concentration data will be summarized using descriptive statistics. Plasma BT7480 concentrations will be plotted against time points (linear and semi-log). Further details are provided in the statistical analysis plan.

[0195] No formal interim analyses are planned in Phase 2.

[0196] Available safety, PK and pharmacodynamic data, including efficacy data, are reviewed on an ongoing basis by the SRC.

[0197] Determining sample size The entire study will enroll approximately 200 patients in total.

[0198] Phase 1 In Phase 1, the total number of patients enrolled will be approximately 110 (including optional cohorts). Sample size will be determined based on observational data and determination of RP2D. Approximately 40 patients are planned to be enrolled in the monotherapy dose escalation cohort. Approximately 12 patients with moderate renal impairment may be enrolled for dose confirmation at a dose based on the overall PK, pharmacodynamics, safety and efficacy in patients with normal renal function and mild renal impairment (creatinine clearance 60 mL / min or greater). After determination of the monotherapy RP2D, approximately 12 patients may be enrolled in the combination therapy dose escalation cohort.

[0199] Upon determination of the RP2D for the monotherapy and combination therapy, approximately 20 additional evaluable patients may be enrolled in each dose expansion cohort for the monotherapy and combination therapy. Patients who do not have at least one post-baseline RECIST 1.1 assessment may be transferred to the dose expansion cohort.

[0200] The 12 patients envisaged in the moderate renal impairment cohort would be sufficient to demonstrate an overall effect on the kidney, such as a more than doubling of the area under the curve in patients with renal impairment. As this is an FIH study, the degree of interindividual variability is currently unknown and therefore a formal sample size calculation cannot be performed.

[0201] In some conditions, such as bladder cancer, as many as 50% of patients may have some degree of renal impairment. This cohort will allow for the inclusion of such patients in early-phase oncology trials while also providing an early estimate of the impact of renal impairment on an agent that is expected to undergo significant renal filtration.

[0202] Phase 2 After dose expansion, the protocol may proceed to include an additional 45 evaluable patients in each cohort in Phase 2. The total number of patients planned to be enrolled in Phase 2 is approximately 90 (including optional cohorts).

