Methods of treating cancer

Abstract

The invention described herein relates to drug delivery conjugates for targeted therapy. The invention described herein relates to methods of treating PSMA-expressing cancers with compounds of Formula 1. The invention described herein also relates to methods of treating PSMA-expressing cancers with compounds of Formula 1 in patients who experience stable disease after treatment with the compound of Formula 1.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority under § 119(e) of the United States Patent Act to U.S. Provisional Application No. 62 / 659,016 filed on 17 April 2018 and U.S. Provisional Application No. 62 / 670,442 filed on 11 May 2018, the entirety of which disclosures are incorporated herein by reference.

[0002] The present invention as described herein relates to a drug delivery conjugate for targeted therapy. The present invention as described herein relates to a method for treating PSMA-expressing cancer with a compound of formula 1. The present invention as described herein also relates to a method for treating PSMA-expressing cancer with a compound of formula 1 in patients who experience disease stabilization after treatment with a compound of formula 1. [Background technology]

[0003] Prostate-specific membrane antigen (PSMA) is a type II cell surface membrane-bound glycoprotein with a molecular weight of approximately 110 kD, comprising an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and a broad extracellular domain (amino acids 44-750). While the functions of the intracellular segment and transmembrane domain are currently considered unimportant, the extracellular domain is involved in several distinct activities. PSMA plays a role in the central nervous system by metabolizing N-acetyl-aspartylglutamate (NAAG) to glutamate and N-acetylaspartate. Therefore, it is sometimes also referred to as N-acetyl-alpha-linked acidic dipeptidase (NAALADase). PSMA is also sometimes referred to as folate hydrolase I (FOLH I) or glutamate carboxypeptidase (GCP II) due to its role in the proximal small intestine in removing poly-γ-glutamated folate and γ-linked glutamate from α-linked glutamate from peptides and small molecules.

[0004] PSMA is named after its high expression levels, primarily in prostate cancer cells, although its specific function in prostate cancer cells remains unresolved. PSMA is overexpressed in malignant prostate tissue compared to other organs of the human body, such as the kidneys, proximal small intestine, and salivary glands. Unlike many other membrane-bound proteins, PSMA rapidly internalizes into cells in a manner similar to cell surface-bound receptors, such as vitamin receptors. PSMA internalizes via clathrin-coated pores and can then either be recycled to the cell surface or translocated to lysosomes. While direct evidence of interconversion has been debated, it has been suggested that the dimeric and monomeric forms of PSMA are interconvertible. Nevertheless, only the dimer of PSMA possesses enzymatic activity, while the monomer does not.

[0005] While the activity of PSMA on the cell surface of prostate cells is under investigation, the inventors recognize that PSMA represents a viable target for the selective and / or specific delivery of bioactive agents, including drug compounds, to such prostate cells. One such drug compound is Compound 1. [ka] (Also known as (3S,10S,14S)-3-[(naphthalene-2-yl)methyl]-1,4,12-trioxo-1-[(1R,4S)-4-[[2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]acetamido]methyl]cyclohexyl]-2,5,11,13-tetraazahexadecane-10,14,16-tricarboxylic acid) Here, 177 Lu forms a complex with this compound and is useful in the treatment of cancer as described in WO2015 / 055318. Compound 1 can be prepared according to the method described in WO2015 / 055318, which is incorporated by reference for the preparation of Compound 1 as described in Examples 3 and 5.

[0006] While not bound by theory, PSMA-617 is thought to consist of the pharmacophore ligand glutamate-urea-lysine, the chelating agent DOTA (which can complex with 177Lu), and a linker that connects these two entities. Furthermore, the urea-based binding motif is thought to enable the drug to bind to the disease site and be internalized by PSMA. In addition, the binding of 177Lu-PSMA-617 is thought to lead to internalization by endocytosis and the sustained retention of the ligand and its bound radioactive cargo within cancer cells.

[0007] Another such compound is PSMA imaging conjugate 4. [ka] (Also known as 4,6,12,19-tetraazadocosane-1,3,7-tricarboxylic acid, 22-[3-[[[2-[[[5-(2-carboxyethyl)-2-hydroxyphenyl]methyl](carboxymethyl)amino]ethyl](carboxymethyl)amino]methyl]-4-hydroxy-phenyl]-5,13,20-trioxo-,(3S,7S)), where, 68 Ga (or a similar radioactive metal isotope) forms a complex with the conjugate and is useful for imaging cancer, as described in Eder M, Schafer M, Bauder-Wust U, Hull WE, Wangler C, Mier W, et al. 68 Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012;23:688-97. PSMA imaging conjugate 4 can be prepared according to the method described in (Eder, 2012), which is incorporated by reference for the preparation of PSMA imaging conjugate 4 as described in the examples. [Overview of the Initiative]

[0008] In some embodiments, the present disclosure provides a method for treating cancer in a patient requiring such treatment, comprising administering a therapeutically effective amount of compound 1 to the patient.

[0009] In some embodiments, the present disclosure provides the use of compound 1 for treating a patient's cancer. In some embodiments, the use involves administering a therapeutically effective amount of compound 1 to the patient.

[0010] In some embodiments, this disclosure provides the use of compound 1 in the preparation of a drug useful for treating cancer in a patient. In some embodiments, the drug contains a therapeutically effective amount of compound 1.

[0011] In some aspects of these embodiments, the cancer is a cancer that expresses PSMA. In some aspects of these embodiments, the compound is at least about 98 percent pure. In some embodiments, the cancer is selected from the group consisting of glioma, carcinoma, sarcoma, lymphoma, melanoma, mesothelioma, nasopharyngeal carcinoma, leukemia, adenocarcinoma, and myeloma.

[0012] In some aspects of these embodiments, cancers include lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, metastatic breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, and parathyroid cancer. The cancer is selected from the group consisting of non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, pleural mesothelioma, bladder cancer, Burkitt lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axial tumor, glioma, brainstem glioma, pituitary adenoma, and adenocarcinoma of the gastroesophageal junction. In some aspects of these embodiments, the cancer is primary or secondary brain cancer. In some aspects of these embodiments, the cancer is prostate cancer. In some aspects of these embodiments, the cancer is metastatic prostate cancer.

[0013] In some aspects of these embodiments, compound 1 is administered in a parenteral dosage form. In some aspects of these embodiments, the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal. In some aspects of these embodiments, the therapeutically effective dose is about 2 GBq to about 13 GBq. In some aspects of these embodiments, the therapeutically effective dose is about 4 GBq to about 11 GBq. In some aspects of these embodiments, the therapeutically effective dose is about 5 GBq to about 10 GBq. In some aspects of these embodiments, the therapeutically effective dose is about 6 GBq to about 9 GBq. In some aspects of these embodiments, the therapeutically effective dose is about 6.5 GBq to about 8.5 GBq. In some aspects of these embodiments, the therapeutically effective dose is about 7 GBq to about 8 GBq. In some aspects of these embodiments, the therapeutically effective dose is about 7.4 GBq. In some aspects of these embodiments, the total dose is in the range of about 15 GBq to about 200 GBq. In some aspects of these embodiments, the total dose is in the range of about 25 GBq to about 185 GBq. In some aspects of these embodiments, the total dose is in the range of about 35 GBq to about 150 GBq. In some aspects of these embodiments, the total dose is in the range of about 40 GBq to about 100 GBq. In some aspects of these embodiments, the total dose is about 44 GBq. In some aspects of these embodiments, the maximum duration of treatment for the subject is about 19 to 23 months.

[0014] In some aspects of these embodiments, the effective therapeutic dose is 2 GBq to 13 GBq. In some aspects of these embodiments, the effective therapeutic dose is 4 GBq to 11 GBq. In some aspects of these embodiments, the effective therapeutic dose is 5 GBq to 10 GBq. In some aspects of these embodiments, the effective therapeutic dose is 6 GBq to 9 GBq. In some aspects of these embodiments, the effective therapeutic dose is 6.5 GBq to 8.5 GBq. In some aspects of these embodiments, the effective therapeutic dose is 7 GBq to 8 GBq. In some aspects of these embodiments, the effective therapeutic dose is 7.4 GBq.

