Bicyclic peptide complex for use in treating cancer

Abstract

The present invention relates to a heterotandem bicyclic peptide complex BT7480, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, and uses thereof.

Description

[0001] BICYCLIC PEPTIDE COMPLEX FOR USE IN TREATING CANCER

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to a heterotandem bicyclic peptide complex BT7480, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof. The present invention provides uses of BT7480, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for treating a cancer in a human patient.

[0004] CROSS REFERENCE TO RELATED APPLICATIONS

[0005] This application claims priority from US 63 / 609,636 filed on 13 December 2023 and US 63 / 692,238 filed on 9 September 2024, the contents of which are hereby incorporated by reference.

[0006] BACKGROUND OF THE INVENTION

[0007] 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 A2; Wu et al. (2007), Science 330, 1066-71), a cyclic peptide with the Arg-Gly-Asp motif binding to integrin aVb3 (355 A2) (Xiong et al. (2002), Science 296 (5565), 151-5) or the cyclic peptide inhibitor upain-1 binding to urokinase-type plasminogen activator (603 A2; Zhao et al. (2007), J Struct Biol 160 (1), 1-10).

[0008] 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.

[0009] Different research teams have previously tethered polypeptides with cysteine residues to a synthetic molecular structure (Kemp and McNamara (1985), J. Org. Chem; Timmerman etal. (2005), ChemBioChem). Meloen and co-workers had used tris(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-l,3,5-triyl)triprop-2-en-l-one, Heinis c / a / . Angew Chem, IntEd. 2014; 53: 1602-1606).

[0010] 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)e-Cys) were displayed on phage and cyclised by covalently linking the cysteine side chains to a small molecule scaffold.

[0011] W02023089308 describes a solid pharmaceutical composition comprising heterotandem bicyclic peptide complex BT7480.

[0012] SUMMARY OF THE INVENTION

[0013] The present invention relates to use of BT7480, or a pharmaceutically acceptable salt thereof, to treat cancer. A Phase I trial is underway for BT7480 (details of which are set out in Example 1 and the results so far are discussed in Examples 3 and 4). As shown in the examples and figures, analysis of the clinical data from the Phase I trial demonstrates striking efficacy for BT7480 against cancer. The clinical data also show particularly effective doses and dosage regimens. BT7480 is shown to have clinical efficacy and clinical biomarkers indicate that BT7480 is a pharmacologically active compound with signals of blood immune activation associated with clinical benefits. Accordingly, in a first aspect of the invention, there is provided a method of treating a cancer in a human patient, comprising administering to the patient BT7480 or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments of any aspect of the invention, the cancer is a solid tumor. In some embodiments of any aspect of the invention, the treating results in the maintenance or reduction of the volume of the solid tumor. As can be seen in examples and figures, BT7480 has been shown to be particularly effective at reducing or maintaining solid tumors.

[0015] In some embodiments of any aspect of the invention, the treating results in an increase in the number of activated CD4 T cells in the blood of the human patient. As can be seen in examples and figures, there is a dose dependent increase in circulating activated CD4 T cells.

[0016] In some embodiments of any aspect of the invention, the treating results in an increase of the level of CXCL9 in the blood of the human patient. As can be seen in examples and figures, there is a dose dependent increase in circulating CXCL9.

[0017] In some embodiments of any aspect of the invention, the treating results in an increase of the level of sCD137 in the blood of the human patient. As can be seen in examples and figures, there is there is a dose dependent increase in circulating sCD137.

[0018] In some embodiments of any aspect of the invention, the treating results in an increase of the level of CXCL10 in the blood of the human patient. As can be seen in examples and figures, there is there is a dose dependent increase in circulating CXCL10.

[0019] In some embodiments of any aspect of the invention, the increase of the level of IFN- gamma in the blood of the human patient. As can be seen in examples and figures, an increase in IFN-gamma has been shown.

[0020] In some embodiments of any aspect of the invention, the cancer is an advanced malignancy. As can be seen in examples and figures, BT7480 has been shown to be particularly effective for advanced malignancies.

[0021] In some embodiments of any aspect of the invention, the cancer is associated with Nectin-4 expression. As can be seen in examples and figures, BT7480 has been shown to be particularly effective for cancer associated with Nectin-4 expression.

[0022] In some embodiments of any aspect of the invention, the cancer is selected from the group consisting of cervical cancer (e.g. cervical squamous cell carcinoma), NSCLC (e.g. lung adenocarcinoma), and anal squamous cell carcinoma. As can be seen in examples and figures, BT7480 has been shown to be particularly effective for such cancers.

[0023] In some embodiments of any aspect of the invention, the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.3 to about 3.5 mg / kg, about 0.6 to about 3.5 mg / kg, about 1.3 to about 3.5 mg / kg, or about 2.6 to about 3.5 mg / kg. As can be seen in examples and figures, BT7480 has been shown to be particularly effective at such doses.

[0024] In a second aspect of the invention, there is provided a method of maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer, comprising administering to the patient BT7480 or a pharmaceutically acceptable salt thereof.

[0025] In a third aspect of the invention, there is provided BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a human patient comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof.

[0026] In a fourth aspect of the invention, there is provided BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof.

[0027] In a fifth aspect of the invention, there is provided a pharmaceutical composition comprising BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a human patient comprising administering to the patient the pharmaceutical composition.

[0028] In a sixth aspect of the invention, there is provided a pharmaceutical composition comprising BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer comprising administering to the patient the pharmaceutical composition.

[0029] In a seventh aspect of the invention, there is provided use of BT7480 or a pharmaceutical acceptable salt thereof, in the manufacture of a medicament for use in a method of treating a cancer in a human patient comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof. In an eighth aspect of the invention, there is provided use of BT7480 or a pharmaceutical 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 human patient suffering from a cancer comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof.

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG. 1 is a diagrammatic depiction of the BT7480-100 Phase 1 study design. The dose regimen for each cohort is shown. Of the three arrows at the top, the right two are future cohorts / trials.

[0032] FIG. 2 depicts the Study schema. * indicates optional cohorts; f indicates optional backfill. Note: Combination therapy will occur after monotherapy for each phase. N = number of patients; RP2D = recommended Phase 2 dose.

[0033] FIG. 3 contains the baseline characteristics for cohorts 1-9 (0.002-2.6 mg / kg QW). QW = dose frequency of once per week.

[0034] FIG. 4 contains a safety summary. There are a low number of related TEAEs and >Grade 3 TEAEs. AESI = adverse events of special interest; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

[0035] FIG. 5 contains a safety summary and shows that BT7480 was generally well tolerated. TEAE = treatment-emergent adverse event.

[0036] FIG. 6 (A) depicts mean BT7480 concentration-time profiles plotted on semi-log scale by dose level. The key is in reverse order compared to the lines in the graph (i.e. from top to bottom on the graph, the lines are 2.6, 1.3, 0.6, 0.3, 0.15, 0.05, 0.02, 0.006, 0.002 mg / kg). (B) depicts BT7480 PK parameter (AUCinf and Cmax) over dose level. (C) depicts mean BT7480 concentration-time profiles at CID 1 and CID 15. The BT7480 clinical PK profile has been consistent and predicable across dose escalation. The preliminary BT7480 PK appears dose proportional, indicating exposures are increasing consistently with dose escalation. The between subject PK variability was moderate. The vast majority of BT7480 exposures were eliminated over a ti / 2 of -6-17 hours. There was no / limited accumulation after once weekly dosing. N = number; SD = standard deviation. C = cycle. D = day of cycle.

[0037] FIG. 7 depicts full target engagement with doses >0.15 mg / kg (Cohort 5), as shown by CD137 receptor occupancy in patient's blood samples (right hand graph). Also depicted are Nectin-4 expression and CD137 expression (left hand graph). ROI = region of interest, RO = receptor occupancy.

[0038] FIG. 8 depicts robust blood PD signals identified at doses >0.3 mg / kg (Cohort 6) in possible association with clinical benefit. Dose dependent increase in circulating activated CD4 T cells (FOXP3+CD25+CD4+) (A), CXCL9 (B, left graph) and sCD137 (B, right graph) following BT7480 treatment. All patients in cohorts 6-9 had either an increase in CXCL9, sCD137 or CD4 T cell activation, with the majority having an increase in all three. Max PD signal = fold change relative to baseline; Increased PD signal = >1 Std dev (both graphs in B) or >1 FC (fold change) (A); Dashed lines = 1 Std dev of baseline samples (both graphs in B); Dashed line = fold change relative to baseline=l (A). sCD137 = soluble CD137. FC = fold change. PD = pharmacodynami c .

[0039] FIG. 9 depicts quantitative modelling indicating the likely BT7480 therapeutic doses. Clinical PK and clinical CD4+ T cell activation data have been used in PK / PD modeling to identify clinical doses that provide near maximal biomarker change. Black line: median prediction (no residual error); Shaded area: 95% prediction interval (with residual error); Vertical dashed lines: mean AUCinfClDl at 0.6, 1.3, 2.6 and 3.5 mg / kg (AUCinf C1D1 of 3.5 mg / kg extrapolated based on AUCinf ClDl at 2.6 mg / kg, assuming dose-proportional PK); Horizontal dashed line: 80% Emax of average fold change of CD4+ T cell activation; y axis represents average fold change (relative to baseline) of FOXP3+CD25+CD4+ T cells at Week 1-4. PK = pharmacokinetic. PD = pharmacodynamic. FIG. 10 depicts BT7480 response by dose across Cohorts 1-9 (0.002-2.6 mg / kg QW) for efficacy evaluable patients, which were defined as all enrolled patients with measurable disease at baseline who received at least one dose of BT7480 and had at least one adequate post-baseline disease assessment. The maximum percent reduction from baseline in sum of diameters of target lesions (%) is shown. Baseline is the last non-missing measurement prior to the first dose of study treatment of BT7480. The maximum percent reduction is the maximum percent reduction determined over the course of the treatment so far. The top horizontal dotted line represents an increase of 20% (marking the line for progressive disease). The middle horizontal dotted line marks 0% change from baseline. The bottom horizontal dotted line marks 30% decrease (marking the line for a partial response). Three patients were excluded due to no post-baseline assessments or lack of adequate post-baseline disease assessment. Responses under response evaluation criteria in solid tumor (RECIST) version 1.1. Example 1 provides general guidelines for RECIST version 1.1.

[0040] FIG. 11 depicts BT7480 response by tumor across Cohorts 1-9 (0.002-2.6 mg / kg QW) for efficacy evaluable patients, which were defined as all enrolled patients with measurable disease at baseline who received at least one dose of BT7480 and had at least one adequate post-baseline disease assessment. The maximum percent reduction from baseline in sum of diameters of target lesions (%) is shown. Baseline is the last non-missing measurement prior to the first dose of study treatment of BT7480. The maximum percent reduction is the maximum percent reduction determined over the course of the treatment so far. The top horizontal dotted line represents an increase of 20% (marking the line for progressive disease). The middle horizontal dotted line marks 0% change from baseline. The bottom horizontal dotted line marks 30% decrease (marking the line for a partial response). Three patients were excluded due to no post-baseline assessments or lack of adequate post-baseline disease assessment. Responses under response evaluation criteria in solid tumor (RECIST) version 1.1. Example 1 provides general guidelines for RECIST version 1.1.

[0041] FIG. 12 depicts a spider plot for Cohorts 1 through 9 (0.002-2.6 mg / kg; N=31). Responses under response evaluation criteria in solid tumor (RECIST) version 1.1. Example 1 provides general guidelines for RECIST version 1.1. The percent change from baseline in sum of diameters of target lesions (%) is shown. Baseline is the last non-missing measurement prior to the first dose of study treatment of BT7480. Only patients with at least one post-baseline assessment are represented. The top horizontal dotted line represents an increase of 20% (marking the line for progressive disease). The middle horizontal dotted line marks 0% change from baseline. The bottom horizontal dotted line marks 30% decrease (marking the line for a partial response). C1D1 = cycle 1 day 1.

[0042] FIG. 13 depicts a spider plot showing 2 out of 2 partial unconfirmed responses in heavily pretreated cervical cancer patients. The percent change from baseline in sum of diameters of target lesions (%) is shown. Baseline is the last non-missing measurement prior to the first dose of study treatment of BT7480. Top line at first data point = 1.3 mg / kg. Bottom line at first data point = 0.6 mg / kg. The top horizontal dotted line represents an increase of 20% (marking the line for progressive disease). The middle horizontal dotted line marks 0% change from baseline. The bottom horizontal dotted line marks 30% decrease (marking the line for a partial response). First patient: female, 75, enrolled in Cohort 7 (0.6 mg / kg QW), Stage IV squamous cell carcinoma of cervix; prior lines of therapy = adjuvant cisplatin plus 3 lines of therapy in metastatic setting including prior CPI; Nectin-4 score = 110. Second patient: female, 42, enrolled in Cohort 8 (1.3 mg / kg QW), Stage IV squamous cell carcinoma of cervix; prior lines of therapy = Neo-adjuvant carboplatin + paclitaxel, adjuvant cisplatin, plus 2 lines of therapy in metastatic setting including prior CPI; Nectin-4 score = 265. Responses under response evaluation criteria in solid tumor (RECIST) version 1.1. Example 1 provides general guidelines for RECIST version 1.1. CPI = checkpoint inhibitor.

[0043] FIG. 14 depicts a spider plot showing 3 heavily pretreated patients with stable disease >7 months. The percent change from baseline in sum of diameters of target lesions (%) is shown. Baseline is the last non-missing measurement prior to the first dose of study treatment of BT7480. Top line at first data point, which then crosses to become bottom line at later data points = 1.3 mg / kg. Bottom lines at first data point which then cross to become top lines at later data points = 0.6 mg / kg. The top horizontal dotted line represents an increase of 20% (marking the line for progressive disease). The middle horizontal dotted line marks 0% change from baseline. The bottom horizontal dotted line marks 30% decrease (marking the line for a partial response). First patient: female, 77, enrolled in Cohort 7 (0.6 mg / kg QW), Stage IV NSCLC (adenocarcinoma); 3 prior lines of therapy in metastatic setting including prior CPI; Nectin-4 score = 225. Second patient: female, 45, enrolled in Cohort 7 (0.6 mg / kg QW), Stage IV NSCLC (adenocarcinoma); 4 prior lines of therapy in metastatic setting including prior CPI; Nectin-4 score = 110. Third patient: female, 53, enrolled in Cohort 8 (1.3 mg / kg QW), Stage IIIC squamous cell carcinoma of anus; 3 prior lines of therapy; Nectin-4 score = 200. Responses under response evaluation criteria in solid tumor (RECIST) version 1.1. Example 1 provides general guidelines for RECIST version 1.1. CPI = checkpoint inhibitor

[0044] FIG. 15 depicts emergence of immune activation consistent with mechanism of action in blood, cohorts >6. (A) depicts activated CD4 T cells in blood (FOXP3+CD25+CD4+). Dotted line = 2-fold change from baseline (average of screening and C1D1 predose). (B) contains a heatmap showing the circulating mechanistic proteins at Cycle 2 Day 15. Log2 fold change from baseline relative to average of screening and C1D1 predose samples. Black box = cohorts >5 (i.e. including “001-011, 0.3 mg / kg, NSCLC” and below). Dashed line boxes = examples of cytokines / chemokines increased in cohorts >5 (i.e. IFN-gamma and CXCL10 for “001-011, 0.3 mg / kg, NSCLC” and below).

[0045] FIG. 16 depicts Cohorts 6-9 have greater increase in CXCL10 compared to cohorts 1-5. Max CXCL10 signal = fold change relative to baseline. Dashed lines indicate 1 standard deviation in log2 FC calculated in baseline samples from subjects with both C1D1 and screening.

[0046] FIG. 17 depicts robust blood PD (pharmacodynamic) signals identified emergent in Cohorts >6 with possible association with clinical benefit. (A) Left hand graph shows dose dependent increase in circulating activated CD4 T cells (FOXP3+CD25+CD4+). Right hand graph shows the co-induction of blood CD4+ T cells and CXCL9. The table provides a summary of the number of patients with increased CXCL9 and / or increased CD4 T cell activation. Max PD (pharmacodynamic) signal = fold change relative to baseline. Dashed lines = 1 Std dev of baseline samples (right graph). Dashed line = fold change relative to baseline=l (left graph). (B) depicts comparison of activated CD4 T cells (FOXP3+CD25+CD4+) in disease control versus non-disease control. Max PD (pharmacodynamic) signal = fold change relative to baseline. Disease control (DC) = BOR (best overall response) is PR (partial response) or SD (stable disease). Non-disease control (NDC) = BOR is PD (progressive disease).

[0047] FIG. 18 depicts that Disease Control patients have an increase in circulating activated CD4 T cells (FOXP3+CD25+CD4+) compared to Non-Disease Control patients. Disease Control (DC) defined as patients with PR (partial response) or SD (stable disease) at any scan regardless of later PD (progressive disease).

[0048] FIG. 19 depicts CXCL9 levels for cohorts 1-9 over time. Y-axis represents fold change relative to baseline. The dose in mg / kg is shown above each graph. Each line represents an individual patient.

[0049] FIG. 20 contains the baseline patient demographics and clinical characteristics for cohorts 1-10 (0.002-3.5 mg / kg QW). QW = dose frequency of once per week. ECOG PS = Eastern Cooperative Oncology Group performance status.a= Of 35 H4C evaluable patients, positivity >1 TPS.b= of 30 mIF evaluable patients, positivity > 1%. H4C = immunohistochemistry; mIF = multiplex immunofluorescence (in particular MultiOmyx™ hyperplexed immunofluorescence). CD 137 positivity was scored using the Combined Positive Score (CPS).

[0050] FIG. 21 contains a safety summary for cohorts 1-10 (0.002-3.5 mg / kg QW). The particular data for cohort 10 (3.5 mg / kg) is shown. There are a low number of TRAEs and >Grade 3 TEAEs. DLT = dose-limiting toxicity; TEAE = Treatment-emergent adverse event; TRAE = Treatment- related adverse event; SAE = serious adverse event; TRSAE = Treatment-related serious adverse event; TESAE = Treatment-emergent serious adverse event. (TRAEs are also referred to herein as related TEAEs.). FIG. 22 depicts confirmed and unconfirmed best overall responses (BORs) for cohorts 1-10 (0.002-3.5 mg / kg QW). Includes patients who received at least one dose of BT7480. CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable; ORR = overall response rate; CBR = clinical benefit rate. ORR (overall response rate) = CR+PR. CBR (clinical benefit rate) = CR+PR+SD. The PR are unconfirmed.a= data cleaning efforts identified one additional unconfirmed partial response, which was rectified as of a date cutoff date of 15 April 2024. One additional patient had been enrolled as of this date.b= unconfirmed.c= For >6 weeks from the start of study drug to assessment date (i.e. when SD is believed to be the best overall response, it must also meet the minimum interval of 6 weeks from the start of study drug to assessment date).d= CR+PR+SD (> 8 weeks) (i.e. for CBR, when SD is believed to be the best overall response, it must also meet the minimum interval of 8 weeks from the start of study drug to progression disease date).

[0051] FIG. 23 depicts the maximum percent reduction from baseline in target lesions across Cohorts 1- 10 (0.002-3.5 mg / kg QW). The maximum percent reduction from baseline in sum of diameters of target lesions (%) is shown. Baseline is the last non-missing measurement prior to the first dose of study treatment of BT7480. The maximum percent reduction is the maximum percent reduction determined over the course of the treatment so far. Unconfirmed best overall response is used. Only patients with at least one post-baseline assessment are represented. The top dotted line represents an increase of 20% (marking the line for progressive disease). The middle line marks 0% change from baseline. The bottom dotted line marks 30% decrease (marking the line for a partial response). There are two unconfirmed partial responses in cervical cancer. From left hand side: bar 1 = 0.002 mg / kg; bar 2 = 0.006 mg / kg; bar 3 = 0.02 mg / kg; bar 4 = 0.05 mg / kg; bars 5-8 = 0.15 mg / kg; bars 9-11 = 0.3 mg / kg; bars 12-17 = 0.6 mg / kg; bars 18-26 = 1.3 mg / kg; bars 27- 33 = 2.6 mg / kg; and bars 34-37 = 3.5 mg / kg. PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable for efficacy; SoD = sum of diameters; Coh = cohort; BLCA = Bladder Carcinoma; BREAS = Breast carcinoma; CRC = Colorectal Carcinoma; ESOPH = Esophageal carcinoma; OVARI = Ovarian carcinoma; TNBC = Triple-Negative Breast carcinoma; UTCC = Urothelial (transitional cell) carcinoma; PANC = pancreatic cancer; NSCLC = non-small cell lung cancer; HNSCC = head and neck squamous cell carcinoma; GI= Gastrointestinal carcinoma; CERVIX=Cervical carcinoma; OTH = other; 001-004 / OTH = peripheral nerve sheath tumor; 004-006 / OTH = thyroid cancer. Responses evaluated under response evaluation criteria in solid tumor (RECIST) version 1.1. Example 1 provides general guidelines for RECIST version 1.1.

[0052] FIG. 24 depicts a spider plot for Cohorts 1 through 10 (0.002-3.5 mg / kg; N=40). The percent change from baseline in sum of diameters of target lesions (%) is shown over time. Baseline is the last non-missing measurement prior to the first dose of study treatment of BT7480. Only patients with at least one post-baseline assessment are represented. C1D1 = Cycle 1 Day 1. The line that ends between 12 and 16 weeks and is just below the top dotted line is 3.5 mg / kg (cohort 10). The line that ends just after 16 weeks and is below the top dotted line is 3.5 mg / kg (cohort 10). The line that ends at 24 weeks is 2.6 mg / kg (cohort 9). Long stable disease (> 8 months) observed in three patients. These are the same three patients described above for Figure 14. At 28 weeks from C1D1 onwards, the three lines represent these three patients: the top two lines are 0.6 mg / kg (cohort 7) and the bottom line is 1.3 mg / kg (cohort 8). The top dotted line represents an increase of 20% (marking the line for progressive disease). The bottom dotted line marks 30% decrease (marking the line for a partial response). Responses evaluated under response evaluation criteria in solid tumor (RECIST) version 1.1. Example 1 provides general guidelines for RECIST version 1.1. C1D1 = cycle 1 day 1. “Coh” = cohort.

[0053] FIG. 25 depicts mean BT7480 concentration-time profiles plotted on semi-log scale by dose level. From top to bottom on the graph, the lines are 3.5, 2.6, 1.3, 0.6, 0.3, 0.15, 0.05, 0.02, 0.006, 0.002 mg / kg). Dose proportional PK was generally observed across the dose range tested. Terminal half-life at 1.3-3.5 mg / kg was approximately 13-18 hours. N = number; SD = standard deviation. C = cycle. D = day of cycle. Data presented as mean ± SD.

[0054] FIG. 26 shows BT7480 demonstrates full target engagement and induction of immune activation signals in patient blood. (A) depicts full target engagement with doses >0.15 mg / kg (Cohort 5), as shown by CD137 receptor occupancy in patient's blood samples. (B) depicts dose dependent increase in circulating activated CD4 T cells (FOXP3+CD25+CD4+) following BT7480 treatment. (C) depicts dose dependent increase in circulating sCD137 following BT7480 treatment. (D) depicts dose dependent increase in circulating CXCL9 following BT7480 treatment. All patients in cohorts 6-10 had either an increase in CXCL9, sCD137 or CD4 T cell activation, with the majority having an increase in all three. Increased PD signal = >1 Std dev (C and D) or >1 FC (fold change) (B). sCD137 = soluble CD137. FC = fold change. RO = receptor occupancy. PD = pharmacodynamic.a= Measured at CID 1, 20 minutes post-end of infusion, divided by the baseline value.b= Maximum value reported, through cycle 2.c= Max value reported through C2D15. Each dot represents one patient; bars and horizontal lines represent the median; whiskers show the maximum and minimum values. Dashed lines = 1 standard deviation from baseline (C and D).

[0055] DETAILED DESCRIPTION OF THE INVENTION

[0056] The present invention provides a method of treating a cancer in a human patient, comprising administering to the patient BT7480 or a pharmaceutically acceptable salt thereof. The present invention also provides a method of maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer, comprising administering to the patient BT7480 or a pharmaceutically acceptable salt thereof.

[0057] BT7480

[0058] The term “BT7480” (also referred to as BCY11863) is a heterotandem bicyclic peptide complex that consists of a Nectin-4 specific peptide BCY8116 linked to two CD137 specific peptides (both of which are BCY8928) via a N-(acid-PEG3)-N-bis(PEG3-azide) linker, shown pictorially as:

[0059]

[0060] The Nectin-4 specific peptide BCY8116 is CiP[lNal][dD]CiiM[HArg]DWSTP[HyP]WCiii (SEQ ID NO: 1). The CD137 specific peptide BCY8928 is Ac-Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A (SEQ ID NO: 2). The CD137 specific peptide BCY8928 comprises an N- and C-terminal extension which are separated by hyphens from the left and right side of the sequence. Ac represents acetyl, HArg represents homoarginine, HyP represents trans-4- hydroxy-L-proline, 1 Nal represents 1- naphthylalanine, tBuAla represents t-butyl-alanine, PYA represents 4-pentynoic acid and Nle represents norleucine. The peptides each comprise three reactive groups which form covalent bonds to a scaffold, and a sequence subtended between said reactive groups which is referred to as the loop sequence, since it forms a loop when the peptide is bound to the scaffold. The reactive groups are cysteines. The peptides form at least two loops on the scaffold. The scaffold is l,l',l"-(l,3,5-triazinane-l,3,5-triyl)triprop-2-en-l-one (TATA). Cyclisation with TATA occurs on Ci, Cii, and Ciii.

[0061] Nectin-4 is a surface molecule that belongs to the nectin family of proteins, which comprises 4 members. Nectins are cell adhesion molecules that play a key role in various biological processes such as polarity, proliferation, differentiation and migration, for epithelial, endothelial, immune and neuronal cells, during development and adult life. They are involved in several pathological processes in humans. They are the main receptors for poliovirus, herpes simplex virus and measles virus. Mutations in the genes encoding Nectin-1 (PVRL1) or Nectin-4 (PVRL4) cause ectodermal dysplasia syndromes associated with other abnormalities. Nectin-4 is expressed during foetal development. In adult tissues its expression is more restricted than that of other members of the family. Nectin-4 is a tumor-associated antigen in 50%, 49% and 86% of breast, ovarian and lung carcinomas, respectively, mostly on tumors of bad prognosis. Its expression is not detected in the corresponding normal tissues. In breast tumors, Nectin-4 is expressed mainly in triple-negative and ERBB2+ carcinomas. In the serum of patients with these cancers, the detection of soluble forms of Nectin-4 is associated with a poor prognosis. Levels of serum Nectin-4 increase during metastatic progression and decrease after treatment. These results suggest that Nectin-4 could be a reliable target for the treatment of cancer. Accordingly, several anti-Nectin-4 antibodies have been described in the prior art. In particular, Enfortumab Vedotin (ASG-22ME) is an antibody-drug conjugate (ADC) targeting Nectin-4 and is currently clinically investigated for the treatment of patients suffering from solid tumors.

[0062] CD137 is a member of the tumor necrosis factor (TNF) receptor family. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4- IBB and induced by lymphocyte activation (ILA). CD137 can be expressed by activated T cells, but to a larger extent on CD8+ than on CD4+ T cells. In addition, CD137 expression is found on dendritic cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation. One characterized activity of CD137 is its costimulatory activity for activated T cells. Crosslinking of CD137 enhances T cell proliferation, IL-2 secretion, survival and cytolytic activity. Further, it can enhance immune activity to eliminate tumors in mice.

[0063] CD137 is a homotrimeric protein and the natural ligand CD137L exists as a homotrimer either expressed on immune cells or secreted. The biology of CD137 is highly dependent on multimerization to induce CD137 activity in immune cells. One way to generate CD137 multimerization is through cellular cross-linking of the CD137 specific agonist through interaction with a specific receptor present on another cell. The advantage of BT7480 is that the presence of the two peptide ligands specific for CD137 provides a more effective clustering of CD137. For example, it has been found that BT7480 demonstrated strong CD137 activation and induces robust IL-2 and IFN-y cytokine secretion, and that BT7480 demonstrated an excellent PK profile with a terminal half-life of 4.1 hours in SD Rats and 5.3 hours in cyno.

