WO2025210599A2 - Polythérapies avec des inhibiteurs de réponse aux dommages de l'adn et [177lu]lu-psma-617 - Google Patents

Polythérapies avec des inhibiteurs de réponse aux dommages de l'adn et [177lu]lu-psma-617

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Publication number
WO2025210599A2
WO2025210599A2 PCT/IB2025/053608 IB2025053608W WO2025210599A2 WO 2025210599 A2 WO2025210599 A2 WO 2025210599A2 IB 2025053608 W IB2025053608 W IB 2025053608W WO 2025210599 A2 WO2025210599 A2 WO 2025210599A2
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Prior art keywords
ddri
psma
inhibitors
pharmaceutically acceptable
inhibitor
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WO2025210599A3 (fr
Inventor
Sravanth Kumar HINDUPUR
Joana PINTO DO COUTO E SILVA
Louise BARYS
Josefine Astrid REBER
Markus Reschke
Tobias SCHMELZLE
Marta Cortes-Cros
Marco RANZANI
Helen Marie Ruth ROBINSON
Graeme Cameron Murray Smith
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Novartis AG
Artios Pharma Ltd
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Novartis AG
Artios Pharma Ltd
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Publication of WO2025210599A2 publication Critical patent/WO2025210599A2/fr
Publication of WO2025210599A3 publication Critical patent/WO2025210599A3/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • 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
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This disclosure relates to combination therapies featuring a radiopharmaceutical targeting prostate specific membrane antigen (PSMA) and a DNA Damage Response inhibitor (DDRi), and their use in increasing treatment efficacy for cancers, such as, e.g., PSMA- expressing cancers.
  • PSMA prostate specific membrane antigen
  • DDRi DNA Damage Response inhibitor
  • Prostate cancer is a leading cause of cancer-related death among men around the world, with an estimated 1.4 million new cases and 375,000 deaths in 2020 (Wang et al. 2022, Prostate Cancer Incidence and Mortality: Global Status and Temporal Trends in 89 countries From 2000 to 2019. Frontiers in Public Health).
  • the tumors of 10-20% of prostate cancer patients become refractory to androgen-deprivation therapy by pharmaceutical or surgical castration, and progress as metastatic castration-resistant prostate cancer (mCRPC) (Juzeniene et al. 2021 , Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer, Cancers).
  • Targeted radioligand therapy offers the possibility to treat cancer lesions in a specific and tumor-selective manner by exploiting cell surface receptors that are mainly expressed in malignant cells, such as, e.g., prostate specific membrane antigen (PSMA).
  • PSMA prostate specific membrane antigen
  • Systemically administered RLT is concentrated at target sites and surrounding cells through radioligand binding.
  • Targeted RLTs bind with high affinity to biomarker-expressing, ligandexpressing, and/or receptor-expressing lesions, delivering DNA strand-breaking radiation.
  • PSMA is an attractive target for prostate cancer therapy because, while it is highly expressed in cancerous cells, including mCRPC cells, it has much lower expression in normal tissues. Accordingly, PSMA has the potential to be a viable target for RLT with minimized radioactivity- related side effects.
  • Pluvicto® [ 177 Lu]Lu-PSMA-617) is one example of an FDA-approved PSMA-based RLT drug for the treatment of PSMA-positive metastatic castration-resistant prostate cancer (
  • the DDRi can be selected from the group consisting of Ataxia- Telangiectasia Mutated (ATM) inhibitors, Ataxia Telangiectasia and Rad3-related (ATR) inhibitors, Poly (ADP-ribose) Polymerase (PARP) inhibitors, DNA-dependent Protein Kinase (DNA-PK) inhibitors, WEE1 protein kinase family inhibitors, Checkpoint Kinase (CHK) inhibitors, DNA polymerase theta (Pol0) inhibitors, RAD51 recombinase (RAD51 ) inhibitors, Ubiquitin-Specific Protease 1 (USP1 ) inhibitors, Polo-Like serine/threonine Kinase 1 (PLK1 ) inhibitors, Aurora kinase inhibitors, mutant p53 reactivators, Poly(ADP-ribose) Glycohydrolase (PARG) inhibitors, Werner Syndrome protein (WRN) inhibitors, and combinations thereof.
  • ATM Ataxi
  • the DDRi can include at least one DNA-PK inhibitor listed in TABLE 4, at least one of XRD-0394, SN-39536, BY101298, XZP-6877 and IMP-11 , or a pharmaceutically acceptable salt thereof.
  • the at least one DNA-PK inhibitor can include: (7-Methyl-2-[(7-methyl-[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)amino]-
  • the DDRi can include at least one ATM inhibitor listed in TABLE 1 , at least one of XRD-0394 and SX-RDS1 , or a pharmaceutically acceptable salt thereof.
  • the at least one ATM inhibitor can include: -(dimethylamino)propoxy]pyridin-3-yl]-3- methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one (AZD0156)), or pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one PARP inhibitor listed in TABLE 3, or a pharmaceutically acceptable salt thereof.
  • the PARP inhibitor is not olaparib.
  • the at least one PARP inhibitor can include: -fluoro-11-(4-fluorophenyl)-12-(2-methyl-1 ,2,4- triazol-3-yl)-2,3,10-triazatricyclo[7.3.1.0 5 ' 13 ]trideca-1 ,5(13),6,8-tetraen-4-one (talazoparib)), or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one WEE1 protein kinase family inhibitor selected from the group consisting of Wee1-like protein kinase inhibitors (WEE1 ) and Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1 ) inhibitors.
  • WEE1 Wee1-like protein kinase inhibitors
  • PLMYT1 Protein Kinase, Membrane Associated Tyrosine/Threonine 1
  • the DDRi can include at least one WEE1 inhibitor listed in TABLE 5, at least one of SC0191 , SY-4835, and IMP7068, or a pharmaceutically acceptable salt thereof.
  • the at least one WEE1 inhibitor can include: -hydroxypropan-2-yl)pyridin-2-yl]-6-[4-(4- methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one (Adavosertib or
  • the DDRi can include at least one PKMYT1 inhibitor listed in TABLE 6, ACR-2316, or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one CHK inhibitor selected from the group consisting of CHK1 selective inhibitors, CHK2 selective inhibitors, and CHK1/2 dual inhibitors.
  • the DDRi can include at least one CHK1 selective inhibitor listed in TABLE 7, VER250840, or a pharmaceutically acceptable salt thereof.
