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WO2025125809A1 - Ligands peptidiques bicycliques spécifiques de la nectine-4 et leurs utilisations - Google Patents

Ligands peptidiques bicycliques spécifiques de la nectine-4 et leurs utilisations Download PDF

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Publication number
WO2025125809A1
WO2025125809A1 PCT/GB2024/053097 GB2024053097W WO2025125809A1 WO 2025125809 A1 WO2025125809 A1 WO 2025125809A1 GB 2024053097 W GB2024053097 W GB 2024053097W WO 2025125809 A1 WO2025125809 A1 WO 2025125809A1
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Prior art keywords
patient
dose
agent
pharmaceutically acceptable
pathway
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English (en)
Inventor
Amy DICKSON
Cong XU
Santiago ARROYO
Sebastien HAZARD
Lei Xu
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BicycleTx Ltd
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BicycleTx Ltd
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Priority claimed from GBGB2417804.8A external-priority patent/GB202417804D0/en
Application filed by BicycleTx Ltd filed Critical BicycleTx Ltd
Publication of WO2025125809A1 publication Critical patent/WO2025125809A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to Bicycle toxin conjugates, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
  • the present invention also provides uses of Bicycle toxin conjugates, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for preventing or treating a disease, disorder, or condition characterized by overexpression of Nectin-4 in diseased tissue.
  • 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.
  • 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.
  • macrocycles bind to surfaces of several hundred square angstrom, as for example the cyclic peptide CXCR4 antagonist CVX15 (400 ⁇ 2 ; Wu et al.
  • MMP-8 matrix metalloproteinase 8
  • 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.
  • the present invention provides a method for treating a cancer in a patient, comprising administering BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1/PD-L1 pathway to the patient.
  • the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising administering BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway to the patient.
  • the invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides an agent that inhibits the PD-1/PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1/PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.
  • the invention provides an agent that inhibits the PD-1/PD-L1 pathway for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1/PD- L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.
  • the invention provides a combination of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides a combination of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides the use of BT8009 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides the use of BT8009 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides the use of an agent that inhibits the PD- 1/PD-L1 pathway in the manufacture of a medicament for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1/PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of an agent that inhibits the PD- 1/PD-L1 pathway in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1/PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.
  • the present invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of treating a cancer in a patient, wherein the patient has previously received or is scheduled to receive an agent that inhibits the PD-1/PD-L1.
  • the present invention provides an agent that inhibits the PD- 1/PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the patient has previously received or is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof.
  • BT8009 is a Bicycle toxin conjugate having a structure as shown below, wherein the molecular scaffold is 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)triprop- 2-en-1-one (TATA), and the peptide ligand comprises the amino acid sequence: ( ⁇ -Ala)-Sar 10 -C 1 P[1Nal][dD]C ii M[HArg]DWSTP[HyP]WC iii (SEQ ID NO: 1) wherein Sar is sarcosine, 1Nal represents 1-naphthylalanine, HArg represents homoarginine, HyP represents hydroxyproline and C i , C ii and C iii represent first, second and third cysteine residues.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 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.
  • 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.
  • 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.
  • the term “about” shall have the meaning of within 10% of a given value or range.
  • the term “about” refers to within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.
  • 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.
  • the examples and figures presented herewith also report the first results from a clinical trial of the BT8009 Bicycle toxin conjugate administered in combination with the anti-PD-1 antibody pembrolizumab.
  • the present invention provides methods for treating a cancer in a patient, comprising administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway.
  • the present invention also provides BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD- L1 pathway for use in methods for treating a cancer in a human patient.
  • the present invention also provides the use of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 in the manufacture of medicaments for use in methods for treating a cancer in a human patient.
  • the present invention provides a method for treating a cancer in a patient, comprising administering to the patient BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides an agent that inhibits the PD-1/PD- L1 pathway for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1/PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.
  • the invention provides a combination of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides the use of BT8009 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides the use of an agent that inhibits the PD-1/PD-L1 pathway in the manufacture of a medicament for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1/PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.
  • the present invention provides an agent that inhibits the PD- 1/PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the patient has previously received or is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof.
  • a patient may have one or more solid tumors.
  • the cancer is a solid tumor.
  • the present invention therefore provides methods for treating a solid tumor in a patient. Thereby, the patient suffering from a cancer may be treated.
  • the present invention therefore provides methods for treating a solid tumor in a patient, comprising administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway.
  • the present invention also provides BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway for use in methods of treating a solid tumor in a patient.
  • the invention also provides the use of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway in the manufacture of a medicament for use in methods of treating a solid tumor.
  • the administration of BT8009 or the pharmaceutically acceptable salt thereof results in maintenance of the volume of a solid tumor, or reduces the volume of a solid tumor.
  • the present invention may be seen to provide methods for maintaining or reducing the volume of a solid tumor in a patient.
  • the present invention thus provides methods for maintaining or reducing the volume of a solid tumor in a patient, comprising administering to the patient BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway.
  • the invention also provides BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway for use in methods of maintaining or reducing the volume of a solid tumor in a patient.
  • the invention also provides the use of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway in the manufacture of medicaments for maintaining or reducing the volume of a solid tumor in a patient.
  • the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising administering BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway to the patient.
  • the invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides an agent that inhibits the PD-1/PD-L1 pathway for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1/PD- L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.
  • the invention provides a combination of BT8009 or a pharmaceutically acceptable salt thereof and an agent that inhibits the PD-1/PD-L1 pathway for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides the use of BT8009 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the BT8009 or a pharmaceutically acceptable salt thereof, and an agent that inhibits the PD-1/PD-L1 pathway.
  • the invention provides the use of an agent that inhibits the PD- 1/PD-L1 pathway in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient, wherein the method comprises administering to the patient the agent that inhibits the PD-1/PD-L1 pathway and BT8009 or a pharmaceutically acceptable salt thereof.
  • maintaining the volume of a solid tumor refers to an increase in the volume of the tumor by no more than 75%, no more than 50%, no more than 25%, no more than 10% or no more than 5%.
  • maintaining the volume of a solid tumor refers to the volume of the tumor being unchanged.
  • reducing the volume of a solid tumor refers to a reduction in the volume of the tumor by 100%, by at least 95%, at least 90%, at least 85%, at least 80%, at least 75% or at least 70%, at least 65%, at least 60%, at least 55%, at least 50%, at least 45%, at least 40%, at least 35%, at least 30%, at least 25%, at least 20%, at least 15%, at least 10% or at least 5%.
  • the change in the volume of the tumor is a change relative to the volume of the tumor prior to the commencement of treatment.
  • reference to a volume of a tumor may refer to a sum of volumes of two or more tumors in a patient (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors). In some embodiments, this can be determined by measuring the sum of an axis (e.g. a short axis or the longest diameter) of two or more solid tumors in the patient.
  • reference to a volume of a tumor may refer to an average volume of two or more tumors in a patient (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors).
  • this can be determined by measuring the sum of an axis (e.g. a short axis or the longest diameter) of two or more solid tumors (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors) in the patient and dividing the sum by the number of tumors measured.
  • maintaining or reducing the volume of a solid tumor in a patient as described herein may refer to maintaining or reducing the sum or average volume of two or more solid tumors (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors) in a patient.
  • maintaining the volume of a solid tumor refers to an increase in the sum or average volume of two or more tumors (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors) of no more than 75%, no more than 50%, no more than 25%, no more than 10% or no more than 5%.
  • maintaining the volume of a solid tumor refers to the sum or average volume of the tumors being unchanged.
  • reducing the volume of a solid tumor refers to a reduction in the sum or average volume of two or more tumors (e.g.
  • the change in the sum or average volume of the tumor is a change relative to the sum or average volume of the tumor prior to the commencement of treatment.
  • the volume of the tumor can be maintained or reduced for a period of time until disease progression is documented.
  • disease progression refers to a measurement of the volume of the tumor of greater than a 75% increase in the volume of the tumor relative to the volume of the tumor prior to the commencement of treatment. In some embodiments, disease progression refers to a measurement of the length of an axis of a tumor (or the sum or average of two or more tumors) of greater than 20%.
  • the volume of the tumor is maintained or reduced for at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months or at least 24 months.
  • the volume of a tumor over time may be measured by determining the length of an axis of the tumor.
  • the volume of a solid tumor over time may be measured by determining the length of the longest diameter of the solid tumor.
  • the volume of a solid tumor over time may be measured by determining the length of the short axis of a tumor.
  • a 20% increase in the length of the an axis or diameter of a solid tumor corresponds to an increase in the volume of the solid tumor of approximately 75% (i.e. 1.2 3 ).
  • 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.
  • the volume of a solid tumor over time may be measured by volumetric assessment e.g. using a three-dimensional scan such as a CT scan or MRI scan.
  • the treatment of a cancer or of a solid tumor may cause a complete response of the cancer or solid tumor to said treatment, i.e. the disappearance of all target lesions and all non-target lesions and normalization of tumor marker level.
  • the treatment of a cancer or solid tumor may cause a partial response of the cancer or solid tumor to said treatment, i.e. at least a 30% decrease in the sum of the lengths of an axis (e.g. the longest diameter (LD)) of the target lesions, taking as reference the baseline sum of the lengths of the axis (e.g. longest diameters) of the lesions.
  • the treatment of a cancer or solid tumor may result in stable disease, i.e.
  • a cancer or solid tumor is an advanced malignancy.
  • the cancer, solid tumor or advanced malignancy is associated with Nectin-4 expression.
  • the patient has locally advanced or metastatic urothelial carcinoma, wherein the patient has not received any prior systemic treatment for said locally advanced or metastatic urothelial carcinoma
  • the patient has locally advanced or metastatic urothelial carcinoma, wherein the patient has received one or more prior systemic therapies for said locally advanced or metastatic urothelial carcinoma.
  • the agent that inhibits the PD-1/PD-L1 pathway blocks the interaction between PD-1 and PD-L1.
  • the agent that inhibits the PD- 1/PD-L1 pathway is a PD-1 antagonist.
  • the agent that inhibits the PD- 1/PDL-L1 pathway is an antibody.
  • the agent that inhibits the PD-1/PD- L1 pathway is an anti-PD-1 antibody. In some embodiments, the agent that inhibits the PD- 1/PD-L1 pathway is an anti-PD-L1 antibody.
  • the anti-PD-1 antibody is selected from the list consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP- 224, AMP-514 and acrixolimab.
  • the anti-PD-1 antibody is pembrolizumab.
  • the anti-PD-L1 antibody is selected from the list consisting of atezolizumab, avelumab, durvalumab, KN035 and cosibelimab.
  • a patient is not previously known being intolerant or hypersensitive to an immune checkpoint inhibitor.
  • a patient has not received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, OX-40 agonist or CTLA-4 inhibitors.
  • a patient has received prior treatment with a PD-1, PD-L1 or PD-L2 inhibitor.
  • a patient has no prior organ transplant (including allogeneic). In some embodiments, a patient is not previously diagnosed with clinically relevant immunodeficiency. In some embodiments, a patient does not have active systemic infection requiring therapy. In some embodiments, a patient does not have any condition requiring treatment with ⁇ 10 mg daily prednisone equivalent or other strong immunosuppressant. In some embodiments, a patient does not have an active autoimmune disease that has required systemic treatment in 2 years (e.g. with the use of disease modifying agents, corticosteroids or immunosuppressive drugs) prior to combination treatment with BT8009 and pembrolizumab.
  • replacement therapy e.g., thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency
  • a patient has type 1 DM well controlled on insulin, alopecia, or vitiligo.
  • a patient does not have a history of interstitial lung disease.
  • BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1/PD-L1 pathway are administered separately.
  • BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1/PD-L1 pathway are administered sequentially.
  • BT8009 or the pharmaceutically acceptable salt thereof is administered first followed by the agent that inhibits the PD-1/PD-L1 pathway. In some embodiments, the agent that inhibits the PD-1/PD-L1 pathway is administered first followed by BT8009 or the pharmaceutically acceptable salt thereof. [0069] In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1/PD-L1 pathway are administered at different frequencies.
  • BT8009 or the pharmaceutically acceptable salt thereof is administered on days 1, 8 and 15 of a 21 day treatment cycle or on days 1 and 8 of a 21 day treatment cycle, whereas the agent that inhibits the PD-1/PD-L1 pathway is administered every three weeks or every six weeks.
  • BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1/PD-L1 pathway may both administered on the first day of a treatment cycle (separately, sequentially or simultaneously, as described herein), whereas on other days in the treatment cycle only BT8009 may be administered.
  • the patient is administered BT8009 or a pharmaceutically acceptable salt thereof, and has received an agent that inhibits the PD-1/PD-L1 pathway within the previous 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks.
  • the patient is administered BT8009 or a pharmaceutically acceptable salt thereof, and is scheduled to receive an agent that inhibits the PD-1/PD-L1 pathway within the next 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks.