[0064] Synthesis of BT7480

[0065] The peptides which form BT7480 may be manufactured synthetically by standard techniques followed by reaction with a TATA scaffold in vitro. When this is performed, standard chemistry may be used. This enables the rapid large scale preparation of soluble material for further downstream experiments or validation. Such methods could be accomplished using conventional chemistry such as that disclosed in Timmerman et al (supra).

[0066] To extend the peptide, it may simply be extended chemically at its N-terminus or C- terminus or within the loops using orthogonally protected lysines (and analogues) using standard solid phase or solution phase chemistry. Standard (bio)conjugation techniques may be used to introduce an activated or activatable N- or C-terminus. Alternatively additions may be made by fragment condensation or native chemical ligation e.g. as described in (Dawson et al. 1994. Synthesis of Proteins by Native Chemical Ligation. Science 266:776-779), or by enzymes, for example using subtiligase as described in (Chang et al. Proc Natl Acad Sci U S A. 1994 Dec 20; 91(26): 12544-8 or in Hikari et al Bioorganic & Medicinal Chemistry Letters Volume 18, Issue 22, 15 November 2008, Pages 6000-6003).

[0067] Alternatively, the peptides may be extended or modified by further conjugation through disulphide bonds. This has the additional advantage of allowing the Nectin-4 and CD137 peptides to dissociate from each other once within the reducing environment of the cell. In this case, the TATA scaffold could be added during the chemical synthesis of the Nectin-4 peptide so as to react with the three cysteine groups; a further cysteine or thiol could then be appended to the N or C-terminus of the Nectin-4 peptide, so that this cysteine or thiol only reacted with a free cysteine or thiol of the CD137 peptides, forming a disulfide -linked bicyclic peptide-peptide conjugate.

[0068] Similar techniques apply equally to the synthesis / coupling of two bicyclic and bispecific macrocycles, potentially creating a tetraspecific molecule.

[0069] Furthermore, addition of other functional groups or effector groups may be accomplished in the same manner, using appropriate chemistry, coupling at the N- or C-termini or via side chains. In one embodiment, the coupling is conducted in such a manner that it does not block the activity of either entity.

[0070] Pharmaceutically acceptable salt

[0071] 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, dodecyl sulfate, 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.

[0072] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Cl-4alkyl)4 salts. 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.

[0073] 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.

[0074] In some embodiments, references to a peptide, molecule or compound include the salt forms of said peptide, molecule or compound. In some embodiments, the pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. In some embodiments, the pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as oxalic, citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or / ?-toluenesulphonic acid. In some embodiments, the pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkaline earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines and heterocyclic amines. In some embodiments, the pharmaceutically acceptable salt is a salt formed with a pharmaceutically acceptable base, in particular a quaternary ammonium salt e.g. tetrabutylammonium salt, or an alkali metal salt, e.g. sodium or potassium salt. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt or acetate salt.

[0075] Isotopic variations

[0076] The peptides used to form BT7480, or a pharmaceutically acceptable salt thereof, may be (radio)isotope-labelled, wherein the (radio)isotope is a pharmaceutically acceptable (radio)isotope. In such embodiments, one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The peptides used to form BT7480, or a pharmaceutically acceptable salt thereof, may comprise metal chelating groups (termed “effector”) that are capable of holding relevant (radio)isotopes. The peptides used to form BT7480, or a pharmaceutically acceptable salt thereof, may comprise (radio)isotopes or isotopically labelled functional groups in the place of certain functional groups.

[0077] Examples of isotopes suitable for inclusion in the peptides used to form BT7480, or a pharmaceutically acceptable salt thereof, comprise isotopes of hydrogen, such as2H (D) and3H (T), carbon, such asnC,13C and14C, chlorine, such as36C1, fluorine, such as18F, iodine, such as123I,125I and131I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, sulfur, such as35S, copper, such as64Cu, gallium, such as67Ga or68Ga, yttrium, such as90Y and lutetium, such as177Lu, and Bismuth, such as213Bi.

[0078] Certain isotopically-labelled peptides used to form BT7480, or a pharmaceutically acceptable salt thereof, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies, and to clinically assess the presence and / or absence of the Nectin-4 target on diseased tissues. The peptides used to form BT7480, or a pharmaceutically acceptable salt thereof, can further have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors. The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc. The radioactive isotopes tritium, i.e.3H (T), and carbon- 14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0079] Substitution with heavier isotopes such as deuterium, i.e.2H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0080] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

[0081] Isotopically-labeled compounds of the peptides used to form BT7480, or a pharmaceutically acceptable salt thereof, can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0082] The cancer and the patient

[0083] For the “method of treating a cancer ” or the “human patient suffering from a cancer ”, the cancer may be any cancer described herein. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is sarcoma, carcinoma, or lymphoma. In some embodiments, the cancer is malignant. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is an advanced malignancy. In some embodiments, the cancer is metastatic or locally advanced in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In some embodiments, the cancer is associated with Nectin-4 expression. In some embodiments, the cancer is an advanced solid tumor associated with Nectin-4 expression. In some embodiments, the cancer is a malignant solid tumor associated with Nectin-4 expression. In some embodiments, the cancer is high Nectin-4 expressing. In some embodiments, the cancer is refractory to standard therapy. In some embodiments, there is no standard therapy judged to be appropriate or to provide clinical benefit to the patient. In some embodiments, the treating results in the improvement of tumor related symptoms. The treating may ameliorate one or more symptoms. One or more symptoms may be completely remedied. In some embodiments, the cancer is associated with CD 137 expression.

[0084] In some embodiments, the cancer is associated with Nectin-4 expression and the cancer is associated with CD137 expression. In some embodiments, the cancer is an advanced malignancy associated with Nectin-4 expression and associated with CD 137 expression. In some embodiments the cancer is stage III or stage IV. In some embodiments, the cancer (e.g. solid tumor) comprises CD137 positive cells (in other words, cells that express CD137).

[0085] In some embodiments, the cancer (e.g. solid tumor) that is “associated with Nectin-4 expression” is positive for Nectin-4 protein expression. A skilled person can readily determine whether a cancer (e.g. solid tumor) is positive for Nectin-4 protein expression. Nectin-4 protein expression may be determined by multiplex immunofluorescence assay, such as MultiOmyx™ hyperplexed immunofluorescence assay. A skilled person would readily be able to perform a multiplex immunofluorescence assay to determine Nectin-4 protein expression (for example using, amongst other reagents, an antibody directed to the extracellular domain of Nectin-4). Nectin-4 expression may be scored using the Combined Positive Score (CPS). A skilled person would readily be able to determine the CPS. For example, regions of interest (ROIs) (e.g. 30 ROIs) can be selected from a slide with a FFPE (Formalin-Fixed Paraffin-Embedded) tissue section from the cancer. The tissue section can then be stained for Nectin-4 protein and imaged. To calculate the CPS, for each region of interest (ROI), the number of positive cells can be divided by the total number of cells and then multiplied by 100, and the median value of all ROIs per slide can be used as the final value. In some embodiments, a CPS of one or more is considered positive for Nectin-4. For example, the CPS may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, or about 50 or more. Nectin-4 protein expression may be determined by immunohistochemistry. A skilled person can readily perform immunohistochemistry to determine Nectin-4 protein expression (for example using, amongst other reagents, an antibody directed to the extracellular domain of Nectin-4). For example, immunohistochemistry may be performed as set out in Example 2. Nectin-4 protein expression may be scored using the H-score method (the sum of the products of the percent of cells x their staining intensity, on a scale of 0-3 where 0 is negative and 3 is strongly stained). A skilled person would readily be able to determine the H-score. In some embodiments, a H-score of one or more is considered positive for Nectin-4. For example, the H-score may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, about 50 or more, about 100 or more, about 150 or more, or about 200 or more. For example, the H-score may be about 100 or more. Nectin-4 protein expression may be determined by tumor proportion score (TPS). A skilled person would readily be able to determine the TPS. In some embodiments, a TPS of about one or more is considered positive for Nectin-4. For example, the TPS may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, or about 50 or more.

[0086] BT7480 has been shown to only require low Nectin-4 expression levels for activity. Without wishing to be bound by theory, BT7480 may mediate activity in patients expressing naturally low or heterogeneous levels of Nectin-4. Thus, in some embodiments, the cancer (e.g. solid tumor) is associated with low or heterogeneous Nectin-4 expression.

[0087] In some embodiments, the cancer (e.g. solid tumor) that is “associated with CD 137 expression” is positive for CD137 protein expression. A skilled person can readily determine whether a cancer (e.g. solid tumor) is positive for CD137 protein expression. CD137 protein expression may be determined by multiplex immunofluorescence assay, such as MultiOmyx™ hyperplexed immunofluorescence assay. A skilled person would readily be able to perform a multiplex immunofluorescence assay to determine CD 137 protein expression (for example using, amongst other reagents, an antibody directed to the extracellular domain of CD137, e.g. clone BLR051F). CD137 expression may be scored using the Combined Positive Score (CPS). A skilled person would readily be able to determine the CPS. For example, regions of interest (ROIs) (e.g. 30 ROIs) can be selected from a slide with a FFPE (Formalin-Fixed Paraffin- Embedded) tissue section from the cancer. The tissue section can then be stained for CD137 protein and imaged. To calculate the CPS, for each region of interest (ROI), the number of positive cells can be divided by the total number of cells and then multiplied by 100, and the median value of all ROIs per slide can be used as the final value. In some embodiments, a CPS of one or more is considered positive for CD137. For example, the CPS may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, or about 50 or more. CD137 protein expression may be determined by immunohistochemistry. A skilled person can readily perform immunohistochemistry to determine CD 137 protein expression (for example using, amongst other reagents, an antibody directed to the extracellular domain of CD137). CD137 protein expression may be scored using the H-score method (the sum of the products of the percent of cells x their staining intensity, on a scale of 0-3 where 0 is negative and 3 is strongly stained). A skilled person would readily be able to determine the H-score. In some embodiments, a H-score of one or more is considered positive for CD137. For example, the H-score may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, about 50 or more, about 100 or more, or about 150 or more. For example, the H-score may be about 100 or more. CD137 protein expression may be determined by tumor proportion score (TPS). A skilled person would readily be able to determine the TPS. In some embodiments, a TPS of about one or more is considered positive for CD137. For example, the TPS may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, or about 50 or more.

[0088] In some embodiments, the cancer 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, pancreatic cancer, head and neck cancer (e.g. HNSCC), cervical cancer, bladder cancer (e.g. urothelial cancer), and melanoma. In some embodiments, the cancer is selected from the group consisting of urothelial (transitional cell) carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, ovarian carcinoma, breast carcinoma, gastric carcinoma, and esophageal carcinoma. In some embodiments, the cancer 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 (e.g.

[0089] HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer). In some embodiments, the cancer is selected from the group consisting of lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), gastric / upper gastrointestinal (GI) cancer, head and neck cancer (e.g. HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer). In some embodiments, the cancer is selected from the group consisting of lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), head and neck cancer (e.g. HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer). In some embodiments, the cancer is selected from the group consisting of lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), head and neck cancer (e.g. HNSCC), cervical cancer, and bladder cancer (e.g. urothelial cancer).

[0090] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma (CHOL), rectal adenocarcinoma (READ), malignant peripheral nerve sheath tumor (MPNST), colorectal cancer (CRC), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), pancreatic cancer (PANC), bladder adenocarcinoma (BLAD), cervical squamous cell carcinoma (CESC); head & neck squamous cell carcinoma (HNSCC), anal squamous cell carcinoma, triple negative breast cancer (TNBC), ovarian cancer (OC), urothelial carcinoma (UC), and gastroesophageal junction adenocarcinoma (GEJ).

[0091] In some embodiments, the cancer is selected from the group consisting of CHOL, peripheral nerve sheath tumor (PNST), CRC, HCC, NSCLC, PANC, bladder cancer, cervical cancer, HNSCC, and anal SCC. In some embodiments, the cancer is selected from the group consisting of NSCLC, bladder cancer, cervical cancer, HNSCC, CRC and anal SCC.

[0092] In some embodiments, the cancer is selected from the group consisting of cervical cancer (e.g. metastatic cervical cancer), HNSCC, and NSCLC (e.g. metastatic NSCLC). In some embodiments, the cancer is selected from the group consisting of cervical cancer (e.g. cervical squamous cell carcinoma), NSCLC (e.g. lung adenocarcinoma), and anal squamous cell carcinoma. In some embodiments, the cancer is Stage IV cervical squamous cell carcinoma. In some embodiments, the cancer is Stage IV NSCLC (adenocarcinoma) or Stage IIIC anal squamous cell carcinoma. There are partial responses in cervical cancer patients (see Example 3 and Figure 13). There are also 3 patients with stable disease >7 months (see Figure 14 and Example 3). Two of the patients have NSCLC and one patient has anal cancer.

[0093] In some embodiments the cancer is stage III or stage IV.

[0094] In some embodiments, the cancer is selected from the group consisting of lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), gastric / upper gastrointestinal (GI) cancer, head and neck cancer (e.g. HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer). Optionally, the cancer is associated with Nectin-4 expression.

[0095] In some embodiments, the cancer is selected from the group consisting of colorectal cancer, bladder cancer (e.g. adenocarcinoma), cervical cancer, pancreatic cancer, NSCLC, HNSCC, breast carcinoma, TNBC, ovarian carcinoma, UTCC, esophageal carcinoma, intrahepatic bile duct cholangiocarcinoma, peripheral nerve sheath tumor, HCC, SSC of anus, and thyroid cancer. Optionally, the cancer is associated with Nectin-4 expression.

[0096] In some embodiments, the cancer is selected from the group consisting of colorectal cancer, cervical cancer, NSCLC, HNSCC, TNBC, ovarian carcinoma, UTCC, intrahepatic bile duct cholangiocarcinoma, HCC, SSC of anus, and thyroid cancer. Optionally, the cancer is associated with Nectin-4 expression.

[0097] In some embodiments, the cancer is selected from the group consisting of colorectal carcinoma, gastrointestinal carcinoma, bladder carcinoma, cervical carcinoma, pancreatic cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, breast carcinoma, TripleNegative Breast carcinoma, ovarian carcinoma, Urothelial (transitional cell) carcinoma, esophageal carcinoma, peripheral nerve sheath tumor, and thyroid cancer. Optionally, the cancer is associated with Nectin-4 expression.

[0098] As set out in Figure 23, a best response of stable disease or partial response has been observed for the following cancer types: colorectal cancer, gastrointestinal carcinoma, NSCLC, HNSCC, TNBC, ovarian carcinoma, cervical cancer, and thyroid cancer. In some embodiments, the cancer is selected from the group consisting of colorectal cancer, gastrointestinal carcinoma, NSCLC, HNSCC, TNBC, ovarian carcinoma, cervical cancer, and thyroid cancer. Optionally, the cancer is associated with Nectin-4 expression.

[0099] In some embodiments, the cancer is selected from the group consisting of colorectal carcinoma, gastrointestinal carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, breast carcinoma, Triple-Negative Breast carcinoma, ovarian carcinoma, cervical carcinoma, and thyroid cancer. Optionally, the cancer is associated with Nectin-4 expression.

[0100] In some embodiments, the cancer is cervical cancer. In some embodiments, the cervical cancer is associated with Nectin-4 expression. In some embodiments, the cervical cancer is an advanced solid tumor associated with Nectin-4 expression. In some embodiments, the cervical cancer is cervical squamous cell carcinoma. In some embodiments, the cervical cancer is Stage IV cervical squamous cell carcinoma. In some embodiments, the cervical cancer has a Nectin-4 H-score of 100 or more. In some embodiments, the cervical cancer is refractory to standard therapy. In some embodiments, the patient has been previously treated as described herein, such as with a checkpoint inhibitor (CPI).

[0101] In some embodiments, the cancer is NSCLC. As can be seen in Figure 23, treatment with BT7480 can result in a stable disease response for NSCLC (e.g. administering BT7480, or a pharmaceutically acceptable salt thereof, at a dose of 0.6 to 3.5 mg / kg, e.g. at a frequency of once a week). In some embodiments, the NSCLC is associated with Nectin-4 expression. In some embodiments, the NSCLC is an advanced solid tumor associated with Nectin-4 expression. In some embodiments, the NSCLC is an adenocarcinoma. In some embodiments, the NSCLC is Stage IV. In some embodiments, the NSCLC has a Nectin-4 H-score of 100 or more. In some embodiments, the NSCLC is refractory to standard therapy. In some embodiments, the patient has been previously treated as described herein, such as with a checkpoint inhibitor (CPI). As can be seen in Figure 14 and 23, treatment with BT7480 can result in a stable disease response for NSCLC (e.g. administering BT7480, or a pharmaceutically acceptable salt thereof, at a dose of 0.6 to 3.5 mg / kg, e.g. at a frequency of once a week).

[0102] In some embodiments, the cancer is anal cancer. In some embodiments, the anal cancer is associated with Nectin-4 expression. In some embodiments, the anal cancer is an advanced solid tumor associated with Nectin-4 expression. In some embodiments, the anal cancer is an anal ACC. In some embodiments, the anal cancer is Stage III (e.g. Stage IIIC). In some embodiments, the anal cancer has a Nectin-4 H-score of 100 or more. In some embodiments, the anal cancer is refractory to standard therapy. In some embodiments, the patient has been previously treated as described herein, such as with a checkpoint inhibitor (CPI).

[0103] In some embodiments, the cancer is associated with Nectin-4 expression and is selected from the group consisting of bladder cancer, esophageal cancer, non-small-cell lung cancer (NSCLC), head and neck cancer, ovarian cancer, breast cancer such as triple-negative breast cancer (TNBC), gastric / upper gastrointestinal (GI) cancer, melanoma, pancreatic cancer, and urothelial cancer.

[0104] In some embodiments, the cancer is associated with Nectin-4 expression and is nonsmall-cell lung cancer (NSCLC). In some embodiments, the cancer is associated with Nectin-4 expression and is ovarian cancer. In some embodiments, the cancer is associated with Nectin-4 expression and is breast cancer such as triple-negative breast cancer (TNBC). In some embodiments, the cancer is associated with Nectin-4 expression and is gastric / upper gastrointestinal (GI). In some embodiments, the cancer is associated with Nectin-4 expression and is pancreatic cancer. In some embodiments, the cancer is associated with Nectin-4 expression and is urothelial cancer. In some embodiments, the cancer is associated with Nectin- 4 expression and is bladder cancer. In some embodiments, the cancer is associated with Nectin-4 expression and is head and neck cancer. In some embodiments, the cancer is associated with Nectin-4 expression and is esophageal cancer. In some embodiments, the cancer is associated with Nectin-4 expression and is melanoma.

[0105] In some embodiments, the cancer is gastrointestinal carcinoma. In some embodiments, the cancer is associated with Nectin-4 expression and is gastrointestinal carcinoma.

[0106] In some embodiments, the cancer is bladder cancer. In some embodiments, the bladder cancer is selected from the group consisting of basal, p53-like, and luminal.

[0107] In some embodiments, the cancer is endometrial cancer. In some embodiments, the endometrial cancer is selected from the group consisting of MMR-D, POLE EDM, p53 WT, p53 abnormal, Type I, Type II, carcinoma, carcinosarcoma, endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, mixed or undifferentiated carcinoma, mixed serous and endometrioid, mixed serous and low-grade endometrioid, and undifferentiated. In some embodiments, the cancer is esophageal cancer. In some embodiments, the esophageal cancer is selected from the group consisting of adenocarcinoma (EAC), squamous cell carcinoma (ESCC), chromosomal instability (CIN), Epstein-Barr virus (EBV), genomically stable (GS), and microsatellite instability (MSI).

[0108] In some embodiments, the cancer is glioblastoma. In some embodiments, the glioblastoma is selected from the group consisting of proneural, neural, classical, and mesenchymal.

[0109] In some embodiments, the cancer is mesothelioma. In some embodiments, the mesothelioma is selected from the group consisting of pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, epithelioid mesothelioma, sarcomatoid mesothelioma, biphasic mesothelioma, and malignant mesothelioma.

[0110] In some embodiments, the cancer is multiple myeloma. In some embodiments, the multiple myeloma is selected from the group consisting of hyperdiploid, non-hyperdiploid, cyclin D translocation, MMSET translocation, MAF translocation, and unclassified.

[0111] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is selected from the group consisting of clear cell, endometrioid, mucinous, highgrade serous and low-grade serous ovarian cancer.

[0112] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is selected from the group consisting of squamous, pancreatic progenitor, immunogenic, and ADEX (Aberrantly Differentiated Endocrine eXocrine) pancreatic cancer.

[0113] In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is selected from the group consisting of AZGP1 (subtype I), MUC1 (subtype II), and MUC1 (subtype III) prostate cancer.

[0114] In some embodiments, a cancer is a lung cancer. In some embodiments, a lung cancer is a met-amplified squamous NSCLC, a squamous cell NSCLC with wild type EGFR, or a T790M EGFR-expressing lung adenocarcinoma.

[0115] In some embodiments, a cancer is a breast cancer. In some embodiments, a breast cancer is a triple negative breast cancer. In some embodiments, a breast cancer is a basaloid triple negative breast cancer. In some embodiments, a cancer is a colon cancer. In some embodiments, a cancer is a colorectal adenocarcinoma. In some embodiments, a colorectal adenocarcinoma is a high pgp- expressing colorectal adenocarcinoma.

[0116] In some embodiments, a cancer is a gastric cancer. In some embodiments, a gastric cancer is a FGFR-amplified gastric cancer.

[0117] In some embodiments, a cancer is a head and neck cancer. In some embodiments, a head and neck cancer is a nasal septum squamous cell carcinoma.

[0118] In some embodiments, a cancer is a sarcoma. In some embodiments, a sarcoma is a fibrosarcoma. In some embodiments, a fibrosarcoma is an N-ras mutant / IDHl mutant soft tissue sarcoma (STS).

[0119] Cancer includes, in one embodiment, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0120] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g. Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.

[0121] Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0122] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma.

[0123] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.

[0124] In some embodiments, a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas. In some embodiments, the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma.

[0125] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.

[0126] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.

[0127] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0128] In some embodiments, a cancer is a viral -associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; see also https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886; https: / / clinicaltrials.gov / ct2 / show / NCT02426892)

[0129] In some embodiments, a cancer is melanoma cancer. In some embodiments, a cancer is breast cancer. In some embodiments, a cancer is lung cancer. In some embodiments, a cancer is small cell lung cancer (SCLC). In some embodiments, a cancer is non-small cell lung cancer (NSCLC).

[0130] In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), cervical cancer, colorectal cancer, urothelial (transitional cell) carcinoma, bladder cancer (e.g. adenocarcinoma), head & neck squamous cell carcinoma (HNSCC), ovarian carcinoma, breast carcinoma, esophageal carcinoma, pancreatic cancer, triple negative breast cancer, intrahepatic bile duct cholangiocarcinoma, peripheral nerve sheath tumor, HCC, thyroid cancer and squamous cell carcinoma of anus.

[0131] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0132] In some embodiments, the cancer is an advanced malignancy and the cancer is associated with Nectin-4 expression. In some embodiments, the cancer is locally advanced or metastatic. In some embodiments, the cancer is refractory to standard therapy. In some embodiments, the cancer is locally advanced or metastatic, and the cancer is refractory to standard therapy. In some embodiments, the cancer is radiographically documented metastatic or locally advanced disease in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

[0133] In some embodiments, the patient has been previously treated for the cancer (e.g. metastatic cancer). In some embodiments, the patient has been previously treated with a checkpoint inhibitor (CPI). In some embodiments, the patient has been previously treated with adjuvant cisplatin. In some embodiments, the patient has been previously treated with a checkpoint inhibitor (CPI) and adjuvant cisplatin. In some embodiments, the patient has been previously treated with neo-adjuvant carboplatin. In some embodiments, the patient has been previously treated with paclitaxel. In some embodiments, the patient has been previously treated with neo-adjuvant carboplatin and paclitaxel. In some embodiments, the patient has been previously treated with a checkpoint inhibitor (CPI), adjuvant cisplatin, neo-adjuvant carboplatin and paclitaxel. As shown in Figure 13, there are 2 out of 2 partial responses and they had prior lines of therapy. Also, as shown in Figure 14, there are 3 previously treated patients with stable disease >7 months. In some embodiments, the patient has been previously treated with adjuvant cisplatin. In some embodiments, the patient has been previously treated with cisplatin. In some embodiments, the patient has been previously treated with Atezolizumab and / or ipatasertib. In some embodiments, the patient has been previously treated with carboplatin, paclitaxel and / or bevacizumab. In some embodiments, the patient has been previously treated with neo-adjuvant carboplatin and / or paclitaxel. In some embodiments, the patient has been previously treated with adjuvant cisplatin, carboplatin / paclitaxel / bevacizumab, cisplatin, and / or Atezolizumab / ipatasertib. In some embodiments, the patient has been previously treated with neo-adjuvant carboplatin / paclitaxel, adjuvant cisplatin, carboplatin / paclitaxel / bevacizumab, and / or Atezolizumab / ipatasertib.

[0134] In some embodiments, the patient has been previously treated with Osimertinib. In some embodiments, the patient has been previously treated with carboplatin, pemetrexed and / or zimberelimab. In some embodiments, the patient has been previously treated with ABBV-637 and / or Osimertini. In some embodiments, the patient has been previously treated with pemetrexed and / or pembrolizumab. In some embodiments, the patient has been previously treated with Bevacizumab. In some embodiments, the patient has been previously treated with docetaxel. In some embodiments, the patient has been previously treated with SGN-STNV. In some embodiments, the patient has been previously treated with 5 Fluorouracil and / or mitomycin C. In some embodiments, the patient has been previously treated with carboplatin and / or paclitaxel. In some embodiments, the patient has been previously treated with Leucovorin calcium, fluorouracil and / or oxaliplatin. In some embodiments, the patient has been previously treated with Osimertinib, carboplatin / pemetrexed / zimberelimab, and / or ABBV-637 / Osimertinib. In some embodiments, the patient has been previously treated with pemetrexed / pembrolizumab, Bevacizumab, docetaxel and / or SGN-STNV. In some embodiments, the patient has been previously treated with 5 Fluorouracil / mitomycin C, carboplatin / paclitaxel, and / or Leucovorin calcium / fluorouracil / oxaliplatin.

[0135] In some embodiments, the patient has a histologically or cytologically confirmed malignant solid tumor associated with Nectin-4 expression, including, for example, urothelial (transitional cell) carcinoma; head and neck squamous cell carcinoma; non-small cell lung cancer; ovarian cancer; breast cancer; gastric cancer; or esophageal carcinoma. In some embodiments, the patient is a urothelial (transitional cell) carcinoma patient. In some embodiments, the patient is a head and neck squamous cell carcinoma patient. In some embodiments, the patient is a non-small cell lung cancer patient. In some embodiments the patient is an ovarian cancer patient. In some embodiments, the patient is a breast cancer patient. In some embodiments, the patient is a gastric cancer patient. In some embodiments, the patient is an esophageal carcinoma patient. In some embodiments, the patient is a cervical carcinoma patient, such as a cervical squamous cell carcinoma patient (e.g. Stage IV). In some embodiments, the patient is an anal squamous cell carcinoma patient (e.g. Stage IIIC). In some embodiments, the patient is a NSCLC adenocarcinoma patient (e.g. Stage IV).

[0136] In some embodiments, the patient is an anal squamous cell carcinoma patient (e.g. Stage III or IIIC).

