Methods of treating cancer

Abstract

To provide drug delivery conjugates for targeted therapy.SOLUTION: The present invention provides a method for treating cancer in a host animal, the method comprising the step of administering to the host animal a therapeutically effective amount of a first compound (I-Lu) having a specific formula (I), wherein the first compound is complexed with 177 Lu, in combination with a therapeutically effective amount of a second compound (I-Ac) having a specific formula (I), wherein the second compound is complexed with 225Ac.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 734,649, filed September 21, 2018, the entire disclosure of which is incorporated herein by reference.

[0002] The present disclosure relates to a drug delivery conjugate for targeted therapy. The present disclosure relates to a method for treating a cancer expressing PSMA with a combination of compounds of formula I-Lu or Ia-Lu and I-Ac or Ia-Ac, comprising: 177 Lu or 225 The present disclosure also relates to a method of treating a PSMA-expressing cancer with a combination of compounds of formula I-Lu or Ia-Lu and I-Ac or Ia-Ac. [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, containing an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and an extensive extracellular domain (amino acids 44-750). The functions of the intracellular segment and the transmembrane domain are currently thought to be unimportant, but the extracellular domain is involved in several different activities. PSMA plays a role in the central nervous system, metabolizing N-acetyl-aspartylglutamate (NAAG) to glutamate and N-acetylaspartate. It is therefore also sometimes 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) for its role in the proximal small intestine in removing gamma-linked glutamate from poly-gamma-glutamated folates and alpha-linked glutamate from peptides and small molecules.

[0004] PSMA is named primarily for its high expression levels in prostate cancer cells, but its specific function on prostate cancer cells remains to be resolved. PSMA expression is very limited in humans, present only in a few cells in salivary gland tissue, kidney tissue, small intestine, and large intestine. PSMA is overexpressed in malignant prostate tissue when compared to other organs of the human body, such as the kidney, proximal small intestine, and salivary glands. Higher PSMA expression is associated with high-grade metastatic and castration-resistant disease. Tumor expression in prostate cancer is typically 100- to 1,000-fold higher. Unlike many other membrane-bound proteins, PSMA is rapidly internalized into cells in a manner similar to cell surface-bound receptors such as vitamin receptors. PSMA can be internalized via clathrin-coated pores and then either recycled to the cell surface or trafficked to lysosomes. It has been suggested that dimeric and monomeric forms of PSMA are interconvertible, although direct evidence of interconversion is debated. Yet, only PSMA dimers, but not monomers, possess enzymatic activity.

[0005] PSMA is also expressed in the vasculature of other tumors, such as thyroid cancer, renal clear cell carcinoma, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, breast cancer, etc. These cancers show a great variety of tumors with different histological subtypes, growth rates, and cell cycles. In some cases, cancers are embedded in normal tissues with different radiation resistance. In addition, hypoxic regions of larger deposits may also result in radiation resistance. These and other factors are known to result in different unique responses to conventional external beam radiation therapy.

[0006] Although the activity of PSMA on the cell surface of prostate cells is under investigation, it has been recognized by the inventors that PSMA represents an applicable target for selective and / or specific delivery of a biologically active agent or combination of biologically active agents, including a drug compound, to such prostate cells. One such drug compound is the compound of formula I, which is described in WO2015 / 055318 and is effective in the treatment of cancer: [ka] During the ceremony, 177 Lu can be complexed with a compound to give I-Lu, or 225 Ac complexes with compound I to provide I-Ac. Compounds I-Lu and I-Ac can be prepared according to the methods described in WO2015 / 055318, which is incorporated by reference for the preparation of compounds I-Lu and I-Ac described in Examples 3 and 5.

[0007] Another such drug compound is compound Ia, which is described in WO2015 / 055318 and is useful in the treatment of cancer. [ka] (also known as (3S,10S,14S)-3-[(naphthalen-2-yl)methyl]-1,4,12-trioxo-1-[(1R,4S)-4-[[2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetamido]methyl]cyclohexyl]-2,5,11,13-tetraazahexadecane-10,14,16-tricarboxylic acid), wherein 177 Lu complexes with compound Ia to provide Ia-Lu, or 225 AC is complexed with compound Ia-Ac to provide compound Ia-Lu and Ia-Ac. Compounds Ia-Lu and Ia-Ac can be prepared according to the method described in WO2015 / 055318, which is incorporated by reference for the preparation of compounds Ia-Lu and Ia-Ac described in Example 3 and Example 5.

[0008] Compound I or Ia can be described as a small molecule that specifically binds to PSMA (prostate-specific membrane antigen) expressed on the surface of prostate cancer cells. Compound I or Ia is a pharmacophore ligand, glutamate-urea-lysine, a chelator, DOTA ( 177 Lu and 225 The urea-based pharmacophore ligands can be characterized as being composed of a urea-based ligand capable of complexing with PSMA and a linker linking the ligand and chelator. Without being bound by theory, it is believed that the urea-based pharmacophore ligands allow the drug to bind at the disease site and be internalized by PSMA. Furthermore, it is believed that binding of I-Lu, I-Ac, Ia-Lu, or Ia-Ac can result in internalization via endocytosis, thereby providing sustained retention of the ligand and its bound radioactive cargo within the cancer cell.

[0009] Previous clinically used radioligand therapy (RLT) has been 131 I, and for the treatment of bone metastases 223 Radium or 89 It contains elements that emit alpha rays, such as strontium.

[0010] 177 Lu has a half-life of 6.7 days. It travels chaotically through tissues over approximately 20-80 cells or 0.5-2 mm, emitting primarily 0.5 MeV energy combinations of negatively charged beta particles (electrons) that cause base damage and single-strand breaks. At high doses, these lesions can interact to convert sublethal damage (SLD) or potentially lethal damage (PLD) into irreparable lethal damage. 177 Lu also emits 113 Kv and 208 kV radiation that can be used for imaging.

[0011] 225Ac, in contrast, has a half-life of 9.9 days and emits alpha particles with 8.38 MV energy. Only 0.5% of the energy is released as a photon emission of 142 Kv. Thus, the majority of radiation particles are positively charged, about 8,000 times larger than beta particles. Furthermore, the energy from these particles is deposited over a relatively short distance (2-3 cells). The result is a high density and high concentration of tissue damage in the form of double-strand breaks with multiple damage sites that represent irreparable fatal damage. This is called High Linear Energy Transfer (LET) or densely ionizing ionization, and delivers an absorbed dose 3-7 times higher than beta.

[0012] Any isotope ( 177 Lu or 225 The type of cellular damage inflicted by each warhead is expected to vary due to differences in the characteristics of each warhead. 177 Lu is believed to provide a longer radiation path length and therefore may be more effective at delivering radiation to neighboring cells. The predominance of single-strand breaks, especially in the presence of oxygen, provides an opportunity to repair sublethal damage (SLD) and / or potentially lethal damage (PLD), providing optimal conditions for normal tissue repair. In contrast, 225 Ac delivers very powerful and high LET radiation, with much more limited potential for normal tissue repair. The radiological biological effectiveness of alpha radiation is at least five times that of beta radiation and dose, and the relative biological effectiveness (RBE) must be taken into account. 225 Ac therapy is also more effective in hypoxic tumor regions because the type of DNA damage delivered does not require the presence of oxygen. 225 A possible drawback of Ac therapy is that the short path length can result in a large amount of damaging radiation that accumulates only within a short distance of 2-4 cells.

[0013] Another such compound is Eder M, Schafer M, Bauder-Wust U, Hull WE, Wangler C, Mier W, et al. 68 PSMA imaging conjugate 4 useful for cancer imaging, described in Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012;23:688-97 [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)), wherein 68 Ga (or a similar radioactive metal isotope) is complexed with the conjugate. 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. Summary of the Invention

[0014] In some embodiments, the disclosure provides a method for treating cancer in a patient in need of such treatment, comprising administering to the patient therapeutically effective amounts of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0015] In some embodiments, the present disclosure provides a use of compound I-Lu or Ia-Lu in combination with compound I-Ac or Ia-Ac to treat cancer in a patient. In some aspects, the use comprises administering to the patient a therapeutically effective amount of compound I-Lu or Ia-Lu and a therapeutically effective amount of compound I-Ac or Ia-Ac.

[0016] In some embodiments, the present disclosure provides the use of a combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac in the preparation of a medicament useful for treating cancer in a patient. In some aspects, the medicament comprises a therapeutically effective combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0017] In some embodiments, the present disclosure provides the use of compound I-Lu or Ia-Lu in the preparation of a medicament useful for treating cancer in a patient in combination with compound I-Ac or Ia-Ac. In some aspects, the medicament comprises a therapeutically effective amount of compound I-Lu or I-Lu.

[0018] In some embodiments, the present disclosure provides the use of compound I-Ac or Ia-Ac in the preparation of a medicament useful for treating cancer in a patient in combination with compound I-Lu or Ia-Lu. In some aspects, the medicament comprises a therapeutically effective amount of compound I-Ac or I-Ac.