[0203] Clinical test analysis items [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0204] [Table 12] NOTE: For steps marked with [X], see Table S4 for sample collection schedule. a. Home visits may be offered to select sites that cannot accommodate collection of chronic PK and pharmacodynamic samples (see Table S4). b. DLT period applies to dose escalation cohorts only. c. An EOT visit must be performed when a patient permanently discontinues BT7480, preferably before starting a new cancer treatment. This visit must occur within 1 week (± 2 days) and 14 days after administration of BT7480 and before the safety FU visit. If a patient terminates without having PD, an investigator's disease assessment according to RECIST 1.1 must be performed unless it has been performed within the past 4 weeks. d. A safety FU visit must occur 30 (± 5) days after the last dose of BT7480. e. Safety After the FU visit, further FU visits will occur every 8 weeks (± 7 days) for the first 12 months, then every 12 weeks (± 28 days) until disease progression, death, or another treatment discontinuation criterion is met. After disease progression, patients will be followed every 12 weeks (± 28 days) for survival until death or up to one year after the last case. Patients may be contacted in clinic or by telephone. g. Visit windows may be extended (see footnotes aa and bb). h. On C1D1, complete all procedures and laboratory tests prior to BT7480 infusion. If screening and laboratory tests are performed within 72 hours (or Day 14 for PK and biomarker sample collection; see Table 4) prior to initiation of the first dose of BT7480, there is no need to repeat screening and laboratory tests on C1D1, with the exception of ECOG performance status, brief physical exam, vital signs, and triplicate repeat 12-lead ECG. i. BT7480 will be administered as an intravenous infusion over 60(-5 / +15) minutes (i.e., an infusion time of 55-75 minutes is permitted) once weekly (or as specified in the SRC). During C1, patients must be assessed for infusion site reactions, including vital signs, within 30 minutes prior to starting, during the infusion (minimum every 30(±10) minutes), at EOI (-5 minutes), and 30 and 60(±10) minutes after the EOI. j. A complete physical examination will include evaluation of the head, ears, nose, throat, cardiovascular system, respiratory system, gastrointestinal system, neurological system, dermatological system, musculoskeletal system, and genitourinary system, if applicable. k. Abbreviated physical examination will include symptom-based examination at the discretion of the investigator. If a screening evaluation was performed within 72 hours prior to initiating C1D1's first dose of BT7480, an abbreviated physical examination (not a full physical examination) will be performed on C1D1. l. Recalculate BT7480 dose for patients who experience a change in body weight of 10% or more. Height will be measured only at Screening and will be used to calculate BMI. m. After the patient has rested in a sitting position for at least 5 minutes, assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature). n. A 12-lead ECG (for safety monitoring) is obtained and evaluated locally before any other procedures and after the patient has rested for at least 3 minutes. Screening, C1D1, and C1D15 tracings are also repeated in triplicate by a central ECG vendor and stored for possible future analysis (Phase 1 dose escalation cohorts only). During cycle 1, ECGs are performed simultaneously with plasma PK sample collection at pre-dose, EOI, and 60 minutes after EOI on D1 and D15. During cycles 2 and beyond, ECGs are performed simultaneously with plasma PK sample collection at pre-dose and EOI on D1. When repeated three times, each recording is separated by approximately 1 minute, and the three ECGs are collected over a 5-minute period. A safety ECG must be performed regardless of whether triplicate ECGs are collected. o. Prior medications will be registered at screening only. Concomitant medications may be administered if medically indicated. Any medications taken by the patient during the study from informed consent until the Safety FU visit will be considered a concomitant medication. All concomitant medications must be recorded on the patient's CRF with the reason for use, date of administration, and amount. p. All AEs, regardless of causality or severity, will be recorded from informed consent through 30 (± 5) days after the last dose of BT7480. Investigators must continue to follow patients until ongoing study drug-related AEs have resolved / stabilized or the condition has become chronic in nature. q. After C4, schedule CBC with differentials on D1 and D15 only. r. Check C1D1 chemistry results before administration. After C4, schedule chemistry only on D1 and D15. s. Complete urinalysis will be performed at Screening, Visit C1, and EOT; may be substituted with dipstick testing with reflex sedimentation at all other visits. t. Pregnancy testing for WOCBP will be performed only at screening (serum), at the start of each treatment cycle beginning with C1 (urine for C1, urine or serum for subsequent cycles), and at safety FU (urine or serum). u. Viral testing and serological markers. v. See Table S4 for details on hourly PK blood sample collection and PK urine sample collection. When a planned dose of BT7480 is withheld due to an AE and administered on a later date in the week, a pre-treatment PK sample should be collected on the actual day of administration and labeled as “unplanned.” w. See Table S4 for details of sample collection for biomarkers planned in this study. x. Provision of baseline tumor tissue (10-15 unstained FFPE slides) is mandatory. Tumor Nectin-4 expression will be analyzed retrospectively for all patients using archived tumor tissue or fresh tumor biopsies taken during screening. Archived tumor tissue should be provided as tissue blocks or 10-15 FFPE unstained slides. y. During Phase 1 monotherapy (dose escalation (cohort 3 onwards) and expansion), patients may provide optional paired (pre-treatment and on-treatment) tumor biopsies. If the patient consents to an optional paired tumor biopsy, both a pre-treatment baseline tumor biopsy and archived tumor tissue will be requested. On-treatment biopsy sample collection is permitted at any time after C1D1 and also at the time of recurrence, if applicable and feasible. During tumor biopsy collection, collect sufficient cores (≥3) to provide material for one frozen PK sample and FFPE blocks (at least 10-15 slides). When collection of tumor tissue using core needle biopsy is not possible, fine needle aspirate samples are acceptable if sufficient sample numbers (≥5) are collected. z. For patients with accessible tumor lesions who are amenable to biopsy and who consent to further biopsies, perform on-treatment tumor biopsies and normal skin biopsies. aa. CT or MRI scans or manual measurements of visual lesions or other types of imaging for disease assessment by the investigator per RECIST 1.1 will be performed at screening; every 8 weeks (± 7 days) for the first 12 months, then every 12 weeks (± 28 days) until disease progression, death, or another discontinuation criterion for response is met. bb. From C3 onwards, investigator disease assessments per RECIST 1.1 will be performed at the start of every odd-numbered cycle (± 7 days) for 12 months, then every 12 weeks (± 28 days) until disease progression, death, or another discontinuation criterion for response is met. AE=adverse event;BMI=body mass index;C=cycle;CBC=complete blood count;CT=computed tomography;D=days in cycle;DLT=dose-limiting toxicity;ECG=electrocardiogram;ECOG=Eastern Cooperative Oncology Group;eCRF=electronic case report form;EOI=end of infusion;EOT=end of treatment;FFPE=formalin-fixed paraffin embedded;FSH=follicle-stimulating hormone;FU=follow-up;h=hours;min=minutes;MRI=magnetic resonance imaging;OS=overall survival;PD=progressive disease;PFS=progression-free survival;PK=pharmacokinetics;RECIST=Response Evaluation Criteria in Solid Tumors;screen=screening;SRC=committee on safety and efficacy;WOCBP=women of childbearing potential.

