[177LU] Lutetium-PSMA I&T Compositions and Dosimetry, Kits, Methods of Making Same, and Methods of Using Same

Abstract

The present disclosure provides: 177 The present invention relates to radiopharmaceutical compositions, methods, and kits containing Lu-PSMA I&T. The compositions, methods, and kits contain a PSMA I&T ratio of 4.4:1.0 to 7.6:1.0. 177 The composition may have a molar ratio of 100 to 1000 Lu. The composition may be formulated as a solution for injection, where the solution is suitable for administration at least 72 hours after formulation. The composition(s) have a radiochemical purity (RCP) of 95% or greater, 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99% or greater, or 99.5% or greater upon administration.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This invention claims priority to the following U.S. provisional patent applications: Nos. 63 / 529,986, 63 / 620,262, 63 / 626,839, 63 / 671,633, 63 / 671,625, 63 / 677,137, and 63 / 677,276, filed July 31, 2023, January 12, 2024, January 30, 2024, July 15, 2024, July 15, 2024, July 30, 2024, and July 30, 2024, respectively, which are incorporated herein in their entirety, including all tables, figures, and claims.

[0002] The present disclosure provides a method for injection or intravenous infusion. 177 Lu] Lutetium-PSMA I&T ([ 177 Lu]Lu-PSMA I&T or 177 Composition of the Lu-PSMA I&T solution, and 177 Regarding kits containing Lu-PSMA I&T. 177 Lu-PSMA The I&T solution and / or kit thereof may be used for prostate cancer radioligand therapy (PRLT). [Background technology]

[0003] Prostate cancer (PC) is the most frequent non-skin cancer and the second leading cause of cancer death in adult men. Overall, increasing survival rates for patients with metastatic castration-resistant prostate cancer (mCRPC) has been challenging, and there is a clinical need for effective treatment strategies for mCRPC patients.

[0004] Prostate-specific membrane antigen (PSMA) is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer, making PSMA a promising molecular target for the diagnosis and therapy of PC, including mCRPC. 177 Lu]Lu-PSMA-617 and [ 177[Lu]Lu-PSMA I&Ts are small molecule inhibitors of PSMA that are highly desirable for targeted radionuclide therapy due to their low toxicity. However, there are currently no studies available to treat prostate cancer. 177 The use of these small molecule inhibitors targeting Lu-bearing PSMA may also result in undesirable absorbed doses of radiation to healthy organs.

[0005] It can be administered to patients that are not targeted for the treatment of cancer, minimizing the unwanted cumulative absorbed dose of radiation to the patient's healthy organ tissues. 177 There remains a need for improved formulations containing [Lu]Lu-PSMA I&T. 177 Provided herein is a solution to overcome these and other problems in the art by providing an improved [Lu]Lu-PSMA I&T composition that results in a lower cumulative absorbed dose of radiation per administration. 177 Lu]Lu-PSMA I&T compositions are provided. Summary of the Invention

[0006] Specifically described herein are methods for administering to a human patient in need thereof. 177 Compositions are provided that are directed to radiopharmaceutical compositions comprising Lu-PSMA I&T. The compositions are formulated as injectable solutions, which are suitable for administration to a human patient in need thereof more than 48 hours, more than 72 hours, more than 96 hours, or more than 100 hours after formulation. The compositions are formulated as injectable solutions, which have a radiochemical purity of 95% or greater at least 48 hours after formulation, at least 72 hours after formulation, at least 96 hours after formulation, at least 100 hours after formulation, or at least 120 hours after formulation.

[0007] The compositions, methods, and kits described herein are suitable for administration to human patients. 177Containing Lu-PSMA I&T, healthy organs show a reduced cumulative absorbed dose after administration.

[0008] The compositions, methods, and kits described herein provide PSMA with a radiochemical purity of 95% or greater and a ratio of 3.0:1.0 to 8.0:1.0 and / or 4.4:1.0 to 7.6:1.0. I&T 177 Lu suitable for administration to human patients 177 This is quite surprising and unexpected, as our own initial testing has shown that this embodiment is not feasible, requiring a PSMA ratio of at least 11.0:1.0 or greater to maintain 95% or greater radiochemical purity for 72 hours or more. I&T 177 This is because it has been suggested that a molar ratio of PSMA to Lu-177 (mol / mol) is required. Indeed, our own initial predictions are that anything below an 11.0:1.0 ratio will likely have unacceptable radiochemical purity (e.g., less than 95%) upon formation and will continue to degrade in a manner that is further unacceptable for human patients 24 hours after formation, 48 hours after formation, 72 hours after formation, or 96 hours after formation. See the following PSMA:Lu-177 (mol / mol) graph, which shows the inadequate predicted radiochemical formation for formulations below 11.0:1.0.

[0009] However, utilizing the specific parameters described herein, PSMA I&T ratios of 3.0:1.0 to 8.0:1.0 and / or 4.4:1.0 to 7.6:1.0 with radiochemical purity of 95% or greater can be achieved. 177 Lu suitable for administration to human patients 177 Provided herein are compositions, methods, and kits described herein that comprise Lu-PSMA I&T, wherein the compositions are stable for 72 hours or more.

[0010] In another embodiment, the compositions, methods, and kits described herein provide a PSMA I&T to [177Lu]Lu3+ ratio (units: μg:mCi) of about 0.20 to about 0.60 with a radiochemical purity of 95% or greater, suitable for administration to a human patient. 177 In another embodiment, the compositions, methods, and kits described herein comprise a PSMA I&T suitable for administration to a human patient, having a radiochemical purity of 95% or greater and a ratio of PSMA I&T to [177Lu]Lu3+ (units: μg:mCi) of 0.60 or less. 177 Lu-PSMA I&T. This is also very surprising and unexpected, as our own initial testing suggested that this embodiment was not feasible and that maintaining 95% or greater radiochemical purity over 72 hours or longer would require having a PSMA I&T to [177Lu]Lu3+ ratio (in μg:mCi) of at least 0.70 or greater. See the PSMA:Lu-177 (mol / mol) graph below, which shows inadequate predicted radiochemical formation for formulations below 0.60.

[0011] However, utilizing the specific parameters described herein, radiochemical purity of 95% or greater and PSMA I&T to [177Lu]Lu3+ ratios (units: μg:mCi) of about 0.20 to about 0.64, about 0.20 to about 0.63, about 0.20 to about 0.62, about 0.20 to about 0.61, or about 0.20 to about 0.60 are suitable for administration to human patients. 177 Provided herein are compositions, methods, and kits described herein that comprise Lu-PSMA I&T, wherein the compositions are stable for 72 hours or more.

[0012] This disclosure 177Further directed is a radiopharmaceutical composition comprising [Lu]Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.0 to 6.0. In some examples, the composition is suitable for administration to a human patient in need thereof at least 90 hours after formulation, and the composition has a radiochemical purity of 95.0% or greater at the time of administration. In some aspects, the radiopharmaceutical composition may comprise a metal scavenger or chelator. The metal scavenger or chelator may comprise DTPA, EDTA, EDDS, DFOA, or a combination thereof. In other embodiments, the metal scavenger or chelator may comprise DTPA but not EDTA. In some aspects, the radiopharmaceutical composition may comprise the absence of gentisic acid and / or gentisate (i.e., no gentisic acid or gentisate).

[0013] Another aspect of the present disclosure is a method for preparing a soluble ... 177 Another embodiment of the present disclosure is a reaction composition comprising [Lu]LuCl3, and about 463-500 μg / mL of PSMA I&T precursor. 177 A reaction composition comprising about 463-500 μg / mL of PSMA I&T precursor, about 4 mL of 0.4 M sodium acetate, about 1.6 mL of 0.05 M hydrochloric acid, and about 150 μL of 20% L-ascorbic acid in a total solution of 6-8 mL. 177 In some examples, the reaction composition comprises: 177 Lu activity ≦61 GBq.

[0014] Another aspect of the present disclosure is 177 In some examples, the reaction composition comprises: [Lu]Lu-, a PSMA I&T precursor, ascorbic acid, acetate buffer, hydrochloric acid, and L-ascorbic acid in solution. 177 and Lu activity ≦296 GBq (i.e., ≦8,000 mCi).

[0015] The present disclosure provides a radiopharmaceutical composition comprising:177 an injectable [Lu]Lu-PSMA I&T and related substances (i.e., unlabeled PSMA I&T and PSMA I&T labeled with other metals) in an amount of about 3 μg / ml to about 16 μg / ml, ascorbic acid in a concentration of about 25 mg / ml to about 40 mg / ml, and a chelating agent in an amount of about 0.075 mg / ml to 0.15 mg / ml; 177 The present disclosure is further directed to a radiopharmaceutical composition comprising a [Lu]Lu-PSMA I&T solution, wherein the pH of the solution is about 3 to about 5, the total volume of the composition is about 15 ml, and when the composition is administered to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity. 177 an injectable [Lu]Lu-PSMA I&T and related substances (i.e., unlabeled PSMA I&T and PSMA I&T labeled with other metals) in an amount of about 1 μg / ml to about 8 μg / ml, ascorbic acid in a concentration of about 25 mg / ml to about 40 mg / ml, and a chelating agent in an amount of about 0.075 mg / ml to 0.15 mg / ml; 177 Lu]Lu-PSMA The present disclosure is further directed to a radiopharmaceutical composition comprising an I&T solution, wherein the pH of the solution is about 3 to about 5, the total volume of the composition is about 15 ml, and when the composition is administered to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity. 177 an injectable [Lu]Lu-PSMA I&T and related substances (i.e., unlabeled PSMA I&T and PSMA I&T labeled with other metals) in an amount of about 3 μg / ml to about 10 μg / ml, ascorbic acid in a concentration of about 25 mg / ml to about 40 mg / ml, and a chelating agent in an amount of about 0.075 mg / ml to 0.15 mg / ml; 177 The present invention is further directed to a radiopharmaceutical composition comprising a [Lu]Lu-PSMA I&T solution, wherein the pH of the solution is from about 3 to about 5, the total volume of the composition is about 15 ml, and wherein, upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0016] This disclosure 177[Lu]Lu-PSMA I&T, ascorbic acid, and ethanol for injection 177

[0013] Further of interest is a radiopharmaceutical composition comprising a [Lu]Lu-PSMA I&T solution. 177 wherein the [Lu]Lu-PSMA I&T is a sufficient amount of radioactivity for its intended use, the total amount of ascorbic acid in the solution is about 210-700 mg, the total amount of ethanol in the solution is about 274-706 mg, and the pH of the solution is about 5 or less, and when the composition is administered to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity and experiences a reduction in prostate specific antigen of greater than about 50%.

[0017] The present disclosure provides a radiopharmaceutical composition comprising: 177 an injectable [Lu]Lu-PSMA I&T in an amount of about 3 μg / ml to about 15 μg / ml, ascorbic acid at a concentration of about 10 mg / ml to about 50 mg / ml, and ethanol at an ethanol concentration of about 0% (v / v), about 1% (v / v) to about 10% (v / v), about 2.5% (v / v%) to about 8.5% (v / v%), about 3.0% (v / v%) to about 8.0% (v / v%), about 3.8% (v / v%) to about 7.5% (v / v%), or about 4.5% (v / v%) to about 7.0% (v / v%); 177 Further directed to a radiopharmaceutical composition comprising a [Lu]Lu-PSMA I&T solution, wherein the pH of the solution is from about 3 to about 5, and wherein upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0018] The present disclosure provides a radiopharmaceutical composition comprising: 177 an injectable [Lu]Lu-PSMA I&T in an amount of about 3 μg / ml to about 15 μg / ml, or about 3 μg / ml to about 12 μg / ml, ascorbic acid in a concentration of about 10 mg / ml to about 50 mg / ml, ethanol in a concentration of about 0% (v / v) to about 10% (v / v), and a chelating agent in an amount of about 0.01 mg / ml to about 0.15 mg / ml or about 177Further directed to a radiopharmaceutical composition comprising a [Lu]Lu-PSMA I&T solution, wherein the pH of the solution is from about 3 to about 5, and wherein upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0019] The present disclosure provides a radiopharmaceutical composition comprising: 177 an injectable [Lu]Lu-PSMA I&T and related substances (i.e., unlabeled PSMA I&T and PSMA I&T labeled with other metals) in an amount of about 4 μg / ml to about 15 μg / ml, ascorbic acid in a concentration of about 25 mg / ml to about 40 mg / ml, and a chelating agent in an amount of about 0.075 mg / ml to 0.15 mg / ml; 177 The present invention is further directed to a radiopharmaceutical composition comprising a [Lu]Lu-PSMA I&T solution, wherein the pH of the solution is from about 3 to about 5, the total volume of the composition is about 15 ml, and wherein, upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0020] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of [ 177 Lu]Lu-PSMA I&T at that dose for 1, 2, 3, 4, 5, 6, 7, or 8 cycles or more [ 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or ≥1, 2, 3, 4, 5, 6, 7, 8 cycles [ 177 Lu]Lu-PSMA I&T treatment resulted in a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy provide The present invention further relates to radiopharmaceutical kits.

[0021] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of [ 177≥ 1, 2, 3, 4, 5, 6, 7, or 8 cycles of [Lu]Lu-PSMA I&T at a dose that results in a cumulative absorbed dose to the kidney of less than 23 Gy 177 Lu]Lu-PSMA I&T therapy, and / or 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of [ 177 Lu]Lu-PSMA I&T treatment is 23.0Gy or less, 22.9Gy or less, 22.8Gy or less, 22.7Gy or less, 22.6Gy or less, 22.5Gy or less, 22.4Gy or less, 22.3Gy or less, 22.2Gy or less, 22.1Gy or less, 22.0 Gy or less, 21.9Gy or less, 21.8Gy or less, 21.7Gy or less, 21.6Gy or less, 21.5Gy or less, 21.4Gy or less, 21.3Gy or less, 21.2Gy or less, 21.1Gy or less, 21.0Gy or less, 20.9Gy

[0023] The present invention further relates to a radiopharmaceutical kit that provides an average predicted cumulative absorbed dose to the kidneys of 20.8 Gy or less, 20.7 Gy or less, 20.6 Gy or less, 20.5 Gy or less, 20.4 Gy or less, 20.3 Gy or less, 20.2 Gy or less, 20.1 Gy or less, 20.0 Gy or less, 19.9 Gy or less, 19.8 Gy or less, 19.7 Gy or less, 19.6 Gy or less, 19.5 Gy or less, 19.4 Gy or less, 19.3 Gy or less, 19.2 Gy or less, or 19.1 Gy or less.

[0022] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of [ 177 Lu]Lu-PSMA I&T at that dose for 1, 2, 3, 4, 5, 6, 7, or 8 cycles or more [ 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles 177Lu]Lu-PSMA I&T treatment is 19.2Gy or less, 19.1Gy or less, 19.0Gy or less, 18.9Gy or less, 18.8Gy or less, 18.7Gy or less, 18.6Gy or less, 18.5Gy or less, 18.4Gy Below, 18.3Gy or less, 18.2Gy or less, 18.1Gy or less, 18.0Gy or less, 17.9Gy or less, 17.8Gy or less, 17.7Gy or less, 17.6Gy or less, 17.5Gy or less, 1

[0023] Further relates to a radiopharmaceutical kit that results in a mean predicted cumulative absorbed dose to the kidneys of 7.4 Gy or less, 17.3 Gy or less, 17.2 Gy or less, 17.1 Gy or less, 17.0 Gy or less, 16.8 Gy or less, 16.7 Gy or less, 16.6 Gy or less, 16.5 Gy or less, 16.4 Gy or less, 16.3 Gy or less, 16.2 Gy or less, 16.1 Gy or less, 16.0 Gy or less, or 15.9 Gy or less.

[0023] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 [Lu]Lu-PSMA I&T solution, and the injection contains a dose of [177Lu-PSMA-I&T and is administered for 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of [ 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles 177 Lu]Lu-PSMA I&T treatment is 15.8Gy or less, 15.7Gy or less, 15.6Gy or less, 15.5Gy or less, 15.4Gy or less, 15.3Gy or less, 15.2Gy or less, 15.1Gy or less, 1 5.0Gy or less, 14.9Gy or less, 14.8Gy or less, 14.7Gy or less, 14.6Gy or less, 14.3Gy or less, 14.2Gy or less, 14.1Gy or less, 14.0Gy or less,

[0023] The present invention further relates to a radiopharmaceutical kit that provides a mean predicted dose with a cumulative absorbed dose to the kidneys of 13.9 Gy or less, 13.8 Gy or less, 13.7 Gy or less, 13.6 Gy or less, 13.5 Gy or less, 13.4 Gy or less, 13.3 Gy or less, 13.2 Gy or less, 13.1 Gy or less, 13.0 Gy or less, 12.9 Gy or less, 12.8 Gy or less, or 12.7 Gy or less.

[0024] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of [ 177 Lu]Lu-PSMA-I&T at that dose for 1, 2, 3, 4, 5, 6, 7, or 8 cycles or more [ 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles 177 Lu]Lu-PSMA I&T treatment is 12.6Gy or less, 12.5Gy or less, 12.4Gy or less, 12.3Gy or less, 12.2Gy or less, 12.1Gy or less, 12.0Gy or less, 11.9Gy or less, 11.8 Gy or less, 11.7Gy or less, 11.6Gy or less, 11.5Gy or less, 11.4Gy or less, 11.3Gy or less, 11.2Gy or less, 11.1Gy or less, 11.0Gy or less, 10.9Gy

[0023] The present invention further relates to a radiopharmaceutical kit that provides a mean predicted dose with a cumulative absorbed dose to the kidneys of 10.8 Gy or less, 10.7 Gy or less, 10.6 Gy or less, 10.5 Gy or less, 10.4 Gy or less, 10.3 Gy or less, 10.2 Gy or less, 10.1 Gy or less, 10.0 Gy or less, 9.9 Gy or less, 9.8 Gy or less, 9.7 Gy or less, 9.6 Gy or less, or 9.5 Gy or less.

[0025] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of [ 177 Lu]Lu-PSMA-I&T at that dose for 1, 2, 3, 4, 5, 6, 7, or 8 cycles or more [ 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles 177

[0023] The present invention further relates to a radiopharmaceutical kit, wherein the [Lu]Lu-PSMA I&T treatment results in a mean predicted dose with a cumulative absorbed dose to the kidney of 9.4 Gy or less, 9.3 Gy or less, 9.2 Gy or less, 9.1 Gy or less, 9.0 Gy or less, 8.9 Gy or less, 8.8 Gy or less, 8.7 Gy or less, 8.6 Gy or less, 8.5 Gy or less, 8.4 Gy or less, 8.3 Gy or less, 8.2 Gy or less, 8.1 Gy or less, 8.0 Gy or less, 7.9 Gy or less, 7.8 Gy or less, 7.7 Gy or less, 7.6 Gy or less, 7.5 Gy or less, 7.3 Gy or less, 7.2 Gy or less, 7.1 Gy or less, 7.0 Gy or less, 6.9 Gy or less, 6.8 Gy or less, 6.7 Gy or less, 6.6 Gy or less, 6.5 Gy or less, or 6.4 Gy or less.

[0026] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of [ 177 Lu]Lu-PSMA-I&T at that dose for 1, 2, 3, 4, 5, 6, 7, or 8 cycles or more [ 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles 177 Lu]Lu-PSMA

[0023] Further related to a radiopharmaceutical kit, wherein the I&T treatment results in a mean predicted dose with a cumulative absorbed dose to the kidneys of 6.3 Gy or less, 6.2 Gy or less, 6.1 Gy or less, 6.0 Gy or less, 5.9 Gy or less, 5.8 Gy or less, 5.7 Gy or less, 5.6 Gy or less, 5.5 Gy or less, 5.4 Gy or less, 5.3 Gy or less, 5.2 Gy or less, 5.1 Gy or less, 5.0 Gy or less, 4.9 Gy or less, 4.8 Gy or less, 4.7 Gy or less, 4.6 Gy or less, 4.5 Gy or less, 4.3 Gy or less, 4.2 Gy or less, 4.1 Gy or less, 4.0 Gy or less, 3.9 Gy or less, 3.8 Gy or less, 3.7 Gy or less, 3.6 Gy or less, 3.5 Gy or less, 3.4 Gy or less, 3.3 Gy or less, or 3.2 Gy or less.

[0027] The present disclosure also provides a radiopharmaceutical kit, comprising: 177a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of [ 177 The present invention relates to a radiopharmaceutical kit comprising a radiopharmaceutical comprising 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 100 mg / kg of 100 ng / mL ...

[0028] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177

[0013] The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises less than 10 mg / ml of gentisate, gentisic acid, an alternative antioxidant, or a combination thereof. In some embodiments, the injection comprises 9.5 mg / ml or less, 9 mg / ml or less, 8.5 mg / ml or less, 8 mg / ml or less, 7.5 mg / ml or less, 7 mg / ml or less, 6.5 mg / ml or less, 6 mg / ml or less, 5.5 mg / ml or less, 5 mg / ml, 4.5 mg / ml or less, 4 mg / ml or less, 3.5 mg / ml or less, 3 mg / ml or less, 2.5 mg / ml or less, 2 mg / ml or less, 1.5 mg / ml or less, 1 mg / ml or less, or 0.5 mg / ml of gentisate, gentisic acid, an alternative antioxidant, or a combination thereof. In one embodiment, the present disclosure relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises less than 10 mg / ml of gentisate, gentisic acid, an alternative antioxidant, or a combination thereof. 177

[0013] The present invention relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection does not contain gentisate, gentisic acid, an alternative antioxidant, or a combination thereof.

[0029] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177The present invention further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution for injection, wherein the injection comprises less than 10 mg / ml of ascorbate, ascorbic acid, an alternative stabilizer or radioprotectant, or a combination thereof. In some embodiments, the injection contains 40 mg / ml or less, 35 mg / ml or less, 33 mg / ml or less, 31 mg / ml or less, 30 mg / ml or less, 25 mg / ml or less, 20 mg / ml or less, 15 mg / ml or less, 10 mg / ml or less, 9.5 mg / ml or less, 9 mg / ml or less, 8.5 mg / ml or less, 8 mg / ml or less, 7.5 mg / ml or less, 7 mg / ml or less, 6.5 mg / ml or less, 6 mg / ml or less, 5.5 mg / ml or less, 5 mg / ml, 4.5 mg / ml or less, 4 mg / ml or less, 3.5 mg / ml or less, 3 mg / ml or less, 2.5 mg / ml or less, 2 mg / ml or less, 1.5 mg / ml or less, 1 mg / ml or less, or 0.5 mg / ml or less of ascorbate, ascorbic acid, alternative stabilizers, or combinations thereof.

[0030] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177The present invention further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises (1) less than 10 mg / ml of gentisate or gentisic acid, and (2) less than 10 mg / ml of ascorbate and / or ascorbic acid. In some embodiments, the injection comprises (1) 9.5 mg / ml or less, 9 mg / ml or less, 8.5 mg / ml or less, 8 mg / ml or less, 7.5 mg / ml or less, 7 mg / ml or less, 6.5 mg / ml or less, 6 mg / ml or less, 5.5 mg / ml or less, 5 mg / ml, 4.5 mg / ml or less, 4 mg / ml or less, 3.5 mg / ml or less, 3 mg / ml or less, 2.5 mg / ml or less, 2 mg / ml or less, 1.5 mg / ml or less, 1 mg / ml or less, or 0.5 mg / ml of gentisate and / or gentisic acid. thidic acid, and (2) 9.5 mg / ml or less, 9 mg / ml or less, 8.5 mg / ml or less, 8 mg / ml or less, 7.5 mg / ml or less, 7 mg / ml or less, 6.5 mg / ml or less, 6 mg / ml or less, 5.5 mg / ml or less, 5 mg / ml, 4.5 mg / ml or less, 4 mg / ml or less, 3.5 mg / ml or less, 3 mg / ml or less, 2.5 mg / ml or less, 2 mg / ml or less, 1.5 mg / ml or less, 1 mg / ml or less, or 0.5 mg / ml or less of ascorbate and / or ascorbic acid.

[0031] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177The present invention further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises (1) less than 10 mg / ml of antioxidant, and (2) less than 40 mg / ml of stabilizer. In some embodiments, the injection comprises (1) less than 9.5 mg / ml, 9 mg / ml, 8.5 mg / ml, 8 mg / ml, 7.5 mg / ml, 7 mg / ml, 6.5 mg / ml, 6 mg / ml, 5.5 mg / ml, 5 mg / ml, 4.5 mg / ml, 4 mg / ml, 3.5 mg / ml, 3 mg / ml, 2.5 mg / ml, 2 mg / ml, 1.5 mg / ml, 1 mg / ml, or 0.5 mg / ml of antioxidant, and (2) less than 40 mg / ml, 35 mg / ml, 33 mg / ml, 31 mg / ml, or 40 mg / ml of stabilizer. 0.5mg / ml or less, 30mg / ml or less, 25mg / ml or less, 20mg / ml or less, 15mg / ml or less, 10mg / ml or less, 9.5mg / ml or less, 9mg / ml or less, 8.5mg / ml or less, 8mg / ml or less, 7.5mg / ml or less, 7mg / ml or less, 6.5mg / ml or less, 6mg / ml or less, 5.5mg / ml or less, 5mg / ml, 4.5mg / ml or less, 4mg / ml or less, 3.5mg / ml or less, 3mg / ml or less, 2.5mg / ml or less, 2mg / ml or less, 1.5mg / ml or less, 1mg / ml or less, or 0.5mg / ml or less of a stabilizer.

[0032] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.8 GBq±0.10 GBq, a dose of 6.8 GBq±0.15 GBq, a dose of 6.8 GBq±0.20 GBq, a dose of 6.8 GBq±0.25 GBq, or a dose of 6.8 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, 7, or 8 cycles of [ 177 Lu]Lu-PSMA I&T solution treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, or 8 cycles of [ 177

[0013] The present invention further relates to a radiopharmaceutical kit, wherein the [Lu]Lu-PSMA I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy cumulative absorbed dose, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, 7, or 8 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0033] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq±0.10 GBq, a dose of 7.4 GBq±0.15 GBq, a dose of 7.4 GBq±0.20 GBq, a dose of 7.4 GBq±0.25 GBq, or a dose of 7.4 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, 7, or 8 cycles of [ 177 Lu]Lu-PSMA I&T solution treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, or 8 cycles of [ 177

[0013] The present invention further relates to a radiopharmaceutical kit, wherein the [Lu]Lu-PSMA I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy cumulative absorbed dose, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, 7, or 8 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0034] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177 and a vial containing at least a single dose of Lu-PSMA I&T solution, the injection of which is to deliver a dose of 7.4 GBq (mean 7.52 ± 0.16 GBq). 177 1, 2, 3, 4, 5, 6, 7, or 8 cycles of Lu-PSMA-I&T at that dose 177 Lu-PSMA I&T solution treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, or 8 cycles 177The present disclosure further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney for 1, 2, 3, 4, 5, 6, 7, or 8 cycles is less than 23 Gy, and no nephrotoxicity is observed. 177 and a vial containing at least a single dose of Lu-PSMA I&T solution, the injection of which is to deliver a dose of 7.4 GBq (mean 7.52 ± 0.16 GBq). 177 Lu-PSMA I&T, 1, 2, 3, 4, 5, 6, 7, or 8 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, 7, or 8 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0035] The present disclosure also provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection is administered at a dose of 6.8 GBq ± 10% GBq, a dose of 6.8 GBq ± 5% GBq, or a dose of 6.8 GBq ± 3% GBq; 177 1, 2, 3, 4, 5, 6, 7, or 8 cycles of Lu-PSMA I&T at that dose 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, or 8 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, 7, or 8 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0036] The present disclosure also provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection is administered at a dose of 7.4 GBq ± 10% GBq, a dose of 7.4 GBq ± 5% GBq, or a dose of 7.4 GBq ± 3% GBq; 177 1, 2, 3, 4, 5, 6, 7, or 8 cycles of Lu-PSMA I&T at that dose 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, or 8 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, 7, or 8 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0037] The present disclosure also provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, the injection of which is to deliver a dose of 7.4 (±10%) GBq; 177 Lu-PSMA I&T and 6 cycles at that dose 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 6 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 6 cycles is less than 23 Gy, with no observed nephrotoxicity.