  • the at least one CHK1 selective inhibitor can include: (1-[5-bromo-4-methyl-2-[[(2S)-morpholin-2- yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea (Rabusertib or LY2603618), or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one CHK2 selective inhibitor listed in TABLE 8, or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one Pol0 inhibitor listed in TABLE 10, at least one of ART4215, ART6043, RP-3467, and GSK101 (GSK4524101/IDE705), or a pharmaceutically acceptable salt thereof.
  • the at least one Pol0 inhibitor can include: -cyano-6- methyl-4-(trifluoromethyl)pyridin-2-yl]-3-hydroxy-A/-methyl-N-(3-methylphenyl)pyrrolidine-2- carboxamide (ART558), ART6043, or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one RAD51 inhibitor listed in TABLE 11 , or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one USP1 inhibitor listed in TABLE 12, at least one of TNG348, HSK39775, FT-3171 (Debio 0432), and ISM3091, or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one PLK1 inhibitor listed in TABLE 13, or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one PARG inhibitor listed in TABLE 16, IDE161 , or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one WRN inhibitor listed in TABLE 17, RO7589831 , HRO761 , or a pharmaceutically acceptable salt thereof.
  • the DDRi and [ 177 Lu]Lu-PSMA-617 can be administered via the same route of administration.
  • the DDRi and [ 177 Lu]Lu-PSMA-617 are formulated in the same dosage form.
  • the DDRi and [ 177 Lu]Lu-PSMA-617 can be formulated as separate dosage forms.
  • the DDRi can be administered via a different route than [ 177 Lu]Lu-PSMA-617.
  • the therapeutically effective amount of the DDRi can be administered over a course of about, or at least about, 5 days.
  • the DDRi can be administered within 20 hours of [ 177 Lu]Lu- PSMA-617 administration.
  • the DDRi can be administered within 4 hours of [ 177 Lu]Lu- PSMA-617 administration.
  • the DDRi can be administered in one or more doses for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration.
  • the therapeutically effective amount of [ 177 Lu]Lu-PSMA-617, the DDRi, or both, is lower than the amount required for a monotherapy response.
  • the monotherapy response can be an objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (OR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof.
  • the therapeutically effective amount of [ 177 Lu]Lu-PSMA-617, the DDRi, or both is at least about 10% to about 50% lower than the amount required for the monotherapy response. In some cases, the therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 is about 10%, 15%, 20%, 25%, 30% 35%, 40%, 45% or about 50% lower than the amount of [ 177 Lu]Lu-PSMA-617 required for the monotherapy response.
  • the therapeutically effective amount of the DDRi is about 10%, 15%, 20%, 25%, 30% 35%, 40%, 45% or about 50% lower than the amount of the DDRi required for the monotherapy response.
  • an anti-cancer response produced by practicing the method is synergized as compared to a method of administering the [ 177 Lu]Lu-PSMA-617 or the DDRi as monotherapy.
  • the present disclosure provides a combination comprising [ 177 Lu]Lu- PSMA-617 and a DDRi for use in treating a PSMA-expressing cancer, wherein the DDRi is selected from the group consisting of Ataxia-Telangiectasia Mutated (ATM) inhibitors, Ataxia Telangiectasia and Rad3-related (ATR) inhibitors, Poly (ADP-ribose) Polymerase (PARP) inhibitors, DNA-dependent Protein Kinase (DNA-PK) inhibitors, WEE1 protein kinase family inhibitors, Checkpoint Kinase (CHK) inhibitors, DNA Polymerase theta (Pol0) inhibitors, RAD51 recombinase (RAD51 ) inhibitors, Ubiquitin-Specific Protease 1 (USP1 ) inhibitors, Polo-Like serine/threonine Kinase 1 (PLK1 ) inhibitors, Aurora kinase inhibitors, mutant p53 reactivators
  • the DDRi can include at least one PARP inhibitor listed in TABLE 3, or a pharmaceutically acceptable salt thereof.
  • the PARP inhibitor is not olaparib.
  • the DDRi can include at least one WEE1 inhibitor listed in TABLE 5, at least one of SC0191 , SY-4835, and IMP7068, or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one PKMYT1 inhibitor listed in TABLE 6, ACR-2316, or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one CHK1 selective inhibitor listed in TABLE 7, VER250840, or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one CHK2 selective inhibitor listed in TABLE 8, or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one CHK1/2 dual inhibitor listed in TABLE 9, or a pharmaceutically acceptable salt thereof. In certain embodiments, the DDRi can include at least one PolO inhibitor listed in TABLE 10, at least one of ART4215, ART6043, RP-3467, and GSK101 (GSK4524101/IDE705) or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one RAD51 inhibitor listed in TABLE 11 , or a pharmaceutically acceptable salt thereof.
  • the DDRi can include at least one PARG inhibitor listed in TABLE 16, IDE161 , or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 is a dose of about 10 MBq to 10 GBq, such as about 100 MBq to about 10 GBq, about 1 GBq to about 10 GBq, about 3 GBq to about 10 GBq, about 5 GBq to about 9 GBq, about 6 GBq to about 8 GBq.
  • the present disclosure provides a method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu- PSMA-617 and administering to the subject a therapeutically effective amount of a DNA
  • the therapeutically effective amount of the DDRi is a dose of from about 1 to 1000 mg/kg, about 10 to 900 mg/kg, about 15 to 800 mg/kg, about 20 to 700 mg/kg, about 25 to 600 mg/kg, about 30 mg to 500 mg/kg, about 35 to 400 mg/kg, about 40 to 300 mg/kg, about 45 to 200 mg/kg, or about 50 to 100 mg/kg, optionally about 100 mg/kg, administered once daily for about 5 days, and the initial dose of the DDRi is administered less than 1 hour prior to [ 177 Lu]Lu-PSMA-617 administration.
  • the present disclosure provides a method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu- PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is: -bromo-4-methyl-2-[[(2S)-morpholin-2- yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea (LY2603618, Rabusertib)) or a pharmaceutically acceptable salt thereof, whereby an anti-cancer response is improved or synergized as compared to a monotherapy response with [ 177 Lu]Lu-PSMA-617 or the DDRi.
  • DDRi DNA Damage Response inhibitor
  • the present disclosure provides a method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu- PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is: -hydroxypropan-2-yl)pyridin-2-yl]-6-
  • DDRi DNA Damage Response inhibitor
  • the present disclosure provides a method of treating a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu- PSMA-617 and administering to the subject a therapeutically effective amount of a DNA
  • DDRi Damage Response inhibitor
  • FIG. 1 depicts the time course for yH2AX and 53BP1 induction in DLD-1 cells with 2.5 MBq/ml 177Lu-DOTA.
