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, for use in combination with an agent that inhibits the PD-1 / PD-L1 pathway in methods of therapy.

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] The present invention provides methods for treating cancer through the combined use of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD- 1 / PD-L1 pathway.

[0007] In one aspect, the present invention provides a method for treating a cancer in a patient, comprising administering BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1 / PD-L1 pathway to the patient.

[0008] In another aspect, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising administering BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway to the patient.

[0009] In a further aspect, the invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway.

[0010] In another aspect, the invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway.

[0011] In another aspect, the invention provides an agent that inhibits the PD-1 / PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the method comprisesadministering to the patient the agent that inhibits the PD-1 / PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

[0012] In a further aspect, the invention provides an agent that inhibits the PD-1 / PD-L1 pathway for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1 / PD- L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, the invention provides a combination of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway.

[0014] In a further aspect, the invention provides a combination of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway.

[0015] In another aspect, the invention provides the use of BT8009 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1 / PD-L1 pathway.

[0016] In a further aspect, the invention provides the use of BT8009 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1 / PD-L1 pathway.

[0017] In another aspect, the invention provides the use of an agent that inhibits the PD- 1 / PD-L1 pathway in the manufacture of a medicament for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1 / PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

[0018] In a further aspect, the invention provides the use of an agent that inhibits the PD- 1 / PD-L1 pathway in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1 / PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

[0019] In yet another aspect, the present invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of treating a cancer in a patient, wherein the patient has previously received or is scheduled to receive an agent that inhibits the PD-1 / PD-L1.

[0020] In a yet further aspect, the present invention provides an agent that inhibits the PD- 1 / PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the patient has previously received or is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. Compounds and Definitions:

[0021] 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.

[0022] 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.BT8009BT8009

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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

[0027] The examples and figures presented herewith report results from the first in-human clinical trial of the BT8009 Bicycle toxin conjugate. The examples and figures presentedherewith also report the first results from a clinical trial of the BT8009 Bicycle toxin conjugate administered in combination with the anti-PD-1 antibody pembrolizumab.

[0028] The present invention provides methods for treating a cancer in a patient, comprising administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway. The present invention also provides BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD- L1 pathway for use in methods for treating a cancer in a human patient. The present invention also provides the use of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 in the manufacture of medicaments for use in methods for treating a cancer in a human patient.

[0029] In one embodiment, the present invention provides a method for treating a cancer in a patient, comprising administering to the patient BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1 / PD-L1 pathway.

[0030] In a further embodiment, the invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway.

[0031] In another embodiment, the invention provides an agent that inhibits the PD-1 / PD- L1 pathway for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1 / PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

[0032] In another embodiment, the invention provides a combination of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway.

[0033] In another embodiment, the invention provides the use of BT8009 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1 / PD-L1 pathway.

[0034] In another embodiment, the invention provides the use of an agent that inhibits the PD-1 / PD-L1 pathway in the manufacture of a medicament for use in a method of treating acancer in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1 / PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

[0035] In a yet further aspect, the present invention provides an agent that inhibits the PD- 1 / PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the patient has previously received or is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, a patient may have one or more solid tumors. In some embodiments, the cancer is a solid tumor. The present invention therefore provides methods for treating a solid tumor in a patient. Thereby, the patient suffering from a cancer may be treated.

[0037] The present invention therefore provides methods for treating a solid tumor in a patient, comprising administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway. The present invention also provides BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway for use in methods of treating a solid tumor in a patient. The invention also provides the use of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway in the manufacture of a medicament for use in methods of treating a solid tumor.

[0038] In some embodiments, the administration of BT8009 or the pharmaceutically acceptable salt thereof results in maintenance of the volume of a solid tumor, or reduces the volume of a solid tumor. Thus, the present invention may be seen to provide methods for maintaining or reducing the volume of a solid tumor in a patient.

[0039] The present invention thus provides methods for maintaining or reducing the volume of a solid tumor in a patient, comprising administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway. The invention also provides BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway for use in methods of maintaining or reducing the volume of a solid tumor in a patient. The invention also provides the use of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway in the manufacture of medicaments for maintaining or reducing the volume of a solid tumor in a patient.

[0040] In another aspect, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising administering BT8009 or apharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway to the patient.

[0041] In another aspect, the invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway.

[0042] In a further aspect, the invention provides an agent that inhibits the PD-1 / PD-L1 pathway for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1 / PD- L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

[0043] In a further aspect, the invention provides a combination of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway.

[0044] In a further aspect, the invention provides the use of BT8009 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1 / PD-L1 pathway.

[0045] In a further aspect, the invention provides the use of an agent that inhibits the PD- 1 / PD-L1 pathway in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1 / PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

[0046] 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.

[0047] 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%.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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%.

[0054] 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.

[0055] The volume of the tumor 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.

[0056] In some embodiments, the volume of a 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 the 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).

[0057] 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.

[0058] 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.

[0059] 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 solid tumor 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.

[0060] Thus in some embodiments, the treatment of a solid tumor by the administration of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD- L1 pathway results in a complete response, partial response or stable disease.

[0061] In some embodiments, a cancer or solid tumor is an advanced malignancy. In some embodiments, the cancer, solid tumor or advanced malignancy is associated with Nectin-4 expression.

[0062] In one embodiment, the patient has locally advanced or metastatic urothelial carcinoma, wherein the patient has not received any prior systemic treatment for said locally advanced or metastatic urothelial carcinoma

[0063] In another embodiment, the patient has locally advanced or metastatic urothelial carcinoma, wherein the patient has received one or more prior systemic therapies for said locally advanced or metastatic urothelial carcinoma.

[0064] In some embodiments, the agent that inhibits the PD-1 / PD-L1 pathway blocks the interaction between PD-1 and PD-L1. In some embodiments, the agent that inhibits the PD- 1 / PD-L1 pathway is a PD-1 antagonist. In some embodiments the agent that inhibits the PD- 1 / PDL-L1 pathway is an antibody. In some embodiments, the agent that inhibits the PD-1 / PD- L1 pathway is an anti-PD-1 antibody. In some embodiments, the agent that inhibits the PD- 1 / PD-L1 pathway is an anti-PD-L1 antibody.

[0065] 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. In one embodiment, the anti-PD-1 antibody is pembrolizumab.

[0066] In some embodiments, the anti-PD-L1 antibody is selected from the list consisting of atezolizumab, avelumab, durvalumab, KN035 and cosibelimab.

[0067] In some embodiments of the present invention, a patient is not previously known being intolerant or hypersensitive to an immune checkpoint inhibitor. In some embodiments, 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, a patient has received prior treatment with a PD-1, PD-L1 or PD-L2 inhibitor. 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 active systemic infection requiring therapy. 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 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 systematictreatment. In some embodiments, a patient has type 1 DM well controlled on insulin, alopecia, or vitiligo. In some embodiments, a patient does not have a history of interstitial lung disease.

[0068] In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway are administered separately. In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway are administered sequentially. In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof is administered first followed by the agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the agent that inhibits the PD-1 / PD-L1 pathway is administered first followed by BT8009 or the pharmaceutically acceptable salt thereof.

[0069] In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway are administered at different frequencies. As described elsewhere herein, in one such embodiment, BT8009 or the pharmaceutically acceptable salt thereof is administered on days 1, 8 and 15 of a 21 day treatment cycle or on days 1 and 8 of a 21 day treatment cycle, whereas the agent that inhibits the PD-1 / PD-L1 pathway is administered every three weeks or every six weeks. Thus, in such representative examples, BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway may both administered on the first day of a treatment cycle (separately, sequentially or simultaneously, as described herein), whereas on other days in the treatment cycle only BT8009 may be administered.

[0070] Optionally, the patient is administered BT8009 or a pharmaceutically acceptable salt thereof, and has received an agent that inhibits the PD-1 / PD-L1 pathway within the previous 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks. Optionally, the patient is administered BT8009 or a pharmaceutically acceptable salt thereof, and is scheduled to receive an agent that inhibits the PD-1 / PD-L1 pathway within the next 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks.

[0071] Optionally, the patient is administered an agent that inhibits the PD-1 / PD-L1 pathway, and has received BT8009 or a pharmaceutically acceptable salt thereof received within the previous 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks. Optionally, the patient is administered an agent that inhibits the PD-1 / PD-L1 pathway, and is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof received within the next 30minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks.