[0038] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq±0.10 GBq, a dose of 7.4 GBq±0.15 GBq, a dose of 7.4 GBq±0.20 GBq, a dose of 7.4 GBq±0.25 GBq, or a dose of 7.4 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over six cycles would be 20.4±10.2 Gy. 177 Further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.5 GBq±0.10 GBq, a dose of 7.5 GBq±0.15 GBq, a dose of 7.5 GBq±0.20 GBq, a dose of 7.5 GBq±0.25 GBq, or a dose of 7.5 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over six cycles would be 20.4±10.2 Gy.

[0039] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177 Further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.1 GBq±0.10 GBq, a dose of 7.1 GBq±0.15 GBq, a dose of 7.1 GBq±0.20 GBq, a dose of 7.1 GBq±0.25 GBq, or a dose of 7.1 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over 6, 7, or 8 cycles would be 20.4±10.2 Gy.

[0040] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177 Further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.8 GBq±0.10 GBq, a dose of 6.8 GBq±0.15 GBq, a dose of 6.8 GBq±0.20 GBq, a dose of 6.8 GBq±0.25 GBq, or a dose of 6.8 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over 6, 7, or 8 cycles would be 20.4±10.2 Gy.

[0041] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177 Further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.5 GBq±0.10 GBq, a dose of 6.5 GBq±0.15 GBq, a dose of 6.5 GBq±0.20 GBq, a dose of 6.5 GBq±0.25 GBq, or a dose of 6.5 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over 6, 7, or 8 cycles would be 20.4±10.2 Gy.

[0042] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177 The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq±0.10 GBq, a dose of 7.4 GBq±0.15 GBq, a dose of 7.4 GBq±0.20 GBq, a dose of 7.4 GBq±0.25 GBq, or a dose of 7.4 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over 6 or 7 cycles would be 23.00 Gy or less, 22.50 Gy or less, 22.00 Gy or less, 21.50 Gy or less, 21.00 Gy or less, 20.50 Gy or less, or 20.40 Gy or less. 177 Further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.5 GBq±0.10 GBq, a dose of 7.5 GBq±0.15 GBq, a dose of 7.5 GBq±0.20 GBq, a dose of 7.5 GBq±0.25 GBq, or a dose of 7.5 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over 6 or 7 cycles would be 23.00 Gy or less, 22.50 Gy or less, 22.00 Gy or less, 21.50 Gy or less, 21.00 Gy or less, 20.50 Gy or less, or 20.40 Gy or less.

[0043] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177Further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.8 GBq±0.10 GBq, a dose of 6.8 GBq±0.15 GBq, a dose of 6.8 GBq±0.20 GBq, a dose of 6.8 GBq±0.25 GBq, or a dose of 6.8 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over 6, 7, or 8 cycles would be 23.00 Gy or less, 22.50 Gy or less, 22.00 Gy or less, 21.50 Gy or less, 21.00 Gy or less, 20.50 Gy or less, or 20.40 Gy or less.

[0044] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177 The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq±0.10 GBq, a dose of 7.4 GBq±0.15 GBq, a dose of 7.4 GBq±0.20 GBq, a dose of 7.4 GBq±0.25 GBq, or a dose of 7.4 GBq±0.30 GBq, wherein the average absorbed dose of the radiopharmaceutical is about 0.1 Gy / MBq to 1.0 Gy / MBq in the kidney of a human patient. 177 The present invention further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.5 GBq±0.10 GBq, a dose of 7.5 GBq±0.15 GBq, a dose of 7.5 GBq±0.20 GBq, a dose of 7.5 GBq±0.25 GBq, or a dose of 7.5 GBq±0.30 GBq, wherein the average absorbed dose of the radiopharmaceutical is between about 0.1 Gy / MBq and 1.0 Gy / MBq in the kidney of a human patient.

[0045] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177The present invention further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.8 GBq±0.10 GBq, a dose of 6.8 GBq±0.15 GBq, a dose of 6.8 GBq±0.20 GBq, a dose of 6.8 GBq±0.25 GBq, or a dose of 6.8 GBq±0.30 GBq, wherein the average absorbed dose of the radiopharmaceutical is between about 0.1 Gy / MBq and 1.0 Gy / MBq in the kidney of a human patient.

[0046] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177 The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq±0.10 GBq, a dose of 7.4 GBq±0.15 GBq, a dose of 7.4 GBq±0.20 GBq, a dose of 7.4 GBq±0.25 GBq, or a dose of 7.4 GBq±0.30 GBq, wherein the mean whole body effective dose of the radiopharmaceutical composition is between about 0.001 mSv / MBq and 0.1 mSv / MBq. 177 The present invention further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.5 GBq±0.10 GBq, a dose of 7.5 GBq±0.15 GBq, a dose of 7.5 GBq±0.20 GBq, a dose of 7.5 GBq±0.25 GBq, or a dose of 7.5 GBq±0.30 GBq, and wherein the average whole body effective dose of the radiopharmaceutical composition is between about 0.001 mSv / MBq and 0.1 mSv / MBq.

[0047] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177The present invention further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.8 GBq±0.10 GBq, a dose of 6.8 GBq±0.15 GBq, a dose of 6.8 GBq±0.20 GBq, a dose of 6.8 GBq±0.25 GBq, or a dose of 6.8 GBq±0.30 GBq, and wherein the average whole body effective dose of the radiopharmaceutical composition is between about 0.001 mSv / MBq and 0.1 mSv / MBq.

[0048] The present disclosure relates to a method of administering a radiopharmaceutical composition, the method comprising administering the radiopharmaceutical composition to a human patient in need thereof, optionally more than 48 hours after formulation, wherein the radiopharmaceutical composition is administered in a dose of 7.4 GBq±0.10 GBq, 7.4 GBq±0.15 GBq, 7.4 GBq±0.20 GBq, 7.4 GBq±0.25 GBq, or 7.4 GBq±0.30 GBq. 177 Lu-PSMA and I&T in a solution comprising a pH of 3.5 to 5.0, the solution optionally comprising ascorbic acid and / or ethanol, the solution optionally comprising a radiochemical purity of greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or greater than 99.5% when administered, for 1, 2, 3, 4, 5, 6, and / or 7 cycles at that dose. 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, and / or 7 cycles 177 The present invention further relates to a method in which Lu-PSMA I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney for cycles 1, 2, 3, 4, 5, 6, and / or 7 is less than 23 Gy, and no nephrotoxicity is observed. In another embodiment, the radiopharmaceutical composition may include radionuclide identification (gamma spectroscopy) of the composition exhibiting gamma ray energy peaks at 113±2 keV and 208±4 keV, with no other significant peaks detected with gamma energies greater than 100 keV.

[0049] The present disclosure relates to a method of administering a radiopharmaceutical composition, the method comprising administering the radiopharmaceutical composition to a human patient in need thereof, optionally more than 48 hours after formulation, wherein the radiopharmaceutical composition delivers a 6.8 GBq±0.10 GBq dose, a 6.8 GBq±0.15 GBq dose, a 6.8 GBq±0.20 GBq dose, a 6.8 GBq±0.25 GBq dose, or a 6.8 GBq±0.30 GBq dose. 177 [Lu]Lu-PSMA I&T in a solution comprising a pH of 3.5 to 4.5, the solution optionally comprising ascorbic acid and / or ethanol, the solution optionally comprising a radiochemical purity of greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or greater than 99.5% when administered, and for 1, 2, 3, 4, 5, 6, 7, and / or 8 cycles of [ 177 [Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, and / or 8 cycles 177 The present invention further relates to a method in which Lu-PSMA I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney for cycles 1, 2, 3, 4, 5, 6, 7, and / or 8 is less than 23 Gy, and no nephrotoxicity is observed. In another embodiment, the radiopharmaceutical composition may include radionuclide identification (gamma spectroscopy) of the composition exhibiting gamma ray energy peaks at 113±2 keV and 208±4 keV, with no other significant peaks detected with gamma energies greater than 100 keV.

[0050] The present disclosure relates to methods of administering a radiopharmaceutical composition, the method comprising administering the radiopharmaceutical composition to a human patient in need thereof, optionally more than 48 hours after formulation, wherein the radiopharmaceutical composition is administered in a dose of 6.5 GBq±0.10 GBq, 6.5 GBq±0.15 GBq, 6.5 GBq±0.20 GBq, 6.5 GBq±0.25 GBq, or 6.5 GBq±0.30 GBq. 177 Lu-PSMA and I&T in a solution comprising a pH of 3.5 to 5.0, the solution optionally comprising ascorbic acid and / or ethanol, the solution optionally comprising a radiochemical purity of greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or greater than 99.5% when administered, for 1, 2, 3, 4, 5, 6, and / or 7 cycles at that dose. 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, 7, and / or 8 cycles 177 The present invention further relates to a method in which Lu-PSMA I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney for cycles 1, 2, 3, 4, 5, 6, 7, and / or 8 is less than 23 Gy, and no nephrotoxicity is observed. In another embodiment, the radiopharmaceutical composition may include radionuclide identification (gamma spectroscopy) of the composition exhibiting gamma ray energy peaks at 113±2 keV and 208±4 keV, with no other significant peaks detected with gamma energies greater than 100 keV.

[0051] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177 The present invention further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq±0.10 GBq, a dose of 7.4 GBq±0.15 GBq, a dose of 7.4 GBq±0.20 GBq, a dose of 7.4 GBq±0.25 GBq, or a dose of 7.4 GBq±0.30 GBq, and wherein radionuclide identification (gamma spectroscopy) of the composition exhibits gamma ray energy peaks at 113±2 keV and 208±4 keV, with no other significant peaks having gamma energies greater than 100 keV being detected.

[0052] The present disclosure also relates to a method, comprising administering to a subject a dose of 0.41±0.18Gy / GBq, 0.41±0.17Gy / GBq, 0.41±0.16Gy / GBq, 0.41±0.15Gy / GBq, 0.41±0.14Gy / GBq, 0.41±0.13Gy / GBq, 0.41±0.12Gy / GBq, 0.41±0.11Gy / GBq, 0.41±0.10Gy / GBq, 0.41±0.14Gy / GBq, 0.41±0.15Gy / GBq, 0.41±0.16Gy / GBq, 0.41±0.17Gy / GBq, 0.41±0.18Gy / GBq, 0.41±0.17Gy / GBq, 0.41±0.16Gy / GBq, 0.41±0.15Gy / GBq, 0.41±0.14Gy / GBq, 0.41±0.13Gy / GBq, 0.41±0.12Gy / GBq, 0.41±0.11Gy / GBq, 0.41±0.10Gy / GBq, 0.41±0.16Gy / GBq, 0.41±0.17Gy / GBq, 0.41±0.18Gy / GBq, 0.41±0.16Gy / GBq, 0.41±0.15Gy / GBq, 0.41±0.14Gy / GBq, 0.41±0.13Gy / GBq, 0.41±0.12Gy / GBq, 0.41±0.11Gy / Provide a mean absorbed dose to the patient's kidneys of 1±0.09 Gy / GBq, 0.41±0.08 Gy / GBq, 0.41±0.07 Gy / GBq, 0.41±0.06 Gy / GBq, 0.41±0.05 Gy / GBq, 0.41±0.04 Gy / GBq, 0.41±0.03 Gy / GBq, 0.41±0.02 Gy / GBq, or 0.41±0.01 Gy / GBq 177 The present disclosure also relates to a method comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof, wherein radionuclide identification (gamma spectroscopy) of the solution shows gamma ray energy peaks at 113±2 keV and 208±4 keV, with no other significant peaks with gamma energies greater than 100 keV being detected. The present disclosure also relates to a method providing a mean absorbed dose to the patient's kidneys of 0.70 Gy / GBq or less, 0.65 Gy / GBq or less, 0.60 Gy / GBq or less, 0.55 Gy / GBq or less, 0.50 Gy / GBq or less, 0.45 Gy / GBq or less, 0.40 Gy / GBq or less, 0.35 Gy / GBq or less, 0.30 Gy / GBq or less, or 0.25 Gy / GBq or less. 177 The present invention relates to a method comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof.

[0053] The present disclosure also provides a method for providing a mean absorbed dose to the salivary glands of a patient that is 0.19±0.18 Gy / GB, 0.19±0.17 Gy / GBq, 0.19±0.16 Gy / GBq, 0.19±0.15 Gy / GBq, 0.19±0.14 Gy / GBq, 0.19±0.13 Gy / GBq, 0.19±0.12 Gy / GBq, 0.19±0.11 Gy / GBq, or 0.19±0.10 Gy / GBq. 177The present disclosure also relates to methods that provide a mean absorbed dose to the patient's salivary glands of 0.30 Gy / GBq or less, 0.25 Gy / GBq or less, 0.25 Gy / GBq or less, 0.20 Gy / GBq or less, 0.15 Gy / GBq or less, 0.10 Gy / GBq or less, or 0.05 Gy / GBq or less, comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof. 177 The present invention relates to a method comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof.

[0054] The present disclosure also provides a method for administering a therapeutically effective amount of 0.40±0.40 Gy / GBq, 0.40±0.39 Gy / GBq, 0.40±0.38 Gy / GBq, 0.40±0.37 Gy / GBq, 0.40±0.36 Gy / GBq, 0.40±0.35 Gy / GBq, 0.40±0.34 Gy / GBq, 0.40±0.33 Gy / GBq, 0.40±0.32 Gy / GBq, 0.40±0.31 Gy / GBq, 0.40±0.30Gy / GBq, 0.40±0.29Gy / GBq, 0.40±0.28Gy / GBq, 0.40±0.27Gy / GBq, 0.40±0.26Gy / GBq, 0.40±0.25Gy / GBq, 0.40±0.24Gy / GBq, 0.40±0.23Gy / GBq, 0.40±0.22Gy / GBq, 0.40±0.21Gy / GBq, 0.40 ±0.20Gy / GBq, 0.40±0.19Gy / GBq, 0.40±0.18Gy / GBq, 0.40±0.17Gy / GBq, 0.40±0.16Gy / GBq, 0.40±0.1 5Gy / GBq, 0.40±0.14Gy / GBq, 0.40±0.13Gy / GBq, 0.40±0.12Gy / GBq, 0.40±0.11Gy / GBq, 0.40±0.10Gy / G Bq, 0.40±0.09Gy / GBq, 0.40±0.08Gy / GBq, 0.40±0.07Gy / GBq, 0.40±0.06Gy / GBq, 0.40±0.05Gy / GBq, 0.40±0.04Gy / GBq, 0.40±0.03Gy / GBq, 0.40±0.02Gy / GBq, or 0.40±0.01Gy / GBq 177The present disclosure also relates to a method comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof, the method providing a mean absorbed dose to the patient's lacrimal gland of 1.10 Gy / GBq or less, 1.05 Gy / GBq or less, 1.00 Gy / GBq or less, 0.95 Gy / GBq or less, 0.90 Gy / GBq or less, 0.85 Gy / GBq or less, 0.80 Gy / GBq or less, 0.75 Gy / GBq or less, 0.70 Gy / GBq or less, 0.65 Gy / GBq or less, 0.60 Gy / GBq or less, 0.55 Gy / GBq or less, 0.50 Gy / GBq or less, 0.45 Gy / GBq or less, 0.40 Gy / GBq or less, or 0.35 Gy / GBq or less. 177 The present invention relates to a method comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof.

[0055] The present disclosure also relates to a method for providing a patient with a mean absorbed dose to the liver that is 0.04±0.10 Gy / GBq, 0.04±0.09 Gy / GBq, 0.04±0.08 Gy / GBq, 0.04±0.07 Gy / GBq, 0.04±0.06 Gy / GBq, 0.04±0.05 Gy / GBq, 0.04±0.04 Gy / GBq, 0.04±0.03 Gy / GBq, 0.04±0.02 Gy / GBq, or 0.04±0.01 Gy / GBq. 177 The present disclosure also relates to a method comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof, the method providing a mean absorbed dose to the patient's liver of 0.10 Gy / GBq or less, 0.09 Gy / GBq or less, 0.08 Gy / GBq or less, 0.07 Gy / GBq or less, 0.06 Gy / GBq or less, 0.05 Gy / GBq or less, 0.04 Gy / GBq or less, 0.03 Gy / GBq or less, 0.02 Gy / GBq or less, or 0.01 Gy / GBq or less. 177 The present invention relates to a method comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof.

[0056] The present disclosure also provides a method for providing a mean absorbed dose to the patient's kidneys that is less than or equal to 0.70 Gy / GBq, a mean absorbed dose to the patient's lacrimal glands that is less than or equal to 1.10 Gy / GBq, and a mean absorbed dose to the patient's salivary glands that is less than or equal to 0.30 Gy / GBq. 177 In another aspect, the disclosure relates to a method comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof, wherein the method provides a mean absorbed dose to the patient's kidneys of 0.60 Gy / GBq or less, a mean absorbed dose to the patient's lacrimal glands of 1.00 Gy / GBq or less, and a mean absorbed dose to the patient's salivary glands of 0.25 Gy / GBq or less. 177 In addition, the present disclosure relates to a method that provides a mean absorbed dose to the patient's kidneys of 0.50 Gy / GBq or less, a mean absorbed dose to the patient's lacrimal glands of 0.90 Gy / GBq or less, and a mean absorbed dose to the patient's salivary glands of 0.20 Gy / GBq or less. 177 The present invention relates to a method comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof.

[0057] The present disclosure provides a method for diagnosing or treating a tumor in a patient in need thereof, the method comprising: 177 The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 5.0, wherein 20 hours after injection, the radiopharmaceutical composition has an activity of at least 20% IA to 30% IA in the whole body.

[0058] The present disclosure provides a method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity in the kidney of at least 8% IA to 10% IA within 20 hours after injection.

[0059] The present disclosure provides a method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity in the parotid gland of at least 0.7% IA to 1% IA within 20 hours after injection.

[0060] The present disclosure provides a method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity of at least 0.2% IA to 0.5% IA in the patient's lymph node lesions within 20 hours after injection.

[0061] The present disclosure provides a method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity of at least 0.1% IA to 0.4% IA in the patient's bone lesions within 20 hours after injection.

[0062] The present disclosure provides a method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an effective half-life of about 30 to 40 hours in the patient's systemic environment.

[0063] Various refinements of the above-described features exist in connection with various aspects of the present disclosure. Additional features may be incorporated into these various aspects as well. These refinements and additional features may exist individually or in any combination. For example, various features discussed below in connection with one or more of the illustrated embodiments may be incorporated alone or in any combination into any of the foregoing aspects of the present disclosure. Again, the brief summary provided above is not intended as a limitation on the claimed subject matter, but is intended only to familiarize the reader with certain aspects and context of the present disclosure.

[0064] The various features, aspects, and advantages of the present disclosure will be better understood from the following detailed description when read in conjunction with the accompanying drawings, in which like characters represent like parts throughout. [Brief explanation of the drawings]

[0065] [Figure 1A] The structural formula of precursor PSMA I&T is shown. [Figure 1B] The structural formula of the R isomer of 177Lu-PSMA I&T is shown. However, PSMA I&T does not have a specification regarding the enantiomeric purity of the R and S isomers. [Figure 2] FIG. 1 is a flow chart diagram of an exemplary method for preparing the disclosed radiopharmaceutical compositions. [Figure 3A] 1 is a flowchart of the synthesis procedure for 177Lu-PSMA I&T in one embodiment. [Figure 3B] 1 is a flowchart of the synthesis procedure for 177Lu-PSMA I&T in one embodiment. [Figure 4] Drawings of exemplary product vials are shown. The pharmaceutical product is carried in Type 1 glass, sterile, pyrogen-free glass vials with fluorine-coated bromobutyl rubber septa. The septa are sealed with crimped aluminum capsules. The glass vials containing the radiopharmaceutical are kept in lead-shielded containers during transport. The shipping container, including the lead shielding and outer packaging, conforms to Type A requirements (IAEA standards). [Figure 5] 1 shows the radiochemical purity of [ 177 Lu]Lu-PSMA I&T measured by HPLC at different time points. [Figure 6A] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 7±0.1 at 0 and 71 hours after EOS, as detailed in Example 3. [Figure 6B] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 7±0.1 at 0 and 71 hours after EOS, as detailed in Example 3. [Figure 7A] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.4 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 71 hours after the end of synthesis (“EOS”), as detailed in Example 3. [Figure 7B] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.4 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 71 hours after the end of synthesis (“EOS”), as detailed in Example 3. [Figure 8A] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 3.5±0.1 at 0 and 90 hours after EOS, as detailed in Example 3. [Figure 8B] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 3.5±0.1 at 0 and 90 hours after EOS, as detailed in Example 3. [Figure 9A] 1 shows HPLC radiochromatograms of a low activity formulation containing 21 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 92 hours after EOS, as detailed in Example 3. [Figure 9B]1 shows HPLC radiochromatograms of a low activity formulation containing 21 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 92 hours after EOS, as detailed in Example 3. [Figure 10A] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 5±0.1 at 0 and 71 hours after EOS, as detailed in Example 3. [Figure 10B] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 5±0.1 at 0 and 71 hours after EOS, as detailed in Example 3. [Figure 11A] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 93 hours after EOS, as detailed in Example 3. [Figure 11B] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 93 hours after EOS, as detailed in Example 3. [Figure 12] Assessment of disease status and treatment decisions at baseline and during treatment are presented. [Figure 13] 1 shows the organ time-activity curves with all regions of interest (ROIs) outlined in one embodiment. Data (dots) represent the average across the 12 subjects analyzed. [Figure 14] 1 shows the mean time-integrated activity coefficient (TIAC) ​​and standard deviation (SD) for all contoured regions for the first six patients in one embodiment. [Figure 15] 1 shows maximum intensity projections of SPECT / CT images acquired for one subject 4 hours, 24 hours, 48 ​​hours, and 168 hours after injection in one embodiment. [Figure 16] The mean TIAC and SD for all contoured regions of the first 12 patients in one embodiment are shown. [Figure 17]1 illustrates a SPLASH study design in one embodiment. [Figure 18] 1 shows the RCP as a function of radiolabeled pH. [Figure 19] RCP as a function of sodium ascorbate concentration (reaction buffer) is shown. [Figure 20] The effect of reaction time and temperature on RCP is shown. [Figure 21] The RCP as a function of the molar ratio is shown. [Figure 22] 1 shows RCP as a function of elapsed time. [Figure 23] 1 shows RCP as a function of elapsed time. [Figure 24] 1 shows a RadioHPLC chromatogram of the 177 Lu-PSMA I&T composition at the time of formation / production (ie, TO) with a PSMA content of approximately 120 μg. [Figure 25] Figure 1 shows the RCP as a function of reaction buffer ageing time. [Figure 26] Organs of a representative patient are outlined. [Figure 27] The maximum intensity prediction of the SPECT / CT image in cycle 1 is shown. [Figure 28] Whole-body time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1 are shown. [Figure 29] Renal time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1 are shown. [Figure 30] Red bone marrow time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1 are shown. [Figure 31] Shown are salivary gland time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1. [Figure 32] GI time-activity curves expressed as percentage of injected activity for each patient imaged in cycle 10 are shown. [Figure 33]Liver time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1 are shown. [Figure 34] Spleen time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1 are shown. [Figure 35] Shown are lacrimal gland time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1. [Figure 36] Shown are the mean time-activity curves for cycle 1 for all source organs on a semi-logarithmic scale. [Figure 37] On a semi-logarithmic scale, plasma time activity curves in percent injected activity per liter are shown for cycle 1 patients (n=27). [Figure 38] Plasma time activity curves in percent injected activity per liter are shown for cycle 3 patients (n=15). [Figure 39] 1 shows the pH of the eight formulations prepared in this report as a function of time. [Figure 40] 1 shows the concentrations of PSMA I&T and related substances at TO, TO+72 hours, and TO+168 hours (times of measurement) for eight formulations prepared at various pH values. [Figure 41A] HPLC-UV chromatogram of the formulation at the time of release (T0 time) with a starting pH of 11.4. [Figure 41B] Figure 1 shows the HPLC-UV chromatogram of the formulation at the end of expiration (T0+72 hours) at a starting pH of 11.4. [Figure 42] Shown is the RCP at the end of expiry (T0+72 hours) of seven of the formulations plotted against the pH of the formulation measured at release (T0 hours). [Figure 43] Shown are the RCP values ​​at TO, TO+72 hours, and TO+168 hours for the four formulations held for 7 days (TO+168 hours). [Figure 44A] HPLC-UV chromatogram of the formulation at the time of release (T0 time) with a starting pH of 13.1. [Figure 44B]Figure 1 shows the HPLC-UV chromatogram of the formulation at the end of expiration (T0+72 hours) at a starting pH of 13.1. [Figure 44C] HPLC-UV chromatograms of formulations at starting pH 13.1 are shown for formulations at starting pH 11.4 at the end of expiration (T0+72 hours). [Figure 44D] HPLC-Radiometric chromatogram of formulation at starting pH 13.1 at end of expiry (T0+72 hours). [Figure 45A] Figure 1 shows HPLC-UV chromatograms at TO+168 hours for two formulations at a starting pH value of 3.6. [Figure 45B] Figure 1 shows HPLC-UV chromatograms at TO+168 hours for two formulations at a starting pH value of 4.1. [Figure 45C] Figure 1 shows HPLC-UV chromatograms at TO+168 hours for two formulations at a starting pH value of 4.5. [Figure 45D] Figure 1 shows HPLC-UV chromatograms at TO+168 hours for two formulations at a starting pH value of 4.9. [Figure 46] The effect of molar ratio on RCP is shown. [Figure 47] 1 shows the RCP of the four formulations prepared in this report plotted against the target DTPA concentration. [Figure 48A] The DTPA content for the formulations prepared in this report at the time of release (T0) and at the end of the expiry period (T0+72 hours) is shown. [Figure 48B] The percent free [Lu]Lu for the formulations prepared in this report at time of release (T0) and end of expiration (T0 + 72 hours) is shown. The dashed line at the top of the graph in Figure 48B indicates the 1% limit specification for the presence of free [Lu]Lu. [Figure 49A] HPLC-UV chromatograms at TO+72 hours are shown for formulations with a target DTPA concentration of 0 ppm. [Figure 49B]HPLC-UV chromatograms at TO+72 hours are shown for formulations with a target DTPA concentration of 10 ppm. [Figure 49C] HPLC-UV chromatograms at TO+72 hours are shown for formulations with a target DTPA concentration of 75 ppm. [Figure 49D] Figure 1 shows the HPLC-UV chromatogram at TO+72 hours for a formulation with a target DTPA concentration of 150 ppm. Relative peak areas are calculated by dividing the area of ​​the designated impurity peak by the sum of the areas of all integrated peaks. [Figure 50] HPLC-UV chromatograms at release (T0 time) of formulations with a target DTPA concentration of 150 ppm are shown. [Figure 51] 1 shows radiochemical purity at different molar ratios according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0066] It will be understood that, for simplicity and clarity of description, where appropriate, reference numerals have been repeated among the different figures to indicate corresponding or analogous elements. Additionally, numerous specific details have been set forth in order to provide a thorough understanding of the examples described herein. However, those skilled in the art will understand that the examples described herein may be practiced without these specific details. In other instances, methods, procedures, and components have not been described in detail so as not to obscure the relevant features being described. Additionally, the specification should not be considered as limiting the scope of the embodiments described herein. The drawings are not necessarily to scale, and the proportions of certain parts may be exaggerated to better illustrate the details and features of the present disclosure. 。

[0067] For example, disclosed herein are small molecule inhibitors of PSMA that possess the favorable attributes of large monoclonal antibodies with reduced negative factors such as low penetration and toxicity. 177Includes Lu-PSMA I&T. 177 Lu-PSMA I&T is a short-lived radiolabeled material from which the product is formulated immediately after final synthesis.