[0205] [Table 13] NOTE: For steps marked with [X], see Table S4 for sample collection schedule. a. Home visits may be offered to select sites that cannot accommodate collection of chronic PK and pharmacodynamic samples (see Table S4). b. An EOT visit must be performed when a patient permanently discontinues BT7480, preferably before starting a new cancer treatment. This visit must occur within 1 week (± 2 days) and 14 days after administration of BT7480 and before the safety FU visit. If a patient terminates without having PD, an investigator's disease assessment according to RECIST 1.1 must be performed unless it has been performed within the past 4 weeks. c. A safety FU visit must occur 30 (± 5) days after the last dose of BT7480. d. Safety After the FU visit, further FU visits will occur every 8 weeks (± 7 days) for the first 12 months, then every 12 weeks (± 28 days) until disease progression, death, or another treatment discontinuation criterion is met. After disease progression, patients will be followed every 12 weeks (± 28 days) for survival until death or up to one year after the last case. Patients may be contacted in clinic or by telephone. f. Visit windows may be extended (see footnotes z and aa). g. On C1D1, complete all procedures and laboratory tests prior to BT7480 infusion. If screening and laboratory tests are performed within 72 hours prior to initiation of the first dose of BT7480 (or on Day 14 for PK and biomarker sample collection; see Table 4), screening and laboratory tests do not need to be repeated on C1D1, with the exception of ECOG performance status, brief physical exam, vital signs, and 12-lead ECG. h. BT7480 is administered as an intravenous infusion over 60(-5 / +15) minutes (i.e., an infusion time of 55-75 minutes is permitted) once weekly. During C1, patients must be assessed for infusion site reactions, including vital signs, within 30 minutes prior to initiation, during the infusion (minimum every 30(±10) minutes), at EOI (-5 minutes), and 30 and 60(±10) minutes after EOI. i. A complete physical examination will include evaluation of the head, ears, nose, throat, cardiovascular system, respiratory system, gastrointestinal system, neurological system, dermatological system, musculoskeletal system, and genitourinary system, if applicable. j. An abbreviated physical examination will include symptom-based examination at the discretion of the investigator. If a screening evaluation was performed within 72 hours prior to initiating C1D1's first dose of BT7480, an abbreviated physical examination (not a full physical examination) will be performed on C1D1. k. Recalculate BT7480 dose for patients who experience a change in body weight of 10% or more. Height will be measured only at Screening and will be used to calculate BMI. l. After the patient has rested in a sitting position for at least 5 minutes, assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature). m. Obtain and locally evaluate a 12-lead ECG (for safety monitoring) before any other procedures and after the patient has rested for at least 3 minutes. During Cycle 1, ECGs will be performed simultaneously with plasma PK sample collection pre-dose, EOI, and 60 minutes post-EOI on D1 and D15. During Cycles 2 and beyond, ECGs will be performed simultaneously with plasma PK sample collection pre-dose and EOI on D1. n. Prior medications are registered at screening only. Concomitant medications may be administered if medically indicated. Any medications taken by the patient during the study from informed consent until the Safety FU visit will be considered a concomitant medication. All concomitant medications must be recorded on the patient's CRF with the reason for use, date of administration, and amount. All AEs, regardless of causality or severity, will be recorded from informed consent through 30 (± 5) days after the last dose of BT7480. Investigators must continue to follow patients until ongoing study drug-related AEs have resolved / stabilized or the condition has become chronic in nature. p. After C4, schedule CBC with differentials on D1 and D15 only. q. Check C1D1 chemistry results before administering. After C4, schedule chemistry only on D1 and D15. r. Complete urinalysis is performed at Screening, C1 visit, and EOT; may be substituted with reflex sedimentation dipstick testing at all other visits. s. Pregnancy testing for WOCBP will be performed only at screening (serum), at the start of each treatment cycle beginning with C1 (urine for C1, urine or serum for subsequent cycles), and at safety FU (urine or serum). t. Viral testing and serological markers. u. See Table S4 for details on hourly PK blood sample collection and PK urine sample collection. When a planned BT7480 dose is withheld due to an AE and administered on a later date in the week, a pre-treatment PK sample should be collected on the day of actual administration and labeled as “unplanned.” v. See Table S4 for details of sample collection for biomarkers planned in this study. w. Provision of baseline tumor tissue (10-15 unstained FFPE slides) is mandatory. Tumor Nectin-4 expression will be analyzed retrospectively for all patients using archived tumor tissue or fresh tumor biopsies taken during screening. Archived tumor tissue should be provided as tissue blocks or 10-15 FFPE unstained slides. x. Patients in the renal impairment cohort may provide an optional paired (pre- and on-treatment) tumor biopsy. If the patient consents to an optional paired tumor biopsy, both a pre-treatment baseline tumor biopsy and archived tumor tissue will be requested. On-treatment biopsy sample collection is permitted at any time after C1D1 and at the time of recurrence, if applicable and feasible. During tumor biopsy collection, collect sufficient cores (≥3) to provide material for one frozen PK sample and an FFPE block (at least 10-15 slides). When collection of tumor tissue using core needle biopsy is not possible, fine needle aspirate samples are acceptable if sufficient sample numbers (≥5) are collected. y. For patients with accessible tumor lesions who are amenable to biopsy and who consent to further biopsies, perform on-treatment tumor biopsies and normal skin biopsies. z. CT or MRI scans or manual measurements of visual lesions or other types of imaging for disease assessment by the investigator per RECIST 1.1 will be performed at screening; every 8 weeks (± 7 days) for the first 12 months; and every 12 weeks (± 28 days) thereafter until disease progression, death, or another discontinuation criterion for response is met. aa. From C3 onwards, investigator disease assessments per RECIST 1.1 will be performed at the start of every odd-numbered cycle (± 7 days) for 12 months, then every 12 weeks (± 28 days) until disease progression, death, or another discontinuation criterion for response is met. AE=adverse event;BMI=body mass index;C=cycle;CBC=complete blood count;CT=computed tomography;D=days in cycle;DLT=dose-limiting toxicity;ECG=electrocardiogram;ECOG=Eastern Cooperative Oncology Group;eCRF=electronic case report form;EOI=end of infusion;EOT=end of treatment;FFPE=formalin-fixed paraffin embedded;FSH=follicle-stimulating hormone;FU=follow-up;h=hours;min=minutes;MRI=magnetic resonance imaging;OS=overall survival;PD=progressive disease;PFS=progression-free survival;PK=pharmacokinetics;RECIST=Response Evaluation Criteria in Solid Tumors;screen=screening;WOCBP=women of childbearing potential.