[0015] In some aspects of these embodiments, the therapeutically effective amount is about 0.1 mg / m 2 ~ about 6.0 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is about 0.1 mg / m 2 ~ about 5.0 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is about 0.1 mg / m 2 ~ about 4.0 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is about 0.1 mg / m 2 ~ about 3.5 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is about 0.1 mg / m 2 ~ about 3.0 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is about 0.1 mg / m 2 ~ about 2.5 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is about 0.1 mg / m 2 ~ about 2.0 mg / m 2 .

[0016] In some aspects of these embodiments, the therapeutically effective amount is 0.1 mg / m 2 ~ 6.0 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is 0.1 mg / m 2 ~ 5.0 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is 0.1 mg / m 2 ~ 4.0 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is 0.1 mg / m 2 ~ 3.5 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is 0.1 mg / m 2 ~ 3.0 mg / m 2 . In some aspects of these embodiments, the therapeutically effective amount is 0.1 mg / m 2 ~ 2.5 mg / m2 In some aspects of these embodiments, the therapeutically effective dose is 0.1 mg / m². 2 ~2.0 mg / m² 2 That is the case.

[0017] In other embodiments, the methods and uses described herein further include imaging of PSMA expression due to cancer. In some embodiments of these embodiments, the imaging step is performed before the administration step. In some embodiments of these embodiments, imaging is performed by radiography, the radiography method is selected from the group consisting of SPECT radiography, PET radiography, IHC, and FISH. In some embodiments of these embodiments, imaging is performed by SPECT radiography.

[0018] In some aspects of these embodiments, the imaging step involves the PSMA ligand imaging conjugate of Equation 2, [ka] or administering a pharmaceutically acceptable salt thereof to a patient, wherein R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and the radionuclide is conjugated.

[0019] In some aspects of these embodiments, the imaging step involves the PSMA ligand imaging conjugate of Equation 3, [ka] or administering a pharmaceutically acceptable salt thereof to a patient, wherein R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and M is a cation of a radionuclide. In some aspects of these embodiments, M of the conjugate or pharmaceutically acceptable salt thereof is selected from the group consisting of gallium isotopes, indium isotopes, copper isotopes, technetium isotopes, and rhenium isotopes. In some aspects of these embodiments, M of the conjugate or pharmaceutically acceptable salt thereof is a technetium isotope.

[0020] In some aspects of these embodiments, the PSMA ligand imaging conjugate is of formula 2a, [ka] or a pharmaceutically acceptable salt thereof, in which a radionuclide is bound to the conjugate. In some aspects of these embodiments, the PSMA ligand imaging conjugate is of formula 3a, [ka] or a pharmaceutically acceptable salt thereof.

[0021] In some aspects of these embodiments, the imaging step involves the PSMA ligand imaging conjugate of Equation 4, [ka] or administering a pharmaceutically acceptable salt thereof to a patient, wherein the radionuclide is bound to a conjugate. In some aspects of these embodiments, the radionuclide is 68 It is Ga.

[0022] In other embodiments, the methods and uses described herein further include determining the patient's PSMA status by imaging. In some embodiments of these embodiments, the imaging method is SPECT imaging. In some embodiments of these embodiments, the patient's PSMA status correlates with the clinical benefit to the patient. In some embodiments of these embodiments, the clinical benefit is selected from the group consisting of inhibition of tumor growth, disease stabilization, partial response, and complete response. In some embodiments of these embodiments, the clinical benefit is disease stabilization. In some embodiments of these embodiments, a PSMA-positive lesion indicates functionally active PSMA.

[0023] In some aspects of these embodiments, the step of determining the PSMA ligand imaging conjugate of Equation 2 is [ka] or administering a pharmaceutically acceptable salt thereof to a patient, wherein R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and the conjugate is bound to a radionuclide.

[0024] In some aspects of these embodiments, the step of determining the PSMA ligand imaging conjugate of Equation 3 is [ka] or administering a pharmaceutically acceptable salt thereof to a patient, wherein R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and M is a cation of a radionuclide.

[0025] In some aspects of these embodiments, M of the conjugate or its pharmaceutically acceptable salt is selected from the group consisting of gallium isotopes, indium isotopes, copper isotopes, technetium isotopes, and rhenium isotopes. In some aspects of these embodiments, M of the conjugate or its pharmaceutically acceptable salt is a technetium isotope. In some aspects of these embodiments, the PSMA ligand imaging conjugate is of formula 2a, [ka] or a pharmaceutically acceptable salt thereof, in which a radionuclide is bound to a conjugate.

[0026] In some aspects of these embodiments, the PSMA ligand imaging conjugate is of formula 3a, [ka] or a pharmaceutically acceptable salt thereof.

[0027] In some aspects of these embodiments, the step of determining the PSMA ligand imaging conjugate of Equation 4 is [ka] or administering a pharmaceutically acceptable salt thereof to a patient, wherein the radionuclide is bound to a conjugate. In some aspects of these embodiments, the radionuclide is 68 It is Ga.

[0028] In other embodiments, the present disclosure provides a method for treating cancer in a patient requiring such treatment, comprising administering a therapeutically effective amount of compound 1 to the patient. [ka] Here, 177 Lu forms a complex with compound 1, and disease stabilization occurs after administration of compound 1 or a pharmaceutically acceptable salt thereof.

[0029] In other embodiments, the Disclosure provides the use of compound 1, [ka] Here, 177 Lu forms a complex with compound 1, and disease stabilization occurs after administration of compound 1 or a pharmaceutically acceptable salt thereof. In some aspects of these embodiments, use involves administering a therapeutically effective amount of compound 1 to the patient.

[0030] In other embodiments, the present disclosure relates to compound 1, [ka] 177 Lu forms a complex with compound 1, providing the use of compound 1 in the preparation of a drug useful for the treatment of cancer in patients, where disease stabilization occurs after administration of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the drug contains a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0031] In some aspects of these embodiments, the patient has been treated with at least one prior treatment. In some aspects of these embodiments, the at least one prior treatment is selected from the group consisting of androgen pathway (axis) systemic therapy, chemotherapy agents, surgery, radiotherapy, immunotherapy, photodynamic therapy, stem cell therapy, and hyperthermia. In some aspects of these embodiments, the at least one prior treatment is a systemic treatment. In some aspects of these embodiments, the systemic treatment is selected from the group consisting of paliphosphamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof. In some aspects of these embodiments, the cancer is a cancer that expresses PSMA. In some aspects of these embodiments, the compound is at least about 98 percent pure.

[0032] Embodiments of the present invention are further described by the following enumerated clauses: 1. A method for treating cancer in a patient in need of such treatment, comprising administering a therapeutically effective amount of a compound of formula 1 or 2 to the patient. [ka] A method by which a compound forms a complex with a metal.

[0033] 2. The method according to Clause 1, wherein the cancer is a PSMA-expressing cancer.

[0034] 3. The method according to claim 1 or 2, wherein the compound of formula 1 is at least about 98 percent pure.

[0035] 4. The method described in any one of the preceding clauses, wherein the cancer is prostate cancer.

[0036] 5. The method described in any one of the preceding paragraphs, wherein the cancer is metastatic castration-resistant prostate cancer.

[0037] 6. The method according to any one of the preceding clauses, wherein the compound of Formula 1 is administered in a parenteral dosage form.

[0038] 7. The method according to Clause 6, wherein the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.

[0039] 8. The method described in any one of the preceding clauses, wherein the therapeutically effective dose is approximately 2 GBq to approximately 13 GBq.

[0040] 9. The method described in any one of the preceding clauses, wherein the therapeutically effective dose is approximately 4 GBq to approximately 11 GBq.

[0041] 10. The method described in any one of the preceding clauses, wherein the therapeutically effective dose is approximately 5 GBq to approximately 10 GBq.