[0137] In some embodiments, the patient has previously received one or more treatment(s) for the cancer. In some embodiments, the patient has been previously untreated for the cancer. In some embodiments, the patient has locally advanced or metastatic disease. In some embodiments, the patient has advanced malignancy which is associated with Nectin-4 expression. In some embodiments, the patient has locally advanced or metastatic disease that is refractory to standard therapy. In some embodiments, the patient has locally advanced or metastatic disease and there is no standard therapy judged to be appropriate or to provide clinical benefit to the patient. In some embodiments, the patient has radiographically documented metastatic or locally advanced disease in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

[0138] In some embodiments, the patient has non-measurable disease. In some embodiments, the patient has measurable disease.

[0139] In some embodiments, the patient has renal insufficiency. In some embodiments, renal insufficiency refers to estimated glomerular filtration rate (eGFR) >30 to 59 mL / min by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Renal insufficiency may be determined by direct measurement of renal function (e.g. radioisotope or 24-hour urine).

[0140] In some embodiments, the patient is at least 18 years of age.

[0141] In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (Score 0: Fully active, able to carry on all pre-disease performance without restriction; Score 1 : Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work).

[0142] In some embodiments, the patient has acceptable organ function, and one or more of the following conditions:

[0143] Renal function with estimated glomerular filtration rate (eGFR) >60 mL / min by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation;

[0144] Total bilirubin < 1.5 x upper limit of normal (ULN);

[0145] Aspartate aminotransferase (AST) < 2.5 * ULN or < 5 * ULN in the presence of liver metastases; Alanine aminotransferase (ALT) < 2.5 x ULN or < 5 x ULN in the presence of liver metastases; and

[0146] International normalized ratio < 1.5 or < institutional ULN. In some embodiment, the patient has been on anticoagulants for >6 months with stable levels of anti coagulation.

[0147] In some embodiments, the patient has renal impairment.

[0148] In some embodiments, the patient has renal impairment with an eGFR >30 to 59 mL / min by the CKD-EPI equation.

[0149] In some embodiments, the patient has acceptable hematologic function, and one or more of the following conditions: Hemoglobin > 9 g / dL;

[0150] Absolute neutrophil count (ANC) > 1500 cells / mm3; and Platelet count > 75,000 cells / mm3.

[0151] In some embodiments, the patient is female, who is not lactating or pregnant as documented by a negative serum pregnancy (beta-human chorionic gonadotropin) test and a negative urine pregnancy test within 72 hours before the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0152] In some embodiments, the patient is not or has not been administered any cytotoxic, small molecule, or other systemic chemotherapy within 14 days prior to the first dose the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0153] In some embodiments, the patient is not or has not been administered any immunotherapy, including monoclonal antibodies, within 28 days or 5 half-lives of the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0154] In some embodiments, the patient is not or has not been administered any cell-based therapy, including chimeric antigen receptor T cell therapy, within 60 days of the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0155] In some embodiments, the patient is not or has not been administered any experimental treatment(s), other than systemic anticancer therapies, within 28 days or 5 half-lives of the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein. In some embodiments, the patient is not or has not been administered any radiation therapy within 28 days of the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0156] In some embodiments, the patient has not had an invasive surgery, excluding placement of vascular access, within 28 days of the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein. In some embodiments, the patient has not had a minimally invasive (laparoscopic, interventional radiology, or robotic) surgery within 14 days of the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0157] In some embodiments, the patient is not having or has not been administered any CD137 targeted therapy prior to the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0158] In some embodiments, the patient has not had any red blood cell transfusions, platelet transfusions, or growth factors within 14 days of the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0159] In some embodiments, the patient has renal impairment, who has received erythropoietic growth factors within 4 weeks of the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0160] In some embodiments, the patient does not have prior treatment-related toxicities that have not resolved to Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 prior to the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0161] In some embodiments, the patient does not have a significant medical condition such as conditions affecting the skin including autoimmune conditions, for example, moderate / severe and active eczema or psoriasis. In some embodiments, the patient does not have an active uncontrolled systemic infection. In some embodiments, the patient does not have organ system dysfunction, including, for example, severe ascites, coagulopathy, or encephalopathy. In some embodiments, the patient does not have any gastrointestinal, skin, or pulmonary co-morbidities.

[0162] In some embodiments, the patient does not have a history of a cerebral vascular event, including, for example, stroke or transient ischemic attack, unstable angina, myocardial infarction, or signs or symptoms of New York Heart Association Class III to IV heart failure documented within 6 months prior to the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0163] In some embodiments, the patient does not have mean resting QTc (e.g., QTcF) > 470 msec on triplicate electrocardiograms (ECGs).

[0164] In some embodiments, a patient does not have any factors that increase the risk of QTc prolongation or the risk of arrhythmic events, including, for example, severe heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, unexplained sudden death under 40 years of age, or any concomitant medication use known to prolong the QT interval and / or cause Torsades de Pointes.

[0165] In some embodiments, the patient does not have any clinically important abnormalities in rhythm, conduction, or morphology of resting ECGs, including, for example, such as complete left bundle branch block or third-degree heart block not controlled by pacemaker or otherwise.

[0166] In some embodiments, the patient does not have uncontrolled diabetes with glycosylated hemoglobin >8%.

[0167] In some embodiments, the patient does not have uncontrolled symptomatic brain metastases.

[0168] In some embodiments, the patient has treated brain metastases, wherein the patient has had no progression for at least 4 weeks after central nervous system-directed treatment.

[0169] In some embodiments, the patient does not have uncontrolled hypertension (with repeated measurement of systolic blood pressure [BP] >160 mmHg or diastolic BP >100 mmHg that is not responsive to intervention).

[0170] In some embodiments, the patient does not have an HIV infection or acquired immune deficiency syndrome. In some embodiments, the patient has HIV infection and meets all the following criteria: a. CD4+ T-cell (CD4+) counts >350 cells / uL; b. on established antiretroviral therapy (ART) for at least 4 weeks; and c. HIV viral load <400 copies / mL.

[0171] In some embodiments, the patient does not have an active hepatitis B virus (HBV) infection. In some embodiments, the patient has a controlled (treated) hepatitis B virus (HBV) infection, wherein an anti-viral therapy for HBV is administered at least 1 month prior to the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0172] In some embodiments, the patient has a controlled (treated) hepatitis B virus (HBV) infection, wherein HBV viral load is < 2000 lU / mL (104 copies / mL) prior to the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0173] In some embodiments, the patient has a controlled (treated) hepatitis B virus (HBV) infection with viral load <2000 HJ / mL (104 copies / mL), and continues receiving the same antiviral HBV therapy throughout treatment.

[0174] In some embodiments, the patient does not have an active hepatitis C virus (HCV) infection.

[0175] In some embodiments, the patient has received HCV treatment and has a sustained virologic response at 12 weeks (SVR12) or 24 weeks (SVR24) for 4 weeks prior to the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0176] In some embodiments, the patient does not have any prior or concurrent malignancy within 3 years prior to the first dose of a pharmaceutical composition of the invention. In some embodiments, the patient does not have any evidence of residual disease from a previously diagnosed malignancy prior to the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0177] In some embodiments, the patient has adequately managed a prior or concurrent malignancy with curative-intent treatment for basal cell carcinoma, squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, cervical carcinoma in situ, melanoma in situ, or ductal carcinoma in situ of the breast.

[0178] In some embodiments, the patient has not received any live or attenuated vaccine within 30 days of the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein. In some embodiments, the patient is not diagnosed with or does not have a clinically relevant immunodeficiency.

[0179] In some embodiments, the patient is not on use of prednisone >10 mg daily or equivalent or another strong systemic immunosuppressant, including, for example, calcineurin inhibitors, anti-proliferative agents, mTOR [mammalian target of rapamycin] inhibitors.

[0180] In some embodiments, the patient has not received intravenous anti-infective treatment within 14 days prior to the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0181] In some embodiments, the patient does not have a fever not attributable to the underlying illness within 14 days prior to the first dose of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0182] In some embodiments, the patient has not had any Prior organ or hematopoietic cell transplant, including allogeneic hematopoietic cell transplant.

[0183] In some embodiments, the patient does not have an autoimmune disease.

[0184] In some embodiments, the patient has well-controlled diabetes mellitus, alopecia, well-controlled thyroid disease, or vitiligo.

[0185] In some embodiments, the patient does not have an active interstitial lung disease or pneumonitis. In some embodiments, the patient does not have a history of interstitial lung disease or pneumonitis requiring treatment with steroids or other immunosuppressive medications. In some embodiments, the patient is an adult human.

[0186] Methods and uses

[0187] For any of the methods or uses described herein, a pharmaceutical composition comprising BT7480, or a pharmaceutically acceptable salt thereof, can be used in place of the BT7480, or a pharmaceutically acceptable salt thereof. As examples, the present invention provides the following:

[0188] The method of the invention as described herein comprising administering a pharmaceutical composition comprising the BT7480 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a human patient comprising administering to the patient the pharmaceutical composition.

[0189] A pharmaceutical composition comprising BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer comprising administering to the patient the pharmaceutical composition.

[0190] In some embodiments, the pharmaceutical composition comprises: the BT7480, or a pharmaceutically acceptable salt thereof; Tris base; mannitol; and sodium hydroxide.

[0191] In some embodiments, the pharmaceutical composition comprises about 66 mg BT7480, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.1 mg Tris base per mg of BT7480 or a pharmaceutically acceptable thereof. In some embodiments, the pharmaceutical composition comprises about 6.6 mg Tris base. In some embodiments, the pharmaceutical composition comprises about 0.4 mg mannitol per mg of BT7480 or a pharmaceutically acceptable thereof. In some embodiments, the pharmaceutical composition comprises about 26.4 mg mannitol. In some embodiments, the amount of sodium hydroxide provides a pH of about 6 to about 8. In some embodiments, the amount of sodium hydroxide provides a pH of about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, 7.9, or about 8.0. In some embodiments, the amount of sodium hydroxide provides a pH of about 7.0 to about 8.0 when the pharmaceutical composition is reconstituted in water. In some embodiments, the amount of sodium hydroxide provides a pH of about 7.0 to about 7.5 when the pharmaceutical composition is reconstituted in water. In some embodiments, the amount of sodium hydroxide provides a pH of about 7.0 to about 7.2 when the pharmaceutical composition is reconstituted in water. In some embodiments, the amount of sodium hydroxide provides a pH of about 7.0 or about 7.5. In some embodiments, the pharmaceutical composition comprises: about 66 mg BT7480 or a pharmaceutically acceptable salt thereof; about 6.6 mg Tris base; about 26.4 mg mannitol; and sodium hydroxide, wherein the amount of sodium hydroxide provides a pH of about 7.0 to about 7.5 when the pharmaceutical composition is reconstituted in water.

[0192] In some embodiments, the pharmaceutical composition is an aqueous pharmaceutical composition. In some embodiments, the pharmaceutical composition has been reconstituted in water from a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition is in powder form. In some embodiments, the solid pharmaceutical composition is a lyophilized powder. In some embodiments, a solid pharmaceutical composition is a sterile lyophilized powder. In some embodiments, the pharmaceutical composition comprises about 60 mg / mL BT7480 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 6 mg / mL Tris base. In some embodiments, the pharmaceutical composition comprises about 24 mg / mL mannitol. The aqueous pharmaceutical composition can be any pH described herein for when the pharmaceutical composition of the invention is reconstituted in water. For example, the aqueous pharmaceutical composition can be at a pH of about 7.0 to about 8.0. As a further example, the aqueous pharmaceutical composition can be at a pH of about 7.0 to about 7.5. As yet a further example, the aqueous pharmaceutical composition can be at a pH of about 7.0 to about 7.2. In some embodiments, the pharmaceutical composition is at a volume of about 1.1 mL. In some embodiments, the pharmaceutical composition comprises: about 60 mg / mL BT7480 or a pharmaceutically acceptable salt thereof; about 6 mg / mL Tris base; about 24 mg / mL mannitol; sodium hydroxide; and water, wherein the pharmaceutical composition is at a pH of about 7.0 to about 7.5. In some embodiments, the pharmaceutical composition further comprises sodium chloride.

[0193] The pharmaceutical composition may be provided in a 4R injection vial. The 4R injection vial may contain or comprise a solid pharmaceutical composition as described herein. The 4R injection vial may contain 66 mg BT7480, or a pharmaceutically acceptable salt thereof, Tris base, mannitol, and sodium hydroxide. The aqueous pharmaceutical composition described herein may comprise BT7480, or a pharmaceutically acceptable salt thereof, Tris base, mannitol, sodium hydroxide, and water. The aqueous pharmaceutical composition may comprise BT7480 at a concentration of 60 mg / mL, Tris base, mannitol, sodium hydroxide, and water. The 4R injection vial may contain or comprise an aqueous pharmaceutical composition as described herein. The 4R injection vial may contain or comprise 1.1 mL aqueous pharmaceutical composition, comprising BT7480 at a concentration of 60 mg / mL, Tris base, mannitol, sodium hydroxide, and water.

[0194] In some embodiments, the aqueous pharmaceutical composition comprises BT7480, or a pharmaceutically acceptable salt thereof, Tris base, mannitol, sodium hydroxide, sodium chloride, and water. In some embodiments, the aqueous pharmaceutical composition is further diluted into 0.9% saline. For example, the aqueous pharmaceutical composition comprising BT7480 (or a pharmaceutically acceptable salt thereof) at a concentration of 60 mg / mL, Tris base, mannitol, sodium hydroxide, and water is further diluted into 0.9% saline. The pharmaceutical composition may be provided in an infusion bag. For example, an infusion bag may contain or comprise BT7480, or a pharmaceutically acceptable salt thereof, Tris base, mannitol, sodium hydroxide, sodium chloride, and water. The infusion bag may contain or comprise the aqueous pharmaceutical composition as described herein.

[0195] In some embodiments, the aqueous pharmaceutical composition comprises an acceptable vehicle or solvent. In some embodiments, the acceptable vehicle or solvent is selected from sterile water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In some embodiments, the acceptable vehicle or solvent is sterile water. In some embodiments, the acceptable vehicle or solvent is a sterile injectable medium.

[0196] The pharmaceutical composition may comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0197] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the pharmaceutical compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as 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, the pharmaceutically acceptable carrier, adjuvant, or vehicle comprises a buffering agent. In some embodiments, the buffering agent comprises or is histidine. In some embodiments, the buffering agent comprises or is sodium hydroxide. In some embodiments, the buffering agent comprises or is hydrochloric acid. In some embodiments, the buffering agent comprises or is Tris base (Tromethamine).

[0198] In some embodiments, the pharmaceutically acceptable carrier, adjuvant, or vehicle comprises a stabilizer or cryoprotectant. In some embodiments, the stabilizer or cryoprotectant is or comprises dimethyl sulfoxide (DMSO). In some embodiments, the stabilizer or cryoprotectant is or comprises ethylene glycol. In some embodiments, a stabilizer or cryoprotectant is or comprises glycerol. In some embodiments, the stabilizer or cryoprotectant is or comprises propylene glycol. In some embodiments, the stabilizer or cryoprotectant is or comprises 2-methyl-2, 4-pentanediol (MPD). In some embodiments, the stabilizer or cryoprotectant is or comprises trehalose. In some embodiments, the stabilizer or cryoprotectant is or comprises formamide. In some embodiments, the stabilizer or cryoprotectant is or comprises proline. In some embodiments, the stabilizer or cryoprotectant is or comprises glycerol 3-phosphate. In some embodiments, the stabilizer or cryoprotectant is or comprises sorbitol. In some embodiments, the stabilizer or cryoprotectant is or comprises diethyl glycol. In some embodiments, the stabilizer or cryoprotectant is or comprises sucrose.

[0199] In some embodiments, the pharmaceutically acceptable carrier, adjuvant, or vehicle comprises a an isotonicity adjusting agent. In some embodiments, the isotonicity adjusting agent is or comprises sodium chloride, dextrose, calcium chloride, or a combination thereof. In some embodiments, the isotonicity adjusting agent is or comprises dextrose. In some embodiments, the isotonicity adjusting agent is or comprises sodium chloride. In some embodiments, the isotonicity adjusting agent is a combination of sodium chloride and dextrose. In some embodiments, the solid pharmaceutical composition comprises:

[0200] BT7480, or a pharmaceutically acceptable salt thereof; about 0.1 mg Tris base per mg of BT7480, or a pharmaceutically acceptable thereof; about 0.4 mg mannitol per mg of BT7480, or a pharmaceutically acceptable thereof; and sodium hydroxide, wherein the amount of sodium hydroxide provides a pH of about 7.0 to 7.5 when the solid pharmaceutical composition is reconstituted in water.

[0201] In some embodiments, the solid pharmaceutical composition, which is a lyophilized powder, comprises: about 66 mg BT7480, or a pharmaceutically acceptable salt thereof; about 6.6 mg Tris base; about 26.4 mg mannitol; and sodium hydroxide, wherein the amount of sodium hydroxide provides a pH of about 7.0 to

[0202] 7.5 when the solid pharmaceutical composition is reconstituted in water.

[0203] In some embodiments, the aqueous pharmaceutical composition comprises: about 60 mg / mL BT7480, or a pharmaceutically acceptable salt thereof; about 6 mg / mL Tris base; about 24 mg / mL mannitol; sodium hydroxide; and water, wherein the aqueous pharmaceutical composition is at a pH of about 7.0 to 7.5.

[0204] In some embodiments, the aqueous pharmaceutical composition is at a volume of about 1.1 mL, and comprises: about 60 mg / mL BT7480, or a pharmaceutically acceptable salt thereof; about 6 mg / mL Tris base; about 24 mg / mL mannitol; sodium hydroxide; and water, wherein the aqueous pharmaceutical composition is at a pH of about 7.0 to 7.5.

[0205] In some embodiments, the aqueous pharmaceutical composition is prepared by reconstituting a solid pharmaceutical composition of the invention in water. In some embodiments, the aqueous pharmaceutical composition is prepared by dissolving the solid pharmaceutical composition as described herein in an injectable medium (e.g., 0.9% w / v saline). In some embodiments, the aqueous pharmaceutical composition is prepared by reconstituting the solid pharmaceutical composition as described herein in water, followed by dilution into 0.9% w / v saline. In some embodiments, the aqueous pharmaceutical composition is diluted into a 0.9% w / v saline IV bag for IV infusion.

[0206] The invention further provides BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a human patient comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof. The method of treating may be any suitable method described herein.

[0207] The invention further provides BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof. In some embodiments, the maintaining or reducing the volume of the solid tumor treats the cancer. The method of maintaining or reducing may be any suitable method described herein.

[0208] The invention further provides use of BT7480 or a pharmaceutical acceptable salt thereof, in the manufacture of a medicament for use in a method of treating a cancer in a human patient comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof. The method of treating may be any suitable method described herein. In some embodiments, the medicament is a pharmaceutical composition comprising BT7480 or a pharmaceutical acceptable salt thereof. The pharmaceutical composition may be any pharmaceutical composition described herein.

[0209] The invention further provides use of BT7480 or a pharmaceutical 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 human patient suffering from a cancer comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof. In some embodiments, the maintaining or reducing the volume of the solid tumor treats the cancer. The method of maintaining or reducing may be any suitable method described herein. In some embodiments, the medicament is a pharmaceutical composition comprising BT7480 or a pharmaceutical acceptable salt thereof. The pharmaceutical composition may be any pharmaceutical composition described herein. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein is administered to the patient at a frequency of once every 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, there are about 6 hours between two administrations of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to the patient. In some embodiments, there are about 12 hours, about 18 hours, or about 24 hours between two administrations of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to the patient. In some embodiments, there are about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 84 hours, about 96 hours, or about 108 hours between two administrations of the BT7480, or a pharmaceutically acceptable salt thereof, or the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to the patient. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient at a frequency of once a week. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient at a frequency of once every two weeks. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient at a frequency of once every three weeks. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient at a frequency of once every four weeks. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to the patient at a frequency of once a month.

[0210] In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered in a 4-week treatment cycle, i.e., a 28-day treatment cycle. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered at a frequency of once a week in a 28-day treatment cycle, for example, on days 1, 8, 15, and 22. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered at a frequency of once every two weeks in a 28-day treatment cycle, for example, on days 1 and 15. In some embodiments, the aqueous pharmaceutical composition as described herein is administered. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered in a 3-week treatment cycle, i.e., a 21-day treatment cycle. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered in week 1 and week 2, but not in week 3, of a 21-day treatment cycle. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered on days 1 and 8 of a 21-day treatment cycle. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered at a frequency of once a week in a 21-day treatment cycle. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition administered on days 1, 8, and 15 in a 21-day treatment cycle.

[0211] As described herein, the present invention provides a method of treating a human cancer in a patient, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof. The cancer may be a solid tumor. The treating may result in the maintenance or reduction of the volume of the solid tumor. As described herein, the present invention also provides a method of maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof. In the methods of the invention, the maintaining or reducing the volume of the solid tumor may treat the cancer.

[0212] “Maintenance” or “maintaining” the volume of the solid tumor refers to the disease not progressing.

[0213] In some embodiments, maintaining the volume of the solid tumor refers to an increase in the volume of the solid 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 the solid tumor refers to the volume of the solid tumor being unchanged.

[0214] In some embodiments, the volume of the solid tumor is reduced by at least 1%, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30%. The volume may be reduced by at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100%. The volume of the solid tumor may be reduced by at least 30%.

[0215] In some embodiments, the volume of the solid tumor may be measured and compared to the volume of the solid tumor at the first administration. In some embodiments, the maintenance or reduction of the volume of the solid tumor is relative to the volume of the solid tumor at the first administration.

[0216] In some embodiments, reference to the volume of the solid tumor may refer to a sum of volumes of two or more solid 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.

[0217] In some embodiments, reference to the volume of the solid tumor may refer to an average volume of two or more solid 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 solid tumors measured.

[0218] Thus, in some embodiments, maintaining or reducing the volume of the solid tumor 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 the patient.

[0219] Thus, in some embodiments, maintaining the volume of the 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 the solid tumor refers to the sum or average volume of the tumors being unchanged.

[0220] 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%.

[0221] Optionally, the change in the sum or average volume of the solid tumor is a change relative to the sum or average volume of the solid tumor at the first administration.

[0222] The volume of the solid 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 solid tumor of greater than a 75% increase in the volume of the solid tumor relative to the volume of the solid tumor at the first administration. In some embodiments, disease progression refers to a measurement of the length of an axis of the solid tumor (or the sum or average of two or more tumors) of greater than 20%. Optionally, the volume of the solid tumor is maintained or reduced for 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. Optionally, the volume of the solid tumor is maintained or reduced for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, or at least 36 weeks. The volume of the tumor may be measured at the time point and compared to the volume of the tumor at the first administration.

[0223] In some embodiments, the volume of the solid tumor may be measured by determining the length of an axis of the solid tumor. In some embodiments, the volume of the solid tumor may be measured by determining the length of the longest diameter of the solid tumor. In some embodiments, the volume of a solid tumor 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 axis or diameter of a solid tumor corresponds to an increase in the volume of the solid tumor of approximately 75% (z.e. 1.23).

[0224] 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.

[0225] In other embodiments, the volume of a solid tumor may be measured by volumetric assessment e.g. using a three-dimensional scan such as a CT scan or MRI scan.

[0226] In some embodiments, the treatment of the cancer or of the solid tumor may cause a complete response of the cancer or the solid tumor to said treatment. In some embodiments, a complete response is 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. In some embodiments, a partial response is 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 the cancer or the solid tumor may result in stable disease. In some embodiments, stable disease is 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.

[0227] In some embodiments, the treating results in the volume of the tumor being no greater than 20% greater than the volume of the tumor at the first administration. In some embodiments, the treating results in the volume of the tumor being no greater than 15% greater than the volume of the tumor at the first administration. In some embodiments, the treating results in the volume of the tumor being no greater than 10% greater than the volume of the tumor at the first administration.

[0228] In some embodiments, the treating results in the volume of the tumor being no greater than 20% greater than the volume of the tumor at the first administration and the volume of the tumor being no less than 30% less than the volume of the tumor at the first administration. In some embodiments, the treating results in the volume of the tumor being no greater than 15% greater than the volume of the tumor at the first administration and the volume of the tumor being no less than 25% less than the volume of the tumor at the first administration. In some embodiments, the treating results in the volume of the tumor being no greater than 10% greater than the volume of the tumor at the first administration and the volume of the tumor being no less than 20% less than the volume of the tumor at the first administration.

[0229] In some embodiments, volume of a solid tumor is measured in accordance with the response evaluation criteria in solid tumors (RECIST) version 1.1 as described in Example 1.

[0230] In some embodiments, the treating results in the patient having stable disease (SD) as defined in the response evaluation criteria in solid tumors (RECIST) version 1.1 as described in Example 1.

[0231] In some embodiments, the treating results in the patient having a partial response (PR) as defined in the response evaluation criteria in solid tumors (RECIST) version 1.1 as described in Example 1.

[0232] In some embodiments, the treating causes the cancer (e.g. solid tumor) to disappear. The treating may cause all the target lesions to disappear. The treating may cause all the non-target lesions to disappear. The treating may cause all the target and non-target lesions to disappear. Optionally, there are no new lesions. In some embodiments, the treating results in the patient having a complete response (CR) as defined in the response evaluation criteria in solid tumors (RECIST) version 1.1 as described in Example 1.

[0233] In some embodiments, disease progression (also referred to as progressive disease (PD)) is as defined in the response evaluation criteria in solid tumors (RECIST) version 1.1 as described in Example 1.

[0234] In some embodiments, the volume of the solid tumor is measured by determining the sum of diameters. The volume of the solid tumor may be measured by determining the sum of diameters and comparing to the sum of diameters at the first administration (e.g. % change). The “sum of diameters” may be calculated in accordance with the response evaluation criteria in solid tumors (RECIST) version 1.1 as described in Example 1.

[0235] The “volume of the tumor at the first administration” and “sum diameters at the first administration” may be determined as close as possible to treatment start and no more than 28 days prior to the first dose.

[0236] In some embodiments, the volume of the solid tumor is maintained or reduced when measured at at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, or at least 36 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the volume of the solid tumor is maintained when measured at at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, or at least 36 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the volume of the solid tumor is reduced when measured at at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, or at least 36 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the solid tumor is maintained or reduced when measured at at least 4 weeks, after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the solid tumor is maintained or reduced when measured at at least 8 weeks, after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the solid tumor is maintained or reduced when measured at at least 12 weeks, after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the solid tumor is maintained or reduced when measured at at least 16 weeks, after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the solid tumor is maintained or reduced when measured at at least 36 weeks, after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the solid tumor is maintained when measured at at least 16 weeks, after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the solid tumor is maintained when measured at at least 28 weeks, after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the solid tumor is maintained when measured at at least 7 months, after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the solid tumor is maintained when measured at at least 36 weeks, after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration.

[0237] In some embodiments, the solid tumor is maintained when measured at at least 8 months, after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the solid tumor is maintained when measured at at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 52 weeks, or at least 56 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The solid tumor may be NSCLC. The solid tumor may be SCC of anus.

[0238] The methods of the present invention can comprise administering a therapeutically effective amount of BT7480, or a pharmaceutical acceptable salt thereof. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, for example reducing or maintaining the volume of a solid tumor.