[0072] In some embodiments, a patient may have received or be scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof or an agent that inhibits the PD-1 / PD-L1 pathway at the point at which the other component of the combination therapy is administered, for example due to the required dosing regimen of each of the components of the combination therapy of the invention. In one embodiment, the patient is administered BT8009 or the pharmaceutically acceptable salt thereof and has received or is scheduled to receive an agent that inhibits the PD-1 / PD-L1 pathway. Thus, the present invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of treating a cancer in a patient, wherein the patient has previously received or is scheduled to receive an agent that inhibits the PD-1 / PD-L1 pathway. In another embodiment, the patient is administered an agent that inhibits the PD-1 / PD-L1 pathway and has received or is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof. Thus, the present invention provides an agent that inhibits the PD-1 / PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the patient has previously received or is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof is administered by IV infusion.

[0074] In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway are administered by separate infusions. In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway are administered by sequential infusions. In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof is administered by a first infusion followed by the agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the agent that inhibits the PD-1 / PD-L1 pathway is administered by a first infusion followed by BT8009 or the pharmaceutically acceptable salt thereof.

[0075] In some embodiments, BT8009 is provided as a liquid formulation or liquid unit dosage form of BT8009 as described herein. In some embodiments, a liquid formulation or a liquid unit dosage form of BT8009 as described herein and the agent that inhibits the PD-1 / PD- L1 pathway are administered by sequential infusions first with a liquid formulation or a liquid unit dosage form of BT8009 as described herein followed by the agent that inhibits the PD- 1 / PD-L1 pathway. In some embodiments, a liquid formulation or a liquid unit dosage form ofBT8009 as described herein and the agent that inhibits the PD-1 / PD-L1 pathway are administered by sequential infusions first with the agent that inhibits the PD-1 / PD-L1 pathway followed by a liquid formulation or a liquid unit dosage form of BT8009 as described herein. In some embodiments, a liquid formulation or a liquid unit dosage form of BT8009 as described herein and the agent that inhibits the PD-1 / PD-L1 pathway are administered separately.

[0076] In some embodiments, BT8009 and the agent that inhibits the PD-1 / PD-L1 pathway are administered simultaneously. In some embodiments, BT8009 and the agent that inhibits the PD-1 / PD-L1 pathway are administered by a single infusion.

[0077] In some embodiments, a patient having a cancer or a solid tumor has been previously untreated for the cancer or solid tumor (i.e. has received no prior lines of treatment for the solid tumor).

[0078] In some embodiments, a patient having a solid tumor has previously received one or more treatments for the cancer or solid tumor. Notably, included herewith are data from a clinical trial of BT8009 administered in combination with the anti-PD-1 antibody pembrolizumab as a late line therapy to a heavily pre-treated cohort of patients who have exhausted existing treatment options. These data show promising efficacy for the combination therapy in combination with an overall safety profile that is comparable to that of BT8009 administered as a monotherapy. A high proportion of the patients in this cohort for which data are presented herewith had previously received one or more immune checkpoint inhibitors, in particular, one or more agents that inhibit the PD-1 / PD-L1 pathway.

[0079] Thus, in one embodiment, a patient having a solid tumor has previously received one or more immune checkpoint inhibitors for the cancer or solid tumor. In one embodiment, a patient having a cancer or solid tumor has previously received one or more agents that inhibits the PD-1 / PD-L1 pathway. In one embodiment, the patient has previously received pembrolizumab. In one embodiment, the patient has previously received nivolumab. In one embodiment, the patient has previously received dostarlimab. In one embodiment, the patient has previously received atezolizumab. 4. General Description of Certain Embodiments of the Invention:

[0080] 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) as described herein.

[0081] 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.

[0082] 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 glycol and 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.

[0083] 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.

[0084] 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.

[0085] 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 istrehalose. 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.

[0086] 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, a liquid pharmaceutical composition comprises a stabilizer or cryoprotectant (e.g., sucrose) at a concentration of about 60 mg / mL.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] In some embodiments, the pharmaceutical composition is 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 a flat 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.

[0091] In some embodiments, a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof, further comprises L-histidine, sucrose, and Polysorbate 20.

[0092] In some embodiments, the solid pharmaceutical composition of BT8009, comprises: 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] In some embodiments, the solid pharmaceutical composition is a lyophilized powder. In some embodiments, the solid pharmaceutical composition is a lyophilized powder at about -20oC. In some embodiments, the solid pharmaceutical composition 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.

[0098] In some embodiments, the pharmaceutical composition is a liquid formulation of BT8009, comprising BT8009, or a pharmaceutically acceptable salt thereof, and water. In some embodiments, the liquid formulation 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 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 is a liquid unit dosage form, which comprises about 11 mg BT8009, or a pharmaceutically acceptable salt thereof. In some embodiments, BT8009concentration in the liquid formulation or a liquid unit dosage form is about 4 mg / mL. In some embodiments, a liquid formulation or a liquid unit dosage form comprise the following components: Concentration Reference to Standard Component Function (mg / mL) 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 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.

[0099] In some embodiments, a liquid formulation or a liquid unit dosage form further comprises saline, for example, about 0.9% w / v saline. In some embodiments, BT8009 concentration in a liquid formulation comprising saline is about 0.1 to 2 mg / mL. In some embodiments, BT8009 concentration in a liquid formulation 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 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.

[0100] In some embodiments, a liquid formulation or a liquid unit dosage form 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.

[0101] In some embodiments, the liquid formulation or a liquid unit dosage form is prepared by dissolving a solid pharmaceutical composition or a solid unit form (e.g. as described herein) in water. In some embodiments, the liquid formulation or liquid unit dosageform is prepared by dissolving a solid pharmaceutical composition or a solid unit form in an injectable medium (e.g., about 0.9% w / v saline). In some embodiments, the liquid formulation or a liquid unit dosage form is prepared by reconstituting a solid pharmaceutical composition or a solid unit form 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.

[0102] In some embodiments, the liquid formulation comprises: 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.

[0103] 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.

[0104] In some embodiments, the liquid unit dosage form is 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.

[0105] In some embodiments, the liquid unit dosage form is of about 1.75-3.25 mL. Optionally the liquid unit dosage form is of about 2-3 mL, optionally 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.

[0106] In some embodiments, the liquid unit dosage form is 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; andwater.

[0107] In some embodiments, the liquid unit dosage form is 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.

[0108] 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.

[0109] In some embodiments, a solid unit dose comprising BT8009 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.

[0110] In some embodiments, the invention provides a kit comprising a pharmaceutical composition comprising BT8009 and pembrolizumab.

[0111] In some embodiments, pharmaceutical compositions comprising BT8009 may further comprise another drug, such as an agent that inhibits the PD-1 / PD-L1 pathway, such as pembrolizumab. In other words, in some embodiments, the pharmaceutical compositions may comprise both BT8009 and the agent that inhibits the PD-1 / PD-L1 pathway, e.g. 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.

[0112] In some embodiments, the methods of the invention comprise 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 is administered by an IV injection. In some embodiments, a liquid formulation or a liquid unit dosage form is administered by an IV infusion. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 5-30 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 30-60 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 60-90 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form 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 is about 55 minutes. In someembodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 60 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 65 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 70 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 75 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 2, 2.5, 3, 3.5, or 4 hours.

[0113] In some embodiments, the invention provides a combination use of a liquid formulation or a liquid unit dosage form as described herein and the agent that inhibits the PD- 1 / PD-L1 pathway, for treating a solid tumor (such as an advanced malignancy), associated with Nectin-4 expression. The liquid formulation or liquid dosage form and the agent that inhibits the PD-1 / PD-L1 pathway may each be administered as described herein.

[0114] In some embodiments, a method of the invention, comprises 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 and further comprises administering the agent that inhibits the PD- 1 / PD-L1 pathway. 5. Dosage Regimens

[0115] 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.

[0116] 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.

[0117] 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 is 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.

[0118] 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]).

[0119] 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.

[0120] 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 / m2or 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.

[0121] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0122] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0123] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the pharmaceutical composition isa 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 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0127] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD- L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0131] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0132] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD- L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0133] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0134] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0135] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0136] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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 dosageform to the patient weekly at a dose of about 5.5 mg / m2by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0137] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0138] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0139] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0140] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, comprisingadministering 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0141] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0142] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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 7.5 mg / m2by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0143] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0144] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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 inventionprovides 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0145] 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. In some embodiments, the methods of the invention thus comprise administering BT8009 or a pharmaceutical composition comprising BT8009 as a flat dose, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway

[0146] 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.