[0042] 11. The method described in any one of the preceding clauses, wherein the therapeutically effective dose is approximately 6 GBq to approximately 9 GBq.

[0043] 12. The method described in any one of the preceding clauses, wherein the therapeutically effective dose is approximately 6.5 GBq to approximately 8.5 GBq.

[0044] 13. The method according to any one of the preceding clauses, wherein the therapeutically effective dose is approximately 7 GBq to approximately 8 GBq.

[0045] 14. The method described in any one of the preceding clauses, wherein the therapeutically effective dose is approximately 7.4 GBq.

[0046] 15. The method described in any one of the preceding clauses, further comprising imaging PSMA expression caused by cancer.

[0047] 16. The method according to Clause 15, wherein imaging is performed before the administration step.

[0048] 17. The method according to Clause 16, wherein imaging is performed by a radiographic method, the radiographic method being selected from the group consisting of SPECT radiography, PET radiography, IHC, and FISH.

[0049] 18. The method described in Clause 17, wherein imaging is performed by SPECT imaging.

[0050] 19. The method described in any one of the clauses 1 to 14, further comprising determining the patient's PSMA status by imaging.

[0051] 20. The method described in Article 19, wherein the imaging method is SPECT imaging.

[0052] 21. The method according to Clause 20, wherein the patient's PSMA status correlates with the clinical benefit to the patient.

[0053] 22. The method according to Clause 21, wherein the clinical benefit is selected from the group consisting of inhibition of tumor growth, disease stabilization, partial response, and complete response.

[0054] 23. The method described in Clause 22, wherein the clinical benefit is disease stabilization.

[0055] 24. The method according to clause 21, wherein at least one PSMA-positive lesion exhibits functionally active PSMA.

[0056] 25. The method described in any one of the preceding paragraphs, wherein the patient has been treated with at least one prior treatment.

[0057] 26. The method according to Clause 25, wherein at least one prior treatment is selected from the group consisting of androgen pathway systemic therapy, chemotherapy, surgery, radiotherapy, immunotherapy, photodynamic therapy, stem cell therapy, and hyperthermia.

[0058] 27. The method according to Clause 26, wherein at least one prior treatment is systemic androgenic drug therapy.

[0059] 28. The method according to Clause 26, wherein at least one prior treatment is selected from the group consisting of abiraterone, orteronel, galeterone, ceviteronel, apalutamide, enzalutamide, and combinations thereof.

[0060] 29. The method according to Clause 25, wherein at least one prior treatment is selected from the group consisting of paliphosphamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof.

[0061] 30. The method according to any one of the preceding clauses, wherein the compound of Formula 1 is administered in combination with the second treatment.

[0062] 31. The method described in Clause 30, wherein the second treatment is the best supportive care.

[0063] 32. The method described in Clause 30, wherein the second treatment is the best standard of care.

[0064] 33. The method described in Clause 30, where the second treatment is the best supportive / standard treatment.

[0065] 34. The method according to clause 30, wherein the second treatment is systemic treatment via the androgen pathway.

[0066] 35. The method according to clause 34, wherein systemic androgenic pathway therapy is selected from the group consisting of abiraterone, orteronel, galeterone, ceviteronel, apalutamide, enzalutamide, and combinations thereof.

[0067] 36. The method according to Clause 30, wherein the second treatment is radiotherapy.

[0068] 37. The method according to Clause 30, wherein the radiotherapy is external beam radiation therapy (EBRT).

[0069] 38. The method according to any one of the preceding clauses, wherein the compound of Formula 1 is administered on a once-weekly schedule.

[0070] 39. The method according to any one of the claims 1 to 37, wherein the compound of Formula 1 is administered on a schedule of once every two weeks.

[0071] 40. The method according to any one of the claims 1 to 37, wherein the compound of Formula 1 is administered on a schedule of once every three weeks.

[0072] 41. The method according to any one of the claims 1 to 37, wherein the compound of Formula 1 is administered on a schedule of once every four weeks.

[0073] 42. The method according to any one of the claims 1 to 37, wherein the compound of Formula 1 is administered on a schedule of once every five weeks.

[0074] 43. The method according to any one of the claims 1 to 37, wherein the compound of Formula 1 is administered on a schedule of once every six weeks.

[0075] 44. The method according to any one of the claims 1 to 37, wherein the compound of Formula 1 is administered on a schedule of once every seven weeks.

[0076] 45. The method according to any one of the claims 1 to 37, wherein the compound of Formula 1 is administered on a schedule of once every 8 weeks.

[0077] 46. ​​The method according to any one of the claims 1 to 37, wherein the compound of Formula 1 is administered on a schedule of once every 4 to 6 weeks.

[0078] 47. The method according to any one of the claims 38 to 46, wherein the compound of Formula 1 is administered for a schedule of approximately 2 to 8 cycles.

[0079] 48. The method according to any one of the claims 38 to 46, wherein the compound of Formula 1 is administered for a schedule of approximately 3 to 7 cycles.

[0080] 49. The method according to any one of the claims 38 to 46, wherein the compound of Formula 1 is administered for a schedule of approximately 4 to 6 cycles.

[0081] 50. A metal that forms a complex with compound 1 or compound 2, 90 Y, 177 Lu, 64 CD, 153 Gd, 155 Gd, 157 Gd, 213 Bi, and 225 The method described in any one of the preceding clauses, selected from the group consisting of Ac.

[0082] 51. The metal that forms a complex with compound 1 is 177 The method described in Article 50, which is Lu.

[0083] 52. The metal that forms a complex with compound 1 is 225The method described in Clause 50, which is Ac. [Brief explanation of the drawing]

[0084] [Figure 1] A schematic diagram of the treatment plan is shown.

[0085] definition According to the present invention, "functionally active PSMA" means a cell surface membrane-bound glycoprotein that binds to a PSMA ligand. PSMA ligands are well known to those skilled in the art, such as those described in U.S. Patent Publication US2010 / 0324008A1, which is incorporated herein by reference.

[0086] According to the present invention, “clinical benefit” means a patient’s response to treatment with compound 1, and response includes, among other clinical benefits as defined by the U.S. Food and Drug Administration, the patient’s overall survival, the ability to receive four or more cycles of treatment with compound 1 (e.g., four weeks of treatment), inhibition of tumor growth, disease stabilization, partial response, and / or complete response.

[0087] According to the present invention, "inhibition of tumor growth" means a reduction in tumor size, complete disappearance of the tumor, or tumor growth in less than 30% of patients throughout the course of treatment with compound 1.

[0088] According to the present invention, "disease stabilization" means that there is no material progression of the disease in the patient throughout the course of treatment with compound 1.

[0089] According to the present invention, "partial response" means a reduction of 30% or more in tumor size in patients treated with compound 1.

[0090] According to the present invention, "complete response" means the disappearance of detectable disease in patients treated with compound 1.

[0091] According to the present invention, “prior treatment” means that the patient has been treated with at least one prior treatment known in the art. Prior treatment may include, but is not limited to, any treatment known to those skilled in the art, such as chemotherapy, surgery, radiotherapy, immunotherapy, photodynamic therapy, stem cell therapy, and hyperthermia. Prior treatment may include, but is not limited to, systemic treatments with abiraterone, orteronel, galeterone, ceviteronel, apalutamide, enzalutamide, paliphosphamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof.

[0092] According to the present invention, the term "alkyl" optionally includes a branched chain of carbon atoms. In certain embodiments, alkyl is advantageously C1-C 24 , C1~C 12It will be further understood that these are limited lengths, including C1-C8, C1-C6, and C1-C4. For example, such particularly limited lengths of alkyl groups, including C1-C8, C1-C6, and C1-C4, may be referred to as lower alkyl groups. In this specification, it will be understood that shorter alkyl, alkenyl, and / or alkynyl groups may impart lower lipophilicity to compounds and therefore have different pharmacokinetic behavior. In the embodiments of the invention described herein, it should be understood that in each case, the enumeration of alkyl refers to the alkyl groups as defined herein, and optionally lower alkyl groups. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, and octyl. As used herein, the “carboxyalkyl” group includes the combination of the “alkyl” group and the “carboxy” group as described herein. As used herein, the "hydroxyalkyl" group includes the combination of the "alkyl" group and the "hydroxy" group as described herein. As used herein, the "aminoalkyl" group includes the combination of the "alkyl" group and the "amino" group as described herein.

