Bicyclic peptide ligands specific for nectin-4 and uses thereof

Abstract

The present invention relates to a Bicycle toxin conjugate BT8009, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, and uses thereof.

Description

BICYCLIC PEPTIDE LIGANDS SPECIFIC FOR NECTIN-4 AND USES THEREOF TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to Bicycle toxin conjugates, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof. The present invention also provides uses of Bicycle toxin conjugates, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for preventing or treating a disease, disorder, or condition characterized by overexpression of Nectin-4 in diseased tissue. BACKGROUND OF THE INVENTION

[0002] Cyclic peptides are able to bind with high affinity and target specificity to protein targets and hence are an attractive molecule class for the development of therapeutics. In fact, several cyclic peptides are already successfully used in the clinic, as for example the antibacterial peptide vancomycin, the immunosuppressant drug cyclosporine or the anti-cancer drug octreotide (Driggers et al. (2008), Nat Rev Drug Discov 7 (7), 608-24). Good binding properties result from a relatively large interaction surface formed between the peptide and the target as well as the reduced conformational flexibility of the cyclic structures. Typically, macrocycles bind to surfaces of several hundred square angstrom, as for example the cyclic peptide CXCR4 antagonist CVX15 (400 Å2; Wu et al. (2007), Science 330, 1066-71), a cyclic peptide with the Arg-Gly-Asp motif binding to integrin αVb3 (355 Å2) (Xiong et al. (2002), Science 296 (5565), 151-5) or the cyclic peptide inhibitor upain-1 binding to urokinase-type plasminogen activator (603 Å2; Zhao et al. (2007), J Struct Biol 160 (1), 1-10).

[0003] Due to their cyclic configuration, peptide macrocycles are less flexible than linear peptides, leading to a smaller loss of entropy upon binding to targets and resulting in a higher binding affinity. The reduced flexibility also leads to locking target-specific conformations, increasing binding specificity compared to linear peptides. This effect has been exemplified by a potent and selective inhibitor of matrix metalloproteinase 8, (MMP-8) which lost its selectivity over other MMPs when its ring was opened (Cherney et al. (1998), J Med Chem 41 (11), 1749-51). The favorable binding properties achieved through macrocyclization are even more pronounced in multicyclic peptides having more than one peptide ring as for example in vancomycin, nisin and actinomycin.

[0004] Different research teams have previously tethered polypeptides with cysteine residues to a synthetic molecular structure (Kemp and McNamara (1985), J. Org. Chem; Timmerman et al. (2005), ChemBioChem). Meloen and co-workers had usedtris(bromomethyl)benzene and related molecules for rapid and quantitative cyclisation of multiple peptide loops onto synthetic scaffolds for structural mimicry of protein surfaces (Timmerman et al. (2005), ChemBioChem). Methods for the generation of candidate drug compounds wherein said compounds are generated by linking cysteine containing polypeptides to a molecular scaffold as for example TATA (1,1',1''-(1,3,5-triazinane-1,3,5-triyl)triprop-2- en-1-one, Heinis et al. Angew Chem, Int Ed.2014; 53:1602–1606).

[0005] Phage display-based combinatorial approaches have been developed to generate and screen large libraries of bicyclic peptides to targets of interest (Heinis et al. (2009), Nat Chem Biol 5 (7), 502-7 and WO 2009 / 098450). Briefly, combinatorial libraries of linear peptides containing three cysteine residues and two regions of six random amino acids (Cys- (Xaa)6-Cys-(Xaa)6-Cys) were displayed on phage and cyclised by covalently linking the cysteine side chains to a small molecule scaffold. SUMMARY OF THE INVENTION

[0006] According to one aspect, the invention provides a method for treating a human patient, comprising administering to the patient BT8009 or a pharmaceutical composition comprising BT8009. In another aspect, the invention provides BT8009 or a pharmaceutical composition comprising BT8009 for use in a method for treating a human patient.

[0007] In another aspect, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient. In another aspect, the 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 aspect, the invention provides a method for maintaining or reducing the volume of a solid tumor in a human patient, comprising administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient.

[0009] In a further aspect, the invention provides BT8009, or a pharmaceutical composition comprising BT8009, for use in a method of treating a solid tumor in a human patient, wherein the method comprises administering to the patient BT5528 or a pharmaceutical composition thereof.

[0010] In another aspect, the invention provides BT8009, or a pharmaceutical composition comprising BT8009, for use in a method of maintaining or reducing the volume of a solid tumor in a human patient, wherein the method comprises administering to the patient BT8009 or a pharmaceutical composition comprising BT8009.

[0011] In another aspect, the invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in a method of treating a solid tumor in a human patient, wherein the method comprises administering to the patient the BT8009.

[0012] In another aspect, the invention provides BT8009 or a pharmaceutically acceptable salt thereof of use in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a human patient, wherein the method comprises administering to the patient the BT8009.

[0013] In another aspect, the invention provides a solid pharmaceutical composition of BT8009 comprising: BT8009, or a pharmaceutically acceptable salt thereof; about 1.31 mg histidine per mg of BT8009, or a pharmaceutically acceptable salt thereof; about 15 mg sucrose per mg of BT8009, or a pharmaceutically acceptable salt thereof; and about 0.025 mg Polysorbate 20 per mg of BT8009, or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, the 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. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. Compounds and Definitions:

[0015] The term “BT8009,” as used herein, is a Bicycle toxin conjugate having a structure as shown below, 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 comprises the amino acid sequence: (β-Ala)-Sar10-C1P[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiii(SEQ ID NO: 1)wherein Sar is sarcosine, 1Nal represents 1-naphthylalanine, HArg represents homoarginine, HyP represents hydroxyproline and Ci, Ciiand Ciiirepresent first, second and third cysteine residues.

[0016] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19,incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, 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 salts, and the like.9008T5B9008T6B

[0017] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. It will be appreciated that salt forms are within the scope of this invention, and references to peptide ligands include the salt forms of said ligands.

[0018] The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.

[0019] As used herein, the term “about” shall have the meaning of within 10% of a given value or range. In some embodiments, the term “about” refers to within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0020] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. 2. Methods of Treatment

[0021] The examples and figures presented herewith report results from the first in-human clinical trial of the BT8009 Bicycle toxin conjugate.

[0022] The present invention provides a method for treating a human patient, comprising administering to the patient 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 human patient. The present invention also provides BT8009 for use in the manufacture of a medicament for use in a method for treating a human patient.

[0023] 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 B8009 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 medicament for use in a method for treating a solid tumor in a human patient. In some embodiments, the solid tumor is an advanced malignancy. In some embodiments, the solid tumor or advanced malignancy is associated with Nectin-4 expression.

[0024] In one embodiment, the invention provides a method for the treatment of adult patients who have not received any prior systemic treatment for locally advanced or metastatic urothelial carcinoma comprising administering BT8009 in combination with pembrolizumab. The invention also provides BT8009, in combination with pembrolizumab, for the treatment of adult patients who have not received any prior systemic therapy for locally advanced or metastatic urothelial carcinoma.

[0025] In another embodiment, the invention provides a method for the treatment of adult patients who have received one or more prior systemic therapies for locally advanced or metastatic urothelial carcinoma comprising administering BT8009 monotherapy. The invention also provides BT8009 monotherapy for the treatment of adult patients who have received ≥1 prior systemic therapy for locally advanced or metastatic urothelial carcinoma.

[0026] In some embodiments, the methods of the invention comprise the administration of BT8009. In some embodiments, the methods of the invention comprise the administration of a pharmaceutically acceptable salt of BT8009. In some embodiments, the methods of the invention comprise the administration of a pharmaceutical composition comprising BT8009, or a pharmaceutically acceptable salt thereof

[0027] In some embodiments, the present invention provides methods for maintaining or reducing the volume of a solid tumor in a patient. In some embodiments, the invention provides methods for maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises the administration of BT8009 or a pharmaceutically acceptable salt thereof.In some embodiments, the invention provides methods for maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises the administration of a pharmaceutical composition comprising BT8009.

[0028] In some embodiments, maintaining the volume of a solid tumor refers to an increase in the volume of the tumor by no more than 75%, no more than 50%, no more than 25%, no more than 10% or no more than 5%. In some embodiments, maintaining the volume of a solid tumor refers to the volume of the tumor being unchanged.

[0029] In some embodiments, reducing the volume of a solid tumor refers to a reduction in the volume of the tumor by 100%, by at least 95%, at least 90%, at least 85%, at least 80%, at least 75% or at least 70%, at least 65%, at least 60%, at least 55%, at least 50%, at least 45%, at least 40%, at least 35%, at least 30%, at least 25%, at least 20%, at least 15%, at least 10% or at least 5%.

[0030] Optionally, the change in the volume of the tumor is a change relative to the volume of the tumor prior to the commencement of treatment.

[0031] In some embodiments, reference to a volume of a tumor may refer to a sum of volumes of two or more tumors in a patient (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors). In some embodiments, this can be determined by measuring the sum of an axis (e.g. a short axis or the longest diameter) of two or more solid tumors in the patient.

[0032] In some embodiments, reference to a volume of a tumor may refer to an average volume of two or more tumors in a patient (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors). In some embodiments, this can be determined by measuring the sum of an axis (e.g. a short axis or the longest diameter) of two or more solid tumors (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors) in the patient and dividing the sum by the number of tumors measured.

[0033] Thus, in some embodiments, maintaining or reducing the volume of a solid tumor in a patient as described herein may refer to maintaining or reducing the sum or average volume of two or more solid tumors (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors) in a patient.

[0034] Thus, in some embodiments, maintaining the volume of a solid tumor refers to an increase in the sum or average volume of two or more tumors (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors) of no more than 75%, no more than 50%, no more than 25%, no more than 10% or no more than 5%. In some embodiments, maintaining the volume of a solid tumor refers to the sum or average volume of the tumors being unchanged.

[0035] In some embodiments, reducing the volume of a solid tumor refers to a reduction in the sum or average volume of two or more tumors (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors) by 100%, by at least 95%, at least 90%, at least 85%, at least 80%, at least 75% or at least 70%, at least 65%, at least 60%, at least 55%, at least 50%, at least 45%, at least 40%, at least 35%, at least 30%, at least 25%, at least 20%, at least 15%, at least 10% or at least 5%.

[0036] Optionally, the change in the sum or average volume of the tumor is a change relative to the sum or average volume of the tumor prior to the commencement of treatment.

[0037] The volume of the tumor (or tumors) can be maintained or reduced for a period of time until disease progression is documented. In some embodiments, disease progression refers to a measurement of the volume of the tumor of greater than a 75% increase in the volume of the tumor relative to the volume of the tumor prior to the commencement of treatment. In some embodiments, disease progression refers to a measurement of the length of an axis of a tumor (or the sum or average of two or more tumors) of greater than 20%. Optionally, the volume of the tumor is maintained or reduced for at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months or at least 24 months.

[0038] In some embodiments, the volume of a solid tumor over time may be measured by determining the length of an axis of the tumor. In some embodiments, the volume of a solid tumor over time may be measured by determining the length of the longest diameter of the solid tumor. In some embodiments, the volume of a solid tumor over time may be measured by determining the length of the short axis of a tumor. By way of representative embodiment, a 20% increase in the length of an axis or diameter of a solid tumor corresponds to an increase in the volume of the solid tumor of approximately 75% (i.e. 1.23).

[0039] The length of an axis of a tumor may be determined, for example, by a CT scan slice, MRI scan slice, caliper measurement or X-ray.

[0040] In other embodiments, the volume of a solid tumor over time may be measured by volumetric assessment e.g. using a three-dimensional scan such as a CT scan or MRI scan.

[0041] In some embodiments, the treatment of a cancer or of a solid tumor may cause a complete response of the cancer or solid tumor to said treatment, i.e. the disappearance of all target lesions and all non-target lesions and normalization of tumor marker level. Optionally, the treatment of a cancer or solid tumor may cause a partial response of the cancer or solidtumor to said treatment, i.e. at least a 30% decrease in the sum of the lengths of an axis (e.g. the longest diameter (LD)) of the target lesions, taking as reference the baseline sum of the lengths of the axis (e.g. longest diameters) of the lesions. Optionally, the treatment of a cancer or solid tumor may result in stable disease, i.e. not more than a 30% decrease in the sum of the axis (e.g. LD), but less than a 20% increase in the sum of the axis (e.g. LD), with no new lesions. 3. Combination Therapies

[0042] In some embodiments, the methods of treatment of the present invention comprise the administration of BT8009, or a pharmaceutical composition comprising BT8009, and the further administration of an anti-PD-1 antibody or an anti-PD-L1 antibody to the human patient.

[0043] In some embodiments, the anti-PD-1 antibody is selected from the list consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP- 224, AMP-514 and acrixolimab.

[0044] In some embodiments, the anti-PD-L1 antibody is selected from the list consisting of atezolizumab, avelumab, durvalumab, KN035 and cosibelimab.

[0045] In some embodiments, the methods of the invention comprise the administration of BT8009, or a pharmaceutical composition comprising BT8009, and the further administration of pembrolizumab to the human patent.

[0046] In one aspect, the invention provides a method of treatment comprising administering to a human patient BT8009 or a pharmaceutical composition comprising BT8009, and further comprising administering to the human patient pembrolizumab. The invention also provides BT8009 or a pharmaceutical composition comprising BT8009 and pembrolizumab for use in a method of treating a human patient. The invention also provides BT8009 or a pharmaceutical composition comprising BT8009 and pembrolizumab for use in the manufacture of a kit for use in the treating a human patient.

[0047] In one aspect, the invention provides methods 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 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 invention also provides BT8009 or a pharmaceutical composition comprising BT8009 and pembrolizumab for use in the manufacture of a kit for use in treating a solid tumor in a humanpatient. In some embodiments, the solid tumor is an advanced malignancy. In some embodiments, the solid tumor or advanced malignancy is associated with Nectin-4 expression.

[0048] 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, the content of which is incorporated herein by reference in its entirety. In some embodiments, pembrolizumab is administered at a dose of about 200 mg once every three weeks. In some embodiments, pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 25 to 45 minutes once every 3 weeks. In some embodiments, pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 25 minutes once every 3 weeks. In some embodiments, pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 30 minutes once every 3 weeks. In some embodiments, pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 35 minutes once every 3 weeks. In some embodiments, pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 40 minutes once every 3 weeks. In some embodiments, pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 45 minutes once every 3 weeks.

[0049] In some embodiments, pembrolizumab is administered at a dose of about 400 mg once every six weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 25 to 45 minutes once every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 25 minutes once every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 30 minutes once every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 35 minutes once every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 40 minutes once every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 45 minutes once every 6 weeks.

[0050] In some embodiments, a liquid formulation or a liquid unit dosage form as described herein and pembrolizumab are administered by sequential infusions first with a liquid formulation or a liquid unit dosage form as described herein followed by pembrolizumab. In some embodiments, a liquid formulation or a liquid unit dosage form as described herein and pembrolizumab are administered by sequential infusions first with pembrolizumab followed by a liquid formulation or a liquid unit dosage form as described herein. In some embodiments,a liquid formulation or a liquid unit dosage form as described herein and pembrolizumab are administered separately.

[0051] In some embodiments of a combination use, a patient is not previously known being intolerant or hypersensitive to an immune checkpoint inhibitor. In some embodiments of a combination use, a patient has not received any prior treatment with stimulatory or co- inhibitory T-cell receptor agents, such as CD137 agonists, OX-40 agonist or CTLA-4 inhibitors. In some embodiments of a combination use, a patient has received prior treatment with a PD-1, PD-L1 or PD-L2 inhibitor. In some embodiments of a combination use, a patient has no prior organ transplant (including allogeneic). In some embodiments of a combination use, a patient is not previously diagnosed with clinically relevant immunodeficiency. In some embodiments of a combination use, a patient does not have active systemic infection requiring therapy. In some embodiments of a combination use, a patient does not have any condition requiring treatment with ≥10 mg daily prednisone equivalent or other strong immunosuppressant. In some embodiments of a combination use, a patient does not have an active autoimmune disease that has required systemic treatment in 2 years (e.g. with the use of disease modifying agents, corticosteroids or immunosuppressive drugs) prior to combination treatment with BT8009 and pembrolizumab. In some embodiments, replacement therapy (e.g., thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not a form of systematic treatment. In some embodiments, a patient has type 1 DM well controlled on insulin, alopecia, or vitiligo. In some embodiments of a combination use, a patient does not have a history of interstitial lung disease.