[0147] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0148] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0149] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0150] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0151] 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 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the pharmaceutical compositionis a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.

[0152] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0153] 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, and further comprise administering an agent that inhibits the PD-1 / PD-L1 pathway. 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.

[0154] 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. 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, and further comprising administering an agent that inhibits the PD-1 / PD-L1 pathway. In some embodiments, the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.

[0155] In some embodiments, the agent that inhibits the PD-1 / PD-L1 pathway is pembrolizumab.

[0156] 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.

[0157] 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.

[0158] In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof is administered weekly at a dose of 5 mg / m2and pembrolizumab is administered once every three weeks at a dose of 200 mg.

[0159] In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof is administered on days 1 and 8 of a 21-day treatment cycle at a dose of 6 mg / m2and pembrolizumab is administered once every three weeks at a dose of 200 mg.

[0160] In some embodiments, the methods of the present invention are associated with an incidence of adverse events and / or severe adverse events that is generally consistent with that of corresponding methods in which BT8009 is administered as a monotherapy (i.e. theincidence where BT8009 is administered without further administering an agent that inhibits the PD-1 / PD-L1 pathway such as pembrolizumab). Put another way, in some embodiments, the methods of the present invention are associated with a substantially similar risk of adverse events and / or severe adverse events as corresponding methods in which BT8009 is administered as a monotherapy. In other words, in some embodiments, the methods of the invention do not increase the incidence and / or risk of adverse events and / or severe adverse events relative to corresponding methods in which BT8009 is administered as a monotherapy. 6. An Advanced Malignancy Associated With Nectin-4 Expression

[0161] In some embodiments, the methods of the invention relate to the treatment of a cancer in a human patient. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is an advanced malignancy. In some embodiments, the cancer, solid tumor or advanced malignancy is associated with Nectin-4 expression. In some embodiments, the cancer is associated with Nectin-4 expression. In some embodiments, the solid tumor is associated with Nectin-4 expression. In some embodiments, the solid tumor is an advanced malignancy associated with Nectin-4 expression. In some embodiments the cancer or 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.

[0162] In some embodiments, a cancer, a solid tumor or 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.

[0163] In some embodiments, a patient having a cancer, a solid tumor or an 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 cancer, a solid tumor or an 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 cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression has been previously untreated may be administered BT8009 and pembrolizumab.

[0164] In some embodiments, a patient having a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 has previously received one or more treatments for the malignancy. In some embodiments, a patient having a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 has previously received one or more treatments for themalignancy may be administered BT8009 as a monotherapy. In some embodiments, a patient having a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 has previously received one or more treatments for the 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.

[0165] In some embodiments, a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is lung cancer, for example, non-small-cell lung cancer (NSCLC). In some embodiments, a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is ovarian cancer. In some embodiments, a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is breast cancer, for example, triple-negative breast cancer (TNBC). In some embodiments, a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is esophageal cancer. In some embodiments, a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is gastric / upper gastrointestinal (GI). In some embodiments, a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is head and neck cancer. In some embodiments, a cancer, a solid tumor or an advanced malignancy associated with Nectin- 4 expression is pancreatic cancer. In some embodiments, a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is urothelial cancer.

[0166] 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.

[0167] 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 thepatient 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.

[0168] 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.

[0169] In some embodiments, the patient meets the inclusion criteria of the Phase I / II and / or Phase II / III trial synopses included herein.

[0170] 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.

[0171] 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.

[0172] 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 andnegative 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).

[0173] In some embodiments, the patient is a patient who has a life expectancy ≥12 weeks after the start of BT8009 treatment.

[0174] 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.

[0175] 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.

[0176] 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. 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.

[0177] 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.

[0178] 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 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. In some embodiments, a patient has been treated with FDA-approved or locally approved therapy.

[0179] 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.

[0180] 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.

[0181] 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 conditionrequiring 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.

[0182] 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 checkpoint inhibitor 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.

[0183] 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.

[0184] In some embodiments, the patient is a patient with solid tumor advanced disease.

[0185] In some embodiments, the patient has renal insufficiency or renal impairment. The terms “renal insufficiency” and “renal impairment” refer to reduced or impaired kidney function relative to normal kidney function, and are used interchangeably herein. The present invention therefore provides a method for treating a human patient having renal insufficiency or renal impairment, comprising administering to the patient BT8009 or a pharmaceutical composition comprising BT8009. The present invention also provides the use of BT8009 in a method for treating a human patient having renal insufficiency or renal impairment. The present invention also provides BT8009 for use in the manufacture of a medicament for use in a method for treating a human patient having renal insufficiency or renal impairment. The present invention also provides a method for treating a solid tumor in a human patient having renal insufficiency or renal impairment comprising administering BT8009 or a pharmaceutical composition comprising BT8009. The present invention provides BT8009 or a pharmaceutical composition comprising BT8009 for use in a method for treating a solid tumor in a humanpatient having renal insufficiency or renal impairment. 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 having renal insufficiency or renal impairment. Optionally the solid tumor is an advanced malignancy. Optionally the solid tumor or advanced malignancy is associated with Nectin-4 expression.

[0186] In some embodiments, the patient has mild renal impairment. In some embodiments, the patient has moderate renal impairment. In some embodiments, the patient has severe renal impairment.

[0187] In some embodiments, a patient having mild renal impairment has renal function of 60-89 mL / min. In some embodiments, a patient having moderate renal impairment has renal function of 30-59 mL / min. In some embodiments, a patient having moderate renal impairment has renal function of 30-49 mL / min. In some embodiments, a patient having severe renal impairment has renal function of 15-29 mL / min. A patient having normal renal function has renal function of at least 90 mL / min.

[0188] In some embodiments, the patient having renal insufficiency or renal impairment has renal function of less than 90 mL / min. In some embodiments, the patient has renal function of at least 60 mL / min. In some embodiments, the patient has renal function of 60-89 mL / min. In some embodiments, the patient having renal insufficiency or renal impairment has renal function of less than 60 mL / min. In some embodiments, the patient having renal insufficiency or renal impairment has renal function of less than 50 CrCL mL / min. In some embodiments, the patient has renal function of at least 30 mL / min. In some embodiments, the patient has renal function of 30-59 mL / min. In some embodiments, the patient has renal function of 30- 49 mL / min. In some embodiments, the patient having renal insufficiency or renal impairment has renal function of less than 30 mL / min. In some embodiments, the patient has renal function of at least 15 mL / min. In some embodiments, the patient having renal insufficiency or renal impairment has renal function of 15-29 mL / min.

[0189] In some embodiments, renal function refers to estimated creatinine clearance (CrCL). In some embodiments, renal function can be estimated using a serum creatinine-based equation. In some embodiments, the extent of renal insufficiency or renal impairment can be defined based on the estimated creatinine clearance (CrCL) value that is calculated for a patient by the Cockcroft-Gault equation: (Creatinine Clearance (CrCL) (in mL / min) = {((140–age (in years)) x weight (in kg)) / (72xSerum Creatine (SCr) (in mg / dlL)}x 0.85 (if female).In some embodiments, the renal function values mentioned herein are estimated creatine clearance values. In some embodiments, renal function values mentioned herein are estimated creatinine clearance values calculated by the Cockcroft-Gault equation (CrCL by C- G).

[0190] There are also alternative equations for estimating renal function. For example, renal function and thus the extent of renal insufficiency or renal impairment can be defined based on the estimated glomerular filtration rate (eGFR). eGFR can be calculated using a contemporary, widely accepted equation for the population being studied, for example the 2021 CKD-EPI Creatinine equation. It is within the capabilities of a skilled person to determine the eGFR of an individual using such an equation. eGFR values are standardized to a body surface area of 1.73 m2and expressed and reported in units of mL / min / 1.73 m2. To individualize GFR, multiply the standardized GFR by the individual’s BSA and divide by 1.73. In some embodiments, the renal function values mentioned herein are estimated GFR values. In some embodiments, the renal function values mentioned herein are eGFR values calculated by the CKD-EPI equation (eGFR by CDK-EPI).

[0191] Measured GFR (using an exogenous marker) or measured CrCL can also be used to determine renal function.