[0093] According to the present invention, the term "heteroalkyl" includes a chain of atoms containing both carbon and at least one heteroatom, which is optionally branched. Exemplary heteroatoms include nitrogen, oxygen, and sulfur. In certain modifications, exemplary heteroatoms also include phosphorus and selenium.

[0094] According to the present invention, the term "aryl" includes monocyclic and polycyclic aromatic carbocyclic groups having 6 to 14 ring carbon atoms, each of which may be optionally substituted. Exemplary aromatic carbocyclic groups described herein include, but are not limited to, phenyl and naphthyl. According to the present invention, the term "heteroaryl" includes aromatic heterocyclic groups having 5 to 10 ring atoms, each of which may be optionally substituted. Exemplary aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetradinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl. According to the present invention, the term "heteroarylalkyl" includes combinations of the "alkyl" group and the "heteroaryl" group as described herein. According to the present invention, the term "arylalkyl" includes combinations of the "alkyl" group and the "aryl" group as described herein, such as the benzyl group.

[0095] As used herein, the term “optionally substituted” includes the substitution of a hydrogen atom on an optionally substituted radical by another functional group. Such other functional groups include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylhetalkyl, heteroaryl, heteroarylalkyl, heteroarylhetalkyl, nitro, sulfonic acid and its derivatives, carboxylic acid and its derivatives, etc. Examples include any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylhetalkyl, heteroaryl, heteroarylalkyl, heteroarylhetalkyl, and / or sulfonic acid being optionally substituted.

[0096] According to the present invention, the term “administration” as used herein includes, but is not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like, all means of introducing Compound 1 and the PSMA ligand imaging conjugate described herein into a patient. Compound 1 and the PSMA ligand imaging conjugate described herein can be administered in unit dosage forms and / or formulations containing conventional non-toxic, pharmaceutically acceptable carriers, adjuvants, and vehicles.

[0097] According to this invention, "becquerel" means the SI derived unit of radioactivity, as is generally understood by those skilled in the art. One becquerel is defined as the activity of a certain amount of radioactive material at which one nucleus decays per second. Thus, the becquerel corresponds to the reverse second, s⁻¹. The becquerel is known to those skilled in the art as the successor to the curie (Ci), the older non-SI unit of radioactivity based on the activity of one gram of radium-226. The curie is defined as 3.7.1010 s⁻¹, or 37 GBq.

[0098] According to this invention, "curie" or "Ci" refers to a unit of radioactivity named after the French physicist and chemist Marie Curie, as is generally understood by those skilled in the art. The prefixes milli and micro are from the metric system, representing 0.001 and 0.000001, respectively. Thus, a millicurie (mCi) is 0.001 curies. A microcurie (μCi) is 0.000001 curies. [Modes for carrying out the invention]

[0099] According to the applicant's invention as described herein, the embodiments of the numbered clauses provided in the above abstract, or any combination thereof, are intended to be combined with any of the embodiments described in the section on embodiments for carrying out the invention of this patent application.

[0100] Referring to Figure 1, the method design can be described according to the schematic diagram shown. In some embodiments, the stratification factor of the design is serum lactate dehydrogenase (LDH) (< / =260IU / Lv.> Examples of endpoints include, but are not limited to, 260 IU / L, the presence of liver metastases, ECOG score (0-1 v.2), and the inclusion of NAAD in the best supportive care / best standard care. In some embodiments, the primary endpoint may be overall survival. In some embodiments, secondary endpoints may include, but are not limited to, radiographic progression-free survival (rPFS), RECIST response, and time to first symptomatic bone-related event (SSE). In some embodiments, additional secondary endpoints may include, but are not limited to, safety and tolerability, health-related quality of life (HRQoL; EQ-5D-5L, FACT-P, and Brief Pain Inventory-Short FORM [BPI-SF]), health economics, progression-free survival (PFS) (radiological, clinical, or PSA progression), PSA levels, alkaline phosphatase levels, and / or lactate dehydrogenase levels, as well as other biochemical responses. In some embodiments, the evaluation criterion for the treatment method described herein may be a patient who has achieved a > / = 50% reduction from baseline, which is confirmed by a second PSA measurement > / = 4 weeks later. In some embodiments, the evaluation criterion for the treatment method described herein may be a patient who has achieved a > / = 40% reduction from baseline, which is confirmed by a second PSA measurement > / = 4 weeks later. In some embodiments, the evaluation criterion for the treatment method described herein may be a patient who has achieved a > / = 30% reduction from baseline, which is confirmed by a second PSA measurement > / = 4 weeks later.

[0101] In one embodiment, the methods described herein can be used for both human clinical medicine and veterinary applications. Thus, the “patient” may be a human or, in the case of veterinary applications, a laboratory, agricultural, livestock, or wild animal to which compound 1 or the PSMA ligand imaging conjugate described herein may be administered. In one embodiment, the patient may be a human, a rodent (e.g., mouse, rat, hamster, etc.), a laboratory animal such as a rabbit, monkey, chimpanzee, livestock such as a dog, cat, and rabbit, an agricultural animal such as a cow, horse, pig, sheep, and goat, as well as a wild animal held in a zoo such as a bear, panda, lion, tiger, leopard, elephant, zebra, giraffe, gorilla, dolphin, and whale.

[0102] In some embodiments, patients with PSMA-positive scans are randomized in a 2:1 ratio to receive either compound 1 plus best supportive care / best standard care, or best supportive care / best standard care only. In some embodiments, best supportive care / best standard care may be determined by the treating physician / principal investigator. In some embodiments, best supportive care / best standard care may be determined by the treating physician / principal investigator, but excludes the investigational drug, cytotoxic chemotherapy, other systemic radioisotopes, and hemisphere radiotherapy. In some embodiments, novel androgenic pathway agents [NAADs] such as abiraterone or enzalutamide are permitted.

[0103] In some embodiments, patients are monitored for survival, disease progression, and adverse events throughout a 6-10 month treatment period. In some embodiments, longer follow-up periods may include collecting updated survival and treatment information, evaluating adverse events, and blood tests for hematological and chemical examinations.