[0206] [Table 14] NOTE: For steps marked with [X], see Table S4 for sample collection schedule. NOTE: In case of combination treatment, EOI refers to the end of BT7480 infusion. a. Home visits may be offered to select sites that cannot accommodate collection of chronic PK and pharmacodynamic samples (see Table S4). b. DLT period applies to dose escalation cohorts only. c. An EOT visit must be performed when a patient permanently discontinues study drug (BT7480 and / or nivolumab), preferably before starting a new cancer treatment. This visit must occur within 1 week (± 2 days) and 14 days after administration of study drug and before the safety FU visit. If a patient terminates without having PD, an investigator's disease assessment according to RECIST 1.1 must be performed unless it has been performed within the past 4 weeks. d. A safety FU must be performed 125 (± 5) days after the last dose of study drug. e. Safety After the FU visit, further FU visits will occur every 8 weeks (± 7 days) for the first 12 months, then every 12 weeks (± 28 days) until disease progression, death, or another treatment discontinuation criterion is met. After disease progression, patients will be followed every 12 weeks (± 28 days) for survival until death or up to one year after the last case. Patients may be contacted in clinic or by telephone. g. Visit windows may be extended (see footnotes cc and dd). h. On C1D1, complete all procedures and laboratory tests prior to BT7480 infusion. If screening and laboratory tests are performed within 72 hours (or Day 14 for PK and biomarker sample collection; see Table 4) prior to initiation of the first dose of BT7480, there is no need to repeat screening and laboratory tests on C1D1, with the exception of ECOG performance status, brief physical exam, vital signs, and triplicate repeat 12-lead ECG. i. BT7480 will be administered as an intravenous infusion over 60(-5 / +15) minutes (i.e., an infusion time of 55-75 minutes is permitted) once weekly (or as specified in the SRC). During C1, patients must be assessed for infusion site reactions, including vital signs, within 30 minutes prior to starting, during the infusion (minimum every 30(±10) minutes), at EOI (-5 minutes), and 30 and 60(±10) minutes after the EOI. j. On nivolumab coadministration days, administer BT7480 first and observe for at least 1 hour, then administer nivolumab 240 mg as an intravenous infusion (after appropriate flushing of the first line or via a separate line) over 30 (-5 / +15) minutes once every 2 weeks according to USPI, SmPC or other local package insert. After completion of nivolumab infusion, observe patients for AEs and infusion-related reactions for at least 30 minutes or according to local package insert or site practice. The total duration of nivolumab administration will be determined based on the patient's response to treatment and the investigator's judgment. k. A complete physical examination will include evaluation of the head, ears, nose, throat, cardiovascular system, respiratory system, gastrointestinal system, neurological system, dermatological system, musculoskeletal system, and genitourinary system, if applicable. l. An abbreviated physical examination will include symptom-based examination at the discretion of the investigator. If a screening evaluation was performed within 72 hours prior to initiating C1D1's first dose of BT7480, an abbreviated physical examination (not a full physical examination) will be performed on C1D1. m. Recalculate BT7480 dose for patients who experience a change in body weight of 10% or more. Height will be measured only at Screening and will be used to calculate BMI. n. After the patient has rested in a seated position for at least 5 minutes, assess vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature). o. A 12-lead ECG (for safety monitoring) is obtained and evaluated locally before any other procedures and after the patient has rested for at least 3 minutes. Screening, C1D1, and C1D15 tracings are also repeated in triplicate by a central ECG vendor and stored for possible future analysis (Phase 1 dose escalation cohorts only). During cycle 1, ECGs are performed simultaneously with plasma PK sample collection at pre-dose, EOI, and 60 minutes after EOI on D1 and D15. During cycles 2 and beyond, ECGs are performed simultaneously with plasma PK sample collection at pre-dose and EOI on D1. When repeated three times, each recording is separated by approximately 1 minute, and the three ECGs are collected over a 5-minute period. A safety ECG must be performed regardless of whether triplicate ECGs are collected. p. Prior medications are registered