[0019] In some embodiments, the present disclosure provides the use of compound I-Lu or Ia-Lu in the preparation of a first medicament useful for treating cancer in a patient in combination with a second medicament comprising compound I-Ac or Ia-Ac. In some aspects, the first medicament comprises a therapeutically effective amount of compound I-Lu or I-Lu, and the second medicament comprises a therapeutically effective amount of compound I-Ac or I-Ac.

[0020] 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% 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.

[0021] In some aspects of these embodiments, the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, gastric cancer, colon cancer, breast cancer, triple negative breast cancer, metastatic breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, cancer of the thyroid gland, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), thyroid cancer, The cancer is selected from the group consisting of: transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, chronic leukemia, acute leukemia, lymphocytic lymphoma, pleural mesothelioma, bladder carcinoma, Burkitt's lymphoma, ureteral carcinoma, kidney carcinoma, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, glioma, brain stem 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.

[0022] In some aspects of these embodiments, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac 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 amount of I-Lu or Ia-Lu is about 2 GBq to about 13 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 4 GBq to about 11 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 5 GBq to about 10 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 6 GBq to about 9 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 6.5 GBq to about 8.5 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 7 GBq to about 8 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 7.4 GBq. In some aspects of these embodiments, the total dosage of I-Lu or Ia-Lu is in the range of about 15 GBq to about 200 GBq. In some aspects of these embodiments, the total dosage of I-Lu or Ia-Lu is in the range of about 25 GBq to about 185 GBq. In some aspects of these embodiments, the total dosage of I-Lu or Ia-Lu is in the range of about 35 GBq to about 150 GBq. In some aspects of these embodiments, the total dosage of I-Lu or Ia-Lu is in the range of about 40 GBq to about 100 GBq. In some aspects of these embodiments, the total dosage of I-Lu or Ia-Lu is about 44 GBq. In some aspects of these embodiments, the maximum duration of treatment for a subject is about 19 to 23 months.

[0023] In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 20 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 4 MBq to about 14 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq to about 10 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 6 MBq to about 8 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 4 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 2 MBq to about 3 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 2.5 MBq.

[0024] In other aspects, the methods and uses described herein further comprise imaging the PSMA expression by cancer. In some aspects of these embodiments, the imaging step is performed before the administration step. In some aspects of these embodiments, the imaging step is performed after the administration step. In some aspects of these embodiments, the imaging is performed by imaging, and the imaging is selected from the group consisting of SPECT imaging, PET imaging, IHC, and FISH. In some aspects of these embodiments, the imaging is performed by SPECT imaging.

[0025] In some aspects of these embodiments, the imaging step comprises administering to the subject a PSMA ligand imaging conjugate of formula 2: [ka] or a pharma- ceutically 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 a radionuclide is attached to the conjugate.

[0026] In some aspects of these embodiments, the imaging step comprises administering to the subject a PSMA ligand imaging conjugate of formula 3: [ka] or a pharma- ceutically acceptable salt thereof to a patient, where 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 a pharma- ceutically acceptable salt thereof, is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium. In some aspects of these embodiments, M of the conjugate, or a pharma- ceutically acceptable salt thereof, is an isotope of technetium.

[0027] In some aspects of these embodiments, the PSMA ligand imaging conjugate is of formula 2a: [ka] or a pharma- ceutical acceptable salt thereof, wherein the radionuclide is attached to the conjugate. In some aspects of these embodiments, the PSMA ligand imaging conjugate is of formula 3a: [ka] or a pharma- ceutically acceptable salt thereof.

[0028] In some aspects of these embodiments, the imaging step comprises administering to the subject a PSMA ligand imaging conjugate of formula 4: [ka] or a pharma- ceutical acceptable salt thereof to a patient, wherein the radionuclide is attached to the conjugate. In some aspects of these embodiments, the radionuclide is 68 It's Ga.

[0029] In some aspects of these embodiments, the imaging step comprises detecting a compound of formula I-Lu or Ia-Lu administered for therapeutic purposes.

[0030] In other aspects, the methods and uses described herein further comprise determining the patient's PSMA status by imaging. In some aspects of these embodiments, the determining step is performed before the administering step. In some aspects of these embodiments, the determining step is performed after the administering step. In some aspects of these embodiments, the imaging is SPECT imaging. In some aspects of these embodiments, the patient's PSMA status is correlated with clinical benefit to the patient. In some aspects of these embodiments, the clinical benefit is selected from the group consisting of tumor growth inhibition, stable disease, partial response, and complete response. In some aspects of these embodiments, the clinical benefit is stable disease. In some aspects of these embodiments, the PSMA-positive lesions exhibit functionally active PSMA.

[0031] In some aspects of these embodiments, the determining step comprises detecting a PSMA ligand imaging conjugate of formula 2: [ka] or a pharma- ceutically 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 linked to a radionuclide.

[0032] In some aspects of these embodiments, the determining step comprises detecting a PSMA ligand imaging conjugate of formula 3: [ka] or a pharma- ceutically acceptable salt thereof to a patient, where 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.

[0033] In some aspects of these embodiments, M of the conjugate, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium. In some aspects of these embodiments, M of the conjugate, or a pharma- ceutically acceptable salt thereof, is an isotope of technetium. In some aspects of these embodiments, the PSMA ligand imaging conjugate is of formula 2a: [ka] or a pharma- ceutically acceptable salt thereof, wherein a radionuclide is attached to the conjugate.

[0034] In some aspects of these embodiments, the PSMA ligand imaging conjugate is of formula 3a: [ka] or a pharma- ceutically acceptable salt thereof.

[0035] In some aspects of these embodiments, the determining step comprises detecting a PSMA ligand imaging conjugate of formula 4: [ka] or a pharma- ceutical acceptable salt thereof to a patient, wherein the radionuclide is attached to the conjugate. In some aspects of these embodiments, the radionuclide is 68 It's Ga.

[0036] In some aspects of these embodiments, the determining step comprises detecting a compound of formula I-Lu or Ia-Lu administered for therapeutic purposes.

[0037] In another embodiment, the disclosure provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective combination of compounds I-Lu and I-Ac; [ka] 177 Lu forms a complex with the compound in I-Lu, 225 The method provides that Ac is complexed with the compound in I-Ac, resulting in a stable disease after combination of the compounds I-Lu and I-Ac.

[0038] In another embodiment, the disclosure provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective combination of compounds Ia-Lu and Ia-Ac; [ka] 177 Lu forms a complex with the compound in Ia-Lu, 225 The method provides that Ac is complexed with compound I in Ia-Ac, resulting in stable disease after combination of compounds Ia-Lu and Ia-Ac.

[0039] In another embodiment, the present disclosure relates to the use of compounds I-Lu and I-Ac, [ka] 177Lu forms a complex with the compound in I-Lu, 225 The use is provided wherein Ac is complexed with compound I in Ia-Ac, resulting in stable disease after the combination of compounds I-Lu and I-Ac is administered. In some aspects of these embodiments, the use comprises administering to a patient a therapeutically effective combination of compounds I-Lu and I-Ac.

[0040] In other embodiments, the disclosure relates to the use of compounds Ia-Lu and Ia-Ac, [ka] 177 Lu forms a complex with the compound in Ia-Lu, 225 Ac is complexed with compound I in Ia-Ac, resulting in stable disease after the combination of compounds Ia-Lu and Ia-Ac is administered. In some aspects of these embodiments, the use includes administering to a patient a therapeutically effective combination of compounds Ia-Lu and Ia-Ac.

[0041] In another embodiment, the disclosure provides the use of compounds I-Lu and I-Ac in the preparation of a medicament useful for treating cancer in a patient, comprising: [ka] 177 Lu forms a complex with compound I in I-Lu, 225 The invention provides a method for treating a medicament comprising administering to a patient a therapeutically effective combination of compounds I-Lu and I-Ac, the method comprising administering to a patient a therapeutically effective combination of compounds I-Lu and I-Ac.

[0042] In another embodiment, the disclosure provides the use of compounds I-Lu and I-Ac in the preparation of a medicament useful for treating cancer in a patient, comprising: [ka] 177Lu forms a complex with compound I in I-Lu, 225 Ac is complexed with compound I in I-Ac, resulting in a stable disease after the combination of compounds I-Lu and I-Ac is administered. In some embodiments, the medicament comprises a therapeutically effective combination of compounds I-Lu and I-Ac.

[0043] In another embodiment, the disclosure provides the use of compounds Ia-Lu and Ia-Ac in the preparation of a medicament useful for treating cancer in a patient, comprising: [ka] 177 Lu forms a complex with compound Ia in Ia-Lu, 225 The present invention provides a use, wherein Ac is complexed with compound Ia in Ia-Ac. In some embodiments, the medicament comprises a therapeutically effective combination of compounds Ia-Lu and Ia-Ac.

[0044] In another embodiment, the disclosure provides the use of compounds Ia-Lu and Ia-Ac in the preparation of a medicament useful for treating cancer in a patient, comprising: [ka] 177 Lu forms a complex with compound Ia in Ia-Lu, 225 Ac is complexed with compound Ia in Ia-Ac, resulting in stable disease after the combination of compounds Ia-Lu and Ia-Ac is administered. In some embodiments, the medicament comprises a therapeutically effective combination of compounds Ia-Lu and Ia-Ac.