[0104] In some embodiments, the patient is 18 years of age or older. In some embodiments, the patient is male. In some embodiments, the patient has been previously diagnosed with prostate cancer. In some embodiments, the patient has been previously diagnosed with metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; a mean life expectancy of at least 6 months; and histological, pathological, and / or cytological confirmation of prostate cancer. 68Positive Ga-PSMA-11 PET / CT scan; previous orchiectomy and / or ongoing androgen deprivation therapy with castration-level serum testosterone (<50 ng / dL or <1.7 nmol / L); prior treatment with at least one NAAD such as enzalutamide and / or abiraterone; prior treatment with at least one or two previous taxane regimens, the taxane regimen including two cycles of minimal taxane exposure, or prior treatment with only one taxane regimen, and a. the patient is unwilling to undergo a second taxane regimen, or b. the patient's physician has assessed age or health status or intolerance. The patient is deemed unsuitable for a second taxane regimen, for example, due to frailty assessed as such; at least one criterion, e.g., a. progression of serum PSA defined as two consecutive increases in PSA above a previous reference value measured at least one week prior, with a minimum starting value of 2.0 ng / mL; b. progression of soft tissue defined as an increase of ≥20% in the sum of the diameters (SOD) of all target lesions (sum of the short axis for nodular lesions and the long axis for non-nodular lesions), based on the minimum SOD or the appearance of one or more new lesions since the start of treatment; and c. progression of bone disease (2+2) such as disease or new bone lesions(multiple) that can be assessed by bone scan. The patient has progressive mCRPC, such as documented progressive mCRPC based on PCWG3 criteria; at least one metastatic lesion is present on baseline CT, MRI, or bone scan taken within 28 days prior to the initiation of therapy with compound 1; the patient has recovered to ≤ grade 2 from all clinically significant toxicity associated with previous therapies, such as prior chemotherapy, radiotherapy, or immunotherapy; and adequate organ function is present, e.g., a. white blood cell (WBC) count ≥ 2.5 × 10^9 / L (2.5 × 10^9 / L is 2.5 × 10^9). 3 / μL and 2.5×K / μL, and 2.5×10 3 (equivalent to / cumm and 2500 / μL) or absolute neutrophil count (ANC) ≥ 1.5 × 10⁻¹⁰ 9 / L(1.5×10 9 / L is 1.5 × 10 3 / μL and 1.5×K / μL, and 1.5×10 3 a. Bone marrow reserve including platelets ≥ 100 × 10^9 / L (100 × 10^9 / L is equivalent to 100 × 10^3 / μL and 100 × K / μL and 100 × 10^3 / cumm and 100,000 / μL), and / or hemoglobin ≥ 9 g / dL (9 g / dL is equivalent to 90 g / L and 5.59 mmol / L), b. Liver, e.g. total bilirubin ≤ 1.5 × upper limit of institutional normal (ULN) (for patients known to have Gilbert's syndrome, ≤ 3 × ULN is permitted), alanine The patient meets one or more criteria selected from the group consisting of: a. aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3.0 × ULN, or 5.0 × ULN in patients with liver metastases; c. renal function, e.g., serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL / min; albumin > 3.0 g / dL (3.0 g / dL is equivalent to 30 g / L); and having received a stable bisphosphonate or denosumab regimen for ≥ 30 days prior to treatment.

[0105] In some embodiments, the patient has a history of CNS metastases that have been treated within approximately 6 months prior to treatment with strontium-89, samarium-153, rhenium-186, rhenium-188, radium-223, or hemispheric irradiation; prior PSMA-targeted radioligand therapy; prior systemic anticancer therapy (e.g., chemotherapy, immunotherapy, or biological therapy [including monoclonal antibodies]) within approximately 28 days prior to treatment; prior administration of the investigational drug within approximately 28 days prior to treatment; known hypersensitivity to the components of the therapy or their analogues; other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy; blood transfusion within approximately 30 days prior to treatment; a history of CNS metastases that have been treated (surgery, radiotherapy, gamma knife), are neurologically stable, asymptomatic, and have not been administered corticosteroids for the purpose of maintaining neurological integrity; and advanced diffuse bone transpositions (super) seen on baseline bone scans. Patients may not be able to receive treatment if they have one or more of the following simultaneous serious (at the physician's discretion) medical conditions: symptomatic or impending spinal cord compression (scan); clinical or radiological findings indicating symptomatic or impending spinal cord compression; a history of congenital long QT syndrome, uncontrolled infection, active hepatitis B or C, or other serious comorbidities that, in the opinion of the principal investigator, would impair treatment or cooperation; or if they have been diagnosed with another malignancy that is expected to alter life expectancy or interfere with disease assessment.

[0106] In various embodiments, the cancer described herein may be a tumorigenic population of cancer cells, including benign and malignant tumors, or the cancer may be non-tumoric. Cancer may arise spontaneously or through processes such as mutations present in the patient's germline or somatic mutations, or it may be induced chemically, virally, or by radiation. Cancers to which the present invention described herein is applicable include, but are not limited to, gliomas, carcinomas, sarcomas, lymphomas, melanomas, mesotheliomas, nasopharyngeal carcinomas, leukemias, adenocarcinomas, and myelomas.

[0107] In some aspects, cancer includes lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, metastatic breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, This may include non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, pleural mesothelioma, bladder cancer, Burkitt lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axial tumor, glioma, brainstem glioma, pituitary adenoma, and adenocarcinoma of the gastroesophageal junction.

[0108] Compound 1 has the following formula: [ka] Here, 177 Lu forms complexes with compounds.

[0109] In other embodiments, any of the various PSMA ligand imaging conjugates detectable by PET imaging, SPECT imaging, etc., can be used. The exact imaging method is not limited to the contrast agents described herein. Collectively, the PSMA ligand imaging conjugates useful for imaging described herein, including those described by formula and agents useful for PET imaging, SPECT imaging, etc., are referred to as "PSMA ligand imaging conjugates."

[0110] In one embodiment, the compound 1 and PSMA ligand imaging conjugate described herein bind to PSMA expressed on cancer cells. In one exemplary embodiment, the compound 1 and PSMA ligand imaging conjugate can differentially bind to PSMA on cancer cells compared to normal cells due to the preferential expression (or overexpression) of PSMA on cancer cells.

[0111] Other embodiments of the methods described herein provide pharmaceutically acceptable salts of Compound 1 and the PSMA ligand imaging conjugate described herein. These pharmaceutically acceptable salts of Compound 1 and the PSMA ligand imaging conjugate described herein include their acid addition salts and base salts.

[0112] Suitable acid addition salts are formed from acids that form non-toxic salts. Exemplary examples include acetates, aspartates, benzoates, besilates, bicarbonates / carbonates, bisulfates / sulfates, borates, camusylates, citrates, edisylates, esylates, formic acid, fumarates, gluceptates, glucons, glucurons, hexafluorophosphates, hibenzates, hydrochlorides / chlorides, hydrobroms / bromids, hydroiodides / iodides, isethionates, lactates, malates, maleates, malons, mesylates, methyl sulfates, naphthylates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, saccharates, stearates, succinates, tartrates, tosylates, and trifluoroacetates.

[0113] Suitable base salts of Compound 1 and the PSMA ligand imaging conjugate described herein are formed from bases that form non-toxic salts. Exemplary examples include arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemi salts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.

[0114] In one embodiment, Compound 1 and the PSMA ligand imaging conjugate described herein can be administered as a formulation accompanied by one or more pharmaceutically acceptable carriers. The carriers may be excipients. The choice of carrier will depend largely on factors such as the specific mode of administration, the effect of the carrier on solubility and stability, and the properties of the dosage form. Suitable pharmaceutical compositions and methods for preparing them for the delivery of Compound 1 and the PSMA ligand imaging conjugate described herein will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science & Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005), which is incorporated herein by reference.

[0115] In one exemplary embodiment, pharmaceutically acceptable carriers include any physiologically compatible solvent, dispersion medium, coating, antimicrobial and antifungal agents, isotonic and absorption retardants, and combinations thereof. In some embodiments, the carrier is suitable for parenteral administration. pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. Supplementary active compounds can also be incorporated into the compositions of the present invention.

[0116] In various embodiments, liquid formulations may include suspensions and solutions. Such formulations may include a carrier, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, as well as one or more emulsifiers and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of solids.

[0117] In one embodiment, the aqueous suspension may contain an active substance mixed with a suitable excipient. Such excipients may include suspending agents, e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents, which may be naturally occurring phosphatides, e.g., lecithin; condensation products of alkylene oxides and fatty acids, e.g., polyoxyethylene stearate; condensation products of ethylene oxides and long-chain aliphatic alcohols, e.g., heptadecaethyleneoxycetanol; condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol, e.g., polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol anhydride, e.g., polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, e.g., ascorbic acid, ethyl, n-propyl, or p-hydroxybenzoate, or one or more colorants.

[0118] In one exemplary embodiment, dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide an active ingredient mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Additional excipients, such as colorants, may also be present.