at screening only. Concomitant medications may be administered if medically indicated. Any medications taken by the patient during the study from informed consent until the Safety FU visit will be considered a concomitant medication. All concomitant medications must be recorded on the patient's CRF with the reason for use, date of administration, and amount. q. All AEs, regardless of causality or severity, will be recorded from informed consent through 125 (± 5) days after the last dose of nivolumab. Investigators must continue to follow patients until ongoing study drug-related AEs have resolved / stabilized or the condition has become chronic in nature. r. After C4, schedule CBC with differentials only on D1 and D15. s. Check C1D1 chemistry results prior to administration. After C4, schedule chemistry only on D1 and D15. t. For patients receiving nivolumab, blood samples will be collected for assessment of antinuclear antibodies, rheumatoid factor, adrenocorticotropic hormone, free T3, free T4, and TSH at screening, C2D1, and every 6 months thereafter until disease progression, death, or another treatment discontinuation criterion is met. u. Complete urinalysis will be performed at Screening, C1 visit, and EOT; may be substituted with reflex sedimentation dipstick testing at all other visits. v. Pregnancy testing for WOCBP will be performed only at screening (serum), at the start of each treatment cycle starting with C1 (urine for C1, urine or serum for subsequent cycles), and at safety FU (urine or serum). w. Viral testing and serological markers. x. See Table S4 for details on hourly PK blood sample collection and PK urine sample collection. When a planned BT7480 dose is withheld due to an AE and administered on a later date in the week, a pre-treatment PK sample should be collected on the actual day of administration and labeled as “unplanned.” y. See Table S4 for blood sampling chart for biomarkers planned in this study. z. Provision of baseline tumor tissue (10-15 unstained FFPE slides) is mandatory. Tumor Nectin-4 expression will be analyzed retrospectively for all patients using archived tumor tissue or fresh tumor biopsies taken during screening. Archived tumor tissue should be provided as tissue blocks or 10-15 FFPE unstained slides. aa. During Phase 1 combination therapy (dose escalation and expansion), patients may provide optional paired (pre-treatment and on-treatment) tumor biopsies. If the patient consents to an optional paired tumor biopsy, both a pre-treatment baseline tumor biopsy and archived tumor tissue will be requested. On-treatment biopsy sample collection is permitted at any time after C1D1 and at the time of recurrence, if applicable and feasible. During tumor biopsy collection, collect sufficient cores (≥3) to provide material for one frozen PK sample and an FFPE block (at least 10-15 slides). When collection of tumor tissue using core needle biopsy is not possible, fine needle aspirate samples are acceptable if a sufficient number of samples (≥5) are collected. bb. For patients with accessible tumor lesions who are amenable to biopsy and who consent to further biopsies, on-treatment tumor biopsies and normal skin biopsies will be performed. cc. CT or MRI scans or manual measurements of visual lesions or other types of imaging for disease assessment by the investigator per RECIST 1.1 will be performed at screening; every 8 weeks (± 7 days) for the first 12 months; and every 12 weeks (± 28 days) thereafter until disease progression, death, or another discontinuation criterion for response is met. dd. From C3 onwards, investigator disease assessments per RECIST 1.1 will be performed at the start of every odd-numbered cycle (± 7 days) for 12 months, then every 12 weeks (± 28 days) until disease progression, death, or another discontinuation criterion for response is met. AE=adverse event;BMI=body mass index;C=cycle;CBC=complete blood count;CT=computed tomography;D=days in cycle;DLT=dose-limiting toxicity;ECG=electrocardiogram;ECOG=Eastern Cooperative Oncology Group;eCRF=electronic case report form;EOI=end of infusion;EOT=end of treatment;FFPE=formalin-fixed paraffin embedded;FSH=follicle-stimulating hormone;FU=follow-up;h=hours;min=minutes;MRI=magnetic resonance imaging;OS=overall survival;PD=progressive disease;PFS=progression-free survival;PK=pharmacokinetics;RECIST=Response Evaluation Criteria in Solid Tumors;screen=screening;SmPC=summary of product characteristics;SOI=start of infusion;SRC=safety evaluation committee;T3=triiodothyronine;T4=thyroxine;TSH=thyroid-stimulating hormone;USPI=United States Prescribing Information;WOCBP=women of childbearing potential.