[0192] In the course of making the present invention, the inventors have identified that patients with renal impairment have a similar BT8009 and MMAE PK profile to patients with normal renal function. This suggests that no specific dose adjustments are required for patients with mild or moderate renal impairment. This was contrary to pre-clinical analyses that were performed. Pre-clinical data also suggest that renal clearance is the major elimination pathway for BT8009. It was, therefore, thought that the pharmacokinetics of BT8009 in patients suffering from renal impairment may not be the same as for patients with normal renal function. The data presented herewith indicate that BT8009 can be administered to a patient having renal impairment or renal insufficiency at the same dose as would be administered to a patient having normal renal function. Thus, in some embodiments, BT8009 or a pharmaceutical composition comprising BT8009 can be administered to a patient having renal insufficiency or renal impairment at a dose for a patient having normal renal function. In some embodiments, BT8009 or a pharmaceutical composition comprising BT8009 can be administered to a patient having renal insufficiency or renal impairment at any of the doses described herein.

[0193] In some embodiments, a patient has been treated with FDA-approved or locally approved therapy.

[0194] 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).

[0195] 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.

[0196] 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.

[0197] 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).

[0198] 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.

[0199] 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.

[0200] In some embodiments, a patient has skin toxicity which resolve to Grade ≤1.

[0201] In some embodiments, a patient does not have active keratitis or corneal ulcerations.

[0202] In some embodiments, a patient does not have Grade ≥2 peripheral neuropathy.

[0203] In some embodiments, a patient does not have a clinically relevant troponin elevation.

[0204] In some embodiments, a patient does not have uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8%.

[0205] 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 dosageform as described herein and has recovered adequately prior to treatment with a liquid formulation or a liquid unit dosage form as described herein.

[0206] In some embodiments, a patient has not received a live or attenuated vaccine within 30 days of study treatment.

[0207] 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).

[0208] 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.

[0209] 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.

[0210] 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 heart failure or symptoms of New York Heart Association Class III-IV documented within 6 months prior to first dose of BT8009.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] In some embodiments, a patient does not have a positive hepatitis B surface antigen and / or anti-hepatitis B core antibody.

[0216] In some embodiments, a patient has a negative polymerase chain reaction (PCR) assay and has an appropriate antiviral therapy.

[0217] In some embodiments, a patient does not have an active hepatitis C infection with positive viral load if hepatitis C virus (HCV) antibody positive.

[0218] In some embodiments, a patient has been treated for hepatitis C infection and has sustained virologic response of ≥12 weeks.

[0219] 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).

[0220] 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.

[0221] 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.

[0222] In some embodiments, a patient does not have prior Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) on any MMAE-conjugated drug. EXEMPLIFICATION

[0223] 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.

[0224] LIST OF ABBREVIATIONS Abbreviation or special term ExplanationADA 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 Form EGFR 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 HarmonisationIND 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 information PK 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 normalUSPI 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

[0225] Number of Patients: Up to approximately 340 patients are planned to be enrolled in this study; approximately 61 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), up to 18 in Part C and up to 10 in Part D.

[0226] Objectives: Primary Objectives

[0227] The objectives of the escalation (Parts A-1 and A-2), renal insufficiency (Part C) and supplementary PK (Part D) 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.) • To further characterise the pharmacokinetics (PK) of BT8009 and MMAE (Part D) 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 moderate to severe renal insufficiency (Part C), d) in patients with advanced solid tumor malignancies having normal renal function or mild renal insufficiency (Part D)• To evaluate the impact of renal impairment on PK of BT8009 and monomethyl auristatin E (MMAE) (Part C) • To assess safety and tolerability of BT8009 in patients with normal renal function or mild renal insufficiency (Part D) • To determine pharmacokinetic (PK) parameters of BT8009 and MMAE (Parts A and C) • To determine incidence of antidrug antibody (ADA) development

[0228] Dose Expansion

[0229] 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

[0230] Study Design

[0231] 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, C and D),and in combination with pembrolizumab (Parts A-2 and B-7). There are four parts to this study: Part A: dose escalation (A-1), dose de-escalation in combination with pembrolizumab (A-2); Part B, dose expansion; Part C, renal insufficiency and Part D supplementary PK.

[0232] Part A

[0233] 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.

[0234] Part B

[0235] Part B is a dose expansion at the BT8009 RP2D(s). The scheme for Part B is shown in Figure 2.

[0236] Part C

[0237] 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.

[0238] Part D is a cohort conducted in patients with normal renal function or mild renal impairment, and locally advanced or metastatic urothelial carcinoma, ovarian cancer, triple- negative breast cancer, or non-small cell lung cancer. Up to 10 patients will be enrolled in Part D including a minimum of 3 patients in the normal renal function cohort (CrCl >90 mL / min), and a minimum of 3 patients in the mild renal impairment cohort (CrCl 60-89 mL / min). Additional PK samples will be collected in Part D in order to further characterize BT8009 and MMAE PK, including renal clearance.

[0239] 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 cohorts (B), renal cohorts (C), and supplementary PK cohorts (D) 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.

[0240] 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) or ≤3 × ULN and conjugated bilirubin ≤1.5 x ULN for patients with Gilbert’s syndrome 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 enrol 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 enrolment. The Sponsor and / or SRC may decide to require enrolment 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. Additional Inclusion Criteria – Part D (Supplementary PK) 33. 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. 34. Patients with solid tumor advanced disease are eligible as follows: 1) patients with renal function >90 mL / min (by C-G); 2) patients with renal function of 60-89 mL / min (by C- G).35. Patients should previously be treated with FDA-approved or locally approved therapy according to the local standards of care / local guidance.

[0241] 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 Terminology Criteria 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 treatment12. 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 in the 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 therapy17. 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 or another active malignancy that would interfere with the safety or efficacy evaluation of the clinical study. 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.

[0242] 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. Active interstitial lung disease or pneumonitis, or a history of interstitial lung disease or pneumonitis requiring treatment with steroids or other immunosuppressive medications

[0243] Additional Exclusion Criteria B-2 and B-3 (EV-naïve urothelial cancer)30. Prior treatment with EV.

[0244] Additional Exclusion Criteria Part B-7 (First-line, cisplatin-ineligible, metastatic urothelial cancer) 31. Prior organ transplant (including allogeneic) 32. Diagnosis of clinically relevant immunodeficiency 33. 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. Active interstitial lung disease or pneumonitis, or a history of interstitial lung disease or pneumonitis requiring treatment with steroids or other immunosuppressive medications 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:

[0245] 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.

[0246] 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.

[0247] 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

[0248] 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.

[0249] 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%.

[0250] All statistical analyses will be using descriptive summary statistics. Response endpoints will be reported using proportion with associated 95% CI. Example 2. BT8009 Formulation

[0251] 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

[0252] 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 / m2cohort;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

[0253] 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.

[0254] 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.

[0255] 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

[0256] Number of Participants: The study will enroll up to 956 participants with locally advanced or metastatic urothelial cancer (UC). Cohort 1 will include up to 641 participants who have not received any prior systemic therapy for locally advanced or metastatic UC andare eligible to receive platinum-based chemotherapy. Cohort 2 will include up to 315 participants who received ≥ 1 prior systemic therapy for locally advanced or metastatic UC.

[0257] Objectives: Primary Objectives

[0258] The objectives of cohort I are: Primary objectives • To evaluate the efficacy of BT8009 in combination with pembrolizumab, 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 randomization to determination of disease progression made by BICR, or death (due to any cause), whichever occurs first. 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 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 randomisation 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 time of randomisation 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 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 characterize the pharmacokinetics of BT8009 and monomethyl auristatin E (MMAE). • 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, and circulating tumor DNA (ctDNA. • To explore relationships between pharmacokinetics (PK) and pharmacodynamic biomarker activity with clinical outcomes, measured by characterization of exposure- response relationships and changes in peripheral biomarkers including soluble target and inflammatory cytokines, ctDNA, and gene signatures.

[0259] The objectives of cohort 2 are: Primary Objectives: • To evaluate the efficacy of BT8009 monotherapy, and in combination with pembrolizumab, 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 percentage of participants who experience a CR, PR or SD per RECIST v1.1 assessed by BICR and by Investigator. • To evaluate PFS per RECIST v1.1 assessed by BICR and by Investigator, measured by the length of time from randomization to first documentation of disease progression perRECIST v1.1 assessed by BICR and Investigator or death (due to any cause) whichever occurs first. • 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 monotherapy, and in combination with pembrolizumab, measured by incidence of TEAEs, and abnormalities in laboratory, ECG, and vital signs. Exploratory • To characterize the pharmacokinetics of BT8009 and MMAE, measured by Pharmacokinetic parameters of BT8009 and MMAE. • 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 and PD-L1 expression, soluble target and inflammatory cytokines, pharmacogenomics, and ctDNA. • To explore relationships between PK and pharmacodynamic biomarker activity of BT8009, and clinical outcomes, measured by characterization of exposure-response relationships and changes in peripheral biomarkers including soluble target and inflammatory cytokines and,ctDNA.