[0119] Suitable emulsifiers may include naturally occurring gums, such as acacia gum or tragacanth gum; naturally occurring phosphatides, such as soy lecithin; and esters containing partial esters derived from fatty acids and hexitol anhydride, such as sorbitan monooleate, as well as condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0120] In other embodiments, isotonic agents, such as sugars, polyhydric alcohols like mannitol and sorbitol, or sodium chloride may be included in the composition. Long-term absorption of the injectable composition can be achieved by including absorption-delaying agents, such as monostearate and gelatin, in the composition.

[0121] Exemplary forms for oral administration include tablets, capsules, elixirs, and syrups.

[0122] Depending on the type of cancer, route of administration, and / or whether Compound 1 and / or PSMA ligand imaging conjugate are administered topically or systemically, a wide range of acceptable doses, including doses in the range of about 1 μg / kg to about 1 g / kg, are intended herein. In some embodiments, acceptable doses are intended herein in units of GBq, including doses in the range of about 2 GBq to about 13 GBq. Doses may be single or divided and administered according to a wide variety of protocols, including qd, bid, tid, or even every other day, every other week (biw), once a week, once a month, once a quarter, etc. In each of these cases, it is understood that the therapeutically effective dose described herein corresponds to the example of administration or to the total dose daily, weekly, monthly, or quarterly, as determined by the administration protocol. In some embodiments, the compound of Formula 1 can be administered once a week, or once every two weeks, or once every three weeks, or once every four weeks, or once every five weeks, or once every six weeks, or once every seven weeks, or once every eight weeks, and so on.

[0123] In one embodiment, Compound 1 or the PSMA ligand imaging conjugate described herein may be administered directly into the bloodstream, muscle, or viscera. Suitable routes for such parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, epidural, intraventricular, intraurethral, ​​intrasternal, intratumoral, intramuscular, and subcutaneous delivery. Suitable means for parenteral administration include needle (including microneedle) syringes, needleless syringes, and injection techniques.

[0124] In one exemplary embodiment, the parenteral formulation is typically an aqueous solution that may contain a carrier or excipient such as a salt, carbohydrate, and buffer (preferably at a pH of 3–9), but for some applications they may be more appropriately formulated as a sterile, non-aqueous solution or as a dry form used in combination with a suitable vehicle such as sterile, pyrogenic-free water. In other embodiments, any of the liquid formulations described herein can be adapted for parenteral administration of compound 1 or the PSMA ligand imaging conjugate described herein. For example, the preparation of parenteral formulations under sterile conditions by lyophilization under sterile conditions can be readily achieved using standard pharmaceutical techniques well known to those skilled in the art. In one embodiment, the solubility of compound 1 or the PSMA ligand imaging conjugate used in the preparation of the parenteral formulation can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancers.

[0125] In various embodiments, formulations for parenteral administration may be formulated for immediate release and / or controlled release. In one exemplary embodiment, the activator of the present invention (i.e., compound 1 or PSMA ligand imaging conjugate) may be administered in a sustained-release formulation, such as a composition comprising a sustained-release polymer. The active compound 1 or PSMA ligand imaging conjugate may be prepared using a carrier that protects compound 1 or PSMA ligand imaging conjugate from rapid release, such as in controlled-release formulations comprising implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, polylactic acid, and polylactic acid, polyglycol copolymer (PGLA) can be used. Methods for preparing such formulations are generally known to those skilled in the art. In another embodiment, the compound 1 or PSMA ligand imaging conjugate described herein, or a composition comprising compound 1 or PSMA ligand imaging conjugate, may be administered sequentially, where appropriate.

[0126] In one embodiment, a kit is provided. When administering a combination of active compound 1 and a PSMA ligand imaging conjugate, two or more pharmaceutical compositions can be combined in the form of a kit suitable for sequential or simultaneous administration of the compositions. Such a kit comprises two or more distinct pharmaceutical compositions, at least one of which comprises compound 1 or a PSMA ligand imaging conjugate as described herein, and means for holding the compositions separately, e.g., a container, a divided bottle, or a divided foil packet. In another embodiment, a composition is provided comprising one or more of the compound 1 or PSMA ligand imaging conjugates as described herein in a container having a label providing instructions for the use of compound 1 or a PSMA ligand imaging conjugate for patient selection and / or treatment.

[0127] In one embodiment, a sterile injectable solution can be prepared by incorporating the required amount of activator into a suitable solvent containing, if necessary, one or a combination of the above components, followed by sterilization by filtration. Typically, the dispersion is prepared by incorporating the active compound 1 or PSMA ligand imaging conjugate into a sterile vehicle containing the dispersion medium and any additional components of the above. For sterile powders for preparing a sterile injectable solution, preferred preparation methods are vacuum drying and lyophilization, which yield any additional desired components from a previously sterilized filtered solution in addition to the active ingredient powder, or the components may be sterilized filtered together.

[0128] The composition can be formulated as a solution, microemulsion, liposome, or other regular structure suitable for high drug concentrations. The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In one embodiment, adequate fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by the use of a surfactant.

[0129] Any effective regimen for administering compound 1 can be used. For example, compound 1 can be administered as a single dose, or the dose can be divided and administered as a multi-dose daily regimen. Furthermore, for example, a staggered regimen of 1 to 5 days per week can be used as an alternative to daily treatment, and for the purposes of the methods described herein, such intermittent or staggered daily regimens are considered equivalent to daily treatment and are therefore intended. In one exemplary embodiment, a patient is treated with multiple injections of compound 1 to treat cancer. In one embodiment, the patient is injected with compound 1 multiple times (preferably about 2 to a maximum of about 50 times) at intervals of, for example, 12 to 72 hours or 48 to 72 hours. Additional injections of compound 1 can be administered to the patient at intervals of several days or months from the initial injection(s), and the additional injections can prevent cancer recurrence.

[0130] Any appropriate therapeutic course with compound 1 can be used. In one embodiment, individual doses and administration regimens are selected to provide a total dose of approximately 15 mg administered over a month. In one exemplary example, compound 1 is administered once daily, five days a week, in weeks 1, 2, and 3 of each four-week cycle, and not in week 4. In another example, compound 1 is administered once daily, three days a week, in weeks 1 and 3 of each four-week cycle, and not in weeks 2 and 4. In yet another example, compound 1 is administered every other week, in weeks 1 and 2, i.e., on days 1, 4, 8, and 11 of a three-week cycle. In yet another example, compound 1 is administered once a week, in weeks 1 and 2, i.e., on days 1 and 8 of a three-week cycle.