[0068] The headings included herein are for ease of reference only and are not intended to limit the disclosure in any way.

[0069] Additional features and advantages of the present disclosure will be set forth in the description that follows, and in part will be obvious from the description, or may be learned by practice of the principles disclosed herein. The features and advantages of the present disclosure may be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. These and other features of the present disclosure will become more fully apparent from the following specification and appended claims, or may be learned by practice of the principles set forth herein. All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0070] I. Definition Definitions that apply throughout the above disclosure are presented here. As used herein, the terms "comprising," "having," and "including" are used interchangeably in their open, non-limiting sense. The terms "a," "an," and "the" are understood to encompass plural and singular. Thus, the term "a mixture thereof" also relates to "mixtures thereof."

[0071] In general, provided ranges are intended to include all specific ranges within a given range and combinations of subranges between given ranges. Thus, a range of 1 to 5 specifically includes 1, 2, 3, 4, and 5, as well as subranges such as 2 to 5, 3 to 5, 2 to 3, 2 to 4, and 1 to 4. All ranges and values ​​disclosed herein are inclusive and combinable. For example, any value or point described herein within a range described herein can serve as a minimum or maximum value for deriving subranges, etc.

[0072] As used herein, "about" refers to numerical values, including integers, fractions, percentages, etc., whether explicitly stated or not. The term "about" generally refers to a range of numerical values, e.g., ±0.5-1%, ±1-5%, or ±5-10% of the recited value, that are considered equivalent to (e.g., have the same function or result as) the recited value.

[0073] As used herein, "PSMA" refers to prostate-specific membrane antigen, also known as folate hydrolase I or glutamate carboxypeptidase II, which is a type II transmembrane protein anchored to the cell membrane of prostate epithelial cells. PSMA is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer. PSMA expression level is directly correlated with androgen independence, metastasis, and the progression of prostate cancer. Therefore, PSMA is currently a promising molecular target for the diagnosis and therapy of metastatic prostate cancer.

[0074] As used herein, "lutetium-177" and " 177 Lu" are used interchangeably. 177 Lu is a beta- and gamma-emitting radionuclide with a physical half-life of 6.7 days. It has maximum and average beta particle energies of 0.498 MeV and 0.133 MeV, respectively. 177 The maximum and average soft tissue penetration depths of Lu are 1.7 mm and 0.23 mm, respectively. There are two major gamma emission lines: 113 keV (6% relative abundance) and 208 keV (11% relative abundance).

[0075] As used herein, " 177 "Lu-PSMA-617" refers to a DOTA derivative with a Glu-urea-Lys motif developed at the German Cancer Research Center (DKFZ) Heidelberg, Germany, for the treatment of patients with metastatic prostate cancer.

[0076] As used herein, "[ 177 Lu]Lu-PSMA I&T" and " 177 The terms "Lu-PSMA I&T" are used interchangeably and are used herein 177 Third generation derivatives of Lu-PSMA compounds for imaging and therapy (I&T) 177 This refers to Lu-PSMA. 177 The chemical name of Lu-PSMA I&T is (3S,7S,26R,29R,32R,37R)-29-benzyl-32-(4-hydroxy-3-iodobenzyl)-5,13,20,28,31,34-hexaoxo-37-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-heptaazaheptatriacontane-1,3,7,26,37-pentacarboxylic acid; lutetium-177(III). 177 The chemical structure of Lu-PSMA I&T is provided in Figure 1B.

[0077] The term "half-life" as used herein refers to biological half-life, e.g., the time required for the blood or plasma concentration of a drug to decrease by half. This decrease in drug concentration reflects its excretion or elimination after absorption is complete and distribution reaches an equilibrium or quasi-equilibrium state. The half-life of a drug in blood is typically measured by plotting the blood concentration time of the drug after intravenous administration to a sample population. Movement of The half-life can be determined graphically from the state plot. The technology It can also be determined using mathematical calculations well known in the art. Furthermore, as used herein, the term "half-life" means drugsAlso included is the "apparent half-life" of a drug, which may be a composite number that accounts for contributions from other processes besides elimination, such as absorption, reuptake, or enterohepatic recycling.

[0078] As used herein, "PRLT" refers to prostate radioligand therapy, and "RLT" refers to radioligand therapy. PRLT in this context involves the systemic intravenous administration of specific radiopharmaceuticals composed of a beta-emitting radionuclide chelated to a small molecule for the purpose of delivering cytotoxic radiation to cancer cells. All compositions and methods described herein can be used to treat PRLT and / or cancer.

[0079] As used herein, the term "CRPC" refers to castration-resistant prostate cancer. In some instances, patients with CRPC may have castrate serum testosterone levels of <50 μg / L or 1.7 nmol / L, as well as one of the following progression patterns: biochemical progression or radiological progression, as defined below. All compositions and methods described herein can be used to treat CRPC and / or cancer.

[0080] As used herein, the term "biochemical progression" refers to three consecutive rises in PSA at one-week intervals, two rises of 50% above the nadir, and a PSA >2 μg / l.

[0081] As used herein, the term "RAC" refers to radioactivity concentration.

[0082] As used herein, the term "radiologic progression" refers to the appearance of new lesions, i.e., either two or more new bone lesions or soft tissue lesions on a bone scan using Response Evaluation Criteria in Solid Tumors (RECIST).

[0083] As used herein, the terms "end of synthesis," "post-formulation," and "end of formulation" are used interchangeably to mean when the process of preparing a composition is complete, which may include quality control by qualified personnel and the time after release of the drug product.

[0084] The term "active agent" or "drug," as used herein, refers to any chemical substance that elicits a biochemical response when administered to a human or animal. A drug may act as a substrate or product of a biochemical reaction, or the drug may interact with a cellular receptor to elicit a physiological response, or the drug may bind to a receptor and block it from eliciting a physiological response.

[0085] The term "adverse event" (AE) is any undesirable medical occurrence in a subject administered an investigational drug, which does not necessarily have a causal relationship to treatment. An AE can be any untoward or unintended sign (e.g., abnormal laboratory finding), symptom, or disease temporarily associated with the use of the drug, whether or not drug-related. This includes any newly occurring event or pre-existing condition that has increased in severity or frequency since administration of the drug.

[0086] The terms "subject" and "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal, including, but not limited to, a human.

[0087] As used herein, "composition" refers to a radiopharmaceutical composition, and vice versa. Thus, "composition" and "radiopharmaceutical composition" may be used interchangeably.

[0088] The term "effective amount" or "effective dose" refers to an amount of a therapy (e.g., radiation provided herein, or another active agent described herein, such as an anti-cancer therapy described herein) that is sufficient to achieve its stated purpose or otherwise achieve the effect for which it is administered. An effective dose can be sufficient to reduce and / or ameliorate the progression, occurrence, recurrence, severity, and / or duration of a given disease, disorder, or condition, and / or its associated symptoms. An effective dose can be a "therapeutically effective dose," which refers to an amount sufficient to provide a therapeutic benefit, such as reducing or ameliorating the advancement or progression of a given disease, disorder, or condition, reducing or ameliorating the recurrence, occurrence, or onset of a given disease, disorder, or condition, and / or improving or enhancing the prophylactic or therapeutic effect(s) of another therapy. A therapeutically effective amount of a composition described herein can also enhance the therapeutic effectiveness of another therapeutic agent.

[0089] The terms "therapies," "therapy," and / or "treatment" refer to any protocol(s), method(s), and / or agent(s) that can be used in the prevention, treatment, management, and / or amelioration of a disease, disorder, or condition, or one or more symptoms thereof. In certain cases, the term refers to radioligand therapy (RLT), as described herein. The term "therapy" may refer to antiviral therapy, antibacterial therapy, antifungal therapy, anticancer therapy, biological therapy, replacement therapy, and / or other therapies useful in the treatment, management, prevention, or amelioration of a disease, disorder, or condition, or one or more symptoms thereof, known to one of ordinary skill in the art, e.g., a medical professional such as a physician.

[0090] The term "cancer" refers to any physiological condition in a mammal characterized by uncontrolled cell growth. Cancers described herein include solid tumors and hematological (blood) cancers, including, but not limited to, mCRPC. "Hematological cancer" refers to any blood-based cancer, including, for example, myeloma, lymphoma, and leukemia. "Solid tumor" or "tumor" refers to all precancerous and cancerous cells and tissues that cause lesions and neoplastic cell growth and proliferation, and abnormal tissue growth, whether malignant or benign. As used herein, "neoplastic" refers to any form of dysregulated or unregulated cell growth that causes abnormal tissue growth, whether malignant or benign.

[0091] The term "treating" or "treatment" refers to any indication of success or improvement in the progression, severity, and / or duration of a disease, lesion, or condition, including any objective or subjective parameter, such as relief, remission, alleviation of symptoms, or making an injury, lesion, or condition more tolerable to a patient, slowing the rate of regression or decline, reducing the debilitation at the end of regression, or improving a patient's physical or mental well-being. When treating cancer or tumors, treatment can include slowing tumor growth, stopping tumor growth, reducing or shrinking the size of a tumor, preventing a tumor from changing shape or morphology, preventing the spread of a tumor (e.g., preventing metastasis), increasing survival rates, and / or decreasing mortality rates.

[0092] The term "enhance" refers to an increase or improvement in the function or activity of a protein or cell after administration of a "treatment" or "therapy" as described herein, as compared to the protein or cell prior to administration or contact with a "treatment" or "therapy" as described herein, or an improvement in the overall well-being of a patient.

[0093] The term "administering" refers to the act of delivering a pharmaceutical or radiopharmaceutical composition described herein to a subject by a parenteral route, including intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration generally occurs after the onset of a disease, disorder, or condition, or a symptom thereof, but in certain cases can occur before the onset of a disease, disorder, or condition, or a symptom thereof (e.g., administration to a patient predisposed to such disease, disorder, or condition). As used herein, for the intravenous route of administration, the terms "injection" and "intravenous infusion" can be used interchangeably.

[0094] II. Introduction The present disclosure provides: 177 The present disclosure is directed to radiopharmaceutical compositions comprising Lu-PSMA I&T. In some embodiments, the compositions may be formulated as radiopharmaceutical solutions for injection or intravenous infusion. The present disclosure provides compounds that function as antitumor agents for targeted radionuclide therapy. 177 The present invention further relates to high-energy, high-purity, and / or low-toxicity radiopharmaceutical compositions comprising Lu-PSMA I&T.

[0095] The present disclosure is also directed to methods of making radiopharmaceutical compositions.Provided herein are methods of increasing the shelf life of radiopharmaceutical products.

[0096] The present disclosure further relates to properties of radiopharmaceutical compositions and methods of using radiopharmaceutical compositions.

[0097] 177 Lu-PSMA I&T is also known by the following synonyms: 177 Lu]lutetium-PSMA I&T, 177 Lu-ITG-PSMA-1, PSMA-TUM3, 177 Lu-DOTAGA-(Iy)fk(Sub-KuE), or 177Lu-(3S,7S)-29-benzyl-32(3-iodo,4-hydroxy)-benzyl-5,12,20,28,31,34-hexaoxo-37-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-heptaazaheptatriacontane-1,3,7,26,37-pentacarboxylic acid. The molecular formula of the unlabeled precursor is C 63 H 92 IN 11 O 23 ·4TFA·3H2O and has a relative molecular weight of 1498 g / mol.

[0098] Labeled substance 177 Lu-PSMA I&T is a non-carrier-doped lutetium-177 (T 1 / 2 =6.6d) can be labeled with solution. 177 Lu-PSMA I&T is a short-lived radiolabeled material from which the product is formulated immediately after final synthesis. Therefore, there are no specifications or batch analyses of the labeled material. Controls are performed on the labeled drug product.

[0099] Synthesized 177 The Lu-PSMA I&T solution may be formulated in an injection-grade aqueous solution containing a stabilizer such as ascorbic acid. The solution may be sterilized by aseptic filtration through a 0.22 μm filter before being dispensed into vials. Administration of the formulated solution may be within 72 hours of completion of synthesis, after quality control and release of the drug product. Administration of the formulated solution may be by injection or intravenous infusion into a human patient in need thereof, after quality control and release of the drug product, within 72 hours of completion of synthesis.

[0100] Ascorbic acid can be used to minimize radioactive degradation of radiolabeled preparations. In addition to ascorbic acid, maintaining the pH of the pharmaceutical product at 5 or less can stabilize the labeled product against radioactive degradation and extend its shelf life. Thus, in another aspect, the present disclosure further provides dosage formulations containing ascorbic acid at a pH of 5 or less, which improve the stability of the radiopharmaceutical composition against radioactive degradation and thus improve the shelf life of the composition.

[0101] The stability-enhancing conditions can be applied as early as possible in the manufacturing process. For example, a solution of ascorbic acid at a pH of 5 or less (e.g., a pH of 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.3, 3.2, 3.1, or 3.0) can be added to a labeled ascorbic acid solution. 177 It can be used in place of water in the purification steps of Lu-PSMA I&T to minimize radiolytic damage.

[0102] The compositions, when administered to a subject, can result in a low hematotoxicity and nephrotoxicity profile, providing better efficacy and fewer adverse effects than monoclonal antibody therapy and other comparable third-line therapies.

[0103] The composition is an improved composition in that it has a shelf life of 72 hours or more after formulation. In addition, the improved composition has a radiochemical purity of greater than 95% at the time of administration. That is, the improved formulation maintains a high level of radiochemical purity for 72 hours or more after formulation. Thus, the improved formulation 177 It is suitable for administration for up to 24 hours or up to 72 hours, or longer, than other compositions containing Lu-PSMA I&T.

[0104] III. Composition especially, 177Disclosed herein is a composition comprising Lu, a PSMA I&T, and one or more optional agents, including a buffer and / or a solvent. In one embodiment, the composition is suitable for administration to a human patient in need thereof.

[0105] In one embodiment, the composition has a radiochemical purity (RCP) of 95% or greater at the time of administration. In another embodiment, the composition has a radiochemical purity (RCP) of 97% or greater at the time of administration. In another embodiment, the composition has a radiochemical purity (RCP) of 97.5% or greater at the time of administration. In another embodiment, the composition has a radiochemical purity (RCP) of 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater at the time of administration.

[0106] In one embodiment, the composition has a radiochemical purity (RCP) of 95% or greater 72 hours after production. In another embodiment, the composition has a radiochemical purity (RCP) of 97% or greater 72 hours after production. In another embodiment, the composition has a radiochemical purity (RCP) of 97.5% or greater 72 hours after production. In another embodiment, the composition has a radiochemical purity (RCP) of 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater 72 hours after production. In another embodiment, the composition has a radiochemical purity (RCP) of 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, or 95% or greater 7 days after production.

[0107] In one embodiment, the composition has a radiochemical purity (RCP) of 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater after 7 days from production.

[0108] In one embodiment, the composition is produced as part of a 4 Ci to 10 Ci batch scale. In another embodiment, the composition is produced as part of a 4 Ci to 15 Ci batch scale.

[0109] A certain dose 177Further disclosed herein is a radiopharmaceutical composition or formulation comprising an Lu-PSMA I&T and at least one of a stabilizer, an antioxidant, a pH adjuster, a metal ion chelator, water, or a combination thereof.

[0110] In one specific embodiment, the stabilizer is ascorbic acid. In another embodiment, the antioxidant may be ethanol, ascorbic acid, gentisic acid, or a combination thereof. In another embodiment, the pH adjuster includes, but is not limited to, sodium hydroxide, sodium bicarbonate, hydrochloric acid, or a combination thereof. In yet another embodiment, the chelating agent may be EDTA or DTPA. In another specific embodiment, the stabilizer is ethanol-free (i.e., 0% ethanol, less than 0.5% ethanol, or less than 1.0% ethanol (w / w) in the composition).

[0111] In one embodiment, the pharmaceutical product or radiopharmaceutical composition (or formulation) is dissolved in an aqueous solution of ascorbic acid containing ethanol. 177 The radiopharmaceutical solution may be a sterile-filtered solution containing a dose of Lu-PSMA I&T. For example, the total amount of ascorbic acid in the solution may be about 25 to about 65 mg / mL, and the total amount of ethanol in the solution may be about 3.8% (v / v) to about 7.5% (v / v). In some embodiments, the total amount of ascorbic acid in the solution is about 21 mg / mL to about 42.5 mg / mL. 177 Lu-PSMA I&T is present in sufficient amounts of radioactivity for its intended use. Experiments conducted with various dosage formulations contain approximately 31 mg / ml ascorbic acid at a pH of approximately 4.5, and radioactivity concentrations of approximately 640 MBq / ml or less. 177 These results suggest that the Lu-PSMA I&T formulation composition can provide sufficient radiochemical stability for 4 days. The sufficient radiochemical stability referred to herein is 177The radiopharmaceutical composition has a radiochemical purity of at least 95%, 95.5% or more, 96.5% or more, 97.0% or more, 97.5% or more, 98.0% or more, 98.5% or more, 99.0% or more, or 99.5% or more of Lu-PSMA I&T at the time of administration.

[0112] In one embodiment, the radiopharmaceutical composition comprises a small amount of ascorbic acid in an aqueous solution and an ethanol solution. 177 In another embodiment, the radiopharmaceutical composition is a sterile-filtered radiopharmaceutical solution containing Lu-PSMA I&T. In another embodiment, the radiopharmaceutical composition is a small amount of ascorbic acid in an aqueous solution without an ethanol solution. 177 A sterile filtered radiopharmaceutical solution containing Lu-PSMA I&T. For example, the radiopharmaceutical composition may be a microdose solution of DTPA or EDTA in aqueous ascorbic acid and ethanol (e.g., with or without ethanol). 177 The product is diluted to a standard radioactivity concentration, and the final volume of the bulk product is then introduced. 177 Varies depending on the starting activity of Lu.

[0113] One aspect of the present disclosure provides a radiopharmaceutical composition having a pH of about 3 to about 9, about 4 to about 9, about 5 to about 9, about 3 to about 8, about 4 to about 8, about 3 to about 5, or about 5 to about 8. The pH of the radiopharmaceutical composition may be about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, It may be about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, or about 9.

[0114] Having a pH of 5 or less can stabilize the radiopharmaceutical composition against radiolysis and extend its shelf life.

[0115] In one embodiment, the pH of the radiopharmaceutical composition is from about 3 to about 5. This pH range can stabilize the radiopharmaceutical composition against radiolysis and extend its shelf life. In yet another embodiment, a radiopharmaceutical composition containing ascorbic acid and having a pH of from about 3.5 to about 5 can have a higher pH value and contain gentisic acid. 177 Lu-PSMA I&T have improved stability and extended shelf life compared to known radiopharmaceutical compositions. In other embodiments, the radiopharmaceutical composition may comprise the absence of gentisic acid (i.e., no gentisic acid). In yet another embodiment, a radiopharmaceutical composition comprising ascorbic acid and having a pH of about 4.0 to about 4.5 has improved stability and extended shelf life.

[0116] The pH of the radiopharmaceutical composition may be 3.0 to 5.0, 3.0 to 3.5, 3.0 to 3.05, 3.05 to 3.1, 3.0 to 3.1, 3.1 to 3.15, 3.1 to 3.2, 3.15 to 3.2, 3.2 to 3.25, 3.0 to 3.25, 3.2 to 3.3, 3.25 to 3.3, 3.3 to 3.35, 3.3 to 3.4, 3.35 to 3.4, 3.4 to 3.45, 3.4 to 3.5, 3.45 ... 3.5, 3.25~3.5, 3.5~3.55, 3.5~3.6, 3.55~3.6, 3.6~3.65, 3.6~3.7, 3.65~3.7, 3.7~3.75, 3.5~3.75, 3.7~3.8, 3.75~3.8, 3.8~3.85, 3.8~3.9, 3.85~3.9, 3.9~3.95, 3.9~4.0, 3.95~4.0, 3.5~4.0, 3.75 ~4.0, 4.0~4.05, 4.0~4.1, 4.05~4.1, 4.1~4.15, 4.1~4.2, 4.15~4.2, 3.5~4.2, 4.2~4.25, 4.0~4.25, 4.2~4.3, 4.25~4.3, 4.3~4.35, 4.3~4.4, 4.35~4.4, 4.4~4.45, 4.4~4.5, 4.45~4.5, 4.25~4.5, 4.0 The pH of the radiopharmaceutical composition may range from 4.5 to 4.55, 4.5 to 4.6, 4.55 to 4.6, 4.6 to 4.65, 4.6 to 4.7, 4.65 to 4.7, 4.7 to 4.75, 4.7 to 4.8, 4.75 to 4.8, 4.8 to 4.85, 4.8 to 4.9, 4.85 to 4.9, 4.9 to 4.95, 4.9 to 5.0, 4.95 to 5.0, 4.5 to 5.0, or 4.75 to 5.0. In some examples, the pH of the radiopharmaceutical composition may be adjusted to a final pH of 3.0, 3.5, 4.0, 4.5, or 5.0. In some embodiments, including those pH numbers and ranges listed above, the pH value comprises ±0.05, ±0.10, ±0.15, ±0.20, or ±0.25.

[0117] In another embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 90%, at least about 95%, at least about 97%, or at least about 99%. In another embodiment, the radiopharmaceutical composition or formulation has a purity of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%.

[0118] In another embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 90%, at least about 95%, at least about 97%, or at least about 99% as measured by HPLC, TLC, or liquid chromatography. In another embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 90.0%, at least about 91.0%, at least about 92.0%, at least about 93.0%, at least about 94.0%, at least about 95.0%, at least about 96.0%, at least about 97.0%, at least about 98.0%, at least about 99.0%, or at least about 99.5% as measured by HPLC or TLC. In some examples, the radiopharmaceutical composition may have a radiochemical purity of 95.0% or greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater upon administration. Figure 5 shows the radiochemical purity of formulations prepared at different pH values.

[0119] In another embodiment, the purity of the radiopharmaceutical composition or formulation is measured by HPLC or TLC at any time after the end of synthesis (EOS). In one embodiment, the purity of the radiopharmaceutical composition or formulation is measured by HPLC or TLC at about 0 hours, about 10 hours, about 20 hours, about 30 hours, about 40 hours, about 50 hours, about 50 hours, about 60 hours, about 70 hours, about 80 hours, about 90 hours, about 100 hours, about 120 hours, and about 168 hours after EOS.

[0120] In one specific embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 99% as measured by HPLC or TLC at 0 hours after EOS. In another specific embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 96.5% as measured by HPLC or TLC at 24 hours after EOS, at least about 93% as measured by HPLC or TLC at 46 hours after EOS, at least about 95% as measured by HPLC or TLC at 67 hours after EOS, and at least about 96% as measured by HPLC or TLC at 92 hours after EOS.

[0121] In another embodiment, the radioactivity is measured with a dose calibrator. 177 The radioactivity of the Lu-PSMA I&T is determined when the dose is dispensed prior to patient administration.

[0122] In yet another embodiment, 177 The radiochemical purity of Lu-PSMA I&T is determined by liquid chromatography and thin layer chromatography with radioactivity detection.

[0123] In one embodiment, bacterial endotoxin content is measured using a PTS tester (PhEur Method D or USP <85> ) is used to determine the sterility of each batch prior to release, and sterility is determined according to Ph Eur and USP <71> The judgment is made according to the following.

[0124] In one embodiment, the radiopharmaceutical composition or formulation is stored at a temperature of about +5° C. to +55° C., about +5° C. to +40° C., about +10° C. to +35° C., or about +20° C. to +30° C. In a specific embodiment, the radiopharmaceutical composition or formulation is stored at a temperature of about +10° C., about +15° C., about +22° C., about +22.5° C., about +25° C., or at room temperature.

[0125] Another aspect of the present disclosure provides a radioactive content of about 70% to 130%. The radioactive content of the radiopharmaceutical composition can be about 90% to 125%, 90% to 120%, 90% to 115%, or 90% to 110%.

[0126] In a specific embodiment, the radioactive content of the formulation is about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, or about 130%.

[0127] Another aspect of the present disclosure provides a radiopharmaceutical composition having a mean whole-body effective dose of about 23±20 Gy (3.3 Gy / GBq), and mean absorbed organ doses of about 26±20 Gy (3.4 Gy / GBq), 24±16 Gy (3.2 Gy / GBq), 8.5±4.7 Gy (1.28 Gy / GBq), and 13±7.4 Gy (1.7 Gy / GBq) for bone metastases, lymph node metastases, liver metastases, and lung metastases, respectively.

[0128] In some embodiments, the radiopharmaceutical composition may have a low radioactivity concentration ("low RAC") of about 563 MBq / ml to about 734 MBq / ml. For example, the radiopharmaceutical composition may have a low activity that may be about 11,580 MBq (313 mCi), about 11,770 MBq (318 mCi), or about 12,520 MBq (338 mCi) in a 20 ml volume of solution. In other embodiments, the radiopharmaceutical composition may have a low radioactivity concentration of at least about 550 MBq / ml, at least about 560 MBq / ml, at least about 570 MBq / ml, at least about 580 MBq / ml, at least about 590 MBq / ml, at least about 600 MBq / ml, at least about 610 MBq / ml, at least about 620 MBq / ml, at least about 630 MBq / ml, at least about 640 MBq / ml, at least about 650 MBq / ml, at least about 660 MBq / ml, at least about 670 MBq / ml, at least about 680 MBq / ml, at least about 690 MBq / ml, at least about 700 MBq / ml, at least about 710 MBq / ml, at least about 720 MBq / ml, at least about 730 MBq / ml, at least about 740 MBq / ml, or at least about 750 MBq / ml. In still other embodiments, the radiopharmaceutical composition may have a low radioactivity concentration of about 550 MBq / ml to about 575 MBq / ml, about 575 MBq / ml to about 600 MBq / ml, about 600 MBq / ml to about 625 MBq / ml, about 625 MBq / ml to about 650 MBq / ml, about 650 MBq / ml to about 675 MBq / ml, about 675 MBq / ml to about 700 MBq / ml, about 700 MBq / ml to about 725 MBq / ml, about 725 MBq / ml to about 750 MBq / ml or about 625 MBq / ml to about 650 MBq / ml.

