Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

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.
• several cyclic peptides are already successfully used in the clinic, as for example the antibacterial peptide vancomycin, the immunosuppressant drug cyclosporine or the anti-cancer drug octreotide (Driggers et al. (2008), Nat Rev Drug Discov 7 (7), 608-24).
• Good binding properties result from a relatively large interaction surface formed between the peptide and the target as well as the reduced conformational flexibility of the cyclic structures.
• macrocycles bind to surfaces of several hundred square angstrom, as for example the cyclic peptide CXCR4 antagonist CVX15 (400 A 2 ; Wu et al. (2007), Science 330, 1066-71), a cyclic peptide with the Arg-Gly-Asp motif binding to integrin aVb3 (355 A 2 ) (Xiong et al. (2002), Science 296 (5565), 151-5) or the cyclic peptide inhibitor upain-1 binding to urokinase-type plasminogen activator (603 A 2 ; Zhao et al. (2007), J Struct Biol 160 (1), 1-10).
• CVX15 400 A 2 ; Wu et al. (2007), Science 330, 1066-71
• a cyclic peptide with the Arg-Gly-Asp motif binding to integrin aVb3 355 A 2
• peptide macrocycles are less flexible than linear peptides, leading to a smaller loss of entropy upon binding to targets and resulting in a higher binding affinity.
• the reduced flexibility also leads to locking target-specific conformations, increasing binding specificity compared to linear peptides.
• MMP-8 matrix metalloproteinase 8
• the invention provides a pharmaceutical composition comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, and Polysorbate 20.
• a pharmaceutical composition comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, and Polysorbate 20 is a lyophilized powder.
• a pharmaceutical composition comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, and Polysorbate 20 is a pharmaceutical formulation in water.
• the invention provides a method for treating advanced malignancies associated with Nectin-4 expression in a patient comprising administering to the patient a pharmaceutical composition as described herein.
• the invention provides a method for treating advanced malignancies associated with Nectin-4 expression in a patient comprising administering to the patient weekly by IV infusion a pharmaceutical formulation comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, and Polysorbate 20 in water.
• the invention provides methods of using a pharmaceutical composition described herein for treating an advanced solid tumor malignancy associated with Nectin-4-expression.
• the invention provides a method for treating advanced malignancies associated with Nectin-4 expression in a patient comprising administering to the patient weekly by IV infusion over 1 hour a pharmaceutical formulation comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, and Polysorbate 20 in water.
• a pharmaceutical formulation comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, and Polysorbate 20 in water is given as a single agent.
• the pharmaceutical formulation comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, and Polysorbate 20 in water is given in combination with nivolumab.
• nivolumab is administered 240 mg over 30 minutes every 2 weeks.
• the pharmaceutical formulation comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, and Polysorbate 20 in water given in combination with nivolumab is administered by sequential infusions first with BT8009 followed by nivolumab.
• the advanced solid tumor malignancy associated with Nectin- 4-expression is selected from the group consisting of non-small-cell lung cancer (NSCLC), ovarian cancer, triple-negative breast cancer (TNBC), gastric/upper gastrointestinal (GI) cancer, pancreatic cancer, and urothelial cancer.
• NSCLC non-small-cell lung cancer
• TNBC triple-negative breast cancer
• GI gastric/upper gastrointestinal cancer
• pancreatic cancer pancreatic cancer
• urothelial cancer urothelial cancer
• the advanced solid tumor malignancy associated with Nectin- 4-expression is non-small-cell lung cancer (NSCLC). In some embodiments, the advanced solid tumor malignancy associated with Nectin-4-expression is ovarian cancer. In some embodiments, the advanced solid tumor malignancy associated with Nectin-4-expression is triple-negative breast cancer (TNBC). In some embodiments, the advanced solid tumor malignancy associated with Nectin-4-expression is gastric/upper gastrointestinal (GI). In some embodiments, the advanced solid tumor malignancy associated with Nectin-4-expression is pancreatic cancer. In some embodiments, the advanced solid tumor malignancy associated with Nectin-4-expression is urothelial cancer. 2. Compounds and Definitions:
• BT8009 is a Bicycle toxin conjugate having a structure as shown below, wherein the molecular scaffold is l,r,l"-(l,3,5-triazinane-l,3,5-triyl)triprop-2-en- 1-one (TATA), and the peptide ligand comprises the amino acid sequence:
• 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.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci 4alkyl)4 salts.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. It will be appreciated that salt forms are within the scope of this invention, and references to peptide ligands include the salt forms of said ligands.