[0239] In some embodiments, the treating results in an increase in the number of activated CD4 T cells in the blood of the human patient. Activated CD4 T cells have been shown to increase following BT7480 treatment (see Example 3 and Figures 8 A, 9, 15 A, 17 and 18). The number of activated CD4 T cells may be measured by determining the number of FOXP3+CD25+CD4+ T cells. The number of FOXP3+CD25+CD4+ T cells may be determined by flow immunophenotyping. In some embodiments, the number of FOXP3+CD25+CD4+ T cells is increased by at least 1.1 -fold, at least 1.2-fold, at least 1.3 -fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 10-fold. In some embodiments, the number of FOXP3+CD25+CD4+ T cells is increased by up to 50- fold, up to 30-fold or up to 15-fold. In some embodiments, the number of FOXP3+CD25+CD4+ T cells is increased by between 1.1-fold and 50-fold, between 1.1 -fold and 30-fold, or between 1.5-fold and 30-fold. In some embodiments, the number of FOXP3+CD25+CD4+ T cells are increased when compared to the number of FOXP3+CD25+CD4+ T cells at the first administration. In some embodiments, the number of FOXP3+CD25+CD4+ T cells are increased when measured at at least 12 hours, at least 24 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, or at least 16 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the number of FOXP3+CD25+CD4+ T cells at the first administration. In some embodiments, the number of FOXP3+CD25+CD4+ T cells are increased when measured at at least 24 hours after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the number of FOXP3+CD25+CD4+ T cells at the first administration. In some embodiments, the number of FOXP3+CD25+CD4+ T cells are increased when measured at at least 2 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the number of FOXP3+CD25+CD4+ T cells at the first administration. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered in a 4-week treatment cycle, and the number of FOXP3+CD25+CD4+ T cells are increased in the first or second treatment cycle. In some embodiments, the number of FOXP3+CD25+CD4+ T cells are increased in patients with disease control when compared to the number of FOXP3+CD25+CD4+ T cells in patients with non-disease control. In some embodiments, the number of FOXP3+CD25+CD4+ T cells are increased in patients with disease control at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, at least 3-fold, at least 4-fold, or at least 5-fold when compared to the number of FOXP3+CD25+CD4+ T cells in patients with non-disease control. In some embodiments, the number of FOXP3+CD25+CD4+ T cells are increased in patients with disease control at least 1.5-fold when compared to the number of FOXP3+CD25+CD4+ T cells in patients with non- disease control. In some embodiments, the number of FOXP3+CD25+CD4+ T cells are increased in patients with disease control up to 10-fold, up to 15-fold, or up to 15-fold when compared to the number of FOXP3+CD25+CD4+ T cells in patients with non-disease control. In some embodiments, the number of FOXP3+CD25+CD4+ T cells are increased in patients with disease control between 1.1 -fold and 15-fold when compared to the number of FOXP3+CD25+CD4+ T cells in patients with non-disease control. In some embodiments, the number of FOXP3+CD25+CD4+ T cells in patients with disease control and the number of FOXP3+CD25+CD4+ T cells in patients with non-disease control are measured at the same period of time from first administration. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered in a 4-week treatment cycle, and the number of FOXP3+CD25+CD4+ T cells are increased in patients with disease control compared to the number of FOXP3+CD25+CD4+ T cells in patients with non-disease control in the first or second treatment cycle. For example, the number of FOXP3+CD25+CD4+ T cells are increased in patients with disease control compared to the number of FOXP3+CD25+CD4+ T cells in patients with non-disease control when measured at cycle 1 day 8, cycle 1 day 15, or cycle 2 day 1. “Disease control” refers to a lack of disease progression. In some embodiments, disease control means the best overall response (BOR) is a partial response (PR) or stable disease (SD). In some embodiments, the patient has a “partial response” if the volume of the tumor is at least 30% less than the volume of the tumor at the first administration. The partial response may be as defined in the response evaluation criteria in solid tumors (RECIST) version 1.1 as described in Example 1. Stable disease may be as defined in the response evaluation criteria in solid tumors (RECIST) version 1.1 as described in Example 1. “Non-disease control” refers to progressive disease (PD). In some embodiments, non-disease control means the BOR is progressive disease (PD). The PD may be as defined in the response evaluation criteria in solid tumors (RECIST) version 1.1 as described in Example 1.

[0240] In some embodiments, the treating results in an increase of the level of CXCL9 in the blood of the human patient. The level of CXCL9 has been shown to increase following BT7480 treatment (see Example 3 and Figures 8B, 15B, 17A and 19). The level of CXCL9 may be determined by Olink. Olink may be carried out according to manufacturer’s instructions. In some embodiments, the level of CXCL9 is increased by at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, or at least 5.5-fold. In some embodiments, the level of CXCL9 is increased by at least 1.5-fold, or at least 2-fold. In some embodiments, the level of CXCL9 is increased by up to 20-fold, up to 15-fold, up to 10- fold, or up to 5-fold. In some embodiments, the level of CXCL9 is increased by between 1.1- fold and 20-fold, between 1.1 -fold and 10-fold, or between 1.5-fold and 10-fold. In some embodiments, the level of CXCL9 is increased when compared to the level of CXCL9 at the first administration. In some embodiments, the level of CXCL9 is increased when measured at at least 50 days or at least 100 days after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of CXCL9 at the first administration. In some embodiments, the level of CXCL9 is increased when measured at at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of CXCL9 at the first administration. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered in a 4-week treatment cycle, and the level of CXCL9 is increased in the first or second treatment cycle. For example, the level of CXCL9 is increased when measured at cycle 1 day 8, cycle 1 day 15, or cycle 2 day 1.

[0241] In some embodiments, the treating results in an increase of the level of soluble CD 137 (sCD137) in the blood of the human patient. The level of sCD137 has been shown to increase following BT7480 treatment (see Example 3 and Figures 8B and 15B). The level of sCD137 may be determined by Olink. Olink may be carried out according to manufacturer’s instructions. In some embodiments, the level of sCD137 is increased by at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, at least 2.5-fold, at least 3 -fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, or at least 5.5- fold. In some embodiments, the level of sCD137 is increased by at least 1.5-fold, or at least 2- fold. In some embodiments, the level of sCD137 is increased by up to 20-fold, up to 15-fold, up to 10-fold, or up to 5-fold. In some embodiments, the level of sCD137 is increased by between 1.1 -fold and 20-fold, between 1.1 -fold and 10-fold, or between 1.5-fold and 10-fold. In some embodiments, the level of sCD137 is increased when compared to the level of sCD137 at the first administration. In some embodiments, the level of sCD137 is increased when measured at at least 50 days or at least 100 days after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of sCD137 at the first administration. In some embodiments, the level of sCD137 is increased when measured at at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of sCD137 at the first administration. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered in a 4-week treatment cycle, and the level of sCD137 is increased in the first or second treatment cycle.

[0242] In some embodiments, the treating results in an increase of the level of CXCL10 in the blood of the human patient. The level of CXCL10 has been shown to increase following BT7480 treatment (see Example 3 and Figures 15B and 16). The level of CXCL10 may be determined by Olink. Olink may be carried out according to manufacturer’s instructions. In some embodiments, the level of CXCL10 is increased by at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, at least 2.5-fold, at least 3 -fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, or at least 5.5- fold. In some embodiments, the level of CXCL10 is increased by at least 1.5-fold, or at least 2- fold. In some embodiments, the level of CXCL10 is increased by up to 20-fold, up to 15-fold, up to 10-fold, or up to 5-fold. In some embodiments, the level of CXCL10 is increased by between 1.1 -fold and 20-fold, between 1.1 -fold and 10-fold, or between 1.5-fold and 10-fold. In some embodiments, the level of CXCL10 is increased when compared to the level of CXCL10 at the first administration. In some embodiments, the level of CXCL10 is increased when measured at at least 50 days or at least 100 days after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of CXCL10 at the first administration. In some embodiments, the level of CXCL10 is increased when measured at at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of CXCL10 at the first administration. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered in a 4-week treatment cycle, and the level of CXCL10 is increased in the first or second treatment cycle. For example, the level of CXCL10 is increased when measured at cycle 2 day 15.

[0243] In some embodiments, the treating results in an increase of the level of IFN-gamma in the blood of the human patient. The level of IFN-gamma has been shown to increase following BT7480 treatment (see Example 3 and Figures 15B). The level of IFN-gamma may be determined by Olink. Olink may be carried out according to manufacturer’s instructions. In some embodiments, the level of IFN-gamma is increased by at least 1.1 -fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, or at least 2.5- fold. In some embodiments, the level of IFN-gamma is increased by up to 20-fold, up to 15-fold, up to 10-fold, or up to 5-fold. In some embodiments, the level of IFN-gamma is increased by between 1.1-fold and 20-fold, between 1.1-fold and 10-fold, or between 1.2-fold and 10-fold. In some embodiments, the level of IFN-gamma is increased when compared to the level of IFN- gamma at the first administration. In some embodiments, the level of IFN-gamma is increased when measured at at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of IFN-gamma at the first administration. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered in a 4-week treatment cycle, and the level of IFN-gamma is increased in the first or second treatment cycle. For example, the level of IFN-gamma is increased when measured at cycle 2 day 15.

[0244] In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of up to about 10 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.002 mg / kg to about 7.5 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.02 mg / kg to about 7.5 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.05 mg / kg to about 7.5 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.1 mg / kg to about 7.5 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.15 mg / kg to about 7.5 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.02 to about 6 mg / kg, about 0.05 to about 6 mg / kg, about 0.15 to about 6 mg / kg, about 0.3 to about 6 mg / kg, about 0.6 to about 6 mg / kg, about 1.3 to about 6 mg / kg, or about 2.6 to about 6 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.002 mg / kg, about 0.006 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.15 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.3 mg / kg, about 2.0 mg / kg, about 2.6 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg, about 3.9 mg / kg, about 4.25 mg / kg, about 5.0 mg / kg, about 5.75 mg / kg, about 6.0 mg / kg, about 6.5 mg / kg, about 7.0 mg / kg, or about 7.5 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about up to about 7.5 mg / kg, about 0.002 to about 7.5 mg / kg, about 0.01 to about 7.5 mg / kg, about 0.1 to about 7.5 mg / kg, about 0.3 to about 7.5 mg / kg, about 0.6 to about 6.0 mg / kg, about 1.3 to about 5.5 mg / kg, about 2.6 to about 5.75 mg / kg, or about 2.6 to about 5.0 mg / kg, or about 3.0 to about 4.0 mg / kg.

[0245] In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 2.0 to about 4.0 mg / kg.

[0246] In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 3.0 to about 4.0 mg / kg.

[0247] In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.3 mg / kg to about 5.0 mg / kg, about 0.3 to about 3.5 mg / kg, about 0.3 to about 2.6 mg / kg, about 0.6 mg / kg to about 5.0 mg / kg, about 0.6 to about 3.5 mg / kg, about 0.6 to about 2.6 mg / kg, about 1.3 mg / kg to about 5.0 mg / kg, about 1.3 to about 3.5 mg / kg, or about 1.3 to about 2.6 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.3 to about 3.5 mg / kg, about 0.6 to about 3.5 mg / kg, about 1.3 to about 3.5 mg / kg, or about 2.6 to about 3.5 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 3.5 mg / kg. The dose may be administered at a frequency of once a week.

[0248] In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.3 mg / kg, about 0.6 mg / kg, about 1.3 mg / kg, about 2.6 mg / kg, or about 3.5 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 2.6 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 3.5 mg / kg. Cohorts 6-9 (0.3 to 2.6 mg / kg) are associated with the induction of CD4 T cell activation (see Example 3 and Figure 8A, Figure 15A and Figure 17A) and the increase in levels of, e.g., sCD137 and CXCL9 (see Figures 8B and 17A). There are partial responses in cervical cancer patients dosed at 0.6 mg / kg and 1.3 mg / kg (see Example 3 and Figure 13). There are also 3 patients with stable disease >5 months (see Figure 14 and Example 3). Two of the patients have NSCLC and were dosed at 0.6 mg / kg, and one patient has anal cancer and was dosed at 1.3 mg / kg.

[0249] In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.05 to about 7.5 mg / kg, about 0.05 to about 5.0 mg / kg, about 0.05 to about 4.25 mg / kg, or about 0.05 to about 3.9 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.05 to about 3.5 mg / kg. As set out in Figure 23, a best response of stable disease or partial response has been observed for doses from 0.05 mg / kg to 3.5 mg / kg.

[0250] In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.6 to about 7.5 mg / kg, about 0.6 to about 5.0 mg / kg, about 0.6 to about 4.25 mg / kg, or about 0.6 to about 3.9 mg / kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.6 to about 3.5 mg / kg.

[0251] In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.6 mg / kg or more, for example, about 0.6 to about 3.5 mg / kg. As can be seen in Figures 22 and 23, stable disease has been observed in particular for cohort 7 (0.6 mg / kg) upwards, and there are also two partial responses. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 1.3 to about 7.5 mg / kg, about 1.3 to about 5.0 mg / kg, about 1.3 to about 4.25 mg / kg, or about 1.3 to about 3.9 mg / kg.

[0252] In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 1.3 to about 3.5 mg / kg. As can be seen in Figure 25, terminal half-life at 1.3 to 3.5 mg / kg was approximately 13 to 18 hours, with minimal BT7480 accumulation at steady state (CID 15) following QW dosing. Furthermore, maximum induction of circulating immune activation markers sCD137, CXCL9 and CD4+ T cells was observed at doses of 1.3 mg / kg or higher, with no hook effect at higher doses (see Figure 26). In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is administered as a monotherapy.

[0253] In some embodiments, the methods of the invention comprise administering to the patient intravenously the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is administered by an IV injection. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is administered by an IV infusion. In some embodiments, the IV infusion of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is over about 5 to about 30 minutes. In some embodiments, the IV infusion of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is over about 30 to about 60 minutes. In some embodiments, an IV infusion of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is over about 55 to about 75 minutes. In some embodiments, an IV infusion of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is over about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, or about 90 minutes. In some embodiments, an IV infusion of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is over about 60 minutes. In some embodiments, an IV infusion of the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is over about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours.

[0254] Reference to “is over” in the context of IV infusion means that the IV infusion lasts for the specified length of time.

[0255] In some embodiments of the invention, the method of the invention further comprises administering to the patient a checkpoint inhibitor. As shown in, e.g. Figure 8B left hand graph and Figure 17A, dose-dependent increases of CXCL9 have been shown. CXCL9 is a predictor of checkpoint inhibitor response (such as PD-1), thus supporting the rationale for a combination therapy. In some embodiments, the checkpoint inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the checkpoint inhibitor (e.g. nivolumab) is administered at a frequency of once every two weeks. In some embodiments, nivolumab is administered at a dose of about 240mg. In some embodiments, nivolumab is administered at a frequency of once every two weeks and is administered at a frequency of once every two weeks. In some embodiments, the checkpoint inhibitor (e.g. nivolumab) is administered by an IV infusion. In some embodiments, the IV fusion is over about 25 to 45 minutes. In some embodiments, the IV infusion is over about 30 minutes. In some embodiments, nivolumab is administered to the patient at a dosage level of 240 mg once every 2 weeks and the IV infusion is over about 30 minutes. In some embodiments, nivolumab is diluted into 0.9% sodium chloride. In some embodiments, nivolumab is diluted into 5% dextrose. In some embodiments, nivolumab is diluted to a final concentration of about 1 mg / mL to about 10 mg / ml before infusion. In some embodiments, (i) the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein, and (ii) the checkpoint inhibitor (e.g. nivolumab) are administered separately. In some embodiments, (i) the BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein, and (ii) the checkpoint inhibitor (e.g. nivolumab) are administered sequentially. In some embodiments, the aqueous pharmaceutical composition as described herein is administered in combination with nivolumab by sequential infusions first with the aqueous pharmaceutical composition followed by nivolumab. In some embodiments, the aqueous pharmaceutical composition as described herein is administered about 1 hour before nivolumab is administered. In some embodiments, the aqueous pharmaceutical composition as described herein is administered about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, or about 50 minutes before nivolumab is administered.

[0256] As described herein, the present invention provides methods and uses in relation to treating cancer in a human patient, and methods and uses in relation to maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression, and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about up to about 7.5 mg / kg, about 0.002 to about 7.5 mg / kg, about 0.01 to about 7.5 mg / kg, about 0.1 to about 7.5 mg / kg, about 0.3 to about 7.5 mg / kg, about 0.6 to about 6.0 mg / kg, about 1.3 to about 5.5 mg / kg, about 2.6 to about 5.75 mg / kg, or about 2.6 to about 5.0 mg / kg, or about 3.0 to about 4.0 mg / kg. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is selected from the group consisting of urothelial (transitional cell) carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, ovarian carcinoma, breast carcinoma, gastric carcinoma, and esophageal carcinoma, and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about up to about 7.5 mg / kg. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is selected from the group consisting lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), esophageal cancer, gastric / upper gastrointestinal (GI) cancer, head and neck cancer (e.g. HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer), and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about up to about 7.5 mg / kg. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is selected from the group consisting lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), esophageal cancer, gastric / upper gastrointestinal (GI) cancer, head and neck cancer (e.g. HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer), and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.3 to about 3.5 mg / kg. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is selected from the group consisting lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), esophageal cancer, gastric / upper gastrointestinal (GI) cancer, head and neck cancer (e.g. HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer), and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.3 to about 3.5 mg / kg, wherein the treating results in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 8 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is selected from the group consisting lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), esophageal cancer, gastric / upper gastrointestinal (GI) cancer, head and neck cancer (e.g. HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer), and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.3 to about 3.5 mg / kg, wherein the treating results in the reduction of the volume of the solid tumor, wherein the volume of the solid tumor is reduced by at least 1% and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is selected from the group consisting lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), esophageal cancer, gastric / upper gastrointestinal (GI) cancer, head and neck cancer (e.g. HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer), and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.3 to about 3.5 mg / kg, wherein the treating results in the reduction of the volume of the solid tumor, wherein the volume of the solid tumor is reduced by at least 5% and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is selected from the group consisting lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), esophageal cancer, gastric / upper gastrointestinal (GI) cancer, head and neck cancer (e.g. HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer), and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.3 to about 3.5 mg / kg, wherein the treating results in the reduction of the volume of the solid tumor, wherein the volume of the solid tumor is reduced by at least 30% and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is cervical cancer (e.g. cervical squamous cell carcinoma), and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.6 to about 3.5 mg / kg (e.g. about 0.6 mg / kg or 1.3 mg / kg), wherein the treating results in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 16 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is cervical cancer (e.g. cervical squamous cell carcinoma), and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.6 to about 3.5 mg / kg (e.g. about 0.6 mg / kg or 1.3 mg / kg), wherein the treating results in the reduction of the volume of the solid tumor, wherein the volume of the solid tumor is reduced by at least 30%, and optionally, the volume of the solid tumor is reduced when measured at at least 4 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is NSCLC (e.g. lung adenocarcinoma), and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.6 to about 3.5 mg / kg (e.g. about 0.6 mg / kg), wherein the treating results in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 16 weeks or at least 32 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is NSCLC (e.g. lung adenocarcinoma), and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.6 to about 3.5 mg / kg (e.g. about 0.6 mg / kg), wherein the treating results in the volume of the tumor being no greater than 15% greater (e.g. 10% greater) than the volume of the tumor at the first administration and the volume of the tumor being no less than 25% less (e.g. 20% less) than the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is anal squamous cell carcinoma, and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.6 to about 3.5 mg / kg (e.g. about 1.3 mg / kg), wherein the treating results in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 16 weeks or at least 32 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is an advanced solid tumor associated with Nectin-4 expression and is anal squamous cell carcinoma, and the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.6 to about 3.5 mg / kg (e.g. about 1.3 mg / kg), wherein the treating results in the volume of the tumor being no greater than 15% greater (e.g. 10% greater) than the volume of the tumor at the first administration and the volume of the tumor being no less than 25% less (e.g. 20% less) than the volume of the tumor at the first administration.

[0257] As described herein, the present invention provides methods and uses in relation to treating cancer in a human patient, and methods and uses in relation to maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is selected from the group consisting of colorectal cancer, gastrointestinal carcinoma, NSCLC, HNSCC, TNBC, ovarian carcinoma, cervical cancer, and thyroid cancer. The cancer may be associated with Nectin-4 expression. The cancer may be an advanced solid tumor associated with Nectin-4 expression. The BT7480, or a pharmaceutically acceptable salt thereof, may be administered at a dose of about 0.05 to about 7.5 mg / kg, such as about 0.05 to about 3.5 mg / kg. The dose may be administered at a frequency of once a week. The treating may result in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the reduction of the volume of the solid tumor, optionally, wherein the volume of the solid tumor is reduced by at least 1% and, further optionally, the volume of the solid tumor is reduced when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is colorectal cancer. The cancer may be associated with Nectin-4 expression. The cancer may be an advanced solid tumor associated with Nectin-4 expression. The BT7480, or a pharmaceutically acceptable salt thereof, may be administered at a dose of about 0.05 to about 7.5 mg / kg, such as about 0.05 to about 3.5 mg / kg. The dose may be administered at a frequency of once a week. The treating may result in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the reduction of the volume of the solid tumor, optionally, wherein the volume of the solid tumor is reduced by at least 1% and, further optionally, the volume of the solid tumor is reduced when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is gastrointestinal carcinoma. The cancer may be associated with Nectin-4 expression. The cancer may be an advanced solid tumor associated with Nectin-4 expression. The BT7480, or a pharmaceutically acceptable salt thereof, may be administered at a dose of about 0.15 to about 7.5 mg / kg, such as about 0.15 to about 3.5 mg / kg. The dose may be administered at a frequency of once a week. The treating may result in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the reduction of the volume of the solid tumor, optionally, wherein the volume of the solid tumor is reduced by at least 1% and, further optionally, the volume of the solid tumor is reduced when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is NSCLC. The cancer may be associated with Nectin-4 expression. The cancer may be an advanced solid tumor associated with Nectin-4 expression. The BT7480, or a pharmaceutically acceptable salt thereof, may be administered at a dose of about 0.6 to about 7.5 mg / kg, such as about 0.6 to about 3.5 mg / kg. The dose may be administered at a frequency of once a week. The treating may result in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 32 weeks or at least 56 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the reduction of the volume of the solid tumor, optionally, wherein the volume of the solid tumor is reduced by at least 1% and, further optionally, the volume of the solid tumor is maintained when measured at at least 8 weeks (e.g. at least 16 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the volume of the tumor being no greater than 15% greater (e.g. 10% greater) than the volume of the tumor at the first administration and the volume of the tumor being no less than 25% less (e.g. 20% less) than the volume of the tumor at the first administration. Optionally, the the volume of the solid tumor is measured at at least 4 weeks (e.g. at least 32 weeks or at least 56 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is HNSCC. The cancer may be associated with Nectin-4 expression. The cancer may be an advanced solid tumor associated with Nectin-4 expression. The BT7480, or a pharmaceutically acceptable salt thereof, may be administered at a dose of about 0.6 to about 7.5 mg / kg, such as about 0.6 to about 3.5 mg / kg. The dose may be administered at a frequency of once a week. The treating may result in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the reduction of the volume of the solid tumor, optionally, wherein the volume of the solid tumor is reduced by at least 1% and, further optionally, the volume of the solid tumor is reduced when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is cervical cancer (e.g. cervical squamous cell carcinoma). The cancer may be associated with Nectin-4 expression. The cancer may be an advanced solid tumor associated with Nectin-4 expression. The BT7480, or a pharmaceutically acceptable salt thereof, may be administered at a dose of about 0.6 to about 7.5 mg / kg, such as about 0.6 to about 3.5 mg / kg. The dose may be administered at a frequency of once a week. The treating may result in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the reduction of the volume of the solid tumor, optionally, wherein the volume of the solid tumor is reduced by at least 1% (e.g. at least 5%, at least 10%, or at least 25%) and, further optionally, the volume of the solid tumor is reduced when measured at at least 4 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is TNBC. The cancer may be associated with Nectin-4 expression. The cancer may be an advanced solid tumor associated with Nectin-4 expression. The BT7480, or a pharmaceutically acceptable salt thereof, may be administered at a dose of about 1.3 to about 7.5 mg / kg, such as about 1.3 to about 3.5 mg / kg. The dose may be administered at a frequency of once a week. The treating may result in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the reduction of the volume of the solid tumor, optionally, wherein the volume of the solid tumor is reduced by at least 1% and, further optionally, the volume of the solid tumor is reduced when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is ovarian cancer. The cancer may be associated with Nectin-4 expression. The cancer may be an advanced solid tumor associated with Nectin-4 expression. The BT7480, or a pharmaceutically acceptable salt thereof, may be administered at a dose of about 1.3 to about 7.5 mg / kg, such as about 1.3 to about 3.5 mg / kg. The dose may be administered at a frequency of once a week. The treating may result in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the reduction of the volume of the solid tumor, optionally, wherein the volume of the solid tumor is reduced by at least 1% and, further optionally, the volume of the solid tumor is reduced when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is thyroid cancer. The cancer may be associated with Nectin-4 expression. The cancer may be an advanced solid tumor associated with Nectin-4 expression. The BT7480, or a pharmaceutically acceptable salt thereof, may be administered at a dose of about 2.6 to about 7.5 mg / kg, such as about 2.6 to about 3.5 mg / kg. The dose may be administered at a frequency of once a week. The treating may result in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the reduction of the volume of the solid tumor, optionally, wherein the volume of the solid tumor is reduced by at least 1% and, further optionally, the volume of the solid tumor is reduced when measured at at least 4 weeks (e.g. at least 8 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. In some embodiments, the invention provides a method of treating a cancer in a human patient comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, (or the pharmaceutical composition as described herein), wherein the cancer is gastrointestinal carcinoma. The cancer may be associated with Nectin-4 expression. The cancer may be an advanced solid tumor associated with Nectin-4 expression. The BT7480, or a pharmaceutically acceptable salt thereof, may be administered at a dose of about 0.6 to about 7.5 mg / kg, such as about 0.6 to about 3.5 mg / kg. The dose may be administered at a frequency of once a week. The treating may result in the maintenance of the volume of the solid tumor and, optionally, the volume of the solid tumor is maintained when measured at at least 4 weeks (e.g. at least 32 weeks or at least 56 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the reduction of the volume of the solid tumor, optionally, wherein the volume of the solid tumor is reduced by at least 1% and, further optionally, the volume of the solid tumor is maintained when measured at at least 12 weeks (e.g. at least 24 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration. The treating may result in the volume of the tumor being no greater than 15% greater (e.g. 10% greater) than the volume of the tumor at the first administration and the volume of the tumor being no less than 25% less (e.g. 20% less) than the volume of the tumor at the first administration. Optionally, the the volume of the solid tumor is measured at at least 4 weeks (e.g. at least 32 weeks or at least 56 weeks) after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration.

[0258] In some embodiments, BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is safe. In some embodiments, BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is tolerable. In some embodiments, BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein is efficacious. In some embodiments, BT7480, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein does not result in any severe adverse events.

[0259] General definitions and nomenclature

[0260] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention belongs. Standard techniques are used for molecular biology, genetic and biochemical methods (see Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., 2001, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel et al., Short Protocols in Molecular Biology (1999) 4thed., John Wiley & Sons, Inc.), which are incorporated herein by reference.

[0261] In light of the disclosure in Nair et al (2003) J Immunol 170(3), 1362-1373, it is envisaged that the peptide sequences disclosed herein would also find utility in their retro-inverso form. For example, the sequence is reversed (i.e. N-terminus becomes C-terminus and vice versa) and their stereochemistry is likewise also reversed (i.e. D-amino acids become L-amino acids and vice versa). For the avoidance of doubt, references to amino acids either as their full name or as their amino acid single or three letter codes are intended to be represented herein as L-amino acids unless otherwise stated. If such an amino acid is intended to be represented as a D-amino acid then the amino acid will be prefaced with a lower case d within square parentheses, for example [dA], [dD], [dE], [dK], [dlNal], [dNle], etc.

[0262] In general, the term “comprising” is intended to mean including but not limited to. For example, the phrase “a method of treating a cancer in a patient, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof” should be interpreted to mean that the method involves administering BT7480, or a pharmaceutically acceptable salt thereof, but the method may also involve, e.g., administering further agents.

[0263] 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 described herein 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.

[0264] As used herein, the term “about” indicates that the given value includes the given value plus or minus 10%, more particularly plus or minus 5%, or more particularly plus or minus 1%.

[0265] As used herein, the term “mg / kg” refers to the milligram of medication per kilogram of the body weight of the subject taking the medication. In some embodiments of the invention, the term “comprising” is replaced with the term “consisting essentially of’ . The term “consisting essentially of” means that specific further components can be present, namely those not materially affecting the essential characteristics of the subject matter.

[0266] In some embodiments of the invention, the term “comprising” is replaced with the term “consisting of” . The term “consisting of’ is intended to be limiting.

[0267] In some embodiments of the invention, the term “have ” can be replaced with the term “comprise ” or the term “consist of” . In some embodiments of the invention, the term “has ” can be replaced with the term “comprises ” or the term “consists of ’ .