  • FIG. 2 depicts induction of DDR markers in DLD-1 cells treated with increasing activities of 177Lu-DOTA.
  • FIG. 3 depicts quantification of the induction of representative DDR markers in LNCaP cells treated for 4h with 177Lu-PSMA-617.
  • FIGs. 6A-C depict the time-course analysis of DU145 PSMA high cells treated with increasing activities of 177Lu-PSMA-617 for 24h.
  • A Analysis of the percentage of confluency.
  • B Cytotoxicity and
  • C apoptosis analysis, using the Cytotox or the Caspase 3/7 dye, respectively. Assay run with IncuCyte.
  • FIGs. 11A-F depict the results of the combination of DNA-PK inhibitor, AZD7648 and 177Lu-DOTA in a panel of cancer cell lines.
  • the cell lines were treated with 177Lu-DOTA alone (solid line) or in combination with 1pM of DNA-PK inhibitor (dashed lines) for 8 days until the viability assay endpoint readout.
  • X axis represents the activity of 177Lu-DOTA (in MBq/mL)
  • Y axis the relative viability normalized for vehicle.
  • FIG. 17A-C depict the accumulation of DDR markers and cell cycle alterations:
  • A Time-course of yH2AX foci induction in PC-3 MP9 cells treated with 177Lu-PSMA-617 alone (solid bars) or in combination with DNA-PKi (1 pM AZD7648 - dashed bars).
  • B Induction of micronuclei
  • C cell cycle alterations in DU 145 PSMA high treated for 4h with 177Lu- PSMA-617 alone or in combination with DNA-PKi (1 pM AZD7648).
  • Radioligand therapy is emerging as a safe and effective targeted approach for treating several types of cancers.
  • Pluvicto® [ 177 Lu]Lu-PSMA-617) is one examples of an FDA- approved 177 Lu-based RLT drug for the treatment of PSMA-positive metastatic castrationresistant prostate cancer (mCRPC).
  • mCRPC PSMA-positive metastatic castrationresistant prostate cancer
  • the group denoted -Cji-sjalkyl includes not only -CH3, but also CD3; not only CH2CH3, but also CD2CD3, etc.
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 15 O and 16 O and 17 O and 18 O.
  • the isotopes may be radioactive or non-radioactive.
  • Radiolabelled compounds of the disclosure may include a radioactive isotope selected from the group comprising 3 H, 11 C, 18 F, 35 S, 122 l, 123
  • the radioactive isotope is selected from the group of 3 H, 11 C and 18 F.
  • those stabilizers are also referred to as “free radical scavengers” or in short “radical scavengers”.
  • Other alternative terms for those stabilizers are “radiation stability enhancers”, “radiolytic stabilizers”, or simply “quenchers”.
  • DNA Damage Response inhibitor refers to a compound capable of blocking cellular surveillance and signaling network that responds to DNA damage and maintains the stability of the genome by one or more of: (1 ) sensing and identifying DNA damage; (2) recruiting repair machinery; (3) halting the cell cycle to provide an opportunity for repair; (4) activating programmed cell death or deactivating cellular replication; and (5) repairing DNA damage.
  • phrases “pharmaceutically acceptable” as employed herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disorder or disease.
  • the term “synergistic effect” refers to the action of two therapeutic agents such as, for example, [ 177 Lu]Lu-PSMA-617 and a DDRi, producing an effect, which is greater than the simple addition of the effects of each compound administered as a monotherapy.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981 )), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T. C. and Talalay. P., Adv. Enzyme Regul. 22: 27-55 (1984)).
  • composition is defined herein to refer to a mixture (e.g., a solution or an emulsion) containing at least one active ingredient or therapeutic agent to be administered to a subject, e.g., a human, in order to prevent or treat a particular disease or condition affecting the subject.
  • carrier or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal and intraarticular injection and infusion.
  • the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 10%, including ⁇ 5%, ⁇ 1%, and ⁇ 0.1 % from the specified value, as such variations are appropriate to perform the disclosed methods, and when a numerical value or range is preceded by “about”, the “about” indicates a deviation of the value or range by ⁇ 20%, ⁇ 10%, or ⁇ 5%, unless a specific deviation is described. In some contexts, the deviation indicated by “about” can be ⁇ 2% or ⁇ 1%.
  • an element means one element or more than one element.
  • the present disclosure provides therapeutic combinations for the treatment or prevention of PSMA-expressing cancers including [177Lu]Lu-PSMA-617 and a DNA Damage Response inhibitor (DDRi).
  • DDRi DNA Damage Response inhibitor
  • ATMi Ataxia-Telangiectasia Mutated (ATM) inhibitors
  • the DDRi is not olaparib. In certain embodiments, the DDRi is not a Poly (ADP-ribose) polymerase (PARP) inhibitor.
  • PARP Poly (ADP-ribose) polymerase
  • DNA-dependent Protein Kinase inhibitors DNA-dependent Protein Kinase inhibitors
  • the group of WEE1 inhibitors can include one or more of SC0191 under development by Biocity Biopharmaceutics, IMP7068, developed by Impact Therapeutics, Inc, and SY-4835, developed by Shouyao holdings, or a pharmaceutically acceptable salt thereof.
  • the DDRi is selected from the group of CHK2 selective inhibitors in TABLE 8, or a pharmaceutically acceptable salt thereof:
  • the DDRi is selected from the group of Ubiquitin-Specific Protease 1 (USP1) inhibitors listed in TABLE 12, or a pharmaceutically acceptable salt thereof:
  • USP1 Ubiquitin-Specific Protease 1
  • the DDRi is selected from the group of Polo-Like serine/threonine Kinase 1 (PLK1 ) inhibitors listed in TABLE 13, or a pharmaceutically acceptable salts thereof:
  • PLK1 inhibitors (PLK1 i)
  • the DDRi is selected from the group of mutant p53 re- activators listed in TABLE 15, or a pharmaceutically acceptable salt thereof:
  • mutant p53 re-activators In addition to the mutant p53 re-activators listed above, the group of mutant p53 reactivators can include PC14586 developed by PMV Pharmaceuticals, Inc., or a pharmaceutically acceptable salt thereof.
  • the DDRi is selected from the group of Poly(ADP-ribose) Glycohydrolase (PARG) inhibitors listed in TABLE 16, or a pharmaceutically acceptable salt thereof:
  • PARG Poly(ADP-ribose) Glycohydrolase
  • the group of PARG inhibitors can include IDE161 developed by IDEAYA Biosciences, or a pharmaceutically acceptable salt thereof.