• 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. In some embodiments, 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. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
• Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
• the invention provides a pharmaceutical composition comprising BT8009, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
• a pharmaceutical composition of the invention comprises about 21.2 mg BT8009, or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition of the invention is a solid pharmaceutical composition.
• a solid pharmaceutical composition of the invention is powders.
• a pharmaceutical composition of the invention is lyophilized powder.
• a solid pharmaceutical composition of the invention is granules.
• the invention provides BT8009, or a pharmaceutically acceptable salt thereof, as a sterile lyophilized powder for solution.
• the BT8009, or a pharmaceutically acceptable salt thereof is contained in a 10 mL Type I clear glass vial with a chlorobutyl stopper and aluminum seal.
• each vial includes 21.2 mg/vial of BT8009, or a pharmaceutically acceptable salt thereof, for reconstitution with 5.0 mL of water for injection (WFI).
• a 4 mg/mL BT8009 solution is generated (the reconstituted drug substance contains histidine, sucrose, and Polysorbate 20), and 5.0 mL of the reconstituted solution is withdrawn to provide a 20 mg dose for further dilution with 0.9% saline and administration via IV infusion.
• a pharmaceutical composition of the invention is a liquid pharmaceutical composition.
• a liquid pharmaceutical composition of the invention is a pharmaceutical formulation in an acceptable vehicle or solvent.
• an acceptable vehicle or solvent is selected from sterile water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
• an acceptable vehicle or solvent is sterile water.
• an acceptable vehicle or solvent is a sterile injectable medium.
• a liquid pharmaceutical composition of the invention comprises about 2-4 mg/mL BT8009, or a pharmaceutically acceptable salt thereof.
• a liquid pharmaceutical composition of the invention comprises about 4 mg/mL BT8009, or a pharmaceutically acceptable salt thereof.
• a pharmaceutically acceptable excipient or carrier 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 histidine.
• a buffering agent is sodium hydroxide.
• a buffering agent is hydrochloric acid.
• a buffering agent is at an amount to adjust pH of a pharmaceutical composition of the invention to about 6-8.
• a buffering agent is histidine at an amount of about 1-3 mg per mg of BT8009, or a pharmaceutically acceptable thereof.
• histidine is at an amount of about 1.31 or 2.62 mg per mg of BT8009, or a pharmaceutically acceptable thereof.
• a liquid pharmaceutical composition of the invention comprises histidine at a concentration of about 5.24 mg/mL.
• a liquid pharmaceutical composition of the invention is at a pH of about 6-8. In some embodiments, a liquid pharmaceutical composition of the invention is at a pH of about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0. In some embodiments, a liquid pharmaceutical composition of the invention is at a pH of about 6.5 or 7.0.
• a pharmaceutically acceptable excipient or carrier comprises a stabilizer or cryoprotectant.
• a stabilizer or cryoprotectant is dimethyl sulfoxide (DMSO).
• DMSO dimethyl sulfoxide
• 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 formamide.
• 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 pharmaceutically acceptable excipient or carrier 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, lauroamidopropyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmidopropyl- 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 surfactant is at an amount of about 0.025, 0.05, or 0.1 mg per mg of BT8009, or a pharmaceutically acceptable thereof.