[0052] In some embodiments of a combination use, BT8009 or the pharmaceutical composition comprising BT8009 and pembrolizumab are administered separately. In some embodiments, BT8009 or the pharmaceutical composition comprising BT8009 and pembrolizumab are administered sequentially. In some embodiments of a combination use, BT8009 or the pharmaceutical composition comprising BT8009 and pembrolizumab are administered simultaneously. In some embodiments, BT8009 or the pharmaceutical composition comprising BT8009 is administered first followed by pembrolizumab. In some embodiments, pembrolizumab is administered first followed by BT8009 or the pharmaceutical composition comprising BT8009.

[0053] In some embodiments, BT8009 and pembrolizumab are administered by separate infusions. In some embodiments, BT8009 and pembrolizumab are administered by sequential infusions. In some embodiments, BT8009 is administered by a first infusion followed by pembrolizumab. In some embodiments, pembrolizumab is administered by a first infusionfollowed by BT8009. In some embodiments, BT8009 is provided as a liquid formulation or liquid unit dosage form as described herein.

[0054] In some embodiments, BT8009 and pembrolizumab are administered simultaneously. In some embodiments, BT8009 and pembrolizumab are administered by a single infusion.

[0055] In some embodiments, a patient having a solid tumor has been previously untreated for the tumor (i.e. has received no prior lines of treatment for the solid tumor). In some embodiments, a patient having a solid tumor who has been previously untreated may be administered BT8009 as a monotherapy. In some embodiments, a patient having a solid tumor has been previously untreated may be administered BT8009 and pembrolizumab.

[0056] In some embodiments, a patient having a solid tumor has previously received one or more treatments for the tumor. In some embodiments, a patient having a solid tumor who has previously received one or more treatments for the tumor may be administered BT8009 as a monotherapy. In some embodiments, a patient having a solid tumor who has previously received one or more treatments for the tumor may be administered BT8009 and pembrolizumab. In some embodiment, a patient who has previously received one or more treatments is resistant or refractory is the one or more prior treatments. 4. General Description of Certain Embodiments of the Invention:

[0057] In some embodiments, the methods of the invention comprise the administration of a pharmaceutical composition as described herein. In some embodiments, the methods of the invention comprise the administration of a pharmaceutical composition (e.g. a solid pharmaceutical composition of BT8009 or a liquid formulation of BT8009) of the invention.

[0058] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutically acceptable excipient or carrier is selected from a buffering agent, a stabilizer or cryoprotectant, and a surfactant.

[0059] In some embodiments, a pharmaceutical composition comprises a buffering agent. In some embodiments, a buffering agent is selected from phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycoland wool fat. In some embodiments, a buffering agent is L-histidine. In some embodiments, a buffering agent is sodium hydroxide. In some embodiments, a buffering agent is hydrochloric acid.

[0060] In some embodiments, a buffering agent is at an amount to adjust pH of a pharmaceutical composition of the invention to about 6-8. In some embodiments, a buffering agent is histidine at an amount of about 1-3 mg per mg of BT8009, or a pharmaceutically acceptable thereof. In some embodiments, histidine is at an amount of about 1.31 or 2.62 mg per mg of BT8009, or a pharmaceutically acceptable thereof. In some embodiments, a liquid pharmaceutical composition of the invention comprises histidine at a concentration of about 5.24 mg / mL.

[0061] In some embodiments, a buffering agent is at an amount to adjust pH of a liquid formulation or a liquid unit dosage form as described herein to about 6-8. In some embodiments, a liquid pharmaceutical composition of the invention is at a pH of about 6-8. In some embodiments, a liquid pharmaceutical composition of the invention (e.g. a liquid formulation or a liquid unit dose form) is at 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 some embodiments, a liquid pharmaceutical composition of the invention is at a pH of about 6.5 or 7.0.

[0062] In some embodiments, a pharmaceutical composition comprises a stabilizer or cryoprotectant. In some embodiments, a stabilizer or cryoprotectant is dimethyl sulfoxide (DMSO). In some embodiments, a stabilizer or cryoprotectant is ethylene glycol. In some embodiments, a stabilizer or cryoprotectant is glycerol. In some embodiments, a stabilizer or cryoprotectant is propylene glycol. In some embodiments, a stabilizer or cryoprotectant is 2- methyl-2, 4-pentanediol (MPD). In some embodiments, a stabilizer or cryoprotectant is trehalose. In some embodiments, a stabilizer or cryoprotectant is mannitol. In some embodiments, a stabilizer or cryoprotectant is galactose. In some embodiments, a stabilizer or cryoprotectant is maltose. In some embodiments, a stabilizer or cryoprotectant is formamide. In some embodiments, a stabilizer or cryoprotectant is proline. In some embodiments, a stabilizer or cryoprotectant is glycerol 3-phosphate. In some embodiments, a stabilizer or cryoprotectant is sorbitol. In some embodiments, a stabilizer or cryoprotectant is diethyl glycol. In some embodiments, a stabilizer or cryoprotectant is sucrose.

[0063] In some embodiments, a stabilizer or cryoprotectant (e.g., sucrose) is at an amount of about 10-35 mg per mg of BT8009, or a pharmaceutically acceptable thereof. In some embodiments, a stabilizer or cryoprotectant (e.g., sucrose) is at an amount of about 15 or 30 mg per mg of BT8009, or a pharmaceutically acceptable thereof. In some embodiments, aliquid pharmaceutical composition comprises a stabilizer or cryoprotectant (e.g., sucrose) at a concentration of about 60 mg / mL.

[0064] In some embodiments, a pharmaceutical composition comprises a surfactant. In some embodiments, a surfactant is a polysorbate (e.g., polysorbate-20, polysorbate-40, polysorbate-60, polysorbate-65, polysorbate-80, polysorbate-85, or a combination thereof). In some embodiments, a surfactant is selected from poloxamers (e.g., poloxamer 188); Triton™; sodium dodecyl sulfate (SDS); sodium laurel 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, myristamidopropyl-betaine, palmidopropyl- betaine, isostearamidopropyl-betaine (e.g. lauroamidopropyl), myristarnidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl ofeyl- taurate; and the Monaquat™ series (Mona Industries, Inc., Paterson, N.J. ), poly ethyl glycol, polyp ropyl glycol, and copolymers of ethylene and propylene glycol (e.g. pluronics, PF68). In some embodiments, a surfactant is Polysorbate 20.

[0065] In some embodiments, a surfactant (e.g., Polysorbate 20) is at an amount of about 0.01-0.15 mg per mg of BT8009, or a pharmaceutically acceptable thereof. In some embodiments, a surfactant (e.g., Polysorbate 20) is at an amount of about 0.025, 0.05, or 0.1 mg per mg of BT8009, or a pharmaceutically acceptable thereof. In some embodiments, a liquid pharmaceutical composition comprises a surfactant (e.g., Polysorbate 20) at a concentration of about 0.1 or 0.2 mg / mL.

[0066] In some embodiments, a pharmaceutical composition comprises an isotonicity adjusting agent. In some embodiments, an isotonicity adjusting agent is sodium chloride, dextrose, calcium chloride, or a combination thereof. In some embodiments, an isotonicity adjusting agent is dextrose. In some embodiments, an isotonicity adjusting agent is sodium chloride. In some embodiments, an isotonicity adjusting agent is a combination of sodium chloride and dextrose.

[0067] In some embodiments, the invention provides a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof. In some embodiments, a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof, comprises a pharmaceutically acceptable excipient or carrier selected from a buffering agent, a stabilizer or cryoprotectant, and a surfactant. In some embodiments, BT8009 may be provided as a pharmaceutical composition which comprises a flat unit dose of BT8009 according to aflat dose as described herein. In some embodiments, the invention provides a solid unit dose comprising about 21.2 mg of a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof, further comprises L-histidine, sucrose, and Polysorbate 20.

[0069] According to one aspect of the invention, the invention provides a pharmaceutical composition which is a solid pharmaceutical composition of BT8009, comprising: BT8009, or a pharmaceutically acceptable salt thereof; about 1.31 mg L-histidine per mg of BT8009, or a pharmaceutically acceptable thereof; about 15 mg sucrose per mg of BT8009, or a pharmaceutically acceptable thereof; and about 0.025 mg Polysorbate 20 per mg of BT8009, or a pharmaceutically acceptable thereof.

[0070] In some embodiments, the pharmaceutical composition is a solid unit dose, comprising: about 21.2 mg BT8009, or a pharmaceutically acceptable salt thereof; about 27.8 mg L-histidine; about 318 mg sucrose; and about 0.53 mg Polysorbate 20.

[0071] In some embodiments, the pharmaceutical composition is a solid unit dose comprising: about 7-13 mg, optionally about 8-12 mg, optionally about 9-11 mg BT8009, or a pharmaceutically acceptable salt thereof; about 9.17-17.03 mg, optionally about 10.48-13.1 mg, optionally about 11.8-14.4 mg L-histidine; about 105-195 mg, optionally about 120-180 mg, optionally about 130-165 mg sucrose; and about 0.175-0.325 mg, optionally about 0.2-0.3 mg, optionally about 0.225-0.275 mg Polysorbate 20.

[0072] In some embodiments, the pharmaceutical composition is a solid unit dose comprising: about 9 mg BT8009, or a pharmaceutically acceptable salt thereof; about 11.8 mg L-histidine;about 135 mg sucrose; and about 0.225 mg Polysorbate 20.

[0073] In some embodiments, the pharmaceutical composition is a solid unit dose comprising: about 11 mg BT8009, or a pharmaceutically acceptable salt thereof; about 14.4 mg L-histidine; about 165 mg sucrose; and about 0.275 mg Polysorbate 20.

[0074] In some embodiments, a solid pharmaceutical composition of the invention is a lyophilized powder. In some embodiments, a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof, is a lyophilized powder at about -20oC. In some embodiments, a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof, is a lyophilized powder at about -15oC to about -25oC, including, for example, about -15oC, -16oC, -17oC, -18oC, -19oC, -20oC, -21oC, -22oC, -23oC, -24oC, or -25oC.

[0075] In some embodiments, the invention provides a liquid formulation of BT8009, comprising BT8009, or a pharmaceutically acceptable salt thereof, and water. In some embodiments, a liquid formulation of the invention further comprises a pharmaceutically acceptable excipient or carrier selected from a buffering agent, a stabilizer or cryoprotectant, and a surfactant. In some embodiments, a liquid formulation of the invention further comprises L-histidine, sucrose, and Polysorbate 20. In some embodiments, a liquid formulation of the invention is a liquid unit dosage form, which comprises about 21.2 mg BT8009, or a pharmaceutically acceptable salt thereof. In some embodiments, a liquid formulation of the invention is a liquid unit dosage form, which comprises about 11 mg BT8009, or a pharmaceutically acceptable salt thereof. In some embodiments, BT8009 concentration in a liquid formulation or a liquid unit dosage form of the invention is about 4 mg / mL. In some embodiments, a liquid formulation or a liquid unit dosage form of the invention comprise the following components: Concentration Reference to Standard Component Function (mg / mL) BT8009 Drug substance 4.0aHSE L-Histidine Buffer 5.24 EP, USPSucrose Stabiliser, cryoprotectant 60.0 EP, NF Polysorbate 20 Non-ionic surfactant 0.1 EP / NF Hydrochloric Acid pH adjustment q.sbEP WFIcSolvent q.sb. to 1 mL EP / USP a: Based on API potency, adjustments will be made to achieve the target drug substance label claim value. b: Quantity sufficient. c: Water for injections (WFI) is driven off during lyophilisation process.

[0076] In some embodiments, a liquid formulation or a liquid unit dosage form of the invention further comprises saline, for example, about 0.9% w / v saline. In some embodiments, BT8009 concentration in a liquid formulation of the invention comprising saline is about 0.1 to 2 mg / mL. In some embodiments, BT8009 concentration in a liquid formulation of the invention comprising saline 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 some embodiments, BT8009 concentration in a liquid formulation of the invention comprising saline 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.

[0077] In some embodiments, a liquid formulation or a liquid unit dosage form of the invention comprises a pharmaceutically acceptable vehicle or solvent. In some embodiments, a pharmaceutically acceptable vehicle or solvent is selected from sterile water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In some embodiments, a pharmaceutically acceptable vehicle or solvent is sterile water. In some embodiments, a pharmaceutically acceptable vehicle or solvent is a sterile injectable medium.

[0078] In some embodiments, the invention provides a liquid formulation or a liquid unit dosage form prepared by dissolving a solid pharmaceutical composition or a solid unit form of the invention in water. In some embodiments, the invention provides a liquid formulation or a liquid unit dosage form prepared by dissolving a solid pharmaceutical composition or a solid unit form of the invention in an injectable medium (e.g., about 0.9% w / v saline). In some embodiments, the invention provides a liquid formulation or a liquid unit dosage form prepared by reconstituting a solid pharmaceutical composition or a solid unit form of the invention in water, followed by dilution with about 0.9% w / v saline. In some embodiments, a liquid formulation or a liquid unit dosage form is diluted into an about 0.9% w / v saline IV bag for IV administration.

[0079] In some embodiments, the invention provides 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. In some embodiments, the liquid formulation comprises hydrochloric acid. In some embodiments, the liquid formulation comprises sodium hydroxide. In some embodiments, the liquid formulation is at a pH of about 7.

[0080] In some embodiments, the invention provides a liquid unit dosage form of about 5.3 mL, 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.

[0081] In some embodiments, the invention provides a liquid unit dosage form of about 1.75-3.25 mL, optionally a liquid unit dosage form of about 2-3 mL, optionally a liquid unit dosage form of about 2.25-2.75 mL, 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.

[0082] In some embodiments, the invention provides a liquid unit dosage form of about 2.25 mL, 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.

[0083] In some embodiments, the invention provides a liquid unit dosage form of about 2.75 mL, 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.

[0084] In some embodiments, the liquid formulation comprises hydrochloric acid. In some embodiments, the liquid formulation comprises sodium hydroxide. In some embodiments, the liquid formulation is at a pH of about 7.

[0085] In some embodiments, a solid unit dose of the invention is stored in a vial. In some embodiments, a liquid unit dosage form comprising BT8009, or a pharmaceutically acceptable salt thereof, and water is stored in a vial. In some embodiments, a vial is a 10 mL Type I clear glass vial with a chlorobutyl stopper and aluminum seal.

[0086] In some embodiments, the invention provides a kit comprising a pharmaceutical composition comprising BT8009 and pembrolizumab.

[0087] In some embodiments, the pharmaceutical compositions may further comprise another drug, such as pembrolizumab. In other words, in some embodiments, the pharmaceutical compositions may comprise both BT8009 and pembrolizumab. Such pharmaceutical compositions may offer a number of potential advantages in safety, convenience, patient compliance, storage and efficacy over either drug being administered individually.

[0088] In some embodiments, the methods of the invention comprises administering to a patient intravenously a liquid formulation or a liquid unit dosage form as described herein. In some embodiments, a liquid formulation or a liquid unit dosage form of the invention is administered by an IV injection. In some embodiments, a liquid formulation or a liquid unit dosage form of the invention is administered by an IV infusion. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form of the invention is about 5-30 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form of the invention is about 30-60 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form of the invention is about 60-90 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form of the invention is about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form of the invention is about 55 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form of the invention is about 60 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form of the invention is about 65 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosageform of the invention is about 70 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form of the invention is about 75 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form of the invention is about 2, 2.5, 3, 3.5, or 4 hours.

[0089] In some embodiments, the 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 in about 0.9% w / v saline before administration. In some embodiment, the solid tumor is an advanced malignancy. In some embodiments, the solid tumor or advanced malignancy is associated with Nectin-4 expression.

