Nectin-4 specific bicyclic peptide ligand and its use

Abstract

This invention relates to the bicyclic toxin conjugate BT8009, its pharmaceutically acceptable salts, its pharmaceutical compositions, and the use thereof.

Description

[Technical Field]

[0001] Technical field of inventions The present invention relates to a bicyclic toxin conjugate, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The present invention also relates to the use of a bicyclic toxin conjugate, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the prevention or treatment of diseases, disorders, or conditions characterized by the overexpression of nectin-4 in affected tissues. [Background technology]

[0002] Background of the Invention Cyclic peptides can bind to protein targets with high affinity and target specificity, making them an attractive group of molecules for therapeutic drug development. In fact, several cyclic peptides, such as the antibacterial peptide vancomycin, the immunosuppressant cyclosporine, and the anticancer drug octreotide, have already achieved successful clinical use (Driggers et al. (2008), Nat Rev Drug Discov 7 (7), 608-24). This good binding property stems from the relatively large interaction surface formed between the peptide and the target, and the low structural flexibility of the cyclic structure. Typically, macrocyclic compounds, such as the cyclic peptide CXCR4 antagonist CVX15 (400Å), are examples of such compounds. 2 ; Wu et al. (2007), Science 330, 1066-71), a cyclic peptide having an Arg-Gly-Asp motif that binds to integrin αVb3 (355Å 2 )(Xiong et al. (2002), Science 296 (5565), 151-5) or upain-1 (603Å), a cyclic peptide inhibitor that binds to urokinase-type plasminogen activators. 2 It binds to surfaces of several hundred square angstroms, as described in Zhao et al. (2007), J Struct Biol 160 (1), 1-10).

[0003] Due to their cyclic configuration, macrocyclic peptides are less flexible than linear peptides, resulting in less entropy loss upon binding to the target and higher binding affinity. This lower flexibility also allows them to lock into target-specific structures, 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 through macrocyclization are further enhanced in polycyclic peptides with more than one peptide ring, such as vancomycin, nisin, and actinomycin.

[0004] Previously, various research teams have linked polypeptides containing cysteine ​​residues to synthetic molecular structures (Kemp and McNamara (1985), J. Org. Chem; Timmerman et al. (2005), ChemBioChem). Meloen and collaborators used tris(bromomethyl)benzene and related molecules for the rapid and quantitative cyclization of multiple peptide loops to a synthetic scaffold for structural mimicry of protein surfaces (Timmerman et al. (2005), ChemBioChem). A method for producing candidate drug compounds is described, in which the compounds are produced by linking cysteine-containing polypeptides to a molecular scaffold such as TATA(1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tripprop-2-en-1-one) (Heinis et al. Angew Chem, Int Ed. 2014; 53:1602-1606).

[0005] A phage display-based combinatorial approach has been developed for the production and screening of large libraries of bicyclic peptides to target organisms of interest (Heinis et al. (2009), Nat Chem Biol 5 (7), 502-7 and WO2009 / 098450). Briefly, a combinatorial library of linear peptides (Cys-(Xaa)6-Cys-(Xaa)6-Cys) containing two regions of three cysteine ​​residues and six random amino acids was displayed on a phage and cyclized by covalent bonding of the cysteine ​​side chain to a small molecule scaffold. [Overview of the project]

[0006] Summary of the Invention In one embodiment, the present invention provides a method for treating a human patient, comprising administering to the patient BT8009 or a pharmaceutical composition comprising BT8009. In another embodiment, the present invention provides BT8009 or a pharmaceutical composition comprising BT8009 for use in a method for treating a human patient.

[0007] In another embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering to the patient BT8009 or a pharmaceutical composition comprising BT8009. In another embodiment, the present invention provides BT8009 or a pharmaceutical composition comprising BT8009 for use in a method for treating a solid tumor in a human patient.

[0008] In another embodiment, the present invention provides a solid pharmaceutical composition of BT8009 comprising BT8009 or a pharmaceutically acceptable salt thereof; about 1.31 mg histidine per 1 mg of BT8009 or a pharmaceutically acceptable salt thereof; about 15 mg sucrose per 1 mg of BT8009 or a pharmaceutically acceptable salt thereof; and about 0.025 mg polysorbate 20 per 1 mg of BT8009 or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, the present invention provides a liquid formulation of BT8009 comprising about 4 mg / mL BT8009, or a pharmaceutically acceptable salt thereof; about 5.24 mg / mL L-histidine; about 60 mg / mL sucrose; about 0.1 mg / mL polysorbate 20; and water.

Mode for Carrying Out the Invention

[0010] Detailed Description of Certain Embodiments 1. Compounds and Definitions: As used herein, the term "BT8009" is a bicyclic toxin conjugate having the following structure, wherein the molecular scaffold is 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA), and the peptide ligand is the amino acid sequence: (β-Ala)-Sar 10 -C i P[1Nal][dD]C ii M[HArg]DWSTP[HyP]WC iii (SEQ ID NO: 1) [wherein, Sar is sarcosine, 1Nal represents 1-naphthylalanine, HArg represents homoarginine, HyP represents hydroxyproline, C i , C ii and C iii represent the first, second and third cysteine residues. ] is included.

[0011] The term "pharmaceutically acceptable salt" as used herein means a salt that, within the bounds of sound medical judgment, is free from excessive toxicity, irritation, or allergic reactions, is suitable for use in contact with human and lower animal tissues, and possesses a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19, detail pharmaceutically acceptable salts, which are incorporated herein by reference. pharmaceutically acceptable salts of the compounds of the present invention include those derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically 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 organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydrogen iodide, and 2-hydroxyethansulfate. This includes honate, 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, etc. [ka] [ka]

[0012] Suitable base-derived salts include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 This includes alkyl) tetrasalts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, when appropriate. Salt forms are within the scope of the invention, and it is recognized that the description of a peptide ligand includes the salt forms of said ligand.

[0013] The salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods, such as those 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 a compound in free acid or base form with a suitable base or acid in water, an organic solvent, or a mixture of the two.

[0014] As used herein, the term "approximately" means within 10% of a given value or range. In one embodiment, the term "approximately" means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0015] Unless otherwise specified, the structures described herein also mean all isomeric forms of the structure (e.g., enantiomers, diastereomers, and geometric (or stereostructural) forms); for example, R and S configurations of each chiral center, Z and E double bond isomers, and Z and E stereostructural isomers. Accordingly, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric (or stereostructural) forms, are within the scope of the present invention. Unless otherwise specified, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise specified, the structures described herein also mean that the compounds differ only by one or more isotopically enriched atoms; for example, substitution of hydrogen with deuterium or tritium, or carbon 13 C- or 14 Compounds having this structure and containing 1C-enriched carbon fall within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention.

[0016] 2. Treatment Method The examples and drawings provided herein report the results of the first human clinical trial of the BT8009 bicyclic toxin conjugate.

[0017] The present invention provides a method for treating a human patient, comprising administering to the patient BT8009 or a pharmaceutical composition containing BT8009. The present invention also provides BT8009 or a pharmaceutical composition containing BT8009 for use in a method for treating a human patient. The present invention also provides BT8009 for use in the manufacture of a pharmaceutical for use in a method for treating a human patient.

[0018] The present invention also provides a method for treating a solid tumor in a human patient, comprising administering BT8009 or a pharmaceutical composition comprising BT8009. The present invention also provides BT8009 or a pharmaceutical composition comprising BT8009 for use in a method for treating a solid tumor in a human patient. The present invention also provides BT8009 for use in the manufacture of a pharmaceutical for use in a method for treating a solid tumor in a human patient. In one embodiment, the solid tumor is an advanced malignant tumor. In one embodiment, the solid tumor or advanced malignant tumor is associated with nectin-4 expression.

[0019] In one embodiment, the present invention provides a method for treating adult patients with locally advanced or metastatic urothelial carcinoma who have not received any prior systemic treatment, comprising administering BT8009 in combination with pembrolizumab. The present invention also provides BT8009 in combination with pembrolizumab for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have not received any prior systemic treatment.

[0020] In another embodiment, the present invention provides a method for treating an adult patient receiving one or more prior systemic therapies for locally advanced or metastatic urothelial carcinoma, comprising administering BT8009 monotherapy. The present invention also provides BT8009 monotherapy for adult patients receiving ≥1 prior systemic therapies for locally advanced or metastatic urothelial carcinoma.

[0021] 3. Combination therapy In one embodiment, the treatment method of the present invention comprises administering BT8009 or a pharmaceutical composition containing BT8009 to a human patient, and further administering an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0022] In one embodiment, the anti-PD-1 antibody is selected from the list consisting of pembrolizumab, nivolumab, semiprimab, dostallimab, retifanlimab, voplaterimab, spartalizumab, camrelizumab, cintilimab, tislerizumab, tripalimab, INCMGA00012, AMP-224, AMP-514, and acrixolimab.

[0023] In one embodiment, the anti-PD-L1 antibody is selected from a list consisting of atezolizumab, avelumab, durvalumab, KN035, and cosivelimab.

[0024] In one embodiment, the method of the present invention comprises administering BT8009 or a pharmaceutical composition containing BT8009 to a human patient, and further administering pembrolizumab.

[0025] In one embodiment, the present invention provides a treatment method comprising administering BT8009 or a pharmaceutical composition containing BT8009 to a human patient, and further administering pembrolizumab to the human patient. The present invention also provides BT8009 or a pharmaceutical composition containing BT8009 and pembrolizumab for use in a treatment method for human patients. The present invention also provides BT8009 or a pharmaceutical composition containing BT8009 and pembrolizumab for use in the manufacture of a kit for use in the treatment of human patients.

[0026] In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering to the patient BT8009 or a pharmaceutical composition comprising BT8009, and further comprising administering to the patient pembrolizumab. The present invention also provides the use of BT8009 or a pharmaceutical composition comprising BT8009 and pembrolizumab in a method for treating a solid tumor in a human patient. The present invention also provides BT8009 or a pharmaceutical composition comprising BT8009 and pembrolizumab for use in the manufacture of a kit for use in the treatment of a solid tumor in a human patient. In one embodiment, the solid tumor is an advanced malignant tumor. In one embodiment, the solid tumor or advanced malignant tumor is associated with nectin-4 expression.

[0027] Pembrolizumab can be administered as described on the label, which can be found at https: / / www.merck.com / product / usa / pi_circulars / k / keytruda / keytruda_pi.pdf, and is incorporated herein by reference in whole. In one embodiment, pembrolizumab is administered at a dose of 200 mg once every three weeks. In one embodiment, pembrolizumab is administered at a dose of approximately 200 mg by intravenous infusion over approximately 25-45 minutes once every three weeks. In one embodiment, pembrolizumab is administered at a dose of approximately 200 mg by intravenous infusion over approximately 25 minutes once every three weeks. In one embodiment, pembrolizumab is administered at a dose of approximately 200 mg by intravenous infusion over approximately 30 minutes once every three weeks. In one embodiment, pembrolizumab is administered at a dose of approximately 200 mg by intravenous infusion over approximately 35 minutes once every three weeks. In one embodiment, pembrolizumab is administered at a dose of approximately 200 mg via IV infusion over approximately 40 minutes once every three weeks. In another embodiment, pembrolizumab is administered at a dose of approximately 200 mg via IV infusion over approximately 45 minutes once every three weeks.

[0028] In one embodiment, pembrolizumab is administered at a dose of approximately 400 mg once every six weeks. In another embodiment, pembrolizumab is administered at a dose of approximately 400 mg by intravenous infusion over approximately 25 to 45 minutes once every six weeks. In another embodiment, pembrolizumab is administered at a dose of approximately 400 mg by intravenous infusion over approximately 25 minutes once every six weeks. In yet another embodiment, pembrolizumab is administered at a dose of approximately 400 mg by intravenous infusion over approximately 30 minutes once every six weeks. In yet another embodiment, pembrolizumab is administered at a dose of approximately 400 mg by intravenous infusion over approximately 35 minutes once every six weeks. In one embodiment, pembrolizumab is administered at a dose of approximately 400 mg once every six weeks via intravenous infusion over approximately 45 minutes.

[0029] In one embodiment, the liquid formulation or liquid dosage form described herein and pembrolizumab are administered by continuous intravenous infusion, first the liquid formulation or liquid dosage form described herein, followed by pembrolizumab. In another embodiment, the liquid formulation or liquid dosage form described herein and pembrolizumab are administered by continuous intravenous infusion, first pembrolizumab, followed by the liquid formulation or liquid dosage form described herein. In yet another embodiment, the liquid formulation or liquid dosage form described herein and pembrolizumab are administered separately.

[0030] In embodiments of combination use, the patient is not previously known to be intolerant to or hypersensitive to immune checkpoint inhibitors. In embodiments of combination use, the patient has not received any prior treatment with stimulant or co-inhibitory T-cell receptor agents such as CD137 agonists, OX-40 agonists, or CTLA-4 inhibitors. In embodiments of combination use, the patient has received prior treatment with PD-1, PD-L1, or PD-L2 inhibitors. In embodiments of combination use, the patient has not received prior organ transplants (not allogeneic). In embodiments of combination use, the patient has not been previously diagnosed with clinically relevant immunodeficiency. In embodiments of combination use, the patient does not have an active systemic infection requiring treatment. In embodiments of combination use, the patient does not have any condition requiring treatment with ≥10 mg prednisone equivalent per day or other strong immunosuppressants. In embodiments of combination use, the patient has not had an active autoimmune disease requiring systemic treatment (e.g., by the use of treatment disease modifiers, corticosteroids, or immunosuppressant drugs) in the two years prior to combination treatment with BT8009 and pembrolizumab. In some embodiments, replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not a systemic treatment. In some embodiments, the patient has type 1 diabetes mellitus, alopecia, or vitiligo, which are well controlled with insulin. In some embodiments of combination use, the patient has no history of interstitial lung disease.

[0031] In some embodiments of combined use, BT8009 or a pharmaceutical composition containing BT8009 and pembrolizumab are administered separately. In some embodiments, BT8009 or a pharmaceutical composition containing BT8009 and pembrolizumab are administered sequentially. In some embodiments, BT8009 or a pharmaceutical composition containing BT8009 is administered first, followed by pembrolizumab. In some embodiments, pembrolizumab is administered first, followed by BT8009 or a pharmaceutical composition containing BT8009.

[0032] In one embodiment, BT8009 and pembrolizumab are administered by separate intravenous infusions. In one embodiment, BT8009 and pembrolizumab are administered by continuous intravenous infusions. In one embodiment, BT8009 is administered in the first infusion, followed by pembrolizumab. In one embodiment, pembrolizumab is administered in the first infusion, followed by BT8009. In one embodiment, BT8009 is provided as a liquid formulation or liquid unit dosage form as described herein.

[0033] In one embodiment, BT8009 and pembrolizumab are administered simultaneously. In another embodiment, BT8009 and pembrolizumab are administered in a single intravenous infusion.

[0034] In one embodiment, a patient with a solid tumor has not been treated for the tumor beforehand (i.e., has not received any of the prior treatment options for the solid tumor). In one embodiment, a patient with an untreated solid tumor may be administered BT8009 as monotherapy. In one embodiment, a patient with an untreated solid tumor may be administered BT8009 and pembrolizumab.

[0035] In one embodiment, a patient with a solid tumor has previously received one or more treatments for the tumor. In one embodiment, a patient with a solid tumor who has previously received one or more treatments for the tumor may be administered BT8009 as monotherapy. In one embodiment, a patient with a solid tumor who has previously received one or more treatments for the tumor may be administered BT8009 and pembrolizumab. In one embodiment, a patient who has previously received one or more treatments is resistant to or refractory to one or more of the preceding treatments.

[0036] 4. General description of one embodiment of the present invention: In one embodiment, the method of the present invention includes the administration of the pharmaceutical composition described herein. In one embodiment, the method of the present invention includes the administration of the pharmaceutical composition of the present invention (for example, a solid pharmaceutical composition of BT8009 or a liquid formulation of BT8009).

[0037] In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable additive or carrier. In one embodiment, the pharmaceutically acceptable additive or carrier is selected from buffers, stabilizers or antifreeze agents, and surfactants.

[0038] In some embodiments, the pharmaceutical composition includes a buffer. In some embodiments, the buffer is selected from phosphoric acid, glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acid, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and lanolin. In some embodiments, the buffer is L-histidine. In some embodiments, the buffer is sodium hydroxide. In some embodiments, the buffer is hydrochloric acid.

[0039] In one embodiment, the buffer is an amount that adjusts the pH of the pharmaceutical composition of the present invention to about 6 to 8. In one embodiment, the buffer is histidine in an amount of about 1 to 3 mg per 1 mg of BT8009 or its pharmaceutically acceptable amount. In one embodiment, the histidine is in an amount of about 1.31 mg or 2.62 mg per 1 mg of BT8009 or its pharmaceutically acceptable amount. In one embodiment, the liquid pharmaceutical composition of the present invention contains histidine at a concentration of about 5.24 mg / mL.