• a liquid pharmaceutical composition comprises a surfactant (e.g., Polysorbate 20) at a concentration of about 0.1 or 0.2 mg/mL.
• a pharmaceutically acceptable excipient or carrier comprises an isotonicity adjusting agent.
• an isotonicity adjusting agent is sodium chloride, dextrose, calcium chloride, or a combination thereof.
• an isotonicity adjusting agent is dextrose.
• an isotonicity adjusting agent is sodium chloride.
• an isotonicity adjusting agent is a combination of sodium chloride and dextrose.
• the invention provides a pharmaceutical composition comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, and Polysorbate 20.
• a pharmaceutical composition of the invention comprises: BT8009, or a pharmaceutically acceptable salt thereof; about 1.31-2.62 mg histidine per mg of BT8009, or a pharmaceutically acceptable thereof; about 15-30 mg sucrose per mg of BT8009, or a pharmaceutically acceptable thereof; and about 0.05-0.1 mg Polysorbate 20 per mg of BT8009, or a pharmaceutically acceptable thereof.
• the invention provides a solid pharmaceutical composition, which is a lyophilized powder, comprising: about 21.2 mg BT8009, or a pharmaceutically acceptable salt thereof; about 27.8 mg histidine; about 318 mg sucrose; and about 1.06 mg Polysorbate 20.
• the invention provides a liquid pharmaceutical composition comprising: about 2-4 mg/mL BT8009, or a pharmaceutically acceptable salt thereof; about 5.24 mg/mL histidine; about 60 mg/mL sucrose; and about 0.2 mg/mL Polysorbate 20.
• the invention provides a liquid pharmaceutical composition prepared by dissolving a solid pharmaceutical composition of the invention in water.
• the invention provides a liquid pharmaceutical composition prepared by dissolving a solid pharmaceutical composition of the invention in an injectable medium (e.g., 0.9% w/v saline or 5% dextrose).
• the invention provides a liquid pharmaceutical composition prepared by reconstituting a solid pharmaceutical composition of the invention in water, followed by dilution with 0.9% w/v saline.
• a liquid pharmaceutical composition is diluted into a 0.9% w/v saline IV bag for IV administration.
• the invention provides a solid pharmaceutical composition comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, and Polysorbate 20.
• the invention provides a liquid pharmaceutical composition comprising BT8009, or a pharmaceutically acceptable salt thereof, histidine, sucrose, Polysorbate 20, and water.
• the components of the pharmaceutical compositions are at the amount, concentration, and ratio as described above.
• the invention provides a method, or a use, for treating an advanced solid tumor malignancy associated with Nectin-4-expression in a patient comprising administering to the patient a pharmaceutical composition as described herein.
• an advanced solid tumor malignancy associated with Nectin-4-expression is selected from non-small-cell lung cancer (NSCLC), ovarian cancer, triple-negative breast cancer (TNBC), gastric/upper gastrointestinal (GI), pancreatic and urothelial cancers.
• NSCLC non-small-cell lung cancer
• TNBC triple-negative breast cancer
• GI gastric/upper gastrointestinal
• pancreatic and urothelial cancers gastric/upper gastrointestinal
• an advanced solid tumor malignancy associated with Nectin-4-expression is an adenocarcinoma subtype of NSCLC (adeno-NSCLC).
• a method of the invention comprises administering to a patient intravenously a pharmaceutical composition as described herein.
• a pharmaceutical composition of the invention is administered by an IV injection.
• a pharmaceutical composition of the invention is administered by an IV infusion.
• an IV infusion of a pharmaceutical composition of the invention lasts about 5-30 minutes.
• an IV infusion of a pharmaceutical composition of the invention lasts about 30-90 minutes.
• an IV infusion of a pharmaceutical composition of the invention lasts about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes.
• an IV infusion of a pharmaceutical composition of the invention lasts about 60 minutes.
• an IV infusion of a pharmaceutical composition of the invention lasts about 2, 2.5, 3, 3.5, or 4 hours.