[0090] In some embodiments, the invention provides a combination use of a liquid formulation or a liquid unit dosage form as described herein and pembrolizumab, for treating a solid tumor (such as an advanced malignancy), associated with Nectin-4 expression. The liquid formulation or liquid dosage form and pembrolizumab may each be administered as described herein. 5. Dosage Regimens

[0091] In some embodiments, BT8009 is administered to a patient once every day. In some embodiments, BT8009 is administered to a patient once every 2, 3, 4, 5, 6, or 7 days. In some embodiments, BT8009 is administered to a patient once every week, or weekly. In some embodiments, BT8009 is administered to a patient once every two weeks. In some embodiments, BT8009 is administered as a liquid formulation or a liquid unit dosage form.

[0092] In some embodiments, a treatment cycle is 4 weeks, i.e., a 28-day treatment cycle. In some embodiments, BT8009 is administered weekly on a 28-day treatment cycle, for example, on days 1, 8, 15, and 22. In some embodiments, BT8009 is administered once every two weeks on a 28-day cycle, for example, on days 1 and 15. In some embodiments, BT8009 is administered as a liquid formulation or a liquid unit dosage form.

[0093] In some embodiments, a treatment cycle is 3 weeks, i.e., a 21-day treatment cycle. In some embodiments, BT8009 is administered in week 1 and week 2, but not in week 3, of a 21-day treatment cycle. In some embodiments, BT8009 s administered on days 1 and 8 of a 21-day treatment cycle. In some embodiments, BT8009 is administered once weekly of a 21- day treatment cycle. In some embodiments, BT8009 administered on days 1, 8, and 15 of a 21-day treatment cycle.

[0094] In some embodiments, BT8009 is administered as a body surface area (BSA)-based dose, which is expressed in units of mg / m2, such as any of the doses discussed herein. A dose in units of mg / m2refers to a dose (in mg) that is administered per m2of the body surface area (BSA) of a patient. A BSA-based dose (in mg / m2) may be determined by dividing a dose (in mg) by the BSA of a patient. The skilled person will be aware of models and formula that may be used to estimate or determine the BSA of a patient based on factors such as the height and weight of the patient. In some embodiments, BSA may be estimated using the Dubois Formula for BSA Dosing (0.007184x (Height(cm))^0.725x(Weight(kg))^0.425 or the Monteller Formula for BSA Dosing (square root [(Height (cm) x Weight (kg)) / 3600]).

[0095] In some embodiments, a patient may have a BSA of 1.37 m2to 2.3 m2. In some embodiments, the patient may have a BSA of 1.37 m2to 1.69 m2. In some embodiments, the patient may have a BSA of 1.69 m2to 1.84 m2. In some embodiments, the patient may have a BSA of 1.84 m2to 1.96 m2. In some embodiments, the patient may have a BSA of 1.96 m2to 2.3 m2.

[0096] In some embodiments, BT8009 is administered at a dose (measured by the amount of the API: BT8009) of about 1-20 mg / m2. In some embodiments, BT8009 is administered at a dose of about 2-15 mg / m2. In some embodiments, BT8009 is administered at a dose of about 2-10 mg / m2. In some embodiments, BT8009 is administered at a dose of about 2 mg / m2, 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, or 10 mg / m2. In some embodiments, a BT8009 is administered at a dose of about 2.5 mg / m2, 3.5 mg / m2, 4.5 mg / m2, 5.5 mg / m2, 6.5 mg / m2, 7.5 mg / m2, 8.5 mg / m2, or 9.5 mg / m2. In one particular embodiment, BT8009 is administered at a dose of about 2-10 mg / m2, optionally at a dose of about 2.5-7.5 mg / m2, optionally at a dose of about 4-6 mg / m2, optionally at a dose of about 5 mg / m2. In another particular embodiment, BT8009 is administered at a dose of about 6-9 mg / m2,optionally at a dose of about 7-8 mg / m2, optionally at a dose of about 7.5 mg / m2 or 6 mg / m2.In some embodiments, BT8009 is administered at a dose of about 4-8 mg / m2, optionally at a dose of about 5-7 mg / m2, optionally at a dose of about 6 mg / m2.

[0097] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 2-10 mg / m2, optionally at a dose of about 2.5-7.5 mg / m2, optionally at a dose of about 4-6 mg / m2, optionally at a dose of about 5 mg / m2. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0098] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly at a dose of about 2-10 mg / m2, optionally at a dose of about 2.5-7.5 mg / m2, optionally at a dose of about 4-6 mg / m2, optionally at a dose of about 5 mg / m2. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly at a dose of about 2-10 mg / m2, optionally at a dose of about 2.5-7.5 mg / m2, optionally at a dose of about 4-6 mg / m2, optionally at a dose of about 5 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0099] In one embodiment, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 5 mg / m2. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0100] In one embodiment, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly at a dose of about 5 mg / m2. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly at a dose of about 5 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0101] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6-9 mg / m2, optionally at a dose of about 7-8 mg / m2, optionally at a dose of about 7.5 mg / m2. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0102] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6-9 mg / m2, optionally at a dose of about 7-8 mg / m2,optionally at a dose of about 7.5 mg / m2. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a dose of about 6-9 mg / m2, optionally at a dose of about 7-8 mg / m2, optionally at a dose of about 7.5 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0103] In one embodiment, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 7.5 mg / m2. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0104] In one embodiment, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 7.5 mg / m2. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a dose of about 6-9 mg / m2, optionally at a dose of about 7-8 mg / m2, optionally at a dose of about 7.5 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0105] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 4-8 mg / m2, optionally at a dose of about 5-7 mg / m2, optionally at a dose of about 6 mg / m2. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0106] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 4-8 mg / m2, optionally at a dose of about 5-7 mg / m2, optionally at a dose of about 6 mg / m2. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is aliquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a dose of about 4-8 mg / m2, optionally at a dose of about 5-7 mg / m2, optionally at a dose of about 6 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0107] In one embodiment, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6 mg / m2. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0108] In one embodiment, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6 mg / m2. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a dose of about 4-8 mg / m2, optionally at a dose of about 5-7 mg / m2, optionally at a dose of about 6 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0109] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 2.5 mg / m2. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0110] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly at a dose of about 2.5 mg / m2. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly at a dose of about 2.5 mg / m2by an IV infusion of about 60 minutes. In someembodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0111] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 5.5 mg / m2. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0112] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly at a dose of about 5.5 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly at a dose of about 5.5 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0113] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 7.5 mg / m2. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0114] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly at a dose of about 7.5 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly at a dose of about 7.5 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0115] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6 mg / m2. In some embodiments, the pharmaceuticalcomposition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0116] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient every two week at a dose of about 6 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0117] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient at a dose of about 7.5 mg / m2once every two weeks. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0118] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient once every two weeks at a dose of about 7.5 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient every two week at a dose of about7.5 mg / m2 by an IV infusion of about 60 minutes. In some embodiments, the liquidformulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0119] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient at a dose of about 10 mg / m2once every two weeks. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0120] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient once every two weeks at a dose of about 10 mg / m2by an IV infusion of about 60 minutes. In some embodiments, theBT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient every two weeks at a dose of about 10 mg / m2by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0121] In some embodiments, BT8009 is administered as a flat dose (i.e. a standard dose that is not dependent on the BSA of a patient which is expressed in units of mg. Administering a drug as a flat dose rather than as a BSA-based dose may offer several advantages whilst providing a similar overall pharmacokinetic profile to using a BSA-based dose. Administering a drug as a flat dose may improve the adverse event (AE) rate associated with a drug compared to a BSA-based dose, whilst maintaining efficacy. Administering a drug as a flat dose may reduce drug wasted associated with preparing and administering a drug to a patient compared to a BSA-based dose. Administering a drug as a flat dose may reduce the likelihood of dosage errors, and may improve convenience of administering the drug in a clinical setting.

[0122] In some embodiments. BT8009 is administered at a flat dose (measured by the amount of the API: BT8009) of about 1.8-36 mg. In some embodiments, BT8009 is administered at a flat dose of about 3.6-27 mg. In some embodiments. In some embodiments, BT8009 is administered at a flat dose of about 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 some embodiments, BT8009 is administered at a flat dose of about 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 one particular embodiment, BT8009 is administered at a flat dose of about 7-11 mg, optionally at a flat dose of about 8-10 mg, optionally at a flat dose of about 9 mg. In another particular embodiment, BT8009 is administered at a flat dose of about 9-13 mg, optionally at a flat dose of about 10-12 mg, optionally at a flat dose of about 11 mg.

[0123] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly flat dose of about 7-11 mg, optionally at a flat dose of about 8-10 mg, optionally at a flat dose of about 9 mg. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0124] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly a flat dose of about 7-11 mg, optionally a flat dose of about 8-10 mg, optionally a flat dose of about 9 mg. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In someembodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly a flat dose of about 7-11 mg, optionally a flat dose of about 8-10 mg, optionally a flat dose of about 9 mg by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0125] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly flat dose of about 9 mg. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0126] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly a flat dose of about 9 mg. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly a flat dose of about 9 mg by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0127] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 or a 21 day treatment cycle at a flat dose of about 9-13 mg, optionally at a flat dose of about 10- 12 mg, optionally at a flat dose of about 11 mg. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0128] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a flat dose of about 9-13 mg, optionally at a flat dose of about 10-12 mg, optionally at a flat dose of about 11 mg. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a flat dose of about 9-13 mg,optionally at a flat dose of about 10-12 mg, optionally at a flat dose of about 11 mg by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0129] In some embodiments, the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 or a 21 day treatment cycle at a flat dose of about 11 mg. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0130] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a flat dose of about 11 mg. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a flat dose of about 11 mg by an IV infusion of about 60 minutes. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0131] In some embodiments, the solid tumor is an advanced malignancy. In some embodiments, the solid tumor or advanced malignancy is associated with Nectin-4 expression.

[0132] In some embodiments, BT8009 is administered to a patient at least 18 years-of-age. Put another way, in some embodiments, the patient is an adult patient.

[0133] In some embodiments, the methods of treating solid tumors of the invention provide methods for maintaining or reducing the volume of a solid tumor in a patient. In some embodiments, the methods for maintaining or reducing the volume of a solid tumor in a patient involve administering BT8009 at a dose as described above. In one embodiment, BT8009 is administered weekly at a dose of 5 mg / m2. In one embodiment, BT8009 is administered on days 1 and 8 of a 21 day treatment cycle at a dose of 6 mg / m2.

[0134] 6. An Advanced Malignancy Associated With Nectin-4 Expression

[0135] The methods of the invention relate to the treatment of a solid tumor in a human patient. In some embodiments, the solid tumor is an advanced malignancy. In some embodiments 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 cancer.

[0136] In some embodiments, the cancer or solid tumor is associated with Nectin-4 expression. In some embodiments, the solid tumor is an advanced malignancy associated with Nectin-4 expression.

[0137] In some embodiments, an advanced malignancy 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 cancer.

[0138] In some embodiments, a patient having a solid tumor, advanced malignancy or advanced malignancy associated with Nectin-4 expression has been previously untreated for the malignancy (i.e. has received no prior lines of treatment for the malignancy). In some embodiments, a patient having a solid tumor, advanced malignancy or advanced malignancy associated with Nectin-4 expression has been previously untreated may be administered BT8009 as a monotherapy. In some embodiments, a patient having a solid tumor, advanced malignancy or advanced malignancy associated with Nectin-4 expression has been previously untreated may be administered BT8009 and pembrolizumab.

[0139] In some embodiments, a patient having a solid tumor, advanced malignancy or advanced malignancy associated with Nectin-4 has previously received one or more treatments for the solid tumor or advanced malignancy. In some embodiments, a patient having a solid tumor, advanced malignancy or advanced malignancy associated with Nectin-4 has previously received one or more treatments for the solid tumor or advanced malignancy may be administered BT8009 as a monotherapy. In some embodiments, a patient having a solid tumor, advanced malignancy or advanced malignancy associated with Nectin-4 has previously received one or more treatments for the solid tumor or advanced malignancy may be administered BT8009 and pembrolizumab. In some embodiment, a patient who has previously received one or more treatments is resistant or refractory is the one or more prior treatments.

[0140] In some embodiments, an advanced malignancy associated with Nectin-4 expression is lung cancer, for example, non-small-cell lung cancer (NSCLC). In some embodiments, an advanced malignancy associated with Nectin-4 expression is ovarian cancer. In some embodiments, an advanced malignancy associated with Nectin-4 expression is breast cancer, for example, triple-negative breast cancer (TNBC). In some embodiments, an advanced malignancy associated with Nectin-4 expression is esophageal cancer. In some embodiments, an advanced malignancy associated with Nectin-4 expression is gastric / upper gastrointestinal (GI). In some embodiments, an advanced malignancy associated with Nectin- 4 expression is head and neck cancer. In some embodiments, an advanced malignancyassociated with Nectin-4 expression is pancreatic cancer. In some embodiments, an advanced malignancy associated with Nectin-4 expression is urothelial cancer.

[0141] In some embodiments, an advanced malignancy associated with Nectin-4 expression is urothelial cancer. In some embodiments, an advanced malignancy associated with Nectin-4 expression is locally advanced urothelial cancer. In some embodiments, an advanced malignancy associated with Nectin-4 expression is malignant urothelial cancer. In some embodiments, a patient having locally advanced urothelial cancer or metastatic urothelial cancer has been previously untreated for the cancer. In some embodiments, a patient having locally advanced urothelial cancer or metastatic cancer has previously received one or more treatments for the cancer, for example one or more other treatments as described herein. In some embodiment, a patient who has previously received one or more treatments is resistant or refractory is the one or more prior treatments.

[0142] In some embodiments, a patient having locally advanced urothelial cancer who has been previously untreated for the cancer may be administered BT8009 as a monotherapy. In some embodiments, a patient having locally advanced urothelial cancer who has been previously untreated for the cancer may be administered BT8009 and pembrolizumab. In some embodiments, a patient having locally advanced urothelial cancer who has previously received one or more treatments for the cancer may be administered BT8009 as a monotherapy. In some embodiments, a patient having locally advanced urothelial cancer who has previously received one or more treatments for the cancer may be administered BT8009 and pembrolizumab.

[0143] In some embodiments, the patient is a patient having an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2. In some embodiments, the patient is a cisplatin-eligible patient having an ECOG Performance Status score of 0, 1 or 2. In some embodiments, the patient is a cisplatin-ineligible urothelial cancer patient having an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 2, wherein the patient has: Hemoglobin ≥10 g / dL, CrCl ≥50 mL / min, and no NYHA Class III heart failure. The ECOG Performance Status scores of 0 and 1 are described herein.

[0144] In some embodiments, the patient is a patient having measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. In some embodiments, the patient is a patient having target lesions that are previously irradiated and have demonstrated progression.

[0145] In some embodiments, the patient meets the inclusion criteria of the Phase I / II and / or Phase II / III trial synopses included herein.

[0146] In some embodiments, the patient is a patient having acceptable organ function. In some embodiments, a patient having acceptable organ function has laboratory data selected from the following: Renal function: creatinine clearance (CrCl) of ≥50 mL / min by the Cockcroft-Gault equation or equivalent and / or eGFR ≥ 30 mL / min (using the CKD-EPI creatinine equation) (Except for 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 International normal ratio (INR) <1.5 or ≤ institutional ULN unless the patient is receiving a stable dose of anticoagulant therapy and PT or aPPT is within therapeutic range of intended use of anticoagulants.

[0147] In some embodiments, the patient is a patient having acceptable hematologic function (no red blood cell or platelet transfusions or growth factors are allowed within 4 weeks of the first dose of BT8009; except for patients with renal impairment). In some embodiments, a patient having acceptable hematologic function has laboratory data selected from the following: Hemoglobin ≥9 g / dL; Absolute neutrophil count (ANC) ≥1500 cells / mm3; and Platelet count ≥75,000 cells / mm3.

[0148] In some embodiments, the patient is a patient who is a women of childbearing potential (WOCBP) that has a negative pregnancy test (negative serum test at screening and negative urine or serum test within 3 days prior to the first dose of a liquid formulation or a liquid unit dosage form as described herein).

[0149] In some embodiments, the patient is a patient who has a life expectancy ≥12 weeks after the start of BT8009 treatment.