[0129] In additional embodiments, the radiopharmaceutical composition may have a high radioactivity concentration ("high RAC") of about 1,270 MBq / ml to about 1,311 MBq / ml. For example, the radiopharmaceutical composition may have a high radioactivity that may be about 12,780 MBq (345 mCi), about 12,810 MBq (346 mCi), or about 13,110 MBq (354 mCi) in a 10 ml volume of solution. In other embodiments, the radiopharmaceutical composition is at least about 1,100 MBq / ml, at least about 1,110 MBq / ml, at least about 1,120 MBq / ml, at least about 1,130 MBq / ml, at least about 1,140 MBq / ml, at least about 1,150 MBq / ml, at least about 1,160 MBq / ml, at least about 1,170 MBq / ml, at least about 1,180 MBq / ml, at least about 1,190 MBq / ml, at least about 1,200 MBq / ml, at least about 1,210 MBq / ml, at least about 1,220 MBq / ml, at least about 1,230 MBq / ml, at least about 1,240 MBq / ml, at least about 1,250 MBq / ml, at least about 1,260 MBq / ml, at least about 1,270 MBq / ml, at least about 1,280 MBq / ml, at least about 1,300 MBq / ml, at least about 1,310 MBq / ml, at least about 1,320 MBq / ml, at least about 1,330 MBq / ml, at least about 1,340 MBq / ml, at least about 1,350 MBq / ml, at least about 1,360 MBq / ml, at least about 1,370 MBq / ml, at least about 1,380 MBq / ml, at least about 1,390 MBq / ml, at least about 1,400 MBq / ml, at least about 1,410 MBq / ml, at least about 1,420 MBq / ml, at least about 1,430 MBq / ml, at least about 1,440 MBq / ml, at least about 1,450 MBq / ml, at least about 1,46 The radioactive material may have a high radioactivity concentration of 20 MBq / ml, at least about 1,230 MBq / ml, at least about 1,240 MBq / ml, at least about 1,250 MBq / ml, at least about 1,260 MBq / ml, at least about 1,270 MBq / ml, at least about 1,280 MBq / ml, at least about 1,290 MBq / ml, at least about 1,300 MBq / ml, at least about 1,310 MBq / ml, at least about 1,320 MBq / ml, at least about 1,330 MBq / ml, at least about 1,340 MBq / ml, or at least about 1,350 MBq / ml. In still other embodiments, the radiopharmaceutical composition may have a high radioactivity concentration of about 1,000 MBq / ml to about 1,400 MBq / ml, about 1,050 MBq / ml to about 1,350 MBq / ml, about 1,100 MBq / ml to about 1,300 MBq / ml, about 1,150 MBq / ml to about 1,250 MBq / ml, about 1,200 MBq / ml to about 1,300 MBq / ml, about 1,250 MBq / ml to about 1,350 MBq / ml, or about 1,250 MBq / ml to about 1,300 MBq / ml.

[0130] (i) 177 Lu-PSMA I&T present in the radiopharmaceutical composition 177The total amount of Lu-PSMA I&T can and will vary. Figures 1A and 1B show the precursor PSMA I&T and 177 The chemical structure of Lu-PSMA I&T is shown.

[0131] In one embodiment, the radiopharmaceutical component ( 177 In yet another embodiment, the mass of the radiopharmaceutical component (Lu-PSMA I&T) in the drug product is less than about 40 μg, less than about 35 μg, less than about 30 μg, less than about 25 μg, less than about 20 μg, less than about 15 μg, or less than about 10 μg per vial. 177 The mass of Lu-PSMA I&T) is about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, or about 10 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 17.2 μg, about 18 μg per vial. About 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg, about 25 μg, about 26 μg, about 27 μg, about 28 μg, about 29 μg, about 30 μg, about 31 μg, about 32 μg, about 33 μg, about 34 μg, about 35 μg, about 36 μg, about 37 μg, about 38 μg, about 39 μg, or about 40 μg 177 Lu-PSMA I&T.

[0132] In one embodiment, present in the pharmaceutical composition 177 The total amount of Lu-PSMA I&T can be varied and will change. In the labeling process, the PSMA I&T ligand may be labeled with the trace metal present to form a chelated trace metal-PSMA I&T complex (i.e., "M-PSMA I&T"). Excess PSMA I&T present in the labeling process may be 177 The amount of M-PSMA I&T and unlabeled PSMA I&T in the composition is hereinafter referred to as "related substances" or "RS." The composition is then 177It may contain both Lu-PSMA I&T, M-PSMA I&T, and unlabeled PSMA I&T. In one embodiment, the PSMA content, including PSMA I&T and related substances (RS), is 250 μg / dose ±15%, ±10%, or ±5%. In another embodiment, the PSMA I&T content is 120 μg / dose ±15%, ±10%, or ±5% to about 250 μg / dose ±15%, ±10%, or ±5%. In another embodiment, the PSMA I&T content is about 100 μg / dose ±15%, ±10%, or ±5% to about 120 μg / dose ±15%, ±10%, or ±5%. In another embodiment, the PSMA I&T content is 120 μg / dose ±15%, ±10%, or ±5% to about 200 μg / dose ±15%, ±10%, or ±5%. In yet another embodiment, the PSMA I&T content is about 40 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%, 50 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%, 60 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%, or 70 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%. In yet another embodiment, the PSMA I&T content is about 40 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%, 50 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%, 60 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%, or 70 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%.In yet another embodiment, the PSMA I&T content is about 40 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%, 50 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%, 60 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%, or 70 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%.

[0133] In another embodiment, the method described herein 177 Lu-PSMA Compositions containing I&T may include about 120 μg / dose to about 250 μg / dose, about 130 μg / dose to about 250 μg / dose, about 140 μg / dose to about 250 μg / dose Amount, about 150μg / dose to about 250μg / dose, about 160μg / dose to about 250μg / dose, about 170μg / dose to about 250μg / dose, about 180μg / dose Amount ~ approx. 250 μg / dose, approx. 190 μg / dose ~ approx. 250 μg / dose, approx. 200 μg / dose ~ approx. 250 μg / dose, approx. 210 μg / dose ~ approx. 250 μg / dose PSMA in an amount of about 220 μg / dose to about 250 μg / dose, about 230 μg / dose to about 250 μg / dose, or about 240 μg / dose to about 250 μg / dose In another embodiment, the I&T content may be 177 Compositions comprising Lu-PSMA I&T may comprise a PSMA I&T content of about 100 μg / dose to about 120 μg / dose, about 105 μg / dose to about 120 μg / dose, about 110 μg / dose to about 120 μg / dose, or about 115 μg / dose to about 120 μg / dose. 177Compositions comprising Lu-PSMA I&T may comprise a PSMA I&T content of about 40 μg / dose to about 100 μg / dose, about 45 μg / dose to about 100 μg / dose, about 50 μg / dose to about 100 μg / dose, about 55 μg / dose to about 100 μg / dose, about 60 μg / dose to about 100 μg / dose, about 65 μg / dose to about 100 μg / dose, about 70 μg / dose to about 100 μg / dose, about 75 μg / dose to about 100 μg / dose, about 80 μg / dose to about 100 μg / dose, about 85 μg / dose to about 100 μg / dose, about 90 μg / dose to about 100 μg / dose, or about 95 μg / dose to about 100 μg / dose. 177 Compositions comprising Lu-PSMA I&T may comprise a PSMA I&T content of about 45 μg / dose to about 95 μg / dose, 50 μg / dose to about 100 μg / dose, 55 μg / dose to about 95 μg / dose, 60 μg / dose to about 95 μg / dose, 65 μg / dose to about 95 μg / dose, 70 μg / dose to about 95 μg / dose, 75 μg / dose to about 95 μg / dose, 80 μg / dose to about 95 μg / dose, 85 μg / dose to about 95 μg / dose, or about 90 μg / dose to about 95 μg / dose. 177 Compositions comprising Lu-PSMA I&T may comprise a PSMA I&T content of about 40 μg / dose to about 90 μg / dose, about 45 μg / dose to about 90 μg / dose, about 50 μg / dose to about 90 μg / dose, about 55 μg / dose to about 90 μg / dose, about 60 μg / dose to about 90 μg / dose, about 65 μg / dose to about 90 μg / dose, about 70 μg / dose to about 90 μg / dose, about 75 μg / dose to about 90 μg / dose, about 80 μg / dose to about 90 μg / dose, or about 85 μg / dose to about 90 μg / dose. 177Compositions comprising Lu-PSMA I&T may include a PSMA I&T content of about 40 μg / dose to about 85 μg / dose, about 45 μg / dose to about 85 μg / dose, about 50 μg / dose to about 85 μg / dose, about 55 μg / dose to about 85 μg / dose, about 60 μg / dose to about 85 μg / dose, about 65 μg / dose to about 85 μg / dose, about 70 μg / dose to about 85 μg / dose, about 75 μg / dose to about 85 μg / dose, or about 80 μg / dose to about 85 μg / dose. In another embodiment, the compositions described herein may include a PSMA I&T content of about 40 μg / dose to about 85 μg / dose, about 45 μg / dose to about 85 μg / dose, about 50 μg / dose to about 85 μg / dose, about 55 μg / dose to about 85 μg / dose, about 60 μg / dose to about 85 μg / dose, about 65 μg / dose to about 85 μg / dose, about 70 μg / dose to about 85 μg / dose, about 75 μg / dose to about 85 μg / dose, or about 80 μg / dose to about 85 μg / dose. 177 Compositions comprising Lu-PSMA I&T may comprise a PSMA I&T content of about 40 μg / dose to about 80 μg / dose, about 45 μg / dose to about 80 μg / dose, about 50 μg / dose to about 80 μg / dose, about 55 μg / dose to about 80 μg / dose, about 60 μg / dose to about 80 μg / dose, about 65 μg / dose to about 80 μg / dose, about 70 μg / dose to about 80 μg / dose, or about 75 μg / dose to about 80 μg / dose. 177 Lu-PSMA Compositions comprising I&T may include about 40 μg / dose to about 75 μg / dose, about 45 μg / dose to about 75 μg / dose, about 50 μg / dose to about 75 μg / dose, about 55 μg / dose PSMA that is a dose ~ about 75μg / dose, about 60μg / dose ~ about 75μg / dose, about 65μg / dose ~ about 75μg / dose, about 70μg / dose ~ about 75μg / dose May contain I&T content.

[0134] In one embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 120 μg per dose, 35 μg to 120 μg per dose, 40 μg to 120 μg per dose, 45 μg to 120 μg per dose, 50 μg to 120 μg per dose, 55 μg to 120 μg per dose, 60 μg to 120 μg per dose, 65 μg to 120 μg per dose, 70 μg to 120 μg per dose, 75 μg to 120 μg per dose, 85 μg to 120 μg per dose, 90 μg to 120 μg per dose, 95 μg to 120 μg per dose, 100 μg to 120 μg per dose, 105 μg to 120 μg per dose, 110 μg to 120 μg per dose, or 115 μg to 120 μg per dose. In one embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 100 μg per dose, 35 μg to 100 μg per dose, 40 μg to 100 μg per dose, 45 μg to 100 μg per dose, 50 μg to 100 μg per dose, 55 μg to 100 μg per dose, 60 μg to 100 μg per dose, 65 μg to 100 μg per dose, 70 μg to 100 μg per dose, 75 μg to 100 μg per dose, 85 μg to 100 μg per dose, or 90 μg to 100 μg per dose. In another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 90 μg per dose, 35 μg to 90 μg per dose, 40 μg to 90 μg per dose, 45 μg to 90 μg per dose, 50 μg to 90 μg per dose, 55 μg to 90 μg per dose, 60 μg to 90 μg per dose, 65 μg to 90 μg per dose, 70 μg to 90 μg per dose, 75 μg to 90 μg per dose, or 85 μg to 90 μg per dose. In another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 80 μg per dose, 35 μg to 80 μg per dose, 40 μg to 80 μg per dose, 45 μg to 80 μg per dose, 50 μg to 80 μg per dose, 55 μg to 80 μg per dose, 60 μg to 80 μg per dose, 65 μg to 80 μg per dose, 70 μg to 80 μg per dose, or 75 μg to 80 μg per dose.In yet another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 70 μg, 35 μg to 70 μg per dose, 40 μg to 70 μg per dose, 45 μg to 70 μg per dose, 50 μg to 70 μg per dose, 55 μg to 70 μg per dose, 60 μg to 70 μg per dose, or 65 μg to 70 μg per dose.

[0135] In one embodiment, the PSMA present in the pharmaceutical composition The amount of I&T and related substances (RS) is about 30 μg to 120 μg per dose, 35 μg to 120 μg per dose, 40 μg to 120 μg per dose, 45 μg to 120 μg per dose, 50 μg to 120 μg per dose, 55 μg to 120 μg per dose, 60 μg to 120 μg per dose, 65 μg to 120 μg per dose, 70 μg to 120 μg per dose, 75 μg to 120 μg per dose, 85 μg to 120 μg per dose, 90 μg to 120 μg per dose, 95 μg to 120 μg per dose, 100 μg to 120 μg per dose, 105 μg to 120 μg per dose, 110 μg to 120 μg per dose, or 115 μg to 120 μg per dose. In one embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 30 μg to 100 μg per dose, 35 μg to 100 μg per dose, 40 μg to 100 μg per dose, 45 μg to 100 μg per dose, 50 μg to 100 μg per dose, 55 μg to 100 μg per dose, 60 μg to 100 μg per dose, 65 μg to 100 μg per dose, 70 μg to 100 μg per dose, 75 μg to 100 μg per dose, 85 μg to 100 μg per dose, or 90 μg to 100 μg per dose. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 30 μg to 90 μg per dose, 35 μg to 90 μg per dose, 40 μg to 90 μg per dose, 45 μg to 90 μg per dose, 50 μg to 90 μg per dose, 55 μg to 90 μg per dose, 60 μg to 90 μg per dose, 65 μg to 90 μg per dose, 70 μg to 90 μg per dose, 75 μg to 90 μg per dose, or 85 μg to 90 μg per dose. The amount of I&T and related substances (RS) is about 30 μg to 80 μg per dose, 35 μg to 80 μg per dose, 40 μg to 80 μg per dose, 45 μg to 80 μg per dose, 50 μg to 80 μg per dose, 55 μg to 80 μg per dose, 60 μg to 80 μg per dose, 65 μg to 80 μg per dose, 70 μg to 80 μg per dose, or 75 μg to 80 μg per dose. The amount of I&T and related substances (RS) is about 30 μg to 70 μg, 35 μg to 70 μg per dose, 40 μg to 70 μg per dose, 45 μg to 70 μg per dose, 50 μg to 70 μg per dose, 55 μg to 70 μg per dose, 60 μg to 70 μg per dose, or 65 μg to 70 μg per dose.

[0136] In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 55 μg to 110 μg per dose, hi another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 75 μg to 100 μg per dose.

[0137] In one embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 80 μg to 110 μg per dose. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 70 μg to 85 μg per dose. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 73 μg to 85 μg per dose. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 90 μg to 115 μg per dose. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 100 μg to 80 μg per dose.

[0138] In one embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 110 μg to 80 μg per dose. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 115 μg to 125 μg per dose. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 115 μg to 130 μg per dose.

[0139] In one embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 45 μg, 50 μg, 57 μg, 60 μg, 70 μg, 75 μg, 80 μg, 85 μg, 99 μg, 100 μg, 115 μg, 80 μg, 125 μg, 130 μg per vial. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 80 μg.

[0140] In one embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 57 μg. In one embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 99 μg.

[0141] In one embodiment, the total volume of the vial containing the PSMA I&T and related substances (RS) is about 5-30 mL. In another embodiment, the total volume of the vial containing the PSMA I&T and related substances (RS) is about 10-20 mL. In another embodiment, the total volume of the vial containing the PSMA I&T and related substances (RS) is about 15-20 mL. In another embodiment, the total volume of the vial containing the PSMA I&T and related substances (RS) is about 15-17 mL. In another embodiment, the total volume of the vial containing the PSMA I&T and related substances (RS) is about 15 mL.

[0142] In one embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 3-8 μg / mL. In another embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 4-7 μg / mL. In another embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 4.5-6.5 μg / mL. In another embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 4.8-6 μg / mL.

[0143] In one embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 4 μg / mL. In another embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 5 μg / mL. In another embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 6 μg / mL. In another embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 7 μg / mL. In another embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 8 μg / mL.

[0144] In one embodiment, the PSMA I&T in the composition 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 5.0:1.0 to 12.0:1.0. 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 5.0:1.0 to 12.0:1.0, 5.0:1.0 to 11.5:1.0, 5.0:1.0 to 11.0:1.0, 5.0:1.0 to 10.5:1.0, 5.0:1.0 to 10.0:1.0, 5.0:1.0 to 9.5:1.0, 5.0:1.0 to 9.0:1.0, 5.0:1.0 to 8.5:1.0, 5.0:1.0 to 8.0:1.0, 5.0:1.0 to 7.5:1.0, 5.0:1.0 to 7.0:1.0, 5.0:1.0 to 6.5:1.0, or 5.0:1.0 to 6.0:1.0. 177The molar ratios to Lu were 4.0:1.0 to 11.0:1.0, 4.0:1.0 to 10.5:1.0, 4.0:1.0 to 10.0:1.0, 4.0:1.0 to 9.5:1.0, 4.0:1.0 to 9.0:1.0, 4.0:1.0 to 8.5:1.0, 4.0:1.0 to 8.0:1.0, 4.0:1.0 to 7.9:1.0, 4.0:1.0 to 7.8:1.0, 4.0 :1.0~7.7:1.0, 4.0:1.0~7.6:1.0, 4.0:1.0~7.5:1.0, 4.0:1.0~7.4:1.0, 4.0:1.0~7.3:1.0, 4.0:1.0~7.2:1.0, 4.0:1.0~7.1:1.0, 4.0:1.0~7.0:1.0, 4.0:1.0~6.5:1.0, or 4.0:1.0~6.0:1.0.

[0145] In one embodiment, upon administration, the PSMA I&T in the composition 177 In another embodiment, the molar ratio of PSMA to Lu is 3.0:1.0 to 11.0:1.0. I&T 177 The molar ratios to Lu were 3.0:1.0 to 11.0:1.0, 3.0:1.0 to 10.5:1.0, 3.0:1.0 to 10.0:1.0, 3.0:1.0 to 9.5:1.0, 30:1.0 to 9.0:1.0, 3.0:1.0 to 8.5:1.0, 3.0:1.0 to 8.0:1.0, 3.0:1.0 to 7.9:1.0, 3.0:1.0 to 7.8:1.0, 3.0: 1.0 to 7.7:1.0, 3.0:1.0 to 7.6:1.0, 3.0:1.0 to 7.5:1.0, 3.0:1.0 to 7.4:1.0, 3.0:1.0 to 7.3:1.0, 3.0:1.0 to 7.2:1.0, 3.0:1.0 to 7.1:1.0, 3.0:1.0 to 7.0:1.0, 3.0:1.0 to 6.5:1.0, or 3.0:1.0 to 6.0:1.0.

[0146] In one embodiment, upon administration, the PSMA I&T in the composition 177In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 11.0:1.0 to 12.0:1.0, 11.1:1.0 to 11.9:1.0, 11.2:1.0 to 11.8:1.0, 11.3:1.0 to 11.7:1.0, or 11.4:1.0 to 11.6:1.0. 177 The molar ratio to Lu is 10.0:1.0 to 11.0:1.0, 10.1:1.0 to 10.9:1.0, 10.2:1.0 to 10.8:1.0, 10.3:1.0 to 10.7:1.0, or 10.4:1.0 to 10.6:1.0.

[0147] In one embodiment, the PSMA I&T in the composition 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 9.0:1.0 to 10.0:1.0, 9.1:1.0 to 9.9:1.0, 9.2:1.0 to 9.8:1.0, 9.3:1.0 to 9.7:1.0, or 9.4:1.0 to 9.6:1.0. 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 8.0:1.0 to 9.0:1.0, 8.1:1.0 to 8.9:1.0, 8.2:1.0 to 8.8:1.0, 8.3:1.0 to 8.7:1.0, or 8.4:1.0 to 8.6:1.0. 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 7.0:1.0 to 8.0:1.0, 7.1:1.0 to 7.9:1.0, 7.2:1.0 to 7.8:1.0, 7.3:1.0 to 7.7:1.0, or 7.4:1.0 to 7.6:1.0. 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 6.0:1.0 to 7.0:1.0, 6.1:1.0 to 6.9:1.0, 6.2:1.0 to 7.8:1.0, 7.3:1.0 to 7.7:1.0, or 7.4:1.0 to 6.6:1.0. 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 5.0:1.0 to 6.0:1.0, 5.1:1.0 to 5.9:1.0, 5.2:1.0 to 5.8:1.0, 5.3:1.0 to 5.7:1.0, or 5.4:1.0 to 5.6:1.0. 177The molar ratio to Lu is 3.0:1.0 to 5.0:1.0, 3.1:1.0 to 4.9:1.0, 3.2:1.0 to 4.8:1.0, 3.3:1.0 to 4.7:1.0, or 3.4:1.0 to 4.6:1.0.

[0148] In another embodiment, the PSMA I&T in the composition 177 The molar ratio of PSMA I&T to Lu in the composition is 4.0:1.0 to 5.0:1.0, about 4.0:1.0 to about 4.5:1.0, about 4.5:1.0 to about 5.0:1.0, 4.1:1.0 to 4.9:1.0, 4.2:1.0 to 4.8:1.0, 4.3:1.0 to 4.7:0:1.0, or 4.4:1.0 to 4.6:1.0. 177 The molar ratio to Lu is about 5.0:1.0 to about 5.5:1.0, about 5.5:1.0 to about 6.0:1.0, about 6.0:1.0 to about 6.5:1.0, about 6.5:1.0 to about 7.0:1.0, about 7.0:1.0 to about 7.5:1.0, about 7.5:1.0 to about 8.0:1.0, about 8.0:1.0 to about 8.5:1.0, about The ratio is 8.5:1.0 to about 9.0:1.0, about 9.0:1.0 to about 9.5:1.0, about 9.5:1.0 to about 10.0:1.0, about 10.0:1.0 to about 10.5:1.0, about 10.5:1.0 to about 11.0:1.0, about 11.0:1.0 to about 11.5:1.0, or about 11.5:1.0 to about 12.0:1.0.

[0149] In some embodiments, present in the radiopharmaceutical composition 177 The total amount of Lu-PSMA I&T can be in the range of about 1.0 μg / ml to about 3 μg / ml, about 1 μg / ml to about 2 μg / ml, about 1 μg / ml to about 2.5 μg / ml, about 1.1 μg / ml to about 2 μg / ml, about 1.1 μg / ml to about 1.9 μg / ml, about 1.1 μg / ml to about 1.9 μg / ml, about 1.1 μg / ml to about 1.7 μg / ml, about 1.1 μg / ml to about 1.6 μg / ml, about 1.1 μg / ml to about 1.5 μg / ml, about 1.1 μg / ml to about 1.4 μg / ml, or about 1.1 μg / ml to about 1.3 μg / ml. 177The total amount of Lu-PSMA I&T can range from about 0.5 μg / ml to about 1.5 μg / ml. In various embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can range from about 0.5 μg / ml to about 1.5 μg / ml. 177 The total amount of Lu-PSMA I&T can be about 0.5 μg / ml, about 0.6 μg / ml, about 0.7 μg / ml, about 0.8 μg / ml, about 0.9 μg / ml, about 1.0 μg / ml, about 1.1 μg / ml, about 1.2 μg / ml, about 1.3 μg / ml, about 1.4 μg / ml, about 1.5 μg / ml, about 1.6 μg / ml, about 1.7 μg / ml, about 1.8 μg / ml, about 1.9 μg / ml, about 2.0 μg / ml, or about 2.1 μg / ml.

[0150] In some embodiments, present in the radiopharmaceutical composition 177 The total amount of Lu-PSMA I&T can be in the range of about 3.0 μg / ml to about 9.0 μg / ml, about 3.5 μg / ml to about 8.5 μg / ml, about 4.0 μg / ml to about 8.0 μg / ml, about 4.5 μg / ml to about 7.5 μg / ml, about 5.0 μg / ml to about 7.0 μg / ml, or about 5.5 μg / ml to about 6.5 μg / ml. In another embodiment, the total amount of Lu-PSMA I&T in the radiopharmaceutical composition can be in the range of about 3.0 μg / ml to about 9.0 μg / ml, about 3.5 μg / ml to about 8.5 μg / ml, about 4.0 μg / ml to about 8.0 μg / ml, about 4.5 μg / ml to about 7.5 μg / ml, about 5.0 μg / ml to about 7.0 μg / ml, or about 5.5 μg / ml to about 6.5 μg / ml. 177 The total amount of Lu-PSMA I&T can range from about 0.5 μg / ml to about 1.5 μg / ml.

[0151] In some embodiments, present in the radiopharmaceutical composition 177 The total amount of Lu-PSMA I&T may be less than 2.0 μg / ml. In other embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 2.0 μg / ml. 177 The total amount of Lu-PSMA I&T may be less than 4.0 μg / ml. In other embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 4.0 μg / ml. 177 The total amount of Lu-PSMA I&T may be less than 5.0 μg / ml. In other embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 5.0 μg / ml. 177 The total amount of Lu-PSMA I&T may be less than 6.0 μg / ml. In other embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 6.0 μg / ml. 177 The total amount of Lu-PSMA I&T can be less than 3.0 μg / ml.

[0152] In some embodiments, present in the radiopharmaceutical composition 177 The total amount of Lu-PSMA I&T can be in the range of about 9 μg / ml to 20 μg / ml, 10 μg / ml to 20 μg / ml, 11 μg / ml to 20 μg / ml, 11 μg / ml to 15 μg / ml, 11 μg / ml to 14 μg / ml, or 11 μg / ml to 13 μg / ml. 177 The total amount of Lu-PSMA I&T can range from about 5 μg / ml to about 15 μg / ml. In various embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can range from about 5 μg / ml to about 15 μg / ml. 177 The total amount of Lu-PSMA I&T can be about 5 μg / ml, 6 μg / ml, 7 μg / ml, 8 μg / ml, 9 μg / ml, 10 μg / ml, 11 μg / ml, 12 μg / ml, 13 μg / ml, 14 μg / ml, 15 μg / ml, 16 μg / ml, 17 μg / ml, or 18 μg / ml. The composition can have less than 12 μg / ml, or less than 6 μg / ml of Lu-PSMA I&T.