[0131] The daily unit dosage of Compound 1 varies significantly depending on the patient's condition, the cancer being treated, the route of administration of Compound 1 as well as its tissue distribution, and the possibility of combination with other therapies such as radiation therapy or additional drugs used in combination with the therapy. The effective amount administered to the patient is based on the physician's assessment of the body surface area, mass, and the patient's condition. The therapeutically effective dosage (also referred to herein as "therapeutically effective amount") can be, for example, in the range of about 0.5 mg / m 2 to about 10.0 mg / m 2 The therapeutically effective dosages described herein can also be about 0.5 mg / m 2 to about 9.5 mg / m 2 about 0.5 mg / m 2 to about 9.0 mg / m 2 about 0.5 mg / m 2 to about 8.5 mg / m 2 about 0.5 mg / m 2 to about 8.0 mg / m 2 about 0.5 mg / m 2 to about 7.5 mg / m 2 about 于0.5 mg / m 2 to about 7.0 mg / m 2 about 0.5 mg / m 2 to about 6.5 mg / m 2 about 0.5 mg / m 2 to about 6.0 mg / m 2 about 0.5 mg / m 2 to about 5.5 mg / m 2 about 0.5 mg / m 2 to about 5.0 mg / m 2 about 0.5 mg / m 2 to about 4.5 mg / m 2 about 0.5 mg / m 2 to about 4.0 mg / m<000008{1]]about 0.5 mg / m 2 to about 3.5 mg / m 2 about 0.5 mg / m 2 to about 3.0 mg / m 2 about 0.5 mg / m 2 to about 2.5 mg / m 2 about 0.5 mg / m 2 to about 2.0 mg / m 2 about 0.5 mg / m 2 to about 1.5 mg / m 2 about 1.0 mg / m2 ~ about 9.5 mg / m 2 、about 1.0 mg / m 2 ~ about 9.0 mg / m 2 、about 1.0 mg / m 2 ~ about 8.5 mg / m 2 、about 1.0 mg / m 2 ~ about 8.0 mg / m 2 、about 1.0 mg / m 2 ~ about 7.5 mg / m 2 、about 1.0 mg / m 2 ~ about 7.0 mg / m 2 、about 1.0 mg / m 2 ~ about 6.5 mg / m 2 、about 1.0 mg / m 2 ~ about 6.0 mg / m 2 、about 1.0 mg / m 2 ~ about 5.5 mg / m 2 、about 1.0 mg / m 2 ~ about 5.0 mg / m 2 、about 1.0 mg / m 2 ~ about 4.5 mg / m 2 、about 1.0 mg / m 2 ~ about 4.0 mg / m 2 、about 1.0 mg / m 2 ~ about 3.5 mg / m 2 、about 1.0 mg / m 2 ~ about 3.0 mg / m 2 、about 1.0 mg / m 2 ~ about 2.5 mg / m 2 、about 1.0 mg / m 2 ~ about 2.0 mg / m 2 、and about 1.0 mg / m 2 ~ about 1.5 mg / m 2 The range includes. Those skilled in the art will readily understand that the therapeutically effective dose can vary within the various ranges provided above based on the above factors. The therapeutically effective dose for any particular patient or group of patients is about 0.5 mg / m 2 ~ about 10.0 mg / m 2 Any numerical value between may be, and these numerical values include 1.0 mg / m 2 、1.5 mg / m 2 、2.0 mg / m 2 、2.5 mg / m 2 、3.0 mg / m2 3.5 mg / m² 2 4.0 mg / m² 2 , 4.5 mg / m² 2 5.0 mg / m² 2 5.5 mg / m² 2 6.0 mg / m² 2 , 6.5 mg / m² 2 7.0 mg / m² 2 7.5 mg / m² 2 8.0 mg / m² 2 8.5 mg / m² 2 9.0 mg / m² 2 9.5 mg / m² 2 and 10.0 mg / m² 2 This includes, but is not limited to, the following. The total dose may be administered as a single dose or in divided doses and may, at the physician's discretion, fall outside the typical range described herein.

[0132] In some embodiments, the compound of Formula 1 can be administered in combination with a second treatment. In some embodiments, the second treatment is best supportive care. In some embodiments, the second treatment is best standard care. In some embodiments, the second treatment is best supportive care / best standard care. In some embodiments, the second treatment is androgenic systemic therapy. In some embodiments, the androgenic systemic therapy is selected from the group consisting of abiraterone, orteronel, galeterone, ceviteronel, apalutamide, enzalutamide, and combinations thereof. In some embodiments, the second treatment is radiotherapy. In some embodiments, the radiotherapy is external beam radiation therapy (EBRT).

[0133] The PSMA ligand imaging conjugate and compound 1 described herein may contain one or more chiral centers, or otherwise may exist as multiple stereoisomers. Therefore, it should be understood that the present invention includes pure stereoisomers, as well as mixtures of stereoisomers such as enantiomers and diastereomers, and mixtures rich in enantiomers or diastereomers. The PSMA ligand imaging conjugate and compound 1 described herein may exist as geometric isomers. Therefore, it should be understood that the present invention includes pure geometric isomers or mixtures of geometric isomers.

[0134] It is understood that the PSMA ligand imaging conjugate and Compound 1 described herein may exist in solvated forms, including non-solvated and hydrated forms. Generally, the solvated forms are equivalent to the non-solvated forms and fall within the scope of the invention. The PSMA ligand imaging conjugate and Compound 1 described herein may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent to the uses intended by the invention and are intended to fall within the scope of the invention.

[0135] In another embodiment, a composition and / or dosage form for administering compound 1 is prepared from compound 1 with a purity of at least about 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.

[0136] In another embodiment, a composition and / or dosage form for administering a PSMA ligand imaging conjugate is prepared from a PSMA ligand imaging conjugate with a purity of at least about 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.

[0137] In another embodiment, a composition and / or dosage form for administering a radiolabeled PSMA ligand imaging conjugate is prepared from a PSMA ligand imaging conjugate with a radiochemical purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%.

[0138] The purity of Compound 1 or the PSMA ligand imaging conjugate described herein can be measured using any conventional technique, including various chromatographic or spectroscopic techniques such as high-pressure or high-performance liquid chromatography (HPLC), nuclear magnetic resonance spectroscopy, TLC, UV absorbance spectroscopy, and fluorescence spectroscopy.

[0139] In another embodiment, the compound 1 or PSMA ligand imaging conjugate described herein is provided in a sterile container or package.

[0140] In one embodiment, the clinical benefit of treatment with compound 1 can be characterized as overall survival (OS). As used herein, the term "overall survival (OS)" means the time from the date of randomization to the date of death from any cause.

[0141] In one embodiment, the clinical benefit to patients from treatment with compound 1 can be characterized using the criteria of the Response Evaluation Criteria in Solid Tumors (RECIST). As an example, the criteria have been adapted from the original WHO Handbook (3), taking into account the measurement of the longest diameter of all target lesions, and include: complete response (CR) - disappearance of all target lesions; partial response (PR) - a total reduction of at least 30% in the longest diameter of target lesions relative to the total longest diameter at baseline; stable disease (SD) - no reduction sufficient to qualify for partial response or an increase sufficient to qualify for progressive disease, relative to the smallest total longest diameter since the start of treatment; progressive disease (PD) - a total increase of at least 20% in the longest diameter of target lesions relative to the smallest total longest diameter recorded since the start of treatment or the appearance of one or more new lesions. In another embodiment, the overall response rate (ORR) is the clinical benefit and is calculated as the percentage of patients who achieve the best response of CR or PR. The overall disease control rate (DCR) can be another clinical benefit and is calculated as the percentage of patients who achieved the best response of complete response (CR), partial response (PR), or stable disease (SD). In some embodiments, the response may be the disease control rate (DCR) as measured by the RECIST v1.1 criteria.

[0142] In another embodiment, the clinical benefit to a patient with treatment with compound 1 can be characterized as radiographic progression-free survival (rPFS). As used herein, “radiographic progression-free survival (rPFS)” means the time from the date of randomization to the date of radiographic disease progression, or to death from any cause, as outlined in the Prostate Cancer Working Group 3 (PCWG3) guidelines. See, for example, Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations from the Prostate Cancer Clinical Trials Work Group 3. J Clin Oncol 2016;34(12):1402-18. In another embodiment, the clinical benefit to a patient with treatment with compound 1 can be characterized as first symptomatic bone-related events (SSEs). Symptomatic bone-related events will be understood to mean clinically significant pathological fractures, bone surgery or radiation to the bone, or spinal cord compression. As used herein, “time to first symptomatic skeletal-related event” means the date of randomization to the first new symptomatic pathological fracture, spinal cord compression, tumor-related orthopedic intervention, or need for radiation therapy to alleviate bone pain, whichever comes first.

[0143] In one exemplary example, overall survival is defined as the time to death of a given patient, as the number of days from the first day the patient received protocol treatment (C1D1) to the date of the patient's death. All death events may be included, regardless of whether the event occurred while the patient was still taking the study drug or after the patient discontinued the study drug. If the patient has not died, the data may be censored at the later of the last outpatient visit date, last contact date, or the date the patient was last known to be alive.

[0144] Alternatively, the clinical benefit to a patient as a result of treatment with compound 1 can be characterized as inhibition of tumor growth, which can be identified in the patient, for example, through imaging studies of the patient's cancer follow-up after treatment with compound 1. For example, inhibition of tumor growth can be characterized by measuring the size of the patient's tumor after administration of compound 1 according to any of the imaging techniques described herein, and inhibition of tumor growth is indicated by a stable tumor size or a reduction in tumor size. Identification of inhibition of tumor growth can be achieved using a variety of techniques, which are, but are not limited to, imaging methods described herein (e.g., CT, MRI, PET, SPECT, or chest X-ray).