[0150] In some embodiments, the patient is a patient with advanced, histologically confirmed urothelial (transitional cell) carcinoma that recurred after or has been refractory to prior therapy.

[0151] In some embodiments, the patient is a patient with advanced, histologically confirmed pancreatic, breast, NSCLC, gastric, esophageal, head and neck, or ovarian tumors that recurred after or has been refractory to prior therapy.

[0152] In some embodiments, the patient is a patient with histologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). In some embodiments, a patient has squamous differentiation or mixed cell types. In some embodiments, a patient does not have resectable locally advanced urothelial carcinoma. In some embodiments, a patient has received prior treatment with a CPI (PD-1 or PD-L1 inhibitor) if locally approved, in the locally advanced or metastatic urothelial cancer setting. In some embodiments, a patient has received CPI therapy in the neoadjuvant / adjuvant setting and has had recurrent or progressive disease either during therapy or within 3 months of therapy completion. In some embodiments, a patient has been treated with prior platinum-containing chemotherapy in the adjuvant / neoadjuvant setting and had recurrent or progressive disease within 12 months of completion or received treatment with a platinum regimen in the locally advanced (unresectable with curative intent) or metastatic setting. In some embodiments, a patient is platinum-naïve and platinum-ineligible, and has not received prior treatment with platinum-containing or other chemotherapy in locally advanced or metastatic setting. In some embodiments, a patient who has received platinum in the adjuvant / neoadjuvant setting and does not progress within 12 months of completion is considered platinum-naïve. In some embodiments, a patient has had progression or recurrence of urothelial cancer during or following receipt of most recent therapy. In some embodiments, a patient has been treated with enfortumab vedotin (EV). In some embodiments, a patient has not been treated with enfortumab vedotin (EV). In some embodiments, a patient has been treated with enfortumab vedotin (EV) and pembrolizumab. In some embodiments, a patient has not been treated with enfortumab vedotin (EV) and pembrolizumab.

[0153] In some embodiments, the patient is a patient, who has histologically confirmed non-mucinous epithelial ovarian (serous, endometrioid, clear cell, carcinosarcoma, and mixed pathologies), fallopian tube, or primary peritoneal cancer that is Stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) or tumor, node and metastasis staging criteria that have progressed following prior therapy. In some embodiments, a patient has been treated with FDA-approved or locally approved therapy.

[0154] In some embodiments, the patient is a TNBC patient, with tumors confirmed negative for ER / PR by immunohistochemistry (IHC) (≤10% positive tumor nuclei, as per ASCO-CAP guideline recommendations) and negative for human epidermal growth factorreceptor 2 (HER2) by IHC (0 and 1) or fluorescent or chromogenic in situ hybridization FISH or CISH) that have progressed following prior therapy. In some embodiments, a patient has been treated with FDA-approved or locally approved therapy.

[0155] In some embodiments, the patient is a patient, with histologically confirmed NSCLC with no actionable mutations, such as no Epidermal Growth Factor Receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion oncogene, or ROS1 that have progressed following prior therapy. In some embodiments, a patient has tumors with squamous cell carcinoma and adenocarcinoma histologies. In some embodiments, a patient has been treated with FDA-approved or locally approved therapy.

[0156] In some embodiments, the patient is a patient with locally advanced or metastatic, histologically confirmed urothelial (transitional cell) carcinoma. In some embodiments, a patient has squamous differentiation or mixed cell types. In some embodiments, a patient does not have resectable locally advanced urothelial carcinoma. In some embodiments, a patient is cisplatin-ineligible, which is determined by one of the following criteria: impaired renal function (creatinine clearance [CrCl] of 30 to 59 mL / min by C-G); hearing loss of ≥ 25 decibels (dB) at two contiguous frequencies; NYHA Class III heart failure; or Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, who meets the following criteria: i. Hemoglobin ≥10 g / dL; ii. CrCl ≥50 mL / min; and iii. May not have NYHA Class III heart failure. In some embodiments, a patient has no prior organ transplant (including allogeneic). In some embodiments, a patient is not previously diagnosed with clinically relevant immunodeficiency. In some embodiments, a patient does not have any condition requiring treatment with ≥10 mg daily prednisone equivalent or other strong immunosuppressant. In some embodiments, a patient does not have an active autoimmune disease that has required systemic treatment (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) within 2 years before treatment with a liquid formulation or a liquid unit dosage form as described herein. In some embodiments, a patient does not have a history of interstitial lung disease. In some embodiments, a patient has not received any systemic anticancer treatment for advanced or metastatic urothelial carcinoma. In some embodiments, a patient has not received prior adjuvant / neoadjuvant platinum-based therapy within 12 months prior to first dose. In some embodiments, a patient has not received prior adjuvant / neoadjuvant immune checkpointinhibitor therapy within 12 months before treatment with a liquid formulation or a liquid unit dosage form as described herein. In some embodiment, a patient has not received prior treatment with an MMAE based conjugate at any time. In some embodiments, a patient has not received prior treatment with a BTC (e.g. BT8009 or another BTC) at any time. In some embodiments, a patient has not received prior treatment with an MMAE based conjugate for urothelial carcinoma at any time. In some embodiments, a patient has not received prior treatment with EV or other MMAE-based ADC for urothelial carcinoma at any time.

[0157] In some embodiments, the patient is a patient with histologically confirmed urothelial (transitional cell) carcinoma, including a patient with squamous differentiation or mixed cell types, ovarian, triple-negative breast, or non-small cell lung cancer.

[0158] In some embodiments, the patient is a patient with solid tumor advanced disease. In some embodiments, a patient has renal insufficiency or real impairment. In some embodiments, a patient has renal function of 30-49 mL / min (by C-G). In some embodiments, a patient has renal function of 15-29 mL / min (by C-G). In some embodiments, a patient has been treated with FDA-approved or locally approved therapy.

[0159] In some embodiments, a patient has not had a chemotherapy treatment within 14 days prior to first dose of a liquid formulation or a liquid unit dosage form as described herein. In some embodiments, a patient has not had an anticancer treatment within 28 days or 5 half- lives, whichever shorter, prior to first dose of a liquid formulation or a liquid unit dosage form as described herein. In some embodiments, a patient has prior toxicities which have resolved to grade ≤1 per Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 (except alopecia which must be no greater than Grade 2).

[0160] In some embodiments, a patient has not had an experimental treatment within 4 weeks of first dose of a liquid formulation or a liquid unit dosage form as described herein.

[0161] In some embodiments, a patient does not have a current treatment with strong inhibitors or strong inducers of CYP3A or inhibitors of P-gp including herbal- or food-based.

[0162] In some embodiments, a patient does not have any sensitivity to any of the ingredients of a liquid formulation or a liquid unit dosage form as described herein, or to monomethyl auristatin E (MMAE).

[0163] In some embodiments, a patient does not have a significant medical condition including but not limited skin (conditions related to or that may confound monitoring for rash including but not limited to autoimmune conditions such as eczema or psoriasis), life- threatening illness, active uncontrolled infection or organ system dysfunction (such as ascites, coagulopathy, encephalopathy), or other reasons which could compromise the patient’s safety,or interfere with or compromise the integrity of the study outcomes including consideration of gastrointestinal, skin and pulmonary co-morbidities and including review of screening chest CT to ensure no clinically significant co-morbidities.

[0164] In some embodiments, a patient has a prior ≤ Grade 2 thyroid endocrinopathy, if appropriately controlled with thyroid hormone and stable for at least 2 months on therapy.

[0165] In some embodiments, a patient has skin toxicity which resolve to Grade ≤1.

[0166] In some embodiments, a patient does not have active keratitis or corneal ulcerations.

[0167] In some embodiments, a patient does not have Grade ≥2 peripheral neuropathy.

[0168] In some embodiments, a patient does not have a clinically relevant troponin elevation.

[0169] In some embodiments, a patient does not have uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8%.

[0170] In some embodiments, a patient has not had major surgery (excluding placement of vascular access) within 4 weeks of first dose of a liquid formulation or a liquid unit dosage form as described herein and has recovered adequately prior to treatment with a liquid formulation or a liquid unit dosage form as described herein.

[0171] In some embodiments, a patient has not received a live or attenuated vaccine within 30 days of study treatment.

[0172] In some embodiments, a patient does not have known active or untreated CNS metastases and / or carcinomatous meningitis. In some embodiments, a patient with treated brain metastasis are stable for at least 4 weeks prior to treatment with a liquid formulation or a liquid unit dosage form as described herein, either without the use of steroids or on stable or decreasing dose of less than or equal to 10 mg daily prednisone or equivalent and are without any symptoms that would confound the evaluation of neurologic and other AEs).

[0173] In some embodiments, a patient does not have uncontrolled hypertension (systolic blood pressure [BP] Systolic BP >=140 mm Hg or diastolic BP >=90 mm Hg, or Systolic BP ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg) prior to first dose of BT8009.

[0174] In some embodiments, a patient does not have a history or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation, or is not in the best interest of the patient to participate in the opinion of the Investigator.

[0175] In some embodiments, a patient does not have a history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heartfailure or symptoms of New York Heart Association Class III-IV documented within 6 months prior to first dose of BT8009.

[0176] In some embodiments, a patient does not have mean resting corrected QT interval (QTcF) >470 msec within 6 months prior to first dose of a liquid formulation or a liquid unit dosage form as described herein.

[0177] In some embodiments, a patient does not have, within 6 months prior to first dose of a liquid formulation or a liquid unit dosage form as described herein, any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval.

[0178] In some embodiments, a patient does not have, within 6 months prior to first dose of a liquid formulation or a liquid unit dosage form as described herein, any clinically important abnormalities in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third degree heart block.

[0179] In some embodiments, a patient does not have human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). In some embodiments, a patient has well controlled HIV, if a) CD4+ T-cell (CD4+) counts ≥350 cells / uL; b) HIV viral load <400 copies / mL; c) Without a history of opportunistic infection within the last 12 months; d) On established antiretroviral therapy (ART) for at least 4 weeks.

[0180] In some embodiments, a patient does not have a positive hepatitis B surface antigen and / or anti-hepatitis B core antibody.

[0181] In some embodiments, a patient has a negative polymerase chain reaction (PCR) assay and has an appropriate antiviral therapy.

[0182] In some embodiments, a patient does not have an active hepatitis C infection with positive viral load if hepatitis C virus (HCV) antibody positive.

[0183] In some embodiments, a patient has been treated for hepatitis C infection and has sustained virologic response of ≥12 weeks.

[0184] In some embodiments, a patient does not have another malignancy within 3 years before the first dose of a liquid formulation or a liquid unit dosage form as described herein. In some embodiments, a patient does not have any residual disease from a previously diagnosed malignancy (excluding adequately treated with curative intent basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia / cervical carcinoma in situ, melanoma in situ, or ductal carcinoma in situ of the breast).

[0185] In some embodiments, a patient does not have an active systemic infection requiring therapy, or fever not attributable to underlying malignancy within the last 14 days prior to first dose of a liquid formulation or a liquid unit dosage form as described herein.

[0186] In some embodiments, a patient does not have a suspicion of relevant and recent systemic viral syndrome or need for quarantine / isolation that is not resolved.

[0187] In some embodiments, a patient does not have prior Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) on any MMAE-conjugated drug. EXEMPLIFICATION

[0188] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. All amino acids, unless noted otherwise, were used in the L- configurations.

[0189] LIST OF ABBREVIATIONS Abbreviation or special term Explanation ADA Anti-drug antibody ADC Antibody-drug conjugate AE Adverse event ALP Alkaline phosphatase ALT Alanine aminotransferase ANC Absolute neutrophil count AR Adverse reaction AST Aspartate aminotransferase BLRM Bayesian Logistic Regression Model BP Blood pressure BSA Body surface area BTC Bicycle toxin conjugate CFR Code of Federal Regulations CHMP Committee for Medicinal Products for Human Use CI Confidence interval Cmax Maximum plasma drug concentration CR Complete response CRM Continual reassessment method CT Computed tomography ctDNA Circulating tumor DNA Development Innovations Sarah Cannon Development Innovations DLT Dose-limiting toxicity DOR Duration of response DRF Dose-range finding ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group eCRF Electronic Case Report FormEGFR Epidermal growth factor receptor EMA European Medicines Agency EOI End of infusion EOT End of treatment EWOC Escalation with overdose control FAS Full Analysis Set Fc Fragment crystallizable (region) FDA Food and Drug Administration, US FFPE Formalin-fixed paraffin-embedded FIH First in human FSH Follicle-stimulating hormone GCP Good Clinical Practice GI Gastrointestinal GLP Good Laboratory Practice HED Human equivalent dose HIPAA Health Insurance Portability and Accountability Act HNSTD Highest non-severely toxic dose HR Heart rate HTN Hypertension IB Investigator Brochure ICF Informed consent form ICH International Council for Harmonisation IND Investigational New Drug INR International normalized ratio irAE Immune-related adverse events IRB Institutional Review Board ISF Investigator Study File IV Intravenous LDH Lactate dehydrogenase MAD Maximum administrated dose MMAE Monomethyl auristatin E MRI Magnetic resonance imaging MTD Maximum tolerated dose NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events NE Not evaluable NHP Non-human primate NSCLC Non-small-cell lung cancer OR Objective response ORR Objective response rate OS Overall survival PD Progressive disease PD-1 Programmed cell death protein 1 PD-L1 Programmed death-ligand 1 PDx Pharmacodynamic PE Physical examination PET Positron emission tomography PFS Progression-free survival PHI Protected health informationPK Pharmacokinetic PR Partial response PT Prothrombin time PTT Partial thromboplastin time QT ECG interval measured from the onset of the QRS complex to the end of the T wave QTc QT interval corrected for heart rate REC Research Ethics Committee RECIST Response Evaluation Criteria in Solid Tumors RP2D Recommended Phase II dose SAE Serious adverse event SAP Statistical Analysis Plan SAR Suspected adverse reaction SAS Safety Analysis Set SD Stable disease SOA Schedule of Assessments SRC Safety Review Committee SUSAR Suspected unexpected serious adverse reaction TEAE Treatment-emergent adverse event TNBC Triple negative breast cancer UAE Unexpected adverse event ULN Upper limit of normal USPI US Package Insert WOCBP Women of childbearing potential 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

[0190] Number of Patients: Up to approximately 329 patients are planned to be enrolled in this study; 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 each in Cohorts B-4, B-5, and B-6; and 20 in Cohort B-7), and up to 18 in Part C.

[0191] Objectives: Primary Objectives

[0192] The objectives of the escalation (Parts A-1 and A-2), and renal insufficiency (Part C) cohorts are: Primary Objectives ^ To assess safety and tolerability of BT8009 in patients with advanced solid tumor malignancies associated with Nectin-4 expression: a) as a monotherapy (Part A-1)b) in combination with pembrolizumab (Part A-2), c) in patients with advanced solid tumor malignancies having renal insufficiency (Part C) ^ To define the maximum tolerated dose (MTD) of BT8009, if observed, and determine the recommended Phase II dose(s) (RP2D[s]) as a monotherapy and in combination with pembrolizumab (Parts A-1 and A-2) (Note, more than 1 RP2D may be declared based on the totality of safety, efficacy, and PK data.) Secondary Objectives ^ To assess preliminary signals of anti-tumor activity achieved with BT8009 administration in patients with advanced solid tumor malignancies associated with Nectin-4 expression using RECIST 1.1: a) as a monotherapy (Parts A-1) b) in combination with pembrolizumab (Parts A-2), c) in patients with advanced solid tumor malignancies having renal insufficiency (Part C) ^ To evaluate the impact of renal impairment on PK of BT8009 and monomethyl auristatin E (MMAE) (Part C) ^ To determine pharmacokinetic (PK) parameters of BT8009 and MMAE ^ To determine incidence of antidrug antibody (ADA) development

[0193] Dose Expansion

[0194] The objectives of the dose expansion cohorts (Part B) are: Primary Objectives ^ To assess the objective response rate (ORR) of BT8009 per Investigator assessment as a monotherapy in patients with EV-exposed (B-1) or EV-naïve (B-2 and B-3) urothelial carcinoma using RECIST V1.1 (metastatic urothelial cancer patients) ^ To assess the ORR of BT8009 as a monotherapy in patients with solid tumor indications associated with Nectin-4 expression (Parts B-4 [ovarian], B5 [TNBC], and B-6 [NSCLC]) using RECIST V1.1 ^ To assess the ORR of BT8009 in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma in combination with pembrolizumab using RECIST 1.1 (B-7) Secondary Objectives ^ To assess safety and tolerability of BT8009 in patients with solid tumor indications associated with Nectin-4 as a monotherapy (Parts B-1-B-6) and in combination with pembrolizumab (Part B-7)^ To assess other parameters of clinical activity ^ To determine pharmacokinetic (PK) parameters of BT8009 and MMAE ^ To determine incidence of ADA development

[0195] Study Design

[0196] This study is a Phase I / II, first-in-human, open-label dose-escalation study of BT8009 given as a single agent (Parts A-1, B and C),and in combination with pembrolizumab (Parts A-2 and B-7). There are three parts to this study: Part A: dose escalation (A-1), dose de- escalation in combination with pembrolizumab (A-2); Part B, dose expansion and Part C, renal insufficiency.