[0153] In the composition 177 The radioactivity / volume of Lu-PSMA I&T can be adjusted according to dose intensity. In one embodiment, the composition contains 0.5 GBq (13.5 mCi) in 1 ml of solution. 177 In other words, the composition may contain 10 GBq (270 mCi) of Lu-PSMA I&T in a 20 ml solution. 177 In another embodiment, the composition may contain 1 GBq (27 mCi) of Lu-PSMA I&T in 1 ml of solution. 177 In other words, the composition may contain 10 GBq (270 mCi) of Lu-PSMA I&T in a 10 ml solution at the time of synthesis. 177 Lu-PSMA I&T may be included.

[0154] In one embodiment, in the radiopharmaceutical composition 177The radioactivity concentration of the Lu-PSMA I&T is less than about 50 mCi / ml, less than about 45 mCi / ml, less than about 40 mCi / ml, less than about 35 mCi / ml, less than about 30 mCi / ml, less than about 25 mCi / ml, less than about 20 mCi / ml, or less than about 15 mCi / ml. 177 The radioactivity concentration of Lu-PSMA I&T is about 5 mCi / ml to about 30 mCi / ml, about 10 mCi / ml to about 20 mCi / ml, about 10 mCi / ml to about 15 mCi / ml, about 10 mCi / ml to about 20 mCi / ml, or about 13 mCi / ml to about 30 mCi / ml. 177 The radioactivity concentration of Lu-PSMA I&T is about 5 mCi / ml, about 10 mCi / ml, about 13.5 mCi / ml, about 15 mCi / ml, about 20 mCi / ml, about 27 mCi / ml, about 30 mCi / ml, about 30 mCi / ml, about 35 mCi / ml or about 40 mCi / ml. 177 The radioactivity concentration of Lu-PSMA I&T is about 10 mCi / ml to about 15 mCi / ml, or about 10 mCi / ml to about 20 mCi / ml.

[0155] In one embodiment, in the radiopharmaceutical composition 177 The radioactivity of the Lu-PSMA I&T is less than about 500 mCi, less than about 450 mCi, less than about 400 mCi, less than about 350 mCi, less than about 300 mCi, less than about 250 mCi, or less than about 200 mCi per vial. 177 The radioactivity of Lu-PSMA I&T is about 10 mCi to about 400 mCi per vial. 177 The radioactivity of Lu-PSMA I&T is about 27mCi, 150mCi, about 160mCi, about 170mCi, about 180mCi, about 190mCi, about 200mCi, about 250mCi, about 270mCi, about 300mCi, about 313mCi, about 318mCi, about 338mCi, about 345mCi, about 346mCi, about 354mCi, about 360mCi, about 370mCi, about 380mCi, and about 390mCi per vial.

[0156] In yet another embodiment, 177 The Lu-PSMA I&T drug product has a standard radioactivity concentration of about 12 mCi / ml or about 32 mCi / ml at the end of production. In one embodiment, 177 The Lu-PSMA I&T drug product has a standard radioactivity concentration of about 13.5 mCi / ml or about 27 mCi / ml at the end of production.

[0157] (ii) antioxidants The antioxidant may act as a buffering agent and / or stabilizer. The total amount of antioxidant in the radiopharmaceutical composition can vary and will vary. Examples of suitable antioxidants include, but are not limited to, ascorbic acid or gentisic acid. The amount of antioxidant in the composition can range from about 10 mg / ml to 90 mg / ml, about 15 mg / ml to 85 mg / ml, about 20 mg / ml to 80 mg / ml, about 25 mg / ml to 75 mg / ml, about 30 mg / ml to 70 mg / ml, about 35 mg / ml to 65 mg / ml, about 40 mg / ml to 60 mg / ml, or about 45 mg / ml to 55 mg / ml. Alternatively stated, the amount of antioxidant in the composition can range from about 10 mg to 90 mg, about 15 mg to 85 mg, about 20 mg to 80 mg, about 25 mg to 75 mg, about 30 mg to 70 mg, about 35 mg to 65 mg, about 40 mg to 60 mg, or about 45 mg to 55 mg per ml.

[0158] In some embodiments, there may be less than 10 mg / ml, less than 9.5 mg / ml, less than 9 mg / ml, less than 8.5 mg / ml, less than 8 mg / ml, less than 7.5 mg / ml, less than 7 mg / ml, less than 6.5 mg / ml, less than 6 mg / ml, less than 5.5 mg / ml, less than 5 mg / ml, less than 4.5 mg / ml, less than 4 mg / ml, less than 3.5 mg / ml, less than 3 mg / ml, less than 2.5 mg / ml, less than 2 mg / ml, less than 1.5 mg / ml, less than 1 mg / ml, or less than 0.5 mg / ml of antioxidant present.

[0159] In certain embodiments, the antioxidant may be ascorbic acid and / or ascorbate, which may minimize or reduce radiodegradation of the radiolabeled composition.

[0160] In some embodiments, the ascorbic acid present in the radiopharmaceutical composition may be in the range of about 10 to about 50 mg, about 20 to about 50 mg, about 30 to about 50 mg, or about 35 to about 45 mg per ml. In other embodiments, the ascorbic acid present in the radiopharmaceutical composition may be in the range of about 5 mg to about 50 mg per ml. In other embodiments, the ascorbic acid or ascorbate may be present at up to 10 mg / ml, up to 9.5 mg / ml, up to 9 mg / ml, up to 8.5 mg / ml, up to 8 mg / ml, up to 7.5 mg / ml, up to 7 mg / ml, up to 6.5 mg / ml, up to 6 mg / ml, up to 5.5 mg / ml, up to 5 mg / ml, up to 4.5 mg / ml, up to 4 mg / ml, up to 3.5 mg / ml, up to 3 mg / ml, up to 2.5 mg / ml, up to 2 mg / ml, up to 1.5 mg / ml, up to 1 mg / ml, or up to 0.5 mg / ml.

[0161] In various embodiments, the ascorbic acid present in the radiopharmaceutical composition may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 31 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 40.5 mg, about 41 mg, about 41.5 mg, about 42 mg, about 42.5 mg, about 43 mg, about 43.5 mg, about 44 mg, about 44.5 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg per ml. For example, the amount of ascorbic acid in 1 ml of the composition can be about 25 mg to 30 mg, about 30 mg to 35 mg, about 35 mg to 40 mg, or about 40 mg to 45 mg per ml.

[0162] In yet another embodiment, the concentration of ascorbic acid in the radiopharmaceutical composition can be from about 10 mg / ml to about 80 mg / ml, from about 10 mg / ml to about 75 mg / ml, from about 10 mg / ml to about 70 mg / ml, from about 15 mg / ml to about 80 mg / ml, from about 15 mg / ml to about 75 mg / ml, from about 15 mg / ml to about 70 mg / ml, from about 20 mg / ml to about 80 mg / ml, from about 20 mg / ml to about 75 mg / ml, from about 25 mg / ml to about 40 mg / ml, from about 20 mg / ml to about 80 mg / ml, from about 20 mg / ml to about 75 mg / ml, or from about 20 mg / ml to about 70 mg / ml.

[0163] In a specific embodiment, the concentration of ascorbic acid in the radiopharmaceutical composition is about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 21 mg / ml, about 25 mg / ml, about 30 mg / ml, about 31 mg / ml, about 35 mg / ml, about 40 mg / ml, about 42.5 mg / ml, about 45 mg / ml, about 50 mg / ml, about 55 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70 mg / ml, about 75 mg / ml, about 80 mg / ml, about 85 mg / ml, about 90 mg / ml, about 95 mg / ml, or about 100 mg / ml.

[0164] In at least one embodiment, the total amount of ascorbic acid in the radiopharmaceutical composition may be about 31 mg / ml, hi further embodiments, the total amount of ascorbic acid in the radiopharmaceutical composition may be about 15 mg / ml, about 21 mg / ml, about 25 mg / ml, about 31 mg / ml, 33 mg / ml, 35 mg / ml, or about 42.5 mg / ml.

[0165] (iii) stabilizers The stabilizer may be separate from the antioxidant. The total amount of stabilizer present in the radiopharmaceutical composition can and will vary. Stabilizers may also be used to limit or reduce radiolysis. The stabilizer may also function as a vehicle for the composition.

[0166] Stabilizers include, but are not limited to, ethanol, para-aminobenzoic acid (PABA), dihydroxybenzoic acid (gentisic acid compound), gentisic acid, cysteine, selenomethionine, ascorbic acid / sodium ascorbate, methionine, and combinations thereof. In some embodiments, the stabilizer comprises ascorbic acid and sodium ascorbate.

[0167] In some embodiments, the stabilizer is ethanol. Ethanol may be present in the pharmaceutical composition at a concentration of about 0.01% (v / v) to about 10% (v / v), 0.01% (v / v) to 3% (v / v), about 0.5% (v / v) to 1% (v / v), about 1% (v / v) to 2% (v / v), about 2% (v / v) to about 3% (v / v), about 3% (v / v) to 4% (v / v), or about 3.5% to 4.5% (v / v). ethanol may be present at about 4% to 5% (v / v), about 4.5% to 5.5% (v / v), about 5% to 6% (v / v), about 5.5% to 6.5% (v / v), about 6% to 7% (v / v), about 6.5% to 7.5% (v / v), or about 7% to 8% (v / v). In some embodiments, the pharmaceutical composition comprises zero (0.00% v / v) ethanol (i.e., ethanol may be absent from the pharmaceutical composition).

[0168] In one embodiment, the total amount of ethanol present in the radiopharmaceutical composition is from about 3% (v / v) to about 8% (v / v), or from 2% (v / v) to about 4% (v / v), or from about 7% (v / v) to about 8% (v / v). In various embodiments, the total amount of ethanol present in the radiopharmaceutical composition can be about 1% (v / v), about 2% (v / v), about 3% (v / v), about 3.5% (v / v), about 3.8% (v / v), about 4% (v / v), about 4.5% (v / v), about 5% (v / v), about 5.5% (v / v), about 6% (v / v), about 6.5% (v / v), about 7% (v / v), about 7.5% (v / v), about 8% (v / v), about 8.5% (v / v), about 9% (v / v), about 9.5% (v / v), or about 10% (v / v).

[0169] In other embodiments, there may be less than 10 mg / ml, less than 9.5 mg / ml, less than 9 mg / ml, less than 8.5 mg / ml, less than 8 mg / ml, less than 7.5 mg / ml, less than 7 mg / ml, less than 6.5 mg / ml, less than 6 mg / ml, less than 5.5 mg / ml, less than 5 mg / ml, less than 4.5 mg / ml, less than 4 mg / ml, less than 3.5 mg / ml, less than 3 mg / ml, less than 2.5 mg / ml, less than 2 mg / ml, less than 1.5 mg / ml, less than 1 mg / ml, or less than 0.5 mg / ml of gentisic acid or gentisate.

[0170] In at least one example, the radiopharmaceutical composition comprises 3.8% (v / v) ethanol, hi another example, the radiopharmaceutical composition comprises 7.5% (v / v).

[0171] Alternatively stated, the total amount of ethanol present in the radiopharmaceutical composition can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 80 mg per ml.

[0172] In some embodiments, the total amount of ethanol present in the radiopharmaceutical composition may range from about 20 mg to about 35 mg per ml, hi other embodiments, the total amount of ethanol in the radiopharmaceutical composition may range from about 43 mg to about 63 mg per ml.

[0173] In some embodiments, the total amount of ethanol present in the radiopharmaceutical composition may range from about 25 mg to about 80 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, or about 70 mg to about 80 mg per ml. In other embodiments, the total amount of ethanol in the radiopharmaceutical composition may range from about 30 mg to about 60 mg per ml.

[0174] In further embodiments, the proportion of ethanol in the radiopharmaceutical composition may be about 300 mg per 10 ml, or about 30 mg / ml. In another embodiment, the proportion of ethanol in the radiopharmaceutical composition may be about 200 mg per 10 ml. In yet another embodiment, the proportion of ethanol in the radiopharmaceutical composition may be about 350 mg per 10 ml.

[0175] Alternatively, the amount of ethanol in the composition can range from about 35 μl / ml to about 75 μl / ml. For example, the amount of ethanol in 1 ml of the composition can be about 35 μl to 40 μl, about 40 μl to 45 μl, about 45 μl to 50 μl, about 50 μl to 55 μl, about 55 μl to 60 μl, about 60 μl to 65 μl, about 65 μl to 70 μl, or about 70 μl to 75 μl. In at least one example, 1 ml of the composition contains 37.5 μl (29.5 mg) of ethanol. In another example, 1 ml of the composition contains 75 μl (58.9 mg) of ethanol.

[0176] (iv) Metal ion chelating agents (chelating agents) In some embodiments, the present disclosure provides a method for the preparation of microdoses. 177A radiopharmaceutical composition is provided comprising an Lu-PSMA I&T solution and at least one metal ion chelating agent, including ethylenediaminetetraacetic acid (EDTA) and its salts, N-(hydroxyethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid (NTA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N''-triacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N''-triacetic acid, 1,4,7-tris(carboxymethyl)-10-(2'-hydroxypropyl)-1,4,7-tris(carboxymethyl ... )-1,4,7,10-tetraazocyclodecane, 1,4,7-triazacyclonane-N,N',N''-triacetic acid, 1,4,8,11-tetraazacyclotetra-decane-N,N',N'',N'''-tetraacetic acid, diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine, bis(aminoethanethiol)carboxylic acid, triethylenetetramine-hexaacetic acid, 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid, or a combination thereof. In one embodiment, the chelating agent can be the sodium salt of EDTA. In one embodiment, the chelating agent can include DTPA and be free of EDTA.

[0177] In some embodiments, the metal ion chelator is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA) and its salts, N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid (NTA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid, 1,4,7,10-tetraaza-cyclododecane-N,N',N''-triacetic acid, 1,4,7,10-tetraaza-cyclododecane-N,N',N''-triacetic acid, 1,4,7,10-tris(carboxymethyl)-10-( 2'-hydroxypropyl)-1,4,7,10-tetraazocyclodecane, 1,4,7-triazacyclonane-N,N',N"-triacetic acid, 1,4,8,11-tetraazacyclotetra-decane-N,N',N'',N'"-tetraacetic acid, diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine, bis(aminoethanethiol)carboxylic acid, triethylenetetramine-hexaacetic acid, and 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid. In one embodiment, the metal ion chelator can be disodium EDTA. In one embodiment, the metal ion chelator can be DPTA.

[0178] In one embodiment, the amount of chelating agent present in the radiopharmaceutical composition may range from about 5 μg to 500 μg, hi some embodiments, the amount of metal ion chelating agent present in the radiopharmaceutical composition may range from about 5 μg to 50 μg.

[0179] In some embodiments, the amount of chelating agent present is about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10.5 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg , about 25μg, about 26μg, about 27μg, about 28μg, about 29μg, about 30μg, about 31μg, about 32μg, about 33μg, about 34μg, about 35μg, about 36μ g, about 37μg, about 38μg, about 39μg, about 40μg, about 45μg, about 50μg, about 60μg, about 70μg, about 80μg, about 90μg, about 100μg, about 1 10μg, about 80μg, about 130μg, about 140μg, about 150μg, about 160μg, about 170μg, about 180μg, about 190μg, about 200μg, about 210 μg, approx. 220 μg, approx. 230 μg, approx. 240 μg, approx. 250 μg, approx. 260 μg, approx. 270 μg, approx. 280 μg, approx. 290 μg, approx. 300 μg, approx. 310 μg g, about 320 μg, about 330 μg, about 340 μg, about 350 μg, about 360 μg, about 370 μg, about 380 μg, about 390 μg, about 400 μg, about 410 μg, about 420 μg, about 430 μg, about 440 μg, about 450 μg, about 460 μg, about 470 μg, about 480 μg, about 490 μg, or about 500 μg.

[0180] The concentration of the metal ion chelating agent in the composition may range from about 5 μg / ml to about 500 μg / ml. In another embodiment, the concentration of the chelating agent present in the radiopharmaceutical composition may range from about 5 μg / ml to about 200 μg / ml. In another embodiment, the concentration of the chelating agent present in the radiopharmaceutical composition may range from about 5 μg / ml to about 75 μg / ml, 10 μg / ml to about 25 μg / ml, about 25 μg / ml to about 50 μg / ml, about 50 μg / ml to about 75 μg / ml, about 75 μg / ml to about 100 μg / ml, about 100 μg / ml to about 125 μg / ml, about 125 μg / ml to about 150 μg / ml, or about 150 μg / ml to about 200 μg / ml.

[0181] In some embodiments, the concentration of chelating agent present is about 5 μg / ml, about 6 μg / ml, about 7 μg / ml, about 8 μg / ml, about 9 μg / ml, about 10.5 μg / ml, about 11 μg / ml, about 12 μg / ml, about 13 μg / ml, about 14 μg / ml, about 15 μg / ml, about 16 μg / ml, about 17 μg / ml, about 18 μg / ml, about 19 μg / ml, about 20 μg / ml, about 21 μg / ml, about 22 μg / ml, about The radiopharmaceutical composition may be present in a concentration of about 23 μg / ml, about 24 μg / ml, about 25 μg / ml, about 26 μg / ml, about 27 μg / ml, about 28 μg / ml, about 29 μg / ml, about 30 μg / ml, about 31 μg / ml, about 32 μg / ml, about 33 μg / ml, about 34 μg / ml, about 35 μg / ml, about 36 μg / ml, about 37 μg / ml, about 38 μg / ml, about 39 μg / ml, about 40 μg / ml, about 45 μg / ml, or about 50 μg / ml. In another embodiment, the concentration of the chelating agent present in the radiopharmaceutical composition may range from about 100 μg / ml to about 125 μg / ml, from about 125 μg / ml to about 150 μg / ml, or from about 150 μg / ml to about 200 μg / ml.

[0182] In other embodiments, the concentration of chelating agent present is about 80 μg / ml, about 90 μg / ml, about 91 μg / ml, about 92 μg / ml, about 93 μg / ml, about 94 μg / ml, about 95 μg / ml, about 96 μg / ml, about 97 μg / ml, about 98 μg / ml, about 99 μg / ml, about 100 μg / ml, about 101 μg / ml, about 102 μg / ml, about 103 μg / ml, about 104 μg / ml, about 105 μg / ml, about 106 μg / ml ml, about 107 μg / ml, about 108 μg / ml, about 109 μg / ml, about 110 μg / ml, about 115 μg / ml, about 120 μg / ml, about 125 μg / ml, about 130 μg / ml, about 135 μg / ml, about 140 μg / ml, about 145 μg / ml, about 150 μg / ml, about 155 μg / ml, about 160 μg / ml, about 170 μg / ml, about 180 μg / ml, about 190 μg / ml, or about 200 μg / ml.

[0183] In alternative embodiments, the amount of metal ion chelator in a radiopharmaceutical composition may be from about 0.001% to about 0.20% (w / w), from about 0.20% to about 0.40% (w / w), from about 0.40% to about 0.60% (w / w), from about 0.60% to about 0.80% (w / w), or from about 0.80% to about 1.00% (w / w) of such radiopharmaceutical composition. In some embodiments, the amount of metal ion chelator present in the radiopharmaceutical composition may be about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, or 0.15% (w / w) of the total weight of the radiopharmaceutical composition.

[0184] For example, the amount of disodium EDTA, diethylenetriaminepentaacetic acid (DTPA), or a combination thereof in 1 ml of the composition can be about 10 μg to 15 μg, about 13 μg to 18 μg, about 15 μg to 20 μg, about 20 μg to 25 μg, about 25 μg to 50 μg, about 50 μg to 75 μg, or about 75 μg to 150 μg. In some embodiments, the amount of disodium EDTA present can be about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10.5 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg, about 25 μg, about 26 μg, about 27 μg, about 28 μg, about 29 μg, about 30 μg, about 31 μg, about 32 μg, about 33 μg, about 34 μg, about 35 μg, about 36 μg, about 37 μg, about 38 μg, about 39 μg, about 40 μg, about 45 μg, or about 50 μg.

[0185] In at least one example, 1 ml of the composition contains 15.5 μg of disodium EDTA. In another example, 1 ml of the composition contains 21 μg of disodium EDTA.

[0186] In one embodiment, the trace metal content in the composition is undetectable. In another embodiment, the Fe metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Cu metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Zn metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Pb metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Co metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Ni metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Zn metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Cr metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Yb metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit.

[0187] In another embodiment, a composition described herein comprises M-PSMA I&T, where M=Cu, Pb, Co, Fe, Ni, Zn, Cr, and / or Yb, and the combined total concentration of M-PSMA I&T is less than 500 ppm, less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 9 ppm, less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm. In another embodiment, the compositions described herein comprise less than 500 ppm, less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 9 ppm, less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm Cu-PSMA I&T. In another embodiment, the compositions described herein comprise less than 500 ppm, less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 9 ppm, less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm Pb-PSMA I&T. In another embodiment, the compositions described herein comprise less than 500 ppm, less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 9 ppm, less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm Co-PSMA I&T. In another embodiment, the compositions described herein comprise less than 500 ppm, less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 9 ppm, less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm Fe-PSMA I&T.In another embodiment, the compositions described herein comprise less than 500 ppm, less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 9 ppm, less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm Ni-PSMA I&T. In another embodiment, the compositions described herein comprise less than 500 ppm, less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 9 ppm, less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm Zn-PSMA I&T. In another embodiment, the compositions described herein comprise less than 500 ppm, less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 9 ppm, less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm Cr-PSMA I&T. In another embodiment, the compositions described herein comprise less than 500 ppm, less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 9 ppm, less than 8 ppm, less than 7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm Yb-PSMA I&T.

[0188] (v) pH adjuster Suitable pH adjusters include, but are not limited to, any one of hydrochloric acid, sodium hydroxide, sodium bicarbonate, or combinations thereof.

[0189] In some embodiments, hydrochloric acid may be used to adjust the pH of the radiopharmaceutical composition. In certain embodiments, the amount of hydrochloric acid in the composition may range from 0 mg / ml to about 2 mg / ml. In some embodiments, the amount of HCl may range from 1.6 ml of 0.05 M HCl to 2 ml of 0.04 M HCl in a production batch. In one embodiment, the batch has an activity of about 10 to 20 Ci. In another embodiment, the batch has an activity of about 16 Ci. The amount of HCl in the composition may be varied to adjust the final formulation pH. In various embodiments, the final formulation pH ranges from pH 3.0 to 5.0. In at least one example, HCl is added to the composition to reach a final pH of 3.5±0.1 to 4.5±0.1.

[0190] In some embodiments, the amount of sodium bicarbonate in the composition may be sufficient to control the pH of the composition between 5.5 and 7.0 prior to the addition of HCl.

[0191] In some embodiments, the amount of NaOH in the composition may be sufficient to control the pH of the composition between 5.5 and 7.0 prior to the addition of HCl.

[0192] (vi) Water The composition may further comprise a sufficient amount of water to make the desired final volume of the injectable solution, for example, water may be added to make a final volume of 1 ml, 10 ml, 15 ml, or 20 ml.

[0193] IV. PROCESSES FOR MAKING RADIOPHARMACEUTICAL COMPOSITIONS The entire manufacturing process is a one-step radiolabeling process using PSMA I&T precursors. Successful labeling depends on temperature, time, and pH. The reaction is carried out in a reactor vial at elevated temperature. For example, the reactor may be heated to a setpoint of 110°C, with the maximum temperature reached in the reaction solution being approximately 95°C. The radiolabeled product is isolated on a C18 cartridge and formulated into the final composition after elution into bulk vials. The final product is dispensed in a Grade A controlled environment.

[0194] In another embodiment, the radiolabeling process uses a PSMA I&T precursor, and the composition is radiolabeled for 5-15 minutes at a temperature of about 65 to about 75°C. In yet another embodiment, the composition is radiolabeled for 5-15 minutes at a temperature of about 65 to about 80°C. In another embodiment, the composition is radiolabeled for 5-15 minutes at a temperature of about 65, about 70, about 75, or about 80°C. In another embodiment, the composition is radiolabeled for 5-15 minutes at a temperature of about 70 to about 80°C. In yet another embodiment, the composition is radiolabeled for 5-15 minutes at a temperature of about 75 to 80°C.

[0195] 177 The Lu-PSMA I&T composition solution may be prepared using the following method 100, for example, as shown in Figure 2. The order of steps may vary, including the order in which the various solutions are prepared.

[0196] In certain embodiments, step 102 may include preparing four solutions for synthesis. The four solutions may include 0.04 M hydrochloric acid, 0.4 M sodium acetate, 20% (w / w) L-ascorbic acid, and about 460 to about 500 μg / ml of PSMA I&T in water. The PSMA I&T precursor may be dissolved in sterile water for injection. For example, depending on the number of doses to be produced, 80 μg to 600 μg of precursor may be used in the reaction. In at least one example, 463 μl / ml of PSMA I&T precursor may be used to produce the composition.

[0197] In some embodiments, step 104 may include preparing an ascorbic acid solution (dilution buffer). In some examples, the ascorbic acid solution may be a 50 mg / ml ascorbic acid solution. The solution pH may be adjusted to 4.5±0.25, 4.5±0.30, 4.5±0.35, 4.5±0.40, 4.5±0.45, or 4.5±0.50. For example, a 50 mg / ml ascorbic acid solution may be prepared and the pH of the solution adjusted to 4.5 using 30% hydrochloric acid. In another example, the ascorbic acid solution may include 33 mg / ml ascorbic acid / sodium ascorbate and 0.1 mg / ml DTPA at a pH of 4.25±0.25.

[0198] In some embodiments, optional step 106 may include preparing a formulation solution / buffer. The formulation solution is prepared from an injection-grade solution containing ascorbic acid, absolute ethanol, and injection-grade water. In one example, the formulation solution is prepared by adding sufficient amounts of the following solutions to a bulk vial: approximately 50 mg / ml ascorbic acid pH 4.5 solution (prepared in step 104), 30% ethanol solution, and water. The formulation solution may contain 31 mg / ml to 42.5 mg / ml ascorbic acid and 3.8% to 7.5% ethanol (v / v%). In some embodiments, the formulation buffer may be adjusted to enable the final composition to have an extended shelf life. In at least one example, the formulation solution contains 31 mg / ml ascorbic acid, 3.8% (v / v) ethanol, and pH 4.5. The formulation buffer is temporarily prepared as part of the synthesis preparation, and a predetermined amount is added to the bulk vial as part of the synthesis preparation.

[0199] In some embodiments, step 108 may include preparing a reaction solution. The reaction solution may include sodium acetate, HCl, and L-ascorbic acid. Alternatively, the reaction solution may include sodium ascorbate. The reaction solution may be prepared in a reactor using the solution prepared in step 102. In one example, the reaction solution may include 4 ml of 0.4 M sodium acetate, a volume of approximately 463 μg / ml PSMA I&T solution, and 150 μl of 20% (w / w) L-ascorbic acid. In another example, the reaction solution may include 0.33 M sodium ascorbate (reaction buffer) and PSMA I&T in a reaction buffer. In some examples, the reaction solution may include 1.6 ml of 0.05 M HCl or 2 ml of 0.04 M HCl (0.08 mmol HCl). The ascorbic acid concentration in the reaction solution may range from 3.75 mg / ml to 5.00 mg / ml.