  • the patient is administered an agent that inhibits the PD-1/PD-L1 pathway, and has received BT8009 or a pharmaceutically acceptable salt thereof received within the previous 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks.
  • the patient is administered an agent that inhibits the PD-1/PD-L1 pathway, and is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof received within the next 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks.
  • a patient may have received or be scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof or an agent that inhibits the PD-1/PD-L1 pathway at the point at which the other component of the combination therapy is administered, for example due to the required dosing regimen of each of the components of the combination therapy of the invention.
  • the patient is administered BT8009 or the pharmaceutically acceptable salt thereof and has received or is scheduled to receive an agent that inhibits the PD-1/PD-L1 pathway.
  • the present invention provides BT8009 or a pharmaceutically acceptable salt thereof for use in a method of treating a cancer in a patient, wherein the patient has previously received or is scheduled to receive an agent that inhibits the PD-1/PD-L1 pathway.
  • the patient is administered an agent that inhibits the PD-1/PD-L1 pathway and has received or is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof.
  • the present invention provides an agent that inhibits the PD-1/PD-L1 pathway for use in a method of treating a cancer in a patient, wherein the patient has previously received or is scheduled to receive BT8009 or a pharmaceutically acceptable salt thereof.
  • BT8009 or the pharmaceutically acceptable salt thereof is administered intravenously.
  • BT8009 or the pharmaceutically acceptable salt thereof is administered by IV infusion.
  • BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1/PD-L1 pathway are administered by separate infusions. In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof and the agent that inhibits the PD-1/PD-L1 pathway are administered by sequential infusions. In some embodiments, BT8009 or the pharmaceutically acceptable salt thereof is administered by a first infusion followed by the agent that inhibits the PD-1/PD-L1 pathway. In some embodiments, the agent that inhibits the PD-1/PD-L1 pathway is administered by a first infusion followed by BT8009 or the pharmaceutically acceptable salt thereof.
  • BT8009 is provided as a liquid formulation or liquid unit dosage form of BT8009 as described herein.
  • a liquid formulation or a liquid unit dosage form of BT8009 as described herein and the agent that inhibits the PD-1/PD- L1 pathway are administered by sequential infusions first with a liquid formulation or a liquid unit dosage form of BT8009 as described herein followed by the agent that inhibits the PD- 1/PD-L1 pathway.
  • a liquid formulation or a liquid unit dosage form of BT8009 as described herein and the agent that inhibits the PD-1/PD-L1 pathway are administered by sequential infusions first with the agent that inhibits the PD-1/PD-L1 pathway followed by a liquid formulation or a liquid unit dosage form of BT8009 as described herein.
  • a liquid formulation or a liquid unit dosage form of BT8009 as described herein and the agent that inhibits the PD-1/PD-L1 pathway are administered separately.
  • BT8009 and the agent that inhibits the PD-1/PD-L1 pathway are administered simultaneously.
  • BT8009 and the agent that inhibits the PD-1/PD-L1 pathway are administered by a single infusion.
  • a patient having a cancer or a solid tumor has been previously untreated for the cancer or solid tumor (i.e. has received no prior lines of treatment for the solid tumor).
  • a patient having a solid tumor has previously received one or more treatments for the cancer or solid tumor.
  • included herewith are data from a clinical trial of BT8009 administered in combination with the anti-PD-1 antibody pembrolizumab as a late line therapy to a heavily pre-treated cohort of patients who have exhausted existing treatment options.
  • a patient having a solid tumor has previously received one or more immune checkpoint inhibitors for the cancer or solid tumor.
  • a patient having a cancer or solid tumor has previously received one or more agents that inhibits the PD-1/PD-L1 pathway.
  • the patient has previously received pembrolizumab.
  • the patient has previously received nivolumab.
  • the methods of the invention comprise the administration of a pharmaceutical composition as described herein.
  • the methods of the invention comprise the administration of a pharmaceutical composition (e.g. a solid pharmaceutical composition of BT8009 or a liquid formulation of BT8009) as described herein.
  • a pharmaceutical composition comprises a pharmaceutically acceptable excipient or carrier.
  • the pharmaceutically acceptable excipient or carrier is selected from a buffering agent, a stabilizer or cryoprotectant, and a surfactant.
  • a pharmaceutical composition comprises a buffering agent.
  • a buffering agent is selected from phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • a buffering agent is L-histidine. In some embodiments, a buffering agent is sodium hydroxide. In some embodiments, a buffering agent is hydrochloric acid. [0083] In some embodiments, a buffering agent is at an amount to adjust pH of a pharmaceutical composition of the invention to about 6-8. In some embodiments, a buffering agent is histidine at an amount of about 1-3 mg per mg of BT8009, or a pharmaceutically acceptable thereof. In some embodiments, histidine is at an amount of about 1.31 or 2.62 mg per mg of BT8009, or a pharmaceutically acceptable thereof. In some embodiments, a liquid pharmaceutical composition of the invention comprises histidine at a concentration of about 5.24 mg/mL.
  • a buffering agent is at an amount to adjust pH of a liquid formulation or a liquid unit dosage form as described herein to about 6-8.
  • a liquid pharmaceutical composition of the invention is at a pH of about 6-8.
  • a liquid pharmaceutical composition of the invention (e.g. a liquid formulation or a liquid unit dose form) is at a pH of about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.
  • a liquid pharmaceutical composition of the invention is at a pH of about 6.5 or 7.0.
  • a pharmaceutical composition comprises a stabilizer or cryoprotectant.
  • a stabilizer or cryoprotectant is dimethyl sulfoxide (DMSO).
  • a stabilizer or cryoprotectant is ethylene glycol.
  • a stabilizer or cryoprotectant is glycerol.
  • a stabilizer or cryoprotectant is propylene glycol.
  • a stabilizer or cryoprotectant is 2- methyl-2, 4-pentanediol (MPD).
  • MPD 2- methyl-2, 4-pentanediol
  • a stabilizer or cryoprotectant is trehalose.
  • a stabilizer or cryoprotectant is mannitol.
  • a stabilizer or cryoprotectant is galactose. In some embodiments, a stabilizer or cryoprotectant is maltose. In some embodiments, a stabilizer or cryoprotectant is formamide. In some embodiments, a stabilizer or cryoprotectant is proline. In some embodiments, a stabilizer or cryoprotectant is glycerol 3-phosphate. In some embodiments, a stabilizer or cryoprotectant is sorbitol. In some embodiments, a stabilizer or cryoprotectant is diethyl glycol. In some embodiments, a stabilizer or cryoprotectant is sucrose.
  • a stabilizer or cryoprotectant e.g., sucrose
  • a stabilizer or cryoprotectant is at an amount of about 10-35 mg per mg of BT8009, or a pharmaceutically acceptable thereof.
  • a stabilizer or cryoprotectant e.g., sucrose
  • a liquid pharmaceutical composition comprises a stabilizer or cryoprotectant (e.g., sucrose) at a concentration of about 60 mg/mL.
  • a pharmaceutical composition comprises a surfactant.
  • a surfactant is a polysorbate (e.g., polysorbate-20, polysorbate-40, polysorbate-60, polysorbate-65, polysorbate-80, polysorbate-85, or a combination thereof).
  • a surfactant is selected from poloxamers (e.g., poloxamer 188); TritonTM; sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl- sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl- sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl- betaine, cetyl-betaine,
  • a surfactant is Polysorbate 20.
  • a surfactant e.g., Polysorbate 20
  • a surfactant is at an amount of about 0.01-0.15 mg per mg of BT8009, or a pharmaceutically acceptable thereof.
  • a surfactant e.g., Polysorbate 20
  • a liquid pharmaceutical composition comprises a surfactant (e.g., Polysorbate 20) at a concentration of about 0.1 or 0.2 mg/mL.
  • a pharmaceutical composition comprises an isotonicity adjusting agent.
  • an isotonicity adjusting agent is sodium chloride, dextrose, calcium chloride, or a combination thereof. In some embodiments, an isotonicity adjusting agent is dextrose. In some embodiments, an isotonicity adjusting agent is sodium chloride. In some embodiments, an isotonicity adjusting agent is a combination of sodium chloride and dextrose. [0090] In some embodiments, the pharmaceutical composition is a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof.
  • a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof comprises a pharmaceutically acceptable excipient or carrier selected from a buffering agent, a stabilizer or cryoprotectant, and a surfactant.
  • BT8009 may be provided as a pharmaceutical composition which comprises a flat unit dose of BT8009 according to a flat dose as described herein.
  • the invention provides a solid unit dose comprising about 21.2 mg of a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof.
  • a solid pharmaceutical composition of BT8009, or a pharmaceutically acceptable salt thereof further comprises L-histidine, sucrose, and Polysorbate 20.
  • the solid pharmaceutical composition of BT8009 comprises: BT8009, or a pharmaceutically acceptable salt thereof; about 1.31 mg L-histidine per mg of BT8009, or a pharmaceutically acceptable thereof; about 15 mg sucrose per mg of BT8009, or a pharmaceutically acceptable thereof; and about 0.025 mg Polysorbate 20 per mg of BT8009, or a pharmaceutically acceptable thereof.
  • the pharmaceutical composition is a solid unit dose, comprising: about 21.2 mg BT8009, or a pharmaceutically acceptable salt thereof; about 27.8 mg L-histidine; about 318 mg sucrose; and about 0.53 mg Polysorbate 20.
  • the pharmaceutical composition is a solid unit dose comprising: about 7-13 mg, optionally about 8-12 mg, optionally about 9-11 mg BT8009, or a pharmaceutically acceptable salt thereof; about 9.17-17.03 mg, optionally about 10.48-13.1 mg, optionally about 11.8-14.4 mg L-histidine; about 105-195 mg, optionally about 120-180 mg, optionally about 130-165 mg sucrose; and about 0.175-0.325 mg, optionally about 0.2-0.3 mg, optionally about 0.225-0.275 mg Polysorbate 20.
  • the pharmaceutical composition is a solid unit dose comprising: about 9 mg BT8009, or a pharmaceutically acceptable salt thereof; about 11.8 mg L-histidine; about 135 mg sucrose; and about 0.225 mg Polysorbate 20.
  • the pharmaceutical composition is a solid unit dose comprising: about 11 mg BT8009, or a pharmaceutically acceptable salt thereof; about 14.4 mg L-histidine; about 165 mg sucrose; and about 0.275 mg Polysorbate 20.
  • the solid pharmaceutical composition is a lyophilized powder. In some embodiments, the solid pharmaceutical composition is a lyophilized powder at about -20 o C.
  • the solid pharmaceutical composition is a lyophilized powder at about -15 o C to about -25 o C, including, for example, about -15 o C, -16 o C, -17 o C, - 18 o C, -19 o C, -20 o C, -21 o C, -22 o C, -23 o C, -24 o C, or -25 o C.
  • the pharmaceutical composition is a liquid formulation of BT8009, comprising BT8009, or a pharmaceutically acceptable salt thereof, and water.
  • the liquid formulation further comprises a pharmaceutically acceptable excipient or carrier selected from a buffering agent, a stabilizer or cryoprotectant, and a surfactant.
  • a liquid formulation of the invention further comprises L-histidine, sucrose, and Polysorbate 20.
  • a liquid formulation is a liquid unit dosage form, which comprises about 21.2 mg BT8009, or a pharmaceutically acceptable salt thereof.
  • a liquid formulation is a liquid unit dosage form, which comprises about 11 mg BT8009, or a pharmaceutically acceptable salt thereof.
  • BT8009 concentration in the liquid formulation or a liquid unit dosage form is about 4 mg/mL.
  • a liquid formulation or a liquid unit dosage form comprise the following components: Concentration Reference to Standard Component Function (mg/mL) BT8009 Drug substance 4.0 a HSE L-Histidine Buffer 5.24 EP, USP Sucrose Stabiliser, cryoprotectant 60.0 EP, NF Polysorbate 20 Non-ionic surfactant 0.1 EP/NF Hydrochloric Acid pH adjustment q.s b EP WFI c Solvent q.s b . to 1 mL EP/USP a: Based on API potency, adjustments will be made to achieve the target drug substance label claim value. b: Quantity sufficient. c: Water for injections (WFI) is driven off during lyophilisation process.
  • WFI Water for injections
  • a liquid formulation or a liquid unit dosage form further comprises saline, for example, about 0.9% w/v saline.
  • BT8009 concentration in a liquid formulation comprising saline is about 0.1 to 2 mg/mL.
  • BT8009 concentration in a liquid formulation comprising saline is about 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, or 1 mg/mL.
  • BT8009 concentration in a liquid formulation comprising saline is about 1.1 mg/mL, 1.2 mg/mL, 1.3 mg/mL, 1.4 mg/mL, 1.5 mg/mL, 1.6 mg/mL, 1.7 mg/mL, 1.8 mg/mL, 1.9 mg/mL, or 2 mg/mL.