[0040] In one embodiment, the buffer is an amount that adjusts the pH of the liquid formulation or liquid unit dosage form described herein to about 6 to 8. In one embodiment, the liquid pharmaceutical composition of the present invention has a pH of about 6 to 8. In one embodiment, the liquid pharmaceutical composition of the present invention (e.g., liquid formulation or liquid unit dosage form) has a pH of about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0. In one embodiment, the liquid pharmaceutical composition of the present invention has a pH of about 6.5 or 7.0.

[0041] In some embodiments, the pharmaceutical composition contains a stabilizer or antifreeze agent. In some embodiments, the stabilizer or antifreeze agent is dimethyl sulfoxide (DMSO). In some embodiments, the stabilizer or antifreeze agent is ethylene glycol. In some embodiments, the stabilizer or antifreeze agent is glycerol. In some embodiments, the stabilizer or antifreeze agent is propylene glycol. In some embodiments, the stabilizer or antifreeze agent is 2-methyl-2,4-pentanediol (MPD). In some embodiments, the stabilizer or antifreeze agent is trehalose. In some embodiments, the stabilizer or antifreeze agent is mannitol. In some embodiments, the stabilizer or antifreeze agent is galactose. In some embodiments, the stabilizer or antifreeze agent is maltose. In some embodiments, the stabilizer or antifreeze agent is formamide. In some embodiments, the stabilizer or antifreeze agent is proline. In some embodiments, the stabilizer or antifreeze agent is glycerol 3-phosphate. In some embodiments, the stabilizer or antifreeze agent is sorbitol. In some embodiments, the stabilizer or antifreeze agent is diethyl glycol. In some embodiments, the stabilizer or antifreeze agent is sucrose.

[0042] In one embodiment, the stabilizer or antifreeze agent (e.g., sucrose) is about 10 to 35 mg per 1 mg of BT8009 or its pharmaceutically acceptable amount. In another embodiment, the stabilizer or antifreeze agent (e.g., sucrose) is about 15 or 30 mg per 1 mg of BT8009 or its pharmaceutically acceptable amount. In another embodiment, the liquid pharmaceutical composition contains the stabilizer or antifreeze agent (e.g., sucrose) at a concentration of about 60 mg / mL.

[0043] In one embodiment, the pharmaceutical composition includes a surfactant. In one embodiment, the surfactant is a polysorbate (e.g., polysorbate-20, polysorbate-40, polysorbate-60, polysorbate-65, polysorbate-80, polysorbate-85, or a combination thereof). In one embodiment, the surfactant is a poloxamer (e.g., poloxamer-188); Triton TM ;Sodium dodecyl sulfate (SDS);Sodium lauryl sulfate;Sodium octyl glycoside;Lauryl sulfobetaine, myristyl sulfobetaine, linoleyl sulfobetaine, stearyl sulfobetaine, Lauryl sarcosine, myristyl sarcosine, linoleyl sarcosine, stearyl sarcosine, linoleyl betaine, myristyl betaine, cetyl betaine, lauroamidopropyl betaine, cocamidopropyl betaine, linoleamidopropyl betaine, myristoamidopropyl betaine, palmidopropyl betaine, isostearamidopropyl betaine (e.g., lauroamidopropyl), myristoamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine;Sodium methyl cocoyl-, or disodium methyl ophthalic taurate;and Monaquat TM The surfactant is selected from the series (Mona Industries, Inc., Paterson, NJ), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronic, PF68). In one embodiment, the surfactant is polysorbate 20.

[0044] In one embodiment, the surfactant (e.g., polysorbate 20) is about 0.01 to 0.15 mg per 1 mg of BT8009 or its pharmaceutically acceptable amount. In another embodiment, the surfactant (e.g., polysorbate 20) is about 0.025, 0.05, or 0.1 mg per 1 mg of BT8009 or its pharmaceutically acceptable amount. In another embodiment, the liquid pharmaceutical composition contains the surfactant (e.g., polysorbate 20) at a concentration of about 0.1 or 0.2 mg / mL.

[0045] In some embodiments, the pharmaceutical composition contains an isotonic agent. In some embodiments, the isotonic agent is sodium chloride, dextrose, calcium chloride, or a combination thereof. In some embodiments, the isotonic agent is dextrose. In some embodiments, the isotonic agent is sodium chloride. In some embodiments, the isotonic agent is a combination of sodium chloride and dextrose.

[0046] In one embodiment, the present invention provides a solid pharmaceutical composition of BT8009 or a pharmaceutically acceptable salt thereof. In one embodiment, the solid pharmaceutical composition of BT8009 or a pharmaceutically acceptable salt thereof comprises a buffer, a stabilizer or an antifreeze agent, and a pharmaceutically acceptable additive or carrier selected from surfactants. In one embodiment, BT8009 may be provided as a pharmaceutical composition comprising a uniform unit dose of BT8009 according to the uniform dose described herein. In one embodiment, the present invention provides a solid unit dose comprising a solid pharmaceutical composition of BT8009 or a pharmaceutically acceptable salt thereof approximately 21.2 mg.

[0047] In one embodiment, a solid pharmaceutical composition of BT8009 or a pharmaceutically acceptable salt thereof further comprises L-histidine, sucrose, and polysorbate 20.

[0048] According to one aspect of the present invention, the present invention: BT8009, or its pharmaceutically acceptable salts; Approximately 1.31 mg of L-histidine per 1 mg of BT8009, or its pharmaceutically acceptable amount; Approximately 15 mg of sucrose per 1 mg of BT8009 or its pharmaceutically acceptable amount; and Approximately 0.025 mg of polysorbate 20 per 1 mg of BT8009 or its pharmaceutically acceptable amount. The present invention provides a pharmaceutical composition which is a solid pharmaceutical composition of BT8009 containing [the specified ingredient].

[0049] In one embodiment, the pharmaceutical composition is: Approximately 21.2 mg of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 27.8 mg of L-histidine; Approximately 318 mg sucrose; and Approximately 0.53 mg of polysorbate 20 This is a solid unit dose that includes [the specified ingredient].

[0050] In one embodiment, the pharmaceutical composition is: Approximately 7-13 mg, preferably approximately 8-12 mg, preferably approximately 9-11 mg of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 9.17–17.03 mg, approximately 10.48–13.1 mg upon request, and approximately 11.8–14.4 mg of L-histidine upon request. Approximately 105-195 mg, and if desired, approximately 120-180 mg, and if desired, approximately 130-165 mg of sucrose; and Approximately 0.175-0.325 mg, approximately 0.2-0.3 mg upon request, approximately 0.225-0.275 mg Polysorbate 20 This is a solid unit dose that includes [the specified ingredient].

[0051] In one embodiment, the pharmaceutical composition is: Approximately 9 mg of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 11.8 mg of L-histidine; Approximately 135 mg sucrose; and Approximately 0.225 mg of polysorbate 20 This is a solid unit dose that includes [the specified ingredient].

[0052] In one embodiment, the pharmaceutical composition is: Approximately 11 mg of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 14.4 mg of L-histidine; Approximately 165 mg sucrose; and Approximately 0.275 mg of polysorbate 20 This is a solid unit dose that includes [the specified ingredient].

[0053] In one embodiment, the solid pharmaceutical composition of the present invention is a lyophilized powder. In one embodiment, the solid pharmaceutical composition of BT8009 or a pharmaceutically acceptable salt thereof is a lyophilized powder at about -20°C. In one embodiment, the solid pharmaceutical composition of BT8009 or a pharmaceutically acceptable salt thereof is a lyophilized powder at about -15°C to about -25°C, including, for example, about -15°C, -16°C, -17°C, -18°C, -19°C, -20°C, -21°C, -22°C, -23°C, -24°C, or -25°C.

[0054] In one embodiment, the present invention provides a liquid formulation of BT8009 comprising BT8009 or a pharmaceutically acceptable salt thereof, and water. In one embodiment, the liquid formulation of the present invention further comprises a pharmaceutically acceptable additive or carrier selected from a buffer, a stabilizer or an antifreeze, and a surfactant. In one embodiment, the liquid formulation of the present invention further comprises L-histidine, sucrose, and polysorbate 20. In one embodiment, the liquid formulation of the present invention is a liquid unit dosage form comprising about 21.2 mg of BT8009 or a pharmaceutically acceptable salt thereof. In one embodiment, the liquid formulation of the present invention is a liquid unit dosage form comprising about 11 mg of BT8009 or a pharmaceutically acceptable salt thereof. In one embodiment, the concentration of BT8009 in the liquid formulation or liquid unit dosage form of the present invention is about 4 mg / mL. In one embodiment, the liquid formulation or liquid unit dosage form of the present invention comprises the following components: [Table 1] a: Adjust based on API efficacy to achieve the target drug substance label value. b: Sufficient amount. c: Remove water for injection (WFI) during the freeze-drying process.

[0055] In one embodiment, the liquid formulation or liquid unit dosage form of the present invention further contains saline solution, for example, about 0.9% w / v saline solution. In one embodiment, the BT8009 concentration in the liquid formulation of the present invention containing saline solution is about 0.1 to 2 mg / mL. In one embodiment, the BT8009 concentration in the liquid formulation of the present invention containing saline solution is about 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, or 1 mg / mL. In one embodiment, the BT8009 concentration in the liquid formulation of the present invention containing saline solution is about 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, or 2 mg / mL.

[0056] In some embodiments, the liquid formulation or liquid unit dosage form of the present invention comprises a pharmaceutically acceptable medium or solvent. In some embodiments, the pharmaceutically acceptable medium or solvent is selected from sterile water, Ringer's solution, USP, and isotonic sodium chloride solution. In some embodiments, the pharmaceutically acceptable medium or solvent is sterile water. In some embodiments, the pharmaceutically acceptable medium or solvent is a sterile injection medium.

[0057] In one embodiment, the present invention provides a liquid formulation or liquid unit dosage form prepared by dissolving the solid pharmaceutical composition or solid unit form of the present invention in water. In one embodiment, the present invention provides a liquid formulation or liquid unit dosage form prepared by dissolving the solid pharmaceutical composition or solid unit form of the present invention in an injection medium (e.g., about 0.9% w / v saline solution). In one embodiment, the present invention provides a liquid formulation or liquid unit dosage form prepared by reconstituting the solid pharmaceutical composition or solid unit form of the present invention with water and subsequently diluting it with about 0.9% w / v saline solution. In one embodiment, the liquid formulation or liquid unit dosage form is diluted in an IV bag of about 0.9% w / v saline solution for IV administration.

[0058] In one embodiment, the present invention: Approximately 4 mg / mL of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 5.24 mg / mL L-histidine; Approximately 60 mg / mL sucrose; Approximately 0.1 mg / mL polysorbate 20; and water The present invention provides a liquid formulation containing the following: In one embodiment, the liquid formulation contains hydrochloric acid. In another embodiment, the liquid formulation contains sodium hydroxide. In another embodiment, the liquid formulation has a pH of about 7.

[0059] In one embodiment, the present invention: Approximately 4 mg / mL of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 5.24 mg / mL L-histidine; Approximately 60 mg / mL sucrose; Approximately 0.1 mg / mL polysorbate 20; and water The product provides a liquid dosage form containing approximately 5.3 mL of [ingredient].

[0060] In one embodiment, the present invention: Approximately 4 mg / mL of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 5.24 mg / mL L-histidine; Approximately 60 mg / mL sucrose; Approximately 0.1 mg / mL polysorbate 20; and water The product is provided in liquid dosage forms of approximately 1.75 to 3.25 mL, optionally in liquid dosage forms of approximately 2 to 3 mL, and optionally in liquid dosage forms of approximately 2.25 to 2.75 mL.

[0061] In one embodiment, the present invention: Approximately 4 mg / mL of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 5.24 mg / mL L-histidine; Approximately 60 mg / mL sucrose; Approximately 0.1 mg / mL polysorbate 20; and water The product provides a liquid dosage form containing approximately 2.25 mL of [ingredient].

[0062] In one embodiment, the present invention: Approximately 4 mg / mL of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 5.24 mg / mL L-histidine; Approximately 60 mg / mL sucrose; Approximately 0.1 mg / mL polysorbate 20; and water The product provides a liquid unit dosage form containing approximately 2.75 mL of [ingredient].

[0063] In one embodiment, the liquid formulation contains hydrochloric acid. In another embodiment, the liquid formulation contains sodium hydroxide. In another embodiment, the liquid formulation has a pH of about 7.

[0064] In one embodiment, the solid unit dosage of the present invention is stored in a vial. In another embodiment, the liquid unit dosage form, comprising BT8009 or a pharmaceutically acceptable salt thereof, and water, is stored in a vial. In another embodiment, the vial is a 10 mL Type I clear glass vial with a chlorobutyl stopper and an aluminum seal.

[0065] In one embodiment, the present invention provides a pharmaceutical composition comprising BT8009 and a kit comprising pembrolizumab.

[0066] In some embodiments, the pharmaceutical composition may further contain other drugs, such as pembrolizumab. In other words, in some embodiments, the pharmaceutical composition may contain both BT8009 and pembrolizumab. Such a pharmaceutical composition may offer several advantages in terms of safety, convenience, patient compliance, storage, and efficacy compared to the administration of the drugs individually.

[0067] In one embodiment, the method of the present invention includes intravenous administration of the liquid formulation or liquid unit dosage form described herein to a patient. In one embodiment, the liquid formulation or liquid unit dosage form of the present invention is administered by IV injection. In one embodiment, the liquid formulation or liquid unit dosage form of the present invention is administered by IV infusion. In one embodiment, the IV infusion of the liquid formulation or liquid unit dosage form of the present invention lasts for about 5 to 30 minutes. In one embodiment, the IV infusion of the liquid formulation or liquid unit dosage form of the present invention lasts for about 30 to 60 minutes. In one embodiment, the IV infusion of the liquid formulation or liquid unit dosage form of the present invention lasts for about 60 to 90 minutes. In one embodiment, the IV infusion of the liquid formulation or liquid unit dosage form of the present invention lasts for about 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, or 90 minutes. In one embodiment, the IV infusion of the liquid formulation or liquid unit dosage form of the present invention lasts for about 55 minutes. In one embodiment, the IV infusion of the liquid formulation or liquid unit dosage form of the present invention lasts for about 60 minutes. In one embodiment, the intravenous infusion of the liquid formulation or liquid unit dosage form of the present invention takes about 65 minutes. In one embodiment, the intravenous infusion of the liquid formulation or liquid unit dosage form of the present invention takes about 70 minutes. In one embodiment, the intravenous infusion of the liquid formulation or liquid unit dosage form of the present invention takes about 75 minutes. In one embodiment, the intravenous infusion of the liquid formulation or liquid unit dosage form of the present invention takes about 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours.

[0068] In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering to the patient a liquid formulation comprising about 4 mg / mL BT8009 or a pharmaceutically acceptable salt thereof; about 5.24 mg / mL L-histidine; about 60 mg / mL sucrose; about 0.1 mg / mL polysorbate 20; and water, wherein the liquid formulation is diluted with about 0.9% w / v saline before administration. In one embodiment, the solid tumor is an advanced malignant tumor. In one embodiment, the solid tumor or advanced malignant tumor is associated with nectin-4 expression.

[0069] In one embodiment, the present invention provides the use of a combination of the liquid formulation or liquid dosage form and pembrolizumab described herein for treating solid tumors (e.g., advanced malignant tumors) associated with nectin-4 expression. The liquid formulation or liquid dosage form and pembrolizumab may each be administered as described herein.

[0070] 5. Dosage regimen In one embodiment, BT8009 is administered to the patient once daily. In another embodiment, BT8009 is administered to the patient once every 2, 3, 4, 5, 6, or 7 days. In another embodiment, BT8009 is administered to the patient once a week or weekly. In another embodiment, BT8009 is administered to the patient once every two weeks. In another embodiment, BT8009 is administered as a liquid formulation or liquid unit dosage form.

[0071] In one embodiment, the treatment cycle is four weeks, i.e., a 28-day treatment cycle. In one embodiment, BT8009 is administered weekly in a 28-day treatment cycle, for example, on days 1, 8, 15, and 22. In one embodiment, BT8009 is administered every two weeks in a 28-day cycle, for example, on days 1 and 15. In one embodiment, BT8009 is administered as a liquid formulation or liquid unit dosage form.

[0072] In one embodiment, the treatment cycle is 3 weeks, i.e., a 21-day treatment cycle. In one embodiment, BT8009 is administered in the first and second weeks of the 21-day treatment cycle, but not in the third week. In one embodiment, BT8009 is administered on the first and eighth days of the 21-day treatment cycle. In one embodiment, BT8009 is administered once a week in the 21-day treatment cycle. In one embodiment, BT8009 is administered on the first, eighth, and fifteenth days of the 21-day treatment cycle.

[0073] In one embodiment, BT8009 is administered as a body surface area (BSA)-based dose, which is mg / m², such as any of the doses described herein. 2 It is expressed in units of mg / m³. 2 The dosage unit is 1 m² of the patient's body surface area (BSA). 2 This refers to the dose (mg) administered per unit area. BSA-based dose (mg / m²) 2 The BSA can be determined by dividing the dose (mg) by the patient's BSA. The equator knows models and formulas that can be used to estimate or determine a patient's BSA based on factors such as the patient's height and weight. In one embodiment, the BSA can be estimated using the Dubois formula for BSA dosing (0.007184 × (height (cm))^0.725 × (weight (kg))^0.425 or the Mostler formula for BSA dosing (square root [(height (cm) × weight (kg)) / 3600]).