[0045] 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 axis systemic treatment, chemotherapeutic agent, surgery, radiation therapy, 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 palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinibe, and combinations thereof. In some aspects of these embodiments, the cancer is a PSMA-expressing cancer. In some aspects of these embodiments, the compound is at least about 98 percent pure.

[0046] In some aspects of these embodiments, I-Lu or Ia-Lu is administered before I-Ac or Ia-Ac. In some aspects of these embodiments, I-Lu or Ia-Lu is administered before I-Ac or Ia-Ac on the same day. In some aspects of these embodiments, I-Lu or Ia-Lu is administered simultaneously with I-Ac or Ia-Ac. In some aspects of these embodiments, I-Ac or Ia-Ac is administered before I-Lu or Ia-Lu. In some aspects of these embodiments, I-Ac or Ia-Ac is administered before I-Lu or Ia-Lu on the same day.

[0047] Certain embodiments are further described by the following enumerated items: 1. A method for treating cancer in a host animal, comprising administering to the host animal a therapeutically effective amount of a first compound having formula I, [ka] 177 A first compound (I-Lu) complexed with Lu is a therapeutically effective amount of a second compound having formula I, [ka] 225 in combination with a second compound (I-Ac), which is complexed with Ac.

[0048] 2. The first compound is a compound of formula Ia, [ka] The compound is 177 The compound according to item 1, complexed with Lu.

[0049] 3. The second compound is a compound of formula Ia, [ka] The compound is 225 3. The method according to claim 1 or 2, wherein said compound is complexed with Ac.

[0050] 4. The method according to any one of items 1 to 3, wherein the cancer is associated with expression of prostate-specific membrane antigen (PSMA).

[0051] 5. The method of any one of the preceding items, wherein the cancer is selected from the group consisting of prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), thyroid cancer, renal cell carcinoma, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and breast cancer.

[0052] 6. The method of any one of the preceding items, wherein the cancer is prostate cancer.

[0053] 7. The method of any one of the preceding items, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0054] 8. The method according to any one of the preceding items, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 20 GBq.

[0055] 9. The method according to any one of the preceding items, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 8 GBq.

[0056] 10. The method of any one of the preceding items, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 7.4 GBq.

[0057] 11. The method according to any one of the preceding items, wherein the therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 10 MBq, or from about 5 MBq to about 10 MBq, or from about 5 MBq to about 7 MBq.

[0058] 12. The method of any one of the preceding items, wherein the therapeutically effective amount of I-Ac or Ia-Ac is about 5 GBq.

[0059] 13. The method of any one of the preceding items, wherein the compound of formula I-Lu or Ia-Lu is administered simultaneously with the compound of formula I-Ac or Ia-Ac.

[0060] 14. The method according to any one of items 1 to 12, wherein the compound of formula I-Lu or Ia-Lu is administered about 1 hour before the compound of formula I-Ac or Ia-Ac, or about 12 hours before the compound of formula I-Ac or Ia-Ac, or about 24 hours before the compound of formula I-Ac or Ia-Ac, or about 48 hours before the compound of formula I-Ac or Ia-Ac, or about 72 hours before the compound of formula I-Ac or Ia-Ac.

[0061] 15. The method according to any one of items 1 to 12, wherein the compound of formula I-Ac or Ia-Ac is administered about 1 hour before the compound of formula I-Lu or Ia-Lu, or about 12 hours before the compound of formula I-Lu or Ia-Lu, or about 24 hours before the compound of formula I-Lu or Ia-Lu, or about 48 hours before the compound of formula I-Lu or Ia-Lu, or about 72 hours before the compound of formula I-Lu or Ia-Lu.

[0062] 16. The method of claim 13, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu once a week for about 1 to about 7 cycles following administration of I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0063] 17. The method of claim 14, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0064] 18. The method of claim 15, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0065] 19. A compound of formula I-Lu for use in the treatment of cancer in a patient, comprising: [ka] 177 a compound of formula I-Lu complexed with Lu, wherein the compound is a therapeutically effective amount of a compound of formula I-Ac, [ka] 225 A compound of formula I-Lu in combination with a compound of formula I-Ac, complexed with Ac.

[0066] 20. The compound is of formula Ia-Lu, [ka] The compound is 177 20. The compound according to item 19, complexed with Lu.

[0067] 21. Compound I-Ac is a compound of formula Ia-Ac, [ka] The compound is 225 20. The compound according to claim 19, complexed with Ac.

[0068] 22. The compound according to any one of items 19 to 21, wherein the cancer is associated with expression of prostate-specific membrane antigen (PSMA).

[0069] 23. The compound according to any one of items 19 to 22, wherein the cancer is selected from the group consisting of prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), thyroid cancer, renal cell carcinoma, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and breast cancer.

[0070] 24. The compound according to any one of items 19 to 23, wherein the cancer is prostate cancer.

[0071] 25. The compound according to any one of items 19 to 24, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0072] 26. The compound according to any one of items 19 to 25, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 20 GBq.

[0073] 27. The compound according to any one of items 19 to 26, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 8 GBq.

[0074] 28. The compound according to any one of items 19 to 27, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 7.4 GBq.

[0075] 29. The compound according to any one of items 19 to 28, wherein the therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 10 MBq, or from about 5 MBq to about 10 MBq, or from about 5 MBq to about 7 MBq.

[0076] 30. The compound according to any one of items 19 to 29, wherein the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq.

[0077] 31. The compound according to any one of items 19 to 30, wherein the compound of formula I-Lu or Ia-Lu is administered simultaneously with the compound of formula I-Ac or Ia-Ac.

[0078] 32. The compound according to any one of items 19 to 30, wherein the compound of formula I-Lu or Ia-Lu is administered about 1 hour before the compound of formula I-Ac or Ia-Ac, or about 12 hours before the compound of formula I-Ac or Ia-Ac, or about 24 hours before the compound of formula I-Ac or Ia-Ac, or about 48 hours before the compound of formula I-Ac or Ia-Ac, or about 72 hours before the compound of formula I-Ac or Ia-Ac.

[0079] 33. The compound according to any one of items 19 to 30, wherein the compound of formula I-Ac or Ia-Ac is administered about 1 hour before the compound of formula I-Lu or Ia-Lu, or about 12 hours before the compound of formula I-Lu or Ia-Lu, or about 24 hours before the compound of formula I-Lu or Ia-Lu, or about 48 hours before the compound of formula I-Lu or Ia-Lu, or about 72 hours before the compound of formula I-Lu or Ia-Lu.

[0080] 34. The compound according to item 31, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles following administration of I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0081] 35. The compound according to item 32, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle following administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac, for about 1 to about 7 cycles.

[0082] 36. The compound according to item 33, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle following administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac, for about 1 to about 7 cycles.

[0083] 37. Use of a compound of formula I-Lu, [ka] The compound is 177 a therapeutically effective amount of a compound of formula I-Ac complexed with Lu; [ka] 225 Use of a compound of formula I-Lu in the preparation of a medicament comprising a therapeutically effective amount of a compound of formula I-Lu in combination with a compound of formula I-Ac, complexed with Ac, for treating cancer in a patient.

[0084] 38. The compound of formula I-Lu is a compound of formula Ia-Lu, [ka] The compound is 177 38. The use according to item 37, wherein the compound is complexed with Lu.

[0085] 39. The compound of formula I-Ac is a compound of formula Ia-Ac, [ka] The compound is 225 38. The use according to item 37, wherein said compound is complexed with Ac.

[0086] 40. The use according to any one of items 37 to 39, wherein the cancer is associated with expression of prostate-specific membrane antigen (PSMA).

[0087] 41. The use according to any one of items 37 to 40, wherein the cancer is selected from the group consisting of prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), thyroid cancer, renal cell carcinoma, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and breast cancer.

[0088] 42. The use according to any one of items 37 to 41, wherein the cancer is prostate cancer.

[0089] 43. The use according to any one of items 37 to 42, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0090] 44. The use according to any one of items 37 to 43, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 20 GBq.

[0091] 45. The use according to any one of items 37 to 44, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 8 GBq.

[0092] 46. ​​The use according to any one of items 37 to 45, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 7.4 GBq.

[0093] 47. The use according to any one of items 37 to 46, wherein the therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 10 MBq, or from about 5 MBq to about 10 MBq, or from about 5 MBq to about 7 MBq.

[0094] 48. The use according to any one of items 37 to 47, wherein the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq.

[0095] 49. The use according to any one of items 37 to 48, wherein the compound of formula I-Lu or Ia-Lu is administered simultaneously with the compound of formula I-Ac or Ia-Ac.

[0096] 50. The use according to any one of items 37 to 49, wherein the compound of formula I-Lu or Ia-Lu is administered about 1 hour before the compound of formula I-Ac or Ia-Ac, or about 12 hours before the compound of formula I-Ac or Ia-Ac, or about 24 hours before the compound of formula I-Ac or Ia-Ac, or about 48 hours before the compound of formula I-Ac or Ia-Ac, or about 72 hours before the compound of formula I-Ac or Ia-Ac.