  • the group of WRN inhibitors can include: RO7589831 , developed by Hoffmann-La Roche, and HRO761 , developed by Novartis.
  • the present disclosure provides methods of treating or preventing a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi).
  • the [177Lu]Lu- PSMA-617 and the DDRi can be as previously described. In certain embodiments, the DDRi is not olaparib.
  • the amount of [177Lu]Lu-PSMA-617 administered and the amount of DDRi administered comprise quantities that are jointly therapeutically effective against a PSMA-expressing cancer.
  • the amount of [177Lu]Lu- PSMA-617 administered and the amount of DDRi administered can be administered in a single formulation or unit dosage form, administered concurrently, but optionally separately, or administered sequentially by any suitable route.
  • the DDRi can be administered via a different route than [ 177 Lu]Lu-PSMA-617.
  • the present disclosure provides methods of treating a PSMA- expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DDRi selected from the group as previously described.
  • the amount of a radiopharmaceutical e.g., [177Lu]Lu-PSMA-617, to be administered to a subject in need thereof, is based on the amount of radiation that will be administered to the subject.
  • the amount of radiation may be reflected as a unitary dose (in MBq) or as an amount of radiation per kg bodyweight (in kBq/kg).
  • a radioactivity-related value e.g. 7.4 GBq (200 mCi) of radioactivity
  • the amount can refer to the radioactivity at the date and time of administration.
  • [177Lu]Lu-PSMA-617 can be administered in combination with the DDRi in a unitary dose of about 7.4 GBq, such as 7.4 GBq (+/- 10%), while achieving one or more improvements in therapeutic efficacy as compared with [177Lu]Lu-PSMA-617 monotherapy.
  • the amount of a DDRi to be administered to a subject in need thereof is based on factors such as the severity of the PSMA-expressing cancer, the characteristics of the subject being treated, e.g., the particular animal or human subject treated, age, weight, and health, frequency of treatments, the route of administration, the severity of side effects of the one or more DDRi compounds and/or the amount of 177Lu]Lu-PSMA-617 being administered.
  • the therapeutically effective amount can be the maximal dose or dosing protocol that avoids significant side effects or toxic effects, an occurrence of unacceptable toxicity.
  • the therapeutically effective amount is the minimal dose that provides an improvement in the extent of response, slowing the symptomatic progression of the cancer, or symptoms thereof, duration of response, progression-free survival, Prostate-Specific Antigen (PSA) level, Alkaline Phosphatase (ALP) level, Lactate Dehydrogenase (LDH) level, pain Intensity, Functional Assessment of Cancer Therapy (FACT) score, health-related quality of life, number of hospitalizations, duration of hospitalization, and/or improvement in overall survival, or an improvement in another clinical measure or parameter.
  • PSA Prostate-Specific Antigen
  • ALP Alkaline Phosphatase
  • LDH Lactate Dehydrogenase
  • FACT Functional Assessment of Cancer Therapy
  • the improvement of a clinical measure or parameter can be by at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, where 100% is defined as the clinical measure or parameter shown by a healthy subject.
  • amount of a DDRi administered in combination with [177Lu]Lu-PSMA-617 can be reduced as compared to a monotherapy method without a reduction in therapeutic efficacy.
  • the amount of the DDRi is a synergistically effective amount.
  • the improvement of a clinical measure or parameter can be by at least 100%, at least 105%, at least 110%, at least 1 15%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, at least 215%, at least 220%, at least 225%, at least 230%, at least 235%, where 240% or at least 250%, where 100% can be defined as the clinical measure or parameter observed after DDRi monotherapy or [177Lu]Lu-PSMA-617 monotherapy.
  • the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the ATR inhibitors listed in TABLE 2, LF0397, IMP-9064, SC0245, and ATRN-119, or a pharmaceutically acceptable salt thereof.
  • the ATR inhibitor is: imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1 H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4- yl]cyclopropyl]-oxo-A 6 -sulfane (ceralasertib (AZD6738)), and the amount administered can be about 160 mg.
  • the ATR inhibitor is:
  • the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the PARP inhibitors listed in TABLE 3, or a pharmaceutically acceptable salt thereof.
  • the PARP does not include olaparib.
  • the PARP inhibitor is:
  • the PARP inhibitor is:
  • the PARP inhibitor is:
  • the PARP inhibitor is:
  • the PARP inhibitor is:
  • 4-iodo-3-nitrobenzamide iniparib (BSI-201 ) and the amount administered can be about 5.6 mg/kg.
  • the PARP inhibitor is: (11 S, 12R)-7-fluoro-11 -(4-fluorophenyl)-12-(2-methyl-1 ,2,4-triazol-3-yl)-2,3, 10- triazatricyclo[7.3.1.0 5 ' 13 ]trideca-1 ,5(13),6,8-tetraen-4-one (talazoparib (BMN 673)) and the amount administered can be about 0.5 or 1 mg.
  • the PARP inhibitor is: 11 -(1 ,3-dihydroisoindol-2-ylmethyl)-2,3, 10, 12-tetrazatricyclo[7.3.1 .05, 13]trideca-
  • the PARP inhibitor is:
  • the PARP inhibitor is:
  • olaparib (KU-0059436, AZD2281 ) and the amount administered can be about 300 mg.
  • the PARP inhibitor is:
  • the PARP inhibitor is: 5-fluoro-1-[[4-fluoro-3-(4-pyrimidin-2-ylpiperazine-1-carbonyl)phenyl]methyl]quinazoline-2,4- dione (Senaparib (IMP4297)) and the amount administered can be about 100 mg.
  • the PARP inhibitor is:
  • the PARP inhibitor is:
  • NMS-293 2-(1-cyclohexylpiperidin-4-yl)-3-oxoisoindoline-4-carboxamide (NMS-293) and the amount administered can be about 100 mg.
  • the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the DNA-PK inhibitors listed in TABLE 4, XRD-0394, SN-39536, XZP-6877, and IMP-11 , or a pharmaceutically acceptable salt thereof.
  • the DNA-PK inhibitor is:
  • the dual CHK1/2 inhibitor is:
  • the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the PolO inhibitors listed in TABLE 10, ART4215, ART6043, RP-3467, and GSK101 (GSK4524101/IDE705), or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the RAD51 inhibitors listed in TABLE 11 , or a pharmaceutically acceptable salt thereof.
  • the RAD51 inhibitor is: propan-2-yl A/-[3-(tert-butylsulfamoyl)-4-[2-[4-(propan-2-yloxycarbonylamino)cyclohexyl]-1 ,3- thiazol-5-yl]phenyl]carbamate (CYT0851 ) and the amount administered can be about 300 or 400 mg.