[0074] In one embodiment, the patient is 1.37m 2 ~2.3m 2 The patient may have a BSA of 1.37m. 2 ~1.69m 2 The patient may have a BSA of 1.69m. 2 ~1.84m 2 The patient may have a BSA of 1.84m. 2 ~1.96m 2 The patient may have a BSA of 1.96m. 2 ~2.3m 2It may have a BSA.

[0075] In one embodiment, BT8009 is administered at approximately 1-20 mg / m². 2 The drug is administered at a dose (measured by the amount of API: BT8009). In one embodiment, BT8009 is administered at approximately 2-15 mg / m². 2 Administer in the following dose. In one embodiment, BT8009 is administered at approximately 2-10 mg / m². 2 Administer in the following dose. In one embodiment, BT8009 is administered at approximately 2 mg / m². 2 , 3 mg / m² 2 , 4 mg / m² 2 , 5 mg / m² 2 , 6 mg / m² 2 , 7 mg / m² 2 , 8 mg / m² 2 , 9 mg / m² 2 , or 10 mg / m² 2 Administer in the following dose. In one embodiment, BT8009 is administered at approximately 2.5 mg / m². 2 3.5 mg / m² 2 , 4.5 mg / m² 2 5.5 mg / m² 2 , 6.5 mg / m² 2 7.5 mg / m² 2 8.5 mg / m² 2 , or 9.5 mg / m² 2 Administer in the following dose. In a particular embodiment, BT8009 is administered at approximately 2-10 mg / m². 2 Approximately 2.5-7.5 mg / m² upon request. 2 The dosage is approximately 4-6 mg / m², depending on the desired amount. 2 The dosage, depending on your preference, is approximately 5 mg / m². 2 Administer at the dose of [number]. In other specific embodiments, BT8009 is administered at approximately 6-9 mg / m². 2 Approximately 7-8 mg / m² upon request. 2 The dosage is approximately 7.5 mg / m², depending on preference. 2 Administer at the specified dose.

[0076] In one embodiment, the method of the present invention involves administering approximately 2-10 mg / m² to the patient weekly. 2 The dosage is approximately 2.5 to 7.5 mg / m², depending on preference. 2The dosage is approximately 4-6 mg / m², depending on the desired amount. 2 The dosage, depending on your preference, is approximately 5 mg / m². 2 The method includes administering BT8009 or a pharmaceutical composition containing BT8009 in a given dose. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over approximately 60 minutes.

[0077] In one embodiment, the present invention is a method for treating a solid tumor in a human patient, comprising administering to the patient approximately 2-10 mg / m² weekly. 2 The dosage is approximately 2.5 to 7.5 mg / m², depending on preference. 2 The dosage is approximately 4-6 mg / m², depending on the desired amount. 2 The dosage, depending on your preference, is approximately 5 mg / m². 2 The present invention provides a method comprising administering BT8009 in a dose. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, wherein the patient is given a liquid formulation or liquid unit dosage form by intravenous infusion of about 2 to 10 mg / m² over about 60 minutes per week. 2 The dosage is approximately 2.5 to 7.5 mg / m², depending on preference. 2 The dosage is approximately 4-6 mg / m², depending on the desired amount. 2 The dosage, depending on your preference, is approximately 5 mg / m². 2 The present invention provides a method comprising administering in a dose. In one embodiment, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0078] In one embodiment, the method of the present invention involves administering approximately 5 mg / m² to the patient weekly. 2 The method includes administering BT8009 or a pharmaceutical composition containing BT8009 in a given dose. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over approximately 60 minutes.

[0079] In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, wherein the patient is given approximately 5 mg / m² weekly. 2The present invention provides a method comprising administering BT8009 in a dose. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, wherein the patient is given a liquid formulation or liquid unit dosage form by intravenous infusion of about 5 mg / m² over about 60 minutes per week. 2 The present invention provides a method comprising administering in a dose. In one embodiment, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0080] In one embodiment, the method of the present invention involves administering BT8009 or a pharmaceutical composition containing BT8009 to a patient at approximately 6-9 mg / m² on days 1 and 8 of a 21-day treatment cycle. 2 The dosage is approximately 7-8 mg / m², depending on the desired amount. 2 The dosage is approximately 7.5 mg / m², depending on preference. 2 This includes administering in a dose. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over approximately 60 minutes.

[0081] In one embodiment, the present invention relates to a method for treating a solid tumor in a human patient, wherein the patient is given BT8009 at approximately 6-9 mg / m² on days 1 and 8 of a 21-day treatment cycle. 2 The dosage is approximately 7-8 mg / m², depending on the desired amount. 2 The dosage is approximately 7.5 mg / m², depending on preference. 2 The present invention provides a method comprising administering a certain dose. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or liquid unit dosage form to the patient by IV infusion over 60 minutes, at a dose of approximately 6-9 mg / m² on days 1 and 8 of a 21-day treatment cycle. 2 The dosage is approximately 7-8 mg / m², depending on the desired amount. 2 The dosage is approximately 7.5 mg / m², depending on preference. 2The present invention provides a method comprising administering in a dose. In one embodiment, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0082] In one embodiment, the method of the present invention involves administering BT8009 or a pharmaceutical composition containing BT8009 to a patient at approximately 7.5 mg / m² on days 1 and 8 of a 21-day treatment cycle. 2 This includes administering in a dose. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over approximately 60 minutes.

[0083] In one embodiment, the present invention relates to a method for treating a solid tumor in a human patient, wherein the patient is given BT8009 at approximately 7.5 mg / m² on days 1 and 8 of a 21-day treatment cycle. 2 The present invention provides a method comprising administering a certain dose. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or liquid unit dosage form to the patient by IV infusion over 60 minutes, at a dose of approximately 6-9 mg / m² on days 1 and 8 of a 21-day treatment cycle. 2 The dosage is approximately 7-8 mg / m², depending on the desired amount. 2 The dosage is approximately 7.5 mg / m², depending on preference. 2 The present invention provides a method comprising administering in a dose. In one embodiment, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0084] In one embodiment, the method of the present invention involves administering approximately 2.5 mg / m² to the patient weekly. 2 The method includes administering BT8009 or a pharmaceutical composition containing BT8009 in a given dose. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over approximately 60 minutes.

[0085] In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, wherein the patient is given approximately 2.5 mg / m² weekly. 2Provided is a method comprising administering BT8009 at a dose of 2 In certain embodiments, BT8009 is provided as a pharmaceutical composition. In certain embodiments, the pharmaceutical composition is a liquid formulation. In certain embodiments, the present invention is a method for treating solid tumors in a human patient, comprising administering to the patient a liquid formulation or a liquid unit dosage form by IV infusion for about 60 minutes per week at a dose of about 2.5 mg / m

[0086] In certain embodiments, the method of the present invention comprises administering to the patient BT8009 or a pharmaceutical composition comprising BT8009 at a dose of about 5.5 mg / m 2 per week. In certain embodiments, the pharmaceutical composition is a liquid formulation. In certain embodiments, the liquid formulation is administered by IV infusion for about 60 minutes.

[0087] In certain embodiments, the present invention is a method for treating solid tumors in a human patient, comprising administering to the patient BT8009 by IV infusion for about 60 minutes at a dose of about 5.5 mg / m 2 per week. In certain embodiments, BT8009 is provided as a pharmaceutical composition. In certain embodiments, the pharmaceutical composition is a liquid formulation. In certain embodiments, the present invention is a method for treating solid tumors in a human patient, comprising administering to the patient a liquid formulation or a liquid unit dosage form by IV infusion for about 60 minutes per week at a dose of about 5.5 mg / m 2 In certain embodiments, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0088] In certain embodiments, the method of the present invention comprises administering to the patient BT8009 or a pharmaceutical composition comprising BT8009 at a dose of about 7.5 mg / m 2 per week. In certain embodiments, the pharmaceutical composition is a liquid formulation. In certain embodiments, the liquid formulation is administered by IV infusion for about 60 minutes.

[0089] In one embodiment, the present invention is a method for treating solid tumors in a human patient, comprising administering BT8009 to the patient at a dose of about 7.5 mg / m 2 by intravenous infusion for about 60 minutes once a week. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention is a method for treating solid tumors in a human patient, comprising administering to the patient a liquid formulation or a liquid unit dosage form at a dose of about 7.5 mg / m 2 by intravenous infusion for about 60 minutes once a week. In one embodiment, the liquid formulation or the liquid dosage form is the liquid formulation or the liquid dosage form of the present invention.

[0090] In one embodiment, the method of the present invention comprises administering BT8009 or a pharmaceutical composition containing BT8009 to the patient at a dose of about 6 mg / m 2 on the first and eighth days of a 21-day treatment cycle. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion for about 60 minutes.

[0091] In one embodiment, the present invention is a method for treating solid tumors in a human patient, comprising administering BT8009 to the patient by intravenous infusion for about 60 minutes on the first and eighth days of a 21-day treatment cycle at a dose of about 6 mg / m 2 . In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention is a method for treating solid tumors in a human patient, comprising administering to the patient a liquid formulation or a liquid unit dosage form by intravenous infusion for about 60 minutes at a dose of about 6 mg / m 2 once every two weeks. In one embodiment, the liquid formulation or the liquid dosage form is the liquid formulation or the liquid dosage form of the present invention.

[0092] In one embodiment, the method of the present invention comprises administering BT8009 or a pharmaceutical composition containing BT8009 to the patient at a dose of about 7.5 mg / m 2This includes administering the drug once every two weeks at a dose. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over approximately 60 minutes.

[0093] In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient via IV infusion over approximately 60 minutes, approximately 7.5 mg / m², every two weeks. 2 The present invention provides a method comprising administering a certain dose. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, wherein the patient is given a liquid formulation or liquid unit dosage form by intravenous infusion over about 60 minutes, once every two weeks, at a dose of about 7.5 mg / m². 2 The present invention provides a method comprising administering in a dose. In one embodiment, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0094] In one embodiment, the method of the present invention involves administering BT8009 or a pharmaceutical composition containing BT8009 to a patient at a dose of approximately 10 mg / m². 2 This includes administering the drug once every two weeks at a dose. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over approximately 60 minutes.

[0095] In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient by intravenous infusion of approximately 10 mg / m² over approximately 60 minutes. 2 The present invention provides a method comprising administering a dose once every two weeks. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or liquid unit dosage form to the patient by intravenous infusion over about 60 minutes at a dose of about 10 mg / m². 2 The present invention provides a method comprising administering a dose once every two weeks. In one embodiment, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0096] In one embodiment, BT8009 is administered in a uniform dose (i.e., a standard dose in mg, independent of the patient's BSA). Administration of the drug as a uniform dose, rather than as a BSA-based dose, may offer several advantages while providing an overall pharmacokinetic profile similar to that of BSA-based dose use. Administration of the drug as a uniform dose reduces the rate of drug-associated adverse events (AEs) compared to BSA-based doses, while maintaining efficacy. Administration of the drug as a uniform dose reduces the amount of drug wasted in connection with drug preparation and administration to patients compared to BSA-based doses. Administration of the drug as a uniform dose may reduce the likelihood of medication errors and improve the convenience of the drug in clinical settings.

[0097] In one embodiment, BT8009 is administered in a uniform dose of approximately 1.8 to 36 mg (measured by the amount of API: BT8009). In one embodiment, BT8009 is administered in a uniform dose of approximately 3.6 to 27 mg. In another embodiment, BT8009 is administered in a uniform dose of approximately 3.6 mg, 5.4 mg, 7.2 mg, 9 mg, 10.8 mg, 12.6 mg, 14.4 mg, 16.2 mg, or 18 mg. In another embodiment, BT8009 is administered in a uniform dose of approximately 4.5 mg, 6.3 mg, 8.1 mg, 9.9 mg, 11.7 mg, 13.5 mg, 15.3 mg, or 17.1 mg. In a particular embodiment, BT8009 is administered in a uniform dose of approximately 7 to 11 mg, optionally a uniform dose of approximately 8 to 10 mg, and optionally a uniform dose of approximately 9 mg. In other specific embodiments, BT8009 is administered in a uniform dose of approximately 9–13 mg, preferably approximately 10–12 mg, or preferably approximately 11 mg.

[0098] In one embodiment, the method of the present invention involves administering to a patient BT8009 or a pharmaceutical composition containing BT8009 in a uniform dose of about 7 to 11 mg per week, preferably about 8 to 10 mg, preferably about 9 mg. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over about 60 minutes.

[0099] In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient in a uniform dose of about 7 to 11 mg weekly, optionally about 8 to 10 mg, or optionally about 9 mg. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering the liquid formulation or liquid unit dosage form to the patient in a uniform dose of about 7 to 11 mg weekly by intravenous infusion over about 60 minutes, optionally about 8 to 10 mg, or optionally about 9 mg. In one embodiment, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0100] In one embodiment, the method of the present invention involves administering to a patient a uniform dose of about 9 mg weekly of BT8009 or a pharmaceutical composition containing BT8009. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over about 60 minutes.

[0101] In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient in a uniform dose of about 9 mg weekly. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering the liquid formulation or liquid unit dosage form to the patient in a uniform dose of about 9 mg weekly by intravenous infusion over about 60 minutes. In one embodiment, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0102] In one embodiment, the method of the present invention involves administering to a patient a uniform dose of BT8009 or a pharmaceutical composition containing BT8009 at a uniform dose of about 9 to 13 mg, preferably about 10 to 12 mg, or preferably about 11 mg, on days 1 and 8 of a 21-day treatment cycle. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over about 60 minutes.

[0103] In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient in a uniform dose of about 9–13 mg, optionally about 10–12 mg, or optionally about 11 mg, on days 1 and 8 of a 21-day treatment cycle. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or liquid unit dosage form to the patient by IV infusion over 60 minutes in a uniform dose of about 9–13 mg, optionally about 10–12 mg, or optionally about 11 mg, on days 1 and 8 of a 21-day treatment cycle. In one embodiment, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0104] In one embodiment, the method of the present invention involves administering to a patient a uniform dose of about 11 mg of BT8009 or a pharmaceutical composition containing BT8009 on days 1 and 8 of a 21-day treatment cycle. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the liquid formulation is administered by intravenous infusion over about 60 minutes.

[0105] In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient in a uniform dose of about 11 mg on days 1 and 8 of a 21-day treatment cycle. In one embodiment, BT8009 is provided as a pharmaceutical composition. In one embodiment, the pharmaceutical composition is a liquid formulation. In one embodiment, the present invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or liquid unit dosage form to the patient by IV infusion over 60 minutes in a uniform dose of about 11 mg on days 1 and 8 of a 21-day treatment cycle. In one embodiment, the liquid formulation or liquid dosage form is the liquid formulation or liquid dosage form of the present invention.

[0106] In one embodiment, the solid tumor is an advanced malignant tumor. In one embodiment, the solid tumor or advanced malignant tumor is associated with nectin-4 expression.

[0107] In one embodiment, BT8009 is administered to a patient who is at least 18 years old. In other words, in one embodiment, the patient is an adult patient.

[0108] 6. Advanced malignant tumors associated with nectin-4 expression

[0109] The methods of the present invention relate to the treatment of solid tumors in human patients. In one embodiment, the solid tumor is an advanced malignant tumor. In one embodiment, the solid tumor is selected from the group consisting of lung cancer (e.g., NSCLC), ovarian cancer, breast cancer (e.g., TNBC), esophageal cancer, gastric / upper gastrointestinal (GI) cancer, head and neck cancer, pancreatic cancer, and urothelial carcinoma. In one embodiment, the solid tumor is associated with nectin-4 expression. In one embodiment, the solid tumor is an advanced malignant tumor associated with nectin-4 expression.

[0110] In one embodiment, the advanced malignancies associated with nectin-4 expression are selected from the group consisting of lung cancer (e.g., NSCLC), ovarian cancer, breast cancer (e.g., TNBC), esophageal cancer, gastric / upper gastrointestinal (GI) cancer, head and neck cancer, pancreatic cancer, and urothelial carcinoma.

[0111] In one embodiment, a patient with an advanced malignancy associated with nectin-4 expression has not been previously treated for the malignancy (i.e., has not received any of the prior treatment options for the malignancy). In one embodiment, a patient with an advanced malignancy associated with nectin-4 expression who has not been previously treated may be administered BT8009 as monotherapy. In one embodiment, a patient with an advanced malignancy associated with nectin-4 expression who has not been previously treated may be administered BT8009 and pembrolizumab.