[0197] Part A

[0198] Part A will evaluate BT8009 in patients with histologically confirmed malignant solid tumors that are Nectin-4 positive. Part A-1 is a dose escalation of monotherapy BT8009 and Part A-2 is a dose de-escalation of BT8009 plus pembrolizumab (Starting at a Part A-1 RP2D and then proceeding to 1 dose level below this dose if the Part A-1 RP2D is not tolerated in combination). The scheme for Part A is shown in Figure 1.

[0199] Part B

[0200] Part B is a dose expansion at the BT8009 RP2D(s). The scheme for Part B is shown in Figure 2.

[0201] Part C

[0202] Part C is a cohort 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 in the severe renal impairment cohort (CrCl 15-29 ml / min). (Part C will not be enrolled in Canada.). The scheme for Part C is shown in Figure 3.

[0203] Study Drugs, Doses, and Modes of Administration: ^ BT8009, in ascending (Part A-1) and descending (Part A2) doses in dose escalation / de- escalation cohorts, respectively and at the RP2D(s) in expansion cohort (B) and renal cohorts (C) administered intravenously as infusion over 1 h (-5 / + 15 min). More than 1 RP2D may be declared by the Safety Review Committee based on the totality of safety, efficacy, and PK data. ^ Pembrolizumab administered 200 mg every 3 weeks over 30 minutes (-5 / + 15 min) on Day 1 for combination therapy in Parts A-2 and B-7.

[0204] Inclusion Criteria – All Patients: Patients must meet the following criteria in order to be included in the research study: 1. Written informed consent, according to local guidelines, signed and dated by the patient or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analyses. 2. At least 18 years-of-age at the time of signature of the informed consent form 3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. Patients who are in Cohort B-7 (cisplatin-ineligible urothelial cancer) can have an ECOG of 2 but must meet additional criteria (see Incl #29). 4. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Target lesions that were previously irradiated may be measurable if demonstrated progression has occurred. 5. Acceptable organ function, as evidenced by the following laboratory data: a. Renal function, as follows: creatinine clearance (CrCl) of ≥50 mL / min by the Cockcroft-Gault equation or equivalent. (Except for patients in the renal impairment cohorts [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. International normal ratio (INR) ≤1.5 or ≤ institutional ULN unless patient is receiving a stable dose of anticoagulant therapy and PT or aPPT is within therapeutic range of intended use of anticoagulants 6. Acceptable hematologic function (no red blood cell or platelet transfusions or growth factors are allowed within 4 weeks of the first dose of BT8009; except for patients in the renal impairment cohorts [Part C]): a. Hemoglobin ≥9 g / dL b. Absolute neutrophil count (ANC) ≥1500 cells / mm3c. Platelet count ≥75,000 cells / mm37. Negative pregnancy test for women of childbearing potential (WOCBP) (negative serum test at screening and negative urine or serum test within 3 days prior to the first dose of BT8009).8. Availability of archived tumor samples or willingness to provide fresh tumor biopsy during screening. 9. Life expectancy ≥12 weeks after the start of BT8009 treatment according to the Investigator’s judgment. 10. Must be willing and able to comply with the protocol, the scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures. Additional Inclusion Criteria – Part A-1 (monotherapy dose-escalation) 11. Must have exhausted all standard treatment options, including appropriate targeted therapies; patients for which no standard therapy is considered appropriate or to provide clinical benefit, as assessed by the Investigator 12. Patients with the following tumor histology: a. Patients with advanced, histologically confirmed urothelial (transitional cell) carcinoma that recurred after or has been refractory to prior therapy; or b. Patients with advanced, histologically confirmed pancreatic, breast, NSCLC, gastric, esophageal, head and neck, or ovarian tumors that recurred after or has been refractory to prior therapy (fresh tumor biopsy or an archived sample testing for Nectin-4 expression) Exceptions: single-subject accelerated cohorts may enroll patients with advanced solid tumors not-restricted to the above definitions, unless the safety review committee (SRC) views otherwise. (Single-subject cohorts will not be enrolled in Canada and the United Kingdom and must have confirmed Nectin-4 positivity for Spain.) The Sponsor may require a) or b) at any time during the enrollment. The Sponsor and / or SRC may decide to require enrollment of specific tumor (sub)types at any point during the escalation to enrich the evaluation of biomarkers, safety, anti-tumor activity, or PK. Additional Inclusion Criteria – Part A-2 (combination with pembrolizumab) 13. Must have exhausted all standard treatment options, including appropriate targeted therapies; patients for which no standard therapy is considered appropriate or to provide clinical benefit, as assessed by the Investigator. 14. Patients with advanced, histologically confirmed urothelial (transitional cell) carcinoma that have progressed following prior therapy. Additional Inclusion Criteria – Part B-1 (EV-exposed urothelial cancer)15. Must have histologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Patients with squamous differentiation or mixed cell types 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 locally approved, in the locally advanced or metastatic urothelial cancer setting. Patients who received CPI therapy in the neoadjuvant / adjuvant setting and had recurrent or progressive disease either during therapy or within 3 months of therapy completion are eligible. Patient must be one of the following: o Treated with prior platinum-containing chemotherapy in the adjuvant / neoadjuvant setting and had recurrent or progressive disease within 12 months of completion or received treatment with a platinum regimen in the locally advanced (unresectable with curative intent) or metastatic setting o Platinum-naïve and platinum-ineligible per Investigator assessment and have not received prior treatment with platinum-containing or other chemotherapy in locally advanced or metastatic setting and are ineligible for treatment with platinum at the time of enrolment. Patients who received platinum in the adjuvant / neoadjuvant setting and did not progress within 12 months of completion will be considered platinum- naïve. 17. Must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy 18. Previously treated with enfortumab vedotin (EV) Additional Inclusion Criteria – B-2 and B-3 (EV-naïve urothelial cancer) 19. Must have histologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Patients with squamous differentiation or mixed cell types 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 locally approved, in the locally advanced or metastatic urothelial cancer setting. Patients who received CPI therapy in the neoadjuvant / adjuvant setting and had recurrent or progressive disease either during therapy or within 3 months of therapy completion are eligible. Patient must be one of the following: o Treated with prior platinum-containing chemotherapy in the adjuvant / neoadjuvant setting and had recurrent or progressive disease within 12 months of completion orreceived treatment with a platinum regimen in the locally advanced (unresectable with curative intent) or metastatic setting o Platinum-naïve and platinum-ineligible and have not received prior treatment with platinum-containing or other chemotherapy in locally advanced or metastatic setting and are ineligible for treatment with platinum at the time of enrolment. Patients who received platinum in the adjuvant / neoadjuvant setting and did not progress within 12 months of completion will be considered platinum-naïve. 21. Must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy Additional Inclusion Criteria – Part B-4 (Ovarian cancer) 22. Patients with histologically confirmed non-mucinous epithelial ovarian (serous, endometrioid, clear cell, carcinosarcoma, and mixed pathologies), fallopian tube, or primary peritoneal cancer that is Stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) or tumor, node and metastasis staging criteria that have progressed following prior therapy. 23. Patients should previously be treated with FDA-approved or locally approved therapy according to the local standards of care / local guidance. Additional Inclusion Criteria – Part B-5 (Triple-negative breast cancer) 24. Patients with tumors confirmed negative for ER / PR by immunohistochemistry (IHC) (≤10% positive tumor nuclei, as per ASCO-CAP guideline recommendations) and negative for human epidermal growth factor receptor 2 (HER2) by IHC (0 and 1) or fluorescent or chromogenic in situ hybridization FISH or CISH) that have progressed following prior therapy. Patients with equivocal HER2 results by IHC should have their negativity status confirmed by FISH. 25. Patients should previously be treated with FDA-approved or locally approved therapy according to the local standards of care / local guidance. Additional Inclusion Criteria – Part B-6 (Non-small cell lung cancer) 26. Patients with histologically confirmed NSCLC with no actionable mutations, such as no Epidermal Growth Factor Receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion oncogene, or ROS1 that have progressed following prior therapy. Tumors with squamous cell carcinoma and adenocarcinoma histologies are permitted.27. Patients should previously be treated with FDA-approved or locally approved therapy according to the local standards of care / local guidance. Additional Inclusion Criteria – Part B-7 (First-line, cisplatin-ineligible, metastatic urothelial cancer) 28. Patients with locally advanced or metastatic, histologically confirmed urothelial (transitional cell) carcinoma. Patients with squamous differentiation or mixed cell types are eligible. Patients with resectable locally advanced urothelial carcinoma are ineligible. 29. Patients must be cisplatin-ineligible. Patients are considered cisplatin-ineligible if they meet at least one of the following criteria at study entry: impaired renal function (creatinine clearance [CrCl] of 30 to 59 mL / min by C-G), hearing loss of ≥ 25 decibels (dB) at two contiguous frequencies, NYHA Class III heart failure, or Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 a. Patients with ECOG PS of 2 must meet the following additional criteria: i. Hemoglobin ≥10 g / dL ii. CrCl ≥50 mL / min iii. May not have NYHA Class III heart failure Additional Inclusion Criteria – Part C (Renal-insufficiency cohort) 30. Patients must have histologically confirmed urothelial (transitional cell) carcinoma (patients with squamous differentiation or mixed cell types are eligible); ovarian; triple- negative breast; or non-small cell lung cancer. 31. Patients with solid tumor advanced disease are eligible as follows: 1) up to 12 patients with renal function of 30-49 mL / min (by C-G); 2) up to 6 patients with renal function of 15- 29 mL / min (by C-G). 32. Patients should previously be treated with FDA-approved or locally approved therapy according to the local standards of care / local guidance.

[0205] Exclusion Criteria – All Patients: Patients who meet any of the following criteria will be excluded from study entry: 1. Chemotherapy treatments within 14 days prior to first dose of study treatment. For other anticancer treatments, treatment within 28 days or 5 terminal half-lives, whichever is shorter. If prior immunotherapy, the last dose must be at least 28 days prior to the first dose of BT8009. Prior toxicities must have resolved to Grade ≤1 per Common TerminologyCriteria for Adverse Events (CTCAE) v 5.0 (except alopecia, which must be no greater than Grade 2). 2. Experimental treatments within 4 weeks of first dose of BT8009. 3. Current treatment with strong inhibitors or strong inducers of CYP3A or inhibitors of P-gp including herbal- or food-based. 4. Known hypersensitivity to any of the ingredients of the investigational product(s), including MMAE. 5. Significant medical condition including but not limited to skin (conditions related to or that may confound monitoring for rash including but not limited to autoimmune conditions such as eczema or psoriasis), life-threatening illness, active uncontrolled infection or organ system dysfunction (such as ascites, coagulopathy, encephalopathy), or other reasons which, in the Investigator opinion, could compromise the patient’s safety, or interfere with or compromise the integrity of the study outcomes, including consideration of gastrointestinal, skin and pulmonary co-morbidities and including review of screening chest CT to ensure no clinically significant co-morbidities. Prior ≤ Grade 2 thyroid endocrinopathy is allowed, if appropriately controlled with thyroid hormone and stable for at least 2 months on therapy. Skin toxicity should resolve to Grade ≤1. 6. Active keratitis or corneal ulcerations. 7. Grade ≥2 peripheral neuropathy. 8. Clinically relevant troponin elevation (considering local reference standards). 9. Uncontrolled diabetes, defined as hemoglobin A1C (HbA1c) ≥8% 10. Major surgery (excluding placement of vascular access) within 4 weeks of first dose of BT8009 and must have recovered adequately prior to starting study therapy 11. Receipt of live or attenuated vaccine within 30 days of study treatment 12. Known active or untreated CNS metastases and / or carcinomatous meningitis. (To be eligible, patients with treated brain metastasis may participate in the study if they are stable for at least 4 weeks prior to the first dose, either without the use of steroids or on stable or decreasing dose of less than or equal to 10 mg daily prednisone or equivalent and are without any symptoms that would confound the evaluation of neurologic and other AEs) 13. Patients with uncontrolled hypertension (systolic blood pressure [BP] Systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) prior to first dose of BT8009 14. History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation, or is not inthe best interest of the patient to participate in the opinion of the Investigator, including but not limited to: a. Patients with history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of New York Heart Association Class III*-IV documented within 6 months prior to first dose of BT8009 or: i. Mean resting corrected QT interval (QTcF) >470 msec ii. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of- age, or any concomitant medication known to prolong the QT interval iii. Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third degree heart block 15. Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). Note: Well controlled HIV will be allowed if the patient meets all the following criteria at inclusion: a) CD4+ T-cell (CD4+) counts ≥350 cells / uL; b) HIV viral load <400 copies / mL; c) Without a history of opportunistic infection within the last 12 months; d) On established antiretroviral therapy (ART) for at least 4 weeks. Use of anti- retroviral therapy is permitted, but should be discussed with the Medical Monitor on a case- by-case basis. 16. Patients with a positive hepatitis B surface antigen and / or anti-hepatitis B core antibody. Patients with a negative polymerase chain reaction (PCR) assay are permitted with appropriate antiviral therapy 17. Active hepatitis C infection with positive viral load if hepatitis C virus (HCV) antibody positive (if antibody is negative then viral load not applicable). Patients who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of ≥12 weeks. 18. History of another malignancy within 3 years before the first dose of BT8009, or any evidence of residual disease from a previously diagnosed malignancy (excluding adequately treated with curative intent basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia / cervical carcinoma in situ, melanoma in situ, or ductal carcinoma in situ of the breast).19. Active systemic infection requiring therapy, or fever not attributable to underlying malignancy within the last 14 days prior to first dose of BT8009. 20. Suspicion of relevant and recent systemic viral syndrome or need for quarantine / isolation that is not resolved in the opinion of the Investigator 21. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and / or follow-up procedures outlined in the protocol. 22. Prior Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) on any MMAE-conjugated drug.

[0206] Additional Exclusion Criteria Part A-2 (combination with pembrolizumab) 23. Prior intolerance or known hypersensitivity to immune checkpoint inhibitor 24. Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, OX-40 agonist or CTLA-4 inhibitors a. Prior treatment with a PD-1, PD-L1 or PD-L2 inhibitor is permitted 25. Prior organ transplant (including allogeneic) 26. Diagnosis of clinically relevant immunodeficiency 27. Any condition requiring treatment with ≥10 mg daily prednisone equivalent or other strong immunosuppressant 28. Has an active autoimmune disease that has required systemic treatment in the past 2 years (e.g. with the use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systematic treatment. Patients with type 1 DM well controlled on insulin, alopecia, or vitiligo are not excluded per this criteria. 29. History of interstitial lung disease

[0207] Additional Exclusion Criteria B-2 and B-3 (EV-naïve urothelial cancer) 30. Prior treatment with EV.