[0268] The singular forms “a”, “an”, and “the ” include plural referents unless the content clearly dictates otherwise.

[0269] As used herein, the term “between” to specify a range includes the specified values. Thus, for example, “between 1.1 fold and 20-fold” includes the values 1.1 and 20.

[0270] All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0271] EXEMPLIFICATION

[0272] Example 1. Phase 1 / 2 Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT7480 in Patients With Nectin-4 Associated Advanced Malignancies

[0273] List of Abbreviations and Definition of Terms

[0274] Abbreviation Definition

[0275] ADA Anti-drug antibody

[0276] AE Adverse event

[0277] AESI Adverse event of special interest

[0278] ALP Alkaline phosphatase

[0279] ALT Alanine aminotransferase

[0280] ANC Absolute neutrophil count

[0281] AST Aspartate aminotransferase

[0282] AUC Area under the curve Abbreviation Definition

[0283] Bicycle TICA Bicycle Tumor-targeted Immune Cell Agonist

[0284] BP Blood pressure

[0285] CAR-T Chimeric antigen receptor T cell

[0286] CBR Clinical benefit rate

[0287] CD Cluster of differentiation

[0288] CEC Central Ethics Committee CFR Code of Federal Regulations CKD-EPI Chronic Kidney Disease Epidemiology Collaboration Cmax Maximum plasma concentration COVID-19 Coronavirus Disease 2019 CR Complete response CRA Clinical Research Associate CRS Cytokine release syndrome CT Computed tomography CTA Clinical trial authorization CTCAE Common Terminology Criteria for Adverse Events ctDNA Circulating tumor deoxyribonucleic acid CYP Cytochrome P450 DILI Drug-induced liver injury DLT Dose-limiting toxicity DNA Deoxyribonucleic acid DoR Duration of response ECG El ectrocardi ogram ECOG Eastern Cooperative Oncology Group eCRF Electronic case report form EDC Electronic data capture eGFR Estimated glomerular filtration rate EIU Exposure In Utero EMA European Medicines Agency EOI End of infusion EOT End of treatment FDA Food and Drug Administration FFPE Formalin-fixed paraffin-embedded FIH First-in-human GCP Good Clinical Practice GLP Good Laboratory Practice GMP Good Manufacturing Practice H Histamine Abbreviation Definition HBV Hepatitis B virus HCV Hepatitis C virus HIV Human immunodeficiency virus ICF Informed consent form ICH International Council for Harmonisation IEC Independent Ethics Committee IL Interleukin INR International normalized ratio irAE Immune-related adverse event IRB Institutional Review Board IRR Infusion-related reaction IV Intravenous(ly) MABEL Minimum anticipated biological effect level MRI Magnetic resonance imaging MTD Maximum tolerated dose mTOR Mammalian target of rapamycin NAb Neutralizing antibody NCI National Cancer Institute NHP Non-human primate NOAEL No-observed-adverse-effect level ORR Overall response rate PD Progressive disease PD-1 Programmed cell death protein 1 PD-L1 Programmed death-ligand 1 PGx Pharmacogenomi c(s) PK Pharmacokinetic(s) PR Partial response Q2W Once every 2 weeks QTc Heart rate-corrected QT interval QTcF Heart rate-corrected QT interval using Fridericia’s formula QW Once weekly RECIST Response Evaluation Criteria in Solid Tumors RNA Ribonucleic acid RO Receptor occupancy RP2D Recommended Phase 2 dose SAE Serious adverse event SD Stable disease SmPC Summary of Product Characteristics Abbreviation Definition

[0289] SOA Schedule of Assessments

[0290] SRC Safety Review Committee

[0291] SUSAR Suspected Unexpected Serious Adverse Reaction

[0292] SVR12 Sustained virologic response at 12 weeks

[0293] SVR24 Sustained virologic response at 24 weeks t% Terminal half-life

[0294] TEAE Treatment-emergent adverse event

[0295] ULN Upper limit of normal

[0296] WHO World Health Organization

[0297] Primary Objectives

[0298] Phase 1

[0299] To assess the safety and tolerability of BT7480, as a monotherapy and in combination with nivolumab, in patients with advanced solid tumors associated with Nectin-4 expression; and

[0300] To assess the safety and tolerability of BT7480 as a monotherapy in patients with renal insufficiency and advanced solid tumors.

[0301] Phase 2

[0302] To assess the clinical activity of BT7480, as a monotherapy and in combination with nivolumab, in patients with advanced solid tumors associated with Nectin-4 expression.

[0303] Secondary Objectives

[0304] Phase 1

[0305] To assess the clinical activity of BT7480, as a monotherapy and in combination with nivolumab, in patients with advanced solid tumors associated with Nectin-4 expression; and

[0306] To assess the clinical activity of BT7480 as a monotherapy in patients with renal insufficiency and advanced solid tumors.

[0307] Phase 2

[0308] To assess the safety and tolerability of BT7480, as a monotherapy and in combination with nivolumab, in patients with advanced solid tumors associated with Nectin-4 expression.

[0309] Phase 1 and Phase 2 To assess additional measures of antitumor efficacy of BT7480 as a monotherapy and in combination with nivolumab;

[0310] To assess the pharmacokinetic (PK) parameters of BT7480, as a monotherapy and in combination with nivolumab, in patients with advanced solid tumors associated with Nectin-4 expression;

[0311] To assess the PK parameters of BT7480 as a monotherapy in patients with renal insufficiency and advanced solid tumors;

[0312] To evaluate the development of anti-drug antibodies (AD As) in patients treated with BT7480; and To evaluate cluster of differentiation (CD)137 target engagement in the peripheral blood of patients treated with BT7480 as a monotherapy and in combination with nivolumab.

[0313] Exploratory Objectives

[0314] Phase 1 and Phase 2

[0315] To evaluate potential pharmacodynamic (transcriptomic and proteomic) activity associated with PK / target engagement in blood and tumor of patients treated with BT7480;

[0316] To evaluate biomarkers associated with pharmacological activity in patients treated with BT7480;

[0317] To evaluate the pharmacogenomics (PGx) in patients treated with BT7480; and

[0318] To evaluate circulating tumor deoxyribonucleic acid (ctDNA) in patients treated with BT7480.

[0319] Inclusion Criteria

[0320] Patients who meet all the following criteria will be eligible to participate in the study:

[0321] 1. Must have locally advanced or metastatic disease that is refractory to standard therapy, or for which no standard therapy is judged to be appropriate or provide clinical benefit, as judged by the Investigator;

[0322] 2. Must have a histologically or cytologically confirmed malignant solid tumor-associated with Nectin-4 expression, including, but not limited to, urothelial (transitional cell) carcinoma; head and neck squamous cell carcinoma; non-small cell lung cancer; and ovarian, breast, gastric, or esophageal carcinoma; Note: The Sponsor, in consultation with the Safety Review Committee (SRC), may decide to require prospective central Nectin-4 testing at any point during the escalation. For those patients for which prospective central Nectin-4 testing is required, pre-screening consent will be obtained prior to prospective Nectin-4 protein expression assessment, and an archived tumor sample or fresh tumor biopsy testing positive for Nectin-4 expression will be required.

[0323] 3. Must have metastatic or locally advanced disease and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1;

[0324] Note: For monotherapy dose escalation, patients with non -measurable disease may also be enrolled into Cohorts 1 through 3, and patients with measurable disease only will be enrolled into Cohort 4 and beyond.

[0325] 4. Must submit fresh or archival tumor tissue;

[0326] 5. Must provide 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 analysis;

[0327] 6. Must be at least 18 years of age;

[0328] 7. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (Score 0: Fully active, able to carry on all pre-disease performance without restriction; Score 1 : Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work);

[0329] 8. Must have acceptable organ function, as evidenced by all of the following laboratory data: a. Renal function with estimated glomerular filtration rate (eGFR) >60 mL / min by the

[0330] Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (direct measurement of renal function [eg, radioisotope or 24-hour urine] are permitted);

[0331] Note: Patients enrolling into the optional renal impairment cohorts should have an eGFR >30 to 59 mL / min by the CKD-EPI equation at screening. a. Total bilirubin <1.5 x upper limit of normal (ULN);

[0332] Note: Patients with Gilbert’s syndrome are eligible if their direct bilirubin is <1.5 x ULN. b. Aspartate aminotransferase (AST) <2.5 x ULN or <5 x ULN in the presence of liver metastases; c. Alanine aminotransferase (ALT) <2.5 x ULN or <5 x ULN in the presence of liver metastases; and d. International normalized ratio (INR) <1.5 or < institutional ULN.

[0333] Note: Patients on anticoagulants for >6 months with stable levels of anti coagulation are eligible.

[0334] 9. Must have acceptable hematologic function, as evidenced by all the following laboratory data: a. Hemoglobin >9 g / dL; b. Absolute neutrophil count (ANC) >1500 cells / mm3; and c. Platelet count >75,000 cells / mm3.

[0335] 10. Female patients must not be lactating or pregnant as documented by a negative serum pregnancy (beta-human chorionic gonadotropin) test at screening and a negative urine pregnancy test within 72 hours before the first dose of study drug. All females will be considered to be of childbearing potential unless they are postmenopausal (with amenorrhea for at least 12 months and follicle-stimulating hormone in the postmenopausal range at screening) or surgically sterile;

[0336] 11. Fertile male patients and female patients of childbearing potential who are at risk of pregnancy must agree to use a highly effective (less than 1% failure rate) protocol -recommended method of birth control in conjunction with an acceptable but not highly effective method (more than 1% failure rate) during their participation in the study, and until 3 months following the last dose of BT7480 and, if applicable, until 5 months following the last dose of nivolumab;

[0337] 12. Fertile male patients must agree to refrain from sperm donation from Day 1 until at least 3 months following the last dose of BT7480 and, if applicable, until 5 months following the last dose of nivolumab;

[0338] 13. Must have life expectancy >12 weeks after the start of study drug per Investigator’s judgment; and

[0339] 14. 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.

[0340] Exclusion Criteria Patients who meet any of the following criteria will be excluded from participation in the study:

[0341] 1. Prior therapy with any of the following: a. Cytotoxic, small molecule, or other systemic chemotherapy within 14 days of the first dose of study drug; b. Immunotherapy, including monoclonal antibodies, within 28 days or 5 half-lives of the first dose of study drug, whichever is shorter; c. Cell-based therapy, including chimeric antigen receptor T cell therapy, within 60 days of the first dose of study drug; d. Experimental treatment(s), other than systemic anticancer therapies, within 28 days or 5 half-lives of the first dose of study drug, whichever is shorter; e. Radiation therapy within 28 days of the first dose of study drug; f. Major surgery, excluding placement of vascular access, within 28 days of the first dose of study drug for invasive surgery or 14 days of the first dose of study drug for minimally invasive (laparoscopic, interventional radiology, or robotic) surgical procedures;

[0342] Note: Patients must have recovered adequately after surgery and prior to starting study drug. g. CD 137 targeted therapy; or h. Red blood cell transfusions, platelet transfusions, or growth factors within 14 days of the first dose of BT7480.

[0343] Note: Patients in the optional renal impairment cohorts may receive erythropoietic growth factors within 4 weeks of the first dose of BT7480, if clinically indicated.

[0344] 2. Prior treatment-related toxicities that have not resolved to Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0;

[0345] 3. Known sensitivity to any of the ingredients of the study drug(s);

[0346] 4. Significant medical condition which, in the Investigator’s opinion, could compromise or interfere with the patient’s safety or integrity of the study outcomes, such as conditions affecting the skin (conditions related to, or that may confound monitoring for rash, including autoimmune conditions such as moderate / severe and active eczema or psoriasis), immediate life-threatening illness (other than cancer), active uncontrolled systemic infection, organ system dysfunction (e.g., severe ascites, coagulopathy, or encephalopathy), or other gastrointestinal, skin, or pulmonary (after review of screening chest computed tomography [CT] if clinically indicated) co-morbidities;

[0347] 5. History of a cerebral vascular event (e.g., stroke or transient ischemic attack), unstable angina, myocardial infarction, or signs or symptoms of New York Heart Association Class III to IV heart failure documented within 6 months prior to the first dose of study drug;

[0348] 6. Mean resting QTc (e.g., QTcF) >470 msec on triplicate electrocardiograms (ECGs) obtained at screening;

[0349] 7. Any factors that increase the risk of QTc prolongation or the risk of arrhythmic events such as severe heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, unexplained sudden death under 40 years of age, or any concomitant medication use known to prolong the QT interval and / or cause Torsades de Pointes;

[0350] 8. Any clinically important abnormalities, as assessed by the Investigator, in rhythm, conduction, or morphology of resting ECGs, such as complete left bundle branch block or third- degree heart block not controlled by pacemaker or otherwise;

[0351] 9. Uncontrolled diabetes with glycosylated hemoglobin >8%;

[0352] 10. Uncontrolled symptomatic brain metastases;

[0353] Note: Patients with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after central nervous system-directed treatment.

[0354] 11. Uncontrolled hypertension (with repeated measurement of systolic blood pressure [BP] >160 mmHg or diastolic BP >100 mmHg that is not responsive to intervention) at screening or prior to initiation of study drug;

[0355] 12. Known HIV infection or acquired immune deficiency syndrome;

[0356] 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. On established antiretroviral therapy (ART) for at least 4 weeks; and c. HIV viral load <400 copies / mL. 13. Active hepatitis B virus (HBV) infection;

[0357] Note: Controlled (treated) hepatitis will be allowed if the patient meets all the following criteria: a. Anti-viral therapy for HBV must be given for at least 1 month prior to the first dose of study drug; b. HBV viral load must be <2000 lU / mL (104 copies / mL) prior to the first dose of study drug; and c. Those on active HBV therapy with viral load <2000 lU / mL (104 copies / mL) should stay on the same anti-viral therapy throughout study treatment.

[0358] 14. Active hepatitis C virus (HCV) infection;

[0359] Note: Successfully treated patients with chronic HCV infection, defined as sustained virologic response at 12 weeks (SVR12) or 24 weeks (SVR24), are allowed if there is a 4-week period between achieving sustained viral response (SVR12 or SVR24) and starting the study drug.

[0360] 15. Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen, particularly those patients with a history of another malignancy within 3 years prior to the first dose of study drug or any evidence of residual disease from a previously diagnosed malignancy, excluding adequately managed with curative-intent treatment for basal cell carcinoma, squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, cervical carcinoma in situ, melanoma in situ, or ductal carcinoma in situ of the breast;

[0361] 16. Receipt of live or attenuated vaccine within 30 days of first dose of study drug;

[0362] 17. Diagnosis of a clinically relevant immunodeficiency;

[0363] 18. Use of prednisone >10 mg daily or equivalent or another strong systemic immunosuppressant (e.g., calcineurin inhibitors, anti-proliferative agents, mTOR [mammalian target of rapamycin] inhibitors);

[0364] 19. Receipt of intravenous (IV) anti-infective treatment or presence of fever not attributable to the underlying illness within 14 days prior to the first dose of study drug;

[0365] 20. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and / or follow-up procedures outlined in the protocol;

[0366] 21. Any clinically significant safety concern related to prior checkpoint inhibitor(s) therapy; 22. Prior organ or hematopoietic cell transplant, including allogeneic hematopoietic cell transplant;

[0367] 23. History of autoimmune disease, except well-controlled diabetes mellitus, alopecia, well-controlled thyroid disease, or vitiligo;

[0368] 24. Active interstitial lung disease or pneumonitis, or a history of interstitial lung disease or pneumonitis requiring treatment with steroids or other immunosuppressive medications; or

[0369] 25. Prior 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, in the opinion of the Investigator, is considered to not be in the best interest of the patient to participate in the study.

[0370] STUDY DESIGN AND DURATION

[0371] This is a Phase 1 / 2 first-in-human (FIH), open-label, dose escalation, dose confirmation, and dose expansion multicenter study to evaluate the safety, PK, and clinical activity of BT7480 in patients with advanced solid tumors associated with Nectin-4 expression. The overall study design is presented in Figure 2. Dose escalation of BT7480 monotherapy, with a possible renal impairment cohort, will be the focus of the Phase 1 portion of the study. A subsequent dose escalation cohort evaluating BT7480 in combination with nivolumab may also be evaluated as part of Phase 1. Enrollment into optional renal impairment cohorts may proceed following determination of the monotherapy recommended Phase 2 dose (RP2D). Phase 2 of the study plans to evaluate the efficacy of BT7480 as a monotherapy or in combination with nivolumab dosed at the RP2D determined in Phase 1. The study is planned to be conducted in up to 20 clinical sites globally.

[0372] The study will enroll patients with histologically or cytologically confirmed malignant solid tumors associated with Nectin-4 expression. Patients must have locally advanced or metastatic disease that is refractory to standard therapy, or for which no standard therapy is judged to be appropriate or provide clinical benefit, as judged by the Investigator.

[0373] Patients must submit fresh or archival tumor tissue at baseline. Tumor-associated Nectin-4 expression levels will be determined for all patients using archival tumor tissue or fresh tumor biopsy collected during screening (or pre-screening, if implemented). The Sponsor, in consultation with the SRC, may decide to require prospective central Nectin-4 testing at any point during the escalation. For those patients for which prospective central Nectin-4 testing is required, pre-screening consent will be obtained prior to prospective Nectin-4 protein expression assessment, and an archived tumor sample or fresh tumor biopsy testing positive for Nectin-4 expression will be required.

[0374] During Phase 1 monotherapy (dose escalation [Cohort 3 onwards], and renal impairment cohorts) and Phase 1 combination therapy (dose escalation cohorts), patients may provide optional paired (pre- and on-treatment) tumor biopsies. If the patient has consented to optional paired tumor biopsies, both a pre-treatment baseline tumor biopsy and archival tumor tissue, if available, are requested. On-treatment biopsy sampling is allowed at any time after Cycle 1 Day 1 and, if applicable and possible, at relapse.

[0375] Safety and tolerability will be assessed from the time of informed consent until the safety follow-up visit by vital signs, physical examinations, 12-lead ECGs, routine clinical laboratory evaluations (chemistry, hematology, coagulation, and urinalysis), AD As, and adverse events (AEs). For cohorts that receive combination therapy with nivolumab, additional monitoring for autoimmune and endocrine disorders is scheduled.

[0376] For disease assessment by Investigator per RECIST 1.1, a CT or magnetic resonance imaging scan, or manual measurement of visual lesions or other types of imaging, should be performed at screening. Starting with Cycle 3, disease assessment by Investigator per RECIST 1.1 should be performed every 8 weeks (±7 days) through 12 months, then every 12 weeks (±28 days) thereafter until disease progression, initiation of a new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first. It is also acknowledged that disease progression may require, in certain circumstances, further evaluation for possible pseudo-progression. For patients that discontinue treatment for reasons other than disease progression, every effort should be made to continue tumor imaging using the same imaging schedule used while on treatment until disease progression, initiation of a new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first.

[0377] PK of BT7480 will be assessed using serial blood and urine samples obtained at prespecified time points. Additionally, tumor concentrations will be analyzed in a similar manner, if available. Pharmacodynamic response to treatment will be assessed by biomarker analyses (e.g., CD137 target engagement [circulating mechanistic proteins and flow cytometry-based receptor occupancy], exploratory transcriptomic and proteomic immune profiling in blood and tumor [inflammatory cytokines, neutralizing antibodies, flow cytometry immunophenotyping, multiplex immunofluorescence, RNA immune profiling]). A single blood sample for germline genomics will be collected pre-dose on Cycle 1 Day 1 and blood samples for ctDNA PGx will be collected at prespecified timepoints.

[0378] The study duration will be approximately 36 months: approximately 24 months for dose escalation and approximately 12 months for dose expansion.

[0379] Patients who meet eligibility criteria during screening (Week -4 up to Week 0) will be enrolled into the study.

[0380] Phase 1 Dose Escalation - BT7480 Monotherapy

[0381] The starting dose for the BT7480 monotherapy dose escalation cohort is planned to be 0.002 mg / kg. Patients will be assigned sequentially to increasing BT7480 doses (see Table 1). BT7480 dose will be escalated in subsequent cohorts after patient(s) enrolled in each cohort have completed both the planned doses as well as the dose-limiting toxicity (DLT) period (28 days post-first dose). Patients who miss a planned dose within the DLT period but experience a DLT will be considered DLT evaluable. The monitoring for liver dysfunction will continue for the entire duration of a patient’s participation in the study.

[0382] Patients with non-measurable disease may also be enrolled into Cohorts 1 through 3, and patients with measurable disease only will be enrolled into Cohort 4 through 13. At least 1 evaluable patient will be enrolled in each of the first 4 cohorts unless a subject in 1 of these cohorts experiences a Grade 2 AE that was at least possibly related to study drug. Should that occur, the next subsequent cohort will contain at least 3 evaluable patients; further expansion with 3 additional subjects is required if a subject experiences a DLT. If a subject experiences a Grade 3 or higher toxicity, that was at least possibly related to study drug, in any of the single patient cohorts then the current cohort will be expanded to 3 patients at least.

[0383] Table 1. Dose Plan: Monotherapy Dose Escalation Cohorts

[0384]

[0385] Subsequent dose escalation cohorts (Cohort 5 onwards or an earlier cohort if a 3-patient expansion of that cohort has been triggered) will enroll patients based on a 3 + 3 design, wherein 3 patients will be initially enrolled and treated at each dose level. The 3 + 3 design and plan of action should a DLT occur are provided in Table 2. In all 3 + 3 cohorts, there will be at least 48 hours between the first patient dosing and subsequent patient dosing. Treatment cycles will occur consecutively, as per the Schedule of Assessments (SOA) in Table 9.

[0386] In the 3 + 3 design, if 1 patient experiences a DLT, 3 additional patients will be treated with the same dose. An evaluation of a cohort of at least 3 patients completing the DLT period (28 days post-first dose) is required prior to proceeding to the next dose level. If >2 patients in a dose level of up to 6 patients experience DLTs, the maximum tolerated dose (MTD) has been exceeded. If >2 patients in a dose level of up to 6 patients experience DLTs and only 3 patients were evaluated at the previous (next lower) dose, then 3 additional patients will be evaluated at the previous (next lower) dose; and if 0 or 1 patient has a DLT, then the Safety Review Committee (SRC) will consider enrolling patients at the intermediate dose level as specified in Table 1. The safety observations at the intermediate dose level escalation will inform the SRC assessment of the MTD. Upon SRC determination that the MTD has been exceeded, the decision to stop dose escalation will be promptly communicated to all sites.

[0387] Table 2. 3 + 3 Design: Monotherapy Dose Escalation Cohorts

[0388] The MTD will be defined according to the above guidelines; however, if subsequent to the SRC decision, further data becomes available that changes the attribution of causality or severity of a given event (e.g., based on subsequent evolution of events, follow-up investigations, or follow-up observations) so that the event no longer meets the DLT definitions provided in the “DOSE-LIMITING TOXOCITY” section, the SRC may decide to recommence with dose escalation and a previous MTD could be revisited. The RP2D, not exceeding the MTD, will be determined by the SRC based on available safety, PK, and pharmacodynamic data, including efficacy data.

[0389] The window of observation for DLTs is designed to assess predominantly acute events. Longer term and possibly immune-related AEs with specific attention applied to liver function, which may accrue over several cycles of therapy, will be considered in the assessments undertaken during each SRC meeting.

[0390] Following completion of the DLT period for each cohort, the SRC will review the available safety, PK, and pharmacodynamic data, including efficacy data, to determine the potential for dose escalation and the recommended dose level for the next cohort. The data must meet the adequate minimum standards (as specified in the SRC Charter) such that the SRC is satisfied to continue with dosing. At a minimum, the data to be reviewed will include available subject disposition and demographics, treatment-emergent and related AEs, dose limiting toxicities, PK, PD, and efficacy data.

[0391] Intra-patient dose escalation: At the discretion of the Medical Monitor and Investigator, patients in preceding lower dose cohorts may receive a higher dose 1 dose level below the highest dose level deemed safe by a formal dose escalation decision by the SRC. For example, if a patient is tolerating 0.006 mg / kg and the 0.05 mg / kg has been deemed safe, the patient may escalate to the 0.02 mg / kg dose. The patient’s clinical experiences in the higher dose cohort will be considered as part of the totality of data by the SRC but will not contribute to formal dose escalation decisions that have already been made.

[0392] Optional backfill cohorts: During dose escalation, selected dose levels may be further expanded (also known as backfilling) to include up to 15 patients per given dose level in order to further evaluate tolerability, PK, pharmacodynamics, and biological activity of BT7480. To help ensure that patients are not unnecessarily enrolled to subtherapeutic dose levels, these dose level expansions will only start when a dose level already declared safe by the SRC also demonstrates evidence of therapeutic exposures, target engagement, or Investigator-assessed response.

[0393] Subsequent dose levels above this would also be eligible for expanded enrollment after being declared safe by the SRC. If slots are available in both the optional backfill cohort as well as the dose escalation cohort simultaneously, enrollment into the dose escalation cohort will take precedent.

[0394] To further ensure patient safety, any AEs that otherwise would have met DLT criteria but occurred in optional backfill cohort patients will be considered DLT-equivalent toxicities, which will not be used for escalation / de-escalation decisions. However, if the observed DLT + DLT equivalent rate at a given dose level from both escalation and optional backfill patients exceeds 33%, further escalation will be paused, and the SRC will evaluate the aggregated safety data to determine whether to proceed with continued enrollment at the given dose level or subsequent dose levels.

[0395] Withdrawn patients or patients who end treatment prior to study completion for reasons other than a DLT and who do not meet the minimum requirements for inclusion in the MTD determining population will be replaced, where necessary, to ensure adequate safety assessment for each dose escalation and the optional renal impairment cohorts.

[0396] Phase 1 Dose Confirmation - Optional BT7480 Monotherapy Renal Impairment Cohorts

[0397] Subsequent to SRC determination of a BT7480 monotherapy dose, 2 cohorts of 6 patients each with moderate renal insufficiency (eGFR >30 to 59 mL / min by the CKD-EPI equation) will be enrolled at a dose based on the totality of PK, pharmacodynamic, safety, and efficacy in patients with normal renal function and mild renal impairment (eGFR >60 mL / min). If there is sufficient concern around the therapeutic index during dose escalation, then the SRC will direct a lower dose for the renal cohort. Six patients with eGFR 50 to 59 mL / min will enroll first, followed by 6 patients with eGFR >30 to 49 mL / min. Treatment cycles will occur consecutively, as per the SOA in Table 10.

[0398] If >2 patients in a renal impairment cohort of <6 patients experience a DLT during the DLT period (28 days post-first dose), the MTD has been exceeded and enrollment will be stopped pending SRC review. The SRC will review the available safety, PK, and pharmacodynamic data, including efficacy data, to determine if additional cohorts / patients are needed. Withdrawn patients or patients who end treatment prior to study completion for reasons other than a DLT and who do not meet the minimum requirements for inclusion in the MTD determining population will be replaced, where necessary, to ensure adequate safety assessment for each cohort.

[0399] Phase 1 Dose Escalation - Optional Combination Therapy

[0400] Subsequent to SRC determination of a BT7480 monotherapy dose, a combination therapy (BT7480 + nivolumab) dose escalation may be opened. The starting dose of BT7480 in combination therapy will be 1 dose level lower than the BT7480 monotherapy RP2D; see Table 3. Patients will enroll based on a 3 + 3 design, wherein 3 patients will be initially enrolled and treated at each dose level. Treatment cycles will occur consecutively, as per the SOA in Table 11.

[0401] If 1 of these 3 patients experiences a DLT during the DLT period (28 days post-first dose), the dose level will be expanded to 6 patients. BT7480 doses will be escalated in the subsequent cohorts after patients enrolled in each cohort have completed the planned doses of BT7480 and nivolumab as well as the DLT period. Patients who miss a planned dose within the DLT period but experience a DLT will be considered DLT evaluable. Table 3. Dose Levels: Combination Therapy Cohorts

[0402] If >2 patients experience a DLT in any cohort of <6 patients, the MTD has been exceeded. Following each cohort, the SRC will review available safety, PK, and pharmacodynamic data, including efficacy data, to determine if additional cohorts / patients are needed. The dose level will never exceed the BT7480 monotherapy RP2D.