[0112] In one embodiment, a patient with an advanced malignancy associated with nectin-4 has received one or more prior treatments for the malignancy. In one embodiment, a patient with an advanced malignancy associated with nectin-4 who has received one or more prior treatments for the malignancy may be administered BT8009 as monotherapy. In one embodiment, a patient with an advanced malignancy associated with nectin-4 who has received one or more prior treatments for the malignancy may be administered BT8009 and pembrolizumab. In one embodiment, a patient who has received one or more prior treatments is resistant to or refractory to one or more prior treatments.

[0113] In one embodiment, the advanced malignant tumor associated with nectin-4 expression is lung cancer, e.g., non-small cell lung cancer (NSCLC). In one embodiment, the advanced malignant tumor associated with nectin-4 expression is ovarian cancer. In one embodiment, the advanced malignant tumor associated with nectin-4 expression is breast cancer, e.g., triple-negative breast cancer (TNBC). In one embodiment, the advanced malignant tumor associated with nectin-4 expression is esophageal cancer. In one embodiment, the advanced malignant tumor associated with nectin-4 expression is gastric / upper digestive tract (GI). In one embodiment, the advanced malignant tumor associated with nectin-4 expression is head and neck cancer. In one embodiment, the advanced malignant tumor associated with nectin-4 expression is pancreatic cancer. In one embodiment, the advanced malignant tumor associated with nectin-4 expression is urothelial carcinoma.

[0114] In one embodiment, the advanced malignant tumor associated with nectin-4 expression is urothelial carcinoma. In one embodiment, the advanced malignant tumor associated with nectin-4 expression is locally advanced urothelial carcinoma. In one embodiment, the advanced malignant tumor associated with nectin-4 expression is malignant urothelial carcinoma. In one embodiment, a patient with locally advanced or metastatic urothelial carcinoma has not received prior treatment for the cancer. In one embodiment, a patient with locally advanced or metastatic cancer has received one or more prior treatments for the cancer, for example, one or more other treatments described herein. In one embodiment, a patient who has received one or more prior treatments is resistant to or refractory to one or more prior treatments.

[0115] In one embodiment, a patient with locally advanced urothelial carcinoma who has not received prior treatment for the cancer may be administered BT8009 as monotherapy. In another embodiment, a patient with locally advanced urothelial carcinoma who has not received prior treatment for the cancer may be administered BT8009 and pembrolizumab. In another embodiment, a patient with locally advanced urothelial carcinoma who has received one or more prior treatments for the cancer may be administered BT8009 as monotherapy. In another embodiment, a patient with locally advanced urothelial carcinoma who has received one or more prior treatments for the cancer may be administered BT8009 and pembrolizumab.

[0116] In one embodiment, the patient is a patient with an East Coast Clinical Oncology Group (ECOG) Performance Status score of 0, 1, or 2. In another embodiment, the patient is a cisplatin-eligible patient with an ECOG Performance Status score of 0, 1, or 2. In yet another embodiment, the patient is a cisplatin-ineligible urothelial carcinoma patient with an ECOG Performance Status score of 2, where the patient has hemoglobin ≥ 10 g / dL, CrCl ≥ 50 mL / min, and no NYHA class III heart failure. ECOG Performance Status scores of 0 and 1 are described herein.

[0117] In one embodiment, the patient is a patient with a measurable disease according to the Guidelines for Evaluation of Treatment Response to Solid Tumors (RECIST) v1.1.1 In another embodiment, the patient is a patient with a target lesion that has been previously treated with radiation and whose progression has been demonstrated.

[0118] In one embodiment, the patient meets the inclusion criteria for the Phase I / II and / or Phase II / III trial summary included herein.

[0119] In one embodiment, the patient is a patient with acceptable organ function. In one embodiment, the patient with acceptable organ function has clinical laboratory values ​​selected from the following: Renal function: Creatinine clearance (CrCl) ≥ 50 mL / min and / or eGFR ≥ 30 mL / min using the Cockcroft-Gault formula or equivalent (using the CKD-EPI creatinine formula) (excluding patients with renal impairment); Total bilirubin ≤ 1.5 × ULN (upper limit of normal); Serum albumin ≥ 2.5 g / dL; Aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver metastases; Alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver metastases; and Unless the patient is receiving a stable dose of anticoagulant therapy, an international normalized ratio (INR) < 1.5 or ≤ tissue ULN and PT or aPPT is within the therapeutic range of the intended use of anticoagulants.

[0120] In one embodiment, the patient is a patient with acceptable hematological function (no red blood cell or platelet transfusions are acceptable, or growth factors are acceptable within 4 weeks of the first dose of BT8009; excluding patients with renal impairment). In one embodiment, a patient with acceptable hematological function has clinical laboratory values ​​selected from the following: Hemoglobin ≥ 9 g / dL; Absolute neutrophil count (ANC) ≥ 1500 cells / mm³ 3 and Platelet count ≥75,000 cells / mm 3 .

[0121] In one embodiment, the patient is a woman of childbearing potential (WOCBP) who has tested negative for pregnancy (negative serological test at screening and negative urine or serological test within 3 days prior to the first administration of the liquid formulation or liquid unit dosage form described herein).

[0122] In one embodiment, the patient is a patient whose life expectancy after the initiation of BT8009 treatment is ≥ 12 weeks.

[0123] In one embodiment, the patient is a patient with histologically confirmed urothelial (transitional cell) carcinoma that has relapsed or is refractory to prior treatment.

[0124] In one embodiment, the patient is a patient with an advanced, histologically confirmed pancreatic, breast, NSCLC, gastric, esophageal, head and neck, or ovarian tumor that has relapsed or is refractory to prior treatment.

[0125] In one embodiment, the patient has histologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). In one embodiment, the patient has squamous cell differentiation or mixed cell type. In one embodiment, the patient does not have resectable locally advanced urothelial carcinoma. In one embodiment, the patient has received prior treatment with a CPI (PD-1 or PD-L1 inhibitor), if approved locally, in a locally advanced or metastatic urothelial carcinoma setting. In one embodiment, the patient has received CPI treatment in a neoadjuvant / adjuvant setting and has experienced relapse or progressive disease during treatment or within 3 months of treatment completion. In one embodiment, the patient has received prior platinum-containing chemotherapy in an adjuvant / neoadjuvant setting and has experienced relapse or progressive disease within 12 months of completion, or has received treatment with a platinum regimen in a locally advanced (unresectable for curative purposes) or metastatic setting. In one embodiment, the patient is platinum-naive and platinum-ineligible and has not received prior treatment with platinum-containing or other chemotherapy in a locally advanced or metastatic setting. In one embodiment, a patient receiving platinum in an adjuvant / neoadjuvant setting and not experiencing disease progression within 12 months of completion is considered platinum-naive. In one embodiment, a patient has experienced progression or recurrence of urothelial carcinoma during or after their most recent treatment. In one embodiment, a patient has been treated with enfortumab vedotin (EV). In one embodiment, a patient has not been treated with enfortumab vedotin (EV). In one embodiment, a patient has been treated with enfortumab vedotin (EV) and pembrolizumab. In one embodiment, a patient has not been treated with enfortumab vedotin (EV) and pembrolizumab.

[0126] In one embodiment, the patient is a patient with histologically confirmed non-mucinous epithelial ovarian (serous, endometrioid, clear cell, carcinosarcoma, and mixed-type) fallopian tube, or primary peritoneal cancer that has progressed after prior treatment and is stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) or tumor, nodule, and metastasis staging criteria. In one embodiment, the patient has been treated with an FDA-approved or locally approved treatment.

[0127] In one embodiment, the patient is a TNBC patient with a tumor that has progressed after prior treatment, is ER / PR negative (≤10% positive tumor nuclei as recommended by the ASCO-CAP guidelines) by immunohistochemistry (IHC), and is confirmed to be human epidermal growth factor receptor 2 (HER2) negative (0 and 1) by IHC or fluorescence or chromogenic in situ hybridization (FISH or CISH). In one embodiment, the patient has been treated with an FDA-approved or locally approved treatment.

[0128] In one embodiment, the patient is a patient with histologically confirmed NSCLC that has progressed after prior treatment and is free of actionable mutations such as epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) fusion oncogenes, or ROS1 absence. In another embodiment, the patient has a tumor with squamous cell carcinoma and adenocarcinoma histological features. In yet another embodiment, the patient has been treated with an FDA-approved or locally approved treatment.

[0129] In one embodiment, the patient has locally advanced or metastatic, histologically confirmed urothelial (transitional cell) carcinoma. In another embodiment, the patient has squamous cell differentiation or mixed cell type. In yet another embodiment, the patient does not have resectable locally advanced urothelial carcinoma. In yet another embodiment, the patient is cisplatin-ineligible as determined by one of the following criteria: Renal dysfunction (creatinine clearance [CrCl] of 30-59 mL / min as measured by CG); Hearing loss of ≥25 decibels (dB) across two consecutive frequencies; NYHA Class III heart failure; or The following criteria are met for an East Coast Cancer Clinical Trials Group (ECOG) Performance Status (PS) 2: i. Hemoglobin ≥ 10 g / dL; ii. CrCl ≥ 50 mL / min; and iii. The patient does not need to have NYHA class III heart failure. In some embodiments, the patient has no prior organ transplant (not allogeneic). In some embodiments, the patient has not been previously diagnosed with clinically relevant immunodeficiency. In some embodiments, the patient does not have any condition requiring treatment with ≥10 mg prednisone equivalent per day or other strong immunosuppressants. In some embodiments, the patient does not have an active autoimmune disease requiring systemic treatment (i.e., with the use of disease modifiers, corticosteroids, or immunosuppressive drugs) within two years prior to treatment with the liquid formulation or liquid unit dosage form described herein. In some embodiments, the patient has no history of interstitial lung disease. In some embodiments, the patient has not received any systemic anticancer treatment for advanced or metastatic urothelial carcinoma. In some embodiments, the patient has not received prior adjuvant / neoadjuvant platinum-based treatment within 12 months prior to the first dose. In some embodiments, the patient has not received prior adjuvant / neoadjuvant immune checkpoint inhibitor treatment within 12 months prior to treatment with the liquid formulation or liquid unit dosage form described herein. In some embodiments, the patient has not received prior treatment with an MMAE-based conjugate at any point in time. In one embodiment, the patient has not received prior treatment with a BTC (e.g., BT8009 or other BTC) at any point in time. In another embodiment, the patient has not received prior treatment with an MMAE-based conjugate for urothelial carcinoma at any point in time. In another embodiment, the patient has not received prior treatment with an EV or other MMAE-based ADC for urothelial carcinoma at any point in time.

[0130] In one embodiment, the patient is a patient with histologically confirmed urothelial (transitional cell) carcinoma, including patients with squamous cell differentiated or mixed cell type, ovarian, triple-negative breast, or non-small cell lung cancer.

[0131] In one embodiment, the patient is a patient with a solid tumor progression disease. In one embodiment, the patient has renal failure or impaired renal function. In one embodiment, the patient has renal function of 30–49 mL / min (by CG). In one embodiment, the patient has renal function of 15–29 mL / min (by CG). In one embodiment, the patient is being treated with an FDA-approved or locally approved treatment.

[0132] In one embodiment, the patient has not received chemotherapy within 14 days prior to the first administration of the liquid formulation or liquid unit dosage form described herein. In one embodiment, the patient has not received anticancer treatment within 28 days or within 5 half-lives, whichever is shorter, prior to the first administration of the liquid formulation or liquid unit dosage form described herein. In one embodiment, the patient has prior toxicity (except alopecia, which must not exceed grade 2) that has recovered to grade ≤ 1 according to the Common Terminology Criteria for Adverse Events (CTCAE) v 5.0.

[0133] In one embodiment, the patient has not undergone any experimental treatment within four weeks of the first administration of the liquid formulation or liquid unit dosage form described herein.

[0134] In one embodiment, the patient is not currently receiving treatment with CYP3A strong inhibitors or strong inducers or P-gp inhibitors, including herbal or food-based ones.

[0135] In one embodiment, the patient has no sensitivity to any of the components of the liquid formulations or liquid unit dosage forms described herein, or to monomethyl auristatin E (MMAE).

[0136] In one embodiment, the patient does not have a significant medical condition, including, but not limited to, a skin condition (including, but not limited to, an autoimmune condition such as eczema or psoriasis, or any condition associated with or that may interfere with monitoring skin lesions), a life-threatening illness, an uncontrolled infection or organ system dysfunction (e.g., ascites, coagulation disorders, encephalopathy), or any other reason that threatens the patient's safety or interferes with or impairs the completeness of the study outcome, including consideration of gastrointestinal, skin, and pulmonary comorbidities and review of a screening chest CT to confirm the absence of clinically significant comorbidities.

[0137] In one embodiment, a patient has the aforementioned ≤ grade 2 thyroid endocrine disorder if it is adequately controlled with thyroid hormones and remains stable for at least two months with treatment.

[0138] In one embodiment, the patient has skin toxicity that recovers to grade ≤ 1.

[0139] In one embodiment, the patient does not have active keratitis or corneal ulcer formation.

[0140] In one embodiment, the patient does not have Grade ≥ 2 peripheral neuropathy.

[0141] In one embodiment, the patient does not have clinically relevant troponin elevation.

[0142] In one embodiment, the patient does not have uncontrolled diabetes, defined as hemoglobin A1c (HbA1c) ≥ 8%.

[0143] In one embodiment, the patient has not undergone major surgery (excluding vascular access placement) within four weeks of the first administration of the liquid formulation or liquid unit dosage form described herein, and has adequately recovered from prior treatment with the liquid formulation or liquid unit dosage form described herein.

[0144] In one embodiment, the patient has not received live or attenuated vaccine within 30 days of the test treatment.

[0145] In one embodiment, the patient is not known to have active or untreated CNS metastases and / or carcinomatous meningitis. In one embodiment, the patient, whose brain metastases have been treated, is stable or reduced on a dose of 10 mg of prednisone per day or less, without steroid use, and is free from any symptoms interfering with the assessment of neurological and other adverse events, and is stable for at least 4 weeks prior to treatment with the liquid formulation or liquid unit dosage form described herein.

[0146] In one embodiment, the patient does not have uncontrolled hypertension (systolic blood pressure [BP] ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg, or systolic BP ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg) prior to the first administration of BT8009.

[0147] In one embodiment, the patient has no history or current evidence of any condition, treatment, or abnormal clinical laboratory values ​​that would interfere with the trial results, prevent the patient from participating, or, in the opinion of the investigator, would not be in the patient's best interest to participate.

[0148] In one embodiment, the patient has no history of cerebrovascular events (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure, or New York Heart Association class III-IV symptoms documented within six months prior to the first administration of BT8009.

[0149] In one embodiment, the patient does not have a mean resting-adjusted QT interval (QTcF) > 470 msec within six months prior to the first administration of the liquid formulation or liquid unit dosage form described herein.

[0150] In one embodiment, the patient has no factors that increase the risk of QTc prolongation or arrhythmic events, such as heart failure, hypokalemia, a family history of congenital long QT syndrome, long QT syndrome, or sudden, unexplained death before age 40, or any concomitant medications known to prolong the QT interval, within six months prior to the first administration of the liquid formulation or liquid unit dosage form described herein.

[0151] In one embodiment, the patient has not had any clinically significant abnormalities of resting electrocardiogram (ECG) rhythm, conduction, or morphology, such as complete left bundle branch block or third-degree heart block, within six months prior to the first administration of the liquid formulation or liquid unit dosage form described herein.

[0152] In one embodiment, the patient does not have human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). In another embodiment, the patient's HIV is well-controlled if a) CD4+ T cell (CD4+) count ≥ 350 cells / μL; b) HIV viral load < 400 copies / mL; c) no history of opportunistic infections within the last 12 months; and d) has been receiving established antiretroviral therapy (ART) for at least 4 weeks.

[0153] In one embodiment, the patient is not positive for hepatitis B surface antigen and / or anti-hepatitis B core antibody.

[0154] In one embodiment, the patient is polymerase chain reaction (PCR) negative and has received appropriate antiviral treatment.

[0155] In one embodiment, if a patient is positive for hepatitis C virus (HCV) antibodies, they do not have an active hepatitis C infection that is positive for viral load.

[0156] In one embodiment, the patient has been treated for hepatitis C infection and has a persistent virological response of ≥12 weeks.

[0157] In one embodiment, the patient has not had any other malignancies within three years prior to the first administration of the liquid formulation or liquid unit dosage form described herein. In another embodiment, the patient has no residual disease from any previously diagnosed malignancies (excluding basal cell carcinoma, cutaneous squamous cell carcinoma, cervical intraepithelial neoplasia / cervical carcinoma in situ, melanoma in situ, or ductal carcinoma in situ that have been appropriately treated for curative purposes).

[0158] In one embodiment, the patient does not have an active systemic infection requiring treatment or a fever not attributable to a root malignancy within 14 days immediately preceding the first administration of the liquid formulation or liquid unit dosage form described herein.

[0159] In one embodiment, the patient does not require quarantine / isolation because there is no suspicion or resolution of related and recent systemic viral syndrome.

[0160] In one embodiment, the patient does not have prior Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) due to any MMAE conjugate drug. [Examples]

[0161] The following examples are intended to illustrate the present invention and should not be construed as limiting them thereto. Unless otherwise specified, all amino acids were used in the L-configuration.