[0260] Overall Design: This study is a global, multicenter, randomized, open-label Phase 2 / 3 trial, with an adaptive design.

[0261] 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.

[0262] Study Design for Cohort 1 (Previously untreated): Participants who have not received any prior systemic treatment for advanced or metastatic UC and are eligible to receive platinum-based chemotherapy will be randomized 1:1:1 as follows: - BT8009 5 mg / m2 (on days 1, 8 and 15 of every 21-day cycle) in combination with pembrolizumab, - BT80096 mg / m2 (on days 1 and 8 of every 21-day cycle) plus pembrolizumab, or- SOC chemotherapy (gemcitabine plus either cisplatin or carboplatin (specified prior to randomization). After completion of 4 to 6 cycles of chemotherapy, participants should receive avelumab as maintenance therapy, if the following criteria are met: (a) absence of disease progression, (b) absence of avelumab-related contraindication, (c) resolution of toxicities from chemotherapy, (d) ECOG PS ≤2, and (e) adequate organ function as defined by the hematology and non-hematology laboratory assessments for Cohort 1.. Participants will be stratified by chemotherapy regimen (cisplatin vs carboplatin), liver metastasis (presence vs absence), and ECOG PS (0 vs 1 / 2). Within the chemotherapy arm, the proportion of participants receiving cisplatin-based chemotherapy will be capped at ~50%. A planned interim analysis (Cohort 1 IA 1) to select the optimal dose of BT8009 in combination with pembrolizumab will be conducted after the first ~30 participants in each BT8009 dose level arm that have been followed for at least 9 weeks from the first dose of study treatment, have discontinued from the study due to any reason, or have experienced disease progression (whichever occurs first). Participant enrollment will not be paused while Cohort 1 IA 1 is being conducted; however, a maximum of 45 additional participants in each BT8009 treatment arm may be enrolled by the time the analysis has been completed.

[0263] Following BT8009 dose selection, enrollment into the treatment arm of the BT8009 non-selected dose will be stopped; however, participants being treated with the BT8009 non- selected dose will be eligible to receive the BT8009 optimal dose, if deemed in their best interest as per Investigator.

[0264] After the optimal BT8009 dose is selected, participants will continue to be randomized 1:1 into BT8009 in combination with pembrolizumab or chemotherapy treatment arms until each arm has ~283 participants. A second interim analysis (Cohort 1 IA2) to evaluate efficacy of BT8009 in combination with pembrolizumab based on ORR by BICR will be performed when ~146 participants in each arm have been followed for at least 9 months from the first dose of study treatment in each arm, have discontinued from the study or have experienced disease progression (whichever occurs first).

[0265] The primary analysis will assess the efficacy of BT8009 in combination with pembrolizumab based on the evaluation of PFS by BICR and will take place when ~475 events have occurred for the comparison of BT8009 optimal dose in combination with pembrolizumab and chemotherapy.

[0266] Study Design for Cohort 2 (Previously treated): Initially, participants who have received ≥ 1 prior line of systemic therapy for their UC will be randomized 1:1 toBT80095 mg / m2 on days 1, 8 and 15 of every 21-day cycle or BT8009 6 mg / m2 on days 1 and 8 of every 21-day cycle. Participants will be stratified by prior treatment with a PD-1 / PD-L1 inhibitor (prior PD-1 / PD- L1 treatment vs no prior PD-1 / PD-L1 treatment) and liver metastasis (presence vs absence). The overall proportion of participants previously treated with PD-1 / PD-L1 therapy will be capped at 50% (Rawji, 2022, Aguilar, 2021). A planned interim analysis (Cohort 2 IA) to select the optimal dose of BT8009 will be conducted after the first 30 participants in each BT8009 dose level arm have been followed for at least 9 weeks from the first dose of study treatment, have discontinued from the study or have experienced disease progression (whichever occurs first). Participant enrollment will not be paused while Cohort 2 IA is being conducted; however, a maximum of 45 additional participants in each BT8009 treatment arm may be enrolled by the time the analysis has been completed.

[0267] Following dose selection, participant enrollment into the BT8009 optimal dose arm will continue, whereas enrollment into the treatment arm of the BT8009 non-selected dose will be stopped. Participants randomized to the BT8009 non-selected dose will be eligible to receive the BT8009 optimal dose, if deemed in the best interest of the participant as per Investigator decision.

[0268] Following BT8009 dose selection at Cohort 2 IA, participants will be randomized to either the Cohort 2 BT8009 optimal dose monotherapy or BT8009 optimal dose in combination with pembrolizumab (at a randomization ratio that will ensure ~120 participants in each arm). When a total of 120 participants in each arm have been followed for at least 9 months have discontinued from study due to any cause or have experienced disease progression (whichever occurs first), the primary analysis of ORR by BICR will be conducted to assess efficacy of BT8009 monotherapy and BT8009 in combination with pembrolizumab.

[0269] 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 planned treatment completion (i.e. ~24 months of pembrolizumab or up to 6 cycles of chemotherapy [Cohort 1 only]), disease progression (treatment should continue until radiographically confirmed by BICR), 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 timeintervals 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).

[0270] 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.

[0271] 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. Should the participant discontinue all study treatments, the Investigator will review provisions for safety follow-up and discuss available treatment options including standard of care. If treatment was discontinued due to reasons other than confirmed disease progression, a tumor assessment is required within 4 weeks of all study treatment(s) discontinuation. In participants who discontinue study treatment due to confirmed disease progression, the tumor assessment at EoT is the final required scan. For participants on combination therapy, if one study treatment is discontinued, tumor assessments will continue per SOA, until all study treatments have been discontinued.

[0272] 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. Serious adverse events related to pembrolizumab or avelumab will be collected for 90 days after the last dose of pembrolizumab, or avelumab, or until initiation of a new anticancer therapy, whichever occurs first.

[0273] After treatment discontinuation, OS and anticancer therapy status will be collected by telephone every 3 months (± 30 days) until death, loss to follow-up, withdrawal of study consent, or study termination by the Sponsor, whichever occurs first. Participant study completion is defined as the conclusion of data collection for the defined study endpoints including all follow-up assessments.

[0274] Study Arms and Duration:

[0275] Cohort 1: Previously untreated:

[0276] Arm 1: BT80095 mg / m2intravenous (IV) over 60 (-5 to +30) minutes on Days 1, 8, and 15 of every 21-day cycle in combination with 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.

[0277] Arm 2: BT80096 mg / m2IV over 60 (-5 to +30) minutes on Days 1 and 8 plus of every 21-day cycle in combination with 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.

[0278] Arm 3: Up to 6 cycles of platinum-based combination chemotherapy: Gemcitabine 1000 mg / m2 IV on days 1 and 8 of every 21 day cycle plus cisplatin 70 mg / m2 IV on Day 1 of every 21-day cycle OR Gemcibatine 1000 mg / m2 IV on days 1 and 8 of every 21 day cycle plus carboplatin area under the curve (AUC) 5 mg / mL per minute (or 4.5 mg / mL, if required by local institutional standards) IV on Day 1 of every 21-day cycle. Eligibility for cisplatin will be based on standard criteria.

[0279] Chemotherapy infusion windows will follow local guidelines. In countries where these interventions are not approved, dosing and administration should follow the USPI. 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.

[0280] If clinically indicated (ie, the participant meets avelumab treatment criteria following completion of 4 to 6 cycles of chemotherapy), participants should receive avelumab as maintenance therapy. Avelumab treatment will begin within 10 weeks after last dose of platinum therapy. Avelumab 800 mg IV will be administered per local guidelines on Days 1 and 15 of every 28-day cycle.

[0281] Cohort 2: Previously treated

[0282] Arm 1: BT80095 mg / m2IV over 60 (-5 to +30) minutes on Days 1, 8, and 15 of every 21-day cycle.

[0283] Arm 2: BT80096 mg / m2IV over 60 (-5 to +30) minutes on Days 1 and 8 of every 21-day cycle.