[0403] If a patient has intercurrent events that are not thought to be related to BT7480, the patient may be considered evaluable for SRC consideration. If a patient has an event that is not a DLT, is related to BT7480, and is considered to be clinically significant by the SRC, that event will be evaluated for dose escalation determinations.

[0404] Withdrawn patients or patients who end treatment prior to study completion for reasons other than a DLT and who do not meet the minimum requirements for inclusion in the MTD determining population will be replaced, where necessary, to ensure adequate safety assessment for each dose escalation and the optional renal impairment cohorts.

[0405] Phase 2 Expansion - Monotherapy and Optional Combination Therapy

[0406] Following the determination of the RP2D for either monotherapy (BT7480) or combination therapy (BT7480 + nivolumab), up to 2 cohorts of patients may enroll in 2 tumor- defined cohorts during Phase 2 of the study. BT7480 will be dosed at the RP2D determined from either the monotherapy or combination therapy cohorts in Phase 1. Treatment cycles will occur as per the SOA in Table 9 for monotherapy and Table 11 for combination therapy.

[0407] DOSE-LIMITING TOXICITY

[0408] Toxicity will be assessed using the NCI CTCAE version 5.0, unless otherwise specified. A toxicity will be considered ‘dose limiting’, provided it meets the DLT definitions, if it occurs during the DLT period (28 days post-first dose), and is related to BT7480. Note that these criteria apply upon the first dose or combination received. The SRC will also take into account whether a supportive care agent is subsequently given. Ongoing measurement of relevant parameters, including ALT, AST, total bilirubin, and alkaline phosphatase (ALP), will extend beyond the DLT period and will be regularly examined by the SRC and individual Investigators alike with an eye on the history of CD137 agonistic targeted agents

[0409] In combination therapy cohorts, toxicities known to be associated with nivolumab will not necessarily be determined to be DLTs unless they are unusual or of markedly increased severity or duration per Investigator determination. Patients in combination therapy cohorts with toxicities known to be directly associated with nivolumab that cause the withdrawal of nivolumab treatment may receive single agent BT7480 per Investigator discretion and remain on the study. Patients in combination therapy cohorts with toxicities assumed or known to be directly associated with BT7480 will also discontinue nivolumab and may remain on study for safety follow-up per Investigator discretion.

[0410] The DLT definitions include the following:

[0411] 1. Hematologic AEs: a. >Grade 4 neutropenia lasting >5 days; b. Febrile neutropenia, defined as ANC <1000 cells / mm3with a single temperature of 38.3°C (101°F) or a sustained temperature of 38°C (100.4°F) for >1 hour; c. >Grade 4 thrombocytopenia; d. Grade 3 thrombocytopenia associated with clinically significant bleeding; or e. >Grade 3 anemia unexplained by underlying disease or pre-existing renal dysfunction (renal impairment cohort).

[0412] 2. Non-hematologic AEs: a. >Grade 3 fatigue lasting >5 days; b. Any >Grade 3 non-hematologic AE of any clinically significant duration occurring during the period from infusion start on Cycle 1 Day 1 through the end of the DLT period (except for >Grade 3 nausea, vomiting, or diarrhea that is responsive to supportive care and lasts <72 hours); c. >Grade 3 hypertension; d. Any related AE leading to the inability to deliver at least 75% of the planned total dose for the DLT period, except in situations other than toxicity (e.g., participant noncompliance, significant contribution of underlying disease condition, or logistical issues with drug delivery); or e. Any elevation in aminotransferases and total bilirubin fulfilling drug-induced liver injury (Hy’s law) criteria, that is, the simultaneous occurrence of the following components per the FDA Guidance Document:

[0413] ■ ALT or AST >3 x ULN (or >3 x baseline for those with hepatic metastases);

[0414] ■ Total bilirubin >2 x ULN (or >2 x baseline for those with hepatic metastases);

[0415] ■ ALP <2 x ULN; and

[0416] ■ No other reason can be found to explain the combination of increased aminotransferases and serum total bilirubin, such as viral hepatitis, alcohol abuse, ischemia, pre-existing liver disease, or another drug capable of causing the observed injury.

[0417] Events that will not automatically be considered a DLT include the following:

[0418] • <Grade 3 nausea, vomiting, or diarrhea lasting <72 hours;

[0419] • >Grade 3 electrolyte abnormality lasting <72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medical interventions;

[0420] • >Grade 3 amylase or lipase that is not associated with symptoms or clinical manifestations of pancreatitis; and

[0421] • AEs clearly related to disease, pre-existing conditions, nivolumab, or environmental factors. Patients who discontinue treatment early due to disease progression or withdrawal will be asked to have all end of treatment safety evaluations performed as described in the “SCHEDULE OF ASSESSMENTS”. Withdrawn patients or patients who end treatment prior to study completion for reasons other than a DLT and who do not meet the minimum requirements for inclusion in the MTD determining population will be replaced, where necessary, to ensure adequate safety assessment for each dose escalation and the optional renal impairment cohorts.

[0422] DOSAGE FORMS AND ROUTE OF ADMINISTRATION

[0423] BT7480

[0424] BT7480 will be provided in 4R injection vials containing 66 mg of BT7480 per vial. The formulation will be reconstituted with 1 mL of water for injections (resulting in a total reconstituted volume of 1.1 mL) to provide BT7480 at a target concentration of 60 mg / mL for further dilution into 0.9% saline infusion bags prior to IV administration (by infusion).

[0425] The dose will be calculated based upon dose cohort assignment and the patient’s body weight in kilograms. Dose readjustments will not be performed during a cycle, unless there is a >10% change in body weight from Day 1 of the cycle.

[0426] Pre-medications (e.g., diphenhydramine, acetaminophen) are recommended at subsequent dosing events as needed, if manageable infusion-related reactions are observed. Steroids should be avoided as pre-medication / prophylaxis.

[0427] BT7480 will be administered as an IV infusion over 60 (-5 / +15) minutes (i.e., infusion periods between 55 and 75 minutes are acceptable), once weekly (or as specified after consultation with the SRC).

[0428] Nivolumab

[0429] Nivolumab will be provided as 40 mg / 4 mL, 100 mg / 10 mL, and 240 mg / 24 mL vials. The dose administered during the study will be 240 mg once every 2 weeks (Q2W).

[0430] Nivolumab should be diluted with either 0.9% sodium chloride injection or 5% dextrose injection to a final concentration ranging from 1 mg / mL to 10 mg / mL. The total volume of infusion must not exceed 160 mL. Pre-medications for nivolumab should be per local standard of care (e.g., acetaminophen, diphenhydramine). Steroids should be avoided as pre-medication / prophylaxis.

[0431] Nivolumab 240 mg, as part of combination therapy, will be administered as an IV infusion over 30 (-5 / +15) minutes Q2W. The total duration of nivolumab administration will be based on patient response to treatment and Investigator judgment.

[0432] On nivolumab-coincident dosing days, BT7480 should be administered first, followed by observation for at least an hour, and then nivolumab should be administered as an IV infusion after proper flushing of the initial line or via a separate line.

[0433] ENDPOINTS

[0434] Primary Endpoints

[0435] Phase 1

[0436] • Incidence and severity of treatment-emergent adverse events (TEAEs), potentially including abnormalities in laboratory assessments, ECG findings, and vital signs using the NCI CTCAE version 5.0.

[0437] Phase 2

[0438] • Overall response rate (ORR), defined as complete response (CR) plus partial response (PR), by RECIST 1.1 based on Investigator assessment; and

[0439] • Clinical benefit rate (CBR), defined as the proportion of patients with CR, PR, or stable disease (SD) for >8 weeks, by RECIST 1.1 based on Investigator assessment.

[0440] Secondary Endpoints

[0441] Phase 1

[0442] • ORR by RECIST 1.1 based on Investigator assessment; and

[0443] • CBR, defined as the proportion of patients with CR, PR, or SD for >8 weeks, by RECIST 1.1 based on Investigator assessment.

[0444] Phase 2

[0445] • Incidence and severity of TEAEs, including abnormalities in laboratory assessments, ECG findings, and vital signs using the NCI CTCAE version 5.0.

[0446] Phase 1 and Phase 2 • Duration of response (DoR), defined as the time between the initial response to therapy (CR or PR) and subsequent disease progression, by RECIST 1.1;

[0447] • Progression-free survival at 6 months and overall, time to progression, duration of response, overall survival at 12 months, and time to response in patients treated with BT7480 as a monotherapy or in combination with nivolumab;

[0448] • PK parameters for BT7480 in patients with normal and decreased renal function treated with BT7480 as a monotherapy or in combination with nivolumab;

[0449] • Incidence of AD As in patients treated with BT7480 as a monotherapy or in combination with nivolumab; and

[0450] • Determination of CD 137 target engagement in peripheral blood of patients treated with BT7480 as a monotherapy or in combination with nivolumab.

[0451] Exploratory Endpoints

[0452] Phase 1 and Phase 2

[0453] • Assessment of potential changes in immune cell activation (transcriptomic and proteomic profiling) in blood and tumor of patients treated with BT7480;

[0454] • Assessment of potential changes in spatial proteomic profiles between immune cells and tumor cells in patients treated with BT7480;

[0455] • Assessment of potential changes in soluble target and inflammatory cytokines in the plasma from baseline in patients treated with BT7480;

[0456] • Assessment of biomarkers from baseline tumor and peripheral blood samples such as, but not limited to, Nectin-4, CD137, programmed cell death protein 1 / programmed death ligand 1 (PD-L1);

[0457] • Evaluation of germline PGx in patients treated with BT7480; and

[0458] • Quantification of ctDNA in patients treated with BT7480.

[0459] PHARMACOKINETIC ASSESSMENTS

[0460] PK characterization of BT7480, as a monotherapy and in combination with nivolumab, will be performed with validated bioanalytical method(s) and will include calculation of the following parameters using noncompartmental analysis: • Maximum plasma concentration (Cmax);

[0461] • Time to C max,

[0462] • Terminal half-life;

[0463] • Area under the plasma concentration-time curve from time 0 to time t;

[0464] • Area under the plasma concentration-time curve from time 0 to infinity;

[0465] • Apparent total body clearance of the drug from plasma; and

[0466] • Apparent volume of distribution.

[0467] The following PK parameters will be calculated using urine concentrations of BT7480 where available:

[0468] • Cumulative amount of BT7480 excreted in the urine;

[0469] • Renal clearance; and

[0470] • Fraction of dose excreted renally.

[0471] CORRELATIVE TESTING:

[0472] Patients must submit fresh or archival tumor tissue at baseline for histologic or cytologic confirmation, for assessment of Nectin-4 expression levels, and additional molecular or genetic characterization such as, but not limited to, markers of immune status (e.g., PD-L1 expression and immune cell infiltration), proliferation (e.g., Ki-67), and / or immunogenic cell death.

[0473] Paired (pre- and on-treatment) tumor biopsies may be collected to investigate intratumoral PK and pharmacodynamic effects of BT7480.

[0474] Pre- and post-dose blood samples will be collected to assess pharmacodynamic response, biomarkers associated with BT7480 response, and treatment resistance biomarkers.

[0475] STATISTICAL ANALYSES:

[0476] The following analysis populations will be defined. Analysis populations will be defined separately for each study phase.

[0477] The Full Analysis Set will include all enrolled patients.

[0478] The Safety Analysis Set will include all patients who receive at least 1 dose of BT7480. The Response-Evaluable Analysis Set will include all patients who receive at least 1 dose of BT7480 and have at least 1 evaluable post-baseline RECIST 1.1 assessment.

[0479] The PK Analysis Set will include all patients who receive at least 1 dose of BT7480 and have at least 3 measurable post-dose plasma concentrations.

[0480] Other analysis sets may be defined as appropriate and, if applicable, will be described in the Statistical Analysis Plan.

[0481] No formal hypothesis testing is planned, and summaries will in general be descriptive. Appropriate summaries will be provided for each assessment based on data type (continuous or categorical).

[0482] Unless described otherwise, analyses will in general be presented separately by study phase and BT7480 dose level (in Phase 1) and cohort (in Phase 2). As appropriate for Phase 1 summaries, renal impairment cohort patients and patients treated with combination therapy may be presented separately depending on the analysis.

[0483] For Phase 2, the primary efficacy analysis will present the point estimates of the ORR and CBR along with the associated 95% exact confidence intervals for the Safety Analysis Set. To be included in the calculation of ORR, the response should be confirmed at the next RECIST 1.1 assessment. If a patient has a response of SD (or better) occurring prior to 8 weeks and no subsequent assessment, then the patient will be counted as a failure in calculation of the CBR. If the Safety Analysis Set and the Response-Evaluable Analysis Set differ, then a sensitivity analysis may be performed using the Response-Evaluable Analysis Set.

[0484] For secondary efficacy analysis, time-to-event endpoints (progression-free survival, time to progression, duration of response, overall survival, and time to response) will be summarized using Kaplan-Meier methods. Additional details regarding censoring rules will be provided in the Statistical Analysis Plan. The level of CD137 target engagement in peripheral blood will be summarized descriptively.

[0485] Safety analyses will be performed using the Safety Analysis Set. Safety assessments will be summarized descriptively with actual values and change from baseline for continuous variables. TEAEs, serious AEs, and DLTs will be summarized by System Organ Class and Preferred Term. Additional summaries of AEs by severity, seriousness, and relationship to study drug(s) will be presented. The incidence of AD As will be summarized. Additional details will be provided in the Statistical Analysis Plan.

[0486] PK parameters for BT7480 will be calculated using standard noncompartmental analysis methods and summarized using descriptive statistics. PK concentration data will be summarized using descriptive statistics. Plasma BT7480 concentrations will be plotted against timepoints (linear and semi-logarithmic). Additional details will be provided in the Statistical Analysis Plan.

[0487] No formal interim analysis is planned in Phase 2.

[0488] Available safety, PK, and pharmacodynamic data, including efficacy data, will be reviewed on an ongoing basis by the SRC.

[0489] SAMPLE SIZE DETERMINATION

[0490] The entire study will enroll a total of approximately 200 patients.

[0491] Phase 1

[0492] In Phase 1, the total number of patients enrolled will be approximately 110 patients (including optional cohorts). The sample size will be determined from the observed data and the RP2D determination. Approximately 80 patients are planned to be enrolled into monotherapy dose escalation cohorts. Approximately 12 patients with moderate renal impairment may be enrolled for dose confirmation at a dose based on the totality of PK, pharmacodynamic, safety, and efficacy in patients with normal renal function and mild renal impairment (eGFR >60 mL / min). Following monotherapy RP2D determination, approximately 12 patients may be enrolled into combination therapy dose escalation cohorts.

[0493] An intended 12 patients for the moderate renal impairment cohorts are deemed sufficient to demonstrate any gross renal effects, for example, more than doubling of the area under the curve in the renally impaired. The degree of inter-individual variation is not currently known as this is a FH4 study, and therefore, a formal sample size calculation cannot be undertaken.

[0494] In some indications such as bladder cancer, as many as 50% of patients might have some degree of renal impairment. This cohort allows for inclusion of such patients in early phase oncology research whilst also giving an initial gross estimate of the impact of renal impairment in this agent which is predicted to undergo significant renal filtration.

[0495] Phase 2

[0496] Upon RP2D determination for monotherapy and combination therapy, the protocol may proceed to include an additional 45 evaluable patients in each cohort for Phase 2. The total number of patients planned to be enrolled in Phase 2 is approximately 90 (including optional cohorts).

[0497] CLINICAL LABORATORY ANALYTES Standard Safety Chemistry Panel

[0498] Albumin

[0499] Alanine aminotransferase

[0500] Alkaline phosphatase Amylase

[0501] Aspartate aminotransferase Bicarbonate / carbon dioxide

[0502] Blood urea nitrogen Calcium

[0503] Chloride Creatine kinase

[0504] Creatinine Estimated glomerular filtration rate [1]

[0505] Glucose Lactate dehydrogenase

[0506] Lipase Magnesium

[0507] Potassium Sodium

[0508] Total bilirubin Total protein

[0509] Uric acid [2]

[0510] 1. Estimated glomerular filtration rate in mL / min will be calculated using the CKD-EPI equation.

[0511] 1. To be analyzed for optional renal impairment cohorts only.

[0512] CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration

[0513] Additional Chemistry Parameters

[0514] Glycosylated hemoglobin

[0515] Endocrinology

[0516] Adrenocorticotropic hormone [1] Follicle-stimulating hormone [2]

[0517] Human chorionic gonadotropin [3] Thyroid hormones [1] [4]

[0518] 1. Only for patients receiving nivolumab. 2. Follicle-stimulating hormone in postmenopausal women with amenorrhea for at least 1 year at screening.

[0519] 3. Serum or urine pregnancy test for women of childbearing potential only.

[0520] 4. Includes free triiodothyronine, free thyroxine, and thyroid-stimulating hormone.

[0521] Hematology

[0522] Hematocrit Hemoglobin

[0523] Platelets Red blood cell count

[0524] White blood cell count and differential [1]

[0525] 1. Must include a 5-part white cell differential count.

[0526] Coagulation

[0527] Fibrinogen International normalized ratio

[0528] Prothrombin time Partial thromboplastin time

[0529] Immunology

[0530] Antinuclear antibody [1] Rheumatoid factor [1]

[0531] 1. Only for patients receiving nivolumab.

[0532] Urinalysis [1]

[0533] Bilirubin Blood

[0534] Glucose Ketones

[0535] Leukocyte esterase Microscopy

[0536] Nitrite pH

[0537] Protein Specific gravity

[0538] Urobilinogen

[0539] 1. A full urinalysis must be performed at screening, Cycle 1 visits, and end of treatment, and may be substituted with a dipstick with reflex sedimentation at all other visits. Viral Testing and Serology

[0540] Hepatitis B core antibody Hepatitis B DNA [1] Hepatitis B surface antigen Hepatitis C antibody Hepatitis C RNA [2] 1. PCR for viral load is to be performed if positive for hepatitis B core antibody or hepatitis B surface antigen.

[0541] 2. PCR for viral load is to be performed if positive for hepatis C antibody.

[0542] DNA = deoxyribonucleic acid; PCR = polymerase chain reaction; RNA = ribonucleic acid.

[0543] RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1

[0544] The general guidelines for the implementation of Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for the Investigator assessment of tumor burden is provided below.

[0545] Baseline disease assessment will include radiographic tumor measurements using computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis, and / or any other areas with suspected disease involvement as close as possible to the treatment start and never more than 28 days prior to first dosing of the study drug. Patients with central nervous system metastases must have brain imaging (MRI preferred; CT with contrast is acceptable if MRI is contraindicated) during screening. For each modality, contrast agent (intravenous and / or oral) should be utilized unless there is a clear contraindication for contrast agent use (eg, decreased renal function, allergy not amenable to standard prophylactic treatment). Chest CT does not require intravenous contrast.

[0546] Starting with Cycle 3, disease assessment by Investigator per RECIST 1.1 should be performed every 8 weeks (±7 days) through 12 months, then every 12 weeks (±28 days) thereafter until disease progression, initiation of a new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first. It is also acknowledged that disease progression may require, in certain circumstances, further evaluation for possible pseudo-progression.

[0547] Measurable and non-measurable lesions

[0548] Patients with at least 1 tumor lesion or a malignant lymph node (either measurable or non-measurable) that can be accurately assessed at baseline will be included in the study.

[0549] Previously irradiated lesions or lesions subject to other local / regional therapy may be considered measurable disease if there has been demonstrated progression.

[0550] Tumor lesions and malignant lymph nodes will be categorized as measurable or non-measurable as follows: • Measurable tumor lesion: The longest diameter of the tumor lesion in the plane of measurement should be recorded. To be considered measurable, tumor lesions must be accurately measured in at least 1 dimension with a minimum size of: o 10 mm by CT scan slice thickness / interval <5 mm; o 10 mm by caliper measurement on clinical exemption; or

[0551] Note: Lesions which cannot be accurately measured with calipers should be recorded as non-measurable. o 20 mm by chest X-ray.

[0552] • Measurable malignant lymph node: To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (recommended slice thickness is <5 mm). At baseline and at follow-up, only the short axis should be measured.

[0553] • Non-measurable lesions: Non-measurable lesions include small tumor lesions (longest diameter <10 mm) or pathological lymph nodes (short axis >10 to <15 mm at baseline).

[0554] Truly non-measurable lesions include leptomeningeal disease, ascites, pleural effusion, pericardial effusion, inflammatory breast disease, lymphangitic involvement of the skin or lungs, and abdominal masses / organomegaly identified during physical examination that is not measurable by CT or MRI.

[0555] Special considerations to lesion measurability

[0556] Bone lesions'. Bone scan, positron emission tomography (PET) scan, or plain X-ray films are not considered adequate imaging techniques to measure bone lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions.

[0557] Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, can be considered measurable if the soft tissue component meets the definition of measurability described above. Blastic bone lesions are considered non-measurable. Cystic lesions'. Cystic lesions thought to represent cystic metastases can be considered measurable lesions if they meet the criteria for measurability from a radiological point of view, but if non-cystic lesions are present in the same patient, these should be selected as target lesions.

[0558] Target and non -target lesions

[0559] Target lesions

[0560] A maximum of 5 measurable lesions (with a maximum of 2 lesions / organ), representative of all involved organs should be identified as target lesions at baseline. Pathological lymph nodes which are defined as measurable (short axis >15 mm by CT scan) may be identified as target lesions.

[0561] Target lesions should be selected based on their size (longest diameter for non -nodal lesions or short axis for nodal lesions) and in addition should lend themselves to reproducible repeated measurements. When the largest lesion does not lend itself to reproducible measurement, the next largest lesion which can be measured reproducibly should be selected.

[0562] A ‘sum of diameters’ (longest diameter for non-nodal lesions or short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are selected as measurable lesions, only the short axis is added into the sum, even if the nodes regress to below 10 mm in the study. The baseline sum of diameters will be used as reference to further characterize any objective tumor regression with regards to measurable disease.

[0563] Some special situations for target lesion measurement are listed below:

[0564] • If a target lesion disappears completely, the longest diameter should be recorded as 0 mm;

[0565] • If a target lesion is believed to be present, is faintly seen, and too small to measure, a default value of 5 mm should be assigned. If an accurate measure can be given, this should be recorded, even if it is below 5 mm;

[0566] • When nodal disease is included in the sum of diameters and the nodes decrease to ‘normal’ size (<10 mm), a measurement may still be reported on scans. This measurement should be recorded even though the nodes are normal, in order to not overstate progression should it be based on an increase in size of the nodes; • If a target lesion splits into 2 or more parts, then the sum of diameters of all parts should be recorded;

[0567] • If 2 or more target lesions merge, then the sum of diameters of the combined lesion should be recorded for 1 of the lesions and 0 mm recorded for the other lesion(s); and

[0568] • If a target lesion cannot be measured accurately due to it being too large, an estimate of the size of the lesion should be provided.

[0569] Non-target lesions

[0570] All other lesions (or sites of disease) including pathological lymph nodes (ie, short axis >10 mm but <15 mm) should be identified as non-target lesions and should be recorded at baseline. Nodes that have a short axis <10 mm are considered non-pathological and should not be recorded or followed. In addition, multiple non-target lesions involving the same organ may be recorded as a single item on the electronic case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).

[0571] Modalities for disease assessment

[0572] The same modality of assessment and the same technique should be used to characterize each identified and recorded lesion at baseline and follow-up visits. All baseline evaluations should be performed as close as possible to the treatment start and never more than 28 days prior to first dosing of the study drug using the following modalities:

[0573] • CT scan or MRI: CT scan with intravenous contrast is the best currently available and reproducible method to measure lesions selected for response assessment. RECIST 1.1 defines measurability of lesions on CT scan based on the assumption that a CT slice thickness is <5 mm. When CT scans have slice thickness >5 mm, the minimum size for a measurable lesion should be twice the slice thickness. When intravenous contrast cannot be administered (eg, allergic reaction to contrast agent), a non-contrast CT of the chest is still preferred over MRI or chest X-ray. MRI is acceptable and can be used when CT scanning is not feasible or is medically contraindicated. • Calipers / color photography with ruler: Clinical lesions will be considered measurable only when they are superficial and are >10 mm diameter as measured using calipers (eg, skin nodules). Documentation by color photography with a ruler is recommended for skin lesions.

[0574] • X-ray: CT scans are more sensitive than X-rays for identifying new lesions, and hence a chest CT scan is preferred over a chest X-ray particularly when progression is an important endpoint. However, lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung tissue.

[0575] • Fluorodeoxyglucose (FDG)-PET scan: FDG-PET scans may be used for identifying new lesions during assessment of progression. New lesions will be recorded if positive FDG uptake (defined as an uptake greater than twice that of the surrounding tissue) is recorded as follows: o In a location not present on baseline FDG-PET scan; or o In a location corresponding to a new lesion identified by CT scan or MRI at the same visit. When a baseline FDG-PET scan is not available or in the absence of evidence of new lesions by CT scan or MRI, a follow-up CT scan or MRI should be scheduled as per protocol or as clinically indicated.

[0576] • Ultrasound: Ultrasound is not useful in the assessment of lesion size and should not be used as a method of measurement. Ultrasound examination can, however, be used to identify the presence of new lesions. If new lesions are identified by an ultrasound during the course of the study, a CT or MRI confirmation is requested.

[0577] • Endoscopy, laparoscopy, tumor markers, cytology, histology: The utilization of these techniques alone will not be used for objective tumor response measurements.

[0578] Tumor response evaluation

[0579] The definition of criteria used to determine objective tumor response is provided in Table 13.

[0580] Table 13. Response Evaluation Criteria per RECIST 1.1

[0581] The evaluation of overall response is provided in Table 14.

[0582] Table 14. Evaluation of Overall Response

[0583] New lesions

[0584] The presence of 1 or more new lesions is assessed as progressive disease (PD). A lesion identified at a follow-up assessment in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate PD. The finding of a new lesion should be unequivocal, ie, not attributable to differences in scanning technique, change in imaging modality, or findings thought to represent something other than a tumor. If a new lesion is equivocal, eg, because of its small size, the treatment and tumor assessments should be continued until the new lesion has been confirmed. If repeat scans confirm there is a new lesion, then the progression date should be declared using the date of the initial scan.

[0585] Special considerations to response evaluation

[0586] Missing assessments and non-evaluable designation'. When no imaging / measurement is done at all at a timepoint, the patient is not evaluable (NE) at that timepoint. If only a subset of lesion measurements is made at an assessment, usually the case is also considered NE at that time point, unless a convincing argument can be made that the contribution of the individual missing lesion(s) would not change the assigned timepoint response. This would be most likely to happen in the case of PD.

[0587] Symptomatic progression'. Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of PD at that time should be reported as “symptomatic deterioration.” Every effort should be made to document objective progression even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective response, it is a reason for stopping study treatment.

[0588] Confirmation of response. Confirmation of response (by repeat scans after 4 weeks or as specified in the protocol) is required when response rate is the primary endpoint but is not required in randomized studies or studies with primary survival endpoints (ie, where response is not a primary endpoint).

[0589] SCHEDULE OF ASSESSMENTS

[0590] Table 9. BT7480 Monotherapy - Phase 1 Dose Escalation and Phase 2 Dose Expansion Cohorts

[0591] Footnotes appear at the end of the table.

[0592] Table 9. BT7480 Monotherapy - Phase 1 Dose Escalation and Phase 2 Dose Expansion Cohorts (Continued)

[0593] Note: For procedures marked [X], see Table 12 for the sampling schedule. a. Pre-screening is only applicable if prospective Nectin-4 testing to determine eligibility is required. b. Home health visits may be offered to some sites that are unable to accommodate extended post-dose PK and pharmacodynamic sample collection (see Table 12). c. The DLT period is applicable to dose escalation cohorts only. d. The EOT visit must be performed when a patient permanently discontinues study drug, preferably before new anticancer therapy(ies) are started. This visit should occur within 1 week (±2 days) and no later than 14 days after the last dose of BT7480, and before the safety FU visit. If the EOT and safety FU visit windows coincide, overlapping assessments do not need to be repeated. If the patient finishes treatment without having PD, disease assessment by Investigator per RECIST 1.1 must be performed at EOT unless it has been done within the past 4 weeks. e. The safety FU visit must occur 30 (+5) days after the last dose of BT7480 or before initiation of new anticancer therapy, whichever comes first. If the EOT and safety FU visit windows coincide, overlapping assessments do not need to be repeated.