• a pharmaceutical composition of the invention is administered to a patient once every 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, a pharmaceutical composition of the invention is administered to a patient weekly. In some embodiments, a pharmaceutical composition of the invention is administered to a patient once every two weeks. [0038] In some embodiments, a pharmaceutical composition of the invention is administered at a dose of about 1-27 mg/m 2 . In some embodiments, a pharmaceutical composition of the invention is administered at a dose of about 2-20 mg/m 2 . In some embodiments, a pharmaceutical composition of the invention is administered at a dose of about 2-20 mg/m 2 .
• a pharmaceutical composition of the invention is administered at a dose of about 2.2, 4.4, 7.3, 11, 14.6, or 19.4 mg/m 2 . In some embodiments, a pharmaceutical composition of the invention is administered at a dose of about 2.5, 5.0, 7.5, 10.0, 13.0, or 17.0 mg/m 2 . In some embodiments, a pharmaceutical composition of the invention is administered at a dose of about 1.5-3.5, 3.5-5.5, 6.5-8.5, 10-12, 13.5-15.5, or 18.5-20.5 mg/m 2 . In some embodiments, a pharmaceutical composition of the invention is administered at a dose of about 1-10 or 10-20 mg/m 2 . In some embodiments, a pharmaceutical composition of the invention is administered at a dose of about 21, 22, 23, 24, 25, 26, or 27 mg/m 2 .
• a pharmaceutical composition of the invention is administered to a patient at least 18 years-of-age.
• a pharmaceutical composition of the invention is administered to a patient having an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
• ECOG Performance Status scores of 0 and 1 are described in Example 1.
• a pharmaceutical composition of the invention is administered to a patient having measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) vl .l.
• RECIST Solid Tumors
• a pharmaceutical composition of the invention is administered to a patient having acceptable organ function.
• a patient having acceptable organ function has laboratory data selected from the following:
• Renal function creatinine clearance of >50 mL/min by the Cockcroft-Gault equation or as measured by 24-hour urine collection;
• Aspartate aminotransferase ⁇ 2.5 x ULN or ⁇ 5 x ULN in the presence of liver metastases
• ALT Alanine aminotransferase
• a pharmaceutical composition of the invention is administered to a patient having acceptable hematologic function.
• a patient having acceptable hematologic function has laboratory data selected from the following:
• ANC Absolute neutrophil count
• a pharmaceutical composition of the invention is administered to 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 pharmaceutical composition of the invention)
• WOCBP women of childbearing potential
• a pharmaceutical composition of the invention is administered to a patient who has a life expectancy >12 weeks after the start of BT8009 treatment according to the Investigator judgment.
• a pharmaceutical composition of the invention is administered to a patient with an advanced, histologically confirmed malignant solid tumor as follows: a) urothelial (transitional cell) carcinoma naive to Nectin-4 directed therapies; or b) having tumor tissue (fresh biopsy or on archived sample less than 12 months old without intervening anti-cancer therapies) testing positive for Nectin-4 expression; or c)solid tumors known to be historically associated with Nectin-4 as follows: pancreatic, TNBC, NSCLC, gastric, esophageal or ovarian.
• a pharmaceutical composition of the invention is administered to a patient with disease that recurred after or been refractory to previous therapy including appropriate targeted therapies, for example EGFR or ALK therapies for relevant oncogene driver NSCLC patients, and are candidates for a Phase I study due to lack of approved or standard options for treatment.
• appropriate targeted therapies for example EGFR or ALK therapies for relevant oncogene driver NSCLC patients
• a pharmaceutical composition of the invention is administered to a patient with solid tumor metastatic recurrent disease confirmed to express Nectin-4 on fresh biopsy or archived tissue (less than 12 months old and with no intervening anti-cancer therapies) are eligible and must have exhausted all standard treatment options, including appropriate targeted therapies, for example EGFR or ALK therapies for relevant oncogene driver NSCLC patients, must have failed at least one prior line of therapy with evidence of radiographic progression on the most recent line of therapy.