[0097] 51. The use according to any one of items 37 to 50, wherein the compound of formula I-Ac or Ia-Ac is administered about 1 hour before the compound of formula I-Lu or Ia-Lu, or about 12 hours before the compound of formula I-Lu or Ia-Lu, or about 24 hours before the compound of formula I-Lu or Ia-Lu, or about 48 hours before the compound of formula I-Lu or Ia-Lu, or about 72 hours before the compound of formula I-Lu or Ia-Lu.

[0098] 52. The use according to item 49, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles following administration of I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0099] 53. The use according to item 50, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0100] 54. The use according to item 51, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0101] 55. A composition comprising a therapeutically effective amount of a compound of formula I-Lu for use in treating cancer in a patient, [ka] The compound is 177 a therapeutically effective amount of a compound of formula I-Ac complexed with Lu; [ka] 225 A composition in combination with a compound of formula I-Ac, complexed with Ac.

[0102] 56. The compound of formula I-Lu is a compound of formula Ia-Lu, [ka] The compound is 177 56. The composition according to item 55, complexed with Lu.

[0103] 57. The compound of formula I-Ac is a compound of formula Ia-Ac, [ka] The compound is 225 56. The composition according to item 55, complexed with Ac.

[0104] 58. The composition according to any one of items 55 to 57, wherein the cancer is associated with expression of prostate-specific membrane antigen (PSMA).

[0105] 59. The composition according to any one of items 55 to 58, wherein the cancer is selected from the group consisting of prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), thyroid cancer, renal cell carcinoma, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and breast cancer.

[0106] 60. The composition according to any one of items 55 to 59, wherein the cancer is prostate cancer.

[0107] 61. The composition according to any one of items 55 to 60, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0108] 62. The composition according to any one of items 58 to 61, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 20 GBq.

[0109] 63. The composition according to any one of items 58 to 62, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 8 GBq.

[0110] 64. The composition according to any one of items 58 to 63, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 7.4 GBq.

[0111] 65. The composition according to any one of items 58 to 64, wherein the therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 10 MBq, or from about 5 MBq to about 10 MBq, or from about 5 MBq to about 7 MBq.

[0112] 66. The composition according to any one of items 58 to 65, wherein the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq.

[0113] 67. The composition according to any one of items 58 to 66, wherein the compound of formula I-Lu or Ia-Lu is administered simultaneously with the compound of formula I-Ac or Ia-Ac.

[0114] 68. The composition according to any one of items 58 to 67, wherein the compound of formula I-Lu or Ia-Lu is administered about 1 hour before the compound of formula I-Ac or Ia-Ac, or about 12 hours before the compound of formula I-Ac or Ia-Ac, or about 24 hours before the compound of formula I-Ac or Ia-Ac, or about 48 hours before the compound of formula I-Ac or Ia-Ac, or about 72 hours before the compound of formula I-Ac or Ia-Ac.

[0115] 69. The composition according to any one of items 58 to 68, wherein the compound of formula I-Ac or Ia-Ac is administered about 1 hour before the compound of formula I-Lu or Ia-Lu, or about 12 hours before the compound of formula I-Lu or Ia-Lu, or about 24 hours before the compound of formula I-Lu or Ia-Lu, or about 48 hours before the compound of formula I-Lu or Ia-Lu, or about 72 hours before the compound of formula I-Lu or Ia-Lu.

[0116] 70. The composition according to item 67, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles following administration of I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0117] 71. The composition according to item 68, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0118] 72. The composition according to item 69, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0119] 73. A medicament comprising a therapeutically effective amount of a compound of formula I-Lu, [ka] The compound is 177 a therapeutically effective amount of a compound of formula I-Ac complexed with Lu; [ka] 225 A medicament comprising in combination a compound of formula I-Ac, complexed with Ac.

[0120] 74. The compound of formula I-Lu is a compound of formula Ia-Lu, [ka] The compound is 177 74. The medicament according to item 73, which is complexed with Lu.

[0121] 75. The compound of formula I-Ac is a compound of formula Ia-Ac, [ka] The compound is 225 74. The medicament according to item 73, which is complexed with Ac.

[0122] 76. The medicament according to any one of items 73 to 75, wherein the medicament provides a synergistic effect against cancer associated with expression of prostate-specific membrane antigen (PSMA).

[0123] 77. The medicament according to any one of items 73 to 76, wherein the cancer is selected from the group consisting of prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), thyroid cancer, renal cell carcinoma, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and breast cancer.

[0124] 78. The medicament according to any one of items 73 to 77, wherein the cancer is prostate cancer.

[0125] 79. The medicament according to any one of items 73 to 78, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0126] 80. The medicament according to any one of items 73 to 79, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 20 GBq.

[0127] 81. The medicament according to any one of items 73 to 80, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 8 GBq.

[0128] 82. The medicament according to any one of items 73 to 81, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 7.4 GBq.

[0129] 83. The medicament according to any one of items 73 to 82, wherein the therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 10 MBq, or from about 5 MBq to about 10 MBq, or from about 5 MBq to about 7 MBq.

[0130] 84. The medicament according to any one of items 73 to 83, wherein the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq.

[0131] 85. The medicament according to any one of items 73 to 84, wherein the compound of formula I-Lu or Ia-Lu is administered simultaneously with the compound of formula I-Ac or Ia-Ac.

[0132] 86. The medicament according to any one of items 73 to 85, wherein the compound of formula I-Lu or Ia-Lu is administered about 1 hour before the compound of formula I-Ac or Ia-Ac, or about 12 hours before the compound of formula I-Ac or Ia-Ac, or about 24 hours before the compound of formula I-Ac or Ia-Ac, or about 48 hours before the compound of formula I-Ac or Ia-Ac, or about 72 hours before the compound of formula I-Ac or Ia-Ac.

[0133] 87. The medicament according to any one of items 73 to 86, wherein the compound of formula I-Ac or Ia-Ac is administered about 1 hour before the compound of formula I-Lu or Ia-Lu, or about 12 hours before the compound of formula I-Lu or Ia-Lu, or about 24 hours before the compound of formula I-Lu or Ia-Lu, or about 48 hours before the compound of formula I-Lu or Ia-Lu, or about 72 hours before the compound of formula I-Lu or Ia-Lu.

[0134] 88. The pharmaceutical composition according to item 87, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0135] 89. The pharmaceutical agent according to item 88, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0136] 90. The pharmaceutical agent according to item 89, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0137] 91. A synergistic composition for use in treating cancer in a patient, comprising a therapeutically effective amount of a compound of formula I-Lu, [ka] The compound is 177 a therapeutically effective amount of a compound of formula I-Ac complexed with Lu; [ka] 225 A synergistic composition in combination with a compound of formula I-Ac, which is complexed with Ac.

[0138] 92. The compound of formula I-Lu is a compound of formula Ia-Lu, [ka] The compound is 177 92. The synergistic composition according to item 91, complexed with Lu.

[0139] 93. The compound of formula I-Ac is a compound of formula Ia-Ac, [ka] The compound is 225 92. The synergistic composition according to item 91, complexed with Ac.

[0140] 94. The synergistic composition according to any one of items 91 to 93, wherein the cancer is associated with expression of prostate-specific membrane antigen (PSMA).

[0141] 95. The synergistic composition according to any one of items 91 to 94, wherein the cancer is selected from the group consisting of prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), thyroid cancer, renal cell carcinoma, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and breast cancer.

[0142] 96. The synergistic composition according to any one of items 91 to 95, wherein the cancer is prostate cancer.

[0143] 97. The synergistic composition according to any one of items 91 to 96, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0144] 98. The synergistic composition according to any one of items 91 to 97, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 20 GBq.

[0145] 99. The synergistic composition according to any one of items 91 to 98, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 8 GBq.

[0146] 100. The synergistic composition according to any one of items 91 to 99, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 7.4 GBq.

[0147] 101. The synergistic composition according to any one of items 91 to 100, wherein the therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 10 MBq, or from about 5 MBq to about 10 MBq, or from about 5 MBq to about 7 MBq.

[0148] 102. The synergistic composition according to any one of items 91 to 101, wherein the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq.

[0149] 103. The synergistic composition according to any one of items 91 to 102, wherein the compound of formula I-Lu or Ia-Lu is administered simultaneously with the compound of formula I-Ac or Ia-Ac.

[0150] 104. The synergistic composition according to any one of items 91 to 103, wherein the compound of formula I-Lu or Ia-Lu is administered about 1 hour before the compound of formula I-Ac or Ia-Ac, or about 12 hours before the compound of formula I-Ac or Ia-Ac, or about 24 hours before the compound of formula I-Ac or Ia-Ac, or about 48 hours before the compound of formula I-Ac or Ia-Ac, or about 72 hours before the compound of formula I-Ac or Ia-Ac.

[0151] 105. The synergistic composition according to any one of items 91 to 104, wherein the compound of formula I-Ac or Ia-Ac is administered about 1 hour before the compound of formula I-Lu or Ia-Lu, or about 12 hours before the compound of formula I-Lu or Ia-Lu, or about 24 hours before the compound of formula I-Lu or Ia-Lu, or about 48 hours before the compound of formula I-Lu or Ia-Lu, or about 72 hours before the compound of formula I-Lu or Ia-Lu.