  • a liquid formulation or a liquid unit dosage form a pharmaceutically acceptable vehicle or solvent.
  • a pharmaceutically acceptable vehicle or solvent is selected from sterile water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
  • a pharmaceutically acceptable vehicle or solvent is sterile water.
  • a pharmaceutically acceptable vehicle or solvent is a sterile injectable medium.
  • the liquid formulation or a liquid unit dosage form is prepared by dissolving a solid pharmaceutical composition or a solid unit form (e.g. as described herein) in water.
  • the liquid formulation or liquid unit dosage form is prepared by dissolving a solid pharmaceutical composition or a solid unit form in an injectable medium (e.g., about 0.9% w/v saline).
  • the liquid formulation or a liquid unit dosage form is prepared by reconstituting a solid pharmaceutical composition or a solid unit form in water, followed by dilution with about 0.9% w/v saline.
  • a liquid formulation or a liquid unit dosage form is diluted into an about 0.9% w/v saline IV bag for IV administration.
  • the liquid formulation comprises: about 4 mg/mL BT8009, or a pharmaceutically acceptable salt thereof; about 5.24 mg/mL L-histidine; about 60 mg/mL sucrose; about 0.1 mg/mL Polysorbate 20; and water.
  • the liquid formulation comprises hydrochloric acid.
  • the liquid formulation comprises sodium hydroxide.
  • the liquid formulation is at a pH of about 7.
  • the liquid unit dosage form is of about 5.3 mL, comprising: about 4 mg/mL BT8009, or a pharmaceutically acceptable salt thereof; about 5.24 mg/mL L-histidine; about 60 mg/mL sucrose; about 0.1 mg/mL Polysorbate 20; and water. [0105] In some embodiments, the liquid unit dosage form is of about 1.75-3.25 mL.
  • the liquid unit dosage form is of about 2-3 mL, optionally about 2.25-2.75 mL, comprising: about 4 mg/mL BT8009, or a pharmaceutically acceptable salt thereof; about 5.24 mg/mL L-histidine; about 60 mg/mL sucrose; about 0.1 mg/mL Polysorbate 20; and water.
  • the liquid unit dosage form is of about 2.25 mL, comprising: about 4 mg/mL BT8009, or a pharmaceutically acceptable salt thereof; about 5.24 mg/mL L-histidine; about 60 mg/mL sucrose; about 0.1 mg/mL Polysorbate 20; and water.
  • the liquid unit dosage form is of about 2.75 mL, comprising: about 4 mg/mL BT8009, or a pharmaceutically acceptable salt thereof; about 5.24 mg/mL L-histidine; about 60 mg/mL sucrose; about 0.1 mg/mL Polysorbate 20; and water.
  • the liquid formulation comprises hydrochloric acid.
  • the liquid formulation comprises sodium hydroxide.
  • the liquid formulation is at a pH of about 7.
  • a solid unit dose comprising BT8009 is stored in a vial.
  • a liquid unit dosage form comprising BT8009, or a pharmaceutically acceptable salt thereof, and water is stored in a vial.
  • a vial is a 10 mL Type I clear glass vial with a chlorobutyl stopper and aluminum seal.
  • the invention provides a kit comprising a pharmaceutical composition comprising BT8009 and pembrolizumab.
  • pharmaceutical compositions comprising BT8009 may further comprise another drug, such as an agent that inhibits the PD-1/PD-L1 pathway, such as pembrolizumab.
  • the pharmaceutical compositions may comprise both BT8009 and the agent that inhibits the PD-1/PD-L1 pathway, e.g. pembrolizumab.
  • Such pharmaceutical compositions may offer a number of potential advantages in safety, convenience, patient compliance, storage and efficacy over either drug being administered individually.
  • the methods of the invention comprise administering to a patient intravenously a liquid formulation or a liquid unit dosage form as described herein.
  • a liquid formulation or a liquid unit dosage form is administered by an IV injection.
  • a liquid formulation or a liquid unit dosage form is administered by an IV infusion.
  • an IV infusion of a liquid formulation or a liquid unit dosage form is about 5-30 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 30-60 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 60-90 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 55 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 60 minutes.
  • an IV infusion of a liquid formulation or a liquid unit dosage form is about 65 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 70 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 75 minutes. In some embodiments, an IV infusion of a liquid formulation or a liquid unit dosage form is about 2, 2.5, 3, 3.5, or 4 hours. [0113] In some embodiments, the invention provides a combination use of a liquid formulation or a liquid unit dosage form as described herein and the agent that inhibits the PD- 1/PD-L1 pathway, for treating a solid tumor (such as an advanced malignancy), associated with Nectin-4 expression.
  • a solid tumor such as an advanced malignancy
  • a method of the invention comprises administering to the patient a liquid formulation comprising: about 4 mg/mL BT8009, or a pharmaceutically acceptable salt thereof; about 5.24 mg/mL L-histidine; about 60 mg/mL sucrose; about 0.1 mg/mL Polysorbate 20; and water, wherein the liquid formulation is diluted in about 0.9% w/v saline before administration and further comprises administering the agent that inhibits the PD- 1/PD-L1 pathway. 5. Dosage Regimens [0115] In some embodiments, BT8009 is administered to a patient once every day.
  • BT8009 is administered to a patient once every 2, 3, 4, 5, 6, or 7 days. In some embodiments, BT8009 is administered to a patient once every week, or weekly. In some embodiments, BT8009 is administered to a patient once every two weeks. In some embodiments, BT8009 is administered as a liquid formulation or a liquid unit dosage form. [0116] In some embodiments, a treatment cycle is 4 weeks, i.e., a 28-day treatment cycle. In some embodiments, BT8009 is administered weekly on a 28-day treatment cycle, for example, on days 1, 8, 15, and 22. In some embodiments, BT8009 is administered once every two weeks on a 28-day cycle, for example, on days 1 and 15.
  • BT8009 is administered as a liquid formulation or a liquid unit dosage form.
  • a treatment cycle is 3 weeks, i.e., a 21-day treatment cycle.
  • BT8009 is administered in week 1 and week 2, but not in week 3, of a 21-day treatment cycle.
  • BT8009 is administered on days 1 and 8 of a 21-day treatment cycle.
  • BT8009 is administered once weekly of a 21- day treatment cycle.
  • BT8009 administered on days 1, 8, and 15 of a 21-day treatment cycle.
  • BT8009 is administered as a body surface area (BSA)-based dose, which is expressed in units of mg/m 2 , such as any of the doses discussed herein.
  • a dose in units of mg/m 2 refers to a dose (in mg) that is administered per m 2 of the body surface area (BSA) of a patient.
  • a BSA-based dose (in mg/m 2 ) may be determined by dividing a dose (in mg) by the BSA of a patient. The skilled person will be aware of models and formula that may be used to estimate or determine the BSA of a patient based on factors such as the height and weight of the patient.
  • BSA may be estimated using the Dubois Formula for BSA Dosing (0.007184x (Height(cm)) ⁇ 0.725x(Weight(kg)) ⁇ 0.425 or the Monteller Formula for BSA Dosing (square root [(Height (cm) x Weight (kg)) / 3600]).
  • a patient may have a BSA of 1.37 m 2 to 2.3 m 2 .
  • the patient may have a BSA of 1.37 m 2 to 1.69 m 2 .
  • the patient may have a BSA of 1.69 m 2 to 1.84 m 2 .
  • the patient may have a BSA of 1.84 m 2 to 1.96 m 2 . In some embodiments, the patient may have a BSA of 1.96 m 2 to 2.3 m 2 .
  • BT8009 is administered at a dose (measured by the amount of the API: BT8009) of about 1-20 mg/m 2 . In some embodiments, BT8009 is administered at a dose of about 2-15 mg/m 2 . In some embodiments, BT8009 is administered at a dose of about 2-10 mg/m 2 .
  • BT8009 is administered at a dose of about 2 mg/m 2 , 3 mg/m 2 , 4 mg/m 2 , 5 mg/m 2 , 6 mg/m 2 , 7 mg/m 2 , 8 mg/m 2 , 9 mg/m 2 , or 10 mg/m 2 .
  • a BT8009 is administered at a dose of about 2.5 mg/m 2 , 3.5 mg/m 2 , 4.5 mg/m 2 , 5.5 mg/m 2 , 6.5 mg/m 2 , 7.5 mg/m 2 , 8.5 mg/m 2 , or 9.5 mg/m 2 .
  • BT8009 is administered at a dose of about 2-10 mg/m 2 , optionally at a dose of about 2.5-7.5 mg/m 2 , optionally at a dose of about 4-6 mg/m 2 , optionally at a dose of about 5 mg/m 2 .
  • BT8009 is administered at a dose of about 6-9 mg/m 2 , optionally at a dose of about 7-8 mg/m 2 , optionally at a dose of about 7.5 mg/m 2 or 6 mg/m 2 .
  • BT8009 is administered at a dose of about 4-8 mg/m 2 , optionally at a dose of about 5-7 mg/m 2 , optionally at a dose of about 6 mg/m 2 .
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 2-10 mg/m 2 , optionally at a dose of about 2.5-7.5 mg/m 2 , optionally at a dose of about 4-6 mg/m 2 , optionally at a dose of about 5 mg/m 2 , and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly at a dose of about 2-10 mg/m 2 , optionally at a dose of about 2.5-7.5 mg/m 2 , optionally at a dose of about 4-6 mg/m 2 , optionally at a dose of about 5 mg/m 2 , and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly at a dose of about 2-10 mg/m 2 , optionally at a dose of about 2.5-7.5 mg/m 2 , optionally at a dose of about 4-6 mg/m 2 , optionally at a dose of about 5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 5 mg/m 2 , and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation.
  • the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly at a dose of about 5 mg/m 2 , and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly at a dose of about 5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6-9 mg/m 2 , optionally at a dose of about 7-8 mg/m 2 , optionally at a dose of about 7.5 mg/m 2 , and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6-9 mg/m 2 , optionally at a dose of about 7-8 mg/m 2 , optionally at a dose of about 7.5 mg/m 2 , and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a dose of about 6-9 mg/m 2 , optionally at a dose of about 7-8 mg/m 2 , optionally at a dose of about 7.5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 7.5 mg/m 2 , and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 7.5 mg/m 2 , and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a dose of about 6-9 mg/m 2 , optionally at a dose of about 7-8 mg/m 2 , optionally at a dose of about 7.5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 4-8 mg/m 2 , optionally at a dose of about 5-7 mg/m 2 , optionally at a dose of about 6 mg/m 2 , and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 4-8 mg/m 2 , optionally at a dose of about 5-7 mg/m 2 , optionally at a dose of about 6 mg/m 2 , and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a dose of about 4-8 mg/m 2 , optionally at a dose of about 5-7 mg/m 2 , optionally at a dose of about 6 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD- L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6 mg/m 2 , and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6 mg/m 2 , and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a dose of about 4-8 mg/m 2 , optionally at a dose of about 5-7 mg/m 2 , optionally at a dose of about 6 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD- L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 2.5 mg/m 2 , and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation.
  • the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly at a dose of about 2.5 mg/m 2 , and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly at a dose of about 2.5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 5.5 mg/m 2 , and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation.
  • the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly at a dose of about 5.5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly at a dose of about 5.5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly dose of about 7.5 mg/m 2 , and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation.
  • the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly at a dose of about 7.5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly at a dose of about 7.5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6 mg/m 2 , and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a dose of about 6 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient every two week at a dose of about 6 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient at a dose of about 7.5 mg/m 2 once every two weeks, and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient once every two weeks at a dose of about 7.5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient every two week at a dose of about 7.5 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient at a dose of about 10 mg/m 2 once every two weeks, and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes. [0144] In some embodiments, the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient once every two weeks at a dose of about 10 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway. In some embodiments, the BT8009 is provided as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient every two weeks at a dose of about 10 mg/m 2 by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • BT8009 is administered as a flat dose (i.e. a standard dose that is not dependent on the BSA of a patient which is expressed in units of mg.
  • Administering a drug as a flat dose rather than as a BSA-based dose may offer several advantages whilst providing a similar overall pharmacokinetic profile to using a BSA-based dose.
  • Administering a drug as a flat dose may improve the adverse event (AE) rate associated with a drug compared to a BSA-based dose, whilst maintaining efficacy.
  • Administering a drug as a flat dose may reduce drug wasted associated with preparing and administering a drug to a patient compared to a BSA-based dose.
  • Administering a drug as a flat dose may reduce the likelihood of dosage errors, and may improve convenience of administering the drug in a clinical setting.
  • the methods of the invention thus comprise administering BT8009 or a pharmaceutical composition comprising BT8009 as a flat dose, and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway [0146]
  • BT8009 is administered at a flat dose (measured by the amount of the API: BT8009) of about 1.8-36 mg.
  • BT8009 is administered at a flat dose of about 3.6-27 mg.