• a pharmaceutical composition of the invention is administered to a patient naive to Nectin-4 directed therapies.
• a pharmaceutical composition of the invention is administered to a patient with a solid tumor advanced disease having exhausted all appropriate standards of care options as follows: 1) patient with GFR (by CG or by 24-hour urine) 40-50 ml/min (or equivalent units) to be enrolled and evaluated first (refer to SRC section) followed by; 2) a patient with GFR 30-40 ml/min (or equivalent units).
• a patient has not had a chemotherapy treatment within 14 days prior to first dose of a pharmaceutical composition of the invention. In some embodiments, a patient has not had an anticancer treatment within 28 days or 5 half-lives, whichever shorter, prior to first dose of a pharmaceutical composition of the invention. In some embodiments, a patient has prior toxicities which have resolved to grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 (except alopecia which must be no greater than Grade 2).
• CCAE Common Terminology Criteria for Adverse Events
• a patient has not had an experimental treatment within 4 weeks of first dose of a pharmaceutical composition of the invention.
• a patient has not had prior treatment with Nectin-4 targeted therapy.
• a patient does not have a current treatment with strong inhibitors or inducers of CYP3A4 or strong inhibitors of P-gp including herbal- or food-based.
• a patient does not have any sensitivity to any of the ingredients of a pharmaceutical composition of the invention, or to monomethyl auristatin E (MMAE).
• MMAE monomethyl auristatin E
• a patient does not have a weight >100 kg (222.2 lbs) or BSA >2.21 m 2 (representing human 100 kg equivalent for height 175 cm).
• a patient does not have a significant medical condition including but not limited eye (conditions related to or that may confound monitoring for dry eye, corneal opacities or keratitis); 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.
• eye condition related to or that may confound monitoring for dry eye, corneal opacities or keratitis
• 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
• 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 does not have a clinically relevant troponin elevation.
• a patient does not have uncontrolled diabetes defined as hemoglobin AIC (HbAlc) >8%.
• a patient has not had major surgery (excluding placement of vascular access) within 4 weeks of first dose of a pharmaceutical composition of the invention and has recovered adequately prior to starting study therapy.
• a patient has not received a live vaccine within 30 days of study treatment.
• a patient does not have uncontrolled, symptomatic brain metastases (must have stable neurologic status following local therapy for at least 4 weeks without the use of steroids or on stable or decreasing dose of less than or equal to 10 mg daily prednisone or equivalent at time of study treatment initiation and must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs).
• BP systolic blood pressure
• 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 or: a. mean resting corrected QT interval (QTcF) >470 msec, b. 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, or c. any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third degree heart block.
• ECGs resting electrocardiograms
• a patient does not have mean resting corrected QT interval (QTcF) >470 msec within 6 months prior to first dose of a pharmaceutical composition of the invention.
• a patient does not have, within 6 months prior to first dose of a pharmaceutical composition of the invention, 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 pharmaceutical composition of the invention, 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 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 has 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 pharmaceutical composition of the invention. In some embodiments, a patient does not have any residual disease from a previously diagnosed malignancy (excluding adequately treated with curative intent basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia/cervical carcinoma in situ or melanoma in situ or ductal carcinoma in situ of the breast). [0076] In some embodiments, a patient does not have systemic IV anti-infective treatment or fever within the last 14 days prior to first dose of a pharmaceutical composition of the invention. [0077] In some embodiments, a patient does not have a suspicion of relevant and recent systemic viral syndrome or need for quarantine/isolation that is not resolved in the opinion of the investigator.
• a patient does not have a psychological, familial, sociological, or geographical conditions that does not permit compliance with the protocol and/or follow-up procedures.
• the invention provides a combination use of a pharmaceutical composition of the invention and Nivolumab, for treating an advanced solid tumor malignancy associated with Nectin-4-expression.