[0145] In one embodiment, a method is provided for determining whether compound 1 is suitable for the treatment of a cancer patient, the method comprising the step of determining the PSMA status of the cancer patient, and if the patient's PSMA status is positive, compound 1 is suitable for the treatment of the patient.

[0146] In one embodiment, a method is provided for evaluating whether compound 1 is suitable for the treatment of a patient having one of the cancers described herein. The method includes the step of visually determining the PSMA status in the patient, and the PSMA status is determined based on an imaging tumor that is PSMA-positive in the patient. If the patient's PSMA status is positive, compound 1 is suitable for the treatment of the patient.

[0147] In the embodiments described above, the clinical benefit of treatment with compound 1 is demonstrated when the patient belongs to the group having a positive PSMA status. In one embodiment, the clinical benefit to the patient may be the patient's overall survival, the ability to receive four or more cycles of treatment with compound 1, inhibition of tumor growth, stable disease, partial response to treatment, complete response to treatment, disease control (i.e., the best outcome is complete response, partial response, or disease stability), and / or complete response (i.e., the best outcome is complete response or partial response). In one exemplary example, the clinical benefit to a patient being treated for pleural mesothelioma or adenocarcinoma (e.g., adenocarcinoma of the gastroesophageal junction) is disease stability.

[0148] In another embodiment, the method described herein includes the following examples. These examples further illustrate additional features of the various embodiments of the invention described herein. However, it should be understood that these examples are illustrative and should not be construed as limiting other embodiments of the invention described herein. Furthermore, it should be understood that other variations of the examples are included in the various embodiments of the invention described herein. [Examples]

[0149] Example 1: A.Design: Patients with PSMA-positive scans were randomized in a 2:1 ratio to receive either compound 1 plus best supportive care / best standard care, or best supportive care / best standard care only. Best supportive care / best standard care was determined by the treating physician / principal investigator. This trial was open-label, and patients were monitored for survival, disease progression, and adverse events throughout the 6-10 month treatment period. Longer follow-up periods included collecting survival and treatment updates, evaluating adverse events, and blood tests for hematological and chemical examinations. During the follow-up period, patients were contacted every 3 months (±1 month) by telephone, email, or letter for 24 months, or until the overall survival censoring rate fell to the level identified by SAP.

[0150] B. Arm 1: Compound 1 and Best Supportive Care / Best Standard Care (BS / BSOC) Approximately 160 patients were randomized to receive the investigational product, compound 1 (equivalent to a dose of 200 mCi), intravenously at a dose of 7.4 GBq (±10%) every 6 weeks (±1 week) for up to 6 cycles, in addition to best supportive care / best standard care (BS / BSOC). After 4 cycles, patients were evaluated for (1) evidence of response, (2) residual disease, and (3) tolerability of compound 1. 177 Before administering Lu-PSMA-617, perform saline irrigation with 10 mL of normal saline to ensure patency of the intravenous line. 177 Lu-PSMA-617 was administered slowly via an intravenous route through an indwelling catheter, followed by saline lavage. The administration time needs to be recorded. The total radioactivity administered needs to be measured (GBq). To date, patients have received 1–6 cycles in a randomized arm. To date, approximately 320 patients have been scanned with Ga-PSMA imaging conjugate 4.

[0151] C. Arm 2: Best Supportive Care / Best Standard Care (BS / BSOC) Alone Patients randomized to this will receive the best supportive care / best standard of care (BS / BSOC) determined by the principal investigator.

[0152] D. Outcome measures: Overall survival (OS) of patients with advanced PSMA-positive mCRPC who received compound 1 in addition to the best supportive / standard therapy.

Claims

1. Formula 1 【Chemistry 1】 A pharmaceutical composition for the treatment of cancer comprising the compound, wherein the compound is １７７ It forms a complex with the metal Lu, and per dose １７７ A pharmaceutical composition that provides approximately 7 GBq to approximately 8 GBq of radioactivity from Lu, wherein the treatment of cancer involves administering the pharmaceutical composition once every 4 to 6 weeks for 4 to 6 cycles.

2. The pharmaceutical composition according to claim 1, wherein the cancer is a PSMA-expressing cancer.

3. The pharmaceutical composition according to claim 1, wherein the compound of formula 1 is at least about 98 percent pure.

4. The pharmaceutical composition according to claim 1, wherein the cancer is prostate cancer or metastatic castration-resistant prostate cancer.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the compound of formula 1 is in a parenteral dosage form.

6. The pharmaceutical composition according to claim 5, wherein the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.

7. The pharmaceutical composition １７７ A pharmaceutical composition according to any one of claims 1 to 4, which provides approximately 7.4 GBq of radioactivity from Lu.

8. The pharmaceutical composition according to any one of claims 1 to 4, further comprising imaging PSMA expression caused by the aforementioned cancer.

9. The pharmaceutical composition according to claim 8, wherein the imaging is performed before administering the pharmaceutical composition to a patient.

10. The pharmaceutical composition according to claim 9, wherein the imaging method is selected from the group consisting of SPECT imaging, PET imaging, IHC, and FISH.

11. The pharmaceutical composition according to claim 10, wherein the imaging is performed by SPECT imaging.

12. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is used in a method that includes determining a patient's PSMA state by imaging.

13. The pharmaceutical composition according to claim 12, wherein the imaging method is SPECT imaging.

14. The pharmaceutical composition according to claim 12 or 13, wherein the PSMA state of the patient correlates with the clinical benefit to the patient.

15. The pharmaceutical composition according to claim 14, wherein the clinical benefit is selected from the group consisting of inhibition of tumor growth, disease stabilization, partial response, and complete response.

16. The pharmaceutical composition according to claim 15, wherein the clinical benefit is disease stabilization.

17. The pharmaceutical composition according to claim 12 or 13, wherein at least one PSMA-positive lesion exhibits functionally active PSMA.

18. The pharmaceutical composition according to any one of claims 1 to 4, wherein the patient has been treated with at least one prior treatment.

19. The pharmaceutical composition according to claim 18, wherein the at least one prior treatment is selected from the group consisting of androgen pathway (axis) systemic therapy, chemotherapy agents, surgery, radiotherapy, immunotherapy, photodynamic therapy, stem cell therapy, and hyperthermia.

20. The pharmaceutical composition according to claim 19, wherein the at least one prior treatment is systemic androgenic pathway drug therapy.

21. The pharmaceutical composition according to claim 19, wherein the at least one prior treatment is selected from the group consisting of abiraterone, orteronel, galeterone, ceviteronel, apalutamide, enzalutamide, and combinations thereof.

22. The pharmaceutical composition according to claim 18, wherein the at least one prior treatment is selected from the group consisting of paliphosphamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof.

23. The pharmaceutical composition according to any one of claims 1 to 4, wherein the compound of formula 1 is administered in combination with a second treatment.

24. The pharmaceutical composition according to claim 23, wherein the second treatment is the best supportive therapy.

25. The pharmaceutical composition according to claim 23, wherein the second treatment is the best standard therapy.

26. The pharmaceutical composition according to claim 23, wherein the second treatment is the best supportive therapy / best standard therapy.

27. The pharmaceutical composition according to claim 23, wherein the second treatment is systemic treatment of the androgen pathway.

28. The pharmaceutical composition according to claim 27, wherein the systemic androgenic pathway treatment is selected from the group consisting of abiraterone, orteronel, galeterone, ceviteronel, apalutamide, enzalutamide, and combinations thereof.

29. The pharmaceutical composition according to claim 23, wherein the second treatment is radiotherapy.

30. The pharmaceutical composition according to claim 29, wherein the radiotherapy is external beam radiation therapy (EBRT).

31. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition provides a total radioactivity of 28 to 48 GBq.

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