  • BT8009 is administered at a flat dose of about 3.6 mg, 5.4 mg, 7.2 mg, 9 mg, 10.8 mg, 12.6 mg, 14.4 mg, 16.2 mg or 18 mg.
  • BT8009 is administered at a flat dose of about 4.5 mg, 6.3 mg, 8.1 mg, 9.9 mg, 11.7 mg, 13.5 mg, 15.3 mg or 17.1 mg.
  • BT8009 is administered at a flat dose of about 7-11 mg, optionally at a flat dose of about 8-10 mg, optionally at a flat dose of about 9 mg.
  • BT8009 is administered at a flat dose of about 9-13 mg, optionally at a flat dose of about 10-12 mg, optionally at a flat dose of about 11 mg.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly flat dose of about 7-11 mg, optionally at a flat dose of about 8-10 mg, optionally at a flat dose of about 9 mg, and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly a flat dose of about 7-11 mg, optionally a flat dose of about 8-10 mg, optionally a flat dose of about 9 mg, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly a flat dose of about 7-11 mg, optionally a flat dose of about 8-10 mg, optionally a flat dose of about 9 mg by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient a weekly flat dose of about 9 mg, and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation.
  • the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient weekly a flat dose of about 9 mg, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient weekly a flat dose of about 9 mg by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 of a 21-day treatment cycle at a flat dose of about 9-13 mg, optionally at a flat dose of about 10- 12 mg, optionally at a flat dose of about 11 mg, and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a flat dose of about 9-13 mg, optionally at a flat dose of about 10-12 mg, optionally at a flat dose of about 11 mg, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a flat dose of about 9-13 mg, optionally at a flat dose of about 10-12 mg, optionally at a flat dose of about 11 mg by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the methods of the invention comprise administering BT8009 or a pharmaceutical composition comprising BT8009 to the patient on days 1 and 8 or a 21 day treatment cycle at a flat dose of about 11 mg, and further comprise administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is administered by an IV infusion of about 60 minutes.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering BT8009 to the patient on days 1 and 8 of a 21 day treatment cycle at a flat dose of about 11 mg, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the BT8009 is provided as a pharmaceutical composition.
  • the pharmaceutical composition is a liquid formulation.
  • the invention provides a method for treating a solid tumor in a human patient, comprising administering a liquid formulation or a liquid unit dosage form to the patient at days 1 and 8 of a 21-day treatment cycle at a flat dose of about 11 mg by an IV infusion of about 60 minutes, and further comprising administering an agent that inhibits the PD-1/PD-L1 pathway.
  • the liquid formulation or liquid dosage form is a liquid formulation or liquid dosage form of the invention.
  • the agent that inhibits the PD-1/PD-L1 pathway is pembrolizumab.
  • Pembrolizumab can be administered as described on the label, which can be found at https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf, the content of which is incorporated herein by reference in its entirety.
  • pembrolizumab is administered at a dose of about 200 mg once every three weeks.
  • pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 25 to 45 minutes once every 3 weeks.
  • pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 25 minutes once every 3 weeks.
  • pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 30 minutes once every 3 weeks. In some embodiments, pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 35 minutes once every 3 weeks. In some embodiments, pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 40 minutes once every 3 weeks. In some embodiments, pembrolizumab is administered at a dose of about 200 mg by an IV infusion of about 45 minutes once every 3 weeks. [0157] In some embodiments, pembrolizumab is administered at a dose of about 400 mg once every six weeks.
  • pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 25 to 45 minutes once every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 25 minutes once every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 30 minutes once every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 35 minutes once every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 40 minutes once every 6 weeks.
  • pembrolizumab is administered at a dose of about 400 mg by an IV infusion of about 45 minutes once every 6 weeks.
  • BT8009 or the pharmaceutically acceptable salt thereof is administered weekly at a dose of 5 mg/m 2 and pembrolizumab is administered once every three weeks at a dose of 200 mg.
  • BT8009 or the pharmaceutically acceptable salt thereof is administered on days 1 and 8 of a 21-day treatment cycle at a dose of 6 mg/m 2 and pembrolizumab is administered once every three weeks at a dose of 200 mg.
  • the methods of the present invention are associated with an incidence of adverse events and/or severe adverse events that is generally consistent with that of corresponding methods in which BT8009 is administered as a monotherapy (i.e. the incidence where BT8009 is administered without further administering an agent that inhibits the PD-1/PD-L1 pathway such as pembrolizumab).
  • the methods of the present invention are associated with a substantially similar risk of adverse events and/or severe adverse events as corresponding methods in which BT8009 is administered as a monotherapy.
  • the methods of the invention do not increase the incidence and/or risk of adverse events and/or severe adverse events relative to corresponding methods in which BT8009 is administered as a monotherapy.
  • An Advanced Malignancy Associated With Nectin-4 Expression the methods of the invention relate to the treatment of a cancer in a human patient.
  • the cancer is a solid tumor.
  • the solid tumor is an advanced malignancy.
  • the cancer, solid tumor or advanced malignancy is associated with Nectin-4 expression.
  • the cancer is associated with Nectin-4 expression.
  • the solid tumor is associated with Nectin-4 expression.
  • the solid tumor is an advanced malignancy associated with Nectin-4 expression.
  • the cancer or solid tumor is selected from the group consisting of lung cancer (e.g., NSCLC), ovarian cancer, breast cancer (e.g., TNBC), esophageal cancer, gastric/upper gastrointestinal (GI) cancer, head and neck cancer, pancreatic cancer, and urothelial cancer.
  • a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is selected from the group consisting of lung cancer (e.g., NSCLC), ovarian cancer, breast cancer (e.g., TNBC), esophageal cancer, gastric/upper gastrointestinal (GI) cancer, head and neck cancer, pancreatic cancer, and urothelial cancer.
  • lung cancer e.g., NSCLC
  • breast cancer e.g., TNBC
  • esophageal cancer e.g., gastric/upper gastrointestinal (GI) cancer
  • GI gastric/upper gastrointestinal
  • head and neck cancer e.g., pancreatic cancer
  • urothelial cancer e.g., a patient having a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression has been previously untreated for the malignancy (i.e. has received no prior lines of treatment for the malignancy).
  • a patient having a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression has been previously untreated may be administered BT8009 as a monotherapy.
  • a patient having a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression has been previously untreated may be administered BT8009 and pembrolizumab.
  • a patient having a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 has previously received one or more treatments for the malignancy.
  • a patient having a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 has previously received one or more treatments for the malignancy may be administered BT8009 as a monotherapy.
  • a patient having a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 has previously received one or more treatments for the malignancy may be administered BT8009 and pembrolizumab.
  • a patient who has previously received one or more treatments is resistant or refractory is the one or more prior treatments.
  • a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is lung cancer, for example, non-small-cell lung cancer (NSCLC).
  • NSCLC non-small-cell lung cancer
  • a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is ovarian cancer.
  • a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is breast cancer, for example, triple-negative breast cancer (TNBC).
  • TNBC triple-negative breast cancer
  • a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is esophageal cancer.
  • a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is gastric/upper gastrointestinal (GI).
  • GI gastric/upper gastrointestinal
  • a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is head and neck cancer.
  • a cancer, a solid tumor or an advanced malignancy associated with Nectin- 4 expression is pancreatic cancer.
  • a cancer, a solid tumor or an advanced malignancy associated with Nectin-4 expression is urothelial cancer.
  • an advanced malignancy associated with Nectin-4 expression is urothelial cancer.
  • an advanced malignancy associated with Nectin-4 expression is locally advanced urothelial cancer.
  • an advanced malignancy associated with Nectin-4 expression is malignant urothelial cancer.
  • a patient having locally advanced urothelial cancer or metastatic urothelial cancer has been previously untreated for the cancer.
  • a patient having locally advanced urothelial cancer or metastatic cancer has previously received one or more treatments for the cancer, for example one or more other treatments as described herein.
  • a patient who has previously received one or more treatments is resistant or refractory is the one or more prior treatments.
  • the patient is a patient having an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2.
  • the patient is a cisplatin-eligible patient having an ECOG Performance Status score of 0, 1 or 2.
  • the patient is a cisplatin-ineligible urothelial cancer patient having an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 2, wherein the patient has: Hemoglobin ⁇ 10 g/dL, CrCl ⁇ 50 mL/min, and no NYHA Class III heart failure.
  • ECOG Performance Status scores 0 and 1 are described herein.
  • the patient is a patient having measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
  • the patient is a patient having target lesions that are previously irradiated and have demonstrated progression.
  • the patient meets the inclusion criteria of the Phase I/II and/or Phase II/III trial synopses included herein.
  • the patient is a patient having acceptable organ function.
  • a patient having acceptable organ function has laboratory data selected from the following: Renal function: creatinine clearance (CrCl) of ⁇ 50 mL/min by the Cockcroft-Gault equation or equivalent and/or eGFR ⁇ 30 mL/min (using the CKD-EPI creatinine equation) (Except for patients with renal impairment); Total bilirubin ⁇ 1.5 ⁇ ULN (upper limit of normal); Serum albumin ⁇ 2.5 g/dL; Aspartate aminotransferase (AST) ⁇ 2.5 ⁇ ULN or ⁇ 5 ⁇ ULN in the presence of liver metastases; Alanine aminotransferase (ALT) ⁇ 2.5 ⁇ ULN or ⁇ 5 ⁇ ULN in the presence of liver metastases; Alanine aminotransferase (ALT) ⁇ 2.5
  • the patient is a patient having acceptable hematologic function (no red blood cell or platelet transfusions or growth factors are allowed within 4 weeks of the first dose of BT8009; except for patients with renal impairment).
  • a patient having acceptable hematologic function has laboratory data selected from the following: Hemoglobin ⁇ 9 g/dL; Absolute neutrophil count (ANC) ⁇ 1500 cells/mm 3 ; and Platelet count ⁇ 75,000 cells/mm 3 .
  • the patient is a patient who is a women of childbearing potential (WOCBP) that has a negative pregnancy test (negative serum test at screening and negative urine or serum test within 3 days prior to the first dose of a liquid formulation or a liquid unit dosage form as described herein).
  • WOCBP women of childbearing potential
  • the patient is a patient who has a life expectancy ⁇ 12 weeks after the start of BT8009 treatment.
  • the patient is a patient with advanced, histologically confirmed urothelial (transitional cell) carcinoma that recurred after or has been refractory to prior therapy.
  • the patient is a patient with advanced, histologically confirmed pancreatic, breast, NSCLC, gastric, esophageal, head and neck, or ovarian tumors that recurred after or has been refractory to prior therapy.
  • the patient is a patient with histologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra).
  • a patient has squamous differentiation or mixed cell types.
  • a patient does not have resectable locally advanced urothelial carcinoma.
  • a patient has received prior treatment with a CPI (PD-1 or PD-L1 inhibitor) if locally approved, in the locally advanced or metastatic urothelial cancer setting.
  • a patient has received CPI therapy in the neoadjuvant/adjuvant setting.
  • a patient has received CPI therapy in the neoadjuvant/adjuvant setting and has had recurrent or progressive disease either during therapy or within 3 months of therapy completion.
  • a patient has been treated with prior platinum-containing chemotherapy in the adjuvant/neoadjuvant setting and had recurrent or progressive disease within 12 months of completion or received treatment with a platinum regimen in the locally advanced (unresectable with curative intent) or metastatic setting.
  • a patient is platinum-na ⁇ ve and platinum-ineligible, and has not received prior treatment with platinum-containing or other chemotherapy in locally advanced or metastatic setting.
  • a patient who has received platinum in the adjuvant/neoadjuvant setting and does not progress within 12 months of completion is considered platinum-na ⁇ ve.
  • a patient has had progression or recurrence of urothelial cancer during or following receipt of most recent therapy.
  • a patient has been treated with enfortumab vedotin (EV). In some embodiments, a patient has not been treated with enfortumab vedotin (EV). In some embodiments, a patient has been treated with enfortumab vedotin (EV) and pembrolizumab. In some embodiments, a patient has not been treated with enfortumab vedotin (EV) and pembrolizumab.
  • the patient is a patient, who has histologically confirmed non-mucinous epithelial ovarian (serous, endometrioid, clear cell, carcinosarcoma, and mixed pathologies), fallopian tube, or primary peritoneal cancer that is Stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) or tumor, node and metastasis staging criteria that have progressed following prior therapy.
  • a patient has been treated with FDA-approved or locally approved therapy.
  • the patient is a TNBC patient, with tumors confirmed negative for ER/PR by immunohistochemistry (IHC) ( ⁇ 10% positive tumor nuclei, as per ASCO-CAP guideline recommendations) and negative for human epidermal growth factor receptor 2 (HER2) by IHC (0 and 1) or fluorescent or chromogenic in situ hybridization FISH or CISH) that have progressed following prior therapy.