• Nivolumab can be administered as described on the label, which can be found at https://www.opdivohcp.com/dosing/dosing-schedules, the content of which is incorporated herein by reference in its entirety.
• Nivolumab is administered 240 mg every 2 weeks.
• Nivolumab is administered 480 mg every 4 weeks.
• Nivolumab is administered as a 30-minute IV infusion.
• a patient is not previously known being intolerance to an immune checkpoint inhibitor. In some embodiments of a combination use, a patient is not known being hypersensitivity to checkpoint inhibitor therapy. In some embodiments of a combination use, a patient has no prior organ transplant. In some embodiments of a combination use, a patient is not previously diagnosed with clinically relevant immunodeficiency. In some embodiments of a combination use, a patient does not have active systemic infection requiring therapy. In some embodiments of a combination use, a patient does not take more than 10 mg daily prednisone equivalent or other strong immunosuppressant. In some embodiments of a combination use, a patient does not have a history of autoimmune disease except alopecia or vitiligo. In some embodiments of a combination use, a patient does not have a history of interstitial lung disease.
• Example 1 Phase I/P Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT8009 in Patients with Advanced Malignancies Associated with Nectin-4 Expression
• Parts A-l, A-2, Part C The primary objectives of the escalation and renal cohorts (Parts A-l, A-2, Part C) are:
• Parts B-l and B-2 The primary objective of the expansion cohort is: • To assess the clinical activity of BT8009 in patients with solid tumor indications associated with Nectin-4 expression as a monotherapy (Part B-l) and in combination with nivolumab (PartB-2) using RECIST 1.1
• Parts A-l and A-2 The secondary objectives of the escalation (Parts A-l and A-2) and the renal cohorts (Part C) are:
• PK pharmacokinetic
• This study is a Phase I/II, first-in-human, open-label dose-escalation study of BT8009 given as a single agent (Parts A-l, B-l and C) and in combination with nivolumab (Parts A-2 and B-2). There are three parts to this study: Part A, dose escalation, Part B, dose expansion and Part C, renal insufficiency.
• Part A dose escalation
• Part B dose expansion
• Part C renal insufficiency
• BT8009 in ascending doses in dose escalation cohorts (A-l and A-2) and at the RP2D in expansion cohorts (B-l and B-2), and renal cohort (C) administered intravenously as infusion over lh.
• Nivolumab administered 240 mg over 30 minutes every 2 weeks for combination therapy in Part A-2 and B-2.
• a patient declines to participate in any voluntary component of the study (e.g., tumor biopsy), there will be no penalty or loss of benefit to the patient, and he/she will not be excluded from other aspects of the study.
• any voluntary component of the study e.g., tumor biopsy
• single-subject accelerated cohorts may enroll patients with advanced solid tumors non-restricted to the above definitions, unless SRC views otherwise. All patients must have disease that recurred after or been refractory to previous therapy including appropriate targeted therapies, for example EGFR or ALK therapies for relevant oncogene driver NSCLC patients, and are candidates for a Phase I study due to lack of approved or standard options for treatment.
• the Sponsor may require a), b), or c) at any time during the enrollment.
• the Sponsor and/or SRC may decide to require enrollment of specific tumor (sub)types at any point during the escalation if it is felt necessary to enrich the evaluation of biomarkers, safety, anti-tumor activity, or PK.
• Nectin-4 patients with solid tumor metastatic recurrent disease confirmed to express Nectin-4 on fresh biopsy or archived tissue (less than 12 months old and with no intervening anti-cancer therapies) are eligible and must have exhausted all standard treatment options, including appropriate targeted therapies, for example EGFR or ALK therapies for relevant oncogene driver NSCLC patients, must have failed at least one prior line of therapy with evidence of radiographic progression on the most recent line of therapy. Patients must be naive to Nectin-4 directed therapies. Sponsor may decide not to allow urothelial (transitional cell) patients. If patient’s tumor has been demonstrated to contain a therapeutically targetable somatic or driver mutation, therapy must be given with appropriate locally-approved therapy, then therapy must have been given based on local standard standards of care.