[0284] Arm 3: BT8009 optimal dose IV over 60 (-5 to +30 minutes) in combination with 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. Enrollment into the Arm 3 will begin after completion of Cohort 2 IA. Inclusion Criteria:

[0285] Participants must meet the following criteria for study entry. 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. 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. 6. Archival or fresh tumor tissue comprising muscle-invasive UC, or locally advanced or metastatic UC should be available for submission to central laboratory. 7. Life expectancy ≥ 12 weeks. 8. Adequate hematologic and organ function: a. Estimated glomerular filtration rate (eGFR) ≥ 30 mL / min (using the CKD-EPI creatinine equation) b. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤3 x ULN for participants with Gilbert disease 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. Alkaline phosphatase (AP) ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver or bone metastases g. 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.9. 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). 10. 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, and 6 months following the last dose of platinum treatment, whichever comes last. 11. 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, and 6 months following the last dose of platinum treatment, 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, and 6 months following the last dose of BT8009, 6 months following the last dose of platinum treatment, whichever comes last. Inclusion criteria specific to Cohort 1: Previously untreated 12. Eligible to receive platinum-based chemotherapy (either cisplatin or carboplatin based chemotherapy based on Investigator decision. 13. 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 adjuvant / neoadjuvant chemotherapy or MMAE-based therapy with recurrence >12 months from completion of therapy. c. Prior neoadjuvant / adjuvant immune checkpoint inhibitor therapy >12 months from completion of therapy. 14. ECOG PS ≤2 15. Adequate bone marrow function including the following: a. Hemoglobin ≥ 9 g / dLb. Absolute neutrophil count (ANC) ≥ 1500 cells / mm3c. Platelet count ≥ 100,000 cells / mm3. Inclusion criteria specific to Cohort 2: Previously treated 1. Participants must have received ≥1 prior systemic treatment for locally advanced or metastatic UC. This includes adjuvant / neoadjuvant platinum-based chemotherapy if recurrence occurred within 12 months of completing therapy. 2. Progression or recurrence of UC during or following receipt of most recent therapy. 3. ECOG performance status ≤ 1. 4. Adequate bone marrow function including the following: a. Hemoglobin ≥ 8 g / dL b. ANC ≥ 1000 cells / mm3 c. Platelet count ≥ 75,000 cells / mm3 Note: Red blood cells (RBCs) should not be given 4 weeks prior to bone marrow function assessment and platelet transfusions or growth factors should not be given 2 weeks prior to bone marrow function assessment. Exclusion Criteria: Participants who meet any of the following criteria will be excluded from study entry. 1. Active keratitis or corneal ulcerations. 2. Requirement, while on study, for treatment with strong inhibitors or strong inducers of human cytochrome P4503A (CYP3A) or inhibitors of P-glycoprotein (P-gp) including herbal- or food-based inhibitors. 3. Any condition requiring treatment with high dose corticosteroids (> 10 mg daily prednisone). 4. Known hypersensitivity or allergy to any of the ingredients of either of the study interventions, or MMAE. 5. Has not adequately recovered from recent major surgery (excluding placement of vascular access). 6. Receipt of live or attenuated vaccine within 30 days of first dose. 7. 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.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. Prior treatment with an agent directed to another stimulatory or co-stimulatory T-cell receptor. Prior treatment with any systemic anticancer therapy within 2 weeks or 5 half-lives, whichever is longer, prior to initiation of study treatment; the following exceptions are permitted: a. Palliative radiotherapy for UC-related bone or soft tissue metastasis completed > 7 days prior to baseline imaging. b. Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) agonists). c. Females with hormone receptor-positive breast cancer who are receiving tamoxifen or aromatase inhibitors adjuvant therapy ≥ 3 years. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 2 weeks or 5 half-lives, whichever is longer, prior to first dose of study treatment. 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 prior Grade ≥ 3 immune-related adverse event while receiving immune checkpoint inhibitor. 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. Active systemic infection or fever not attributable to underlying malignancy requiring 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 by Fredericia QT correction. 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.26. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 27. 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. Exclusion criteria specific to Cohort 1: Previously untreated 28. Prior treatment with a checkpoint inhibitor for any other malignancy within the last 12 months. Exclusion criteria specific to Cohort 2: Previously treated 29. Received more than 1 prior platinum-based chemotherapy regimen for locally advanced or metastatic urothelial cancer. This includes neoadjuvant / adjuvant chemotherapy if recurrence occurred within 12 months of completing therapy. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen. 30. Prior treatment with enfortumab vedotin or any other MMAE-based therapy. 31. Prior participation in any study in which BT8009 was being investigated (including Cohort 1 of this study). 32. Ongoing clinically significant toxicity (Grade ≥ 2) associated with prior treatment for UC (including radiotherapy or surgery). 1. prior platinum-based

[0286] 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.

[0287] BT8009 Dose Selection: BT8009 doses investigated in the study are 5 mg / m2(on Days 1, 8, and 15 of every 21-day cycle) and 6 mg / m2(on Days 1 and 8 of every 21-day cycle). These 2 dose regimens were selected based on the pharmacokinetic (PK), safety, and efficacy data from Study BT8009-100. 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. Information from Study BT8009-100 (NCT04561362) will also be utilized to inform the development of pharmacometric models (population PK, exposure-efficacy and exposure-safety). Clinical results will be evaluated usingpharmacometric analyses, as well as a utility-based approach to quantify the benefit-risk will be derived. The utility score which will be based on binary efficacy / toxicity outcomes will be used to facilitate the selection of the optimal dose of BT8009 during the IA, conducted separately for each cohort. Other factors such as participant convenience will also be taken into consideration.

[0288] Statistical Methodology:

[0289] Cohort 1: Previously untreated

[0290] The total target sample size for Cohort 1 is up to ~641 participants.

[0291] Eligible participants will be randomized 1:1:1 to receive BT80095 mg / m2 (on days 1, 8 and 15 of every 21-day cycle) in combination with pembrolizumab, BT80096 mg / m2(on days 1 and 8 of every 21-day cycle) in combination with pembrolizumab, or chemotherapy. Participants will be stratified by chemotherapy regimen (cisplatin vs carboplatin), liver metastasis (presence vs absence) and ECOG PS (0 vs 1 / 2).

[0292] An interim analysis (Cohort 1 IA 1) to select the optimal dose of BT8009 in combination with pembrolizumab will be conducted after the first 30 participants in each BT8009 dose level arm have been followed for at least 9 weeks 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 will not be paused while Cohort 1 IA 1 is being conducted; however, a maximum of 45 additional participants in each BT8009 treatment arm may be enrolled by the time the analysis has been completed..

[0293] Although the dose selection analysis will include only the first 30 participants in each BT8009 dose level arm, safety data from all enrolled participants up to Cohort 1 IA1 will be considered as supportive evidence.

[0294] Following dose selection, 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.

[0295] The family-wise type I error rate (alpha) for this study is strongly controlled at 0.025 (one-sided). An administrative one-sided alpha of 0.0005 will be used for the IA1, although there is no plan to conduct any analyses of BT8009 doses in combination with pembrolizumab vs chemotherapy during dose selection. The remaining type 1 error rate (alpha = 0.0245) will be split between ORR analysis at IA2 (alpha = 0.02) and PFS primary analysis (alpha = 0.0045).The actual alpha allocated to PFS primary analysis will be either 0.0245 or 0.0045 depending on the ORR analysis outcome at IA2.

[0296] When ~146 participants in the BT8009 optimal dose in combination with pembrolizumab have been followed for at least 9 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 by BICR. Assuming the true ORR of 65% for BT8009 optimal dose in combination with pembrolizumab and 45% for chemotherapy, 146 participants in each arm will provide approximate 90% power to detect an ORR difference of 20% at one-sided type I error of 0.02.

[0297] The total sample size for Cohort 1 is mainly determined by the primary endpoint, i.e., PFS by BICR. Participants will continue to be randomized 1:1 into BT8009 optimal dose in combination with pembrolizumab and chemotherapy treatment arms until each arm has ~283 participants.

[0298] The primary analysis of PFS will take place when ~475 events have occurred for the comparison of BT8009 optimal dose in combination with pembrolizumab and chemotherapy, based on the following assumptions: - One-sided alpha of 0.0045 - Approximately 98% power - Median PFS of 13 months for BT8009 optimal dose in combination with pembrolizumab versus 8.5 months for chemotherapy (corresponding to a hazard ratio [HR] of 0.65) - Dropout rate of 10% annually - No interim analysis of PFS by BICR.