[0207] [Table 15] The exact timing of sample collection must be recorded on the appropriate electronic incentive report and request page. b. In the case of combination therapy, EOI refers to the end of BT7480 infusion. c. Immediately prior to the end of the BT7480 infusion, a blood sample for PK analysis will be drawn. d. Home visits may be provided for some facilities that cannot accommodate collection of samples at 48 (± 12), 72 (± 12) and 96 (± 12) hours post EOI on C1D1 and C1D15. e. Collect urine from SOI through 6 hours after EOI and record total excretion. Total excretion is not required at 24, 48, 72, and 96 hours. f. At the PK blood sampling time, one sample will be collected between 24 (± 3) hours and 72 (± 12) hours after the EOI. g. Collect samples only at C2D1. h. In the event of an infusion-related reaction or suspected cytokine release syndrome being observed, a blood sample should be obtained immediately. i. Collect samples only at C1D1. ADA = anti-drug antibody; C = cycle; CD = cluster of differentiation; circ. = circulation; ctDNA = circulating tumor deoxyribonucleic acid; D = days in cycle; EOI = end of infusion; EOT = end of treatment; h = hours; m = minutes; mech. = mechanism; NAb = neutralizing antibody; PGx = pharmacogenomic; PK = pharmacokinetic; RNA = ribonucleic acid; RO = receptor occupancy; scr = screening; SOI = start of infusion.