• At least 6 patients per cohort must have at least 1 tumor lesion amenable to biopsy and must be willing to undergo a biopsy prior to first dose of BT8009 and following any dose in Cycle 1
• Patients with solid tumor advanced disease having exhausted all appropriate standards of care options are eligible as follows: 1) 6 patients with GFR (by CG or by 24-hour urine) 40-50 ml/min (or equivalent units) to be enrolled and evaluated first (refer to SRC section) followed by; 2) 6 patients with GFR 30-40 ml/min (or equivalent units). Sponsor may opt to specify tumor (sub)type or Nectin-4 selected.
• MMAE monomethyl auristatin E
• Significant medical condition including but not limited eye (conditions related to or that may confound monitoring for dry eye, comeal opacities or keratitis); 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.
• HIV human immunodeficiency virus
• AIDS acquired immune deficiency syndrome
• hepatitis B surface antigen and/or anti -hepatitis B core antibody.
• Patients with a negative polymerase chain reaction (PCR) assay are permitted with appropriate antiviral therapy 17.
• Active hepatitis C infection with positive viral load if hepatitis C virus (HCV) antibody positive (if antibody is negative then viral load not applicable).
• Patients who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of >12 weeks.
• All patients will be required to provide archive tumor material or fresh tumor biopsy for assessment of expression levels of Nectin-4 and additional molecular genetic characterization (i.e. assessment of specific somatic mutations, etc.). This material should be provided as a tissue block or 10-15 paraffin-dipped unstained slides.
• Pre- and post-dose tumor biopsies will be collected to investigate intratumoral PK/Pharmacodynamic effects of BT8009.
• Pre- and one post-dose tumor biopsy will be optional except for the mandatory subset of patients in Part B (6 per cohort).
• the post-dose biopsy will be required in Cycle 1 after any dose as long as it is within 4 to 36 hours after the BT8009 dose.
• Optional biopsies for any patient may be taken in
• Cycles 2, 3, or 4. 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 (applies separately to A-l and A-2): The actual number of dose levels to be explored in this study will depend on determination of the non-tolerable dose based on dose- limiting toxicities (DLTs). The MTD will be defined based on DLTs (see Section 5). Other safety data, as well as PK profiles observed during the conduct of the study and any trends for anti-tumor activity. Treatment cycles will occur consecutively as per the SOA. If one patient experiences a DLT at a given dose level then an additional 3 patients will be treated with the same dose. Evaluation of a cohort of at least 3 patients completing 1 cycle of treatment (28 days) is required prior to proceeding to the next dose level. Additional details are found in Section 5.
• Futility analyses will be performed on each expansion cohort in Part B (B-l and B-2). Simon two- stage design to test the null hypothesis that P ⁇ 0.17 versus the alternative that P > 0.380
• ORR > 21%) After testing the drug on the first 14 efficacy evaluable patients, the trial will be terminated if 3 or fewer respond (ORR > 21%). If the trial goes on to the second stage, a total of 40 (26 additional patients) efficacy evaluable patients will be studied. If the total number responding is ⁇ 10, then the drug will be stopped.
• the maximum number of patients recruited into the study is 146; 34 from Part A-l, 20 from Part A-2, 40 from each of the two Part B cohorts and 12 from the Part C renal cohort.
• 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 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 0.9% saline and administration via IV infusion.
• 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 5% dextrose 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 is used to adjust the pH of the fill solution to target pH 7.0 (not 7.4), within the effective buffering range of the histidine buffer.
• the absolute amount required is dependant of the actual amount of L-histidine employed in the batch, this is indicated as ‘quantity sufficient’ to reach pH 7.0.

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