[0152] 106. The synergistic composition according to item 103, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0153] 107. The synergistic composition according to item 104, further comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle for about 1 to about 7 cycles after administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0154] 108. The synergistic composition according to item 105, comprising administering a therapeutically effective amount of a compound of formula I-Lu or Ia-Lu in a weekly cycle following administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac, for about 1 to about 7 further cycles.

[0155] definition As used herein, "functionally active PSMA" refers to a cell surface membrane-associated glycoprotein that binds to a PSMA ligand. It will be understood that PSMA ligands are well known to those of skill in the art, such as those described in U.S. Patent Publication No. US2010 / 0324008A1, which is incorporated herein by reference.

[0156] As used herein, "clinical benefit" means a patient's response to treatment with a combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac, including patient overall survival, ability to undergo four or more cycles of therapy (e.g., four weeks of therapy) with compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac, inhibition of tumor growth, stable disease, complete response, and / or complete response, among other clinical benefits as defined by the U.S. Food and Drug Administration.

[0157] As used herein, "inhibition of tumor growth" means a reduction in tumor size, complete disappearance of the tumor, or growth of a patient's tumor by less than 30% over the course of therapy with a combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0158] As used herein, "stable disease" means that there is no material progression of disease in a patient over the course of therapy with a combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0159] As used herein, "partial response" means a reduction in tumor size of 30% or more in patients treated with the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0160] As used herein, "complete response" means disappearance of detectable disease in a patient treated with a combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac.

[0161] As used herein, "pre-treatment" means that the patient has been treated with at least one pre-treatment known in the art. It is understood that pre-treatment can be any treatment known to those skilled in the art, including but not limited to chemotherapy, surgery, radiation therapy, immunotherapy, photodynamic therapy, stem cell therapy, hyperthermia, etc. Pre-treatment can include systemic treatment, including but not limited to abiraterone, orteronel, galeterone, ceviteronel, apalutamide, enzalutamide, palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinibe, and combinations thereof.

[0162] As used herein, the term "alkyl" includes a chain of carbon atoms, which is optionally branched. In certain embodiments, alkyl is advantageously a C1-C 24 , C1~C 12It will be further understood that the alkyl groups are of limited length, including C1-C8, C1-C6, and C1-C4. Illustratively, such specifically limited length alkyl groups, including C1-C8, C1-C6, and C1-C4, may be referred to as lower alkyl. It is understood herein that shorter alkyl, alkenyl, and / or alkynyl groups may impart less lipophilicity to the compound and thus have different pharmacokinetic behavior. In embodiments of the invention, it should be understood that in each instance, reference to alkyl refers to alkyl as defined herein, and optionally lower alkyl. 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, octyl, and the like. As used herein, a "carboxyalkyl" group includes a combination of an "alkyl" group and a "carboxy" group as described herein. As used herein, a "hydroxyalkyl" group includes a combination of an "alkyl" group and a "hydroxy" group as described herein. As used herein, an "aminoalkyl" group includes a combination of an "alkyl" group and an "amino" group as described herein.

[0163] As used herein, the term "heteroalkyl" includes a chain of atoms that includes both carbon and at least one heteroatom, and is optionally branched. Exemplary heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, exemplary heteroatoms also include phosphorus and selenium.

[0164] As used herein, 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, naphthyl, and the like. As used herein, 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, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, and the like. As used herein, the term "heteroarylalkyl" includes a combination of an "alkyl" group as described herein and a "heteroaryl" group as described herein. As used herein, the term "arylalkyl" includes a combination of an "alkyl" group as described herein and an "aryl" group as described herein, such as a benzyl group.

[0165] The term "optionally substituted" as used herein includes the replacement of hydrogen atoms with other functional groups on the optionally substituted radical. Such other functional groups include, by way of example, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acid and its derivatives, carboxylic acid and its derivatives, and the like. By way of example, any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and / or sulfonic acid are optionally substituted.

[0166] As used herein, the term "administration" as used herein includes all means of introducing the compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac combinations and / or PSMA ligand imaging conjugates described herein into a patient, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, etc. The compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac combinations and / or PSMA ligand imaging conjugates described herein may be administered in unit dosage forms and / or formulations containing conventional non-toxic pharma- ceutically acceptable carriers, adjuvants, and vehicles.

[0167] As used herein, "becquerel" refers to the SI derived unit of radioactivity as commonly understood by those skilled in the art. One becquerel is defined as the activity of a quantity of radioactive material that results in one nucleus decaying per second. Thus, the becquerel is equivalent to the inverse second, s-1. The becquerel is known to those skilled in the art as the successor to the curie (Ci), an older non-SI unit of radioactivity based on the activity of one gram of radium-226. A curie is defined as 3.7.1010s-1 or 37 GBq.

[0168] As used herein, "curie" or "Ci" refers to a unit of radioactivity named after the French physicist and chemist Marie Curie, as commonly understood by those of skill in the art. The prefixes milli and micro are from the metric system and represent 0.001 and 0.000001, respectively. Thus, a millicurie (mCi) is 0.001 curie. A microcurie (μCi) is 0.000001 curie. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0169] Any of the numbered item embodiments provided in the Summary above, or any combination thereof, are contemplated in combination with any of the embodiments described in the Detailed Description section of this patent application.

[0170] Referring to FIG. 1, the method design can be described according to the schematic diagram shown. In some embodiments, the stratification factors of the design include serum lactate dehydrogenase (LDH) (< / =260IU / Lv.> 260 IU / L), presence of liver metastases, ECOG score (0-1v.2), inclusion of NAAD in best support / best standard of care, etc. In some embodiments, the primary endpoint may be overall survival. In some embodiments, secondary endpoints include, but are not limited to, imaging progression-free survival (rPFS), RECIST response, time to first symptomatic skeletal-related event (SSE), etc. In some embodiments, additional secondary endpoints include, but are not limited to, safety and tolerability, health-related quality of life (HRQoL; EQ-5D-5L, FACT-P and pain progression (Brief Pain Inventory-Short FORM) [BPI-SF]), health economics, progression-free survival (PFS) (radiological, clinical, or PSA progression), biochemical response such as PSA level, alkaline phosphatase level, and / or lactate dehydrogenase level. In some embodiments, the endpoint of the treatment methods described herein may be patients achieving a > / =50% reduction from baseline, as confirmed by a second PSA measurement > / =4 weeks. In some embodiments, the endpoint of the treatment methods described herein may be patients achieving a > / =40% reduction from baseline, as confirmed by a second PSA measurement > / =4 weeks. In some embodiments, the endpoint of the treatment methods described herein may be patients achieving a > / =30% reduction from baseline, as confirmed by a second PSA measurement > / =4 weeks.

[0171] In one embodiment, the methods described herein can be used for both human clinical medicine and veterinary applications.Thus, a "patient" can be administered the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac and / or PSMA ligand imaging conjugate described herein, and can be a human, or in the case of veterinary applications, can be a laboratory animal, agricultural animal, livestock, or wild animal.In one aspect, a patient can be a human, a laboratory animal such as rodents (e.g., mice, rats, hamsters, etc.), rabbits, monkeys, chimpanzees, livestock such as dogs, cats, and rabbits, agricultural animals such as cows, horses, pigs, sheep, goats, and wild animals kept in zoos, such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.

[0172] In some embodiments, patients with PSMA positive scans can be randomized in a 2:1 ratio to receive either a combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac plus best supportive care / best standard therapy, or best supportive care / best standard therapy alone. In some embodiments, best supportive care / best standard therapy can be determined by the treating physician / investigator. In some embodiments, best supportive care / best standard therapy can be determined by the treating physician / investigator, but excludes investigational drugs, cytotoxic chemotherapy, other systemic radioisotopes, and half-body radiation therapy. In some embodiments, novel androgen pathway drugs [NAADs] such as abiraterone or enzalutamide are permitted.

[0173] In some embodiments, patients are monitored for survival, disease progression, and adverse events throughout the 6-10 month treatment period. In some embodiments, the long-term follow-up period may include collection of survival and treatment updates, assessment of adverse events, and blood for hematology and chemistry testing.