  • IHC immunohistochemistry
  • HER2 human epidermal growth factor receptor 2
  • a patient has been treated with FDA-approved or locally approved therapy.
  • the patient is a patient, with histologically confirmed NSCLC with no actionable mutations, such as no Epidermal Growth Factor Receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion oncogene, or ROS1 that have progressed following prior therapy.
  • EGFR Epidermal Growth Factor Receptor
  • ALK anaplastic lymphoma kinase
  • ROS1 ROS1 that have progressed following prior therapy.
  • a patient has tumors with squamous cell carcinoma and adenocarcinoma histologies.
  • a patient has been treated with FDA-approved or locally approved therapy.
  • the patient is a patient with locally advanced or metastatic, histologically confirmed urothelial (transitional cell) carcinoma.
  • a patient has squamous differentiation or mixed cell types. In some embodiments, a patient does not have resectable locally advanced urothelial carcinoma. In some embodiments, a patient is cisplatin-ineligible, which is determined by one of the following criteria: impaired renal function (creatinine clearance [CrCl] of 30 to 59 mL/min by C-G); hearing loss of ⁇ 25 decibels (dB) at two contiguous frequencies; NYHA Class III heart failure; or Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, who meets the following criteria: i. Hemoglobin ⁇ 10 g/dL; ii.
  • a patient has no prior organ transplant (including allogeneic).
  • a patient is not previously diagnosed with clinically relevant immunodeficiency.
  • a patient does not have any condition requiring treatment with ⁇ 10 mg daily prednisone equivalent or other strong immunosuppressant.
  • a patient does not have an active autoimmune disease that has required systemic treatment (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) within 2 years before treatment with a liquid formulation or a liquid unit dosage form as described herein.
  • a patient has not received prior treatment with an MMAE based conjugate for urothelial carcinoma at any time.
  • a patient has not received prior treatment with EV or other MMAE-based ADC for urothelial carcinoma at any time.
  • the patient is a patient with histologically confirmed urothelial (transitional cell) carcinoma, including a patient with squamous differentiation or mixed cell types, ovarian, triple-negative breast, or non-small cell lung cancer.
  • the patient is a patient with solid tumor advanced disease.
  • the patient has renal insufficiency or renal impairment.
  • the terms “renal insufficiency” and “renal impairment” refer to reduced or impaired kidney function relative to normal kidney function, and are used interchangeably herein.
  • the present invention therefore provides a method for treating a human patient having renal insufficiency or renal impairment, comprising administering to the patient BT8009 or a pharmaceutical composition comprising BT8009.
  • the present invention also provides the use of BT8009 in a method for treating a human patient having renal insufficiency or renal impairment.
  • the present invention also provides BT8009 for use in the manufacture of a medicament for use in a method for treating a human patient having renal insufficiency or renal impairment.
  • the present invention also provides a method for treating a solid tumor in a human patient having renal insufficiency or renal impairment comprising administering BT8009 or a pharmaceutical composition comprising BT8009.
  • the present invention provides BT8009 or a pharmaceutical composition comprising BT8009 for use in a method for treating a solid tumor in a human patient having renal insufficiency or renal impairment.
  • the present invention also provides BT8009 for use in the manufacture of a medicament for use in a method for treating a solid tumor in a human patient having renal insufficiency or renal impairment.
  • the solid tumor is an advanced malignancy.
  • the solid tumor or advanced malignancy is associated with Nectin-4 expression.
  • the patient has mild renal impairment.
  • the patient has moderate renal impairment. In some embodiments, the patient has severe renal impairment. [0187] In some embodiments, a patient having mild renal impairment has renal function of 60-89 mL/min. In some embodiments, a patient having moderate renal impairment has renal function of 30-59 mL/min. In some embodiments, a patient having moderate renal impairment has renal function of 30-49 mL/min. In some embodiments, a patient having severe renal impairment has renal function of 15-29 mL/min. A patient having normal renal function has renal function of at least 90 mL/min. [0188] In some embodiments, the patient having renal insufficiency or renal impairment has renal function of less than 90 mL/min.
  • the patient has renal function of at least 60 mL/min. In some embodiments, the patient has renal function of 60-89 mL/min. In some embodiments, the patient having renal insufficiency or renal impairment has renal function of less than 60 mL/min. In some embodiments, the patient having renal insufficiency or renal impairment has renal function of less than 50 CrCL mL/min. In some embodiments, the patient has renal function of at least 30 mL/min. In some embodiments, the patient has renal function of 30-59 mL/min. In some embodiments, the patient has renal function of 30- 49 mL/min. In some embodiments, the patient having renal insufficiency or renal impairment has renal function of less than 30 mL/min.
  • the patient has renal function of at least 15 mL/min. In some embodiments, the patient having renal insufficiency or renal impairment has renal function of 15-29 mL/min.
  • renal function refers to estimated creatinine clearance (CrCL). In some embodiments, renal function can be estimated using a serum creatinine-based equation.
  • the renal function values mentioned herein are estimated creatine clearance values.
  • renal function values mentioned herein are estimated creatinine clearance values calculated by the Cockcroft-Gault equation (CrCL by C- G).
  • eGFR estimated glomerular filtration rate
  • eGFR can be calculated using a contemporary, widely accepted equation for the population being studied, for example the 2021 CKD-EPI Creatinine equation. It is within the capabilities of a skilled person to determine the eGFR of an individual using such an equation. eGFR values are standardized to a body surface area of 1.73 m 2 and expressed and reported in units of mL/min/1.73 m 2 . To individualize GFR, multiply the standardized GFR by the individual’s BSA and divide by 1.73.
  • the renal function values mentioned herein are estimated GFR values.
  • the renal function values mentioned herein are eGFR values calculated by the CKD-EPI equation (eGFR by CDK-EPI).
  • Measured GFR using an exogenous marker
  • measured CrCL can also be used to determine renal function.
  • the inventors have identified that patients with renal impairment have a similar BT8009 and MMAE PK profile to patients with normal renal function. This suggests that no specific dose adjustments are required for patients with mild or moderate renal impairment. This was contrary to pre-clinical analyses that were performed. Pre-clinical data also suggest that renal clearance is the major elimination pathway for BT8009.
  • BT8009 can be administered to a patient having renal impairment or renal insufficiency at the same dose as would be administered to a patient having normal renal function.
  • BT8009 or a pharmaceutical composition comprising BT8009 can be administered to a patient having renal insufficiency or renal impairment at a dose for a patient having normal renal function.
  • BT8009 or a pharmaceutical composition comprising BT8009 can be administered to a patient having renal insufficiency or renal impairment at any of the doses described herein.
  • a patient has been treated with FDA-approved or locally approved therapy.
  • a patient has not had a chemotherapy treatment within 14 days prior to first dose of a liquid formulation or a liquid unit dosage form as described herein.
  • a patient has not had an anticancer treatment within 28 days or 5 half- lives, whichever shorter, prior to first dose of a liquid formulation or a liquid unit dosage form as described herein.
  • a patient has prior toxicities which have resolved to grade ⁇ 1 per Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 (except alopecia which must be no greater than Grade 2).
  • CCAE Common Terminology Criteria for Adverse Events
  • a patient has not had an experimental treatment within 4 weeks of first dose of a liquid formulation or a liquid unit dosage form as described herein.
  • a patient does not have a current treatment with strong inhibitors or strong inducers of CYP3A or inhibitors of P-gp including herbal- or food-based.
  • a patient does not have any sensitivity to any of the ingredients of a liquid formulation or a liquid unit dosage form as described herein, or to monomethyl auristatin E (MMAE).
  • MMAE monomethyl auristatin E
  • a patient does not have a significant medical condition including but not limited skin (conditions related to or that may confound monitoring for rash including but not limited to autoimmune conditions such as eczema or psoriasis), life- threatening illness, active uncontrolled infection or organ system dysfunction (such as ascites, coagulopathy, encephalopathy), or other reasons which could compromise the patient’s safety, or interfere with or compromise the integrity of the study outcomes including consideration of gastrointestinal, skin and pulmonary co-morbidities and including review of screening chest CT to ensure no clinically significant co-morbidities.
  • skin condition related to or that may confound monitoring for rash
  • autoimmune conditions such as eczema or psoriasis
  • life- threatening illness such as active uncontrolled infection or organ system dysfunction (such as ascites, coagulopathy, encephalopathy), or other reasons which could compromise the patient’s safety, or interfere with or compromise the integrity of the study outcomes including consideration of gastrointestinal, skin and pulmonary co-morbidities and including review of screening
  • a patient has a prior ⁇ Grade 2 thyroid endocrinopathy, if appropriately controlled with thyroid hormone and stable for at least 2 months on therapy.
  • a patient has skin toxicity which resolve to Grade ⁇ 1.
  • a patient does not have active keratitis or corneal ulcerations.
  • a patient does not have Grade ⁇ 2 peripheral neuropathy.
  • a patient does not have a clinically relevant troponin elevation.
  • a patient does not have uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ⁇ 8%.
  • a patient has not had major surgery (excluding placement of vascular access) within 4 weeks of first dose of a liquid formulation or a liquid unit dosage form as described herein and has recovered adequately prior to treatment with a liquid formulation or a liquid unit dosage form as described herein.
  • a patient has not received a live or attenuated vaccine within 30 days of study treatment.
  • a patient does not have known active or untreated CNS metastases and/or carcinomatous meningitis.
  • a patient with treated brain metastasis are stable for at least 4 weeks prior to treatment with a liquid formulation or a liquid unit dosage form as described herein, either without the use of steroids or on stable or decreasing dose of less than or equal to 10 mg daily prednisone or equivalent and are without any symptoms that would confound the evaluation of neurologic and other AEs).
  • a patient does not have a history or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation, or is not in the best interest of the patient to participate in the opinion of the Investigator.
  • a patient does not have a history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of New York Heart Association Class III-IV documented within 6 months prior to first dose of BT8009.
  • a patient does not have mean resting corrected QT interval (QTcF) >470 msec within 6 months prior to first dose of a liquid formulation or a liquid unit dosage form as described herein.
  • QTcF mean resting corrected QT interval
  • a patient does not have, within 6 months prior to first dose of a liquid formulation or a liquid unit dosage form as described herein, any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval.
  • a patient does not have, within 6 months prior to first dose of a liquid formulation or a liquid unit dosage form as described herein, any clinically important abnormalities in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third degree heart block.
  • ECGs resting electrocardiograms
  • a patient does not have human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
  • HIV human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • a patient has well controlled HIV, if a) CD4+ T-cell (CD4+) counts ⁇ 350 cells/uL; b) HIV viral load ⁇ 400 copies/mL; c) Without a history of opportunistic infection within the last 12 months; d) On established antiretroviral therapy (ART) for at least 4 weeks.
  • ART antiretroviral therapy
  • a patient does not have a positive hepatitis B surface antigen and/or anti-hepatitis B core antibody.
  • a patient has a negative polymerase chain reaction (PCR) assay and has an appropriate antiviral therapy.
  • PCR polymerase chain reaction
  • a patient does not have an active hepatitis C infection with positive viral load if hepatitis C virus (HCV) antibody positive.
  • HCV hepatitis C virus
  • a patient has been treated for hepatitis C infection and has sustained virologic response of ⁇ 12 weeks.
  • a patient does not have another malignancy within 3 years before the first dose of a liquid formulation or a liquid unit dosage form as described herein.
  • a patient does not have any residual disease from a previously diagnosed malignancy (excluding adequately treated with curative intent basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia/cervical carcinoma in situ, melanoma in situ, or ductal carcinoma in situ of the breast).
  • a patient does not have an active systemic infection requiring therapy, or fever not attributable to underlying malignancy within the last 14 days prior to first dose of a liquid formulation or a liquid unit dosage form as described herein.
  • a patient does not have a suspicion of relevant and recent systemic viral syndrome or need for quarantine/isolation that is not resolved.
  • a patient does not have prior Stevens-Johnson syndrome (SJS)/ toxic epidermal necrolysis (TEN) on any MMAE-conjugated drug.
  • SJS Stevens-Johnson syndrome
  • TEN toxic epidermal necrolysis
  • Part A dose escalation (A-1), dose de-escalation in combination with pembrolizumab (A-2); Part B, dose expansion; Part C, renal insufficiency and Part D supplementary PK.
  • Part A will evaluate BT8009 in patients with histologically confirmed malignant solid tumors that are Nectin-4 positive.
  • Part A-1 is a dose escalation of monotherapy BT8009
  • Part A-2 is a dose de-escalation of BT8009 plus pembrolizumab (Starting at a Part A-1 RP2D and then proceeding to 1 dose level below this dose if the Part A-1 RP2D is not tolerated in combination).
  • Part A is shown in Figure 1.
  • Part B is a dose expansion at the BT8009 RP2D(s).
  • the scheme for Part B is shown in Figure 2.