[0594] f. Additional FU visits after the safety FU visit will be performed every 8 weeks (±28 days) for the first 12 months and every 12 weeks (±28 days) thereafter until disease progression, initiation of new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first. g. After disease progression, patients will be followed every 12 weeks (±28 days) for survival until death or for up to 1 year after the last patient is accrued. Patients may be contacted via outpatient visits or by telephone. h. The visit window may be extended (see footnotes dd and ee). i. On C1D1, complete all procedures and laboratory assessments before starting BT7480 infusion. If screening and laboratory assessments are performed within 72 h prior to starting the first dose ofBT7480, they do not need to be repeated on CID 1 except for ECOG performance status, an abbreviated physical examination, vital signs, and triplicate 12-lead ECGs. j. Administer BT7480 as an IV infusion over 60 (-5 / +15) min (ie, infusion periods between 55 and 75 min are acceptable), QW (or as specified). EOI should be defined as the end time of initial study drug administration before flushing the line. During Cl, the patient must be assessed for infusion related reactions After consultation with SRC, BT7480 may be administered every other week beginning at Cohort 7 of Monotherapy Dose Escalation. If patients are enrolled in the bi-weekly dosing cohort, BT7480 will be administered on DI and D15 and dosing on D8 and D22 will not occur. The exact anatomical location of study drug administration must be captured on the appropriate eCRF. k. After consultation with SRC, prospective testing for Nectin-4 may be required. Pre-screening consent will be obtained prior to prospective Nectin-4 protein expression assessment. l. If pre-screening is implemented, informed consent should only be obtained on receipt of a positive result of Nectin-4 expression on the baseline tumor tissue. m. A full physical examination will include an evaluation of the following: head, ears, nose, throat, cardiovascular, respiratory, gastrointestinal, neurological, dermatological, and musculoskeletal systems and if applicable, the genitourinary system. n. An abbreviated physical examination will include a symptom -based examination per Investigator’s discretion. On CID 1, perform an abbreviated physical examination (and not a full physical examination) if screening assessments have been performed within 72 h prior to starting the first dose of BT7480 on C1D1. o. Recalculate BT7480 dose for patients who experience a >10% change in body weight. Height is only measured at screening and will be used to calculate BMI. p. Assess vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, and temperature) after the patient has rested in the sitting position for at least 5 min. During Cl, vital signs will be collected prior to SOI, during infusion (minimum of every 30 [± 10] min), at EOI (±10) min, post-EOI at 30 and 60 (±10) min, and on C1D1 only post-EOI at 120 (±10) min. During C2 onwards, vital signs will be collected prior to SOI, during infusion (minimum of every 30 [± 10] min), at EOI (±10) min, and post-EOI at 30 and 60 (±10) min. If patients are enrolled in the bi-weekly dosing cohort, vital signs on D8 and D22 will be collected once. q. Obtain 12-lead ECGs (for safety monitoring) after the patient has rested for at least 3 min and assess locally. In addition, screening, C1D1, and C1D15 tracings will be done by a central ECG vendor and stored for possible future analysis (Phase 1 dose escalation cohorts only). During C 1 , ECGs are done on D 1 and D 15 at pre-SOI, EOI, and 60 min post-EOI at the same time as plasma PK sampling (±5 min) . During C2 onwards, ECGs are done on DI pre-SOI and EOI at the same time as plasma PK sampling (±5 min). Pre-SOI ECGs should be obtained before other procedures. All 12-lead ECGs (including those for safety monitoring) will be done in triplicate, and each recording will be separated by approximately 1 min such that the 3 ECGs are collected within a 5 -min window.

[0595] r. Prior medications will be recorded at screening only. Concomitant medications may be given as medically indicated. Any medication taken by the patient during the study, from the time of informed consent until the safety FU visit, will be considered a concomitant medication. All concomitant medications must be recorded in the patient’s eCRF along with the reason for use, dates of administration, and dosages. s. All AEs, regardless of causality or seriousness, will be recorded from the time of informed consent until 30 (+5) days after the last dose of BT7480. The Investigator must continue to follow the patient until resolution / stabilization of any ongoing study drug -related AEs or until the condition becomes chronic in nature. t. After C4, schedule CBC with differential counts on DI and D15 only. See ‘CLINICAL LABORATORY ANALYTES’ section for the complete list of analytes for hematology and coagulation. u. Review C1D1 chemistry results prior to dosing. After C4, schedule chemistry on DI and D15 only. See ‘CLINICAL LABORATORY ANALYTES’ section for the complete list of analytes for chemistry. v. Perform a full urinalysis at screening, Cl visits, and EOT; may substitute dipstick with reflex sedimentation at all other visits. w. Perform pregnancy test for WOCBP only at screening (serum), at the beginning of each treatment cycle starting with C 1 (urine for C 1 , and urine or serum for subsequent cycles), and at safety FU (urine or serum). x. See ‘CLINICAL LABORATORY ANALYTES’ section for viral testing and serology markers. y. See Table 12 for details on PK blood sampling and PK urine sampling by the hour. When a planned BT7480 dose is held due to an AE and administered on a later day in the week, a pre-treatment PK sample should be collected on the actual dosing date and labeled as ‘unscheduled’. z. See Table 12 for details on sample collection for biomarkers planned for this study. aa. Provision of baseline tumor tissue (10 to 15 unstained FFPE slides) is mandatory. The Sponsor, in consultation with the SRC, may decide to require prospective central Nectin-4 testing at any point during the escalation. Pre-screening consent will be obtained prior to prospective Nectin- 4 protein expression assessment. Tumoral Nectin-4 expression will be analyzed for all patients using archival tumor tissue or fresh tumor biopsy collected during screening (or pre-screening, if implemented). Tumor tissue should be provided as a tissue block or as 10 to 15 FFPE unstained slides. bb. During Phase 1 monotherapy (dose escalation [Cohort 3 onwards]), patients may provide optional paired (pre- and on-treatment) tumor biopsies. If the patient has consented to optional paired tumor biopsies, both a pre-treatment baseline tumor biopsy and archival tumor tissue are requested. On-treatment biopsy sampling is allowed at any time after C1D1 and, if applicable and possible, at relapse. During tumor biopsy collection, collect sufficient cores (>3) to provide material for a single frozen PK sample and an FFPE block yielding at least 10 to 15 slides. If collection of tumor tissue using a core needle biopsy is not possible, fine needle aspirate samples will be acceptable if sufficient samples (>5) are collected. cc. For patients with an accessible tumor lesion that is feasible to biopsy and has consented to additional biopsies, perform an on-treatment tumor biopsy and normal skin biopsy. dd. For disease assessment by Investigator per RECIST 1.1, perform a CT or MRI scan, or manual measurement of visual lesions or other types of imaging at screening; every 8 weeks (±7 days) for first 12 months, and every 12 weeks (±28 days) thereafter until disease progression, initiation of new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first. ee. Starting with C3, perform disease assessment by Investigator per RECIST 1.1 every 8 weeks (±7 days) through 12 months, then every 12 weeks (±28 days) thereafter until disease progression, initiation of new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first.

[0596] AE = adverse event; BMI = body mass index; C = Cycle; CBC = complete blood count; CT = computed tomography; D = Cycle Day; DLT = doselimiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOI = end of infusion; EOT = end of treatment; FFPE = formalin-fixed paraffin-embedded; FSH = follicle-stimulating hormone; FU = follow-up; h = hour(s); HbAlC = hemoglobin A1C; min = minute(s); MRI = magnetic resonance imaging; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PK = pharmacokinetic(s); QW = once per week; RECIST = Response Evaluation Criteria in Solid Tumors; screen = screening; SOI = start of infusion; SRC = Safety Review Committee; WOCBP = women of childbearing potential.

[0597] Table 10. BT7480 Monotherapy - Dose Confirmation Renal Impairment Cohort (Optional) - Phase 1

[0598] Footnotes appear at the end of the table.

[0599] Table 10. BT7480 Monotherapy - Dose Confirmation Renal Impairment Cohort (Optional) - Phase 1 (Continued) a. Pre-screening is only applicable if prospective Nectin-4 testing to determine eligibility is required. b. Home health visits may be offered to some sites that are unable to accommodate extended post-dose PK and pharmacodynamic sample collection (see Table 12). c. The EOT visit must be performed when a patient permanently discontinues study drug, preferably before new anticancer therapy(ies) are started. This visit should occur within 1 week (±2 days) and no later than 14 days after the last dose of BT7480, and before the safety FU visit. If the EOT and safety FU visit windows coincide, overlapping assessments do not need to be repeated. If the patient finishes treatment without having PD, disease assessment by Investigator per RECIST 1.1 must be performed at EOT, unless it has been done within the past 4 weeks. d. The safety FU visit must occur 30 (+5) days after the last dose of BT7480 or before initiation of new anticancer therapy(ies), whichever comes first. If the EOT and safety FU visit windows coincide, overlapping assessments do not need to be repeated. e. Additional FU visits after the safety FU visit will be performed every 8 weeks (±28 days) for the first 12 months and every 12 weeks (±28 days) thereafter until disease progression, initiation of new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first. f. After disease progression, patients will be followed every 12 weeks (±28 days) for survival until death or for up to 1 year after the last patient is accrued. Patients may be contacted via outpatient visits or by telephone. g. The visit window may be extended (see footnotes cc and dd).

[0600] h. On C1D1, complete all procedures and laboratory assessments before starting BT7480 infusion. If screening and laboratory assessments are performed within 72 h prior to starting the first dose of BT7480, they do not need to be repeated on C1D1 except for ECOG performance status, an abbreviated physical examination, vital signs, and 12-lead ECGs. i. Administer BT7480 as an IV infusion over 60 (-5 / +15) min (ie, infusion periods between 55 and 75 min are acceptable), QW (or as specified). EOI should be defined as the end time of initial study drug administration before flushing the line. During Cl, the patient must be assessed for infusion -related reactions. After consultation with SRC, BT7480 may be administered every other week (eg, C1D1 and C1D15) beginning at Cohort 7 of Monotherapy Dose Escalation. If patients are enrolled in the bi-weekly dosing cohort, BT7480 will be administered on DI and D15 and dosing on D8 and D22 will not occur. The exact anatomical location of study drug administration must be captured on the appropriate eCRF. j. After consultation with SRC, prospective testing for Nectin-4 may be required. Pre-screening consent will be obtained prior to prospective Nectin-4 protein expression assessment. k. If pre-screening is implemented, informed consent should only be obtained on receipt of a positive result of Nectin-4 expression on the baseline tumor tissue. l. A full physical examination will include an evaluation of the following: head, ears, nose, throat, cardiovascular, respiratory, gastrointestinal, neurological, dermatological, and musculoskeletal systems and if applicable, the genitourinary system. m. An abbreviated physical examination will include a symptom -based examination per Investigator’s discretion. On CID 1, perform an abbreviated physical examination (and not a full physical examination) if screening assessments have been performed within 72 h prior to starting the first dose of BT7480 on C1D1. n. Recalculate BT7480 dose for patients who experience a >10% change in body weight. Height is only measured at screening and will be used to calculate BMI. o. Assess vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, and temperature) after the patient has rested in the sitting position for at least 5 min. During Cl, vital signs will be collected prior to SOI, during infusion (minimum of every 30 [±10] min), at EOI (±10) min, post-EOI at 30 and 60 (±10) min, and on C1D1 only post-EOI at 120 (±10) min. During C2 onwards, vital signs will be collected prior to SOI, during infusion (minimum of every 30 [± 10] min), at EOI (±10), and post-EOI at 30 and 60 (±10) min. If patients are enrolled in the biweekly dosing cohort, vital signs on D8 and D22 will be collected once. p. Obtain 12-lead ECGs (for safety monitoring) after the patient has rested for at least 3 min and assess locally. During Cl, ECGs are done on DI and D15 at pre-SOI, EOI, and 60 min post-EOI at the same time as plasma PK sampling (±5 min). During C2 onwards, ECGs are done on DI pre-SOI and EOI at the same time as plasma PK sampling (±5 min). Pre-SOI ECGs should be obtained before other procedures. All 12-lead ECGs will be done in triplicate, and each recording will be separated by approximately 1 min such that the 3 ECGs are collected within a 5 -min window. q. Prior medications will be recorded at screening only. Concomitant medications may be given as medically indicated. Any medication taken by the patient during the study, from the time of informed consent until the safety FU visit, will be considered a concomitant medication. All concomitant medications must be recorded in the patient’s eCRF along with the reason for use, dates of administration, and dosages. r. All AEs, regardless of causality or seriousness, will be recorded from the time of informed consent until 30 (+5) days after the last dose of BT7480. The Investigator must continue to follow the patient until resolution / stabilization of any ongoing study drug -related AEs or until the condition becomes chronic in nature.

[0601] s. After C4, schedule CBC with differential counts on DI and D15 only. See ‘CLINICAL LABORATORY ANALYTES’ section for the complete list of analytes for hematology and coagulation. t. Review C1D1 chemistry results prior to dosing. After C4, schedule chemistry on DI and D15 only. See ‘CLINICAL LABORATORY ANALYTES’ section for the complete list of analytes for chemistry. u. Perform a full urinalysis at screening, Cl visits, and EOT; may substitute dipstick with reflex sedimentation at all other visits. v. Perform pregnancy test for WOCBP only at screening (serum), at the beginning of each treatment cycle starting with C 1 (urine for C 1 and urine or serum for any subsequent cycles), and at safety FU (urine or serum). w. See ‘CLINICAL LABORATORY ANALYTES’ section for viral testing and serology markers. x. See Table 12 for details on PK blood sampling and PK urine sampling by the hour. When a planned BT7480 dose is held due to an AE and administered on a later day in the week, a pre-treatment PK sample should be collected on the actual dosing date and labeled as ‘unscheduled’. y. See Table 12 for details on sample collection for biomarkers planned for this study. z. Provision of baseline tumor tissue (10 to 15 unstained FFPE slides) is mandatory. The Sponsor, in consultation with the SRC, may decide to require prospective central Nectin-4 testing at any point during the escalation. Tumoral Nectin-4 expression will be analyzed for all patients using archival tumor tissue or fresh tumor biopsy collected during screening (or pre-screening, if implemented). Pre-screening consent will be obtained prior to prospective Nectin-4 protein expression assessment. Tumor tissue should be provided as a tissue block or as 10 to 15 FFPE unstained slides. aa. Patients in renal impairment cohorts may provide optional paired (pre- and on-treatment) tumor biopsies If the patient has consented to optional paired tumor biopsies, both a pre-treatment baseline tumor biopsy and archival tumor tissue are requested. On-treatment biopsy sampling is allowed at any time after CID 1 and, if applicable and possible, at relapse. During tumor biopsy collection, collect sufficient cores (>3) to provide material for a single frozen PK sample and an FFPE block yielding at least 10 to 15 slides. If collection of tumor tissue using a core needle biopsy is not possible, fine needle aspirate samples will be acceptable if sufficient samples (>5) are collected. bb. For patients with an accessible tumor lesion that is feasible to biopsy and has consented to additional biopsies, perform an on-treatment tumor biopsy and normal skin biopsy. cc. For disease assessment by Investigator per RECIST 1.1, perform a CT or MRI scan, or manual measurement of visual lesions or other types of imaging at screening; every 8 weeks (±7 days) for first 12 months; and every 12 weeks (±28 days) thereafter until disease progression, initiation of new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first. dd. Starting with C3, perform disease assessment by Investigator per RECIST 1.1 every 8 weeks (±7 days) through 12 months, then every 12 weeks (±28 days) thereafter until disease progression, initiation of new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first.

[0602] AE = adverse event; BMI = body mass index; C = Cycle; CBC = complete blood count; CT = computed tomography; D = Cycle Day; DLT = doselimiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOI = end of infusion; EOT = end of treatment; FFPE = formalin-fixed paraffin-embedded; FSH = follicle-stimulating hormone; FU = follow-up; h = hour(s); HbAlC = hemoglobin A1C; min = minute(s); IV = Intravenous(ly); MRI = magnetic resonance imaging; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PK = pharmacokinetic(s); QW = once per week; RECIST = Response Evaluation Criteria in Solid Tumors; screen = screening; SOI = start of infusion; SRC = Safety Review Committee; WOCBP = women of childbearing potential.

[0603] Table 11. Combination Therapy (Optional) - Phase 1 Dose Escalation and Phase 2 Dose Expansion Cohorts

[0604] Footnotes appear at the end of the table.

[0605] Table 11. Combination Therapy (Optional) - Phase 1 Dose Escalation and Phase 2 Dose Expansion Cohorts (Continued)

[0606] Note: For procedures marked [X], see Table 12 for the sampling schedule.

[0607] Note: For combination therapy, EOI refers to the end of BT7480 infusion. a. Pre-screening is only applicable if prospective Nectin-4 testing to determine eligibility is required. b. Home health visits may be offered to some sites that are unable to accommodate extended post-dose PK and pharmacodynamic sample collection (see Table 12). c. The DLT period is applicable for dose escalation cohorts only. d. The EOT visit must be performed when a patient permanently discontinues study drug (BT7480 and / or nivolumab), preferably before new anticancer therapy(ies) are started. This visit should occur within 1 week (±2 days) and no later than 14 days after the last dose of study drug, and before the safety FU visit. If the EOT and safety FU visit windows coincide, overlapping assessments do not need to be repeated. If the

[0608] patient finishes treatment without having PD, disease assessment by Investigator per RECIST 1.1 must be performed at EOT unless it has been done within the past 4 weeks. e. The safety FU must occur 125 (+5) days after the last dose of study drug or before initiation of new anticancer therapy(ies), whichever comes first. If the EOT and safety FU visit windows coincide, overlapping assessments do not need to be repeated. f. Additional FU visits after the safety FU visit will be performed every 8 weeks (±28 days) for the first 12 months and every 12 weeks (±28 days) thereafter until disease progression, initiation of new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first. g. After disease progression, patients will be followed every 12 weeks (±28 days) for survival until death or for up to 1 year after the last patient is accrued. Patients may be contacted via outpatient visits or by telephone. h. The visit window may be extended (see footnotes ff and gg). i. On C1D1, complete all procedures and laboratory assessments before starting BT7480 infusion. If screening and laboratory assessments are performed within 72 h prior to starting the first dose of BT7480, they do not need to be repeated on C1D1 except for ECOG performance status, an abbreviated physical examination, vital signs, and triplicate 12-lead ECGs. j. Administer BT7480 as an IV infusion over 60 (-5 / +15) min (ie, infusion periods between 55 and 75 min are acceptable), QW (or as specified). EOI should be defined as the end time of initial study drug administration before flushing the line. After consultation with SRC, BT7480 may be administered every other week (eg, C1D1 and CID 15) beginning at Cohort 7 of Monotherapy Dose Escalation. If subjects are scheduled for bi-weekly dosing based upon SRC recommendations, dosing on D8 and D22 will not occur. The exact anatomical location of study drug administration must be captured on the appropriate eCRF. k. On nivolumab -coincident dosing days, administer BT7480 first, observe for at least an hour, and then administer nivolumab 240 mg as an IV infusion (after proper flushing of the initial line or via a separate line) over 30 (-5 / +15) min once every 2 weeks as per the USPI, SmPC, or other local labeling. After completion of nivolumab infusion, observe the patient for at least 30 min or per local labeling or institutional practices for AEs and infusion-related reactions. The total duration of nivolumab administration will be based on patient response to treatment and Investigator judgment. The exact anatomical location of study drug administration must be captured on the appropriate eCRF. l. After consultation with SRC, prospective testing for Nectin-4 may be required. Pre-screening consent will be obtained prior to prospective Nectin-4 protein expression assessment. m. If pre-screening is implemented, informed consent should only be obtained on receipt of a positive result of Nectin-4 expression on the baseline tumor tissue. n. A full physical examination will include an evaluation of the following: head, ears, nose, throat, cardiovascular, respiratory, gastrointestinal, neurological, dermatological, and musculoskeletal systems and if applicable, the genitourinary system. o. An abbreviated physical examination will include a symptom -based examination per Investigator’s discretion. On CID 1, perform an abbreviated physical examination (and not a full physical examination) if screening assessments have been performed within 72 h prior to starting the first dose of BT7480 on C1D1. p. Recalculate BT7480 dose for patients who experience a >10% change in body weight. Height is only measured at screening and will be used to calculate BMI. q. Assess vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, and temperature) after the patient has rested in the sitting position for at least 5 min. During Cl, vital signs will be collected prior to SOI, during infusion (minimum of every 30 [± 10] min), at EOI (±10) min, post-EOI at 30 and 60 (±10) min, and on C1D1 only post-EOI at 120 (±10) min. During C2 onwards, vital signs are collected prior to SOI,

[0609] during infusion (minimum of every 30 [± 10] min), at EOI (±10) min, and post-EOI at 30 and 60 (±10) min. If patients are enrolled in the biweekly dosing cohort, vital signs on D8 and D22 will be collected once. r. Obtain 12-lead ECGs (for safety monitoring) after the patient has rested for at least 3 min and assess locally. In addition, screening, C1D1, and C1D15 tracings will be done by a central ECG vendor and stored for possible future analysis (Phase 1 dose escalation cohorts only). During C 1 , ECGs are done on D 1 and D 15 at pre-SOI, EOI, and 60 min post-EOI at the same time as plasma PK sampling (±5 min) . During C2 onwards, ECGs are done on DI pre-SOI and EOI at the same time as plasma PK sampling (±5 min). Pre-SOI ECGs should be obtained before other procedures. All 12-lead ECGs (including those for safety monitoring) will be done in triplicate, and each recording will be separated by approximately 1 min such that the 3 ECGs are collected within a 5 -min window. s. Prior medications will be recorded at screening only. Concomitant medications may be given as medically indicated. Any medication taken by the patient during the study, from the time of informed consent until the safety FU visit, will be considered a concomitant medication. All concomitant medications must be recorded in the patient’s eCRF along with the reason for use, dates of administration, and dosages. t. All AEs, regardless of causality or seriousness, will be recorded from the time of informed consent until 125 +5) days after the last dose of nivolumab. The Investigator must continue to follow the patient until re solution / stabilization of any ongoing study drug-related AEs or until the condition becomes chronic in nature. u. After C4, schedule CBC with differential counts on DI and D15 only. See ‘CLINICAL LABORATORY ANALYTES’ section for the complete list of analytes for hematology and coagulation. v. Review C1D1 chemistry results prior to dosing. After C4, schedule chemistry on DI and D15 only. See ‘CLINICAL LABORATORY ANALYTES’ section for the complete list of analytes for chemistry. w. For patients receiving nivolumab, collect blood samples for the assessment of antinuclear antibody, rheumatoid factor, adrenocorticotrophic hormone, free T3, free T4, and TSH at screening, C2D1, and every 6 months thereafter until disease progression, death, or another withdrawal criterion is met. x. Perform a full urinalysis at screening, Cl visits, and EOT; may substitute dipstick with reflex sedimentation at all other visits. y. Perform pregnancy test for WOCBP only at screening (serum), at the beginning of each treatment cycle starting with C 1 (urine for C 1 , and urine or serum for subsequent cycles), and at safety FU (urine or serum). z. See ‘CLINICAL LABORATORY ANALYTES’ section for viral testing and serology markers. aa. See Table 12 for details on PK blood sampling and PK urine sampling by the hour. When a planned BT7480 dose is held due to an AE and administered on a later day in the week, a pre-treatment PK sample should be collected on the actual dosing date and labeled as ‘unscheduled.’ bb. See Table 12 for the blood collection chart for biomarkers planned for this study. cc. Provision of baseline tumor tissue (10 to 15 unstained FFPE slides) is mandatory. The Sponsor, in consultation with the SRC, may decide to require prospective central Nectin-4 testing at any point during the escalation. Pre-screening consent will be obtained prior to prospective Nectin- 4 protein expression assessment. Tumoral Nectin-4 expression will be analyzed for all patients using archival tumor tissue or fresh tumor biopsy collected during screening (or pre-screening, if implemented). Tumor tissue should be provided as a tissue block or as 10 to 15 FFPE unstained slides. dd. During Phase 1 combination therapy dose escalation, patients may provide optional paired (pre- and on-treatment) tumor biopsies. If the patient has consented to optional paired tumor biopsies, both a pre-treatment baseline tumor biopsy and archival tumor tissue are requested. On- treatment biopsy sampling is allowed at any time after CID 1 and, if applicable and possible, at relapse. During tumor biopsy collection, collect

[0610] sufficient cores (>3) to provide material for a single frozen PK sample and an FFPE block yielding at least 10 to 15 slides. If collection of tumor tissue using a core needle biopsy is not possible, fine needle aspirate samples will be acceptable if sufficient samples (>5) are collected. ee. For patients with an accessible tumor lesion that is feasible to biopsy and has consented to additional biopsies, perform an on-treatment tumor biopsy and normal skin biopsy. ff For disease assessment by Investigator per RECIST 1.1, perform a CT or MRI scan, or manual measurement of visual lesions or other types of imaging at screening; every 8 weeks (±7 days) for first 12 months; and every 12 weeks (±28 days) thereafter until disease progression, initiation of new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first. gg. Starting with C3, perform disease assessment by Investigator per RECIST 1.1 every 8 weeks (±7 days) through 12 months, then every 12 weeks (±28 days) thereafter until disease progression, initiation of new anticancer therapy, withdrawal of consent, death, or study closure, whichever comes first.

[0611] AE = adverse event; BMI = body mass index; C = Cycle; CBC = complete blood count; CT = computed tomography; D = Cycle Day; DLT = doselimiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOI = end of infusion; EOT = end of treatment; FFPE = formalin-fixed paraffin-embedded; FSH = follicle-stimulating hormone; FU = follow-up; h = hour(s); min = minute(s); HbAlC = hemoglobin A1C; MRI = magnetic resonance imaging; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PK = pharmacokinetic(s); QW = once per week; RECIST = Response Evaluation Criteria in Solid Tumors; screen = screening; SmPC = Summary of Product Characteristics; SOI = start of infusion; SRC = Safety Review Committee; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; USPI = United States Prescribing Information; WOCBP = women of childbearing potential.

[0612] Table 12. Peripheral Biomarker Sample Collection Chart - Monotherapy and Combination Therapy - Phase 1 and Phase 2 a. The exact timing of sample collection must be captured on the appropriate electronic case report form and requisition page(s) . b. For combination therapy, EOI refers to the end time of BT7480 administration before flushing the line. c. PK collections at 48 (±12), 72 (±12), and 96 (±12) h post-EOI must be at least 12 h apart. d. Home health visits may be offered to some sites that are unable to accommodate sample collection at 48 (±12), 72 (±12), and 96 (±12) h post- EOI on ClDl and ClD15. e. CD137 RO, circ. mech. proteins, and PK blood samples should not be obtained from the study drug(s) infusion site (eg, if study drug is administered via central venous catheter at any visit, samples should be collected from a peripheral vein). See the Laboratory Manual for further details. The exact anatomical location of sample collection must be captured on the appropriate eCRF page(s). f. Collect urine from SOI to 6 h post-EOI and record the total voided volume. Total voided volume is not required at 24, 48, 72, and 96 h.

[0613] g. CD137 RO assessment 3 h post-EOI should be performed only on C1D1. h. Collect sample once between 24 (±6) to 96 (±12) h post-EOI at the time of PK blood sampling. i. Collect sample on C2D1 only. j . Blood sample should also be collected immediately in the event an infusion-related reaction or suspected cytokine release syndrome is observed. k. Collect sample on CID 1 only.