[0174] 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 previously been diagnosed with prostate cancer. In some embodiments, the patient has previously been 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 life expectancy of at least 6 months; histological, pathological, and / or cytological confirmation of prostate cancer; 68Patients were excluded if: a. the patient was unwilling to undergo a second taxane regimen or b. the patient's physician determined that the patient was older or had a poorer overall health evaluation; c. the patient had a positive Ga-PSMA-11 PET / CT scan; d. previous orchiectomy and / or ongoing androgen deprivation therapy and castrate levels of serum testosterone (<50 ng / dL or <1.7 nmol / L); d. had previously received at least one NAAD, such as enzalutamide and / or abiraterone; e.g. had previously been treated with at least one or two prior taxane regimens, where the taxane regimen included a minimum exposure of two cycles of taxane, or had only received one prior taxane regimen; and ) or frailty as assessed by intolerance; the patient is deemed unsuitable to receive a second taxane regimen due to at least one criterion, e.g., a. serum PSA progression, defined as two consecutive increases in PSA above the previous reference value measured at least one week prior, with a minimum starting value of 2.0 ng / mL; b. soft tissue progression, defined as a ≥ 20% increase in the sum of the diameters (SOD) of all target lesions (short axis for nodal lesions and long axis for nonnodal lesions) based on the minimum SOD after initiation of treatment or the appearance of one or more new lesions; and c. bone disease progression, e.g., evaluable disease by bone scan or new bone lesion(s) (2+2 Progressive mCRPC, such as documented progressive mCRPC based on PCWG3 criteria; at least one metastatic lesion present on a baseline CT, MRI, or bone scan obtained within 28 days prior to initiation of therapy with the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac; recovery from all clinically significant toxicities associated with prior therapy, such as prior chemotherapy, radiation therapy, or immunotherapy, to grade 2 or less; adequate organ function, e.g., a. white blood cell (WBC) count ≥ 2.5 x 109 / L (2.5 x 10^9 / L is 2.5 x 10 3 / µL, and 2.5 × K / µL, and 2.5 × 10 3 / cumm and equivalent to 2500 / μL) or absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L(1.5×10 9 / L is 1.5 x 10 3 / μL, and 1.5 × K / μL, and 1.5 × 10 3 / cumm, and 1500 / μL), 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 bone marrow reserve with hemoglobin ≥ 9g / dL (9g / dL is equivalent to 90g / L and 5.59mmol / L), b. liver, e.g., total bilirubin ≤ 1.5× upper limit of normal (ULN) (patients known to have Gilbert's syndrome are allowed ≤ 3×ULN), ala and c. renal, e.g., serum creatinine ≦1.5×ULN, or creatinine clearance ≧50 mL / min; albumin >3.0 g / dL (3.0 g / dL corresponds to 30 g / L); and receiving a stable bisphosphonate or denosumab regimen ≧30 days prior to treatment.

[0175] In some embodiments, the patient is selected from the group consisting of: prior treatment with strontium-89, samarium-153, rhenium-186, rhenium-188, radium-223, or half-body irradiation within about 6 months prior to treatment; prior PSMA-targeted radioligand therapy; prior systemic anti-cancer therapy (e.g., chemotherapy, immunotherapy, or biologic therapy [including monoclonal antibodies]) within about 28 days prior to treatment; prior administration of an investigational agent within about 28 days prior to treatment; known hypersensitivity to any component of the therapy or its analogues; any other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy; blood transfusion within about 30 days of treatment; history of CNS metastases that have undergone therapy (surgery, radiation therapy, gamma knife) and are neurologically stable, asymptomatic, and not receiving corticosteroids to maintain neurological integrity; advanced diffuse bone metastases (superficial bone metastases) seen on baseline bone scan. scan); symptomatic spinal cord compression, or clinical or radiological evidence indicating impending spinal cord compression; concurrent serious (in physician's judgment) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital long QT syndrome, uncontrolled infection, active hepatitis B or C, or other significant comorbid medical condition that in the investigator's opinion would impair treatment or cooperation, or if diagnosed with other malignancies that may be expected to alter life expectancy or interfere with disease evaluation.

[0176] In various embodiments, the cancers described herein may be a cancer cell population that is tumorigenic, including benign and malignant tumors, or the cancer may be non-tumorigenic.Cancers may occur spontaneously or by processes such as mutations or somatic mutations present in the germline of a patient, or may be chemically, virally, or radiation-induced.Cancers applicable to the present disclosure described herein include, but are not limited to, gliomas, carcinomas, sarcomas, lymphomas, melanomas, mesotheliomas, nasopharyngeal carcinomas, leukemias, adenocarcinomas, and myelomas.

[0177] In some embodiments, the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, gastric cancer, colon cancer, breast cancer, triple negative breast cancer, metastatic breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, The cancer may be non-small cell lung cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, glioma, brain stem glioma, pituitary adenoma, and adenocarcinoma of the gastroesophageal junction. Compound Ia has the formula: [ka] 177 Lu forms a complex with the compound in Ia-Lu, 225 Ac is complexed with the compound in Ia-Ac.

[0178] In other embodiments, any of a variety of PSMA ligand imaging conjugates detectable by PET imaging, SPECT imaging, and the like can be used. The exact mode of imaging is not limited to the imaging agents described herein. Collectively, the PSMA ligand imaging conjugates useful for imaging described herein, including those described by the formulas, and agents useful for PET imaging, SPECT imaging, and the like, are referred to as "PSMA ligand imaging conjugates."

[0179] In one embodiment, the compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac and / or the PSMA ligand imaging conjugate described herein bind to PSMA expressed on cancer cells. In one exemplary aspect, the compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac and / or the 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.

[0180] In some embodiments, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac as well as the PSMA ligand imaging conjugates described herein may be administered as a formulation associated with one or more pharma- ceutically acceptable carriers. In some aspects of these embodiments, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is co-formulated. In some aspects of these embodiments, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is administered as a separately formulated drug. The carrier may be an excipient. The choice of carrier will depend largely on factors such as the particular mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of the combination of compounds Ia-Lu and I-Ac or Ia-Ac as well as the PSMA ligand imaging conjugates described herein and methods for their preparation 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), incorporated herein by reference.

[0181] In one exemplary embodiment, pharmaceutically acceptable carriers include any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., and combinations thereof.In some embodiments, carriers are suitable for parenteral administration.Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.Additional active compounds can also be incorporated into the compositions of the present disclosure.

[0182] In various embodiments, liquid formulations can include suspensions and solutions.Such formulations can include carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents.Liquid formulations can also be prepared by reconstitution of solids.

[0183] In one embodiment, aqueous suspensions may contain the active substance mixed with suitable excipients. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing agents or wetting agents, which may be naturally occurring phosphatides, such as lecithin; condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxide and long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol; condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ascorbic acid, ethyl, n-propyl, or p-hydroxybenzoate, or one or more coloring agents.

[0184] In one exemplary embodiment, dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Additional excipients, such as coloring agents, may also be present.

[0185] Suitable emulsifying agents may be naturally occurring gums, such as gum acacia or gum tragacanth; naturally occurring phosphatides, such as soya lecithin; and esters including partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0186] In other embodiments, isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride can be included in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.

[0187] Exemplary forms for oral administration include tablets, capsules, elixirs, syrups, and the like.

[0188] A wide range of acceptable dosages is contemplated herein, including doses of I-Ac or Ia-Ac that fall within the range of about 1 Mbq to about 4 MBq, depending on the type of cancer, route of administration, and / or combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac and / or PSMA ligand imaging conjugates as described herein, and whether they are administered locally or systemically. In some embodiments, acceptable dosages for I-Lu or Ia-Lu are contemplated herein in GBq units, including doses that fall within the range of about 2 GBq to about 13 GBq. Doses can be single or divided and can be administered according to a wide variety of protocols, including qd, bid, tid, or even every other day, every other week (biw), weekly, monthly, quarterly, etc. In each of these cases, it is understood that the therapeutically effective amounts described herein correspond to examples of administration or correspond to total doses daily, weekly, monthly, or quarterly, as determined by the administration protocol. In some embodiments, the combination of compounds of formula I-Lu or Ia-Lu and I-Ac or Ia-Ac can be administered on independent schedules, such as once, 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.

[0189] In one embodiment, the combination of compound I-Lu or Ia-Lu and I-Ac or Ia-Ac or PSMA ligand imaging conjugate described herein may be directly administered into bloodstream, muscle, or internal organs.Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intraventricular, intraurethral, ​​intrasternal, intracranial, intratumoral, intramuscular and subcutaneous delivery.Suitable means for parenteral administration include needle (including microneedle) injector, needleless injector, and injection technology.

[0190] In one exemplary aspect, parenteral formulations are typically aqueous solutions that may include carriers or excipients such as salts, carbohydrates, and buffers (preferably at a pH of 3-9), although for some applications, they may be more suitably formulated as sterile non-aqueous solutions or as dry forms for use in combination with a suitable vehicle, such as sterile pyrogen-free water. In other embodiments, any of the liquid formulations described herein may be adapted for parenteral administration of I-Lu or Ia-Lu and I-Ac or Ia-Ac or PSMA ligand imaging conjugates described herein. Preparation of parenteral formulations under sterile conditions, for example, by lyophilization under sterile conditions, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. In one embodiment, the solubility of the compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac combinations or PSMA ligand imaging conjugates used in the preparation of parenteral formulations can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancers.

[0191] In various embodiments, the formulation for parenteral administration may be formulated for immediate release and / or modified release. In one exemplary aspect, the combination of active agents of the present disclosure (i.e., compound I-Lu or Ia-Lu and I-Ac or Ia-Ac or PSMA ligand imaging conjugate) may be administered in a sustained release formulation, for example, a composition that includes a delayed release polymer. The active compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac or PSMA ligand imaging conjugate can be prepared with a carrier that protects the compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac or PSMA ligand imaging conjugate from rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic acid, polyglycolic copolymer (PGLA) can be used. Methods for preparing such formulations are generally known to those skilled in the art. In another embodiment, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac or a PSMA ligand imaging conjugate described herein, or a composition comprising compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac or a PSMA ligand imaging conjugate, may be administered sequentially, as needed.