[0200] In one embodiment, step 110 includes: 177 In some embodiments, the method may include preparing Lu by 177 Lu can be provided in HCl. 177 Lu]LuCl3 can be provided in 0.04M or 0.05M HCl. For example, 40-44 GBq / ml 177 Lu can be provided in 0.04 M HCl. In another example, less than 61 GBq 177 Lu can be provided in 0.05M HCl. 177 Lu]LuCl3 may be transferred into the reactor, 177 The [Lu]LuCl vial may be rinsed with an additional required volume of 0.04 M hydrochloric acid (prepared in step 102), which is then also transferred into the reactor.

[0201] The reaction volume can range from 6 ml to 8 ml. The volume can depend on the amount of precursor used.

[0202] In one embodiment, step 112 includes 177The method may include radiolabeling with Lu. The reaction mixture may be heated to a maximum of about 75°C, a maximum of about 80°C, a maximum of about 85°C, a maximum of about 90°C, or a maximum of about 95°C. In one example, the set point for heating is 110°C, and the actual maximum temperature reached is about 95°C. The reaction volume may be heated for a maximum of 5 minutes, a maximum of 10 minutes, a maximum of 15 minutes, or a maximum of 20 minutes. In at least one example, the reaction mixture is heated at a set point of 110°C for 15 minutes. In at least one additional example, the reaction mixture is heated at a set point of 75°C for 10 minutes.

[0203] In certain embodiments, optional step 114 can include purifying the reaction mixture. For example, the solution can be run through a cassette / cartridge containing a hydrophobic, reversed-phase, silica-based bonded phase (e.g., C18 Sep-Pak). In at least one example, the reaction mixture can be passed through a C18 Sep-Pak cartridge, and the cartridge can be rinsed with water. 177 The Lu-PSMA I&T product is retained within the cartridge. In some embodiments, the reaction mixture may not be purified.

[0204] In some embodiments, step 116 may include eluting or diluting the final product. 177 The Lu-PSMA I&T is diluted to the desired radioactivity concentration with the dilution buffer prepared in step 104. The composition may be eluted using 1.5 ml of ethanol-water in a 1:1 ratio. The cassette may then be flushed with 8.5 ml of ascorbic acid 50 mg / ml. A formulation solution may then be added to form the final composition. In at least one example, 177The Lu-PSMA I&T is eluted from the C18 cartridge into a bulk vial using 1.5 ml of 50% (v / v) ethanol, followed by 8.5 ml of the 50 mg / ml pH 4.5 ascorbic acid solution (prepared in step 104), which is then diluted with the formulation solution / buffer (prepared in step 106 and already in the bulk vial). The resulting solution may have a pH of 3.5-4.5. In some embodiments, the pH may be adjusted. In one example, the pH of the 50 mg / ml ascorbic acid solution is adjusted to 3.5-4.5. In another example, the pH is adjusted to 5.0 or below.

[0205] Stability-enhancing conditions, such as an ascorbic acid solution, perhaps at a pH of about 5 or less, should preferably be applied as early in the process as possible. For example, an ascorbic acid solution at a pH of 5 or less may be used in place of water in step 114 to minimize radiolytic damage.

[0206] The final composition can be formulated as a solution suitable for injection. The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk composition is the amount of the introduced 177 Varies depending on the starting radioactivity of Lu. This solution meets the sterility and bacterial endotoxin requirements according to the European Pharmacopoeia and the United States Pharmacopoeia, which confirm an acceptable manufacturing process from a microbiological point of view.

[0207] In some embodiments, in step 118, the final composition may be sterile filtered. The sterile filter may be a 0.22 μm sterile filter. The final product may be passed through a 0.22 μm sterile filter and dispensed into single-dose vials containing the appropriate volume and activity referenced to a predetermined calibration time. For example, the final composition may be passed through a 0.22 μm sterile filter in a Class A environment and dispensed into doses containing the appropriate volume and activity for the calibration time.

[0208] Figure 3A provides an example of a process for making a radiopharmaceutical composition by purifying the reaction mixture and formulation solution with ethanol, and Figure 3B provides an example of a process for making a radiopharmaceutical composition without purification and without ethanol.

[0209] 177 Provided herein are methods for increasing the shelf life of a radiopharmaceutical product comprising Lu-PSMA I&T. The methods may include adjusting the pH of the composition to 3.5, 3.75, 4.0, 4.25, or 4.5, adjusting the amount of ascorbic acid in the composition, and / or adjusting the radioactivity to extend the shelf life of the composition by 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.25, 2.5, 2.75, or 3 days. For example, a radiopharmaceutical composition may have a shelf life of 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 days. In certain embodiments, adjusting the pH, radioactivity, and / or ascorbic acid may increase the radiochemical purity of the composition to at least 99%, at least 98.5%, at least 98%, at least 97.5%, at least 97%, at least 96.5%, at least 96%, at least 95.5%, or at least 95% for up to 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 days.

[0210] Targeted pharmaceutical formulations according to the present disclosure are as provided in Table 1A. [Table 1A]

[0211] In another embodiment, the preparation of composition 4 disclosed in Table 1A above may be carried out using a one-step radiolabeling process carried out in the following steps:

[0212] Successful labeling is dependent on temperature, time, and pH. The reaction is carried out in a reactor vial at elevated temperature. For example, the reactor may be preheated to a setpoint of 100°C for 5 minutes, then reduced to 85°C to achieve a reaction temperature of approximately 75°C for 10 minutes. The radiolabeled product is formulated into the final composition, sterile filtered, and dispensed in a Grade A controlled environment.

[0213] 177 The Lu-PSMA I&T composition solution may be prepared as shown in Figure 2b (201, 202, 203). The order of steps may vary, including the order in which the various solutions are prepared.

[0214] In some embodiments, step 201 may include preparing a reaction buffer for synthesis. The solution may include 82 mg / mL sodium ascorbate in water at pH > 5. The PSMA-I&T precursor may be dissolved in the reaction buffer, as shown in step 202. For example, depending on the batch size, 1000 μg to 5000 μg of precursor may be used in the reaction.

[0215] In one embodiment, the [ 177 The amount of [Lu]LuCl3 can range from 50 mCi up to 15,200 mCi. The corresponding amount of PSMA I&T used during radiolabeling can range from 0.1 to 0.9 μg / mCi. For example, 15,000 mCi of [ 177 Lu]LuCl3 and 4200 μg of PSMA I&T are added to the reaction vessel during radiolabeling.

[0216] In some embodiments, step 203 can include preparing an ascorbic acid solution (dilution buffer). In some examples, the ascorbic acid solution can be a 33 mg / ml ascorbic acid solution. The solution pH can be adjusted to 4.25±0.05, 4.25±0.10, 4.25±0.15, 4.25±0.20, or 4.25±0.25. For example, the ascorbic acid solution can include 33 mg / ml ascorbic acid / sodium ascorbate and 0.1 mg / ml DTPA at a pH of 4.25±0.25.

[0217] In one embodiment, step 204 includes: 177 In some embodiments, the method may include preparing Lu by 177 Lu can be provided in HCl. 177 Lu]LuCl3 can be provided in 0.05 M HCl. For example, 2 Ci / ml 177 Lu can be provided in 0.05M HCl. 177 Lu]LuCl3 may be transferred into the reactor, 177 The [Lu]LuCl vial may be rinsed with an additional required volume of 82 mg / mL sodium ascorbate (prepared in step 201), which is then also transferred into the reactor.

[0218] The reaction volume can range from 8 ml to 15 ml. The volume used for the radiolabeling reaction is 177 Lu] LuCl3.

[0219] In one embodiment, step 204 includes using PSMA-I&T. 177 The method may include radiolabeling with Lu. The reaction mixture may be heated to a temperature of up to about 70°C, up to about 75°C, up to about 80°C, up to about 85°C, up to about 90°C, or up to about 95°C. In one example, the set point for heating is 85°C, and the actual maximum temperature reached is about 75°C. The reaction volume may be heated for up to 5 minutes, up to 10 minutes, up to 15 minutes, up to 20 minutes, up to 25 minutes, up to 30 minutes, up to 35 minutes, up to 40 minutes, or up to 45 minutes. In at least one example, the reaction mixture is heated at a set point of 80°C for 10 minutes. In at least one additional example, the reaction mixture is heated at a set point of 70°C for 10 minutes.

[0220] Stability-enhancing conditions, such as an ascorbic acid solution, perhaps at a pH of about 5 or less, should preferably be applied as early in the process as possible. For example, an ascorbic acid solution at a pH of 5 or less may be used in place of water in step 205 to minimize radiolytic damage.

[0221] The final composition can be formulated as a solution suitable for injection. The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk composition is the amount of the introduced 177 Varies depending on the starting activity of Lu.

[0222] In some embodiments, in step 206, the final composition may be sterile filtered. The sterile filter may be a 0.22 μm sterile filter. The final product may be passed through a 0.22 μm sterile filter and dispensed into single-dose vials containing the appropriate volume and activity referenced to a predetermined calibration time. For example, the final composition may be passed through a 0.22 μm sterile filter in a Class A environment and dispensed into doses containing the appropriate volume and activity for the calibration time.

[0223] FIG. 3B provides an example of a process for making a radiopharmaceutical composition without purification and without the inclusion of ethanol.

[0224] 177 Provided herein are methods for increasing the shelf life of radiopharmaceutical products containing Lu-PSMA I&T. The methods may include adjusting the pH of the composition to 4.0, 4.25, 4.5, or 4.75 by adjusting the amount of ascorbic acid in the composition, and / or adjusting the radioactivity to extend the shelf life of the composition by 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.25, 2.5, 2.75, or 3 days. For example, a radiopharmaceutical composition may have a shelf life of 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, or 4 days. In certain embodiments, adjusting the pH, radioactivity, and / or ascorbic acid may increase the radiochemical purity of the composition to at least 99%, at least 98.5%, at least 98%, at least 97.5%, at least 97%, at least 96.5%, at least 96%, at least 95.5%, or at least 95% for up to 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4 days.

[0225] V. Stability A stable, non-radiolabeled standard can be used to identify the product peak in HPLC analysis. The formulation can be prepared from an injection-grade solution containing ascorbic acid, a chelating agent (EDTA, DTPA, or a combination thereof), optionally absolute ethanol, and injection-grade water. The formulation matrix can be temporarily prepared as part of the synthetic preparation, and a predetermined amount is added to a bulk vial as part of the synthetic preparation.

[0226] Without being limited to any one theory, the radioactivity, the amount of ascorbic acid, and / or the pH of the solution may affect the shelf life of the composition. Surprisingly, a lower concentration of ascorbic acid in the composition (e.g., 31 mg / ml versus 42.5 mg / ml), a pH of 4.5 or less, a low RAC, and / or a combination thereof may result in a higher stability profile and a longer shelf life of the composition compared to a composition having a pH of 5 or more, a high RAC, and / or a combination thereof. For example, this can be seen in Figure 5. The shelf life can generally be determined based on the radiochemical purity of the composition after formulation or at the end of the expiration date of the composition. The radiochemical purity may be confirmed by HPLC.

[0227] In one or more embodiments, the dosage formulation has a radioactivity concentration of 640 MBq / ml or less, 31 mg / ml ascorbic acid, and a pH of about 4.5. 177 The Lu-PSMA I&T formulation composition can provide sufficient stability for 4 days.

[0228] In some embodiments, a composition having a low radioactivity concentration (e.g., 588.5 MBq / ml), a pH of 4.5, and 31 mg / ml ascorbic acid has a radiochemical purity of 99.1% at 0 hours after EOS, 98.7% at 20 hours after EOS, 98.0% at 44 hours after EOS, 97.4% at 69 hours after EOS, and 97.0% at 93 hours after EOS. A composition having a low radioactivity concentration (e.g., 626 MBq / ml), a pH of 5.0, and 31 mg / ml ascorbic acid has a radiochemical purity of 99.2% at 0 hours after EOS, 98.4% at 25 hours after EOS, 97.3% at 47 hours after EOS, and 96.5% at 71 hours after EOS. A composition having a low radioactivity concentration (e.g., 579 MBq / ml), pH 4.5, and 21 mg / ml ascorbic acid has a radiochemical purity of 99.4% at 0 hours after EOS, 98.3% at 19 hours after EOS, 97.5% at 46 hours after EOS, 96.8% at 71 hours after EOS, and 96.0% at 92 hours after EOS. A composition having a high radioactivity concentration (e.g., 1,278 MBq / ml), pH 4.5, and 42.5 mg / ml ascorbic acid has a radiochemical purity of 99.4% at 0 hours after EOS, 98.0% at 24 hours after EOS, 96.7% at 46 hours after EOS, 95.3% at 67 hours after EOS, and 95.2% at 71 hours after EOS.

[0229] The radiopharmaceutical composition may be stored at a temperature ranging from 2°C to 40°C, about 2°C to 5°C, about 5°C to 10°C, about 10°C to 15°C, about 15°C to 20°C, about 20°C to 25°C, about 25°C to 30°C, about 30°C to 35°C, or about 35°C to 40°C.

[0230] In certain embodiments, the radiopharmaceutical composition is stored at a temperature of about 5° C. to 40° C., about 10° C. to 35° C., or about 20° C. to 30° C. In a specific embodiment, the radiopharmaceutical composition is stored at a temperature of about 10° C., about 15° C., about 22° C., about 22.5° C., about 25° C., or at room temperature.

[0231] In one embodiment, the radiopharmaceutical composition is stored at about 22.5° C. In another embodiment, the radiopharmaceutical composition is stored at room temperature.

[0232] VI. Specific Radiopharmaceutical Compositions In some embodiments, the pharmaceutical product is a microdose of 42.5 mg / ml of ascorbic acid in water containing 7.5% (v / v) or 59 mg / ml of ethanol. 177 The sterile filtered radiopharmaceutical solution containing Lu-PSMA I&T solution is diluted to a standard radioactivity concentration, and therefore the final volume of the bulk product varies depending on the starting radioactivity introduced. The composition of the final product is listed in Table 1B ( 177 Lu-PSMA I&T composition 1) [Table 1B]

[0233] In yet another embodiment, the pharmaceutical product is a microdose of 31 mg / ml of ascorbic acid in water containing 3.8% (v / v) or 30 mg / ml of ethanol at a pH of about 4.5. 177 A sterile filtered radiopharmaceutical solution containing Lu-PSMA I&T solution. The product is diluted to a standard radioactivity concentration, and therefore the final volume of the bulk product varies depending on the starting radioactivity introduced. The composition is described in Table 1C below ( 177 Lu-PSMA I&T composition 2): [Table 1C]

[0234] In yet another embodiment, the pharmaceutical product comprises a small amount of [ 177 The radiopharmaceutical solution contains [Lu]Lu-PSMA I&T solution. The product is diluted to a standard radioactivity concentration, and therefore the final volume of the bulk product varies depending on the starting radioactivity introduced. The composition is described in Table 1D below ( 177 Lu-PSMA I&T composition 3): [Table 1D]

[0235] VII. Formulating a Pharmaceutical Product The pharmaceutical product may be delivered in a Type 1 glass, sterile, pyrogen-free glass vial with a fluorine-coated bromobutyl rubber septum. The septum is sealed with a crimped aluminum seal. The glass vial containing the radiopharmaceutical is maintained in a lead-shielded container during transport. The shipping container, including the lead shielding and outer packaging, complies with Type A requirements (IAEA standards). Figure 4 depicts a drawing of a product vial that may be used in this embodiment.

[0236] In one embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 10 ml to about 20 ml, about 20 ml to about 30 ml, about 30 ml to about 40 ml, about 40 ml to about 50 ml, about 50 ml to about 60 ml, about 60 ml to about 70 ml, about 70 ml to about 80 ml, about 80 ml to about 90 ml, or about 90 ml to about 100 ml. In a specific embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 1 ml, about 5 ml, about 7 ml, about 8 ml, about 9 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, or about 30 ml. In one embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 11 ml, about 12 ml, about 13 ml, about 14 ml, about 15 ml, about 16 ml, about 17 ml, about 18 ml, about 19 ml, about 20 ml, about 25 ml, or about 30 ml.

[0237] In one embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 100 ml to about 200 ml, about 200 ml to about 300 ml, about 300 ml to about 400 ml, about 400 ml to about 500 ml, about 500 ml to about 600 ml, about 600 ml to about 700 ml, about 700 ml to about 800 ml, about 800 ml to about 900 ml, or about 900 ml to about 1000 ml. In a specific embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 200 ml, about 225 ml, about 250 ml, about 275 ml, about 300 ml, about 325 ml, about 350 ml, about 375 ml, about 400 ml, about 425 ml, about 450 ml, about 475 ml, about 500 ml, about 525 ml, about 550 ml, about 575 ml, about 600 ml, about 625 ml, about 650 ml, about 675 ml, about 700 ml, about 725 ml or about 750 ml.

[0238] In a specific embodiment, the final volume in the dose vial is adjusted to 7 ml to 10 ml, 10 ml to 15 ml, or 15 ml to 20 ml to provide the amount of radioactivity required for the day and time of injection.

[0239] In another embodiment, 177 Lu-PSMA I&T injection is supplied as a single-dose vial or a multi-dose vial. For example, a single-dose 177 Provided herein is a radiopharmaceutical kit comprising a vial containing the Lu-PSMA I&T injection product composition. In one embodiment, 177 The strength of the Lu-PSMA I&T injection product composition is about 0.1 GBq / ml, about 0.2 GBq / ml, about 0.3 GBq / ml, about 0.4 GBq / ml, about 0.5 GBq / ml, about 0.6 GBq / ml, about 0.7 GBq / ml, about 0.8 GBq / ml, about 0.9 GBq / ml, about 1.0 GBq / ml, about 1.1 GBq / ml, about 1.2 GBq / ml, about 1.3 GBq / ml, about 1.4 GBq / ml, about 1.5 GBq / ml, about 1.6 GBq / ml, about 1.7 GBq / ml, about 1.8 GBq / ml, about 1.9 GBq / ml, or about 2.0 GBq / ml. In another embodiment, 177The strength of the Lu-PSMA I&T injection product composition is less than about 2.0 GBq / ml, less than about 1.5 GBq / ml, less than about 1.0 GBq / ml, or less than about 0.5 GBq / ml.

[0240] In yet another embodiment, 177 The shelf life of the [Lu]Lu-PSMA I&T injection product composition is about 30 hours to about 90 hours, about 40 hours to about 80 hours, or about 48 hours to about 72 hours. 177 The shelf life of the [Lu]Lu-PSMA I&T injection product composition is about 30 hours, about 35 hours, about 40 hours, about 45 hours, about 48 hours, about 50 hours, about 55 hours, about 60 hours, about 65 hours, about 70 hours, about 72 hours, about 75 hours, about 80 hours, about 85 hours, or about 90 hours.

[0241] In some embodiments, the radiopharmaceutical composition is prepared in a manner sufficient for administration to a patient. 177 The radiopharmaceutical composition should have a radiochemical purity of 95% or greater for [Lu]Lu-PSMA I&T. The combined radiochemical impurities in the composition may be less than 5%. In various embodiments, the radiopharmaceutical composition may have a chemical purity such that the Lu-PSMA I&T is present in the composition at a concentration of less than about 12 μg / ml, less than about 11 μg / ml, less than about 10 μg / ml, less than about 9 μg / ml, less than about 8 μg / ml, less than about 7 μg / ml, less than about 6 μg / ml, less than about 5 μg / ml, less than about 4 μg / ml, less than about 3 μg / ml, less than about 2 μg / ml, less than about 1.75 μg / ml, less than about 1.5 μg / ml, or less than about 1 μg / ml.

[0242] In some embodiments, the radiopharmaceutical composition comprises a colloid in an amount of less than about 5% radioactivity, less than about 4.5% radioactivity, less than about 4% radioactivity, less than about 3.5% radioactivity, less than about 3% radioactivity, less than about 2.5% radioactivity, less than about 2% radioactivity, less than about 1.5% radioactivity, less than about 1% radioactivity, less than about 0.5% radioactivity, less than about 0.3% radioactivity, less than about 0.2% radioactivity, or less than about 0.1% radioactivity. 177In one embodiment, the radiopharmaceutical composition administered to a human patient in need thereof may have less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% colloidal Lu. 177 Contains Lu.

[0243] In some embodiments, the radiopharmaceutical composition is less than about 17.5 EU / ml, less than about 17 EU / ml, less than about 16.5 EU / ml, less than about 16 EU / ml, less than about 15.5 EU / ml, less than about 15 EU / ml, less than about 14.5 EU / ml, less than about 14 EU / ml. The bacterial endotoxin may be less than about 13.5 EU / ml, less than about 13 EU / ml, less than about 12.5 EU / ml, less than about 12 EU / ml, less than about 11.5 EU / ml, less than about 11 EU / ml, less than about 10.5 EU / ml, less than about 10 EU / ml, less than about 9.5 EU / ml, less than about 9 EU / ml, less than about 8.5 EU / ml, less than about 8 EU / ml, less than about 7.5 EU / ml, less than about 7 EU / ml, less than about 6.5 EU / ml, less than about 6 EU / ml, less than about 5.5 EU / ml, less than about 5 EU / ml, less than about 4.5 EU / ml, less than about 4 EU / ml, less than about 3.5 EU / ml, less than about 3 EU / ml, less than about 2.5 EU / ml, less than about 2 EU / ml, less than about 1.5 EU / ml, less than about 1 EU / ml, less than about 0.5 EU / ml, or may be free of bacterial endotoxin.

[0244] In certain embodiments, the radiochemical purity of the composition is 95% or greater 1 day, up to 2 days, up to 3 days, up to 4 days, or up to 5 days after formulation. In additional embodiments, the radiochemical purity of the composition is 95% or greater 24 hours, up to 36 hours, up to 48 hours, up to 72 hours, or up to 96 hours after formulation. In further embodiments, the radiochemical purity of the composition is suitable for injection or administration to a patient in need thereof more than 72 hours after formulation, more than 96 hours after formulation, or more than 100 hours after formulation. The radiopharmaceutical composition may have a radiochemical purity of at least 95%, at least 95.5%, at least 96%, at least 96.5%, at least 97%, at least 97.5%, at least 98%, at least 98.5%, or at least 99% 24 hours, 48 ​​hours, 72 hours, and / or 96 hours after formulation. In some examples, the radiopharmaceutical composition may have a radiochemical purity of 95.0% or greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater upon administration. For example, a radiopharmaceutical composition may have a radiochemical purity of greater than 95% after 46-48 hours from formulation, greater than 96% after 46-48 hours from formulation, greater than 97% after 46-48 hours from formulation, greater than 95% after 69-72 hours from formulation, greater than 96% after 69-72 hours from formulation, greater than 97% after 69-72 hours from formulation, greater than 95% after 90-93 hours from formulation, greater than 96% after 90-93 hours from formulation, and / or greater than 97% after 90-93 hours from formulation.

[0245] In some examples, the radiochemical purity of the composition may range from about 99.0% to about 99.4% at 0 hours after EOS. In various embodiments, the radiochemical purity of the composition may range from about 96.5% to about 98.7% at 19 to 25 hours after EOS. In other examples, the radiochemical purity of the composition may range from about 93.3% to about 98.0% at 44 to 47 hours after EOS. In additional examples, the radiochemical purity of the composition may range from about 91.2% to about 97.4% at 69 to 71 hours after EOS. In some examples, the radiochemical purity of the composition may range from about 95% to about 97.0% at 90 to 93 hours after EOS.

[0246] In another embodiment, 177 Lu]Lu-PSMA I&T injection is supplied as a single-dose vial or a multi-dose vial.

[0247] In yet another embodiment, patients requiring radioligand therapy during treatment receive a single intravenous radioactive dose at the beginning of a treatment cycle. A treatment cycle is 1 to 10 weeks long. In one embodiment, treatment includes 1 to 6 treatment cycles. In another embodiment, dose reductions or dose escalations are introduced during treatment.

[0248] In one embodiment, the patient dose volume is calculated according to the administered radioactive dose.

[0249] In another embodiment, 177 [Lu]Lu-PSMA I&T is infused slowly intravenously (IV) over approximately 10 minutes, followed by 500-1000 mL of Ringer's solution or normal saline. If the total blood volume exceeds 5000 mL, an additional 7 mL injection will have no effect. This dose is administered every 6 weeks for 4 cycles.

[0250] In yet another embodiment, patients requiring radioligand therapy during treatment receive a single intravenous radioactive dose at the beginning of a treatment cycle. A treatment cycle is 1 to 10 weeks long. In one embodiment, treatment includes 1 to 6 treatment cycles. In another embodiment, dose reductions or dose escalations are introduced during treatment.

[0251] In one embodiment, the patient dose volume is calculated according to the administered radioactive dose.

[0252] VIII. Methods for diagnosing or treating prostate cancer Provided herein are methods for diagnosing or treating a tumor in a patient in need thereof, the methods comprising: 177 This may involve administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5.

[0253] In some embodiments, the average absorbed dose of the radiopharmaceutical composition is between about 0.1 mGy / MBq and 0.5 mGy / MBq, between about 0.5 mGy / MBq and 1.0 mGy / MBq, between 0.5 mGy / MBq and 0.6 mGy / MBq, between 0.6 mGy / MBq and 0.7 mGy / MBq, between 0.7 mGy / MBq and 0.8 mGy / MBq, between 0.8 mGy / MBq and 0.9 mGy / MBq, between 0.9 mGy / MBq and 1.0 mGy / MBq, between 1 mGy / MBq and 1.5 mGy / MBq, between 1.0 mGy / MBq and 1.1 mGy / MBq, between 1.1 mGy / MBq and 1.2 mGy / MBq in the kidneys of a patient. MBq, 1.2mGy / MBq~1.3mGy / MBq, 1.3mGy / MBq~1.4mGy / MBq, or 1.4mGy / MBq~1.5mGy / MBq, 1.5mGy / MBq~2.5mGy / MBq, 2.5mGy / MBq~3.5mGy / MBq, 2.5mGy / MBq~ It can be 2.7mGy / MBq, 2.7mGy / MBq~2.9mGy / MBq, 2.9mGy / MBq~3.1mGy / MBq, 3.1mGy / MBq~3.3mGy / MBq, 3.3mGy / MBq~3.5mGy / MBq, or 3.5mGy / MBq~4.5mGy / MBq. In some embodiments, the average absorbed dose of the radiopharmaceutical composition may be about 1 mGy / MBq to 1.5 mGy / MBq, 1.0 mGy / MBq to 1.1 mGy / MBq, 1.1 mGy / MBq to 1.2 mGy / MBq, 1.2 mGy / MBq to 1.3 mGy / MBq, 1.3 mGy / MBq to 1.4 mGy / MBq, or 1.4 mGy / MBq to 1.5 mGy / MBq in the patient's parotid gland. In some embodiments, the average absorbed dose of the radiopharmaceutical composition may be about 2.5 mGy / MBq to 3.5 mGy / MBq, 2.5 mGy / MBq to 2.7 mGy / MBq, 2.7 mGy / MBq to 2.9 mGy / MBq, 2.9 mGy / MBq to 3.1 mGy / MBq, 3.1 mGy / MBq to 3.3 mGy / MBq, or 3.3 mGy / MBq to 3.5 mGy / MBq in the bone lesion of the patient.In some embodiments, the average absorbed dose of the radiopharmaceutical composition may be about 3.5 mGy / MBq to 4.5 mGy / MBq, 3.5 mGy / MBq to 3.7 mGy / MBq, 3.7 mGy / MBq to 3.9 mGy / MBq, 3.9 mGy / MBq to 4.1 mGy / MBq, 4.1 mGy / MBq to 4.3 mGy / MBq, or 4.3 mGy / MBq to 4.5 mGy / MBq in the patient's lymph node lesions.