  • the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the USP1 inhibitors listed in TABLE 12, TNG348, HSK39775, FT-3171 (Debio 0432), and ISM3091 (XL309), or a pharmaceutically acceptable salt thereof.
  • the PLK1 inhibitor is:
  • the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the Aurora kinase inhibitors listed in TABLE 14 and WJ05129, or a pharmaceutically acceptable salt thereof.
  • the Aurora kinase inhibitors is the Aurora kinase A inhibitor
  • WJ05129 and the amount administered can be about 1.25, 2.5, 5, 7.5, or 10 mg.
  • the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the mutant p53 re-activators listed in TABLE 15 and PC14586, or a pharmaceutically acceptable salt thereof.
  • the mutant p53 re-activator is:
  • the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the PARG inhibitors listed in TABLE 16 and IDE161 , or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating a PSMA-expressing cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of [177Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of one or more of the WRN inhibitors listed in TABLE 17, RO7589831 and HRO761 , or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 can be about 10%, 15%, 20%, 25%, 30% 35 O/ - /I no/ - /I C % or about 50% lower than the amount of [ 177 Lu]Lu-PSMA-617 required for an objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (OR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof observed with [ 177 Lu]Lu-PSMA-617 monotherapy.
  • ORR objective response rate
  • DCR disease control rate
  • PFS progression free survival
  • DOR duration of response
  • OS overall survival
  • PR partial response
  • PSA response rate radiographic response rate
  • change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers or a combination thereof observed with [ 177 Lu]Lu-
  • the therapeutically effective amount of the DDRi can be about 10%, 15%, 20%, 25%, 30% 35%, 40%, 45% or about 50% lower than the amount of the DDRi required for an objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof observed with DDRi monotherapy.
  • ORR objective response rate
  • DCR disease control rate
  • PFS progression free survival
  • DOR duration of response
  • OS overall survival
  • C complete response
  • PR partial response
  • PSA response rate radiographic response rate
  • change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers or a combination thereof observed with DDRi monotherapy.
  • practicing a method as described above produces a synergistic response in the subject, such as a synergistic anti-cancer response, as compared to a method of administering the [ 177 Lu]Lu-PSMA-617 or the DDRi as monotherapy.
  • practicing a method as described above widens the therapeutic index of administering the [ 177 Lu]Lu-PSMA-617 or the DDRi as monotherapy.
  • practicing a method as described above can widen the therapeutic index of [ 177 Lu]Lu- PSMA-617 monotherapy or DDRi monotherapy by at least about 10% to about 50%.
  • the method may include administering [177Lu]Lu-PSMA-617, about every 4 to 8 weeks for a number of cycles.
  • the therapeutically effective amount of [177Lu]Lu-PSMA-617 e.g., about 3 GBq to about 10 GBq as described above, can be administered to the subject about every 4 to 8 weeks, such as about every 4 to 6 weeks, about every 6 to 8 weeks, about every 4 to 5 weeks, about every 5 to 8 weeks, about every 4 to 7 weeks, about every 5 to 6 weeks, about every 5 to 7 weeks, and about every 6 to 7 weeks.
  • the number of weeks and/or number of cycles of [177Lu]Lu- PSMA-617 administration in the present methods can be reduced as compared to [177Lu]Lu- PSMA-617 monotherapy without a reduction in therapeutic efficacy. In certain embodiments, the number of weeks and/or number of cycles of [177Lu]Lu-PSMA-617 administration required to achieve desired clinical measure or parameter can be reduced as compared to [177Lu]Lu- PSMA-617 monotherapy.
  • the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered to the subject about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, or about every 8 weeks.
  • the therapeutically effective amount of [177Lu]Lu-PSMA-617 e.g., about 3 GBq to about 10 GBq as described above, can be administered to the subject can be administered for a duration as described above for 4 to 6 cycles.
  • the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered about every 4 to 8 weeks for 4 cycles, for 5 cycles, or for 6 cycles.
  • the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered about every 4 to 6 weeks for 4 to 6 cycles, about every 6 to 8 weeks for 4 to 6 cycles, about every 6 to 8 weeks for 4 cycles, about every 6 to 8 weeks for 5 cycles, about every 6 to 8 weeks for 6 cycles, about every 4 to 5 weeks for 4 to 6 cycles, about every 4 to 7 weeks for 4 to 6 cycles, about every 5 to 8 weeks for 4 to 6 cycles, about every 5 to 6 weeks for 4 to 6 cycles, about every 5 to 7 weeks for 4 to 6 cycles, about every 6 to 7 weeks for 4 to 6 cycles, about every 4 weeks for 4 to 6 cycles, about every 4 weeks for 4 to 6 cycles, about every 5 weeks for 4 to 6 cycles, about every 6 weeks for 4 to 6 cycles, about every 7 weeks for 4 to 6 cycles, about every 8 weeks for 4 to 6 cycles, about every 4 weeks for 4 cycles, about every 4 weeks for 6 cycles, about every 4 weeks for 6 cycles, about every 6 weeks for 4 cycles, about every 6 weeks for 4 cycles, about every 6 weeks for 4 cycles
  • the therapeutically effective amount of [177Lu]Lu-PSMA-617 can be administered about every 5 weeks for 4 cycles, about every 5 weeks for 6 cycles, about every 7 weeks for 4 cycles, about every 7 weeks for 6 cycles, about every 4 weeks for 5 cycles about every 6 weeks for 5 cycles, about every 8 weeks for 5 cycles, about every 5 weeks for
  • Duration or frequency of administering the therapeutically effective amount of the DDRi can vary depending on the compound used, the subject being treated and the particular PSMA-expressing cancer being treated.
  • the duration or frequency can be the maximal duration or frequency protocol that avoids significant side effects or toxic effects or an occurrence of unacceptable toxicity.
  • the duration or frequency is the minimal duration or frequency that provides an improvement in the clinical measure or parameter, as described above, or the minimal duration or frequency for a synergistic effect.