[0192] In one embodiment, a kit is provided. When administering the combination of active compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac and the PSMA ligand imaging conjugate, two or more pharmaceutical compositions may be combined in the form of a kit suitable for sequential or simultaneous administration of the compositions. Such a kit comprises two or more separate pharmaceutical compositions, at least one of which comprises the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac or the PSMA ligand imaging conjugate described herein, and a means for separately holding the compositions, such as a container, a divided bottle, or a divided foil packet. In another embodiment, one or more of the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac or the PSMA ligand imaging conjugate described herein are provided in a container with a label that provides instructions for the use of the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac or the PSMA ligand imaging conjugate for patient selection and / or treatment.

[0193] In one embodiment, sterile injectable solution can be prepared by incorporating the required amount of active agent into a suitable solvent containing one or combination of above-mentioned components as necessary, followed by sterilization by filtration.Typically, dispersion is prepared by incorporating the active combination of compound I-Lu or Ia-Lu and I-Ac or Ia-Ac or PSMA ligand imaging conjugate into a sterile vehicle containing dispersion medium and any additional components from above.For the case of sterile powder for preparing sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying, which allows the powder of active ingredient plus any additional desired ingredient to be obtained from the solution previously sterile-filtered, or the ingredients may be sterile-filtered together.

[0194] The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high drug concentration.The carrier can be, for example, a solvent or dispersion medium, including water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof.In one embodiment, the proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants.

[0195] Any effective regimen for administering the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac can be used. For example, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac can be administered as a single dose, or the dose can be divided and administered as a regimen of multiple daily doses. In addition, a staggered regimen, for example, from 1 to 5 days per week, can be used as an alternative to daily treatment, and for purposes of the methods described herein, such intermittent or staggered daily regimens are contemplated as being equivalent to daily treatment. In an exemplary embodiment, a patient is treated with multiple injections of the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac to treat cancer. In one embodiment, a patient is injected multiple times (preferably from about 2 to up to about 50 times) of the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac, for example, at intervals of 12 to 72 hours or 48 to 72 hours. Additional injections of the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac can be administered to the patient at intervals of days or months after the initial injection(s), and the additional injections can prevent recurrence of cancer. In another exemplary embodiment, the patient is treated with a single injection of compounds I-Lu or Ia-Lu and compounds I-Ac or Ia-Ac in any injection order on the same day, followed by multiple injections of I-Lu or Ia-Lu to treat cancer. In some embodiments, the patient is injected with compounds I-Lu or Ia-Lu multiple times (preferably about 2 to up to about 50 times) at intervals of 12 to 72 hours, 48 ​​to 72 hours, or once a week, or once every two weeks, after receiving the first injection of each of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac on the same day, in any order or simultaneously.

[0196] Any suitable course of therapy with the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac can be used. In an exemplary embodiment, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is administered in a single daily dose 5 days per week, on the first, second and third week of each four-week cycle, and not on the fourth week. In an alternative embodiment, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is administered in a single daily dose 3 days per week, on the first and third week of each four-week cycle, and not on the second and fourth week. In an alternative embodiment, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is administered twice per week, on the first and second week, i.e., on the first, fourth, eighth and eleventh day of each three-week cycle. In an alternative embodiment, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is administered once per week on weeks 1 and 2, i.e., days 1 and 8 of a three week cycle. In an alternative embodiment, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is administered on a single day, in any order, or simultaneously, followed by administration of compounds I-Lu or Ia-Lu in a weekly cycle for about two to about six cycles. In an alternative embodiment, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac are administered on a single day in any order or simultaneously, followed by administration of compound I-Lu or Ia-Lu in a weekly cycle for about 2 to about 6 cycles, followed by administration of compound I-Lu or Ia-Lu and I-Ac or Ia-Ac in a single day in any order or simultaneously, followed by administration of compound I-Lu or Ia-Lu in a weekly cycle for about 2 to about 6 cycles.

[0197] In an alternative embodiment, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac are administered within about 2-72 hours of each other in any order, followed by administration of compound I-Lu or Ia-Lu in a weekly cycle for about 2 to about 6 cycles. In an alternative embodiment, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac are administered within about 2-72 hours of each other in any order, followed by administration of compound I-Lu or Ia-Lu in a weekly cycle for about 2 to about 6 cycles, followed by administration of compound I-Lu or Ia-Lu and I-Ac or Ia-Ac on a single day in any order or simultaneously, followed by administration of compound I-Lu or Ia-Lu in a weekly cycle for about 2 to about 6 cycles.

[0198] Dose levels of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac can be measured in GBq and MBq, respectively. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 2 GBq to about 20 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 2 GBq to about 13 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 4 GBq to about 11 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 5 GBq to about 10 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 6 GBq to about 9 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 6 GBq to about 8 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 6.5 GBq to about 8.5 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 7 GBq to about 8 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 7.4 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is in the range of about 15 GBq to about 200 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is in the range of about 25 GBq to about 185 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is in the range of about 35 GBq to about 150 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is in the range of about 40 GBq to about 100 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is about 44 GBq. In some embodiments, the maximum duration of treatment for a subject is about 19 to 23 months.

[0199] In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is between 2 GBq and 20 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is between 2 GBq and 13 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is between 4 GBq and 11 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is between 5 GBq and 10 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is between 6 GBq and 9 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is between 6 GBq and 8 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is between 6.5 GBq and 8.5 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is between 7 GBq and 8 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is 7.4 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 15 GBq to 200 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 25 GBq to 185 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 35 GBq to 150 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 40 GBq to 100 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is 44 GBq. In some embodiments, the maximum duration of treatment for a subject is about 19 to 23 months.

[0200] In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 20 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 10 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 4 MBq to about 14 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq to about 10 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 6 MBq to about 8 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq to about 7 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 4 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 2 MBq to about 3 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 2.5 MBq.

[0201] In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 1 MBq to 20 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 1 MBq to 10 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 4 MBq to 14 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 5 MBq to 10 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 6 MBq to 8 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 5 MBq to 7 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 1 MBq to 4 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 2 MBq to 3 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 5 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 2.5 MBq.

[0202] The PSMA ligand imaging conjugates and compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac described herein may contain one or more chiral centers or may otherwise exist as multiple stereoisomers.Therefore, it should be understood that the present disclosure includes pure stereoisomers, as well as mixtures of stereoisomers, such as enantiomers, diastereomers, and mixtures enriched in enantiomers or diastereomers.The PSMA ligand imaging conjugates and compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac described herein may exist as geometric isomers.Therefore, it should be understood that the present disclosure includes pure geometric isomers or mixtures of geometric isomers.

[0203] It is understood that the PSMA ligand imaging conjugates and compounds I-Lu, I-Ac and Ia-Lu, Ia-Ac described herein may exist in unsolvated forms, as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure. The PSMA ligand imaging conjugates and compounds I-Lu, I-Ac and Ia-Lu, Ia-Ac described herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent to the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0204] In another embodiment, the composition and / or dosage form for administration of the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is prepared from compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac with a 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%. In another embodiment, the composition and / or dosage form for administration of the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is prepared from compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac with a purity of at least 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%.

[0205] In another embodiment, compositions and / or dosage forms for administration of the PSMA ligand imaging conjugate are prepared from the PSMA ligand imaging conjugate with a 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%. In another embodiment, compositions and / or dosage forms for administration of the PSMA ligand imaging conjugate are prepared from the PSMA ligand imaging conjugate with a purity of at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.

[0206] In another embodiment, compositions and / or dosage forms for administering a radiolabeled PSMA ligand imaging conjugate are prepared from the 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%. In another embodiment, compositions and / or dosage forms for administering a PSMA ligand imaging conjugate are prepared from the PSMA ligand imaging conjugate with a purity of at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least about 98%, or at least 99%, or at least 99.5%.

[0207] The purity of compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac or the PSMA ligand imaging conjugates 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, fluorescence spectroscopy, and the like.

[0208] In another embodiment, the compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac or PSMA ligand imaging conjugates described herein are provided in a sterile container or package.

[0209] In one embodiment, the clinical benefit of the patient to the combination of compound I-Lu or Ia-Lu and I-Ac or Ia-Ac treatment can be characterized as overall survival (OS).As used herein, the term "overall survival (OS)" refers to the time from the date of randomization to the date of death from any cause.

[0210] In one embodiment, the clinical benefit of patients to treatment with the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac can be characterized using the Response Evaluation Criteria in Solid Tumors (RECIST). Illustratively, the criteria are adapted from the original WHO handbook (3), taking into account the measurement of the longest diameter of all target lesions: complete response (CR) - disappearance of all target lesions; partial response (PR) - reduction of the sum of the longest diameters of target lesions by at least 30% based on baseline sum longest diameter; stable disease (SD) - not enough shrinkage to qualify for partial response and not enough increase to qualify for progressive disease based on the smallest sum longest diameter since the start of treatment; progressive disease (PD) - increase of the sum of the longest diameters of target lesions by at least 20% based on the smallest sum longest diameter recorded since the start of treatment or the appearance of one or more new lesions. In another aspect, the overall disease 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 achieve the best response of CR, PR, or SD. In some embodiments, the response can be the disease control rate (DCR) as measured by RECIST v1.1 criteria.