[0254] Treatment aimed at eradicating the primary tumor, typically by surgery or radiation, is unsuccessful in approximately 30% of men, who develop recurrent disease, usually manifesting first as elevated plasma prostate-specific antigen (PSA) and then as metastasis to distant sites (Stephenson et al. J Clin Oncol, 2005;23:8253-61). Given that prostate cancer cells depend on the androgen receptor (AR) for their growth and survival, the standard treatment for patients with recurrent disease is androgen deprivation therapy (ADT) with gonadotropin-releasing hormone analogs (GnRHa), with or without antiandrogens.

[0255] Treatment outcomes with ADT are generally predictable: a decline in PSA, followed by tumor regression, a period of PSA stability without tumor growth, followed by an increase in PSA, and regrowth, defined as castration-resistant disease. Nearly all men with advanced prostate cancer eventually develop castration-resistant disease. Progression of prostate cancer despite castrate-level testosterone represents a transition to a lethal disease stage. Docetaxel with prednisone, cabazitaxel with prednisone, enzalutamide, and abiraterone with prednisone are the standard of care for men with metastatic castration-resistant prostate cancer (mCRPC) according to the National Comprehensive Cancer Network (NCCN) guidelines (Mohler et al., NCCN Clinical practice guidelines in oncology. Prostate Cancer, (Version 2. 2019). JNCCN.org; 17(5), 479-505).

[0256] Abiraterone, enzalutamide, and docetaxel with prednisone are all indicated for patients with mCRPC as first-line treatment, whereas cabazitaxel with prednisone is only indicated for patients with mCRPC who have progressed on docetaxel. George et al. reported the treatment sequence for mCRPC patients in a real-world clinical setting in the United States (George et al. 2020). In the United States, a higher proportion of patients receive androgen receptor axis-targeted therapy (ARAT; i.e., abiraterone and enzalutamide) as first-line treatment rather than docetaxel. Similarly, a higher proportion of mCRPC patients receive alternative ARAT (abiraterone followed by enzalutamide, or vice versa) as second-line treatment.

[0257] Targeted radionuclide therapy is an emerging treatment option for many different cancers, including lymphoma, melanoma, and neuroendocrine tumors (Kraeber-Bodere et al., Semin Oncol, 2014, 41, 613-22; Mier et al., J Nucl Med, 2014, 55, 9-14; Bodei et al., Eur J Nucl Med Mol Imaging, 2015, 42, 5-19). Prostate-specific membrane antigen (PSMA) is an important target for radionuclide diagnosis and treatment of PC. Although PSMA is normally expressed in prostate cells and some extraprostatic tissues, its overexpression in prostate cancer cells makes it an attractive target for therapeutic agents with the potential to limit systemic toxicity (Silver et al., Clin Cancer Res. 1997 Jan;3(1):81-5. PMID:9815541). 131 Early clinical experience with PSMA-based radionuclide therapy of PC using I-labeled PSMA showed promising results, with a PSA reduction of more than 50% in 60% of all treated prostate cancer patients and mild hematologic toxicity (Zechmann et al., Eur J Nucl Med Mol Imaging, 2014, 41, 1280-92).

[0258] IX. Administration Further provided herein are methods of administering the radiopharmaceutical composition.The radiopharmaceutical composition may be administered by injection or infusion to a human patient in need thereof.

[0259] There can be about six main modes of administration.

[0260] First, it cools the salivary glands, reducing the risk of salivary gland radiation damage to the patient. 177 Ice packs are placed on the parotid and submandibular glands 30 minutes before and up to four hours after administration of Lu-PSMA I&T. There is no scientific evidence that cooling the salivary glands is an effective therapy for sparing these glands from radiation, however, it is well tolerated and not harmful to patients.

[0261] Second, use a urinary catheter in incontinent patients within the first 48 hours to avoid any contamination.

[0262] Third, 6.5–7.5 GBq (range: 6.0–8.0 GBq) 177 Lu-PSMA I&T activity. The dose can be reduced to 4.0-5.0 GBq in cases of renal dysfunction (e.g., creatinine within 1.0-1.5 UNL). Preliminary results suggest that 7.4 GBq of activity can be safely administered; however, more data are needed to determine whether the dose should be increased.

[0263] Fourth, the active ingredient is administered intravenously as a slow bolus (over approximately 1 to 15 minutes), followed by 500 to 1000 ml of Ringer's solution or NaCl solution. Patients should be encouraged to urinate as frequently as possible and drink approximately 2 liters of water per day. In patients with dilated non-obstructive renal disease, the administration of diuretics may be beneficial.

[0264] Fifth, with an average of 3 to 5 cycles of RLT every 5 to 8 weeks, up to 11 cycles have been reported. If PSA continues to increase or if performance status worsens after the first two cycles, the indication for further RLT should be reevaluated. If PSA falls below 1.0 μg / L during a therapy cycle, or if post-injection SPECT studies are not sufficiently informative, PSMA imaging can be used to assess the presence of small PSMA-positive metastases after completion of RLT. In the event of a significant decline in platelets or white blood cells, the time interval between two cycles can be extended.

[0265] Sixth, at least one whole-body scan (preferably SPECT( / CT)) should be performed 24–48 hours after injection. Concomitant corticosteroid therapy (e.g., prednisolone 20 mg / day) during the first 2 weeks after administration is recommended for patients with diffuse bone and bone marrow metastases, as well as for patients with brain metastases.

[0266] In some embodiments, the method may include injecting the radiopharmaceutical composition into a patient in need thereof more than 48 hours after formulation. In some examples, the radiopharmaceutical composition comprises: 177 The Lu-PSMA I&T and ascorbic acid may be contained in a solution having a pH of 3.5 to 4.5, and the solution may have a radiochemical purity of greater than 96% upon administration. In certain embodiments, the pH of the solution is about 3.5 to 4.2. The composition may contain less than 6 μg / ml of Lu-PSMA I&T, about 7 μg / ml to about 18 μg / ml of disodium EDTA, about 25 μl / ml to about 45 μl / ml of ethanol, and / or about 15 to about 35 mg / ml of ascorbic acid. The composition may have a radioactivity of about 0.5 GBq / ml or about 13.5 mCi / ml and may have a radiochemical purity of at least 98% 44 hours after formulation, at least 97% 69 hours after formulation, and / or at least 97% 93 hours after formulation.

[0267] The pharmaceutical composition may be administered every 5 to 8 weeks for 2 to 11 cycles / treatments. In some embodiments, a patient may receive up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 treatments, with treatments administered every 4, 5, 6, 7, or 8 weeks. In some examples, a patient may receive up to 4 treatments, with each treatment administered every 6 weeks.

[0268] In various embodiments, patients receive a dose of 0.5 GBq to 10 GBq per dose cycle. 177Lu-PSMA I&T may be administered. For example, the radiopharmaceutical composition may contain a standard activity of about 200 mCi at the time of administration, with a standard activity concentration of about 27 mCi / mL at the end of manufacture; therefore, the final volume of the dose vial may be adjusted to 7-15 mL to provide the amount of radioactivity required for the day and time of injection. In some embodiments, the dose vial contains 10-20 mL. In at least one example, a patient may receive a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) for each treatment. In one aspect, a patient may receive a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) for each of four, five, six, seven, or more treatments. In another aspect, a patient may receive a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) for each of four or more treatments, five or more, six or more, seven or more, or eight or more treatments. In yet another embodiment, the patient may receive a dose of about 200 mCi (≧7.1 GBq) for each of 4, 5, 6, 7, 8, or more treatments. In another example, the patient may receive a dose of about 6.8 GBq±0.3 GBq for each treatment. In one embodiment, the patient may receive a dose of about 6.8 GBq±0.3 GBq for each of 4, 5, 6, 7, 8, or more treatments.

[0269] In various embodiments, the patient receives a dose of about 0.5 GBq to about 10 GBq, about 1.0 GBq to about 9.0 GBq, about 1.5 GBq to about 8.5 GBq, about 2.0 GBq to about 8.0 GBq, about 2.5 GBq to about 7.5 GBq, or about 3.0 GBq to about 7.0 GBq. 177Lu-PSMA I&T may be administered, wherein the patient's total cumulative dose to the kidney per administration is 3.9 Gy or less, 3.8 Gy or less, 3.7 Gy or less, 3.6 Gy or less, 3.5 Gy or less, 3.4 Gy or less, 3.3 Gy or less, 3.2 Gy or less, 3.1 Gy or less, 3.0 Gy or less, 2.9 Gy or less, 2.8 Gy or less, 2.7 Gy or less, 2.6 Gy or less, 2.5 Gy or less, or 2.4 Gy or less, and the patient may receive 1, 2, 3, 4, 5, 6, 7, 8, or more treatments (i.e., treatment cycles), or a dose for each treatment of 4, 5, 6, 7, 8, or more treatments (i.e., treatment cycles). In various embodiments, the patient receives about 0.5 GBq to about 10.0 GBq, about 0.5 GBq to about 9.5 GBq, about 0.5 GBq to about 9.0 GBq, about 0.5 GBq to about 8.5 GBq, about 0.5 GBq to about 8.0 GBq, about 0.5 GBq to about 7.5 GBq, about 1.0 GBq to about 10.0 GBq, about 1.0 GBq to about 9.5 GBq, about 1.0 GBq to about 9.0 GBq, about 1.0 GBq to about 8.5 GBq, about 1.0 GBq to about 10 ... GBq to approximately 1.0 GBq, approximately 1.0 GBq to approximately 7.5 GBq, approximately 1.5 GBq to approximately 10.0 GBq, approximately 1.5 GBq to approximately 9.5 GBq, approximately 1.5 GBq to approximately 9.0 GBq, approximately 1.5 GBq to approximately 8.5 GBq, approximately 1.5 GBq to approximately 8.0 GBq, approximately 1.5 GBq to approximately 7.5 GBq, approximately 2.0 GBq to approximately 10.0 GBq, approximately 2.0 GBq to approximately 9.5 GBq, approximately 2.0 GBq to approximately 9.0 GBq, approximately 2.0 GBq q to approximately 8.5GBq, approximately 2.0GBq to approximately 8.0GBq, approximately 2.5GBq to approximately 10.0GBq, approximately 2.5GBq to approximately 2.5GBq, approximately 2.5GBq to approximately 9.0GBq, approximately 2.5GBq to approximately 8.5GBq, approximately 2.5GBq to approximately 8.0GBq, approximately 2.5GBq to approximately 7.5GBq, approximately 3.0GBq to approximately 10.0GBq, approximately 3.0GBq to approximately 9.5GBq, approximately 3.0GBq to approximately 9.0GBq, approximately 3.0GBq Approximately 8.5 GBq, approximately 3.0 GBq to approximately 8.0 GBq, approximately 3.0 GBq to approximately 7.5 GBq, approximately 3.5 GBq to approximately 10.0 GBq, approximately 3.5 GBq to approximately 9.5 GBq, approximately 3.5 GBq to approximately 9.0 GBq, approximately 3.5 GBq to approximately 8.5 GBq, approximately 3.5 GBq to approximately 8.0 GBq, approximately 3.5 GBq to approximately 7.5 GBq, approximately 0.5 GBq to approximately 7.5 GBq, approximately 0.5 GBq to approximately 7.4 GBq, approximately 1.0 GBq to approximately 7.4GBq, approximately 1.5GBq to approximately 7.4GBq, approximately 2.0GBq to approximately 7.4GBq, approximately 2.5GBq to approximately 7.4GBq, approximately 3.0GBq to approximately 7.4GBq, approximately 3.5GBq to approximately 7.4GBq, approximately 4.0GBq to approximately 7.4GBq, approximately 4.5GBq to approximately 7.4GBq, approximately 5.0GBq to approximately 7.4GBq, approximately 5.5GBq to approximately 7.4GBq, approximately 6.0GBq At a dose of about 7.4 GBq, about 6.5 GBq to about 7.4 GBq, about 6.6 GBq to about 7.4 GBq, about 6.7 GBq to about 7.4 GBq, about 6.8 GBq to about 7.4 GBq, about 6.9 GBq to about 7.4 GBq, about 7.0 GBq to about 7.4 GBq, about 7.1 GBq to about 7.4 GBq, about 7.2 GBq to about 7.4 GBq, or about 7.3 GBq to about 7.4 GBq. 177 Lu-PSMA I&T may be administered, wherein the patient's total cumulative dose to the kidney per administration is 3.9 Gy or less, 3.8 Gy or less, 3.7 Gy or less, 3.6 Gy or less, 3.5 Gy or less, 3.4 Gy or less, 3.3 Gy or less, 3.2 Gy or less, 3.1 Gy or less, 3.0 Gy or less, 2.9 Gy or less, 2.8 Gy or less, 2.7 Gy or less, 2.6 Gy or less, 2.5 Gy or less, or 2.4 Gy or less, and the patient may receive a dose for each treatment of 1, 2, 3, 4, 5, 6, 7, 8, or more treatments (i.e., treatment cycles). In various other embodiments, the patient receives between about 0.5 GBq and about 6.8 GBq, between about 1.0 GBq and about 6.8 GBq, between about 1.5 GBq and about 6.8 GBq, between about 2.0 GBq and about 6.8 GBq, between about 2.5 GBq and about 6.8 GBq, between about 3.0 GBq and about 6.8 GBq, between about 3.5 GBq and about 6.8 GBq, between about 4.0 GBq and about 6.8 GBq, between about 4.5 GBq and about 6.8 GBq, between about 5 GBq and about 6.8 GBq, between about 6 GBq and about 6.8 GBq, between about 7 GBq and about 7.8 GBq, between about 8 GBq and about 8.8 GBq, between about 9 GBq and about 9.8 GBq, between about 10 GBq and about 10.8 GBq, between about 11 GBq and about 11.8 GBq, between about 12 GBq and about 12.8 GBq, between about 13 GBq and about 13.8 GBq, between about 14 GBq and about 14.8 GBq, between about 15 GBq and about 15.8 GBq, between about 16 GBq and about 16.8 GBq, between about 17 GBq and about 17.8 GBq, between about 18 GBq and about 18.8 GBq, between about 19 GBq and about 20 GBq, between about 21 GBq and about 22.8 GBq, between about 23 GBq and about 24.8 GBq, between about 25 GBq and about 26.8 GBq, between about 26 GBq and about 28.8 GBq, between about 29 GBq and about 30.8 GBq, between about 31 GBq and about 32.8 GBq, between about 32 at a dose of about 0.0 GBq to about 6.8 GBq, about 5.5 GBq to about 6.8 GBq, about 6.0 GBq to about 6.8 GBq, about 6.1 GBq to about 6.8 GBq, about 6.2 GBq to about 6.8 GBq, about 6.3 GBq to about 6.8 GBq, about 6.4 GBq to about 6.8 GBq, about 6.5 GBq to about 6.8 GBq, about 6.6 GBq to about 6.8 GBq, or about 6.7 GBq to about 7.4 GBq 177Lu-PSMA I&T may be administered, wherein the patient's total cumulative dose to the kidney per administration is 3.9 Gy or less, 3.8 Gy or less, 3.7 Gy or less, 3.6 Gy or less, 3.5 Gy or less, 3.4 Gy or less, 3.3 Gy or less, 3.2 Gy or less, 3.1 Gy or less, 3.0 Gy or less, 2.9 Gy or less, 2.8 Gy or less, 2.7 Gy or less, 2.6 Gy or less, 2.5 Gy or less, or 2.4 Gy or less, and the patient may receive a dose for each treatment of 1, 2, 3, 4, 5, 6, 7, 8, or more treatments (i.e., treatment cycles).

[0270] In various embodiments, a patient may receive more than 10 treatments, and the treatments may be administered every 4, 5, 6, 7, or 8 weeks, so long as the patient's total cumulative dose to the kidneys after all treatments remains below 23 Gray (Gy). For example, a patient may receive more than 10, more than 15, more than 20, more than 25, more than 30, more than 35, more than 40, more than 45, more than 50, more than 55, more than 60, more than 65, more than 70, or more than 75 treatments, and the treatments may be administered every 4, 5, 6, 7, or 8 weeks, so long as the patient's total cumulative dose to the kidneys after all treatments remains below 23 Gray (Gy).

[0271] In some embodiments, 177 The administration of [Lu]Lu-PSMA I&T to the patient's kidneys was 0.46 Gy / GBq ± 0.23 Gy / GBq (i.e., administered 177 In some additional embodiments, the absorbed dose is 0.46 Gy per GBq of Lu-PSMA I&T. 177 Administration of Lu-PSMA I&T results in an absorbed dose to the patient's kidney of 0.46 Gy / GBq or less.

[0272] In various embodiments, 177 The administration of [Lu]Lu-PSMA I&T to the patient's kidney was 0.43 Gy / GBq ± 0.05 Gy / GBq (i.e., administered [ 177In some additional embodiments, [Lu]Lu-PSMA results in an absorbed dose of 0.43 Gy per GBq of I&T. 177 Administration of [Lu]Lu-PSMA I&T results in an absorbed dose to the patient's kidney of 0.43 Gy / GBq or less.

[0273] In other embodiments, 177 The administration of [Lu]Lu-PSMA I&T to the patient's kidney was 0.41 Gy / GBq ± 0.15 Gy / GBq (i.e., administered [ 177 In some additional embodiments, [Lu]Lu-PSMA results in an absorbed dose of 0.41 Gy per GBq of I&T. 177 Administration of [Lu]Lu-PSMA I&T results in an absorbed dose to the patient's kidney of 0.41 Gy / GBq or less.

[0274] In various embodiments, 177 The administration of [Lu]Lu-PSMA I&T to the patient's submandibular gland was 0.67 Gy / GBq ± 0.33 Gy / GBq (i.e., administered [ 177 In some additional embodiments, [Lu]Lu-PSMA results in an absorbed dose of 0.67 Gy per GBq of I&T. 177 Administration of [Lu]Lu-PSMA I&T results in an absorbed dose to the patient's submandibular gland of 0.67 Gy / GBq or less.

[0275] In other embodiments, 177 The administration of [Lu]Lu-PSMA I&T was 0.40 Gy / GBq ± 0.37 Gy / GBq to the patient's submandibular gland (i.e., administered [ 177 In some additional embodiments, the [Lu]Lu-PSMA I&T provides an absorbed dose of 0.40 Gy per GBq of I&T. 177 Administration of [Lu]Lu-PSMA I&T results in an absorbed dose to the patient's submandibular gland of 0.40 Gy / GBq or less.

[0276] In other embodiments, 177 The administration of [Lu]Lu-PSMA I&T to the patient's salivary glands was 0.10 Gy / GBq ± 0.06 Gy / GBq (i.e., administered [177 In some additional embodiments, the I&T provides an absorbed dose of 0.10 Gy per GBq of [Lu]Lu-PSMA I&T. 177 Administration of Lu-PSMA I&T results in an absorbed dose to the patient's salivary glands of 0.10 Gy / GBq or less.

[0277] In various embodiments, 177 The administration of [Lu]Lu-PSMA I&T to the patient's salivary glands was 0.13 Gy / GBq ± 0.08 Gy / GBq (i.e., administered [ 177 In some additional embodiments, [Lu]Lu-PSMA results in an absorbed dose of 0.13 Gy per GBq of I&T. 177 Administration of [Lu]Lu-PSMA I&T results in an absorbed dose to the patient's salivary glands of 0.13 Gy / GBq or less.

[0278] In other embodiments, 177 The administration of [Lu]Lu-PSMA I&T to the patient's salivary glands was 0.18 Gy / GBq ± 0.16 Gy / GBq (i.e., administered [ 177 In some additional embodiments, [Lu]Lu-PSMA results in an absorbed dose of 0.18 Gy per GBq of I&T. 177 Administration of [Lu]Lu-PSMA I&T results in an absorbed dose to the patient's salivary glands of 0.18 Gy / GBq or less.

[0279] In various embodiments, 177 The administration of [Lu]Lu-PSMA I&T to the patient's liver was 0.03 Gy / GBq ± 0.02 Gy / GBq (i.e., administered [ 177 In some additional embodiments, the [Lu]Lu-PSMA I&T provides an absorbed dose of 0.03 Gy per GBq of I&T. 177 Administration of [Lu]Lu-PSMA I&T results in an absorbed dose to the patient's liver of 0.03 Gy / GBq or less.

[0280] In other embodiments, 177The administration of [Lu]Lu-PSMA I&T to the patient's liver was 0.04 Gy / GBq ± 0.02 Gy / GBq (i.e., administered 177 In some additional embodiments, the absorbed dose is 0.04 Gy per GBq of Lu-PSMA I&T. 177 Administration of Lu-PSMA I&T results in an absorbed dose to the patient's liver of 0.04 Gy / GBq or less.

[0281] 177 The administration of Lu-PSMA I&T can be described as a mathematical formula to ensure that the patient's total cumulative dose to the kidney after all treatments remains below 23 Gy. An exemplary formula for determining the acceptable number of cycles is shown below.

number

[0282] In various embodiments, patients receive 1 GBq of IV iodine for 53 treatments. 177 Lu-PSMA I&T, 2 GBq for 26 treatments 177 Lu-PSMA I&T, 3 GBq for 17 treatments 177 Lu-PSMA I&T, 4 GBq for 13 treatments 177 Lu-PSMA I&T, 5GBq for 10 treatments 177 Lu-PSMA I&T, 6 GBq for 8 treatments 177 Lu-PSMA I&T, 7 GBq for 7 treatments 177Lu-PSMA I&T, 8 GBq for 6 treatments 177 Lu-PSMA I&T, 9GBq for 5 treatments 177 Lu-PSMA I&T, 10 GBq for 5 treatments 177 Lu-PSMA I&T, etc. may also be administered.

[0283] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.5 GBq±0.10 GBq, a dose of 6.5 GBq±0.15 GBq, a dose of 6.5 GBq±0.20 GBq, a dose of 6.5 GBq±0.25 GBq, or a dose of 6.5 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0284] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.6 GBq±0.10 GBq, a dose of 6.6 GBq±0.15 GBq, a dose of 6.6 GBq±0.20 GBq, a dose of 6.6 GBq±0.25 GBq, or a dose of 6.6 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0285] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.7 GBq±0.10 GBq, a dose of 6.7 GBq±0.15 GBq, a dose of 6.7 GBq±0.20 GBq, a dose of 6.7 GBq±0.25 GBq, or a dose of 6.7 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles of the dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0286] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.8 GBq±0.10 GBq, a dose of 6.8 GBq±0.15 GBq, a dose of 6.8 GBq±0.20 GBq, a dose of 6.8 GBq±0.25 GBq, or a dose of 6.8 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0287] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.9 GBq±0.10 GBq, a dose of 6.9 GBq±0.15 GBq, a dose of 6.9 GBq±0.20 GBq, a dose of 6.9 GBq±0.25 GBq, or a dose of 6.9 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0288] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.0 GBq±0.10 GBq, a dose of 7.0 GBq±0.15 GBq, a dose of 7.0 GBq±0.20 GBq, a dose of 7.0 GBq±0.25 GBq, or a dose of 7.0 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0289] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.1 GBq±0.10 GBq, a dose of 7.1 GBq±0.15 GBq, a dose of 7.1 GBq±0.20 GBq, a dose of 7.1 GBq±0.25 GBq, or a dose of 7.1 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles of the dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0290] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.2 GBq±0.10 GBq, a dose of 7.2 GBq±0.15 GBq, a dose of 7.2 GBq±0.20 GBq, a dose of 7.2 GBq±0.25 GBq, or a dose of 7.2 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles of the dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0291] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.3 GBq±0.10 GBq, a dose of 7.3 GBq±0.15 GBq, a dose of 7.3 GBq±0.20 GBq, a dose of 7.3 GBq±0.25 GBq, or a dose of 7.3 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles of the dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0292] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq ± 0.10 GBq, a dose of 7.4 GBq ± 0.15 GBq, a dose of 7.4 GBq ± 0.20 GBq, a dose of 7.4 GBq ± 0.25 GBq, or a dose of 7.4 GBq ± 0.30 GBq, and six cycles of the dose. 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0293] In various embodiments, the present disclosure provides a radiopharmaceutical kit comprising: 177 a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.5 GBq±0.10 GBq, a dose of 7.5 GBq±0.15 GBq, a dose of 7.5 GBq±0.20 GBq, a dose of 7.5 GBq±0.25 GBq, or a dose of 7.5 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles of [ 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles of [ 177 The present invention further relates to a radiopharmaceutical kit, wherein the [Lu]Lu-PSMA I&T treatment provides a mean predicted cumulative absorbed dose to the kidney of less than 23 Gy and / or the predicted or actual cumulative absorbed dose to the kidney over 6 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0294] In various embodiments, the present disclosure provides a radiopharmaceutical kit comprising: 177 [Lu]Lu-PSMA I&T solution, and the injection contains a 7.4 GBq (mean 7.52 ± 0.16 GBq) dose of [ 177 Lu]Lu-PSMA-I&T and 6 cycles at that dose [ 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles of [ 177

[0013] The present disclosure further relates to a radiopharmaceutical kit, wherein the [Lu]Lu-PSMA I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy cumulative absorbed dose, and / or the predicted or actual cumulative absorbed dose to the kidney for 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy and no nephrotoxicity is observed. 177 [Lu]Lu-PSMA I&T solution, and the injection contains a 7.4 GBq (mean 7.52 ± 0.16 GBq) dose of [ 177 Lu]Lu-PSMA-I&T for 1, 2, 3, 4, 5, 6, or 7 cycles 177

[0013] The present invention further relates to a radiopharmaceutical kit, wherein the [Lu]Lu-PSMA I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy cumulative absorbed dose, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0295] The present disclosure also provides a radiopharmaceutical kit, comprising: 177

[0033] The present invention relates to a method for administering a medicament for the treatment of psoriasis, the method comprising administering to a subject a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution ... 177 Lu-PSMA-I&T and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles of [ 177

[0013] The present invention further relates to a radiopharmaceutical kit, wherein the [Lu]Lu-PSMA I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy cumulative absorbed dose, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0296] The present disclosure also provides a radiopharmaceutical kit, comprising: 177 a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection is administered at a dose of 6.8 GBq + / - 10% GBq, a dose of 6.8 GBq + / - 5% GBq, or a dose of 6.8 GBq + / - 3% GBq 177 Lu]Lu-PSMA-I&T, and 1, 2, 3, 4, 5, 6, or 7 cycles of [ 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles of [ 177

[0013] The present invention further relates to a radiopharmaceutical kit, wherein the [Lu]Lu-PSMA I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy cumulative absorbed dose, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0297] The present disclosure also provides a radiopharmaceutical kit, comprising: 177 and a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection is administered at a dose of 7.4 GBq + / - 10% GBq, a dose of 7.4 GBq + / - 5% GBq, or a dose of 7.4 GBq + / - 3% GBq. 177 1, 2, 3, 4, 5, 6, or 7 cycles of Lu-PSMA-I&T at that dose 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177

[0013] The present invention further relates to a radiopharmaceutical kit, wherein the [Lu]Lu-PSMA I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy cumulative absorbed dose, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0298] The present disclosure also provides a radiopharmaceutical kit, comprising: 177[Lu]Lu-PSMA I&T solution, and the injection contains a vial containing at least a single dose of a 7.4 (+ / - 10%) GBq dose of [ 177 Lu]Lu-PSMA I&T, and 6 cycles of [ 177 Lu]Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 6 cycles of [ 177 Lu]Lu-PSMA The present invention further relates to a radiopharmaceutical kit, wherein the I&T treatment provides a mean predicted dose to the kidney of less than 23 Gy cumulative absorbed dose, and / or the predicted or actual cumulative absorbed dose to the kidney over 6 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0299] The present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq±0.10 GBq, a dose of 7.4 GBq±0.15 GBq, a dose of 7.4 GBq±0.20 GBq, a dose of 7.4 GBq±0.25 GBq, or a dose of 7.4 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over six cycles would be 20.4±10.2 Gy. 177

[0023] The present invention further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of [Lu]Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.5 GBq±0.10 GBq, a dose of 7.5 GBq±0.15 GBq, a dose of 7.5 GBq±0.20 GBq, a dose of 7.5 GBq±0.25 GBq, or a dose of 7.5 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over six cycles would be 20.4±10.2 Gy.