Claims

1. A compound having the following structure: 【Chemistry 1】 1. A solid pharmaceutical composition comprising BT7480 or a pharmaceutically acceptable salt thereof, Tris base, mannitol and sodium hydroxide.

2. A solid pharmaceutical composition as described in claim 1, comprising (i) about 0.1 mg of Tris base per 1 mg of BT7480 or a pharmaceutically acceptable salt thereof, and / or (ii) about 0.4 mg of mannitol per 1 mg of BT7480 or a pharmaceutically acceptable salt thereof.

3. 10. The solid pharmaceutical composition of claim 1, wherein the amount of sodium hydroxide is an amount that results in a pH of about 7.0 to 7.5 when the solid pharmaceutical composition is reconstituted in water.

4. about 66 mg of BT7480 or a pharmaceutically acceptable salt thereof; Approximately 6.6 mg of Tris base; about 26.4 mg mannitol; and Sodium hydroxide in an amount that results in a pH of about 7.0 to 7.5 when the solid pharmaceutical composition is reconstituted in water.

2. The solid pharmaceutical composition of claim 1, comprising:

5. An aqueous pharmaceutical composition comprising BT7480 or a pharmaceutically acceptable salt thereof, Tris base, mannitol, sodium hydroxide and water. (a) about 60 mg / mL BT7480 or a pharmaceutically acceptable salt thereof; (b) about 6 mg / mL Tris base, and / or (c) approximately 24 mg / mL mannitol 6. The aqueous pharmaceutical composition of claim 5, comprising:

7. 6. The aqueous pharmaceutical composition according to claim 5, wherein the pH of the aqueous pharmaceutical composition is about 7.0 to 7.

5.

8. (a) a volume of about 1.1 mL; (b) The following: about 60 mg / mL BT7480 or a pharmaceutically acceptable salt thereof; Approximately 6 mg / mL Tris base; approximately 24 mg / mL mannitol; sodium hydroxide; and water and the pH of the aqueous pharmaceutical composition is about 7.0 to 7.5; and / or (c) further containing sodium chloride; 6. The aqueous pharmaceutical composition according to claim 5.

9. A solid pharmaceutical composition for treating Nectin-4-associated advanced malignant tumors, as described in any one of claims 1 to 4, which is administered in the form of an aqueous pharmaceutical composition reconstituted in water or dissolved in an injection vehicle.

10. The solid pharmaceutical composition of claim 9, wherein the aqueous pharmaceutical composition is administered intravenously.

11. 10. The solid pharmaceutical composition of claim 9, wherein the Nectin-4-associated advanced malignant tumor is selected from the group consisting of non-small cell lung cancer (NSCLC), ovarian cancer, triple-negative breast cancer (TNBC), gastric / upper gastrointestinal (GI) cancer, pancreatic cancer, urothelial cancer, bladder cancer, head and neck cancer, esophageal cancer, and melanoma.

12. 10. The solid pharmaceutical composition of claim 9, wherein the aqueous pharmaceutical composition is administered once a week or once every two weeks.

13. BT7480 or a pharmaceutically acceptable salt thereof (i) up to about 7.5 mg / kg; (ii) about 0.02-6 mg / kg, about 0.05-6 mg / kg, about 0.15-6 mg / kg, about 0.3-6 mg / kg, about 0.6-6 mg / kg, about 1.3-6 mg / kg, or about 2.6-6 mg / kg; or (iii) about 0.002 mg / kg, about 0.006 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.15 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.3 mg / kg, about 2.0 mg / kg, about 2.6 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg, about 3.9 mg / kg, about 4.25 mg / kg, about 5.0 mg / kg, about 5.75 mg / kg, about 6.0 mg / kg, about 6.5 mg / kg, about 7.0 mg / kg or about 7.5 mg / kg 10. The solid pharmaceutical composition according to claim 9, wherein the solid pharmaceutical composition is administered at a dose of

14. 10. The solid pharmaceutical composition of claim 9, wherein the aqueous pharmaceutical composition is administered by IV infusion over about 60 minutes.