  • Part C is a cohort conducted in patients with moderate to severe renal impairment and locally advanced or metastatic urothelial carcinoma, ovarian cancer, triple-negative breast cancer, or non-small cell lung cancer. Up to 12 patients will be enrolled in the moderate renal impairment cohort (CrCl 30-49 ml/min) and up to 6 in the severe renal impairment cohort (CrCl 15-29 ml/min). (Part C will not be enrolled in Canada.). The scheme for Part C is shown in Figure 3.
  • Part D is a cohort conducted in patients with normal renal function or mild renal impairment, and locally advanced or metastatic urothelial carcinoma, ovarian cancer, triple- negative breast cancer, or non-small cell lung cancer. Up to 10 patients will be enrolled in Part D including a minimum of 3 patients in the normal renal function cohort (CrCl >90 mL/min), and a minimum of 3 patients in the mild renal impairment cohort (CrCl 60-89 mL/min). Additional PK samples will be collected in Part D in order to further characterize BT8009 and MMAE PK, including renal clearance.
  • Inclusion Criteria – All Patients Patients must meet the following criteria in order to be included in the research study: 1. Written informed consent, according to local guidelines, signed and dated by the patient or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analyses. 2. At least 18 years-of-age at the time of signature of the informed consent form 3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. Patients who are in Cohort B-7 (cisplatin-ineligible urothelial cancer) can have an ECOG of 2 but must meet additional criteria (see Incl #29). 4.
  • ECOG Eastern Cooperative Oncology Group
  • Renal function as follows: creatinine clearance (CrCl) of ⁇ 50 mL/min by the Cockcroft-Gault equation or equivalent. (Except for patients in the renal impairment cohorts [Part C])
  • TrCl creatinine clearance
  • b. Total bilirubin ⁇ 1.5 ⁇ upper limit of normal (ULN) or ⁇ 3 ⁇ ULN and conjugated bilirubin ⁇ 1.5 x ULN for patients with Gilbert’s syndrome
  • Serum albumin ⁇ 2.5 g/dL d.
  • Aspartate aminotransferase AST ⁇ 2.5 ⁇ ULN or ⁇ 5 ⁇ ULN in the presence of liver metastases e.
  • Alanine aminotransferase (ALT) ⁇ 2.5 ⁇ ULN or ⁇ 5 ⁇ ULN in the presence of liver metastases f.
  • International normal ratio (INR) ⁇ 1.5 or ⁇ institutional ULN unless patient is receiving a stable dose of anticoagulant therapy and PT or aPPT is within therapeutic range of intended use of anticoagulants 6.
  • Acceptable hematologic function no red blood cell or platelet transfusions or growth factors are allowed within 4 weeks of the first dose of BT8009; except for patients in the renal impairment cohorts [Part C]): a.
  • Hemoglobin ⁇ 9 g/dL Absolute neutrophil count (ANC) ⁇ 1500 cells/mm 3 c. Platelet count ⁇ 75,000 cells/mm 3 7.
  • Negative pregnancy test for women of childbearing potential (WOCBP) negative serum test at screening and negative urine or serum test within 3 days prior to the first dose of BT8009).
  • WOCBP childbearing potential
  • the Sponsor and/or SRC may decide to require enrolment of specific tumor (sub)types at any point during the escalation to enrich the evaluation of biomarkers, safety, anti-tumor activity, or PK.
  • Additional Inclusion Criteria – Part A-2 (combination with pembrolizumab) 13. Must have exhausted all standard treatment options, including appropriate targeted therapies; patients for which no standard therapy is considered appropriate or to provide clinical benefit, as assessed by the Investigator. 14.
  • Additional Inclusion Criteria – Part B-1 (EV-exposed urothelial cancer) 15.
  • urothelial carcinoma i.e., cancer of the bladder, renal pelvis, ureter, or urethra. Patients with squamous differentiation or mixed cell types are eligible. Patients with resectable locally advanced urothelial carcinoma are ineligible. 16. Patients must have received prior treatment with a CPI (PD-1 or PD-L1 inhibitor) if locally approved, in the locally advanced or metastatic urothelial cancer setting. Patients who received CPI therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease either during therapy or within 3 months of therapy completion are eligible.
  • CPI PD-1 or PD-L1 inhibitor
  • Patient must be one of the following: o Treated with prior platinum-containing chemotherapy in the adjuvant/neoadjuvant setting and had recurrent or progressive disease within 12 months of completion or received treatment with a platinum regimen in the locally advanced (unresectable with curative intent) or metastatic setting o Platinum-na ⁇ ve and platinum-ineligible per Investigator assessment and have not received prior treatment with platinum-containing or other chemotherapy in locally advanced or metastatic setting and are ineligible for treatment with platinum at the time of enrolment. Patients who received platinum in the adjuvant/neoadjuvant setting and did not progress within 12 months of completion will be considered platinum- na ⁇ ve. 17. Must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy 18.
  • Previously treated with enfortumab vedotin (EV) Additional Inclusion Criteria – B-2 and B-3 (EV-na ⁇ ve urothelial cancer) 19.
  • urothelial carcinoma i.e., cancer of the bladder, renal pelvis, ureter, or urethra.
  • Patients with squamous differentiation or mixed cell types are eligible.
  • Patients with resectable locally advanced urothelial carcinoma are ineligible.
  • Patients must have received prior treatment with a CPI (PD-1 or PD-L1 inhibitor) if locally approved, in the locally advanced or metastatic urothelial cancer setting.
  • CPI PD-1 or PD-L1 inhibitor
  • Patient who received CPI therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease either during therapy or within 3 months of therapy completion are eligible.
  • Patient must be one of the following: o Treated with prior platinum-containing chemotherapy in the adjuvant/neoadjuvant setting and had recurrent or progressive disease within 12 months of completion or received treatment with a platinum regimen in the locally advanced (unresectable with curative intent) or metastatic setting o Platinum-na ⁇ ve and platinum-ineligible and have not received prior treatment with platinum-containing or other chemotherapy in locally advanced or metastatic setting and are ineligible for treatment with platinum at the time of enrolment.
  • platinum-na ⁇ ve Patients who received platinum in the adjuvant/neoadjuvant setting and did not progress within 12 months of completion will be considered platinum-na ⁇ ve. 21. Must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy Additional Inclusion Criteria – Part B-4 (Ovarian cancer) 22. Patients with histologically confirmed non-mucinous epithelial ovarian (serous, endometrioid, clear cell, carcinosarcoma, and mixed pathologies), fallopian tube, or primary peritoneal cancer that is Stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) or tumor, node and metastasis staging criteria that have progressed following prior therapy. 23.
  • Patients should previously be treated with FDA-approved or locally approved therapy according to the local standards of care/local guidance. Additional Inclusion Criteria – Part B-5 (Triple-negative breast cancer) 24. Patients with tumors confirmed negative for ER/PR by immunohistochemistry (IHC) ( ⁇ 10% positive tumor nuclei, as per ASCO-CAP guideline recommendations) and negative for human epidermal growth factor receptor 2 (HER2) by IHC (0 and 1) or fluorescent or chromogenic in situ hybridization FISH or CISH) that have progressed following prior therapy. Patients with equivocal HER2 results by IHC should have their negativity status confirmed by FISH. 25. Patients should previously be treated with FDA-approved or locally approved therapy according to the local standards of care/local guidance.
  • IHC immunohistochemistry
  • HER2 human epidermal growth factor receptor 2
  • Additional Inclusion Criteria – Part B-6 (Non-small cell lung cancer) 26. Patients with histologically confirmed NSCLC with no actionable mutations, such as no Epidermal Growth Factor Receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion oncogene, or ROS1 that have progressed following prior therapy. Tumors with squamous cell carcinoma and adenocarcinoma histologies are permitted. 27. Patients should previously be treated with FDA-approved or locally approved therapy according to the local standards of care/local guidance. Additional Inclusion Criteria – Part B-7 (First-line, cisplatin-ineligible, metastatic urothelial cancer) 28.
  • EGFR Epidermal Growth Factor Receptor
  • ALK anaplastic lymphoma kinase
  • urothelial (transitional cell) carcinoma Patients with locally advanced or metastatic, histologically confirmed urothelial (transitional cell) carcinoma. Patients with squamous differentiation or mixed cell types are eligible. Patients with resectable locally advanced urothelial carcinoma are ineligible. 29. Patients must be cisplatin-ineligible. Patients are considered cisplatin-ineligible if they meet at least one of the following criteria at study entry: impaired renal function (creatinine clearance [CrCl] of 30 to 59 mL/min by C-G), hearing loss of ⁇ 25 decibels (dB) at two contiguous frequencies, NYHA Class III heart failure, or Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 a.
  • impaired renal function creatinine clearance [CrCl] of 30 to 59 mL/min by C-G
  • dB decibels
  • NYHA Class III heart failure or Eastern Cooperative Oncology Group (ECOG) performance status
  • Patients with ECOG PS of 2 must meet the following additional criteria: i. Hemoglobin ⁇ 10 g/dL ii. CrCl ⁇ 50 mL/min iii. May not have NYHA Class III heart failure Additional Inclusion Criteria – Part C (Renal-insufficiency cohort) 30. Patients must have histologically confirmed urothelial (transitional cell) carcinoma (patients with squamous differentiation or mixed cell types are eligible); ovarian; triple- negative breast; or non-small cell lung cancer. 31.
  • Patients with solid tumor advanced disease are eligible as follows: 1) up to 12 patients with renal function of 30-49 mL/min (by C-G); 2) up to 6 patients with renal function of 15- 29 mL/min (by C-G). 32. Patients should previously be treated with FDA-approved or locally approved therapy according to the local standards of care/local guidance. Additional Inclusion Criteria – Part D (Supplementary PK) 33. Patients must have histologically confirmed urothelial (transitional cell) carcinoma (patients with squamous differentiation or mixed cell types are eligible; ovarian; triple- negative breast; or non-small cell lung cancer. 34.
  • Patients with solid tumor advanced disease are eligible as follows: 1) patients with renal function >90 mL/min (by C-G); 2) patients with renal function of 60-89 mL/min (by C- G). 35. Patients should previously be treated with FDA-approved or locally approved therapy according to the local standards of care/local guidance. [0241] Exclusion Criteria – All Patients: Patients who meet any of the following criteria will be excluded from study entry: 1. Chemotherapy treatments within 14 days prior to first dose of study treatment. For other anticancer treatments, treatment within 28 days or 5 terminal half-lives, whichever is shorter. If prior immunotherapy, the last dose must be at least 28 days prior to the first dose of BT8009.
  • Significant medical condition including but not limited to skin (conditions related to or that may confound monitoring for rash including but not limited to autoimmune conditions such as eczema or psoriasis), life-threatening illness, active uncontrolled infection or organ system dysfunction (such as ascites, coagulopathy, encephalopathy), or other reasons which, in the Investigator opinion, could compromise the patient’s safety, or interfere with or compromise the integrity of the study outcomes, including consideration of gastrointestinal, skin and pulmonary co-morbidities and including review of screening chest CT to ensure no clinically significant co-morbidities.
  • Prior ⁇ Grade 2 thyroid endocrinopathy is allowed, if appropriately controlled with thyroid hormone and stable for at least 2 months on therapy. Skin toxicity should resolve to Grade ⁇ 1. 6.
  • HbA1c hemoglobin A1C
  • any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of- age, or any concomitant medication known to prolong the QT interval iii.
  • Any clinically important abnormalities assessed by the Investigator
  • ECGs resting electrocardiograms
  • ECGs resting electrocardiograms
  • PCR polymerase chain reaction
  • HCV hepatitis C virus
  • Patients who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of ⁇ 12 weeks. 18. History or another active malignancy that would interfere with the safety or efficacy evaluation of the clinical study. 19. Active systemic infection requiring therapy, or fever not attributable to underlying malignancy within the last 14 days prior to first dose of BT8009. 20. Suspicion of relevant and recent systemic viral syndrome or need for quarantine/isolation that is not resolved in the opinion of the Investigator 21.
  • Diagnosis of clinically relevant immunodeficiency 27 Any condition requiring treatment with ⁇ 10 mg daily prednisone equivalent or other strong immunosuppressant 28. Has an active autoimmune disease that has required systemic treatment in the past 2 years (e.g. with the use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systematic treatment. Patients with type 1 DM well controlled on insulin, alopecia, or vitiligo are not excluded per this criteria. 29.
  • Additional Exclusion Criteria B-2 and B-3 (EV-na ⁇ ve urothelial cancer) 30. Prior treatment with EV.
  • Additional Exclusion Criteria Part B-7 (First-line, cisplatin-ineligible, metastatic urothelial cancer) 31.
  • Prior organ transplant (including allogeneic) 32.
  • Diagnosis of clinically relevant immunodeficiency 33. Any condition requiring treatment with ⁇ 10 mg daily prednisone equivalent or other strong immunosuppressant 34.