  • the therapeutically effective amount of the DDRi is administered in one or more doses within 24 hours of [ 177 Lu]Lu-PSMA-617 administration, within 22 hours of [ 177 Lu]Lu-PSMA-617 administration, within 20 hours of [ 177 Lu]Lu-PSMA-617 administration, within 18 hours of [ 177 Lu]Lu-PSMA-617 administration, within 16 hours of [ 177 Lu]Lu-PSMA-617 administration, within 14 hours of [ 177 Lu]Lu-PSMA-617 administration, within 12 hours of [ 177 Lu]Lu-PSMA-617 administration, within 10 hours of [ 177 Lu]Lu-PSMA-617 administration, within 8 hours of [ 177 Lu]Lu-PSMA-617 administration, within 6 hours of [ 177 Lu]Lu-PSMA-617 administration, within 4 hours of [ 177 Lu]Lu-PSMA-617 administration, within 3 hours of [ 177 Lu]Lu-PSMA-617 administration, within 2 hours of [ 177 Lu]Lu-PSMA-617
  • the therapeutically effective amount of the DDRi is administered in one or more doses and the therapetucially effective amount of [ 177 Lu]Lu-PSMA-617 is administered in one or more doses concurrently (optionally in separate dosage forms)
  • the therapeutically effective amount of the DDRi is administered in one or more doses for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 20 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 24 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 28 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 32 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 36 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 40 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 44 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 48 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 52 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 56 hours after [ 177 Lu]Lu-PSMA-617 administration, for at least 60 hours after [ 177 Lu]L
  • the range encompassed by “at least about 5 days” can include at least about 1 , 2, 3, or 4 weeks, at least about 1 , 2, 3, 4, 5, or 6 months. In some cases, at least about 5 days can be 4 to 8 weeks, for one or more cycles. The cycles can occur with the same periodicity as a 177Lu]Lu-PSMA-617 cycle, or can occur at different intervals of therapy.
  • Administration for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration or over a course of about, or at least about, 5 days can occur at regular intervals (e.g., q.d., b.i.d., t.i.d., or on alternating days), on specific days of a [ 177 Lu]Lu-PSMA-617 cycle, or continuously.
  • the DDRi is administered within 24 hours of [ 177 Lu]Lu-PSMA- 617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration, or any time interval between 16 hours and about, or at least about, 5 days after [ 177 Lu]Lu-PSMA- 617 administration.
  • the DDRi is administered within 22 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA- 617 administration, or any time interval between 16 hours and about 5 days after [ 177 Lu]Lu- PSMA-617 administration.
  • the DDRi is administered within 20 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA- 617 administration, or any time interval between 16 hours and about 5 days after [ 177 Lu]Lu- PSMA-617 administration.
  • the DDRi is administered within 18 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about 5 days after [ 177 Lu]Lu-PSMA-617 administration, or any time interval between 16 hours and about, or at least about, 5 days after [ 177 Lu]Lu- PSMA-617 administration.
  • the DDRi is administered within 16 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about 5 days after [ 177 Lu]Lu-PSMA-617 administration, or any time interval between 16 hours and about, or at least about, 5 days after [ 177 Lu]Lu- PSMA-617 administration.
  • the DDRi is administered within 14 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA- 617 administration, or any time interval between 16 hours and about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration.
  • the DDRi is administered within 12 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu- PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration, or any time interval between 16 hours and about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration.
  • the DDRi is administered within 10 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration, or any time interval between 16 hours and about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration.
  • the DDRi is administered within 8 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration, or any time interval between 16 hours and about 5 days after [ 177 Lu]Lu-PSMA-617 administration.
  • the DDRi is administered within 6 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration, or any time interval between 16 hours and about 5 days after [ 177 Lu]Lu-PSMA-617 administration.
  • the DDRi is administered within 4 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration, or any time interval between 16 hours and about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration.
  • the DDRi is administered within 2 hours of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration, or any time interval between 16 hours and about 5 days after [ 177 Lu]Lu-PSMA-617 administration.
  • the DDRi is administered within 1 hour of [ 177 Lu]Lu-PSMA-617 administration and for at least 16 hours after [ 177 Lu]Lu-PSMA-617 administration (e.g., over a course of about, or at least about, 5 days after [ 177 Lu]Lu-PSMA-617 administration, or any time interval between 16 hours and about 5 days after [ 177 Lu]Lu-PSMA-617 administration.
  • the PSMA-expressing cancer is prostate cancer.
  • the prostate cancer is PSMA-positive oligometastatic prostate cancer (OMPC).
  • OMPC oligometastatic prostate cancer
  • the prostate cancer is metastatic prostate cancer.
  • the metastatic prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).
  • mHSPC PSMA-positive metastatic hormone-sensitive prostate cancer
  • a prostate specific membrane antigen (PSMA)-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is: chloro-4- fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol
  • the therapeutically effective amount of the DDRi can be a dose of from about 1 to 1000 mg/kg, about 10 to 900 mg/kg, about 15 to 800 mg/kg, about 20 to 700 mg/kg, about 25 to 600 mg/kg, about 30 mg to 500 mg/kg, about 35 to 400 mg/kg, about 40 to 300 mg/kg, about 45 to 200 mg/kg, or about 50 to 100 mg/kg, optionally about 100 mg/kg, administered twice daily for about, or at least about, 5 days, or about 50 mg, about 100 mg, about 150 mg, or about 250 mg daily.
  • kits for treating prostate cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is -Methyl-2-[(7-methyl-[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)amino]-
  • DDRi DNA Damage Response inhibitor
  • the prostate cancer is prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer (PSMA-positive mCRPC).
  • a method of treating PSMA-expressing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is -Methyl-2-[(7-methyl-[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)amino]-
  • DDRi DNA Damage Response inhibitor
  • the therapeutically effective amount of the DDRi can be a dose of from about 1 to 1000 mg/kg, about 10 to 900 mg/kg, about 15 to 800 mg/kg, about 20 to 700 mg/kg, about 25 to 600 mg/kg, about 30 mg to 500 mg/kg, about 35 to 400 mg/kg, about 40 to 300 mg/kg, about 45 to 200 mg/kg, or about 50 to 100 mg/kg, optionally about 100 mg/kg, administered once daily.
  • a method of treating PSMA-expressing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is: -(dimethylamino)propoxy]pyridin-3- yl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one (AZD0156)), or pharmaceutically acceptable salt thereof, whereby an anti-cancer response is synergized as compared to a monotherapy response with [ 177 Lu]Lu-PSMA-617 or the DDRi.
  • DDRi DNA Damage Response inhibitor
  • a method of treating PSMA-expressing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is: -bromo-4-methyl-2-[[(2S)-morpholin-2- yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea (LY2603618, Rabusertib) or a pharmaceutically acceptable salt thereof, whereby an anti-cancer response is improved or synergized as compared to a monotherapy response with [ 177 Lu]Lu-PSMA-617 or the DDRi.