15. The treatment (a) administering nivolumab; (b) administering nivolumab, wherein the nivolumab is administered at a dose level of 240 mg once every two weeks; and / or (c) administering nivolumab, wherein the nivolumab is administered by IV infusion over about 30 minutes.

10. The solid pharmaceutical composition of claim 9, further comprising:

16. The solid pharmaceutical composition of claim 9, wherein BT7480 or a pharmaceutically acceptable salt thereof is administered at (i) a dosage level of 0.002 mg / kg, or (ii) a dosage level of 0.006 mg / kg or less, 0.02 mg / kg or less, 0.05 mg / kg or less, 0.15 mg / kg or less, 0.3 mg / kg or less, 0.6 mg / kg or less, 1.3 mg / kg or less, 2.0 mg / kg or less, 2.6 mg / kg or less, 3.0 mg / kg or less, 3.5 mg / kg or less, 4.25 mg / kg or less, 5.0 mg / kg or less, 5.75 mg / kg or less, 6.5 mg / kg or less, 7.0 mg / kg or less, or 7.5 mg / kg or less.

17. An aqueous pharmaceutical composition described in any one of claims 5 to 8 for treating nectin-4-associated advanced malignant tumors.

18. The aqueous pharmaceutical composition of claim 17, wherein the aqueous pharmaceutical composition is administered intravenously.

19. The aqueous pharmaceutical composition of claim 17, wherein the Nectin-4-associated advanced malignant tumor is selected from the group consisting of non-small cell lung cancer (NSCLC), ovarian cancer, triple-negative breast cancer (TNBC), gastric / upper gastrointestinal (GI) cancer, pancreatic cancer, urothelial cancer, bladder cancer, head and neck cancer, esophageal cancer and melanoma.

20. The aqueous pharmaceutical composition of claim 17, wherein the aqueous pharmaceutical composition is administered once a week or once every two weeks.

21. BT7480 or a pharmaceutically acceptable salt thereof (i) up to about 7.5 mg / kg; (ii) about 0.02-6 mg / kg, about 0.05-6 mg / kg, about 0.15-6 mg / kg, about 0.3-6 mg / kg, about 0.6-6 mg / kg, about 1.3-6 mg / kg, or about 2.6-6 mg / kg; or (iii) about 0.002 mg / kg, about 0.006 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.15 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.3 mg / kg, about 2.0 mg / kg, about 2.6 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg, about 3.9 mg / kg, about 4.25 mg / kg, about 5.0 mg / kg, about 5.75 mg / kg, about 6.0 mg / kg, about 6.5 mg / kg, about 7.0 mg / kg or about 7.5 mg / kg 18. The aqueous pharmaceutical composition of claim 17, wherein the composition is administered at a dose of 22. The aqueous pharmaceutical composition of claim 17, wherein the aqueous pharmaceutical composition is administered by IV infusion over approximately 60 minutes.

23. The treatment (a) administering nivolumab; (b) administering nivolumab, wherein the nivolumab is administered at a dose level of 240 mg once every two weeks; and / or (c) administering nivolumab, wherein the nivolumab is administered by IV infusion over approximately 30 minutes.

18. The aqueous pharmaceutical composition of claim 17, further comprising:

24. The aqueous pharmaceutical composition of claim 17, wherein BT7480 or a pharmaceutically acceptable salt thereof is administered at (i) a dosage level of 0.002 mg / kg, or (ii) a dosage level of 0.006 mg / kg or less, 0.02 mg / kg or less, 0.05 mg / kg or less, 0.15 mg / kg or less, 0.3 mg / kg or less, 0.6 mg / kg or less, 1.3 mg / kg or less, 2.0 mg / kg or less, 2.6 mg / kg or less, 3.0 mg / kg or less, 3.5 mg / kg or less, 4.25 mg / kg or less, 5.0 mg / kg or less, 5.75 mg / kg or less, 6.5 mg / kg or less, 7.0 mg / kg or less, or 7.5 mg / kg or less.

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