[0208] Additional Exclusion Criteria Part B-7 (First-line, cisplatin-ineligible, metastatic urothelial cancer) 31. Prior organ transplant (including allogeneic) 32. Diagnosis of clinically relevant immunodeficiency33. Any condition requiring treatment with ≥10 mg daily prednisone equivalent or other strong immunosuppressant 34. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) 35. History of interstitial lung disease 36. Received any systemic anticancer treatment for advanced or metastatic urothelial carcinoma 37. Received prior adjuvant / neoadjuvant platinum-based therapy within 12 months prior to first dose 38. Received prior adjuvant / neoadjuvant immune checkpoint inhibitor therapy within 12 months prior to first dose 39. Received prior treatment with EV or other MMAE-based ADC for urothelial carcinoma at any time Correlative Testing:

[0209] All patients will be required to provide archive tumor material or fresh tumor biopsy for assessment of expression levels of Nectin-4 and additional molecular genetic characterization including but not limited to markers of immune checkpoint status (e.g., PD- L1 tumor expression), or proliferation (e.g. Ki-67, pHH3) and / or immunogenic cell death. This material should be provided as a tissue block or 10-15 paraffin-dipped unstained slides.

[0210] Optional post-dose biopsies may be collected to investigate intratumoral PK / Pharmacodynamic effects of BT8009. Post dose biopsies will be requested from at least 6 patients in Part B. Post-dose biopsies may be taken in Cycles 1-4 for patients in Part A-1, and in Cycle 1 only for all other patients, within 4 hours to 7 days after the BT8009 dose. Refer to the schedule of assessments (SOA) for further details.

[0211] Pre- and post-dose blood samples will also be collected to assess pharmacodynamic, response, and treatment resistance biomarkers, such as somatic mutations in circulating tumor DNA (ctDNA), ADA and pharmacogenomic analysis. Statistical Methodology

[0212] Dose-escalation / de-escalation (applies separately to A-1 and A-2) starts with the single subject (A-1 only) and primarily utilizes the 3+3 escalation. BLRM with EWOC principle would also be applied to cumulative DLT / safety data for SRC considerations on dose escalation recommendations.

[0213] For cohorts B-1 to B-6 in Part B, Simon’s two-stage design will be used to test whether the ORR warrants continuation to the next phase. The design would allow early futility check and minimize the expected total sample size, with Type I error rate of 0.05 and power of 80%.

[0214] All statistical analyses will be using descriptive summary statistics. Response endpoints will be reported using proportion with associated 95% CI. Example 2. BT8009 Formulation

[0215] The BT8009 drug product is formulated as a sterile lyophilized powder for solution. The medicinal product is contained in a 10 mL Type I clear glass vial with a chlorobutyl stopper and aluminum seal. The labelled strength of each vial includes 21.2 mg / vial for reconstitution with 5.0 mL of water for injection (WFI). With a displacement volume of 0.3 mL, a 4 mg / mL BT8009 solution is generated (the reconstituted drug substance contains L-histidine, sucrose, and Polysorbate 20), and 5.0 mL of the reconstituted solution will be withdrawn to provide a 20 mg dose for further dilution with about 0.9% saline and administration via IV infusion. Example 3. Review of BT8009 Phase I trial results and outlook

[0216] BT8009 demonstrates anti-tumor activity in heavily pre-treated urothelial (Figures 5-7), lung (Figures 8A, 9A) and breast cancer (Figures 8B, 9B) patients with signs of differentiation compared to antibodies and potential for industry-leading product profile. BT8009 demonstrates a 50% ORR and 75% clinical benefit rate (Figure 7), including 1 (13% complete response in urothelial cancer at 5 mg / m2qw dose (Figure 5-7). The breadth of responses at other dose cohorts and other cancer types illustrates the drug’s potential. BT8009 shows durable responses, with tumor reductions maintained over time (Figure 6). Median duration of response still has not been reached among urothelial patients in the 5 mg / m2 cohort;at least 11 months as at data cut-off point of the clinical trial (20 September 2022). The median duration of response is estimated to be approximately 14 months with 2 out of 4 responders still on therapy. Figures 10-16 show the incidence of treatment-emergent adverse events (TEAEs) in the trial. These are the first in human data for a bicycle toxin conjugate targeting Nectin-4. These data indicate positive efficacy and safety profiles. In addition, these data show that BT8009 has potential advantages over existing treatments such as enfortumab vedotin. Example 4: Modelling supporting dosage strategies

[0217] Modeling and simulation evaluations, including population PK and exposure- response modelling analysis were conducted for various dosing strategies (flat, weight-based and BSA-based dosing) using pharmacokinetics (PK), efficacy and safety data from the ongoing Phase I trial data. The PK exposure (AUC and Cmax) of BT8009 and MMAE were predicted from the population PK model and subsequently probabilities of adverse events (AE) were simulated from exposure-safety logistic regression modeling. The modelling predicted that utilization of a flat dosing of BT8009 (in mg) would result in similar PK and safety outcomes relative to BSA-based dosing (in mg / m2). Flat dosing has practical and clinical advantages over BSA-based dosing, including ease of dose preparation, reduced chance of dosing errors and minimized drug wastage, and is more convenient in clinical practice.

[0218] Figure 17 shows the rate of treatment-related adverse events (TRAE) at different exposures to MMAE from BSA based dosing. Higher AE rate was observed in higher BSA, which suggests flat dose could help to balance the AE across different body size.

[0219] Population PK and exposure-safety modelling support a switch to a flat (fixed) dose. Data indicate that BSA or body weight-based dosing may lead to higher adverse events (AE) and the need for weight-based caps (e.g. Padcev). BT8009 in a flat (fixed) dose e.g. 9 mg instead of 5 mg / m2is broadly equivalent to BSA dosing on mean PK exposure and provide similar PK variability as BSA dosing, but may improve AE based on safety evaluation while maintaining efficacy (Figure 18). This will simplify administration of BT8009 and reduce dosing errors and drug wastage. Example 5. Phase II / III Study of the Efficacy of BT8009 Monotherapy or in Combination for Locally Advanced or Metastatic Urothelial Cancer

[0220] Number of Participants: The study will enroll a total of ~750 participants with locally advanced or metastatic urothelial cancer (UC). Cohort 1 will include ~555 participants who have not received any prior systemic therapy for locally advanced or metastatic UC. Cohort 2 will include ~195 participants who received ≥ 1 prior systemic therapy for locally advanced or metastatic UC.

[0221] Objectives: Primary Objectives

[0222] The objectives of cohort I are: Primary objectives ^ To evaluate the efficacy of BT8009 in combination with pembrolizumab as compared to standard of care (SOC) chemotherapy, measured by progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)assessed by blinded central independent review (BICR), measured by the length of time from date of first dose to determination of disease progression made by BICR, or death (due to any cause). Secondary objectives ^ To assess clinical activity by the objective response rate (ORR) per RECIST v1.1 assessed by BICR and by the Investigator, measured by the percentage of participants in the analysis population who have achieved either confirmed complete response (CR) or partial response (PR) per RECIST v1.1 assessed by BICR and by the Investigator. ^ To evaluate overall survival (OS), defined as the length of time from date of first dose until the date of death from any cause. ^ To assess clinical activity by duration of response (DOR) measured by the time from first documentation of objective response (that is subsequently confirmed) as per RECIST v1.1 assessed by BICR and Investigator to the first documentation of objective tumor progression (as per RECIST v1.1), or to death (due to any cause) and disease control rate (DCR) measured by the percentage of participants who experience a CR, PR, or stable disease (SD) per RECIST v1.1 assessed by BICR and by the Investigator. ^ To evaluate PFS per RECIST v1.1 by the Investigator measured by the length of time from date of first dose to determination of disease progression made by the Investigator, or death (due to any cause). ^ To evaluate the safety and tolerability of BT8009 in combination with pembrolizumab, measured by the incidence of treatment emergent adverse events (TEAEs) and abnormalities in laboratory, electrocardiogram and vital signs. ^ To characterize the pharmacokinetics of BT8009 and monomethyl auristatin E (MMAE). ^ To evaluate health-related quality of life (HRQOL) (Changes in Euroqol-5 Dimensions (EQ-5D) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)). Exploratory ^ To explore the incidence and titers of anti-drug antibodies (ADAs) against BT8009 and pembrolizumab and to explore the potential relationship between any potential immunogenic response and pharmacokinetics, safety, and efficacy. ^ To explore relationships between peripheral and tumor biomarkers and clinical activity - baseline tumor and peripheral biomarkers including Nectin-4 and programmed death-ligand 1 (PD-L1) expression, soluble target and inflammatory cytokines, tumor mutations, pharmacogenomics, circulating tumor DNA (ctDNA), and gene signatures. ^ To explore relationships between pharmacokinetics (PK) and pharmacodynamic biomarker activity with clinical outcomes, measured by changes in tumor and peripheral biomarkers including Nectin-4 protein expression and somatic mutations in tumor tissue, soluble target and inflammatory cytokines, ctDNA, and gene signatures.

[0223] The objectives of cohort 2 are: Primary Objectives: ^ To evaluate the efficacy of BT8009 monotherapy, as measured by ORR per RECIST v1.1 assessed by BICR, measured by the percentage of participants in the analysis population who have achieved either confirmed CR or PR per RECIST v1.1 assessed by BICR. Secondary Objectives: ^ To evaluate ORR per RECIST v1.1 assessed by the Investigator, measured by the percentage of participants in the analysis population who have achieved either confirmed CR or PR as per RECIST v1.1 assessed by the Investigator. ^ To evaluate DOR, measured by the time from first documentation of objective response (that is subsequently confirmed) as per RECIST v1.1 assessed by BICR and Investigator to the first documentation of objective tumor progression (as per RECIST v1.1), or to death (due to any cause), DCR, measured by the percentage of participants who experience a CR, PR, or SD per RECIST v1.1 assessed by BICR and Investigator, and PFS measured by the length of time from date of first dose to determination of disease progression made by BICR and Investigator, or death (due to any cause) per RECIST v1.1 assessed by BICR and by Investigator. ^ To evaluate OS, defined as length of time from date of first dose until the date of death from any cause. ^ To evaluate the safety and tolerability of BT8009, measured by incidence of TEAEs, and abnormalities in laboratory, ECG, and vital signs. ^ To evaluate severe cutaneous adverse reactions (SCARs) and peripheral neuropathy - Incidence and severity of SCAR and peripheral neuropathy events, as classified by Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) broad (scope) terms.^ To characterize the pharmacokinetics of BT8009 and MMAE, measured by Pharmacokinetic parameters of BT8009 and MMAE. ^ To assess HRQOL, measured by changes in EQ-5D and EORTC QLQ-C30. Exploratory ^ To explore the incidence and titers of ADAs against BT8009 and to explore the potential relationship between any potential immunogenic response and pharmacokinetics, safety, and efficacy. ^ To explore relationships between peripheral and tumor biomarkers and clinical activity – baseline tumor and peripheral biomarkers including Nectin-4 expression, soluble target and inflammatory cytokines, tumor mutations, pharmacogenomics, ctDNA, and gene signatures. ^ To explore relationships between PK and pharmacodynamic biomarker activity of BT8009, and clinical outcomes, measured by changes in tumor and peripheral biomarkers including Nectin-4 protein expression and somatic mutations in tumor tissue, soluble target and inflammatory cytokines, ctDNA, and gene signatures.

[0224] Overall Design: This study is a global, multicenter, randomized, open-label Phase 2 / 3 trial, with an adaptive design.

[0225] Brief Summary: The purpose of this study is to measure the efficacy and safety of BT8009 in combination with pembrolizumab versus (vs) standard of care (SOC) chemotherapy (Cohort 1) and BT8009 monotherapy (Cohort 2) in participants with locally advanced or metastatic UC.

[0226] Study Design for Cohort 1(Previously untreated): Participants who have not received any prior systemic treatment for advanced or metastatic UC will be randomized 1:1:1 to BT8009 9 mg plus pembrolizumab, BT8009 11 mg plus pembrolizumab, or SOC chemotherapy (gemcitabine plus either cisplatin or carboplatin, based on Investigator choice, followed by avelumab maintenance, if indicated). Participants will be stratified by cisplatin eligibility (cisplatin eligible vs cisplatin ineligible), liver metastases (yes vs no), and Eastern Cooperative Oncology Group (ECOG) Performance Status (0 / 1 vs 2). Within the chemotherapy arm, the proportion of participants receiving cisplatin-based chemotherapy will be capped at ~50%. An interim analysis (IA 1) on the first ~30 participants in each BT8009 dose level arm that have been followed for at least 4 months from the first dose of study treatment, have discontinued from the study due to any reason, or have experienced disease progression (whichever occurs first) will be performed to select the BT8009 optimal dose incombination with pembrolizumab. Participant enrollment into the BT8009 optimal dose in combination with pembrolizumab and chemotherapy arms will continue, whereas enrollment into the treatment arm of the BT8009 dose that was not selected based on results from IA1 will be stopped.

[0227] When ~120 participants in the BT8009 selected dose in combination with pembrolizumab have been followed for at least 6 months from the first dose of study treatment, have discontinued from the study due to any reason, or have experienced disease progression (whichever occurs first), a second interim analysis (IA2) will be performed to evaluate the efficacy of BT8009 in combination with pembrolizumab based on the evaluation of ORR by BICR.

[0228] Participants will continue to be randomized 1:1 into BT8009 optimal dose in combination with pembrolizumab and chemotherapy treatment arms until each arm has ~215 participants. The primary analysis will assess the efficacy BT8009 in combination with pembrolizumab based on the evaluation of PFS by BICR and will take place when ~357 events for the comparison of BT8009 selected dose in combination with pembrolizumab and chemotherapy have occurred. The final analysis will include an evaluation of overall survival (OS).

[0229] Study Design for Cohort 2 (Previously treated): Participants who have received ≥ 1 prior line of systemic therapy for their UC will be randomized 2:2:1 to BT8009 9 mg monotherapy, BT800911 mg monotherapy, or enfortumab vedotin. An interim analysis on the first ~30 participants in each BT8009 arm that have been followed for at least 4 months from the first dose of study treatment, have discontinued from the study due to any cause, or have experienced disease progression (whichever occurs first), will be performed to select the BT8009 optimal dose. Participant enrollment into the BT8009 optimal dose and enfortumab vedotin arms will continue, whereas enrollment into the treatment arm of the BT8009 dose that was not selected based on results from IA1 will be stopped.

[0230] When a total of 110 participants in the BT8009 optimal dose arm have been followed for at least 6 months, have discontinued from study due to any cause, or have experienced disease progression (whichever occurs first), the primary analysis will be conducted to assess efficacy of BT8009 monotherapy based on the evaluation of ORR by BICR.

[0231] Treatment and Study Discontinuation (both Cohorts): In both cohorts, study treatments will continue until one of the treatment discontinuation criteria is met. Treatment discontinuation criteria include disease progression (radiographically confirmed per RECISTv1.1), irreversible or intolerable toxicity, Investigator’s decision to withdraw the participant, participant’s decision to discontinue study treatment, confirmed pregnancy, severe noncompliance with trial treatment or procedure requirements, loss to follow-up, death, or Sponsor’s decision to terminate the study. For participants who discontinue study treatment for reasons other than radiographical progression, efficacy assessment will be performed at the specified time intervals until disease progression, initiation of a new anticancer therapy, withdrawal of consent, loss to follow-up, death, or study termination by the Sponsor, whichever occurs first. Study discontinuation is defined as withdrawal of study consent, loss to follow- up, death, or study termination by the Sponsor (whichever occurs first).

[0232] In Cohort 1, treatment with pembrolizumab will continue until disease progression, unacceptable toxicity, or a treatment duration of up to 24 months. If one of the study treatments (BT8009 or pembrolizumab) is discontinued due to treatment-related toxicity, the participant can continue the other study treatment, if deemed in the best interest of the participant by the Investigator. Chemotherapy treatment is limited to up to 6 treatment cycles.

[0233] Tumor Assessment Schedule (both Cohorts): Participants will undergo tumor status assessments at Screening and every 9 weeks (± 5 days) for the first 54 weeks following Cycle 1, Day 1. After 54 weeks, participants will undergo tumor status assessments every 12 weeks (± 7 days). Cycle timing will not be delayed in case of treatment interruptions, and tumor status assessments should occur according to the schedule of activities (SOA), regardless of whether study treatment is interrupted.