  • Post-dose biopsies may be taken in Cycles 1-4 for patients in Part A-1, and in Cycle 1 only for all other patients, within 4 hours to 7 days after the BT8009 dose. Refer to the schedule of assessments (SOA) for further details.
  • Pre- and post-dose blood samples will also be collected to assess pharmacodynamic, response, and treatment resistance biomarkers, such as somatic mutations in circulating tumor DNA (ctDNA), ADA and pharmacogenomic analysis.
  • ctDNA circulating tumor DNA
  • ADA pharmacogenomic analysis.
  • Dose-escalation/de-escalation starts with the single subject (A-1 only) and primarily utilizes the 3+3 escalation.
  • BLRM with EWOC principle would also be applied to cumulative DLT/safety data for SRC considerations on dose escalation recommendations.
  • Simon’s two-stage design will be used to test whether the ORR warrants continuation to the next phase. The design would allow early futility check and minimize the expected total sample size, with Type I error rate of 0.05 and power of 80%.
  • All statistical analyses will be using descriptive summary statistics. Response endpoints will be reported using proportion with associated 95% CI.
  • Example 2. BT8009 Formulation [0251] The BT8009 drug product is formulated as a sterile lyophilized powder for solution.
  • the medicinal product is contained in a 10 mL Type I clear glass vial with a chlorobutyl stopper and aluminum seal.
  • the labelled strength of each vial includes 21.2 mg/vial for reconstitution with 5.0 mL of water for injection (WFI).
  • WFI water for injection
  • a 4 mg/mL BT8009 solution is generated (the reconstituted drug substance contains L-histidine, sucrose, and Polysorbate 20), and 5.0 mL of the reconstituted solution will be withdrawn to provide a 20 mg dose for further dilution with about 0.9% saline and administration via IV infusion.
  • BT8009 Phase I trial results and outlook [0252] BT8009 demonstrates anti-tumor activity in heavily pre-treated urothelial ( Figures 5-7), lung ( Figures 8A, 9A) and breast cancer ( Figures 8B, 9B) patients with signs of differentiation compared to antibodies and potential for industry-leading product profile. BT8009 demonstrates a 50% ORR and 75% clinical benefit rate (Figure 7), including 1 (13% complete response in urothelial cancer at 5 mg/m 2 qw dose ( Figure 5-7). The breadth of responses at other dose cohorts and other cancer types illustrates the drug’s potential. BT8009 shows durable responses, with tumor reductions maintained over time ( Figure 6).
  • FIG. 10-16 show the incidence of treatment-emergent adverse events (TEAEs) in the trial. These are the first in human data for a bicycle toxin conjugate targeting Nectin-4. These data indicate positive efficacy and safety profiles. In addition, these data show that BT8009 has potential advantages over existing treatments such as enfortumab vedotin.
  • TEAEs treatment-emergent adverse events
  • Example 4 Modelling supporting dosage strategies [0253] Modeling and simulation evaluations, including population PK and exposure- response modelling analysis were conducted for various dosing strategies (flat, weight-based and BSA-based dosing) using pharmacokinetics (PK), efficacy and safety data from the ongoing Phase I trial data.
  • the PK exposure (AUC and Cmax) of BT8009 and MMAE were predicted from the population PK model and subsequently probabilities of adverse events (AE) were simulated from exposure-safety logistic regression modeling.
  • the modelling predicted that utilization of a flat dosing of BT8009 (in mg) would result in similar PK and safety outcomes relative to BSA-based dosing (in mg/m 2 ).
  • FIG. 17 shows the rate of treatment-related adverse events (TRAE) at different exposures to MMAE from BSA based dosing. Higher AE rate was observed in higher BSA, which suggests flat dose could help to balance the AE across different body size.
  • TRE treatment-related adverse events
  • Cohort 2 will include up to 315 participants who received ⁇ 1 prior systemic therapy for locally advanced or metastatic UC.
  • Objectives Primary Objectives
  • the objectives of cohort I are: Primary objectives • To evaluate the efficacy of BT8009 in combination with pembrolizumab, measured by progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) assessed by blinded central independent review (BICR), measured by the length of time from date of randomization to determination of disease progression made by BICR, or death (due to any cause), whichever occurs first.
  • ADAs anti-drug antibodies
  • pembrolizumab To explore the incidence and titers of anti-drug antibodies (ADAs) against BT8009 and pembrolizumab and to explore the potential relationship between any potential immunogenic response and pharmacokinetics, safety, and efficacy.
  • peripheral and tumor biomarkers and clinical activity - baseline tumor and peripheral biomarkers including Nectin-4 and programmed death- ligand 1 (PD-L1) expression, soluble target and inflammatory cytokines, tumor mutations, pharmacogenomics, and circulating tumor DNA (ctDNA.
  • PD-L1 programmed death- ligand 1
  • the objectives of cohort 2 are: Primary Objectives: • To evaluate the efficacy of BT8009 monotherapy, and in combination with pembrolizumab, as measured by ORR per RECIST v1.1 assessed by BICR, measured by the percentage of participants in the analysis population who have achieved either confirmed CR or PR per RECIST v1.1 assessed by BICR.
  • Study Design for Cohort 1 (Previously untreated): Participants who have not received any prior systemic treatment for advanced or metastatic UC and are eligible to receive platinum-based chemotherapy will be randomized 1:1:1 as follows: - BT8009 5 mg/m2 (on days 1, 8 and 15 of every 21-day cycle) in combination with pembrolizumab, - BT80096 mg/m2 (on days 1 and 8 of every 21-day cycle) plus pembrolizumab, or - SOC chemotherapy (gemcitabine plus either cisplatin or carboplatin (specified prior to randomization).
  • avelumab After completion of 4 to 6 cycles of chemotherapy, participants should receive avelumab as maintenance therapy, if the following criteria are met: (a) absence of disease progression, (b) absence of avelumab-related contraindication, (c) resolution of toxicities from chemotherapy, (d) ECOG PS ⁇ 2, and (e) adequate organ function as defined by the hematology and non-hematology laboratory assessments for Cohort 1.
  • Participants will be stratified by chemotherapy regimen (cisplatin vs carboplatin), liver metastasis (presence vs absence), and ECOG PS (0 vs 1/2). Within the chemotherapy arm, the proportion of participants receiving cisplatin-based chemotherapy will be capped at ⁇ 50%.
  • a planned interim analysis (Cohort 1 IA 1) to select the optimal dose of BT8009 in combination with pembrolizumab will be conducted after the first ⁇ 30 participants in each BT8009 dose level arm that have been followed for at least 9 weeks from the first dose of study treatment, have discontinued from the study due to any reason, or have experienced disease progression (whichever occurs first). Participant enrollment will not be paused while Cohort 1 IA 1 is being conducted; however, a maximum of 45 additional participants in each BT8009 treatment arm may be enrolled by the time the analysis has been completed.
  • BT8009 dose selection Following BT8009 dose selection, enrollment into the treatment arm of the BT8009 non-selected dose will be stopped; however, participants being treated with the BT8009 non- selected dose will be eligible to receive the BT8009 optimal dose, if deemed in their best interest as per Investigator. [0264] After the optimal BT8009 dose is selected, participants will continue to be randomized 1:1 into BT8009 in combination with pembrolizumab or chemotherapy treatment arms until each arm has ⁇ 283 participants.
  • a second interim analysis (Cohort 1 IA2) to evaluate efficacy of BT8009 in combination with pembrolizumab based on ORR by BICR will be performed when ⁇ 146 participants in each arm have been followed for at least 9 months from the first dose of study treatment in each arm, have discontinued from the study or have experienced disease progression (whichever occurs first).
  • the primary analysis will assess the efficacy of BT8009 in combination with pembrolizumab based on the evaluation of PFS by BICR and will take place when ⁇ 475 events have occurred for the comparison of BT8009 optimal dose in combination with pembrolizumab and chemotherapy.
  • Study Design for Cohort 2 (Previously treated): Initially, participants who have received ⁇ 1 prior line of systemic therapy for their UC will be randomized 1:1 to BT80095 mg/m2 on days 1, 8 and 15 of every 21-day cycle or BT8009 6 mg/m2 on days 1 and 8 of every 21-day cycle. Participants will be stratified by prior treatment with a PD-1/PD-L1 inhibitor (prior PD-1/PD- L1 treatment vs no prior PD-1/PD-L1 treatment) and liver metastasis (presence vs absence). The overall proportion of participants previously treated with PD-1/PD-L1 therapy will be capped at 50% (Rawji, 2022, Aguilar, 2021).
  • a planned interim analysis (Cohort 2 IA) to select the optimal dose of BT8009 will be conducted after the first 30 participants in each BT8009 dose level arm have been followed for at least 9 weeks from the first dose of study treatment, have discontinued from the study or have experienced disease progression (whichever occurs first). Participant enrollment will not be paused while Cohort 2 IA is being conducted; however, a maximum of 45 additional participants in each BT8009 treatment arm may be enrolled by the time the analysis has been completed. [0267] Following dose selection, participant enrollment into the BT8009 optimal dose arm will continue, whereas enrollment into the treatment arm of the BT8009 non-selected dose will be stopped.
  • Participants randomized to the BT8009 non-selected dose will be eligible to receive the BT8009 optimal dose, if deemed in the best interest of the participant as per Investigator decision.
  • Participants will be randomized to either the Cohort 2 BT8009 optimal dose monotherapy or BT8009 optimal dose in combination with pembrolizumab (at a randomization ratio that will ensure ⁇ 120 participants in each arm).
  • pembrolizumab at a randomization ratio that will ensure ⁇ 120 participants in each arm.
  • the primary analysis of ORR by BICR will be conducted to assess efficacy of BT8009 monotherapy and BT8009 in combination with pembrolizumab.
  • Treatment and Study Discontinuation (both Cohorts): In both cohorts, study treatments will continue until one of the treatment discontinuation criteria is met.
  • Treatment discontinuation criteria include planned treatment completion (i.e. ⁇ 24 months of pembrolizumab or up to 6 cycles of chemotherapy [Cohort 1 only]), disease progression (treatment should continue until radiographically confirmed by BICR), irreversible or intolerable toxicity, Investigator’s decision to withdraw the participant, participant’s decision to discontinue study treatment, confirmed pregnancy, severe noncompliance with trial treatment or procedure requirements, loss to follow-up, death, or Sponsor’s decision to terminate the study.
  • Tumor Assessment Schedule (both Cohorts): Participants will undergo tumor status assessments at Screening and every 9 weeks ( ⁇ 5 days) for the first 54 weeks following Cycle 1, Day 1. After 54 weeks, participants will undergo tumor status assessments every 12 weeks ( ⁇ 7 days).
  • EOT and Follow-up Timepoints (Safety and Long-term) (both Cohorts): An end of treatment (EOT) visit should occur within 7 ( ⁇ 2) days of the decision to discontinue all study treatments. Should the participant discontinue all study treatments, the Investigator will review provisions for safety follow-up and discuss available treatment options including standard of care. If treatment was discontinued due to reasons other than confirmed disease progression, a tumor assessment is required within 4 weeks of all study treatment(s) discontinuation. In participants who discontinue study treatment due to confirmed disease progression, the tumor assessment at EoT is the final required scan.
  • tumor assessments will continue per SOA, until all study treatments have been discontinued.
  • a safety follow-up visit will occur 30 (+ 5) days after the last dose of all study treatments or prior to starting a new anticancer therapy, whichever comes first.
  • Serious adverse events related to pembrolizumab or avelumab will be collected for 90 days after the last dose of pembrolizumab, or avelumab, or until initiation of a new anticancer therapy, whichever occurs first.
  • OS and anticancer therapy status will be collected by telephone every 3 months ( ⁇ 30 days) until death, loss to follow-up, withdrawal of study consent, or study termination by the Sponsor, whichever occurs first.
  • Participant study completion is defined as the conclusion of data collection for the defined study endpoints including all follow-up assessments.
  • Study Arms and Duration [0275]
  • Pembrolizumab infusion will be started 30 minutes following the completion of the BT8009 infusion.
  • Arm 2 BT80096 mg/m 2 IV over 60 (-5 to +30) minutes on Days 1 and 8 plus of every 21-day cycle in combination with pembrolizumab 200 mg IV over 30 (-5 to +10) minutes on Day 1 of every 21-day cycle.
  • Pembrolizumab infusion will be started 30 minutes following the completion of the BT8009 infusion.
  • Arm 3 Up to 6 cycles of platinum-based combination chemotherapy: Gemcitabine 1000 mg/m2 IV on days 1 and 8 of every 21 day cycle plus cisplatin 70 mg/m2 IV on Day 1 of every 21-day cycle OR Gemcibatine 1000 mg/m2 IV on days 1 and 8 of every 21 day cycle plus carboplatin area under the curve (AUC) 5 mg/mL per minute (or 4.5 mg/mL, if required by local institutional standards) IV on Day 1 of every 21-day cycle. Eligibility for cisplatin will be based on standard criteria. [0279] Chemotherapy infusion windows will follow local guidelines. In countries where these interventions are not approved, dosing and administration should follow the USPI.