[0162] List of Abbreviations [Table 2] [Table 3] [Table 4]

[0163] Example 1. Phase I / II study of the safety, pharmacokinetics, and preliminary clinical activity of BT8009 in patients with advanced malignancies associated with nectin-4 expression. Number of patients: This trial is planned to enroll a maximum of approximately 329 patients; approximately 60 in Part A-1, up to 15 in Part A-2, up to 236 in Part B (up to 43 each in cohorts B-1, B-2, and B-3; up to 29 in cohorts B-4, B-5, and B-6; and up to 20 in cohort B-7), and up to 18 in Part C.

[0164] Purpose: Main purpose

[0165] The objectives of the dose escalation (parts A-1 and A-2) and the renal impairment (part C) cohort are: Main purpose ●Evaluation of the safety and tolerability of BT8009 in patients with advanced solid tumors associated with nectin-4 expression: a) as monotherapy (Part A-1), b) in combination with pembrolizumab (Part A-2), c) in patients with advanced solid tumors and renal impairment (Part C) ● If observed, determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of BT8009 as monotherapy or in combination with pembrolizumab (Parts A-1 and A-2) (Note: More than one RP2D may be reported based on the overall safety, efficacy, and PK data.) secondary purpose ●Preliminary signaling of antitumor activity achieved with BT8009 administration in patients with advanced solid tumors associated with nectin-4 expression using RECIST 1.1: a) as monotherapy (Part A-1), b) in combination with pembrolizumab (Part A-2), c) in patients with advanced solid tumors with renal impairment (Part C) ● Evaluation of renal dysfunction in response to BT8009 and monomethyl auristatin E (MMAE) pharmacokinetics (Part C) ● Determination of pharmacokinetic (PK) parameters for BT8009 and MMAE ● Determination of the event of anti-drug antibody (ADA) development

[0166] Dosage expansion

[0167] The objectives of the dose expansion cohort (Part B) are: Main purpose ● Evaluation of the objective response rate (ORR) of BT8009 as monotherapy in patients with EV-exposed (B-1) or EV-naive (B-2 and B-3) urothelial carcinoma using RECIST V1.1 (patients with metastatic urothelial carcinoma) ● Evaluation of ORR of BT8009 as monotherapy in patients with nectin-4 expression-related solid tumor indications (parts B-4 [ovarian], B5 [TNBC], and B-6 [NSCLC]) using RECIST V1.1. ● Evaluation of ORR of BT8009 in combination with pembrolizumab using RECIST 1.1 in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (B-7) secondary purpose ●Evaluation of the safety and tolerability of BT8009 in patients with nectin-4-related solid tumor indications as monotherapy (Parts B-1-B-6) and in combination with pembrolizumab (Part B-7). ● Evaluation of other parameters of clinical activity ● Determination of pharmacokinetic (PK) parameters of BT8009 and MMAE ● Determining the events that led to the occurrence of ADA

[0168] Test design

[0169] This trial is a Phase I / II, first-in-human, open-label dose-escalation study of BT8009 administered as monotherapy (Parts A-1, B, and C) and in combination with pembrolizumab (Parts A-2 and B-7). The trial has three parts: Part A: dose escalation (A-1), dose tapering in combination with pembrolizumab (A-2); Part B: dose expansion; and Part C: renal impairment.

[0170] Part A

[0171] Part A compares BT8009 in patients with histologically confirmed malignant solid tumors that are nectin-4 positive. Part A-1 is dose escalation of BT8009 monotherapy, and Part A-2 is dose escalation of BT8009 plus pembrolizumab (starting at Part A-1 RP2D, then progressing one dose level lower if Part A-1 RP2D is not tolerated in combination). The scheme for Part A is shown in Figure 1.

[0172] Part B

[0173] Part B involves dose expansion in BT8009 RP2D. The scheme for Part B is shown in Figure 2.

[0174] Part C

[0175] Part C is a cohort to be conducted in patients with moderate to severe renal impairment and locally advanced or metastatic urothelial carcinoma, ovarian cancer, triple-negative breast cancer, or non-small cell lung cancer. Up to 12 patients will be enrolled in the moderate renal impairment cohort (CrCl 30–49 ml / min) and up to 6 patients in the severe renal impairment cohort (CrCl 15–29 ml / min). (Part C is not enrolled in Canada.) The Part C scheme is shown in Figure 3.

[0176] Test drug, dosage, and method of administration: ●The BT8009 data for increasing (Part A-1) and decreasing (Part A2) doses in the dose escalation / decrease cohorts, as well as the RP2D(B) in the expanded cohort and the renal cohort (C), respectively. Administered intravenously over 1 hour (-5 / +15 minutes). More than one RP2D may be reported from the overall safety, efficacy, and PK data. ● Pembrolizumab is administered at a dose of 200 mg over 30 minutes (-5 / +15 minutes) on day 1 every 3 weeks as a combination therapy of parts A-2 and B-7.

[0177] Inclusion criteria - all patients: To participate in the research study, patients must meet the following criteria: 1. Written informed consent signed and dated by the patient or legal guardian prior to any trial-specific procedure, sampling, or analysis. 2. At least 18 years of age at the time of signing the informed consent form. 3. US East Coast Cancer Group (ECOG) Performance Status Score of 0 or 1. Patients in Cohort B-7 (cisplatin-ineligible urothelial carcinoma) may be ECOG 2, but must meet further criteria (see Incl #29). 4. Patients must have a measurable disease according to the Guidelines for Evaluating the Effectiveness of Treatment for Solid Tumors (RECIST) v1.1. The previously radiotherapy-treated target lesion must be measurable if it is proven that progression is occurring. 5. Acceptable organ function as demonstrated by the following clinical test values: a. The following renal function: Creatinine clearance (CrCl) of ≥50 mL / min as measured by the Cockcroft-Gault formula or equivalent. (Excluding patients in the renal impairment cohort [Part C]) b. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) c. Serum albumin ≥ 2.5 g / dL d. Aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver metastases. e. Alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver metastases. f. Unless the patient is receiving a stable dose of anticoagulant therapy, an international normalized ratio (INR) ≤ 1.5 or ≤ tissue ULN and PT or aPPT is within the therapeutic range of the intended use of the anticoagulant. 6. Acceptable hematological functions (no red blood cell or platelet transfusions or growth factors within 4 weeks of the first dose of BT8009; excluding patients in the renal impairment cohort [Part C]): a. Hemoglobin ≥ 9 g / dL b. Neutrophil absolute count (ANC) ≥ 1500 cells / mm³ 3 c. Platelet count ≥75,000 cells / mm 3 7. For women of childbearing potential (WOCBP), a negative pregnancy test (negative serological test at screening and negative urine or serological test within 3 days prior to the first dose of BT8009). 8. Archived tumor samples are available or the doctor is willing to provide fresh tumor biopsies during screening. 9. Based on the clinical trial physician's judgment, the life expectancy after initiation of BT8009 treatment is ≥ 12 weeks. 10. Participants must be willing and able to follow the protocol, scheduled visits, treatment plan, trial constraints, clinical tests, contraception guidelines, and other trial procedures. Further inclusion criteria - Part A-1 (Dose escalation in monotherapy) 11. All standard treatment options, including appropriate targeted therapy, must have been exhausted; patients for whom there are no standard treatments deemed appropriate or clinically beneficial by the investigator. 12. Patients with the following tumor histology: a. Patients with advanced, histologically confirmed urothelial (transitional cell) carcinoma that has recurred or is refractory to previous treatment; or b. Patients with advanced, histologically confirmed pancreatic, breast, NSCLC, gastric, esophageal, head and neck, or ovarian tumors that have relapsed or are refractory to previous treatment (for nectin-4 expression, fresh tumor biopsy or archived sample testing) Exception: A single-target accelerated cohort may be enrolled patients with advanced solid tumors not limited to the above definition, unless the Safety Review Board (SRC) expresses a different view. (Single-target cohorts are not enrolled in Canada and the UK, and in Spain, nectin-4 positivity must be confirmed.) The sponsor may require a) or b) at any point during enrollment. The sponsor and / or SRC may determine the need to enroll a particular tumor (sub)type at any point during escalation to enhance the evaluation of biomarkers, safety, antitumor activity, or PK. Further inclusion criteria - Part A-2 (combination with pembrolizumab) 13. All standard treatment options, including appropriate targeted therapy, must have been exhausted; patients for whom there are no standard treatments that are considered appropriate or clinically beneficial, as assessed by the investigator. 14. Patients with histologically confirmed urothelial (transitional cell) carcinoma that has progressed, advanced, or is progressive after previous treatment. Further inclusion criteria - Part B-1 (EV-exposed urothelial carcinoma) 15. The patient must have histologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Patients with squamous differentiated or mixed cell type are eligible. Patients with resectable locally advanced urothelial carcinoma are ineligible. 16. Patients must have received prior treatment with a CPI (PD-1 or PD-L1 inhibitor), if approved locally, in a setting of locally advanced or metastatic urothelial carcinoma. Patients who have received CPI treatment in a neoadjuvant / adjuvant setting and have experienced relapse or progressive disease during treatment or within 3 months of completing treatment are eligible. Patients must meet one of the following criteria: ○ Patients who have previously received platinum-containing chemotherapy with an adjuvant / neoadjuvant setting have experienced relapse or progressive disease within 12 months of completion, or have received treatment with a platinum regimen for locally advanced (unresectable for curative purposes) or metastatic disease. Patients who are platinum-naive or platinum-ineligible based on the investigator's assessment, have not received prior treatment with platinum-containing or other chemotherapy in a locally advanced or metastatic setting, and are ineligible for platinum treatment at the time of enrollment. Patients who received platinum in an adjuvant / neoadjuvant setting and did not complete treatment within 12 months are considered platinum-naive. 17. Must have had progression or recurrence of urothelial carcinoma during or after the most recent treatment. 18. Treatment with enfortumab vedotin (EV) first. Further inclusion criteria - B-2 and B-3 (EV naive urothelial carcinoma) 19. The patient must have histologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Patients with squamous differentiated or mixed cell type are eligible. Patients with resectable locally advanced urothelial carcinoma are ineligible. 20. Patients must have received prior treatment with a CPI (PD-1 or PD-L1 inhibitor), if approved locally, in a setting of locally advanced or metastatic urothelial carcinoma. Patients who have received CPI treatment in a neoadjuvant / adjuvant setting and have experienced relapse or progressive disease during treatment or within 3 months of completing treatment are eligible. Patients must meet one of the following criteria: ○ Patients who have previously received platinum-containing chemotherapy with an adjuvant / neoadjuvant setting have experienced relapse or progressive disease within 12 months of completion, or have received treatment with a platinum regimen for locally advanced (unresectable for curative purposes) or metastatic disease. Patients who are platinum-naive, platinum-ineligible, or have locally advanced or metastatic disease and have not received prior treatment with platinum-containing or other chemotherapy, and are ineligible for platinum treatment at the time of enrollment. Patients who received platinum in an adjuvant / neoadjuvant setting but did not complete the treatment within 12 months are considered platinum-naive. 21. Must have had progression or recurrence of urothelial carcinoma during or after recent treatment. Further inclusion criteria - Part B-4 (Ovarian Cancer) 22. Patients with histologically confirmed non-mucinous epithelial ovarian (serous, endometrioid, clear cell, carcinosarcoma, and mixed forms), fallopian tube, or primary peritoneal cancer that has progressed after prior treatment and is stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) or tumor, nodule, and metastatic staging criteria. 23. The patient must have previously been treated with an FDA-approved or locally approved treatment according to local standards of care / local guidance. Further inclusion criteria - Part B-5 (Triple-negative breast cancer) 24. Patients with tumors that have progressed after previous treatment, confirmed to be ER / PR negative (≤10% positive tumor nuclei as recommended by ASCO-CAP guidelines) by immunohistochemistry (IHC), and confirmed to be human epidermal growth factor receptor 2 (HER2) negative (0 and 1) by IHC or fluorescence or chromogenic in situ hybridization (FISH or CISH). Patients whose HER2 results are uncertain by IHC must have their negative status confirmed by FISH. 25. The patient must have previously been treated with an FDA-approved or locally approved treatment according to local standards of care / local guidance. Further inclusion criteria - Part B-6 (Non-small cell lung cancer) 26. Patients with histologically confirmed NSCLC that has progressed after previous treatment and is free of actionable mutations such as epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) fusion oncogenes, or ROS1 absence. Tumors with squamous cell carcinoma and adenocarcinoma histology are acceptable. 27. The patient must have previously been treated with an FDA-approved or locally approved treatment according to local standards of care / local guidance. Further inclusion criteria - Part B-7 (First-line treatment, cisplatin ineligible, metastatic urothelial carcinoma) 28. Patients with locally advanced or metastatic urothelial (transitional cell) carcinoma, or histologically confirmed urothelial (transitional cell) carcinoma. Patients with squamous differentiated or mixed cell type are eligible. Patients with resectable locally advanced urothelial carcinoma are ineligible. 29. Patients must be cisplatin ineligible. Patients will be considered cisplatin ineligible if they meet at least one of the following criteria to enter the study: renal impairment (creatinine clearance [CrCl] of 30–59 mL / min by CG), hearing loss of ≥25 decibels (dB) at two consecutive frequencies, NYHA class III heart failure, or an ECOG (East Coast Cancer Group) performance status (PS) of 2. a. Patients with an ECOG PS of 2 must meet the following additional criteria: i. Hemoglobin ≥ 10 g / dL ii. CrCl≧50mL / min iii. Not having NYHA class III heart failure is acceptable. Further inclusion criteria - Part C (renal insufficiency cohort) 30. Patients must have histologically confirmed urothelial (transitional cell) carcinoma (patients with squamous cell differentiation or mixed cell type are eligible); ovarian; triple-negative breast; or non-small cell lung cancer. 31. Patients with progressive solid tumors are eligible as follows: 1) up to 12 patients with renal function of 30-49 mL / min (as measured by CG); 2) up to 6 patients with renal function of 15-29 mL / min (as measured by CG). 32. The patient must have previously been treated with an FDA-approved or locally approved treatment according to local standard treatment / local guidance.

[0178] Exclusion criteria - all patients: Patients who meet any of the following criteria will be excluded from trial entry: 1. Chemotherapy must be administered within 14 days prior to the first dose of the study treatment. For other anticancer treatments, the treatment must be administered within 28 days or within 5 terminal phase half-lives, whichever is shorter. If the previous immunotherapy was administered, the final dose must be at least 28 days prior to the first dose of BT8009. The previous toxicity must have recovered to grade ≤ 1 according to the Common Terminology Criteria for Adverse Events (CTCAE) v 5.0. (Excluding alopecia that must not exceed Grade 2.) 2. Experimental treatment within 4 weeks of the first administration of BT8009. 3. Current treatment with strong inhibitors or inducers of CYP3A or P-gp inhibitors, including herbal or food-based agents. 4. Known hypersensitivity to any component of the investigational product, including MMAE. 5. Significant medical conditions, including but not limited to skin conditions (including autoimmune conditions such as eczema or psoriasis, or conditions associated with or that may interfere with monitoring skin lesions), life-threatening illness, uncontrolled infection or organ system dysfunction (e.g., ascites, coagulation disorders, encephalopathy), or, in the opinion of the investigator, any other reason that would interfere with or impair the completeness of the trial outcomes, including consideration of gastrointestinal, skin, and pulmonary comorbidities and review of screening chest CT to confirm the absence of clinically significant comorbidities. Prior ≤ Grade 2 thyroid endocrine disorders are acceptable if they are adequately controlled with thyroid hormones and stable for at least two months with treatment. Skin toxicity must recover to Grade ≤ 1. 6. Active keratitis or corneal ulcer formation. 7. Grade ≥ 2 peripheral neuropathy. 8. Clinically relevant troponin elevation (considering local reference standards). 9. Uncontrolled diabetes mellitus, defined as hemoglobin A1c (HbA1c) ≥ 8% 10. Major surgery (excluding vascular access placement) within 4 weeks of the first administration of BT8009 must be adequately recovered before the start of the study treatment. 11. The animal has received live or attenuated vaccine within 30 days of the test treatment. 12. Known active or untreated CNS metastases and / or carcinomatous meningitis. (To be eligible, patients with treated brain metastases may participate in the study if they are stable or have been reduced to a dose of 10 mg prednisone or less per day without steroid use and have been free from any symptoms interfering with the assessment of neurological and other adverse events for at least 4 weeks prior to the first dose.) 13. Patients with uncontrolled hypertension (systolic blood pressure [BP] ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg) prior to the first administration of BT8009. 14. A history or current evidence of any condition, treatment, or abnormal clinical laboratory values ​​that would interfere with the trial results, prevent patient participation, or, in the opinion of the investigator, would not be in the patient's best interest: a. Patients with a history of documented cerebrovascular events (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure, or symptoms of New York Heart Association class III-IV within 6 months prior to the first administration of BT8009, or: i. Average resting corrected QT interval (QTcF)>470msec ii. Any factors that increase the risk of QTc prolongation or arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, a family history of long QT syndrome or sudden unexplained death before age 40, or any concomitant medications known to prolong the QT interval. iii. Any clinically significant abnormalities in the rhythm, conduction, or morphology of the resting electrocardiogram (ECG), such as in complete left bundle branch block or third-degree heart block (as assessed by the investigating physician). 15. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). Note: Well-controlled HIV is acceptable if the patient meets all of the following criteria at the time of participation: a) CD4+ T cell (CD4+) count ≥ 350 cells / μL; b) HIV viral load < 400 copies / mL; c) no history of opportunistic infections within the past 12 months; d) currently receiving established antiretroviral therapy (ART) for at least 4 weeks. The use of antiretroviral therapy is acceptable but must be reviewed individually with a medical monitor. 16. Patients who are positive for hepatitis B surface antigen and / or anti-hepatitis B core antibody. Patients who test negative for polymerase chain reaction (PCR) assay are acceptable with appropriate antiviral treatment. 17. If positive for hepatitis C virus (HCV) antibodies, active hepatitis C infection with a positive viral load (if antibodies are negative, viral load is not applicable). Patients being treated for hepatitis C infection may participate if they have documented a sustained virologic response of ≥ 12 weeks. 18. A history of another malignancy within 3 years prior to the first administration of BT8009, or any evidence of residual disease from a previously diagnosed malignancy (excluding basal cell carcinoma, cutaneous squamous cell carcinoma, cervical intraepithelial neoplasia / carcinoma in situ, melanoma in situ, or non-invasive ductal carcinoma of the breast that has been appropriately treated for curative intent). 19. Active systemic infection requiring treatment within 14 days prior to the first administration of BT8009, or fever not attributable to underlying malignancy. 20. In the opinion of the investigator, a need for quarantine / isolation due to suspected or unresolved recent systemic viral syndrome 21. Psychiatric, familial, sociological, or geographical conditions that would prevent compliance with the protocol and / or follow-up procedures outlined in the protocol. 22. Prior Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) with any MMAE conjugate drug.