[0614] ADA = anti-drug antibody; C = Cycle; CD = cluster of differentiation; circ. = circulating; ctDNA = circulating tumor deoxyribonucleic acid; D = Cycle Day; EOI = end of infusion; EOT = end of treatment; h = hour(s); m = minute(s); mech. = mechanistic; NAb = neutralizing antibody; PGx = pharmacogenomic(s); PK = pharmacokinetic(s); Pre-SOI = pre-start of infusion, pre-dose; RNA = ribonucleic acid; RO = receptor occupancy; scr = screening; SOI = start of infusion.

[0615] Example 2 - methods

[0616] BT7480 PK parameters

[0617] Blood samples for PK were collected from patients at predose, 30 minutes post start of infusion, end of infusion, 20 minutes, 1, 3, 6, 24, 48, 72, 96 hours post end of infusion on C1D1 and C1D15. Plasma concentrations of BT7480 were measured using a validated liquid chromatography-tandem mass spectrometry method with the lowest limit of quantification of 2.0 ng / ml. Maximum plasma concentration (Cmax) and area under the concentration-time curve values from time zero to infinity (AUCO-co) were calculated using a non-compartmental analysis approach.

[0618] MultiOmyx™ hyperplexed immunofluorescence assay

[0619] MultiOmyx™ hyperplexed immunofluorescence assay was performed to evaluate the expression of Nectin-4 and / or CD137 in human tumor FFPE (Formalin-Fixed Paraffin- Embedded) samples. To briefly sum up, a slide with a FFPE tissue section was presented to a pathologist for tissue annotation and selection of 30 regions of interest (ROIs) for image analysis. Staining was performed on a tissue section using multiple rounds of staining and dye inactivation. Within each staining round, two cyanine dye labeled (Cy3, Cy5) antibodies were paired together. Antibody clone BLR051F was used for analyzing CD137 expression. After each staining round, the staining signal was imaged followed by dye inactivation, enabling repeated rounds of staining. For each region of interest (ROI), the number of positive cells was divided by the total number of cells and then multiplied by 100. The median value of all ROIs per slide was used as the final value, referred to as the Combined Positive Score (CPS). A value of 1 or greater was considered positive.

[0620] Nectin-4 IHC Protocol

[0621] Reagents / Probes / Antibodies

[0622] Equipment

[0623] Procedure followed 1. Fix and embed the tissue, cut and mount the sections to positively charged slides, deparaffinize and rehydrate the section per standard practice

[0624] 2. Load the samples into the Leica Bond III

[0625] 3. Incubate with Bond Dewax solution for 2 minutes at room temperature

[0626] 4. Incubate with alcohol for 2 minutes at room temperature 5. Wash with B ond Wash S oluti on

[0627] 6. Incubate with Bond Epitope Retrieval Solution 1 for 20 minutes at 100°C

[0628] 7. Rinse with Bond wash solution 8. Block with Bond Peroxide Block for 5 minutes at ambient

[0629] 9. Rinse with Bond Wash Solution

[0630] 10. Block with Dako Protein Block for 10 minutes at ambient

[0631] 11. Rinse with Bond Wash Solution

[0632] 12. Incubate with anti-Nectin-4 antibody (10 ug / ml) diluted in Dako Background Reducing Diluent for 30 min at ambient

[0633] 13. Rinse with Bond wash solution

[0634] 14. Incubate with Post Primary for 15 minutes at ambient

[0635] 15. Rinse with Bond wash solution

[0636] 16. Incubate with Bond Polymer for 15 minutes at ambient

[0637] 17. Rinse with Bond wash solution

[0638] 18. Incubate with Bond Mixed DAB Refine Reagent (Part 1) followed by Bond Mixed DAB Refine Reagent (Part 2) for 10 minutes at ambient

[0639] 19. Rinse with DI water

[0640] 20. Incubate with Bond Hematoxylin for 5 minutes at ambient

[0641] 21. Rinse with DI water

[0642] 22. Rinse with Bond wash solution

[0643] 23. Rinse with DI water

[0644] 24. Unload, dehydrate in graded alcohols and clear in xylene for 7 min at ambient

[0645] 25. Coverslip

[0646] Nectin-4 IHC Scoring

[0647] The Nectin-4 staining results were scored using the H-score method (the sum of the products of the percent of cells x their staining intensity, on a scale of 0-3 where 0 is negative and 3 is strongly stained), or by determining the tumor proportion score (TPS). Example 3 - Analysis of initial BT7480 Phase I trial results

[0648] The baseline characteristics are set out in Figure 3. The overall safety data for BT7480 shows a low number of related TEAEs and >Grade 3 TEAEs (see Figure 4). No AESI reported. Further, BT7480 has generally been well tolerated (see Figure 5).

[0649] The BT7480 clinical PK profile has been consistent and predicable across dose escalation (see Figure 6). In particular, the preliminary BT7480 PK appears dose proportional, indicating exposures are increasing consistently with dose escalation. The between subject PK variability was moderate. The vast majority of BT7480 exposures were eliminated over a ti / 2 of -6-17 hours (see Figure 6A). There was no / limited accumulation after once weekly dosing (see Figure 6C showing the comparison of CID 1 and CID 15).

[0650] The majority (>70%) of patient tumors express Nectin-4, as assessed by Nectin-4 immunohistochemistry (IHC). See Figure 7 left hand graph. For a subset of 22 patients, >60% of tumors express Nectin-4 and CD137, as assessed by Nectin-4 immunohistochemistry (IHC) and MultiOmyx(TM) methods, respectively. BT7480 also demonstrated full target engagement with doses >0.15 mg / kg (Cohort 5), as shown by CD137 receptor occupancy in patient's blood samples. See Figure 7 right hand graph. BT7480 demonstrated robust blood PD (pharmacodynamic) signals at doses >0.3 mg / kg (Cohort 6) in possible association with clinical benefit. There is a dose dependent increase in circulating activated CD4 T cells (FOXP3+CD25+CD4+) (see Figure 8 A, Figure 15A and Figure 17A), CXCL9 (see Figure 8B left hand graph and Figure 17A) and sCD137 (see Figure 8B right hand graph) following BT7480 treatment. There is also an increase in activated CD4 T cells (FOXP3+CD25+CD4+) in disease control versus non-disease control (see Figure 17B and 18). Figure 19 also depicts CXCL9 levels over time for cohorts 1-9. Levels of activated CD4 T cells (FOXP3+CD25+CD4+) were determined by flow immunophenotyping. Blood CXCL9, CXCL10 and sCD137 levels were measured by Olink according to manufacturer’s instructions. All patients in cohorts 6-9 had either an increase in CXCL9 level and CD4 T cell activation, with the majority having an increase in both. The number of patients with increased CXCL9 and CD4 T cell activation are shown in Figure 17A. The heatmap in Figure 15 B shows as increase in CXCL10 and IFN-gamma for cohorts 6-8 and Figure 16 shows that cohorts 6-9 have a greater increase in CXCL10 compared to cohorts 1-5. Clinical PK and clinical CD4+ T cell activation data have been used in PK / PD modeling to identify clinical doses that provide near maximal biomarker change (see Figure 9).

[0651] BT7480 has a promising emerging efficacy. BT7480 response by dose (Figure 10) and by tumor (Figure 11) across Cohorts 1-9 (0.002-2.6 mg / kg QW) for efficacy evaluable patients are shown. The responses are also depicted in a spider plot (Figure 12). As shown in Figure 13, there are 2 out of 2 partial unconfirmed responses in heavily pretreated cervical cancer patients. One patient’s prior lines of therapy = adjuvant cisplatin plus 3 lines of therapy in metastatic setting including prior CPI. More specifically, their prior lines of treatment were adjuvant cisplatin, carboplatin / paclitaxel / bevacizumab, cisplatin, and Atezolizumab / ipatasertib. One patient’s prior lines of therapy = Neo-adjuvant carboplatin + paclitaxel, adjuvant cisplatin, plus 2 lines of therapy in metastatic setting including prior CPI. More specifically, their prior lines of treatment were neo-adjuvant carboplatin / paclitaxel, adjuvant cisplatin, carboplatin / paclitaxel / bevacizumab, and Atezolizumab / ipatasertib. Also, as shown in Figure 14, there are 3 heavily pre-treated patients with stable disease >7 months. Two of the patients have NSCLC and one patient has anal cancer. One NSCLC patient’s prior lines of therapy = 3 prior lines of therapy in metastatic setting including prior CPI. More specifically, their prior lines of treatment were Osimertinib, carboplatin / pemetrexed / zimberelimab, and ABBV-637 / Osimertinib. One NSCLC patient’s prior lines of therapy = 4 prior lines of therapy in metastatic setting including prior CPI. More specifically, their prior lines of treatment were pemetrexed / pembrolizumab, Bevacizumab, docetaxel and SGN-STNV. The patient with anal cancer had three prior lines of therapy. More specifically, their prior lines of treatment were 5 Fluorouracil / mitomycin C, carboplatin / paclitaxel, and Leucovorin calcium / fluorouracil / oxaliplatin.

[0652] BT7480 has shown an emerging safety and tolerability profile with a low number of severe adverse events. Robust clinical biomarkers indicate that BT7480 is a pharmacologically active compound with signals of blood immune activation associated with potential clinical benefit. Two unconfirmed clinical responses have been observed in cervical cancer and three prolonged stable disease (> 7 months) have been observed in NSCLC and anal cancer. Overall, BT7480 has a promising emerging efficacy and tolerability profile. Example 4 - Analysis of further BT7480 Phase I trial results

[0653] Further results have been obtained from the BT7480 Phase I trial (data cuts taken 12 February 2024 and 15 April 2024). The further results build on the results reported in Example 3, and provide further evidence for BT7480 having promising efficacy and safety profiles across a range of solid tumors.

[0654] As of 12 February 2024, 39 patients had received BT7480 (0.002-3.5 mg / kg QW IV), with a median age of 62 years (see Figure 20, which sets out the baseline characteristics for cohorts 1-10). NSCLC was the most common tumor type (n=l 1; 28%) of which all evaluable patients (n=8) were Nectin-4+.

[0655] The overall safety data for BT7480 continues to show a low number of related TEAEs and >Grade 3 TEAEs, and BT7480 continues to be generally well tolerated (see Figure 21). In more detail, any grade TRAEs occurred in 49% of patients with the most common being fatigue (23%) and headache (10%) (Figure 21). None of the patients receiving the highest dose (3.5 mg / kg; n=6) experienced either of these TRAEs; TRAEs were only reported in one patient (25%) in this group. A low rate of Grade >3 TRAEs (5% of patients) and of TRSAEs (8% of patients) were reported (Figure 21), including no patients receiving the highest dose of BT7480 (3.5 mg / kg). There were no reports of drug-induced liver injury (an event of interest). Two patients experienced a DLT (0.6 mg / kg: mucosal inflammation; 2.6 mg / kg: increased ALT(alanine aminotransferase) / AST(Aspartate aminotransferase)) (Figure 21). The maximum tolerated dose has not yet been reached.

[0656] BT7480 response by dose (Figures 22 and 23) across Cohorts 1-10 (0.002-3.5 mg / kg QW) for are shown. The responses are also depicted in a spider plot (Figure 24). Among all treated patients, a best overall response of stable disease (SD) was reported in 12 patients, and there were two unconfirmed PRs, both of which were in patients with cervical cancer. The two cervical cancer patients were heavily pre-treated, and the patient’s prior lines of therapy are as set out in Example 3 above. SD has been observed notably starting in Cohort 7 (0.6 mg / kg QW). Among patients with NSCLC, 4 patients (36%) reported a best overall response of SD. SD was prolonged (>8 months) for three patients (Figure 24), two treated with 0.6 mg / kg (NSCLC) and one treated with 1.3 mg / kg (anal squamous cell carcinoma). The patient’s prior lines of therapy are as set out in Example 3 above.

[0657] Dose proportional PK was generally observed across the dose range tested at CID 1 (see Figure 25. Terminal half-life at 1.3-3.5 mg / kg was approximately 13-18 hours, with minimal BT7480 accumulation at steady state (CID 15) following QW dosing.

[0658] Further to Example 3 and Figure 7, biomarker analyses showed target saturation in peripheral blood at doses >0.15 mg / kg (Figure 26 A). Also, maximum induction of circulating immune activation markers (sCD137, CXCL9, and CD4+ T cells) was observed at doses >1.3 mg / kg with no hook effect at higher doses (Figure 26 B-D).

[0659] BT7480 was well tolerated and showed preliminary antitumor activity in patients with advanced Nectin-4-associated solid tumors. BT7480 continues to show an emerging safety and tolerability profile with a low number of severe adverse events. Two unconfirmed clinical responses have been observed in cervical cancer, and three prolonged stable disease (> 8 months) have been observed in NSCLC (n=2) and anal cancer (n=l). Preliminary biomarker analyses support BT7480 dual targeting of CD 137 and Nectin-4 as demonstrated by enhanced immune cell activation. BT7480 exhibited a PK profile most analogous to that of small molecules, with rapid distribution and a moderate rate of elimination. BT7480 exhibited dose-dependent increase in PK with minimal accumulation at steady-state with a QW regimen. This study remains ongoing, with additional cohorts planned to investigate BT7480 in combination with nivolumab. Overall, BT7480 has a promising efficacy and tolerability profile.

Claims

CLAIMS1. A method of treating a cancer in a human patient, comprising administering to the patient BT7480 or a pharmaceutically acceptable salt thereof.

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

3. The method of claim 2, wherein the treating results in the maintenance or reduction of the volume of the solid tumor.

4. A method of maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer, comprising administering to the patient BT7480 or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein maintaining or reducing the volume of the solid tumor treats the cancer.

6. The method of any one of claims 2 to 5, wherein the volume of the solid tumor is reduced by at least 1%, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30%.

7. The method of claim 6, wherein the volume of the solid tumor is measured by determining the sum of diameters.

8. The method of any one of claims 3-7, wherein the volume of the solid tumor is maintained or reduced when measured at at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, or at least 36 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the volume of the tumor at the first administration.

9. The method of any one of the preceding claims, wherein the treating results in an increase in the number of activated CD4 T cells in the blood of the human patient.

10. The method of claim 9, wherein the number of activated CD4 T cells is measured by determining the number of FOXP3+CD25+CD4+ T cells.

11. The method of claim 10, wherein the number of FOXP3+CD25+CD4+ T cells is increased by at least 1.1 -fold, at least 1.2-fold, at least 1.3 -fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 10-fold.

12. The method of claim 11, wherein the number of FOXP3+CD25+CD4+ T cells are increased when measured at at least 12 hours, at least 24 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, or at least 16 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the number of FOXP3+CD25+CD4+ T cells at the first administration.

13. The method of any one of the preceding claims, wherein the treating results in an increase of the level of CXCL9 in the blood of the human patient.

14. The method of claim 13, wherein the level of CXCL9 is increased by at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, or at least 5.5-fold.

15. The method of claim 13 or 14, wherein the level of CXCL9 is increased when measured at at least 50 days or at least 100 days after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of CXCL9 at the first administration.

16. The method of any one of claims 13 to 15, wherein the level of CXCL9 is increased when measured at at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks,at least 6 weeks, at least 7 weeks, or at least 8 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of CXCL9 at the first administration.

17. The method of any one of claims 13 to 16, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered in a 4-week treatment cycle, and the level of CXCL9 is increased in the first or second treatment cycle.

18. The method of any one of the preceding claims, wherein the treating results in an increase of the level of sCD137 in the blood of the human patient.

19. The method of claim 18, wherein the level of sCD137 is increased by at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, or at least 5.5-fold.

20. The method of claim 18 or 19, wherein the level of sCD137 is increased when measured at at least 50 days or at least 100 days after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of sCD137 at the first administration.

21. The method of any one of claims 18 to 20, wherein the level of sCD137 is increased when measured at at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of sCD137 at the first administration.

22. The method of any one of claims 18 to 21, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered in a 4-week treatment cycle, and the level of sCD137 is increased in the first or second treatment cycle.

23. The method of any one of the preceding claims, wherein the treating results in the increase of the level of CXCL10 in the blood of the human patient24. The method of claim 23, wherein the level of CXCL10 is increased by at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, or at least 5.5-fold.

25. The method of claim 23 or 24, wherein the level of CXCL10 is increased when measured at at least 50 days or at least 100 days after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of CXCL10 at the first administration.

26. The method of any one of claims 23 to 25, wherein the level of CXCL10 is increased when measured at at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of CXCL10 at the first administration.

27. The method of any one of claims 23 to 26, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered in a 4-week treatment cycle, and the level of CXCL10 is increased in the first or second treatment cycle.

28. The method of any one of the preceding claims, wherein the treating results in the increase of the level of IFN-gamma in the blood of the human patient.

29. The method of claim 28, wherein the level of IFN-gamma is increased by at least 1.1- fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.7-fold, at least 2-fold, or at least 2.5-fold.

30. The method of claim 28 or 29, wherein the level of IFN-gamma is increased when measured at at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks after first administration of BT7480, or a pharmaceutically acceptable salt thereof, and compared to the level of IFN-gamma at the first administration.

31. The method of any one of the preceding claims, wherein the cancer is malignant and / or metastatic.

32. The method of any one of the preceding claims, wherein the cancer is an advanced malignancy.

33. The method of any one of the preceding claims, wherein the cancer is associated with Nectin-4 expression.

34. The method of any one of the preceding claims, wherein the cancer is an advanced solid tumor associated with Nectin-4 expression.

35. The method of any one of the preceding claims, wherein the cancer is a malignant solid tumor associated with Nectin-4 expression.

36. The method of any one of the preceding claims, wherein the cancer is associated with CD 137 expression.

37. The method of any one of the preceding claims, wherein the cancer 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, pancreatic cancer, head and neck cancer (e.g. HNSCC), cervical cancer, bladder cancer (e.g. urothelial cancer), and melanoma.

38. The method of any one of the preceding claims, wherein the cancer is selected from the group consisting of urothelial (transitional cell) carcinoma, head and neck squamous cellcarcinoma, non-small cell lung cancer, ovarian carcinoma, breast carcinoma, gastric carcinoma, and esophageal carcinoma.

39. The method of any one of the preceding claims, wherein the cancer 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 (e.g. HNSCC), malignant peripheral nerve sheath tumor (MPNST), cervical cancer, and bladder cancer (e.g. urothelial cancer).

40. The method of any one of the preceding claims, wherein the cancer is selected from the group consisting of lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), head and neck cancer (e.g. HNSCC), cervical cancer, and bladder cancer (e.g. urothelial cancer).

41. The method of any one of the preceding claims, wherein the cancer is selected from the group consisting of cholangiocarcinoma (CHOL), rectal adenocarcinoma (READ), malignant peripheral nerve sheath tumor (MPNST), colorectal cancer (CRC), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), pancreatic cancer (PANC); bladder adenocarcinoma (BLAD), cervical squamous cell carcinoma (CESC), head & neck squamous cell carcinoma (HNSCC), anal squamous cell carcinoma, triple negative breast cancer (TNBC), ovarian cancer (OC), urothelial carcinoma (UC), and gastroesophageal junction adenocarcinoma (GEJ).

42. The method of any one of the preceding claims, wherein the cancer is selected from the group consisting of colorectal cancer, gastrointestinal carcinoma, NSCLC, HNSCC, TNBC, ovarian carcinoma, cervical cancer, and thyroid cancer.

43. The method of any one of the preceding claims, wherein the cancer is selected from the group consisting of cervical cancer (e.g. metastatic cervical cancer), HNSCC, and NSCLC (e.g. metastatic NSCLC).

44. The method of any one of the preceding claims, wherein the cancer is selected from the group consisting of cervical cancer (e.g. cervical squamous cell carcinoma), NSCLC (e.g. lung adenocarcinoma), and anal squamous cell carcinoma.

45. The method of any one of the preceding claims, wherein the cancer is cervical cancer (e.g. cervical squamous cell carcinoma).

46. The method of any one of the preceding claims, wherein the cancer is Stage IV cervical squamous cell carcinoma.

47. The method of any one of claims 1-44, wherein the cancer is NSCLC (e.g. lung adenocarcinoma).

48. The method of any one of claims 1-44, wherein the cancer is anal squamous cell carcinoma (e.g. Stage III).

49. The method of any one of claims 1-44, 47 or 48, wherein the cancer is Stage IV NSCLC (adenocarcinoma) or Stage IIIC anal squamous cell carcinoma.

50. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a frequency of once a week or once every two weeks.

51. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered in a 3-week treatment cycle, and wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered in week 1 and week 2, but not in week 3.

52. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of up to about 7.5 mg / kg, about 0.002 to about 7.5 mg / kg, about 0.01 to about 7.5 mg / kg, about 0.1 to about 7.5 mg / kg,about 0.3 to about 7.5 mg / kg, about 0.6 to about 6.0 mg / kg, about 1.3 to about 5.5 mg / kg, about 2.6 to about 5.75 mg / kg, about 2.6 to about 5.0 mg / kg, or about 3.0 to about 4.0 mg / kg.

53. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.05 to about 7.5 mg / kg, about 0.05 to about 5.0 mg / kg, about 0.05 to about 4.25 mg / kg, or about 0.05 to about 3.9 mg / kg.

54. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.05 to about 3.5 mg / kg.

55. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.6 to about 7.5 mg / kg, about 0.6 to about 5.0 mg / kg, about 0.6 to about 4.25 mg / kg, about 0.6 to about 3.9 mg / kg, or about 0.6 to about 3.5 mg / kg.

56. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1.3 to about 7.5 mg / kg, about 1.3 to about 5.0 mg / kg, about 1.3 to about 4.25 mg / kg, or about 1.3 to about 3.9 mg / kg.

57. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 2.0 to about 4.0 mg / kg, or about 3.0 to about 4.0 mg / kg.

58. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.3 mg / kg to about 5.0 mg / kg, about 0.3 to about 3.5 mg / kg, about 0.3 to about 2.6 mg / kg, about 0.6 mg / kg to about5.0 mg / kg, about 0.6 to about 3.5 mg / kg, about 0.6 to about 2.6 mg / kg, about 1.3 mg / kg to about5.0 mg / kg, about 1.3 to about 3.5 mg / kg, or about 1.3 to about 2.6 mg / kg.

59. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.3 to about 3.5 mg / kg, about 0.6 to about 3.5 mg / kg, about 1.3 to about 3.5 mg / kg, or about 2.6 to about 3.5 mg / kg.

60. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 2.6 mg / kg or about 3.5 mg / kg.

61. The method of any one of the proceeding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 3.5 mg / kg.

62. The method of any of the preceding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

63. The method of any of claims 1 to 61, further comprising administering to the patient a checkpoint inhibitor.

64. The method of claim 63, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

65. The method of claim 64, wherein the anti-PD-1 antibody is nivolumab.

66. The method of claim 65, wherein nivolumab is administered at a frequency of once every two weeks.

67. The method of claim 65 or 66, wherein nivolumab is administered at a dose of about 240mg.

68. The method of any one of claims 63 to 67, wherein (i) the BT7480, or a pharmaceutically acceptable salt thereof, and (ii) the checkpoint inhibitor (e.g. nivolumab) are administered separately.

69. The method of any one of claims 63 to 68, wherein (i) the BT7480, or a pharmaceutically acceptable salt thereof, and (ii) the checkpoint inhibitor (e.g. nivolumab) are administered sequentially.

70. The method of any of the preceding claims, wherein the BT7480, or a pharmaceutically acceptable salt thereof, is administered by an IV infusion.

71. The method of claim 70, wherein the IV fusion is over about 55 to about 75 minutes.

72. The method of claim 70 or 71, wherein the IV fusion is over about 60 minutes.

73. The method of any one of claims 63 to 72, wherein the checkpoint inhibitor (e.g. nivolumab) is administered by an IV infusion.

74. The method of claim 73, wherein the IV infusion is over about 25 to 45 minutes.

75. The method of claim 73 or 74, wherein the IV infusion is over about 30 minutes.

76. The method of any of the preceding claims, wherein the patient has previously received one or more treatment(s) for the cancer.

77. The method of any one of claims 1 to 75, wherein the patient has been previously untreated for the cancer.

78. The method of any one of the preceding claims, wherein the method comprises administering a pharmaceutical composition comprising the BT7480 or a pharmaceutically acceptable salt thereof.

79. The method of claim 78, wherein the pharmaceutical comprises: the BT7480 or a pharmaceutically acceptable salt thereof;Tris base; mannitol; and sodium hydroxide.

80. The method of claim 78 or 79, wherein the pharmaceutical comprises about 66 mg BT7480, or a pharmaceutically acceptable salt thereof.

81. The method of any one of claims 78 to 80, wherein the pharmaceutical composition comprises about 0.1 mg Tris base per mg of BT7480 or a pharmaceutically acceptable thereof, or about 6.6 mg Tris base.

82. The method of any one of claims 78 to 81, wherein the pharmaceutical composition comprises about 0.4 mg mannitol per mg of BT7480 or a pharmaceutically acceptable thereof, or about 26.4 mg mannitol.

83. The method of any one of claims 79 to 82, wherein the amount of sodium hydroxide provides a pH of about 7.0 to about 8.0 or about 7.0 to about 7.5 when the pharmaceutical composition is reconstituted in water.

84. The method of any one of claims 78 to 83, wherein the pharmaceutical composition comprises: about 66 mg BT7480 or a pharmaceutically acceptable salt thereof; about 6.6 mg Tris base; about 26.4 mg mannitol; and sodium hydroxide, wherein the amount of sodium hydroxide provides a pH of about 7.0 to about 7.5 when the pharmaceutical composition is reconstituted in water.

85. The method of any one of claims 78 to 84, which is an aqueous pharmaceutical composition.

86. The method of any one of claims 78 to 85, wherein the pharmaceutical composition has been reconstituted in water from a solid pharmaceutical composition.

87. The method of claim 86, wherein the solid pharmaceutical composition is a lyophilized powder.

88. The method of any one of claims 85 to 87, wherein the pharmaceutical composition comprises about 60 mg / mL BT7480 or a pharmaceutically acceptable salt thereof.

89. The method of any one of claims 85 to 88, wherein the pharmaceutical composition comprises about 6 mg / mL Tris base.

90. The method of any one of claims 85 to 89, wherein the pharmaceutical composition comprises about 24 mg / mL mannitol.

91. The method of any one of claims 85 to 90, wherein the pharmaceutical composition is at a pH of about 7.0 to about 8.0 or about 7.0 to about 7.5.

92. The method of any one of claims 85 to 91, wherein the pharmaceutical composition is at a volume of about 1.1 mL.

93. The method of any one of claims 85 to 92, wherein the pharmaceutical composition comprises: about 60 mg / mL BT7480 or a pharmaceutically acceptable salt thereof; about 6 mg / mL Tris base; about 24 mg / mL mannitol; sodium hydroxide; and water, wherein the pharmaceutical composition is at a pH of about 7.0 to about 7.5.

94. The method of any one of claims 85 to 93, wherein the pharmaceutical composition further comprises sodium chloride.

95. BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a human patient comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof.

96. BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof.

97. A pharmaceutical composition comprising BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a human patient comprising administering to the patient the pharmaceutical composition.

98. A pharmaceutical composition comprising BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of maintaining or reducing the volume of a solid tumor in a human patient suffering from a cancer comprising administering to the patient the pharmaceutical composition.

99. Use of BT7480 or a pharmaceutical acceptable salt thereof, in the manufacture of a medicament for use in a method of treating a cancer in a human patient comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof.

100. Use of BT7480 or a pharmaceutical 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 human patient suffering from a cancer comprising administering to the patient the BT7480 or a pharmaceutically acceptable salt thereof.

101. The BT7480, or a pharmaceutically acceptable salt thereof, for use of claim 95 or 96, the pharmaceutical composition for use of claim 97 or 98, or the use of claim 99 or 100, wherein the method is the method of any one of claims 1 to 94.

102. The use of any one of claims 99 to 101, wherein the medicament is a pharmaceutical composition comprising BT7480 or a pharmaceutical acceptable salt thereof.

103. The use of any one of claims 99 to 102, wherein the medicament is the pharmaceutical composition as defined in any one of claims 78 to 94.

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