[0211] In another embodiment, the clinical benefit of patients to the combination of compound I-Lu or Ia-Lu and I-Ac or Ia-Ac treatment can be characterized as radiological progression-free survival (rPFS).As used herein, "radiographic progression-free survival (rPFS)" refers to the time from randomization to radiological disease progression or 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 of patients to treatment with I-Lu or Ia-Lu and I-Ac or Ia-Ac can be characterized as the time to first symptomatic skeletal-related event (SSE). It is understood that a symptomatic skeletal-related event means a clinically significant pathological fracture, bone surgery or radiation to bone, or spinal cord compression. As used herein, "time to first symptomatic skeletal-related event" refers to the date of randomization to the first new symptomatic pathological fracture, spinal cord compression, tumor-related orthopedic intervention, or the need for radiation therapy to relieve bone pain, whichever occurs first.

[0212] In one illustrative example, overall survival is the time to death for a given patient, defined as the number of days from the first day the patient receives protocol treatment (C1D1) to the date of the patient's death. All death events can be included, regardless of whether the event occurs while the patient is still taking the study drug or after the patient has stopped the study drug. If the patient has not died, the data can be censored at the date of the last visit, the date of the last contact, or the date the patient was last found alive, whichever is later.

[0213] Alternatively, the clinical benefit of the patient as a result of the treatment with the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac can be characterized as the inhibition of tumor growth, which can be identified in the patient, for example, by imaging the progress of the cancer of the patient after treatment with I-Lu or Ia-Lu and I-Ac or Ia-Ac.For example, the inhibition of tumor growth can be characterized by measuring the size of the tumor in the patient after administration of I-Lu or Ia-Lu and I-Ac or Ia-Ac according to any of the imaging techniques described herein, and the inhibition of tumor growth is indicated by a stable tumor size or a reduction in tumor size.It will be understood that the identification of the inhibition of tumor growth can be achieved using various techniques, which are, but are not limited to, the imaging methods described herein (e.g., CT, MRI, PET imaging, SPECT imaging or chest X-ray).

[0214] In one embodiment, a method is provided for determining whether a combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is indicated for the treatment of a patient with cancer, the method comprising determining a PSMA status in a patient with cancer, and if the patient's PSMA status is positive, then a combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is indicated for the treatment of the patient.

[0215] In one embodiment, a method is provided for evaluating whether the combination of compound I-Lu or Ia-Lu and I-Ac or Ia-Ac is indicated for the treatment of a patient with one of the cancers described herein.The method comprises visually determining the PSMA status of the patient, the PSMA status being based on imaging the tumor that is PSMA positive in the patient, and if the PSMA status of the patient is positive, the combination of compound I-Lu or Ia-Lu and I-Ac or Ia-Ac is indicated for the treatment of the patient.

[0216] In the above embodiment, when the patient belongs to the group with positive PSMA status, the clinical benefit of treatment with the combination of compound I-Lu or Ia-Lu and I-Ac or Ia-Ac is shown.In one embodiment, the clinical benefit to the patient can be the overall survival of the patient, the ability to receive 4 or more cycles of therapy with the combination of compound I-Lu or Ia-Lu and I-Ac or Ia-Ac, inhibition of tumor growth, stable disease, partial response of the patient to therapy, complete response of the patient to therapy, disease control (i.e., the best result obtained is a complete response, partial response, or stable disease), and / or total response of disease (i.e., the best result obtained is a complete response or partial response).In one illustrative example, the clinical benefit of the patient undergoing treatment for pleural mesothelioma or adenocarcinoma (e.g., adenocarcinoma of the gastroesophageal junction) is stable disease.

[0217] In another embodiment, the method described herein includes the following examples. The examples further illustrate additional features of various embodiments of the present disclosure. However, it should be understood that the examples are illustrative and should not be construed as limiting other embodiments of the present disclosure. In addition, it is understood that other variations of the examples are included in various embodiments of the present disclosure. In addition, it will be understood that all ranges described herein, such as those described in connection with various embodiments, are illustrative and are not intended to be limiting. One of ordinary skill in the art will understand that all ranges described by lower and upper limits, such as from about 1 to about 20, include all possible values ​​included in the lower and upper limits, and include all possible ranges of values ​​available by the set of possible values ​​included in the lower and upper limits. EXAMPLES

[0218] Example 1: Patients with a PSMA positive scan will receive a single dose of compound Ia-Ac on day 1 in cycle 1 of the clinical regimen of 7.4 GBq compound Ia-Lu, administered six times per week for up to five cycles. Subjects will be reviewed weekly for evaluation of adverse events (onset, duration, grade, and relationship to treatment) during cycle 1 only. DLTs will be determined by AEs during cycle 1 only.

[0219] Subjects will be restaged at the end of every 2 cycles. At each restaging, patients will be evaluated by PSMA PET and fluoride PET / CT bone scan. Assessment of bone disease consistent with PCWG23 criteria. PSA assessments will be performed at least twice weekly according to institutional practice.

Claims

1. A composition for the treatment of cancer, characterized by containing a therapeutically effective amount of a compound of formula I-Lu and being used in combination with a therapeutically effective amount of a compound of formula I-Ac. Here, the compound of formula I-Lu １７７ Compound I forms a complex with Lu, and the compound of formula I-Ac is ２２５ Compound I forms a complex with Ac, and compound I is given by formula 【Chemistry 1】 It is, and here, The aforementioned cancer is a cancer that expresses prostate-specific membrane antigen (PSMA), A composition comprising the compound of formula I-Lu and the compound of formula I-Ac administered simultaneously on a single day or in any order within approximately 2 to 72 hours.

2. The compound of formula I-Lu is the compound of formula Ia-Lu, where the compound of formula Ia-Lu is １７７ Compound Ia forms a complex with Lu, and compound Ia is given by formula 【Chemistry 2】 The composition according to claim 1.

3. The compound of formula I-Ac is the compound of formula Ia-Ac, where the compound of formula Ia-Ac is ２２５ Compound Ia forms a complex with Ac, and compound Ia is given by formula 【Transformation 3】 The composition according to claim 1.

4. The composition according to any one of claims 1 to 3, wherein the cancer is selected from the group consisting of prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), thyroid cancer, renal cell carcinoma, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and breast cancer.

5. The composition according to any one of claims 1 to 3, wherein the cancer is prostate cancer.

6. The composition according to any one of claims 1 to 3, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

7. The composition according to any one of claims 4 to 6, wherein the therapeutically effective amount of I-Lu or Ia-Lu is about 2 GBq to about 20 GBq.

8. The composition according to any one of claims 4 to 6, wherein the therapeutically effective amount of I-Lu or Ia-Lu is about 6 GBq to about 8 GBq.

9. The composition according to any one of claims 4 to 6, wherein the therapeutically effective amount of I-Lu or Ia-Lu is about 7.4 GBq.

10. The composition according to any one of claims 4 to 9, wherein the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 10 MBq, or about 5 MBq to about 10 MBq, or about 5 MBq to about 7 MBq.

11. The composition according to any one of claims 4 to 9, wherein the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq.

12. The composition according to any one of claims 4 to 11, wherein the compound of formula I-Lu or Ia-Lu is co-formulated with the compound of formula I-Ac or Ia-Ac.

13. The composition according to any one of claims 4 to 11, wherein the compound of formula I-Lu or Ia-Lu is administered simultaneously with the compound of formula I-Ac or Ia-Ac.

14. The composition according to claim 13, further comprising administering a therapeutically effective amount of the compound of formula I-Lu or Ia-Lu in weekly cycles for about 1 to about 7 cycles, after the administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

15. The composition according to any one of claims 4 to 11, wherein the compound of formula I-Lu or Ia-Lu is administered about 1 hour before the compound of formula I-Ac or Ia-Ac, or about 12 hours before the compound of formula I-Ac or Ia-Ac, or about 24 hours before the compound of formula I-Ac or Ia-Ac, or about 48 hours before the compound of formula I-Ac or Ia-Ac, or about 72 hours before the compound of formula I-Ac or Ia-Ac.

16. The composition according to claim 15, further comprising administering a therapeutically effective amount of the compound of formula I-Lu or Ia-Lu in weekly cycles for about 1 to about 7 cycles, after the administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

17. The composition according to any one of claims 4 to 11, wherein the compound of formula I-Ac or Ia-Ac is administered about 1 hour before the compound of formula I-Lu or Ia-Lu, or about 12 hours before the compound of formula I-Lu or Ia-Lu, or about 24 hours before the compound of formula I-Lu or Ia-Lu, or about 48 hours before the compound of formula I-Lu or Ia-Lu, or about 72 hours before the compound of formula I-Lu or Ia-Lu.

18. The composition according to claim 17, further comprising administering a therapeutically effective amount of the compound of formula I-Lu or Ia-Lu in weekly cycles for about 1 to about 7 cycles, after the administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

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