[0179] Additional exclusion criteria Part A-2 (in combination with pembrolizumab) 23. Prior intolerance or known hypersensitivity to immune checkpoint inhibitors 24. Having received any prior treatment with stimulatory or coinhibitory T cell receptor agents such as CD137 agonist, OX-40 agonist, or CTLA-4 inhibitor a. Prior treatment with a PD-1, PD-L1, or PD-L2 inhibitor is allowed 25. Prior organ transplantation (including allografts) 26. Diagnosis of clinically relevant immunodeficiency 27. Any condition requiring treatment with ≥ 10 mg prednisone equivalent per day or other strong immunosuppressive agents 28. Having an active autoimmune disease that required systemic treatment in the past 2 years (e.g., with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapies (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered a form of systemic treatment. Patients with type 1 DM well-controlled with insulin, alopecia areata, or vitiligo are not excluded by this criterion. 29. History of interstitial lung disease

[0180] Additional exclusion criteria B-2 and B-3 (EV-naïve urothelial carcinoma) 30. Prior treatment with EV.

[0181] Additional exclusion criteria Part B-7 (first choice, cisplatin-ineligible, metastatic urothelial carcinoma) 31. Prior organ transplantation (including allografts) 32. Diagnosis of clinically relevant immunodeficiency 33. Any condition requiring treatment with ≥10 mg prednisone equivalent per day or other strong immunosuppressive agents 34. Having an active autoimmune disease that required systemic treatment in the past 2 years (i.e., with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) 35. History of interstitial lung disease 36. Having received any systemic anti-cancer treatment for advanced or metastatic urothelial carcinoma 37. Having received prior adjuvant / neoadjuvant platinum-based treatment within 12 months before the first dose 38. Having received prior adjuvant / neoadjuvant immune checkpoint inhibitor treatment within 12 months before the first dose 39. Having received prior treatment with EV or other MMAE-based ADC for urothelial carcinoma at some point

[0182] Correlation study: All patients require the provision of archived tumor material or fresh tumor biopsy for further analysis of molecular genetic characteristics, including, but not limited to, nectin-4 expression levels and immune checkpoint status (e.g., PD-L1 tumor expression), or markers of proliferation (e.g., Ki-67, pHH3) and / or immunogenic cell death. This material should be provided as tissue blocks or 10-15 paraffin-immersed unstained slides.

[0183] Optional post-administration biopsies may be collected to investigate the intratumoral PK / pharmacodynamic effects of BT8009. Post-administration biopsies will be requested from at least six patients in Part B. Post-administration biopsies may be taken within 4 hours to 7 days after BT8009 administration for patients in Part A-1 during cycles 1-4, and for all other patients during cycle 1 only. See the Evaluation Schedule (SOA) for further details.

[0184] Pre- and post-administration blood samples are also collected for evaluation of pharmacodynamic, response, and treatment resistance biomarkers, such as somatic mutations in circulating tumor DNA (ctDNA), ADA, and genomic pharmacological analysis.

[0185] statistical methods Dose escalation / decreasing (applied separately to A-1 and A-2) is initiated in one subject (A-1 only), and a 3+3 escalation is primarily used. BLRM using the EWOC principle is also applied to cumulative DLT / safety data for SRC considerations in dose escalation recommendations.

[0186] For cohorts B-1 to B-6 in Part B, Simon's two-stage design is used to test whether ORR warrants persist into the next phase. The design allows for early futility confirmation and minimization of the predicted total sample size, with a Type I error of 0.05 and a power of 80%.

[0187] The overall statistical analysis uses descriptive summary statistics. Response endpoints are reported using proportions along with their associated 95% confidence intervals (CIs).

[0188] Example 2. BT8009 formulation The BT8009 drug is formulated as a sterile lyophilized powder for solution. The drug is placed in a 10 mL Type I clear glass vial with a chlorobutyl stopper and aluminum seal. The label strength of each vial is 21.2 mg / vial for reconstitution in 5.0 mL of water for injection (WFI). A 4 mg / mL BT8009 solution is produced by displacing 0.3 mL of the drug (the reconstituted drug substance contains L-histidine, sucrose, and polysorbate 20). 5.0 mL of the reconstituted solution is withdrawn to obtain a 20 mg dose, which is further diluted with approximately 0.9% saline and administered by IV infusion.

[0189] Example 3. Review and Opinion on the Results of the BT8009 Phase I Clinical Trial Compared to antibodies, BT8009 exhibits antitumor activity in previously severely treated urothelial (Figures 5-7), lung (Figures 8A, 9A), and breast cancer (Figures 8B, 9B) patients with signs of differentiation, demonstrating the potential of an industry-leading product profile. BT8009 is administered at 5 mg / m². 2 The qw dose showed a 50% ORR and 75% clinical benefit rate (Figure 7), including one (13%) complete response in urothelial carcinoma (Figures 5-7). The breadth of responses in other dose cohorts and other cancer types explains the drug's potential. BT8009 demonstrated a sustained response, and tumor reduction was maintained over time (Figure 6). The median response time was 5 mg / m². 2 In the cohort, urothelial patients had not yet reached response; at least 11 months (September 20, 2022) at the clinical trial data cutoff. The median response time was estimated to be approximately 14 months, with 2 out of 4 responders still receiving treatment. Figures 10–16 show the incidence of targeted adverse events (TEAEs) that occurred under the investigational treatment during the trial. These are the first-in-human data for the bicyclic toxin conjugate targeting nectin-4. These data demonstrate a positive efficacy and safety profile. Furthermore, these data suggest that BT8009 has potential advantages over existing treatments such as enfortumab vedotin.

[0190] Example 4: Modeling supporting the dosing strategy Modeling and simulation evaluations, including population PK and exposure-response modeling analyses, were performed for various dosing strategies (uniform, body weight-based, and BSA-based dosing) using pharmacokinetic (PK), efficacy, and safety data from ongoing Phase I clinical trial data. PK exposures (AUC and Cmax) for BT8009 and MMAE were estimated from population PK models, followed by the simulation of adverse event (AE) probabilities using exposure-safety logistic regression modeling. From the modeling, it was found that the use of uniform dosing of BT8009 (mg) was superior to that of BSA-based dosing (mg / m²). 2 Similar PK and safety outcomes are expected. Uniform dosing offers practical and clinical advantages over BSA-based dosing, including easier dose adjustment, reduced potential for medication errors, and minimized drug waste, making it more convenient in clinical practice.

[0191] Figure 17 shows the treatment-related adverse event (TRAE) rates for various exposures to MMAEs from BSA-based dosing. Higher AE rates were observed with higher BSA levels, suggesting that uniform dosing helps balance AEs across different body sizes.

[0192] Population PK and exposure-safety modeling support switching to a uniform (fixed) dose. Data indicate that BSA or body weight-based dosing can result in high adverse events (AEs), necessitating body weight-based regulation (e.g., Padsev). 5 mg / m² 2 Instead, a uniform (fixed) dose, such as 9 mg of BT8009, is broadly equivalent to BSA administration in terms of mean PK exposure and provides similar PK variability to BSA administration, but can improve adverse events based on safety assessments while maintaining efficacy (Figure 18). This simplifies the administration of BT8009 and reduces medication errors and drug waste.

[0193] Example 5. Phase II / III trial of the efficacy of BT8009 monotherapy or combination therapy for locally advanced or metastatic urothelial carcinoma. Number of participants: This trial will enroll approximately 750 participants with locally advanced or metastatic urothelial carcinoma (UC). Cohort 1 will include approximately 555 participants with locally advanced or metastatic UC who have not received any prior systemic therapy. Cohort 2 will include approximately 195 participants with locally advanced or metastatic UC who have received ≥1 prior systemic therapy.

[0194] Objectives: Primary objective The objectives of Cohort I are: Primary objective ● Evaluation of the efficacy of combination of pembrolizumab and BT8009 compared to standard of care (SOC) chemotherapy, measured by progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for determination of treatment effect of solid tumors evaluated by blinded central independent review (BICR), from the first dose date until disease progression is determined by BICR or death (from any cause), measured by the length of the period. Secondary objectives ● Evaluation of clinical activity by objective response rate (ORR) according to RECIST v1.1, measured by the percentage of participants in the analysis set in whom achievement of complete response (CR) or partial response (PR) is confirmed, evaluated by BICR and the investigator, according to RECIST v1.1. ● Evaluation of overall survival (OS), defined as the length of the period from the first dose date until death from any cause. ● Evaluation of clinical activity measured by duration of response (DOR), measured by the period from the first documentation of an objective response (subsequently confirmed) according to RECIST v1.1, evaluated by BICR and the investigator, until the first documentation of objective tumor progression (according to RECIST v1.1) or death (from any cause), and disease control rate (DCR), measured by the percentage of participants who experience CR, PR, or stable disease (SD) according to RECIST v1.1, evaluated by BICR and the investigator. ● Physician-administered PFS assessment in accordance with RECIST v1.1, measured by the length of time between the first administration date and the determination of disease progression or death (of any cause) by the investigator. ● Evaluation of the safety and tolerability of BT8009 in combination with pembrolizumab, measured by the incidence of adverse events (TEAEs) occurring during investigational treatment, as well as abnormalities in laboratory values, electrocardiograms, and vital signs. ● Pharmacokinetic characterization of BT8009 and monomethyl auristatin E (MMAE). ● Health-related quality of life (HRQOL) (changes in Euroqol-5 Dimensions (EQ-5D) and the European Organisation for Research and Treatment of Cancer quality of life questionnaire core 30 (EORTC QLQ-C30)). search ● Exploration of the incidence and titer of anti-drug antibodies (ADAs) against BT8009 and pembrolizumab, and the correlation of any potential immunogenic responses with potential relationships to pharmacokinetics, safety, and efficacy. ● Exploring the correlation between peripheral and tumor biomarkers and clinical activity - Baseline tumor and peripheral biomarkers include nectin-4 and programmed death-ligand 1 (PD-L1) expression, soluble targets and inflammatory cytokines, tumor mutations, genomic pharmacology, circulating tumor DNA (ctDNA), and gene signatures. ● Exploring the correlation between pharmacokinetic (PK) and pharmacodynamic biomarker activity and clinical outcomes, measured by changes in tumor and peripheral biomarkers, including nectin-4 protein expression, somatic mutations, soluble targets and inflammatory cytokines, ctDNA, and gene signatures, in tumor tissue.

[0195] The objectives of Cohort 2 are: Main purpose: ●Evaluation of the efficacy of BT8009 monotherapy, as measured by ORR, as assessed by BICR and in accordance with RECIST v1.1, and by the percentage of participants in the analysis population who achieved CR or PR according to RECIST v1.1. Secondary purpose: ● Assessment of ORR, as assessed by the investigator and in accordance with RECIST v1.1, measured by the percentage of participants in the analysis population who achieved CR or PR according to RECIST v1.1. ●DOR, measured by BICR and investigators as the time from the first documented objective response (followed confirmation) in accordance with RECIST v1.1 to the first documented objective tumor progression (in accordance with RECIST v1.1) or death (of any cause); DCR, measured by BICR and investigators as the percentage of participants who experienced CR, PR, or SD in accordance with RECIST v1.1; and PFS, measured by BICR and investigators as the length of time from the first administration to the determination of disease progression or death (of any cause) in accordance with RECIST v1.1. ● Overall survival (OS) is defined as the length of time from the first administration date until death from any cause. ● Evaluation of the safety and tolerability of BT8009, measured by the incidence of TEAEs and abnormalities in laboratory values, ECG, and vital signs. ● Evaluation of severe skin adverse reactions (SCARs) and peripheral neuropathy - Incidence and severity of CARs and peripheral neuropathy events classified according to Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) broad (scope) terms. ●Characterization of the pharmacokinetics of BT8009 and MMAE as measured by their pharmacokinetic parameters. ●Assessment of HRQOL measured by changes in EQ-5D and EORTC QLQ-C30. search ● Exploration of the incidence and titer of ADA in relation to BT8009, and exploration of potential relationships between any potential immunogenic responses and pharmacokinetics, safety, and efficacy. ● Exploring the correlation between peripheral and tumor biomarkers and clinical activity - Baseline tumor and peripheral biomarkers include nectin-4 expression, soluble targets and inflammatory cytokines, tumor mutations, genomic pharmacology, ctDNA, and gene signatures. ● Evaluation of the correlation between BT8009 PK and pharmacodynamic biomarker activity and clinical outcomes, measured by changes in tumor and peripheral biomarkers, including nectin-4 protein expression and somatic mutations, soluble targets and inflammatory cytokines, ctDNA, and gene signatures in tumor tissue.

[0196] Overall design: This is an adaptive, multicenter, randomized, open-label phase 2 / 3 clinical trial.

[0197] Summary: The objective of this study is to measure the efficacy and safety of BT8009 in combination with pembrolizumab versus standard-of-care (SOC) chemotherapy (Cohort 1) and BT8009 monotherapy (Cohort 2) in participants with locally advanced or metastatic ulcerative colitis (UC).

[0198] Cohort 1 study design (pre-treated): Participants with advanced or metastatic UC who had not received any prior systemic treatment were randomized in a 1:1:1 ratio at the investigator's discretion to receive BT8009 9 mg + pembrolizumab, BT8009 11 mg + pembrolizumab, or SOC chemotherapy (gemcitabine and cisplatin or carboplatin, followed by avelumab maintenance, if indicated). Participants were stratified by cisplatin eligibility (cisplatin eligible vs. cisplatin ineligible), liver metastases (yes vs. no), and East Coast Cancer Group (ECOG) performance status (0 / 1 vs. 2). Within the chemotherapy arm, the proportion of participants receiving cisplatin-based chemotherapy was limited to approximately 50%. An interim analysis (IA1) will be conducted for the first approximately 30 participants in each BT8009 dose-level arm who have been at least 4 months since the first dose of the study treatment, have discontinued the study for any reason, or have experienced disease progression (whichever occurred first) to select the optimal dose of BT8009 in combination with pembrolizumab. Participant enrollment will continue in the optimal dose of BT8009 in combination with pembrolizumab arm, while enrollment in treatment arms for BT8009 doses not selected based on the IA1 results will be stopped.

[0199] If approximately 120 participants in the BT8009 selection dose in combination with pembrolizumab have been present for at least 6 months since the first dose of the study treatment, have discontinued the study for any reason, or have experienced disease progression (whichever occurred first), a second interim analysis (IA2) will be conducted to evaluate the efficacy of BT8009 in combination with pembrolizumab based on assessment of ORR by BICR.

[0200] Participants will be randomized in a 1:1 ratio to either the optimal dose of BT8009 in combination with pembrolizumab or the chemotherapy arm until each arm has approximately 215 participants. The primary analysis will evaluate the efficacy of BT8009 in combination with pembrolizumab based on PFS assessment using BICR, and will be conducted when approximately 357 events occur in the comparison between the BT8009 selection dose in combination with pembrolizumab and chemotherapy. The final analysis will include an assessment of overall survival (OS).