[0234] EOT and Follow-up Timepoints (Safety and Long-term) (both Cohorts): An end of treatment (EOT) visit should occur within 7 (± 2) days of the decision to discontinue all study treatments. If treatment was discontinued due to reasons other than confirmed disease progression, a tumor assessment is required within 2 weeks of all study treatment(s) discontinuation. For participants on combination therapy (i.e., BT8009 in combination with pembrolizumab, gemcitabine in combination with cisplatin or carboplatin, or enfortumab vedotin in combination with pembrolizumab, all in Cohort 1), if one study treatment is discontinued, tumor assessments will continue per SOA, until all study treatments have been discontinued.

[0235] A safety follow-up visit will occur 30 (+ 5) days after the last dose of all study treatments or prior to starting a new anticancer therapy, whichever comes first. In Cohort 1, immune-related adverse events and serious adverse events related to pembrolizumab will be collected for 90 days after the last dose of pembrolizumab or until initiation of a new anticancer therapy, whichever occurs first.

[0236] After disease progression is confirmed by BICR, survival and anticancer therapy status will be collected every 3 months (± 30 days) until death, loss to follow-up, withdrawal of study consent, or study termination by the Sponsor, whichever occurs first.

[0237] Study Arms and Duration:

[0238] Cohort 1: Previously untreated:

[0239] Arm 1: BT80099 mg intravenous (IV) over 60 (-5 to +30) minutes on Days 1, 8, and 15 of every 21-day cycle plus pembrolizumab 200 mg IV over 30 (-5 to +10) minutes on Day 1 of every 21-day cycle. Pembrolizumab infusion will be started 30 minutes following the completion of the BT8009 infusion.

[0240] Arm 2: BT800911 mg IV over 60 (-5 to +30) minutes on Days 1 and 8 plus of every 21-day cycle plus pembrolizumab 200 mg IV over 30 (-5 to +10) minutes on Day 1 of every 21-day cycle. Pembrolizumab infusion will be started 30 minutes following the completion of the BT8009 infusion.

[0241] Arm 3: Up to 6 cycles of platinum-based combination chemotherapy per Investigator choice of either: Cisplatin 70 mg / m2 IV over 60 minutes on Day 1 (or Day 2, if required by local guidelines) plus 1000 mg / m2 IV gemcitabine over 30 minutes on Days 1 and 8 of every 21-day cycle OR Carboplatin area under the curve (AUC) 5 mg / mL per minute (or 4.5 mg / mL, if required by local institutional standards) IV over 60 minutes on Day 1 (or Day 2, if required by local institutional standards) plus 1000 mg / m2 IV gemcitabine over 30 minutes on Days 1 and 8 of every 21-day cycle.

[0242] Infusion of cisplatin or carboplatin will be administered 30 minutes after the completion of the gemcitabine infusion. A participant may switch per Investigator decision from cisplatin to carboplatin during the trial, if required by clinical factors such as impairment of renal function.

[0243] Avelumab is allowed, per Investigator choice, as maintenance therapy for participants who achieved CR, PR, or SD following chemotherapy. Avelumab 800 mg IV over 60 minutes will be administered on Days 1 and 15 of every 28-day cycle.

[0244] Arm 4: Enfortumab vedotin 1.25 mg / kg IV (up to a maximum of 125 mg for participants ≥ 100 kg) over 30 minutes on Days 1 and 8 of every 21-day cycle plus pembrolizumab 200 mg IV over 30 (-5 to +10) minutes on Day 1 of every 21-day cycle. The Sponsor may choose to add this treatment arm based on a possible shift in the UC standard ofcare landscape. Enfortumab vedotin infusion will be completed 30 minutes prior to the start of the pembrolizumab infusion.

[0245] Cohort 2: Previously treated

[0246] Arm 1: BT80099 mg IV over 60 (-5 to +30) minutes on Days 1, 8, and 15 of every 21-day cycle.

[0247] Arm 2: BT800911 mg IV over 60 (-5 to +30) minutes on Days 1 and 8 of every 21-day cycle.

[0248] Arm 3: Enfortumab vedotin 1.25 mg / kg IV (up to a maximum of 125 mg for participants ≥ 100 kg) over 30 minutes on Days 1, 8, and 15 of every 28-day cycle.

[0249] Inclusion Criteria:

[0250] Participants must meet the following criteria for study entry.

[0251] Cohort 1: Previously untreated 1. Able to understand the study procedures and agree to participate in the study by providing written informed consent. 2. ≥ 18 years of age on day of signing informed consent. 3. Histologically or cytologically confirmed locally advanced (unresectable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, and urethra. a. Participants with mixed histologies are required to have a dominant transitional cell pattern (≥ 50%) 4. Measurable disease as defined by RECIST v1.1. a. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions post irradiation. 5. Participants must not have received prior systemic therapy for locally advanced or metastatic UC with the following exceptions: a. Prior local intravesical chemotherapy, local surgery when full resection is not achieved, local immunotherapy, and radiotherapy are permitted if completed at least 4 weeks prior to the initiation of study treatment and all acute toxicities have resolved. b. Prior neoadjuvant chemotherapy with recurrence >12 months from completion of therapy. c. Prior adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. d. Prior neoadjuvant / adjuvant immune checkpoint inhibitor therapy >12 months from completion of therapy.Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Eligible to receive platinum-based chemotherapy (either cisplatin- or carboplatin-based chemotherapy). Note: once cisplatin cap of 50% is reached, participants who are eligible to receive cisplatin-based chemotherapy will no longer be considered eligible for the study. Archival or fresh tumor tissue comprising muscle-invasive UC or metastatic UC. Life expectancy ≥ 12 weeks. Adequate hematologic and organ function: a. Hemoglobin ≥ 9 g / dL b. Absolute neutrophil count (ANC) ≥ 1500 cells / mm3 c. Platelet count ≥ 75,000 cells / mm3 d. Estimated glomerular filtration rate (eGFR) ≥ 30 mL / min (using the CKD-EPI creatinine equation) 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. International normal ratio (INR) ≤ 1.5 ULN or ≤ institutional ULN unless participant is receiving a stable dose of anticoagulant therapy and PT or PPT is within therapeutic range of intended use of anticoagulants. Negative pregnancy test for women of childbearing potential (WOCBP) (negative serum test at Screening and negative urine or serum test within 72 hours prior to the first dose). WOCBP and male participants with female partners of childbearing potential willing to follow highly effective contraception at least as conservative as Clinical Trial Facilitation Group (CTFG) recommendations of < 1% failure rate starting at Screening, throughout the study period, and for at least 1 month following the last dose of avelumab, 4 months following the last dose of pembrolizumab, 6 months following the last dose of BT8009, 6 months following the last dose of platinum treatment, and 12 months following the last dose of enfortumab vedotin, whichever comes last.13. Fertile male participants must agree to refrain from sperm donation from first dose until at least 1 month following the last dose of avelumab, 4 months following the last dose of pembrolizumab, 6 months following the last dose of BT8009, 6 months following the last dose of platinum treatment, and 9 months following the last dose of enfortumab vedotin, whichever comes last. Women must not breastfeed or donate eggs from first dose until 1 month following the last dose of avelumab, 4 months following the last dose of pembrolizumab, 6 months following the last dose of BT8009, 6 months following the last dose of platinum treatment, and 9 months following the last dose of enfortumab vedotin, whichever comes last.

[0252] Cohort 2: Previously treated 1. Able to understand the study procedures and agree to participate in the study by providing written informed consent. 2. ≥ 18 years of age on day of signing informed consent. 3. Histologically or cytologically confirmed locally advanced (unresectable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, and urethra. a. Participants with mixed histologies are required to have a dominant transitional cell pattern (≥ 50%). 4. Measurable disease as defined by RECIST v1.1. a. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 5. ECOG performance status ≤ 1. 6. Participants must have received ≥1 prior systemic treatment for locally advanced or metastatic UC. 7. Progression or recurrence of UC during or following receipt of most recent therapy. 8. Representative FFPE tumor specimen in paraffin block (block preferred) or at least 15 unstained slides. If archival tumor samples are not available, then a fresh biopsy must be provided. 9. Life expectancy ≥ 12 weeks. 10. Adequate hematologic and organ function: a. Hemoglobin ≥ 9 g / dL b. ANC ≥ 1500 cells / mm3 c. Platelet count ≥ 75,000 cells / mm3 d. eGFR of ≥ 30 mL / min (using the CKD-EPI creatinine equation) e. Total bilirubin ≤ 1.5 × upper limit of normal ULNf. 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. INR ≤ 1.5 ULN or ≤ institutional ULN unless participant is receiving a stable dose of anticoagulant therapy and PT or PPT is within therapeutic range of intended use of anticoagulants. 11. Negative pregnancy test for WOCBP (negative serum test at Screening and negative urine or serum test within 72 hours prior to the first dose). 12. WOCBP and male participants with female partners of childbearing potential willing to follow highly effective contraception at least as conservative as Clinical Trial Facilitation Group (CTFG) recommendations of < 1% failure rate starting at Screening, throughout the study period, and for at least 6 months following the last dose of BT8009 and 12 months following the last dose of enfortumab vedotin. 13. Fertile male participants must agree to refrain from sperm donation from first dose until at least 6 months following the last dose of BT8009 or 9 months following the last dose of enfortumab vedotin. Women must not breastfeed or donate eggs from first dose until 6 months following the last dose of BT8009 and 12 months following the last dose of enfortumab vedotin.

[0253] Exclusion Criteria: Participants who meet any of the following criteria will be excluded from study entry. Cohort 1: Previously untreated 1. Prior treatment with enfortumab vedotin or any other MMAE-based therapy. 2. Prior treatment with a checkpoint inhibitor for any other malignancy. 3. Prior treatment with an agent directed to another stimulatory or co-inhibitory T-cell receptor. 4. Received anti-cancer treatment for any other cancer with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1 to 3 that is not completed 4 weeks prior to first dose of study treatment. 5. Active keratitis or corneal ulcerations. 6. Current treatment with strong inhibitors or strong inducers of human cytochrome P450 3A4 (CYP3A4) or inhibitors of P-glycoprotein (P-gp) including herbal- or food-based inhibitors.Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Any condition requiring treatment with high dose corticosteroids (> 10 mg daily prednisone). Known hypersensitivity or allergy to any of the ingredients of either of the study interventions, or MMAE. Major surgery (excluding placement of vascular access) within 4 weeks of first dose. RBCs or platelet transfusions or growth factors within 4 weeks of first dose. Receipt of live or attenuated vaccine within 30 days of first dose. 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 for at least 4 weeks prior to the first dose, either without the use of steroids or on stable or decreasing dose of ≤ 10 mg daily prednisone or equivalent and are without any symptoms that would confound the evaluation of neurologic and other AEs. Uncontrolled diabetes, defined as hemoglobin A1C (HbA1c) ≥ 8%. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 2 peripheral neuropathy. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Uncontrolled hypertension (HTN) (systolic blood pressure (BP) ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg) prior to first dose. Prior allogeneic stem cell or solid organ transplantation. Active interstitial lung disease or pneumonitis, or a history of interstitial lung disease or pneumonitis requiring treatment with steroids or other immunosuppressive medications. Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). a. Well controlled HIV will be allowed if the participant meets all the following criteria at inclusion: i. CD4+ counts ≥ 350 cells / uL; ii. HIV viral load < 400 copies / mL; iii. Without a history of opportunistic infection within the last 12 months;iv. On established ART for at least 4 weeks. Use of ART should be discussed with the Medical Monitor on a case-by-case basis. Known active hepatitis B, defined as positive surface antigen and / or anti-hepatitis B core antibody. Participants with a negative polymerase chain reaction assay are permitted with appropriate antiviral therapy. Known active hepatitis C infection with positive viral load if HCV antibody positive (if antibody is negative then viral load not applicable). Participants who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of ≥ 12 weeks. History or another active malignancy that would interfere with the safety or efficacy evaluation of the clinical study. Any prior Grade ≥ 3 immune-related adverse event while receiving immune check point inhibitor therapy. Active systemic infection requiring therapy. Fever not attributable to underlying malignancy or received therapeutic oral or IV antibiotics within 14 days prior to start of study treatment. Participants receiving prophylactic antibiotics are eligible. Suspicion of relevant and recent systemic viral syndrome or need for quarantine / isolation that is not resolved prior to study treatment in the opinion of the Investigator. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s ability to take part in the full duration of the trial, or is not in the best interest of the participant to take part, in the opinion of the treating Investigator. Participants with history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of NYHA Class III*-IV documented within 6 months prior to first dose of BT8009 or: a. Mean resting corrected QT interval (QTc) > 470 msec. b. Any factors that increase the risk of QTc prolongation such as congenital long QT syndrome, family history of long QT syndrome. c. Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block.29. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 30. Prior Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) / Drug reaction with eosinophilia and systemic symptoms (DRESS), Acute generalized exanthematous pustulosis (AGEP), Erythema multiforme, Symmetric drug-related intertriginous and flexural exanthema (SDRIFE), or Baboon syndrome. 31. Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 1 month following the last dose of avelumab, 4 months following the last dose of platinum treatment, 6 months following the last dose of BT8009, and 9 months (males) and 12 months (WOCBP) following the last dose of enfortumab vedotin, whichever comes last. Cohort 2: Previously treated 1. Prior treatment with any systemic anti-cancer therapy within 4 weeks prior to initiation of study treatment; the following exception is 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 any time. 3. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to first dose of study treatment. 4. Ongoing clinically significant toxicity (≥ Grade 2) associated with prior treatment for UC (including radiotherapy or surgery). 5. Active keratitis or corneal ulcerations. 6. Current treatment with strong inhibitors or strong inducers of human CYP3A or inhibitors of P-gp including herbal- or food-based inhibitors. 7. Known hypersensitivity or allergy to any of the ingredients of either of the study interventions, or MMAE. 8. Major surgery (excluding placement of vascular access) within 4 weeks of first dose. 9. RBCs or platelet transfusions or growth factors within 4 weeks of first dose. 10. Receipt of live or attenuated vaccine within 30 days of 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 for at least 4 weeks prior to the first dose, either without the use of steroids or on stable or decreasing dose of ≤ 10 mg daily prednisone orequivalent and are without any symptoms that would confound the evaluation of neurologic and other AEs. Uncontrolled diabetes, defined as HbA1c ≥ 8%. NCI CTCAE Grade ≥ 2 peripheral neuropathy. Uncontrolled HTN (systolic BP Systolic BP ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg) prior to first dose. Known HIV or AIDS. a. Well controlled HIV will be allowed if the participant meets all the following criteria at inclusion: i. CD4+ counts ≥ 350 cells / uL; ii. HIV viral load < 400 copies / mL; iii. Without a history of opportunistic infection within the last 12 months; iv. On established ART for at least 4 weeks. Use of ART should be discussed with the Medical Monitor on a case-by-case basis. Known active hepatitis B, defined as positive surface antigen and / or anti-hepatitis B core antibody. Participants with a negative polymerase chain reaction assay are permitted with appropriate antiviral therapy. Known active hepatitis C infection with positive viral load if HCV antibody positive (if antibody is negative then viral load not applicable). Participants who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of ≥ 12 weeks. History or another active malignancy that would interfere with the safety or efficacy evaluation of the clinical study. Active systemic infection requiring therapy. Fever not attributable to underlying malignancy or received therapeutic oral or IV antibiotics within 14 days prior to start of study treatment. Participants receiving prophylactic antibiotics are eligible. Suspicion of relevant and recent systemic viral syndrome or need for quarantine / isolation that is not resolved prior to study treatment in the opinion of the Investigator. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s ability to take part in the full duration of the trial, or is not in the best interest of the participant to take part, in the opinion of the treating Investigator, including but not limited to:a. Participants with history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of NYHA Class III*-IV documented within 6 months prior to first dose of study treatment or: i. Mean resting QTc > 470 msec. ii. Any factors that increase the risk of QTc prolongation such as congenital long QT syndrome, family history of long QT syndrome. iii. Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block. 23. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 24. Prior Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) / Drug reaction with eosinophilia and systemic symptoms (DRESS), Acute generalized exanthematous pustulosis (AGEP), Erythema multiforme, Symmetric drug-related intertriginous and flexural exanthema (SDRIFE), or Baboon syndrome. 25. Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 6 months following the last dose of BT8009 and 9 months (males) and 12 months (WOCBP) following the last dose of enfortumab vedotin.