[0299] The secondary endpoint OS will be tested sequentially when the primary null hypothesis of PFS by BICR is rejected.

[0300] For OS analysis, a group sequential method using O’Brien-Fleming boundary per Lan and DeMets method will be used to control the overall one-sided type I error. Assuming a median OS of 23 months for BT8009 optimal dose in combination with pembrolizumab vs 18.5 months for chemotherapy (corresponding to a HR of 0.80) and dropout rate of 10% annually, with 283 participants in each arm, ~384 OS events would be expected for the OS interim analysis at the time of PFS primary analysis. The final analysis of OS would be expected after ~431 OS events have occurred.

[0301] For time to event endpoints including PFS and OS, log-rank test stratified by randomization stratification factors including chemotherapy regimen, liver metastasis, and ECOG PS at baseline will be used to compare optimal dose for BT8009 in combination with pembrolizumab and chemotherapy. The hazard ratio and corresponding 95% confidence interval (CI) 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% CI 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.

[0302] Cohort 2: Previously treated

[0303] The total target sample size for Cohort 2 is ~315 participants.

[0304] Participants will be randomized in 1:1 ratio to receive BT80095 mg / m2or, BT8009 6 mg / m2. Participants will be stratified by prior treatment with a PD-1 / PD-L1 (prior PD-1 / PD- L1 treatment vs no prior PD-1 / PD-L1 treatment) and liver metastasis (presence vs absence). The overall proportion of participants previously treated with PD-1 / PD-L1 therapy will be capped at 50% (Rawji, 2022, Aguilar, 2021).

[0305] A planned interim analysis (Cohort 2 IA) to select the optimal dose of BT8009 will be conducted after the first 30 participants in each BT8009 dose level arm (Arm 1 and Arm 2) have been followed for at least 9 weeks 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 will not be paused while Cohort 2 IA is being conducted; however, a maximum of 45 additional participants in each BT8009 treatment arm may be enrolled by the time the analysis has been completed.

[0306] Following dose selection, participant enrollment into BT8009 optimal dose arm will continue , whereas enrollment into the treatment arm with the BT8009 dose that was not selected will be stopped.

[0307] Once the BT8009 optimal dose is selected, BT8009 in combination with pembrolizumab (Arm 3) will open to participant enrollment and randomized against the BT8009 monotherapy optimal dose arm. The randomization ratio will be adjusted based on the number of participants enrolled up to Cohort 2 IA for a total randomization ratio of 1:1 between the 2 arms.

[0308] With 120 participants in BT8009 optimal dose, assuming the true ORR of 40%, the chance of observing ORR with lower limit of the 2-sided 95% CI excluding a historical ORRof 25% is approximately 90%. With 120 participants in BT8009 optimal dose in combination with pembrolizumab, assuming the true ORR of 55%, the chance of observing ORR with lower limit of the 2-sided 95% CI excluding a historical ORR of 40% is approximately 90%.

[0309] Once the 120 participants in each arm have been followed for at least 9 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), a primary analysis will be conducted 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.

[0310] The Schema for the trial is shown in Figure 20. Example 6. Pharmacokinetics of BT8009 in Patients Having Renal Impairment.

[0311] Contrary to pre-clinical analyses, data from participants in BT8009-100 with mild to moderate renal impairment indicate similar BT8009 and MMAE PK across participants with normal renal function, mild renal impairment, and moderate renal impairment.

[0312] The impact of renal function on BT8009 and MMAE PK was evaluable using available PK data as of the data cutoff. Based on CrCL (Cockcroft-Gault equation) calculated at C1D1, there were 27, 40, and 30 participants with normal renal function (CrCL > 90 mL / min), mild renal impairment (CrCL: 60-89 mL / min), and moderate renal impairment (CrCL > 30-59 mL / min) for analysis (Figure 21).

[0313] Evaluation of dose-normalized PK parameters for BT8009 and MMAE showed similar values for participants with mild or moderate renal impairment relative to those with normal renal function (Figure 22). The geometric ratios for participants with moderate renal impairment vs normal renal function were all near 1 for BT8009 and MMAE exposures. Moreover, the 90% CI for almost all scenarios evaluated crossed 1, indicating no statistically significant difference. MMAE and BT8009 clearance were found to be similar across participants with normal kidney function vs mild renal impairment vs moderate renal impairment (Figure 23 A and B). Therefore, no dose adjustments are recommended for participants with mild or moderate renal impairment. Example 7. Preliminary Data for BT8009 in Combination with Pembrolizumab

[0314] As of a first data cutoff, incidence of TEAE and TESAE for the sample size (n=6) were generally consistent with the BT8009 monotherapy profile (Figure 24). This finding is surprising and encouraging, and adds to the promising safety profile for BT8009. To date, all6 participants enrolled in A-2 have reported a TEAE. The most frequently reported related TEAEs were Grade 1-3 nausea and diarrhea (4 participants each, 66.7%). Three (50%) participants reported 5 SAEs; of those, pyrexia, neutropenic colitis, and hyponatremia were considered related to BT8009 and neutropenic colitis was considered related to pembrolizumab. There were no treatment-related fatalities and no emerging safety signals based on these data. These are the first data to show that the combination of BT8009 and pembrolizumab is not associated with any unexpected safety signals, and reinforce the promising safety profile that is emerging for BT8009 compared to antibody drug conjugate therapies such as EV.

[0315] As of a further later data cut, 7 participants with locally advanced or metastatic UC were enrolled in Part A-2 combination therapy and had received a median of 4 prior lines of systemic therapies (min = 1; max = 9). One participant (14.3%) had a confirmed PR and one participant (14.3%) had an unconfirmed PR. Four patients had confirmed SD. One participant was not evaluable. No participant had a best overall response of PD. A waterfall plot (Figure 25A) and a spider plot (Figure 25B) show the efficacy data for the combination therapy, which is summarized in Figure 25C. One patient was excluded from the analysis shown in the waterfall plot due to no post-baseline assessment. Clinical benefit rate (CBR) defined as CR + (confirmed) PR + stable disease ≥16 weeks for this subpopulation was 71%. The incidence of treatment-related adverse events observed for patients receiving BT8009 at a dose of 5 mg / m2weekly was compared with the rate of adverse events for 113 patients receiving the corresponding dose of BT8009 who were enrolled in the trial, including patients in the dose escalation cohort (cohort A-1), dose expansion cohort (cohort B) and renal insufficiency cohort (cohort C). A safety summary (Figure 26A), a breakdown of treatment-related adverse events (Figure 26B) and events of specific monitoring (Figure 26C) for BT8009 + pembrolizumab vs BT8009 monotherapy confirm that the combination therapy shows acceptable tolerability.

[0316] The patients initially investigate in this study had received at least one prior line of therapy and had exhausted all treatment options. Significantly, of the 7 participants in the A- 2 cohort who received BT8009 and pembrolizumab, 6 patients had previously been treated with one or more immune checkpoint inhibitors. A breakdown of the checkpoint inhibitors that these patients had previously received is provided in the table below. The promising ORR and CBR observed for the combination therapy in this cohort is therefore surprising, as this suggests that patients who had received prior lines of therapy including a checkpoint inhibitor, and who might be expected to be refractory to treatment with therapeutic agents that areadministered in combination with a checkpoint inhibitor, can be treated with a combination of BT8009 and an agent that inhibits the PD-1 / PD-L1 pathway such as pembrolizumab. Number of patients with Prior Part A-2 (BT8009 + pembrolizumab) Systemic Therapies by category N=7 N (%) Checkpoint inhibitor 6 (86) Pembrolizumab 5 (57) Atezolizumab 1 (14) Nivolumab 1 (14) Dostarlimab 1 (14) Example 8. Dose Expansion for BT8009 in Combination with Pembrolizumab

[0317] BT8009 and pembrolizumab combination therapy was administered to a further cohort of 22 patients with locally advanced or metastatic urothelial cancer. These patients were cisplatin-ineligible and were administered BT8009 and pembrolizumab as a first line therapy. 20 patients were included in efficacy analysis (patients who have received at least 1 dose of BT8009 or pembrolizumab and had a post-baseline scan). The combination of BT8009 and pembrolizumab showed promising antitumor activity in these patients, with an overall response rate (ORR) of 60% and a disease control rate of 85% in these patients (Figure 27A). Data are also shown for Cohort K of the EV-103 trial (O'Donnell J Clin Oncol 41:4107-4117 2023), where patients were administered enfortumab vedotin in combination with pembrolizumab. A waterfall plot showing best response for efficacy evaluable patients (including 7 unconfirmed responses) is shown in Figure 27B (one efficacy evaluable patient does not appear on the water plot as best overall response was not evaluable). 15 patients remain on therapy at time of data cut. 9 patients with a response remain on therapy. mDOT is currently 11.1 weeks. As of the time of the data cut, mDOR is not mature. Patient data are also represented in a spider plot showing the percent change from baseline in the sum of diameters of target lesions; patients receiving BT8009 and pembrolizumab combination therapy show prolonged responses (Figure 27C).