[0201] Cohort 2 study design (prior treatment): Participants who have already received ≥1 systemic treatment for UC will be randomized in a 2:2:1 ratio to receive BT8009 9 mg monotherapy, BT8009 11 mg monotherapy, or enfortumab vedotin. An interim analysis will be conducted on the first approximately 30 participants in each BT8009 arm who have discontinued the study for any reason or experienced disease progression (whichever occurred first) at least 4 months after the first dose of the study treatment to select the optimal BT8009 dose. Participant enrollment will continue in the optimal BT8009 dose and enfortumab vedotin arms, while enrollment in the treatment arms for BT8009 doses not selected based on the IA1 results will be stopped.

[0202] A primary analysis will be conducted to evaluate the efficacy of BT8009 monotherapy based on ORR assessment by BICR in all 110 participants in the BT8009 optimal dose arm when at least 6 months have passed, the trial has been discontinued for any reason, or disease progression has occurred (whichever occurs first).

[0203] Treatment and Discontinuation (Both Cohorts): In both cohorts, the study treatment will be continued until one of the discontinuation criteria is met. The discontinuation criteria include disease progression (confirmed by radiography according to RECIST v1.1), irreversible or unbearable toxicity, investigator's decision to discontinue participant, participant's decision to discontinue the study treatment, confirmation of pregnancy, severe non-compliance with the study treatment or procedure requirements, loss of follow-up, death, or sponsor's decision to terminate the study. For participants who discontinue the study treatment for reasons other than radiographic progression, efficacy assessments will be conducted at specific intervals until the first of the following occurs: disease progression, initiation of new anti-cancer therapy, withdrawal of consent, loss of follow-up, death, or sponsor's termination of the study. Discontinuation is defined as withdrawal of consent, loss of follow-up, death, or sponsor's termination of the study (whichever occurs first).

[0204] In Cohort 1, pembrolizumab treatment will be continued until disease progression, unacceptable toxicity occurs, or the treatment period is up to 24 months. If one of the study treatments (BT8009 or pembrolizumab) is discontinued due to treatment-related toxicity, the participant may continue the other study treatment if the investigator deems it to be in the participant's best interest. Chemotherapy treatment is limited to a maximum of 6 treatment cycles.

[0205] Tumor Status Assessment Schedule (Both Cohorts): Participants will undergo tumor status assessments at screening, after day 1 of cycle 1, and every 9 weeks (±5 days) during the first 54 weeks. After 54 weeks, participants will undergo tumor status assessments every 12 weeks (±7 days). Cycle timing should not be delayed in the event of treatment interruption, and tumor status assessments should be conducted according to the study schedule (SOA), regardless of whether or not the study treatment is interrupted.

[0206] EOT and Follow-up T Time Points (Safety and Long-Term) (Both Cohorts): End-of-Treatment (EOT) outpatient visits must be performed within 7 (±2) days of the decision to discontinue all study treatments. If treatment is discontinued for reasons other than confirmation of disease progression, tumor evaluation is required within 2 weeks of discontinuation of all study treatments. For participants in combination therapy (i.e., BT8009 and pembrolizumab combination, gemcitabine and cisplatin or carboplatin combination, or enfortumab vedotin and pembrolizumab combination, all cohort 1), if one study treatment is discontinued, tumor evaluation should continue according to the Service of Analysis (SOA) until all study treatments are discontinued.

[0207] Safety follow-up visits will be conducted 30(+5) days after the last dose of any study treatment or before the initiation of new anticancer therapy, whichever comes first. In Cohort 1, pembrolizumab-related immune-related adverse events and severe adverse events will be monitored until 90 days after the last dose of pembrolizumab or before the initiation of new anticancer therapy, whichever comes first.

[0208] After disease progression is confirmed by BICR, survival and anti-cancer treatment status will be collected every three months (±30 days) until the first of the following occurs: death, loss of follow-up, withdrawal of consent to the trial, or termination of the trial by the sponsor.

[0209] Test arm and duration:

[0210] Cohort 1: Untreated first:

[0211] Arm 1: BT8009 9 mg intravenously (IV) for 60 (-5 to +30) minutes on days 1, 8, and 15 of every 21-day cycle + pembrolizumab 200 mg IV for 30 (-5 to +10) minutes on day 1 of every 21-day cycle. Pembrolizumab infusion should be started 30 minutes after completion of BT8009 infusion.

[0212] Arm 2: BT8009 11 mg IV over 60 (-5 to +30) minutes on day 1 and day 8 of every 21-day cycle + pembrolizumab 200 mg IV over 30 (-5 to +10) minutes on day 1 of every 21-day cycle. Pembrolizumab infusion should be started 30 minutes after completion of BT8009 infusion.

[0213] Arm 3: Up to 6 cycles of one of the following platinum-based combination chemotherapy regimens, at the investigator's discretion: Cisplatin 70 mg / m² over 60 minutes on day 1 of each 21-day cycle 2 IV (or on day 2 if required by local guidelines) + 1000 mg / m² over 30 minutes on days 1 and 8. 2 IV gemcitabine or Carboplatin area under the curve (AUC) 5 mg / mL / min (or 4.5 mg / mL if required by local tissue standards) over 60 minutes on day 1 (or day 2 if required by local tissue standards) of each 21-day cycle; 1000 mg / m² over 30 minutes on days 1 and 8 of IV+. 2 IV gemcitabine.

[0214] Cisplatin or carboplatin infusions are administered 30 minutes after the completion of gemcitabine infusions. Participants may be switched from cisplatin to carboplatin during the trial at the discretion of the investigator if necessary due to clinical factors such as renal impairment.

[0215] Avelumab is acceptable, at the investigator's discretion, as maintenance therapy for participants who have achieved complete response (CR), partial response (PR), or stable disease (SD) after chemotherapy. Avelumab 800 mg IV is administered over 60 minutes on days 1 and 15 of every 28-day cycle.

[0216] Arm 4: Enfortumab vedotin 1.25 mg / kg IV over 30 minutes on days 1 and 8 of every 21-day cycle (up to 125 mg for participants ≥ 100 kg) + pembrolizumab 200 mg IV over 30 minutes (-5 to +10) on day 1 of every 21-day cycle. Sponsors may choose to add this treatment arm based on the potential for a shift towards the UC standard treatment landscape. The enfortumab vedotin infusion should be completed 30 minutes before the start of the pembrolizumab infusion.

[0217] Cohort 2: Treatment first

[0218] Arm 1: BT8009 9 mg IV for 60 (-5 to +30) minutes on days 1, 8, and 15 of each 21-day cycle.

[0219] Arm 2: BT8009 11 mg IV for 60 (-5 to +30) minutes on days 1 and 8 of every 21-day cycle.

[0220] Arm 3: Enfortumab vedotin 1.25 mg / kg IV over 30 minutes on days 1, 8, and 15 of every 28-day cycle (up to 125 mg for participants ≥ 100 kg).

[0221] Admission criteria:

[0222] Participants must meet the following criteria to enter the exam.

[0223] Cohort 1: Untreated first 1. You understand the examination procedures and can consent to participate in the examination by submitting written informed consent. 2. The person must be 18 years of age or older at the time of signing informed consent. 3. Histologically or cytologically confirmed locally advanced (unresectable) or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, and urethra. a. It is necessary that the participant migration cell pattern exhibiting mixed histology is dominant (≥50%). 4. A measurable disease as defined by RECIST v1.1. a. Target lesions located in areas previously treated with radiation are considered measurable if it is proven that progression has occurred in such lesions after irradiation. 5. Participants must not have received prior systemic treatment for locally advanced or metastatic UC, with the following exceptions: a. Prior local intravesical chemotherapy, local surgery if complete resection is not achieved, local immunotherapy, and radiotherapy are acceptable if they were completed at least four weeks prior to the start of the study procedure and all acute toxicity has been resolved. b. The previous neoadjuvant chemotherapy with relapse > 12 months after completion of treatment. c. Cystectomy following adjuvant chemotherapy with recurrence > 12 months after completion of treatment. d. Neoadjuvant / adjuvant immune checkpoint inhibitor treatment more than 12 months after completion of treatment. 6. Performance status of the East Coast Cancer Clinical Group (ECOG) is ≤2. 7. Eligibility requires platinum-based chemotherapy (cisplatin- or carboplatin-based chemotherapy). Note: Once the 50% cisplatin limit is reached, participants who are eligible to receive cisplatin-based chemotherapy will no longer be considered eligible for the trial. 8. Archived or fresh tumor tissue, including muscle-invasive UC or metastatic UC. 9. Life expectancy is ≥ 12 weeks. 10. Appropriate hematological and organ function: a. Hemoglobin ≥ 9 g / dL b. Neutrophil absolute count (ANC) ≥ 1500 cells / mm³ 3 c. Platelet count ≥75,000 cells / mm 3 d. Estimated glomerular filtration rate (eGFR) ≥ 30 mL / min (using the CKD-EPI creatinine formula) e. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) f. Serum albumin ≥ 2.5 g / dL g. Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN in the presence of liver metastases h. Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN in the presence of liver metastases i. Alkaline phosphatase (AP) ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver or bone metastases. j. Unless the participant is receiving a stable dose of anticoagulant therapy, an international normalized ratio (INR) ≤ 1.5 or ≤ tissue ULN and PT or PPT is within the therapeutic range of the intended use of the anticoagulant. 11. For women of childbearing potential (WOCBP), a negative pregnancy test is required (negative serological test at the time of screening and negative urine or serological test within 72 hours prior to administration). 12. Male participants with WOCBP and female partners who may have children should follow a highly effective contraceptive, at least as effective as the contraceptive recommended by the Clinical Trial Facilitation Group with a failure rate of <1%, starting from screening, throughout the trial period, and until at least one month after the first dose of avelumab, four months after the last dose of pembrolizumab, six months after the last dose of BT8009, six months after the last dose of platinum treatment, and twelve months after the last dose of enfortumab vedotin, whichever is later. 13. Male participants of fertile capacity must agree not to donate sperm from the first dose until at least one month after the last dose of avelumab, four months after the last dose of pembrolizumab, six months after the last dose of BT8009, six months after the last dose of platinum treatment, and nine months after the last dose of enfortumab vedotin, whichever is later. Female participants must agree not to breastfeed or donate eggs from the first dose until at least one month after the last dose of avelumab, four months after the last dose of pembrolizumab, six months after the last dose of BT8009, six months after the last dose of platinum treatment, and nine months after the last dose of enfortumab vedotin, whichever is later.

[0224] Cohort 2: Treatment first 1. You understand the examination procedures and can consent to participate in the examination by submitting written informed consent. 2. The person must be 18 years of age or older at the time of signing informed consent. 3. Histologically or cytologically confirmed locally advanced (unresectable) or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, and urethra. a. It is necessary that the participant migration cell pattern exhibiting mixed histology is dominant (≥50%). 4. A measurable disease as defined by RECIST v1.1. a. Target lesions located in areas previously treated with radiation are considered measurable if it is proven that progression is occurring in such lesions. 5. ECOG performance status ≤ 1. 6. Participants must have received systemic treatment for locally advanced or metastatic ulcerative colitis (UC) of ≥1. 7. Progression or recurrence of UC during or after recent treatment. 8. A representative FFPE tumor specimen in paraffin block form (block form preferred) or at least 15 unstained slides. If an archived tumor sample is not available, a fresh biopsy must be provided. 9. Life expectancy is ≥ 12 weeks. 10. Appropriate hematological and organ function: a. Hemoglobin ≥ 9 g / dL b. ANC≧1500 cells / mm 3 c. Platelet count ≥75,000 cells / mm 3 d. eGFR ≥ 30 mL / min (using the CKD-EPI creatinine formula) e. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) f. Serum albumin ≥ 2.5 g / dL g. AST ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver metastases h. ALT ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver metastases. i. AP ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver or bone metastases j. Unless the participant is receiving a stable dose of anticoagulant therapy, an INR ≤ 1.5 ULN or ≤ tissue ULN and PT or PPT is within the therapeutic range of the intended use of anticoagulants. 11. For WOCBP, a negative pregnancy test is required (negative serological test at screening and negative urine or serological test within 72 hours prior to administration). 12. Male participants with WOCBP and female partners who may have children should follow a highly effective contraceptive, at least as effective as the contraceptive recommended by the Clinical Trial Facilitation Group with a failure rate of <1%, starting from screening, throughout the trial period, and for at least 6 months after the last dose of BT8009 and 12 months after the last dose of enfortumab vedotin. 13. Male participants of fertile age must agree not to donate sperm from the first dose until at least 6 months after the last dose of BT8009 or 9 months after the last dose of enfortumab vedotin. Female participants must agree not to breastfeed or donate eggs from the first dose until 6 months after the last dose of BT8009 and 12 months after the last dose of enfortumab vedotin.

[0225] Exclusion criteria: Participants who meet any of the following criteria will be excluded from the exam entry. Cohort 1: Untreated first 1. Prior treatment with enfortumab vedotin or any other MMAE-based therapy. 2. Prior treatment with checkpoint inhibitors for any other malignant tumor. 3. Prior treatment with drugs targeting other stimuli or co-inhibitory T cell receptors. 4. The patient received any other anti-cancer treatment for cancer with the investigational drug, chemotherapy, or biologics that was not completed within 4 weeks prior to the first dose of the study treatment, and who was not otherwise excluded by exclusion criteria 1-3. 5. Active keratitis or corneal ulcer formation. 6. Current treatment with strong inhibitors or inducers of human cytochrome P450 3A4 (CYP3A4), including herbal or food-based inhibitors, or with P-glycoprotein (P-gp) inhibitors. 7. Having an active autoimmune disease requiring systemic treatment in the past two years (i.e., with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). 8. Any condition requiring treatment with high-dose corticosteroids (>10 mg prednisone per day). 9. Known hypersensitivity or allergy to any of the components of the study intervention or to any MMAE. 10. Major surgery within 4 weeks of the first administration (excluding vascular access placement). 11. RBC or platelet transfusion or growth factor within 4 weeks of the first administration. 12. Received live or attenuated vaccine within 30 days of the first dose. 13. Known active or untreated CNS metastases and / or carcinomatous meningitis. a. Participants with treated brain metastases may participate in the study if they are stable or have reduced their dose to 10 mg of prednisone per day or less without the use of steroids, and are free from any symptoms interfering with the assessment of neurological and other adverse events for at least four weeks prior to the first dose. 14. Uncontrolled diabetes mellitus, defined as hemoglobin A1c (HbA1c) ≥ 8%. 15. Peripheral neuropathy of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 2. 16. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures (at least once a month). 17. Uncontrolled hypertension (HTN) prior to the first dose (systolic blood pressure (BP) ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg). 18. Allogeneic stem cell or solid organ transplantation as described above. 19. Active interstitial lung disease or pneumonia requiring treatment with steroids or other immunosuppressive drugs, or a history of interstitial lung disease or pneumonia. 20. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). a. Well-controlled HIV is permitted if the participant meets all of the following criteria at the time of participation: i. CD4+ count ≥350 cells / μL; ii. HIV viral load <400 copies / mL; iii. No history of opportunistic infections in the past 12 months; iv. ART must be established for at least four weeks. The use of ART must be considered individually with a medical monitor on a case-by-case basis. 21. Known active hepatitis B, defined as positive for surface antigen and / or anti-hepatitis B core antibody. Participants negative for polymerase chain reaction assay are acceptable with appropriate antiviral treatment. 22. If HCV antibody is positive, the patient has a known active hepatitis C infection with a positive viral load (if antibody is negative, viral load is not applicable). Patients treated for hepatitis C infection can participate if a sustained virological response of ≥12 weeks has been documented. 23. A medical history or other active malignancy that interferes with the interpretation of safety or efficacy evaluations in a clinical trial. 24. Any prior Grade ≥ 3 immune-related adverse event while receiving immune checkpoint inhibitor therapy. 25. Active systemic infection requiring treatment. 26. Participants have received treatment with oral or IV antibiotics for fever or other non-root malignant tumor within 14 days prior to the start of the study procedure. Participants receiving prophylactic antibiotics are eligible. 27. In the opinion of the investigating physician, there is a need for quarantine / isolation due to suspected or unresolved related and recent systemic viral syndrome. 28. In the opinion of the investigating physician, any medical history or current evidence of any condition, treatment, or abnormal clinical laboratory values ​​that would interfere with the outcome of the trial, would interfere with the participant's ability to participate in the trial for the entire duration, or would not be beneficial to the participant. Participants with a history of cerebrovascular events (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure, or NYHA class III*-IV symptoms documented within 6 months prior to the first administration of BT8009, or: a. Average resting corrected QT interval (QTc) >470 msec. b. Any factor that increases the risk of QTc prolongation, such as congenital long QT syndrome or a family history of long QT syndrome. c. Any clinically significant abnormalities in the rhythm, conduction, or morphology of the resting ECG (as assessed by the investigating physician), e.g., complete left bundle branch block, third-degree heart block. 29. Known mental or substance abuse disorder that interferes with collaboration with the need for the clinical trial. 30. The aforementioned Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) / drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), erythema multiforme, symmetrical drug-associated intertriginous and flexural rash (SDRIFE), or baboon syndrome. 31. Prediction of pregnancy, lactation, having a child, or becoming a father within the duration of the study, starting from the screening visit, up to one month after the last dose of avelumab, four months after the last dose of platinum treatment, six months after the last dose of BT8009, and nine months (for men) and twelve months (WOCBP) after the last dose of enfortumab vedotin, whichever is later. Cohort 2: Treatment first 1. Prior treatment in any systemic anti-cancer therapy within four weeks prior to the start of the trial treatment; the following exceptions are permitted: a. Palliative radiotherapy for bone metastases or soft tissue lesions completed >7 days prior to baseline imaging. 2. Prior treatment with MMAE-based therapy at some point in time. 3. Participation in any other investigational drug or treatment or other clinical trial with therapeutic intent within 4 weeks prior to the first dose of the study treatment. 4. Ongoing clinically significant toxicity (≥ Grade 2) associated with prior treatment for UC (including radiotherapy or surgery). 5. Active keratitis or corneal ulcer formation. 6. Current treatment with P-gp inhibitors, including strong human CYP3A inhibitors or strong inducers, or herbal or food-based inhibitors. 7. Known hypersensitivity or allergy to any component of the study intervention or to any MMAE. 8. Major surgery within 4 weeks of the first administration (excluding vascular access placement). 9. RBC or platelet transfusion or growth factor within 4 weeks of the first administration. 10. Received live or attenuated vaccine within 30 days of the first dose. 11. Known active or untreated CNS metastases and / or carcinomatous meningitis. a. Participants with treated brain metastases may participate in the study if they are stable or have reduced their dose to 10 mg of prednisone per day or less without the use of steroids, and are free from any symptoms interfering with the assessment of neurological and other adverse events for at least four weeks prior to the first dose. 12. Uncontrolled diabetes mellitus, defined as HbA1c ≥ 8%. 13. NCI CTCAE grade ≥ 2 peripheral neuropathy. 14. Uncontrolled HTN (systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure ≥ 95 mm Hg) prior to the first dose. 15. Known HIV or AIDS. a. Well-controlled HIV is permitted if the participant meets all of the following criteria at the time of participation: i. CD4+ count ≥350 cells / μL; ii. HIV viral load <400 copies / mL; iii. No history of opportunistic infections in the past 12 months; iv. ART must be established for at least four weeks. The use of ART must be considered individually with a medical monitor on a case-by-case basis. 16. Known active hepatitis B, defined as positive for surface antigen and / or anti-hepatitis B core antibody. Participants negative for polymerase chain reaction assay are acceptable with appropriate antiviral treatment. 17. If HCV antibody-positive, known active hepatitis C infection with a positive viral load (viral load is not applicable if antibody-negative). Patients treated for hepatitis C infection can participate if a sustained virological response of ≥12 weeks has been documented. 18. A medical history or other active malignancy that interferes with the interpretation of safety or efficacy evaluations in a clinical trial. 19. Active systemic infection requiring treatment. 20. Participants have received treatment with oral or IV antibiotics for fever or other non-radicular malignancy within 14 days prior to the start of the study procedure. Participants receiving prophylactic antibiotics are eligible. 21. In the opinion of the investigating physician, there is a need for quarantine / isolation due to suspected or unresolved related and recent systemic viral syndrome. 22. In the opinion of the investigating physician, any medical history or current evidence of any condition, treatment, or abnormal clinical laboratory values, including but not limited to, that would interfere with the outcome of the trial, impede the participant's ability to participate in the trial for the entire duration, or would not be beneficial to the participant: a. Participants with a history of cerebrovascular events (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure, or NYHA class III*-IV symptoms documented within 6 months prior to the first administration of BT8009, or: i. Average resting QTc>470msec. ii. Any factor that increases the risk of QTc prolongation, such as congenital long QT syndrome or a family history of long QT syndrome. iii. Any clinically significant abnormalities in the rhythm, conduction, or morphology of the resting ECG (as assessed by the investigating physician), e.g., complete left bundle branch block, third-degree heart block. 23. Known mental or substance abuse disorder that interferes with collaboration with the need for the clinical trial. 24. The aforementioned Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) / drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), erythema multiforme, symmetrical drug-associated intertriginous and flexural rash (SDRIFE), or baboon syndrome. 25. Predicting pregnancy, breastfeeding, having a child, or becoming a father, starting with a screening visit, up to 6 months after the last dose of BT8009 and 9 months (for men) and 12 months (for women) after the last dose of enfortumab vedotin.