  • DDRi DNA Damage Response inhibitor
  • a method of treating PSMA-expressing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is: -hydroxypropan-2-yl)pyridin-2-yl]-6- [4-(4-methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one (Adavosertib or MK-1775), or a pharmaceutically acceptable salt thereof, whereby an anti-cancer response is improved or synergized as compared to a monotherapy response with [ 177 Lu]Lu-PSMA-617 or the DDRi.
  • DDRi DNA Damage Response inhibitor
  • a method of treating PSMA-expressing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is: -fluoro-11-(4-fluorophenyl)-12-(2-methyl-
  • DDRi DNA Damage Response inhibitor
  • a method of treating PSMA-expressing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is: cyano-6-methyl-4-
  • kits for treating prostate cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is ART6043, or a pharmaceutically acceptable salt thereof.
  • DDRi DNA Damage Response inhibitor
  • the prostate cancer is prostatespecific membrane antigen-positive metastatic castration-resistant prostate cancer (PSMA- positive mCRPC).
  • PSMA- positive mCRPC prostatespecific membrane antigen-positive metastatic castration-resistant prostate cancer
  • methods of treating PSMA-expressing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is ART6043, or a pharmaceutically acceptable salt thereof, whereby an anti-cancer response is improved or synergized as compared to a monotherapy response with [ 177 Lu]Lu-
  • DDRi DNA Damage Response inhibitor
  • the improvement can include an extended response (e.g., extended survival) as compared to the monotherapy response with [ 177 Lu]Lu-PSMA-617 or the DDRi.
  • an extended response e.g., extended survival
  • the therapeutically effective amount of the DDRi can be about 100 mg/kg.
  • the DDRi can be administered daily for least about 5 days (e.g., at least about 20 days).
  • a method of treating PSMA-expressing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of [ 177 Lu]Lu-PSMA-617 and administering to the subject a therapeutically effective amount of a DNA Damage Response inhibitor (DDRi), wherein the DDRi is ((S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methyl- morpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-A 6 -sulfanone (ART0380)), or a pharmaceutically acceptable salt thereof, whereby an anti-cancer response is synergized as compared to a monotherapy response with [ 177 Lu]Lu-PSMA-617 or the DDRi.
  • DDRi DNA Damage Response inhibitor
  • the PSMA-expressing cancer can be prostate cancer (e.g., metastatic prostate cancer or metastatic castration-resistant prostate cancer (mCRPC) optionally PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC), optionally PSMA-positive oligometastatic prostate cancer (OMPC)) and/or PSMA-positive cancer in the biochemical recurrence (BCR) setting, optionally PSMA-positive cancer in the high-risk BCR setting, the therapeutically effective amount of [ 177 Lu]Lu-PSMA- 617 can be a dose of from about 10 MBq to 10 GBq, such as from about 0.1 GBq to 10 GBq, from about 1 GBq to 10 GBq, from about 3 GBq to 10 GBq, from about 5 GBq to about 9 GBq, or from about 6 GBq to about 8 GBq (optionally about 7.4 GBq), the DDRi can be administered for about, or at least about, 5 days, and/or the initial
  • compositions may be administered parenterally. Accordingly, in certain embodiments, the compositions are formulated for delivery by any of these routes of administration.
  • a pharmaceutical composition may be formulated for and administered by parenteral administration.
  • a pharmaceutical composition of the present disclosure may be formulated for and administered by intravenous administration.
  • the present disclosure provides the following aqueous solution:
  • any one of the aqueous solutions of the embodiments above can be provided as a sterile, preservative-free, clear, colorless to slightly yellow solution.
  • the aqueous solution is provided as ready-to-use solution.
  • the present disclosure further provides an individual patient dose unit containing a volume of any one of the aqueous solutions as described in any one of the embodiments above.
  • the individual patient dose unit volume is about 7.5 to about 12.5 mL of any one of the aqueous solutions as described in any one of the embodiments above.
  • the patient dose unit can be in the form of a vial, e.g. a single-dose vial, e.g. a colorless borosilicate (type I) glass vial, e.g. of about 30 mL size, e.g. closed with a bromobutyl rubber stopper (stopper with silicate filler and inorganic coloring system) and a seal, such as an aluminum seal, or in the form of a pre-filled syringe or cartridge, e.g. a cartridge that can be loaded into a device for infusion/injection, e.g. a cartridge for a syringe or an infusion system.
  • the aqueous solutions of the present disclosure can be dispensed in a vial and then transferred into a syringe.
  • the dose unit can be provided in a lead shielded container.
  • the lead shielded container can be placed in a plastic sealed container.
  • the dose unit can be shipped in a Type A packaging system (according to the corresponding regulations of the International Air Transport Association (IATA) and International Carriage of Dangerous Good by Road (ADR)).
  • the Type A packaging can be designed to meet the radiological protection requirements.
  • the aqueous solutions of any of the embodiments above can be injected intravenously (IV, by bolus injection or infusion) or intraarterially, or intratumorally.
  • the aqueous solutions of any of the embodiments above can be administered to the patient by slow intravenous push within approximately 1 to 10 minutes (either with a syringe pump or infusion pump or manually), e.g. via an intravenous catheter that is pre-filled with e.g. 0.9% sterile sodium chloride solution.
  • the second method involves beta decay of the short-lived radioisotope 177 Yb (half-life of 1 .9 hours), which is produced by neutron capture of enriched 176 Yb (> 99%) target.
  • separation of 177 Lu from 176 Yb is feasible leading to a composition comprising only the 177 Lu isotope.
  • Such compositions provide non-carrier-added 177 Lu, in short 177 Lu (N.C.A.).
  • reaction solution comprising: a. 177 Lu(l 11) ions in a volumetric activity of at least 17 GBq/mL, b. a target binding organic molecule comprising an organic moiety which has binding affinity to prostate specific membrane antigen and a chelating moiety for chelating Lu(lll) ions (i.e., a compound according to formula (I)
  • the molar ratio between the target binding organic molecule and the group of all Lu(lll) ions including 177 Lu(lll) ions, 176 Lu(lll) ions, 175 Lu(lll), and metastable 177m Lu(lll) ions can be at least 1.2, or between 1.5 and 3.5.
  • the reaction solution can include a pharmaceutically acceptable buffer to provide a pH in the range of 2 to 8, which is suitable for the reaction between the 177 Lu(ll I) ions and the target binding organic molecule.
  • the pharmaceutically acceptable buffer provides a pH in the range of 4 to 6.
  • step (1) can include mixing the individual components described herein at below atmospheric pressure to form the reaction solution.
  • a pressure below atmospheric pressure can be within a pressure range that is suitable to remove gaseous components from a container up to removing gaseous components from a solution, but minimizes or avoids substantial evaporation of the solvent (water).