[0318] BT8009 and pembrolizumab combination therapy continues to show promising tolerability. Treatment-related adverse events were as anticipated in a front-line population. Of BT8009 + pembrolizumab patients, only one Grade 4 event was reported, and therer were no Grade 5 events. Treatment-emergent AEs (TEAE) and treatment-emergent serious AEs(TESAE) were defined as AEs / SAEs starting or worsening on or after first date of dose, up to 30 days post last date of dose. Any SAEs related to BT8009 occurring after 30 days post last date of dose are also flagged as TEAEs. A patient with multiple events within a category is counted only once in that category. Symptoms of metastasis or the metastasis itself are not reported AE / SAE. Patients were grouped based on the planned dose received at C1D1 and subsequent dose changes were not considered. A summary of TRAEs is shown in Figure 28A. Data are also shown for Cohort K of the EV-103 trial (O’Donnell ibid) – this cohort had 3 TRAEs leading to death reported (Grade 5). The majority of dose modifications for patients receiving weekly BT8009 and pembrolizumab were interruptions, with minimal patients discontinuing treatment due to treatment emergent adverse events (TEAEs) (Figure 28B). TRAE leading to EV or pembrolizumab dose modifications are also shown for Cohort K of the EV-103 trial (O’Donnell ibid). The initial safety of the combination is consistent with the overall safety profile of BT8009 with most events low grade (Figure 28C). Data are also shown for Cohort K of the EV-103 trial (O’Donnell ibid). Common EV-103 Cohort K TRAEs also included alopecia (46%), dysgeusia (30%), weight decrease (30%), hyperglycemia (13% any grade, 7% ≥ Grade 3), and pneumonitis (9% any grade, 5% ≥ Grade 3). Overall the TRAEs of clinical interest for BT8009 + pembrolizumab were of low frequency and severity (Figure 28D). 3 patients had BT8009 dose reductions due to a related skin reaction. A single grade 3 rash event improved to grade 1 with dose interruption and systemic steroid and treatment resumed at a reduced dose; 2 further patients managed with dose interruption. The median onset of rash was ~2 weeks (6, 44 days), median onset of pruritus was ~2 weeks (7, 69 days). Data are also shown for Cohort K of the EV-103 trial (O’Donnell ibid).DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT

[0319] 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.

[0320] 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.

[0321] 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 cancer in a patient, comprising administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway.

2. The method of claim 1, wherein the cancer is a solid tumor.

3. A method for maintaining or reducing the volume of a solid tumor in a patient, comprising administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway.

4. The method of claim 2 or 3, wherein the solid tumor is an advanced malignancy.

5. The method of any one of claims 1 to 4, wherein the cancer, solid tumor or advanced malignancy is associated with Nectin-4 expression.

6. The method of any one of claims 1 to 5, wherein the patient has locally advanced or metastatic urothelial carcinoma.

7. The method of claim 6, wherein the patient has not received any prior systemic treatment for said locally advanced or metastatic urothelial carcinoma.

8. The method of claim 6, wherein the patient has received one or more prior systemic therapies for said locally advanced or metastatic urothelial carcinoma.

9. The method of claim 8, wherein patient has been treated with prior platinum- containing chemotherapy.

10. The method of claim 9, comprising administering BT8009 or the pharmaceutically acceptable salt thereof 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.

11. The method of claim 9, comprising administering BT8009 or the pharmaceutically acceptable salt thereof 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.

12. The method of claim 9, comprising administering BT8009 or the pharmaceutically acceptable salt thereof 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.

13. The method of claim 9, comprising administering BT8009 or the pharmaceutically acceptable salt thereof 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.

14. The method of any one of claim 1 to 13, wherein the agent that inhibits the PD-1 / PD- L1 pathway is anti-PD-1 antibody or an anti-PD-L1 antibody.

15. The method of any one of claims 1 to 14, wherein the agent that inhibits the PD-1 / PD- L1 pathway 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, atezolizumab, avelumab, durvalumab, KN035 and cosibelimab.

16. The method of any one of claims 1 to 15, wherein the agent that inhibits the PD-1 / PD- L1 pathway is pembrolizumab.

17. The method of claim 16, wherein pembrolizumab is administered at a dose of 200 mg.

18. The method of claim 16 or 17, wherein pembrolizumab is administered once every 3 weeks at a dose of about 200 mg.

19. The method of any one of claims 1 to 18, wherein BT8009 or the pharmaceutically acceptable salt thereof and / or the agent that inhibits the PD-1 / PD-L1 pathway are administered intravenously.

20. The method of any one of claims 1 to 19, wherein BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway are administered separately, sequentially or simultaneously.

21. The method of any one of claims 1 to 20, wherein BT8009 or the pharmaceutically acceptable salt thereof is administered weekly at a dose of 5 mg / m2and pembrolizumab is administered once every three weeks at a dose of 200 mg.

22. The method of any one of claims 1 to 20, wherein BT8009 or the pharmaceutically acceptable salt thereof is administered on days 1 and 8 of a 21-day treatment cycle at a dose of 6 mg / m2and pembrolizumab is administered once every three weeks at a dose of 200 mg.

23. The method of any of claims 1 to 22, wherein the cancer, solid tumor or advanced malignancy 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.

24. The method of any one of claims 4 to 23, wherein the advanced malignancy associated with Nectin-4 expression is locally advanced or metastatic urothelial cancer.

25. The method of any one of claims 1 to 24, wherein the patient has renal insufficiency.

26. The method of claim 25, wherein the patient has renal function of less than 90 mL / min, optionally wherein the patient has renal function of 60-89 mL / min.

27. The method of claim 25 or 26, wherein the patient has renal function of less than 60 mL / min, optionally wherein the patient has renal function of 30-59 mL / min.

28. The method of any one of claims 25 to 27, wherein the patient has renal function of less than 30 mL / min, optionally wherein the patient has renal function of 15-29 mL / min.

29. The method of any one of claims 26 to 28, wherein the renal functional value is estimated creatinine clearance calculated by the Cockcroft Gault equation (CrCL by C- G).

30. The method of any one of claims 25 to 29, comprising administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient at a dose for a patient having normal renal function, optionally wherein the dose is a dose as defined in any one of claims 10-13.

31. BT8009 or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD- 1 / PD-L1 pathway.

32. BT8009 or a pharmaceutically acceptable salt thereof, for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway.

33. An agent that inhibits the PD-1 / PD-L1 pathway, for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1 / PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

34. An agent that inhibits the PD-1 / PD-L1 pathway, for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering the agent that inhibits the PD-1 / PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

35. A combination of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway.

36. A combination of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1 / PD-L1 pathway.

37. Use of BT8009 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating a cancer, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway.

38. Use of BT8009 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1 / PD-L1 pathway.

39. Use of an agent that inhibits the PD-1 / PD-L1 pathway in the manufacture of a medicament for use in a method of treating a cancer, wherein the method comprises administering to the patient the agent that inhibits the PD-1 / PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

40. Use of an agent that inhibits the PD-1 / PD-L1 pathway in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1 / PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.

41. BT8009 or a pharmaceutically acceptable salt thereof for use in a method of treating a cancer in a patient that has previously received or is scheduled to receive an agent that inhibits the PD-1 / PD-L1 pathway.

42. An agent that inhibits the PD-1 / PD-L1 pathway for use in a method of treating a cancer in a patient that has previously received or is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof.

43. The BT8009 or a pharmaceutically acceptable salt thereof for use, agent for use, combination for use, or use of any one of claims 31 to 42, wherein the method is the method of any one of claims 1 to 30.

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