[0226] Independent Data Monitoring Committee: An independent data monitoring committee (IDMC), comprised of external experts, will be established to review the trial data. The frequency of IDMC meetings, scope of responsibilities, and composition will be determined by a separate charter.

[0227] BT8009 Dose Elevation: The optimal dose of BT8009 will be selected based on a comprehensive review of the evidence obtained during the dose escalation phases of the BT8009–230 trial, including but not limited to safety, efficacy, and PK evaluations. Clinical outcomes will be assessed using pharmacometric modeling (population PK and exposure-response modeling), and a utility-based approach will be used to quantify benefit-risk. The optimal dose of BT8009 during IAs, conducted separately for each cohort, will be selected using a utility score based on a binary efficacy / toxicity score with previously identified cutoff values. Other factors, such as participant convenience and / or regimen flexibility, will also be considered. Participant enrollment will not be discontinued during the dose escalation IA.

[0228] Statistical methods:

[0229] Cohort 1: Untreated first

[0230] The total target sample size for Cohort 1 is 555 participants.

[0231] Eligible participants will be stratified by cisplatin eligibility (cisplatin eligible vs. cisplatin ineligible), liver metastases (yes vs. no), and ECOG PS (0 / 1 vs. 2), and randomized in a 1:1:1 ratio to receive BT8009 9 mg in combination with pembrolizumab, BT8009 11 mg in combination with pembrolizumab, or SOC chemotherapy.

[0232] An interim dose-escalation analysis (IA1) of BT8009 will be conducted in each BT8009 dose level + pembrolizumab arm when approximately 30 participants have been present for at least 4 months since the first dose of the study treatment, have discontinued the study for any reason, or have experienced disease progression (whichever occurred first). The method used to select the optimal BT8009 dose will be described in the BT8009 dose-escalation section above. Participant enrollment will continue in the optimal BT8009 dose arm in combination with pembrolizumab, while enrollment in the treatment arms for the unselected BT8009 doses will be stopped.

[0233] If approximately 120 participants in the BT8009 selection dose in combination with pembrolizumab have been present for at least 6 months since the first dose of the study treatment, have discontinued the study for any reason, or have experienced disease progression (whichever occurred first), a second interim analysis (IA2) will be conducted to evaluate the efficacy of BT8009 in combination with pembrolizumab based on ORR. In the 120 participants in the BT8009 optimal dose and pembrolizumab combination arm, assuming a true ORR of 60%, the probability of observing an ORR at the lower limit of the two-sided 95% confidence interval, excluding the 45% historical ORR, is approximately 90%. ORRs are descriptively summarized in two-sided 95% CIs using the Cloppa-Pearson method for each treatment arm.

[0234] Enrollment in BT8009 optimal dose and chemotherapy in combination with pembrolizumab will continue with 1:1 randomization until each treatment arm has approximately 215 participants. Once the sponsor decides to conduct a combination trial arm of enfortumab vedotin and pembrolizumab, approximately 95 additional participants will be added to Cohort 1, and these participants will be randomized to each treatment arm in a 1:1:1 ratio.

[0235] The total sample size for Cohort 1 is determined by the primary endpoint, i.e., PFS by BICR. The primary analysis of PFS will be performed when approximately 357 events occur in the comparison of BT8009-selective doses with pembrolizumab and chemotherapy, with further estimations: ● 2.5% of Type 1 errors on one side ● Approximately 98% detection rate ●BT8009 optimal dose: 13 months in combination with pembrolizumab vs. 8.5 months with chemotherapy (corresponding to an HR of 0.65) ● Annual dropout rate of 10% ● No interim analysis of PFS was performed.

[0236] Secondary endpoints, including ORR, OS, DOR, DCR, and PFS, are tested sequentially by the investigators when the primary hypothesis for PFS by BICR is rejected.

[0237] We compare the choice doses for BT8009 and pembrolizumab combination and chemotherapy for time to event endpoints, including PFS and OS, using a log-rank test stratified by randomization stratification factors including baseline cisplatin eligibility, liver metastases, and ECOG performance status. Hazard ratios and corresponding 95% confidence intervals from a stratified Cox proportional hazards regression model are also presented. Central PFS, OS, and DOR are estimated using the Kaplan-Meier method and reported with corresponding 95% confidence intervals for each treatment arm. ORR is compared between treatment arms using the Cochrane-Mantel-Henzel test, stratified by the same stratification factors used for time to event analysis. Differences in response rates between treatment arms are estimated and presented with corresponding 95% confidence intervals.

[0238] Cohort 2: Treatment first

[0239] The total target sample size for Cohort 2 is 195 participants.

[0240] Participants will be randomized in a 2:2:1 ratio to receive either BT8009 9 mg, BT8009 11 mg, or enfortumab vedotin.

[0241] An interim analysis (IA) will be conducted in each BT8009 dose-level arm when approximately 30 participants have been present for at least four months since the first dose of the study treatment, have discontinued the study for any reason, or have experienced disease progression (whichever occurs first) to select the optimal BT8009 dose. The method used to select the optimal BT8009 dose is described in the BT8009 dose escalation section above. Participant enrollment for the optimal BT8009 dose will be pending, while enrollment for the treatment arm for the unselected BT8009 dose will be stopped.

[0242] Following the initial intervention (IA), enrollment in the BT8009 selective dose and the enfortumab vedotin arm will continue in a 2:1 randomization ratio until 110 participants are in the BT8009 optimal dose and 55 participants are in the enfortumab vedotin arm. In the 110 participants in the BT8009 monotherapy selective dose, assuming a true ORR of 40%, the probability of observing an ORR at the lower limit of the two-sided 95% confidence interval, excluding the 25% historical ORR, is approximately 90%.

[0243] In the BT8009 monotherapy arm, 110 participants will be present for at least 6 months, discontinue the trial for any reason, or experience disease progression (whichever occurred first). A primary analysis will be performed to evaluate the efficacy of BT8009 monotherapy based on the assessment of ORR by BICR in Cohort 2. The primary endpoint ORR by BICR will be descriptively summarized for each treatment arm using the Cloppa-Pearson method, with two-sided 95% confidence intervals.

[0244] The clinical trial scheme is shown in Figure 20.

[0245] Description and composition of the drug The BT8009 pharmaceutical is provided for clinical use as a white to off-white sterile lyophilized powder for reconstitution in 10 mL Type I clear glass vials with butyl stoppers and aluminum seals. Manufacturing instructions: Each vial contains 5.3 mL of 4 mg / mL bulk solution before lyophilization, providing 21.2 g of BT8009 per vial. For use, the BT8009 pharmaceutical is reconstituted with 5.0 mL of sterile WFI (returning to the reconstitution volume of 5.3 mL solution), providing BT8009 at a target concentration of 4 mg / mL for further dilution with 0.9% saline before IV administration (infusion). A 0.3 mL excess ensures that a volume of 5 mL is extracted from the vial, providing a maximum dose of 20 mg for further dilution.

[0246] Use hydrochloric acid and / or sodium hydroxide to adjust the pH of the packing solution to the target pH 7.0 within the effective buffering range of the L-histidine buffer. The absolute amount required depends on the actual amount of L-histidine used in the batch, which is indicated as a 'sufficient amount' to reach pH 7.0.

[0247] Table 1 shows the composition and quantitative composition of the BT8009 drug (21.2 mg / vial). [Table 5] a. Adjust based on API effectiveness to achieve the target drug substance label value. b. Adequate quantity. c. Remove water for injection (WFI) during the freeze-drying process. [Brief explanation of the drawing]

[0248] [Figure 1-23] Not mentioned in the original text

Claims

1. A method for treating a human patient, comprising administering to the patient BT8009 or a pharmaceutical composition containing BT8009.

2. A method for treating a solid tumor in a human patient, comprising administering BT8009 or a pharmaceutical composition comprising BT8009, wherein the solid tumor is an advanced malignant tumor, and optionally the solid tumor or advanced malignant tumor is associated with nectin-4 expression.

3. The patient was given BT8009 or a pharmaceutical composition containing BT8009 at a rate of approximately 2 to 10 mg / m² per week. ２ The dosage is approximately 2.5 to 7.5 mg / m², depending on preference. ２ The dosage, depending on the preference, is approximately 4-6 mg / m². ２ The dosage, depending on your preference, is approximately 5 mg / m². ２ The method according to claim 1 or 2, comprising administering in the specified dose.

4. The patient was administered BT8009 or a pharmaceutical composition containing BT8009 at a dose of approximately 6-9 mg / m² on days 1 and 8 of a 21-day treatment cycle. ２ The dosage, depending on the preference, is approximately 7-8 mg / m². ２ The dosage, depending on preference, is approximately 7.5 mg / m². ２ The method according to claim 1 or 2, comprising administering in the specified dose.

5. The method according to claim 1 or 2, comprising administering to the patient BT8009 or a pharmaceutical composition containing BT8009 in a uniform dose of about 7 to 11 mg per week, preferably a uniform dose of about 8 to 10 mg, preferably a uniform dose of about 9 mg.

6. The method according to claim 1 or 2, comprising administering to the patient BT8009 or a pharmaceutical composition containing BT8009 in a uniform dose of about 9 to 13 mg, preferably about 10 to 12 mg, or preferably about 11 mg, on the 1st and 8th days of a 21-day treatment cycle.

7. The method according to any one of claims 1 to 6, further comprising administering an anti-PD-1 antibody or an anti-PD-L1 antibody to a human patient, wherein the anti-PD-1 antibody is optionally pembrolizumab.

8. The method according to claim 7, wherein pembrolizumab is administered in a dose of 200 mg; optionally, pembrolizumab is administered in a dose of approximately 200 mg once a week.

9. The method according to claim 7 or 8, wherein BT8009 or a pharmaceutical composition containing BT8009 and pembrolizumab are administered separately; optionally, BT8009 or a pharmaceutical composition containing BT8009 and pembrolizumab are administered by continuous intravenous infusion.

10. The method according to any one of claims 2 to 9, wherein the advanced malignant tumor associated with nectin-4 expression is selected from the group consisting of lung cancer (e.g., NSCLC), ovarian cancer, breast cancer (e.g., TNBC), esophageal cancer, gastric / upper gastrointestinal (GI) cancer, head and neck cancer, pancreatic cancer, and urothelial carcinoma.

11. The method according to any one of claims 2 to 10, wherein the patient has previously received one or more treatments for a solid tumor or malignant tumor.

12. The method according to claim 11, wherein the patient is administered BT8009 as monotherapy.

13. The method according to any one of claims 2 to 10, wherein the patient has not previously received treatment for a solid tumor or malignant tumor.

14. The method according to claim 13, wherein the patient is administered BT8009 and an anti-PD-1 antibody or an anti-PD-L1 antibody, and optionally the patient is administered BT8009 and pembrolizumab.

15. The method according to any one of claims 11 to 14, wherein the advanced malignant tumor associated with nectin-4 expression is locally advanced or metastatic urothelial carcinoma.

16. BT8009, or a pharmaceutically acceptable salt thereof; Approximately 1.31 mg of histidine per 1 mg of BT8009 or its pharmaceutically acceptable salt; Approximately 15 mg of sucrose per 1 mg of BT8009 or its pharmaceutically acceptable salt; and Approximately 0.025 mg of polysorbate 20 per 1 mg of BT8009 or its pharmaceutically acceptable salt. A pharmaceutical composition which is a solid pharmaceutical composition of BT8009 containing [the specified ingredient].

17. Approximately 21.2 mg of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 27.8 mg of histidine; Approximately 318 mg sucrose; and Approximately 0.53 mg of polysorbate 20 The pharmaceutical composition according to claim 16, comprising a solid unit dose.

18. Approximately 11 mg of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 14.4 mg of L-histidine; Approximately 165 mg sucrose; and Approximately 0.275 mg of polysorbate 20 The pharmaceutical composition according to claim 16, comprising a solid unit dose.

19. A pharmaceutical composition according to any one of claims 16 to 18, wherein it is a freeze-dried powder.

20. Approximately 4 mg / mL of BT8009, or a pharmaceutically acceptable salt thereof; Approximately 5.24 mg / mL L-histidine; Approximately 60 mg / mL sucrose; Approximately 0.1 mg / mL polysorbate 20; and water A pharmaceutical composition which is a liquid formulation of BT8009 containing [the specified ingredient].

21. The pharmaceutical composition according to claim 20, wherein the liquid formulation has a pH of approximately 7.

22. The pharmaceutical composition according to claim 20 or claim 21, which is a liquid unit dosage form of approximately 5.3 ml.

23. The pharmaceutical composition according to claim 20 or claim 21, wherein the liquid unit dosage form is approximately 2.75 ml.

24. The pharmaceutical composition according to any one of claims 16 to 23, further comprising pembrolizumab.

25. The method according to any one of claims 1 to 15, wherein the pharmaceutical composition is one of the compositions of claims 16 to 24.

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