  • Infusion of cisplatin or carboplatin will be administered 30 minutes after the completion of the gemcitabine infusion.
  • a participant may switch per Investigator decision from cisplatin to carboplatin during the trial, if required by clinical factors such as impairment of renal function.
  • participants should receive avelumab as maintenance therapy.
  • Avelumab treatment will begin within 10 weeks after last dose of platinum therapy.
  • Avelumab 800 mg IV will be administered per local guidelines on Days 1 and 15 of every 28-day cycle.
  • Cohort 2 Previously treated [0282] Arm 1: BT80095 mg/m 2 IV over 60 (-5 to +30) minutes on Days 1, 8, and 15 of every 21-day cycle. [0283] Arm 2: BT80096 mg/m 2 IV over 60 (-5 to +30) minutes on Days 1 and 8 of every 21-day cycle. [0284] Arm 3: BT8009 optimal dose IV over 60 (-5 to +30 minutes) in combination with pembrolizumab 200 mg IV over 30 (-5 to +10 minutes) on day 1 of every 21 day cycle. Pembrolizumab infusion will be started 30 minutes following the completion of the BT8009 infusion. Enrollment into the Arm 3 will begin after completion of Cohort 2 IA.
  • Inclusion Criteria [0285] Participants must meet the following criteria for study entry. 1. Able to understand the study procedures and agree to participate in the study by providing written informed consent. 2. ⁇ 18 years of age on day of signing informed consent. 3. Histologically or cytologically confirmed locally advanced (unresectable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, and urethra. a. Participants with mixed histologies are required to have a dominant transitional cell pattern ( ⁇ 50%) 4. Measurable disease as defined by RECIST v1.1. a. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions post irradiation. 5.
  • Total bilirubin ⁇ 1.5 ⁇ upper limit of normal (ULN) or ⁇ 3 x ULN for participants with Gilbert disease
  • Serum albumin ⁇ 2.5 g/dL
  • Aspartate aminotransferase (AST) ⁇ 2.5 ⁇ ULN or ⁇ 5 ⁇ ULN in the presence of liver metastases
  • Alanine aminotransferase (ALT) ⁇ 2.5 ⁇ ULN or ⁇ 5 ⁇ ULN in the presence of liver metastases
  • AP Alkaline phosphatase (AP) ⁇ 2.5 ⁇ ULN or ⁇ 5 ⁇ ULN in the presence of liver or bone metastases g.
  • b Prior adjuvant/neoadjuvant chemotherapy or MMAE-based therapy with recurrence >12 months from completion of therapy.
  • c Prior neoadjuvant/adjuvant immune checkpoint inhibitor therapy >12 months from completion of therapy. 14.
  • ECOG PS ⁇ 2 Adequate bone marrow function including the following: a. Hemoglobin ⁇ 9 g/dL b. Absolute neutrophil count (ANC) ⁇ 1500 cells/ mm 3 c. Platelet count ⁇ 100,000 cells/mm 3 . Inclusion criteria specific to Cohort 2: Previously treated 1. Participants must have received ⁇ 1 prior systemic treatment for locally advanced or metastatic UC.
  • Active keratitis or corneal ulcerations 1. Requirement, while on study, for treatment with strong inhibitors or strong inducers of human cytochrome P4503A (CYP3A) or inhibitors of P-glycoprotein (P-gp) including herbal- or food-based inhibitors. 3. Any condition requiring treatment with high dose corticosteroids (> 10 mg daily prednisone). 4. Known hypersensitivity or allergy to any of the ingredients of either of the study interventions, or MMAE. 5. Has not adequately recovered from recent major surgery (excluding placement of vascular access). 6. Receipt of live or attenuated vaccine within 30 days of first dose. 7. Known active or untreated CNS metastases and/or carcinomatous meningitis. a.
  • Participants with treated brain metastases may participate in the study if they are stable for at least 4 weeks prior to the first dose, either without the use of steroids or on stable or decreasing dose of ⁇ 10 mg daily prednisone or equivalent and are without any symptoms.
  • Uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ⁇ 8%.
  • Uncontrolled hypertension (HTN) systolic blood pressure (BP) ⁇ 150 mm Hg or diastolic BP ⁇ 95 mm Hg) prior to first dose.
  • Prior allogeneic stem cell or solid organ transplantation Prior allogeneic stem cell or solid organ transplantation. Active interstitial lung disease or pneumonitis, or a history of interstitial lung disease or pneumonitis requiring treatment with steroids or other immunosuppressive medications. Prior treatment with an agent directed to another stimulatory or co-stimulatory T-cell receptor. Prior treatment with any systemic anticancer therapy within 2 weeks or 5 half-lives, whichever is longer, prior to initiation of study treatment; the following exceptions are permitted: a. Palliative radiotherapy for UC-related bone or soft tissue metastasis completed > 7 days prior to baseline imaging. b. Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) agonists). c.
  • GnRH gonadotropin-releasing hormone
  • An interim analysis (Cohort 1 IA 1) to select the optimal dose of BT8009 in combination with pembrolizumab will be conducted after the first 30 participants in each BT8009 dose level arm have been followed for at least 9 weeks months from the first dose of study treatment, have discontinued from the study due to any cause, or have experienced disease progression (whichever occurs first). Methods used to select the optimal BT8009 dose are described in the BT8009 dose selection section above. Participant enrollment will not be paused while Cohort 1 IA 1 is being conducted; however, a maximum of 45 additional participants in each BT8009 treatment arm may be enrolled by the time the analysis has been completed..
  • the dose selection analysis will include only the first 30 participants in each BT8009 dose level arm, safety data from all enrolled participants up to Cohort 1 IA1 will be considered as supportive evidence.
  • participant enrollment into the BT8009 optimal dose in combination with pembrolizumab and chemotherapy arms will continue, whereas enrollment into the treatment arm with the BT8009 dose that was not selected will be stopped.
  • the family-wise type I error rate (alpha) for this study is strongly controlled at 0.025 (one-sided). An administrative one-sided alpha of 0.0005 will be used for the IA1, although there is no plan to conduct any analyses of BT8009 doses in combination with pembrolizumab vs chemotherapy during dose selection.
  • the actual alpha allocated to PFS primary analysis will be either 0.0245 or 0.0045 depending on the ORR analysis outcome at IA2.
  • OS analysis a group sequential method using O’Brien-Fleming boundary per Lan and DeMets method will be used to control the overall one-sided type I error. Assuming a median OS of 23 months for BT8009 optimal dose in combination with pembrolizumab vs 18.5 months for chemotherapy (corresponding to a HR of 0.80) and dropout rate of 10% annually, with 283 participants in each arm, ⁇ 384 OS events would be expected for the OS interim analysis at the time of PFS primary analysis. The final analysis of OS would be expected after ⁇ 431 OS events have occurred.
  • Cohort 2 Previously treated [0303] The total target sample size for Cohort 2 is ⁇ 315 participants. [0304] Participants will be randomized in 1:1 ratio to receive BT80095 mg/m 2 or, BT8009 6 mg/m 2 . Participants will be stratified by prior treatment with a PD-1/PD-L1 (prior PD-1/PD- L1 treatment vs no prior PD-1/PD-L1 treatment) and liver metastasis (presence vs absence). The overall proportion of participants previously treated with PD-1/PD-L1 therapy will be capped at 50% (Rawji, 2022, Aguilar, 2021).
  • a planned interim analysis (Cohort 2 IA) to select the optimal dose of BT8009 will be conducted after the first 30 participants in each BT8009 dose level arm (Arm 1 and Arm 2) have been followed for at least 9 weeks from the first dose of study treatment, have discontinued from the study due to any cause, or have experienced disease progression (whichever occurs first). Methods used to select the optimal BT8009 dose are described in the BT8009 dose selection section above. Participant enrollment will not be paused while Cohort 2 IA is being conducted; however, a maximum of 45 additional participants in each BT8009 treatment arm may be enrolled by the time the analysis has been completed.
  • MMAE and BT8009 clearance were found to be similar across participants with normal kidney function vs mild renal impairment vs moderate renal impairment ( Figure 23 A and B). Therefore, no dose adjustments are recommended for participants with mild or moderate renal impairment.
  • FIG. 27B A waterfall plot showing best response for efficacy evaluable patients (including 7 unconfirmed responses) is shown in Figure 27B (one efficacy evaluable patient does not appear on the water plot as best overall response was not evaluable).
  • 15 patients remain on therapy at time of data cut.
  • 9 patients with a response remain on therapy.
  • mDOT is currently 11.1 weeks.
  • mDOR is not mature.
  • Patient data are also represented in a spider plot showing the percent change from baseline in the sum of diameters of target lesions; patients receiving BT8009 and pembrolizumab combination therapy show prolonged responses (Figure 27C). [0318] BT8009 and pembrolizumab combination therapy continues to show promising tolerability.
  • Treatment-related adverse events were as anticipated in a front-line population. Of BT8009 + pembrolizumab patients, only one Grade 4 event was reported, and therer were no Grade 5 events.
  • Treatment-emergent AEs (TEAE) and treatment-emergent serious AEs (TESAE) were defined as AEs/SAEs starting or worsening on or after first date of dose, up to 30 days post last date of dose. Any SAEs related to BT8009 occurring after 30 days post last date of dose are also flagged as TEAEs. A patient with multiple events within a category is counted only once in that category. Symptoms of metastasis or the metastasis itself are not reported AE/SAE.
  • a single grade 3 rash event improved to grade 1 with dose interruption and systemic steroid and treatment resumed at a reduced dose; 2 further patients managed with dose interruption.
  • the median onset of rash was ⁇ 2 weeks (6, 44 days), median onset of pruritus was ⁇ 2 weeks (7, 69 days).
  • Data are also shown for Cohort K of the EV-103 trial (O’Donnell ibid).
  • BT8009 drug product will be supplied for clinical use as a white to off white sterile lyophilised powder for reconstitution in a 10 ⁇ mL Type I clear glass vial with a butyl stopper and aluminium seal. During manufacture, each vial is filled with 5.3 mL of 4 mg/mL bulk solution prior to lyophilisation, providing 21.2 ⁇ mg of BT8009 per vial.
  • BT8009 drug product is reconstituted with 5.0 ⁇ mL of sterile WFI (to return a reconstituted volume of 5.3 ⁇ mL solution) providing BT8009 at a target concentration of 4 ⁇ mg/mL for further dilution with 0.9% saline prior to IV administration (infusion).
  • the 0.3 mL excess ensures an extractable volume of 5 mL from the vial providing up to a 20 mg dose for further dilution.
  • Hydrochloric acid and/or sodium hydroxide is used to adjust the pH of the fill solution to target pH 7.0, within the effective buffering range of the L-histidine buffer.
  • Table 1 Composition of BT8009 Drug Product Concentration Reference to Component Function (mg/mL) Standard BT8009 Drug substance 4.0 a HSE L-Histidine Buffer 5.24 EP, USP Sucrose Stabiliser, cryoprotectant 60.0 EP, NF Polysorbate 20 Non-ionic surfactant 0.1 EP/NF Hydrochloric Acid pH adjustment q.s b EP Sodium hydroxide pH adjustment q.s b EP WFI c Solvent q.s b . to 1 mL EP/USP a. Based on API potency, adjustments will be made to achieve the target drug substance label claim value. b. Quantity sufficient. c. Water for injections (WFI) is driven off during lyophilisation process.
  • WFI Water for injections

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Abstract

La présente invention concerne un conjugué de toxine bicyclique BT8009, ou des sels pharmaceutiquement acceptables de celui-ci, ou des compositions pharmaceutiques de celui-ci, destinés à être utilisés en combinaison avec un agent qui inhibe la voie PD-1/PD-L1 dans des méthodes de thérapie.
PCT/GB2024/053097 2023-12-13 2024-12-12 Ligands peptidiques bicycliques spécifiques de la nectine-4 et leurs utilisations Pending WO2025125809A1 (fr)

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Citations (4)

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WO2022038158A1 (fr) * 2020-08-17 2022-02-24 Bicycletx Limited Conjugués "bicycle" spécifiques de la nectine-4 et leurs utilisations
WO2024246547A1 (fr) * 2023-06-01 2024-12-05 Bicycletx Limited Ligands peptidiques bicycliques spécifiques de la nectine 4 et leurs utilisations
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WO2009098450A2 (fr) 2008-02-05 2009-08-13 Medical Research Council Procédés et compositions
WO2022038158A1 (fr) * 2020-08-17 2022-02-24 Bicycletx Limited Conjugués "bicycle" spécifiques de la nectine-4 et leurs utilisations
WO2024246547A1 (fr) * 2023-06-01 2024-12-05 Bicycletx Limited Ligands peptidiques bicycliques spécifiques de la nectine 4 et leurs utilisations
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