[0254] Independent Data Monitoring Committee: An Independent Data Monitoring Committee (IDMC) consisting of external experts will be established for the review of the study data. The IDMC meeting frequency, scope of responsibilities, and composition will be specified by a separate charter.

[0255] BT8009 Dose Selection: The BT8009 optimal dose will be selected based on a thorough review of the totality of evidence generated in the dose selection phase of study BT8009-230 including, but not limited to, the evaluation of safety, efficacy, and PK. Clinical results will be evaluated using pharmacometric modelling (population PK and exposure- response modeling), and a utility-based approach to quantify the benefit-risk will be derived. The utility score which will be based on binary efficacy / toxicity scores with prespecified cutoff values will be used to select the optimal dose of BT8009 during the IA, conducted separately for each cohort. Other factors such as participant convenience and / or flexibility of regimens will also be taken into consideration. Participant enrollment will not be paused while the dose selection IAs are being performed.

[0256] Statistical Methodology:

[0257] Cohort 1: Previously untreated

[0258] The total target sample size for Cohort 1 is 555 participants.

[0259] Eligible participants will be stratified by cisplatin eligibility (cisplatin eligible vs cisplatin ineligible), liver metastasis (yes vs no), and ECOG PS (0 / 1 vs 2) and randomized 1:1:1 to receive BT80099 mg in combination with pembrolizumab, BT800911 mg in combination with pembrolizumab, or SOC chemotherapy.

[0260] A BT8009 dose selection interim analysis (IA 1) will be performed when ~30 participants in each of the BT8009 dose level plus pembrolizumab arms have been followed for at least 4 months from the first dose of study treatment, have discontinued from the study due to any cause, or have experienced disease progression (whichever occurs first). Methods used to select the optimal BT8009 dose are described in the BT8009 dose selection section above. Participant enrollment into the BT8009 optimal dose in combination with pembrolizumab and chemotherapy arms will continue, whereas enrollment into the treatment arm with the BT8009 dose that was not selected will be stopped.

[0261] When ~120 participants in the BT8009 selected dose in combination with pembrolizumab have been followed for at least 6 months from the first dose of study treatment, have discontinued from the study due to any reason, or have experienced disease progression (whichever occurs first), a second interim analysis (IA2) will be performed to evaluate efficacy of BT8009 in combination with pembrolizumab based on ORR. With 120 participants in the BT8009 optimal dose in combination with pembrolizumab arm, assuming the true ORR of 60%, the chance of observing ORR with lower limit of the 2-sided 95% confidence interval excluding a historical ORR of 45% is approximately 90%. ORR will be summarized descriptively with 2-sided 95% CI using Clopper-Pearson method by treatment arm.

[0262] Enrollment into BT8009 optimal dose in combination with pembrolizumab and chemotherapy will continue in 1:1 randomization until each treatment arm has ~215 participants. If the Sponsor decides to implement the enfortumab vedotin in combination with pembrolizumab study arm, an additional ~95 participants will be added to Cohort 1 and participants will be randomized in 1:1:1 ratio to the respective treatment arms.

[0263] The total sample size for Cohort 1 is determined by the primary endpoint, i.e., PFS by BICR. The primary analysis of PFS will take place when ~357 events for the comparison of BT8009 selected dose in combination with pembrolizumab and chemotherapy have occurred, based on the following assumptions: ^ One-sided 2.5% Type I error^ Approximately 98% power ^ Median PFS of 13 months for BT8009 optimal dose in combination with pembrolizumab vs 8.5 months for chemotherapy (corresponding to a HR of 0.65) ^ Dropout rate of 10% annually ^ No interim analysis of PFS.

[0264] The secondary endpoints that include ORR, OS, DOR, DCR, and PFS by Investigator will be tested sequentially when the primary hypothesis of PFS by BICR is rejected.

[0265] For time to event endpoints including PFS and OS, log-rank test stratified by randomization stratification factors including cisplatin eligibility, liver metastasis, ECOG performance status at baseline will be used to compare selected dose for BT8009 in combination with pembrolizumab and chemotherapy. The hazard ratio and corresponding 95% confidence interval from the stratified Cox proportional hazards regression model will also be presented. The median PFS, OS, and DOR will be estimated using the Kaplan-Meier method and will be reported along with the corresponding 95% confidence interval by treatment arm. ORR will be compared between treatment arms using Cochran-Mantel-Haenszel test, stratified by the same stratification factors used in time to event analyses. The difference in response rates between the treatment arms will be estimated along with the corresponding 95% confidence interval.

[0266] Cohort 2: Previously treated

[0267] The total target sample size for Cohort 2 is 195 participants.

[0268] Participants will be randomized in 2:2:1 ratio to receive BT80099 mg, BT800911 mg or enfortumab vedotin.

[0269] An interim analysis (IA) will be performed to select the BT8009 optimal dose when ~30 participants in each BT8009 dose level arm have been followed for at least 4 months from the first dose of study treatment, have discontinued from the study due to any cause, or have experienced disease progression (whichever occurs first). Methods used to select the optimal BT8009 dose are described in the BT8009 dose selection section above. Participant enrollment into the BT8009 optimal dose will continue, whereas enrollment into the treatment arm with the BT8009 dose that was not selected will be stopped.

[0270] Following IA, enrollment into BT8009 selected dose and enfortumab vedotin arms will continue in 2:1 randomization ratio until there are 110 participants in the BT8009 optimal dose and 55 participants in enfortumab vedotin arm. With 110 participants in the selected dosefor BT8009 monotherapy, assuming the true ORR of 40%, the chance of observing ORR with lower limit of the 2-sided 95% confidence interval excluding a historical ORR of 25% is approximately 90%.

[0271] Once the 110 participants in the BT8009 monotherapy arm have been followed for at least 6 months, have discontinued from the study due to any cause, or have experienced disease progression (whichever occurs first), a primary analysis will be conducted to assess efficacy of BT8009 monotherapy based on the evaluation of ORR by BICR in Cohort 2. The primary endpoint ORR by BICR will be summarized descriptively with 2-sided 95% CI using Clopper-Pearson method by treatment arm.

[0272] The Schema for the trial is shown in Figure 20. Example 6. Further review of BT8009 Phase I trial results and outlook

[0273] A further later data cut was made in the BT8009 Phase I trial. The data at the point of the data cut confirm the results reported in Example 3, and provide further evidence for BT8009 having promising efficacy and safety profiles across a range of solid tumors.

[0274] BT8009 demonstrates promising anti-tumor efficacy in EV-naïve mUC patients. Figure 21A shows a BT8009 waterfall plot across all EV-naïve urothelial cancer patients dosed at 5 mg / m2 weekly. The efficacy evaluable data set is used which is defined as all enrolled patients with measurable disease at baseline who received at least one dose of BT8009 and had at least one adequate post-baseline disease assessment. Percentages are presented as the nearest integer. Eight patients were excluded due to no post-baseline assessment. A ninth patient was excluded from the waterfall plot as target lesion data was non-evaluable in the single post- baseline assessment. One patient (4%) showed a complete response, nine patients (35%) showed a partial response and a further seven patients (27%) had stable disease. The overall response rate (complete response + partial response) was 38% (95% confidence interval 20- 59%). The clinical benefit rate (complete response + partial response + stable disease beyond 16 weeks) was 58%. Responses under response evaluation criteria in solid tumor (RECIST) v1.1. Confirmation of objective tumor response is not required for this summary presentation. Includes 2 unconfirmed PRs. The median duration of response is 11 weeks (range 1-101 weeks). Figure 21B shows a BT8009 spider plot across the same patients, and shows that BT8009 demonstrates a long duration of response in EV-naïve mUC patients (median duration of follow-up is 3.3 months). Patient demographic data for this cohort are shown in Figure 21C.

[0275] BT8009 also shows promising responses in other solid tumors. Figure 22A shows a BT8009 waterfall plot for ovarian cancer. The overall response rate was 20%, and the clinical benefit rate was 50%. The median duration of response was 1.8 months. Figure 22B shows aBT8009 waterfall plot for triple negative breast cancer (TNBC). The overall response rate was 20%, and the clinical benefit rate was 27%. The median duration of response was 4.2 months, one patient with a partial response was ongoing). Figure 22C shows a BT8009 waterfall plot for non-small cell lung cancer. The overall response rate was 13%, and the clinical benefit rate was 63%. The median duration of response was 3.4 months. Efficacy evaluable set is used which is defined as all enrolled patients with measurable disease at baseline who received at least one dose of BT8009 and had at least one adequate post-baseline disease assessment. Percentages are presented as the nearest integer. Responses under response evaluation criteria in solid tumor (RECIST) v1.1. Confirmation of objective tumor response is not required for this summary presentation. Includes 2 unconfirmed PR in ovarian, 1 unconfirmed PR in TNBC and 1 unconfirmed PR in NSCLC. Two patients were excluded from ovarian, 5 patients from TNBC and 12 patients from NSCLC due to no post-baseline assessment. All the excluded patients were ongoing except the 2 patients in ovarian, 2 patients in TNBC and 4 patients in NSCLC. One additional TNBC patient is excluded from the figure as measurement of all target lesions was not performed at the single post-baseline assessment. All patients were dosed at 5 mg / m2weekly with the exception of those indicated with an asterisk.

[0276] BT8009 continues to demonstrate promising tolerability. Figure 23A shows the overall safety population baseline characteristics and Figure 23B shows the overall safety profile for BT8009 as of the date of the data cut. Figure 23C shows that most BT8009 treatment-related adverse events were GI-related and low grade. Figure 23D shows that BT8009 treatment-related adverse events of specific monitoring were of low frequency and severity. Figure 24E shows that BT8009 treatment-related peripheral neuropathy was low- grade. Treatment-related peripheral neuropathy was also frequently reversible. The median time to onset of peripheral neuropathy was 1.7 months, and peripheral neuropathy resolved or improved (GR1 or better) in 44% of patients with a median time of resolution / improvement of 2.6 weeks. Only 11% of the patients with a history of baseline peripheral neuropathy developed related worsening peripheral neuropathy while on treatment and 2 / 3 of the cases ended with complete resolution.DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT

[0277] BT8009 drug product will be supplied for clinical use as a white to off white sterile lyophilised powder for reconstitution in a 10 mL Type I clear glass vial with a butyl stopper and aluminium seal. During manufacture, each vial is filled with 5.3 mL of 4 mg / mL bulk solution prior to lyophilisation, providing 21.2 mg of BT8009 per vial. At the point of use, BT8009 drug product is reconstituted with 5.0 mL of sterile WFI (to return a reconstituted volume of 5.3 mL solution) providing BT8009 at a target concentration of 4 mg / mL for further dilution with 0.9% saline prior to IV administration (infusion). The 0.3 mL excess ensures an extractable volume of 5 mL from the vial providing up to a 20 mg dose for further dilution.

[0278] Hydrochloric acid and / or sodium hydroxide is used to adjust the pH of the fill solution to target pH 7.0, within the effective buffering range of the L-histidine buffer. The absolute amount required is dependant of the actual amount of L-histidine employed in the batch, this is indicated as ‘quantity sufficient’ to reach pH 7.0.

[0279] The complete statement of the composition and quantitative composition of BT8009 drug product (21.2 mg / vial) is presented in Table 1. Table 1: Composition of BT8009 Drug Product Concentration Reference to Component Function (mg / mL) Standard BT8009 Drug substance 4.0aHSE L-Histidine Buffer 5.24 EP, USP Sucrose Stabiliser, cryoprotectant 60.0 EP, NF Polysorbate 20 Non-ionic surfactant 0.1 EP / NF Hydrochloric Acid pH adjustment q.sbEP Sodium hydroxide pH adjustment q.sbEP WFIcSolvent q.sb. to 1 mL EP / USP a. Based on API potency, adjustments will be made to achieve the target drug substance label claim value. b. Quantity sufficient. c. Water for injections (WFI) is driven off during lyophilisation process.

Claims

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

2. A method for treating a solid tumor in a human patient, comprising administering BT8009 or a pharmaceutical composition comprising BT8009..

3. A method for maintaining or reducing the volume of a solid tumor in a human patient, comprising administering BT8009 or a pharmaceutical composition comprising BT8009.

4. The method of claim 2 or 3, wherein the solid tumor is an advanced malignancy, optionally wherein the solid tumor or advanced malignancy is associated with Nectin-4 expression.

5. The method of any one of claims 1 to 4, comprising administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 2-10 mg / m2, optionally at a dose of about 2.5-7.5 mg / m2, optionally at a dose of about 4-6 mg / m2, optionally at a dose of about 5 mg / m2.

6. The method of any one of claims 1 to 4, comprising administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6-9 mg / m2, optionally at a dose of about 7-8 mg / m2, optionally at a dose of about 7.5 mg / m2or about 6 mg / m2.

7. The method of any one of claims 14, comprising administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly flat dose of about 7- 11mg, optionally at a flat dose of about 8-10 mg, optionally at a flat dose of about 9 mg.

8. The method of any one of claims 1 to 4, comprising administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle a flat dose of about 9-13 mg, optionally at a flat dose of about 10-12 mg, optionally at a flat dose of about 11 mg.

9. The method of any of claims 1-8, further comprising administering an anti-PD-1 antibody or an anti-PD-L1 antibody to the human patient, optionally wherein the anti-PD-1 antibody is pembrolizumab.

10. The method of claim 9, wherein pembrolizumab is administered at a dose of 200 mg; optionally wherein pembrolizumab is administered once every 3 weeks at a dose of about 200 mg.

10. The method of claim 9 or claim 10, wherein BT8009 or the pharmaceutical composition comprising BT8009 and pembrolizumab are administered separately, sequentially or simultaneously; optionally wherein BT8009 or the pharmaceutical composition comprising BT8009 and pembrolizumab are administered by sequential infusions.

12. The method of any of claims 2-11, wherein the solid tumor, advanced malignancy or advanced malignancy 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 cancer.

13. The method of any one of claims 2 to 12, wherein the patient has previously received one or more treatments for the solid tumor or advanced malignancy.

14. The method of claim 13, wherein the patient is administered BT8009 as a monotherapy.

15. The method of any one of claims 2 to 12, wherein the patient has been previously untreated for the solid tumor or malignancy.

16. The method of claim 15, wherein the patient is administered BT8009 and an anti-PD-1 antibody or an anti-PD-L1 antibody, optionally wherein the patient is administered BT8009 and pembrolizumab.

17. The method of any one of claims 13 to 16, wherein the advanced malignancy associated with Nectin-4 expression is locally advanced or metastatic urothelial cancer.

18. A pharmaceutical composition which is a solid pharmaceutical composition of BT8009 comprising: BT8009, or a pharmaceutically acceptable salt thereof; about 1.31 mg histidine per mg of BT8009, or a pharmaceutically acceptable salt thereof; about 15 mg sucrose per mg of BT8009, or a pharmaceutically acceptable salt thereof; and about 0.025 mg Polysorbate 20 per mg of BT8009, or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition of claim 18, which is a solid unit dose comprising: about 21.2 mg BT8009, or a pharmaceutically acceptable salt thereof; about 27.8 mg histidine; about 318 mg sucrose; and about 0.53 mg Polysorbate 20.

20. The pharmaceutical composition of claim 18, which is a solid unit dose comprising: about 11 mg BT8009, or a pharmaceutically acceptable salt thereof; about 14.4 mg L-histidine; about 165 mg sucrose; and about 0.275 mg Polysorbate 20.

21. The pharmaceutical composition of any one of claims 18 to 20, which is a lyophilized powder.

22. A pharmaceutical composition which is 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.

23. The pharmaceutical composition of claim 22, wherein the liquid formulation is at a pH of about 7.

24. The pharmaceutical composition of claim 22 or claim 23, which is a liquid unit dosage form of about 5.3 ml.

25. The pharmaceutical composition of claim 22 or claim 23, which is a liquid unit dosage form of about 2.75 ml.

26. The pharmaceutical composition of any one of claims 18 to 25, which further comprises pembrolizumab.

27. The method of any of claims 1-17, wherein the pharmaceutical composition is a composition as defined in any of claims 18-26.

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