  • the pressure can be at least 150 mbar, 200 mbar, 250 mbar or 300 mbar below atmospheric pressure.
  • the pressure can be up to 400 mbar, 500 mbar, 650 mbar or 700 mbar below atmospheric pressure.
  • the pressure can be at least about 250 mbar and up to 500 mbar below atmospheric pressure.
  • step (1 ) can include degassing solutions of the individual components described herein by letting an inert gas bubble through the solutions or purging the headspace above the individual solutions by an inert gas and then mixing the individual solutions under an inert gas atmosphere.
  • step (1 ) can include degassing solutions of the individual components by letting an inert gas bubble through the solutions or purging the headspace above the individual solutions using an inert gas and then mixing the individual solutions at below atmospheric pressure to form the reaction solution.
  • Below atmospheric pressure can include a pressure as described above.
  • step (1 ) can include providing the reaction solution in a container, such as one single container.
  • Providing the reaction solution in a container can include applying a pressure below atmospheric pressure as described above prior to the above step of mixing.
  • the reaction solution can have an activity of at least 5 Ci, such as from about 5 to 20 Ci, about 5 to 15 Ci, about 5 to 12 Ci, about 5.4 to 12 Ci, about 7 to 12 Ci, or about 8 to 12 Ci.
  • step (2) the target binding organic molecule and the 177 Lu(lll) ions, which are comprised in the reaction solution, are reacted with each other at below atmospheric pressure to obtain a radionuclide complex composed of the target binding organic molecule and the 177 Lu(lll) ions in a single container for radiolabeling.
  • Below atmospheric pressure includes applying a pressure as described above under step (1 ). Carrying out the reaction at below atmospheric pressure reduces radiolytic degradation.
  • Step (2) can include carrying out the reaction in one single container.
  • the single container for radiolabeling can include an oxygen concentration lower than 7 mg/L or 6 mg/L, or 5 mg/L, or 4 mg/L, or 3 mg/L, or 2 mg/L or 1 mg/L (all values at 25°C).
  • Oxygen can be substantially absent in the single container.
  • a low oxygen concentration in the single container reduces radiolytic degradation. Due to a low oxygen concentration, a volumetric activity of at least 17 GBq/ml, at least 18 GBq/ml, at least 19 GBq/ml, at least 20 GBq/ml, at least 25 GBq/mL, or at least 30 GBq/mL 177 Lu(ll I) ions can be included in the single container. Upper limits for volumetric activity of 177 Lu(l 11) ions can be 20, 25, 30, 40, or 50 GBq/mL.
  • step (2) a molar excess of the target binding organic molecule over the 177 Lu(l II) ions as described above is reacted, to ensure high radiochemical labelling yields.
  • the process does not require or include any purification steps to remove free (i.e., non-chelated) 177 Lu(lll) ions.
  • a Solid-phase extraction (SPE) purification step with tC18 sorbent cartridge can be used to remove free (non-chelated) 177 Lu(lll) ions, however, use of this sorbent cartridge may require the elution of the product with ethanol, which can be undesired (A. Mathur et al., Cancer Biother. Radiopharm. 2017, 32, 266-273).
  • the use of a tC18 sorbent cartridge can also result in removal of stabilizers, which then need to be added again (S. Maus et al., Int. J. Diagnostic imaging, 2014, 1 , 5-12).
  • step (2) the step of reacting the target binding organic molecule with the 177 Lu(l 11) ions at below atmospheric pressure to obtain the radionuclide complex can be carried out over 2 to 15 minutes, 4 to 10 minutes, or 5 min ⁇ 0.5 min.
  • step (2) the step of reacting the target binding organic molecule with the 177 Lu(l 11) ions at below atmospheric pressure to obtain the radionuclide complex can be carried out at 80 to 100°C, 90 to 98°C, or 94°C ⁇ 4 °C. Generally, temperatures lower than 90 °C do not ensure quantitative labelling yields.
  • the radionuclide complex can be obtained in a solution with a volume within 15 to 19 ml.
  • the process for manufacturing a [ 177 Lu]Lu-PSMA-617 solution can further include a step of:
  • step (3) recovering the radionuclide complex, which is formed in step (2) to obtain a mother solution.
  • the mother solution can be used for and is suitable for preparing a dispensing solution, which can be is dispensed into multiple patient doses (vials) destined for subsequent administration to a patient without further material change.
  • the mother solution comprises 177 Lu(lll) ions in a volumetric activity of at least 10 GBq/mL, a [ 177 Lu]Lu- PSMA-617 radionuclide complex, one or more stabilizers against radiolytic degradation, and an oxygen concentration lower than 50 mg/L.
  • step (3) recovering the radionuclide complex can include using water-for-injection (WFI) for rinsing.
  • WFI water-for-injection
  • WFI can be added to the single container of step (2) after completion of the reaction and the solution formed in the single container is introduced or transferred into the mother solution container as described above. This ensures complete (or almost complete) transfer of the solution comprising the radionuclide complex, while maintaining a relatively high volumetric activity concentration.
  • mice Female nude Crl:NU(NCr)-Foxn1 nu-Homozygous mice (Charles River, Germany). Animals were 14 weeks of age at time of application of the compound. Animals were housed under optimized hygienic conditions in type XJ cages (max.
  • PC3 FOLH1 MP9 PSMA tumors were established by subcutaneous injection of 5x10 6 cells in 200 pL HBSS (Sigma #H8264): Matrigel® Matrix (Corning, 354234) (50%:50%) into the right flank of nude mice.
  • AZD7648 and M3814 were administered orally 10 minutes before the i.v. injection of 4 MBq [ 177 Lu]Lu-PSMA-617 (0.1 nmol).
  • mice were randomized into groups of three, and freshly prepared test articles were injected through the lateral tail vein or gavage in a volume of 10mL/kg.
  • organs blood, liver, spleen, kidneys, and tumor
  • Each tissue sample was counted for the activities of radioelement using a gamma-counter. Samples of the injectate were used as decay correction standards. Final bar graphs are expressed as % injected dose per gram of tissue.

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Abstract

La présente invention concerne des polythérapies à base de [177Lu]Lu-PSMA-617 et d'un inhibiteur de réponse aux dommages de l'ADN (DDRi), et leur utilisation dans le traitement de cancers, tels que des cancers exprimant le PSMA.
PCT/IB2025/053608 2024-04-05 2025-04-04 Polythérapies avec des inhibiteurs de réponse aux dommages de l'adn et [177lu]lu-psma-617 Pending WO2025210599A2 (fr)

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