[0300] In some embodiments, the present disclosure provides: 177 In another embodiment, the kit comprises a predetermined amount of a composition comprising Lu-PSMA I&T. 177The molar ratio to Lu is from 5.0:1.0 to 12.0:1.0. In another embodiment, the composition is suitable for administration to a human patient in need thereof.

[0301] Upon administration of the radiopharmaceutical composition to a patient, the patient may maintain low levels of hematotoxicity and nephrotoxicity, hi some embodiments, the reduction in prostate specific antigen (PSA) is greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, or greater than about 80%.

[0302] 177 Further provided herein are methods of treating patients with cancer and / or mCRPC by administering a radiopharmaceutical composition comprising Lu-PSMA I&T. The methods may further include imaging the patient using PSMA-PET prior to administering the radiopharmaceutical composition to document and confirm that the patient is mCRPC positive. For example, the patient may have a PSMA-PET scan (e.g., [ 68 Ga]Ga-PSMA-11 or [ 18 In one embodiment, provided herein is a method of imaging cancer in a human patient. In another embodiment, the method comprises: 177 In another embodiment, the method further comprises administering to a human patient a composition comprising the Lu-PSMA I&T. 177 The molar ratio to Lu is 5.0:1.0 to 12.0:1.0.

[0303] Indications and contraindications 177 RLT with Lu-PSMA I&T may be indicated for the treatment of patients with cancer and / or mCRPC who do not have any other approved therapeutic options planned by a multidisciplinary team. In certain embodiments, provided herein are methods of treating cancer in a patient in need thereof.

[0304] In another embodiment, the method comprises: 177 In another embodiment, the method further comprises administering to a human patient a composition comprising Lu-PSMA I&T. 177 In another embodiment, the molar ratio of PSMA I&T to Lu is 1.0:1.0 to 12.0:1.0, 3.0:1.0 to 12.0:1.0, or 5.0:1.0 to 12.0:1.0. 177 The molar ratio of PSMA I&T to Lu is 1.0:1.0 to 8.0:1.0, 1.5:1.0 to 8.0:1.0, 2.0:1.0 to 8.0:1.0, 2.5:1.0 to 8.0:1.0, 3.0:1.0 to 8.0:1.0, 3.5:1.0 to 8.0:1.0, or 4.0:1.0 to 8.0:1.0. 177 The molar ratio of PSMA I&T to Lu is 4.1:1.0 to 7.9:1.0, 4.2:1.0 to 7.8:1.0, 4.3:1.0 to 7.7:1.0, 4.4:1.0 to 7.6:1.0, 4.5:1.0 to 7.5:1.0, 4.6:1.0 to 7.4:1.0, 4.7:1.0 to 7.3:1.0, 4.8:1.0 to 7.2:1.0, 4.9:1.0 to 7.1:1.0, or 5.0:1.0 to 7.0:1.0. 177 The molar ratio of PSMA I&T to Lu is 5.0:1.0 to 7.6:1.0, 5.1:1.0 to 7.5:1.0, 5.2:1.0 to 7.4:1.0, 5.3:1.0 to 7.3:1.0, or 5.4:1.0 to 7.2:1.0. 177The molar ratios to Lu were 8.0:1.0 to 10.0:1.0, 8.1:1.0 to 10.0:1.0, 8.2:1.0 to 10.0:1.0, 8.3:1.0 to 10.0:1.0, 8.4:1.0 to 10.0:1.0, 8.5:1.0 to 10.0:1.0, 8.6:1.0 to 10.0:1.0, 8.7:1.0 to 10.0:1.0, 8.8:1.0 to 10.0:1.0, and 8.9:1.0 to 10.0:1.0. 9.0:1.0 to 10.0:1.0, 9.1:1.0 to 10.0:1.0, 9.2:1.0 to 10.0:1.0, 9.3:1.0 to 10.0:1.0, 9.4:1.0 to 10.0:1.0, 9.5:1.0 to 10.0:1.0, 9.6:1.0 to 10.0:1.0, 9.7:1.0 to 10.0:1.0, 9.8:1.0 to 10.0:1.0, or 9.9:1.0 to 10.0:1.0. 177 The molar ratios to Lu were 8.0:1.0 to 11.0:1.0, 8.1:1.0 to 11.0:1.0, 8.2:1.0 to 11.0:1.0, 8.3:1.0 to 11.0:1.0, 8.4:1.0 to 11.0:1.0, 8.5:1.0 to 11.0:1.0, 8.6:1.0 to 11.0:1.0, 8.7: 1.0~11.0:1.0, 8.8:1.0~11.0:1.0, 8.9:1.0~11.0:1.0, 9.0:1.0~11.0:1.0, 9.1:1.0~11.0:1.0, 9.2:1.0~11.0:1.0, 9.3:1.0~11.0:1.0, 9.4:1.0~11.0:1.0, 9. 5:1.0~11.0:1.0, 9.6:1.0~11.0:1.0, 9.7:1.0~11.0:1.0, 9.8:1.0~11.0:1.0, 9.9:1.0~11.0:1.0, 10.0:1.0~11.0:1.0, 10.1:1.0~11.0:1.0, 10.2:1.0~11.0:1 10.0, 10.3:1.0 to 11.0:1.0, 10.4:1.0 to 11.0:1.0, 10.5:1.0 to 11.0:1.0, 10.6:1.0 to 11.0:1.0, 10.7:1.0 to 11.0:1.0, 10.8:1.0 to 11.0:1.0, or 10.9:1.0 to 11.0:1.0. 177The molar ratios to Lu were 3.0:1.0–12.0:1.0, 3.5:1.0–12.0:1.0, 4.0:1.0–12.0:1.0, 4.4:1.0–12.0:1.0, 4.4:1.0–11.5:1.0, 4.4:1.0–11.0:1.0, 4.4:1.0–10.5:1.0, 4.4:1.0–10.0:1.0, 4.4:1.0–9.5:1.0, and 4.4:1.0–9. The ratio may be 0:1.0, 4.4:1.0 to 8.5:1.0, 4.4:1.0 to 8.0:1.0, 4.4:1.0 to 7.5:1.0, 4.4:1.0 to 7.0:1.0, 4.4:1.0 to 6.5:1.0, 4.4:1.0 to 6.0:1.0, 4.5:1.0 to 5.9:1.0, 4.6:1.0 to 4.7:1.0, 4.8:1.0 to 5.7:1.0, or 4.9:1.0 to 5.6:1.0. 177 The molar ratios to Lu were 5.0:1.0 to 12.0:1.0, 5.0:1.0 to 11.5:1.0, 5.0:1.0 to 11.0:1.0, 5.0:1.0 to 10.5:1.0, 5.0:1.0 to 10.0:1.0, 5.0:1.0 to 9.5:1.0, 5.0:1.0 to 9.0:1.0, 5.0:1.0 to 8.5:1.0, 5.0:1.0 to 8.0: The ratio may be 5.0:1.0 to 7.5:1.0, 5.0:1.0 to 7.0:1.0, 5.0:1.0 to 6.5:1.0, 5.0:1.0 to 6.0:1.0, 5.1:1.0 to 5.9:1.0, 5.2:1.0 to 5.8:1.0, 5.3:1.0 to 5.7:1.0, 5.4:1.0 to 5.6:1.0, or 5.45:1.0 to 5.55:1.0. 177The molar ratios to Lu were 8.0:1.0 to 12.0:1.0, 8.0:1.0 to 11.5:1.0, 8.0:1.0 to 11.0:1.0, 8.0:1.0 to 10.5:1.0, 8.0:1.0 to 10.4:1.0, 8.0:1.0 to 10.3:1.0, 8.0:1.0 to 10.2:1.0, 8.0:1.0 to 10.1:1.0, 8.0:1.0 to 10.0 ... The ratio may be 8.0:1.0 to 9.9:1.0, 8.0:1.0 to 9.8:1.0, 8.0:1.0 to 9.7:1.0, 8.0:1.0 to 9.6:1.0, 8.0:1.0 to 9.5:1.0, 8.0:1.0 to 9.4:1.0, 8.0:1.0 to 9.3:1.0, 8.0:1.0 to 9.2:1.0, 8.0:1.0 to 9.1:1.0, or 8.0:1.0 to 9.0:1.0. 177 The molar ratio to Lu can be 9.0:1.0 to 12.0:1.0, 9.0:1.0 to 11.5:1.0, 9.0:1.0 to 11.0:1.0, 9.0:1.0 to 10.5:1.0, 9.0:1.0 to 10.4:1.0, 9.0:1.0 to 10.3:1.0, 9.0:1.0 to 10.2:1.0, 9.0:1.0 to 10.1:1.0, 9.0:1.0 to 10.0:1.0, 9.0:1.0 to 9.9:1.0, 9.0:1.0 to 9.8:1.0, 9.0:1.0 to 9.7:1.0, 9.0:1.0 to 9.6:1.0, or 9.0:1.0 to 9.5:1.0.

[0305] PSMA I&T 177 The molar ratio of Lu to Lu can be 11.0:1.0 to 12.0:1.0, 11.1:1.0 to 11.9:1.0, 11.2:1.0 to 11.8:1.0, 11.3:1.0 to 11.7:1.0, or 11.4:1.0 to 11.6:1.0. 177 The molar ratio of Lu to Lu can be 10.0:1.0 to 11.0:1.0, 10.1:1.0 to 10.9:1.0, 10.2:1.0 to 10.8:1.0, 10.3:1.0 to 10.7:1.0, or 10.4:1.0 to 10.6:1.0. 177The molar ratio of Lu to Lu can be 9.0:1.0 to 10.0:1.0, 9.1:1.0 to 9.9:1.0, 9.2:1.0 to 9.8:1.0, 9.3:1.0 to 9.7:1.0, or 9.4:1.0 to 9.6:1.0. 177 The molar ratio of Lu to Lu can be 8.0:1.0 to 9.0:1.0, 8.1:1.0 to 8.9:1.0, 8.2:1.0 to 8.8:1.0, 8.3:1.0 to 8.7:1.0, or 8.4:1.0 to 8.6:1.0. 177 The molar ratio of Lu to Lu can be 7.0:1.0 to 8.0:1.0, 7.1:1.0 to 7.9:1.0, 7.2:1.0 to 7.8:1.0, 7.3:1.0 to 7.7:1.0, or 7.4:1.0 to 7.6:1.0. 177 The molar ratio of Lu to Lu can be 6.0:1.0 to 7.0:1.0, 6.1:1.0 to 6.9:1.0, 6.2:1.0 to 7.8:1.0, 7.3:1.0 to 7.7:1.0, or 7.4:1.0 to 6.6:1.0. 177 The molar ratio of Lu to Lu can be 5.0:1.0 to 6.0:1.0, 5.1:1.0 to 5.9:1.0, 5.2:1.0 to 5.8:1.0, 5.3:1.0 to 5.7:1.0, or 5.4:1.0 to 5.6:1.0. 177 The molar ratio to Lu can be 4.4:1.0 to 5:0:1.0, 4.5:1.0 to 5:0:1.0, 4.6:1.0 to 5:0:1.0, 4.7:1.0 to 5:0:1.0, 4.8:1. to 5:0:1.0, or 4.9:1. to 5:0:1.0.

[0306] The molar ratio of PSMA I&T to 177Lu is about 5.0:1.0 to about 5.5:1.0, about 5.5:1.0 to about 6.0:1.0, about 6.0:1.0 to about 6.5:1.0, about 6.5:1.0 to about 7.0:1.0, about 7.0:1.0 to about 7.5:1.0, about 7.5:1.0 to about 8.0:1.0, and about 8.0:1.0 to about 8.5:1.0. , about 8.5:1.0 to about 9.0:1.0, about 9.0:1.0 to about 9.5:1.0, about 9.5:1.0 to about 10.0:1.0, about 10.0:1.0 to about 10.5:1.0, about 10.5:1.0 to about 11.0:1.0, about 11.0:1.0 to about 11.5:1.0, or about 11.5:1.0 to about 12.0:1.0.

[0307] In another embodiment, the compositions, kits, and methods described herein can have a ratio of PSMA I&T to [177Lu]Lu3+ at μg:mCi of 0.65 or less, 0.64 or less, 0.63 or less, 0.62 or less, 0.61 or less, or 0.60 or less. In another embodiment, the compositions, kits, and methods described herein can have a ratio of PSMA I&T to [177Lu]Lu3+ at μg:mCi of about 0.20 to about 0.64, about 0.20 to about 0.63, about 0.20 to about 0.62, about 0.20 to about 0.61, or about 0.20 to about 0.60 ... The ratio of I&T to [177Lu]Lu3+ is about 0.21 to about 0.59, about 0.22 to about 0.58, about 0.23 to about 0.57, about 0.24 to about 0.56, about 0.25 to about 0.55, about 0.26 to about 0.54, about 0.27 to about 0.53, about 0.28 to about 0.52, about 0.29 to about 0. 51, about 0.30 to about 0.50, about 0.31 to about 0.49, about 0.32 to about 0.48, about 0.33 to about 0.47, about 0.34 to about 0.46, about 0.35 to about 0.45, about 0.36 to about 0.44, about 0.37 to about 0.43, about 0.38 to about 0.42, or about 0.39 to about 0.41. In another embodiment, in the compositions, kits, and methods described herein, the ratio of PSMA I&T to [177Lu]Lu3+ in μg:mCi can be about 0.50 to about 0.64, about 0.50 to about 0.63, about 0.50 to about 0.62, about 0.50 to about 0.61, about 0.50 to about 0.60, about 0.50 to about 0.59, about 0.50 to about 0.58, about 0.50 to about 0.57, about 0.50 to about 0.56, about 0.50 to about 0.55, about 0.50 to about 0.54, about 0.50 to about 0.53, about 0.50 to about 0.52, or about 0.50 to about 0.51.In another embodiment, in the compositions, kits, and methods described herein, the ratio of PSMA I&T to [177Lu]Lu3+ in μg:mCi is about 0.40 to about 0.64, about 0.40 to about 0.63, about 0.40 to about 0.62, about 0.40 to about 0.61, about 0.40 to about 0.60, about 0.40 to about 0.59, about 0.40 to about 0.58, about 0.40 to about 0.57, about 0.40 to about 0.56, about 0.40 to about 0.55, about 0.40 to about 0.54, about 0. In another embodiment, the compositions, kits, and methods described herein may be used to administer PSMA in μg:mCi. The ratio of I&T to [177Lu]Lu3+ is about 0.35 to about 0.64, about 0.35 to about 0.63, about 0.35 to about 0.62, about 0.35 to about 0.61, about 0.35 to about 0.60, about 0.35 to about 0.59, about 0.35 to about 0.58, about 0.35 to about 0.57, about 0.35 to about 0.56, about 0.35 to about 0.55, about 0.35 to about 0.54, about 0.35 to about 0.53, about 0.35 to about 0.52, about 0.35 to about 0.5 1, about 0.35 to about 0.50, about 0.35 to about 0.49, about 0.35 to about 0.48, about 0.35 to about 0.47, about 0.35 to about 0.46, about 0.35 to about 0.45, about 0.35 to about 0.44, about 0.35 to about 0.43, about 0.35 to about 0.42, about 0.35 to about 0.41, about 0.35 to about 0.40, about 0.35 to about 0.39, about 0.35 to about 0.38, about 0.35 to about 0.37, or about 0.35 to about 0.36.In another embodiment, in the compositions, kits, and methods described herein, the ratio of PSMA I&T to [177Lu]Lu3+ in μg:mCi is about 0.30 to about 0.64, about 0.30 to about 0.63, about 0.30 to about 0.62, about 0.30 to about 0.61, about 0.30 to about 0.60, about 0.30 to about 0.59, about 0.30 to about 0.58, about 0.30 to about 0.57, about 0.30 to about 0.56, about 0.30 to about 0.55, about 0.30 to about 0.54, about 0.30 to about 0.53, about 0.30 to about 0.52, about 0.30 to about 0.51, about 0.30 to about 0.50, about 0.30 to about 0.49, about 0.30 to about 0.5 It can be 0 to about 0.48, about 0.30 to about 0.47, about 0.30 to about 0.46, about 0.30 to about 0.45, about 0.30 to about 0.44, about 0.30 to about 0.43, about 0.30 to about 0.42, about 0.30 to about 0.41, about 0.30 to about 0.40, about 0.30 to about 0.39, about 0.30 to about 0.38, about 0.30 to about 0.37, about 0.30 to about 0.36, about 0.30 to about 0.35, about 0.30 to about 0.34, about 0.30 to about 0.33, about 0.30 to about 0.32, or about 0.30 to about 0.31.In another embodiment, the compositions, kits, and methods described herein comprise administering to a subject a therapeutically effective amount of PSMA in μg:mCi. The ratio of I&T to [177Lu]Lu3+ is about 0.25 to about 0.64, about 0.25 to about 0.63, about 0.25 to about 0.62, about 0.25 to about 0.61, about 0.25 to about 0.60, about 0.25 to about 0.59, about 0.25 to about 0.58, about 0.25 to about 0.57, about 0.25 to about 0.56, about 0.25 to about 0.55, about 0.25 to about 0.54, about 0.25 to about 0.53, about 0.25 to about 0.52, about 0.25 to about 0.51, about 0.25 to about 0.50, about 0.25 to about 0.49, about 0.25 to about 0.48, about 0.25 to about 0.47, about 0.25 to about 0.46 , about 0.25 to about 0.45, about 0.25 to about 0.44, about 0.25 to about 0.43, about 0.25 to about 0.42, about 0.25 to about 0.41, about 0.25 to about 0.40, about 0.25 to about 0.39, about 0.25 to about 0.38, about 0.25 to about 0.37, about 0.25 to about 0.36, about 0.25 to about 0.35, about 0.25 to about 0.34, about 0.25 to about 0.33, about 0.25 to about 0.32, about 0.25 to about 0.31, about 0.25 to about 0.30, about 0.25 to about 0.29, about 0.25 to about 0.28, about 0.25 to about 0.27, or about 0.25 to about 0.26. In another embodiment, in the compositions, kits, and methods described herein, the ratio of PSMA I&T to [177Lu]Lu3+ in μg:mCi can be about 0.20 to about 0.30.

[0308] In another embodiment, the patient is treatment naive. In another embodiment, the patient is not treatment naive.

[0309] In one embodiment, the pharmaceutical composition is administered to a cancer patient as a first-line therapy. In another embodiment, the pharmaceutical composition is administered to a patient as a regimen. In another embodiment, the administered pharmaceutical composition has a radiochemical purity of greater than 95% at the time of administration.

[0310] In one embodiment, the method of treating cancer extends the time to disease progression of the cancer in the patient. In another embodiment, the method of treating cancer extends the survival of the patient. In another embodiment, the method of treating cancer increases the progression-free survival of the patient. In another embodiment, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0311] In some embodiments, patients also have histologically or pathologically confirmed prostate adenocarcinoma without a predominant small cell component and progressive disease according to one or more of the following criteria: a) progression of serum / plasma PSA, defined as two consecutive increases in PSA relative to a previous reference value, measured at least one week apart with a minimum starting value of >2 ng / mL; or b) measurable disease progression (RECIST 1.1) or the presence of at least two new bone lesions (PCWG3 criteria), and / or have received previous treatment with next-generation androgen receptor (AR)-directed therapy (e.g., abiraterone, enzalutamide, apalutamide, darolutamide). In additional embodiments, patients may have effective castration with serum testosterone levels below 50 ng / dL and may plan to continue chronic medical or surgical castration. Patients with mCRPC should receive hormonal therapy and chemotherapy, as well as bone-targeted therapy, if indicated.

[0312] In at least one example, 177 Patients requiring RLT using Lu-PSMA I&T may meet the following criteria:

[0313] 1) mCRPC with PSMA-positive metastatic disease based on PSMA-PET or SPECT imaging. There are no restrictions on the number or location of metastases, i.e., bone or soft tissue metastases. For example, attention should be paid to patients with diffuse bone marrow, perineural, and brain metastases.

[0314] 2) After initial hormone therapy (LH-RH agonist / antagonist), patients with progressive disease (i.e., biochemical and / or radiological progression) despite newly developed hormone therapies (abiraterone / enzalutamide) or these medications can be avoided by patients with progressive disease despite chemotherapy (docetaxel and cabazitaxel), or patients who are unsuitable for or avoid chemotherapy.

[0315] 3) due to extraosseous or diffuse bone marrow metastases or avoided by the patient; 153 Sm-EDTMP or [ 223 Ra]RaCl2 or other locally available radiopharmaceuticals for bone-targeted therapy. Even patients who do not adequately respond to bone-targeted therapy for pain relief or pain exacerbation may benefit from such therapy. 177 RLT using Lu-PSMA I&T can be evaluated.

[0316] 4) Life expectancy greater than 4-6 months.

[0317] 5) Salvage therapy decisions made by the institution's interdisciplinary tumor board.

[0318] In summary, patients with mCRPC should receive hormonal therapy and chemotherapy, as well as bone-targeted therapy, when indicated. Contraindications to any of these therapies should be discussed and documented in a multidisciplinary tumor board setting.

[0319] Contraindications are: (1) WBC ≤ 1 × 10 9 / l. (2) Hb≦80g / L. (If symptomatic anemia occurs, red blood cell transfusion is required before treatment.) 177RLT with Lu-PSMA I&T may have a positive effect on bone marrow depression, reducing the need for transfused blood due to tumor regression in the bone marrow. It should be noted that pure anemia without thrombocytopenia and leukopenia is not a contraindication to RLT. (3) Platelets ≤ 70 × 10 9 / l. (4) Renal failure with creatinine >1.5UNL and creatinine clearance <30mL / min (5) Absolute obstruction in renal excretion. (6) Previous chemotherapy or bone-targeted radionuclide therapy and extended external beam radiation field to bone marrow (pelvis, spine) if administered within 4 weeks before RLT (7) ECOG performance status >2. (8) Hypersensitivity to any of the active substances or excipients.

[0320] After a patient in need thereof has been identified, the activity of the radiopharmaceutical composition may be confirmed prior to administration. 177 The radioactivity of the Lu-PSMA I&T composition can be 6.5-7.5 GBq, or can be in the range of 6.0-8.0 GBq. The radioactivity can be reduced to 4.0-5.0 GBq in cases of renal dysfunction (e.g., creatinine within 1.0-1.5 UNL).

[0321] The radiopharmaceutical composition solution may be infused intravenously as a slow bolus (over approximately 10-15 minutes), followed by 500-1000 ml of Ringer's solution or NaCl solution. Patients may be encouraged to urinate as frequently as possible and to drink approximately 2 liters of water per day. Patients with extensive non-obstructive renal disease may be given diuretics.

[0322] The pharmaceutical composition may be administered as a cycle of 2 to 11 RLTs every 5 to 8 weeks. If PSA continues to increase or if the patient's performance status worsens after the first two cycles, the indication for further RLT may be reevaluated. If PSA falls below 1.0 μg / L during a therapy cycle, or if post-injection SPECT studies are not sufficiently informative, PSMA imaging may be performed to assess the presence of small PSMA-positive metastases after completion of RLT. In the event of a significant decrease in platelets or white blood cells, the time interval between two cycles may be extended.

[0323] At least one whole-body scan (preferably by SPECT / CT) may be performed 24-48 hours after injection. Patients with diffuse bone and bone marrow metastases, as well as patients with brain metastases, may be administered concomitant corticosteroid therapy (e.g., prednisolone 20 mg / day) for the first two weeks after administration of the radiopharmaceutical composition.

[0324] In some embodiments, after administration of the radiopharmaceutical composition, patients may have improved radiographic progression-free survival (rPFS). Patients administered the radiopharmaceutical composition may have an rPFS of about 6 to about 12 months after initiation of administration of the radiopharmaceutical composition. In various embodiments, patients administered the radiopharmaceutical composition may have an rPFS of at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months after initiation of administration of the radiopharmaceutical composition. For example, 177 Treatment of patients with Lu-PSMA I&T may increase rPFS from 6 months with standard therapy to up to 10 months with the radiopharmaceutical composition. Radiographic progression-free survival may be defined as the time from randomization to radiographic progression (using PCWG3 and RECIST 1.1 criteria as assessed by blinded independent central review [BICR]) or death from any cause.

[0325] In certain embodiments, patients may experience improved overall survival (OS) after initiating administration of the radiopharmaceutical composition. Patients administered the radiopharmaceutical composition may have an overall survival of about 18 to about 26 months after initiating administration of the radiopharmaceutical composition. In various embodiments, patients administered the radiopharmaceutical composition may have an OS of at least 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, or 26 months after initiating administration of the radiopharmaceutical composition. For example, 177 Treating patients with Lu-PSMA I&T can increase OS from 18 months with standard therapy to up to 25 months with the radiopharmaceutical composition.

[0326] In another embodiment, the patient may experience an improvement in second radiographic progression-free survival (rPFS 2) after starting administration of the radiopharmaceutical composition.

[0327] In some embodiments, the patient may have an improved progression-free survival after initiating administration of the radiopharmaceutical composition. In additional embodiments, the patient may have an improved second progression-free survival after initiating administration of the radiopharmaceutical composition. The second progression-free survival may be a second occurrence of PCWG3 progression, clinical / symptomatic progression and / or pain progression, or death from any cause.

[0328] In one embodiment, the patient has an improved PSA after starting administration of the radiopharmaceutical composition. 50 May have a response rate. PSA 50 The response rate can be the rate of patients achieving a 50% or greater decrease in PSA from the baseline PSA assessment.

[0329] In certain embodiments, patients may have an improved time to first symptomatic skeletal event (SSE) after starting administration of the radiopharmaceutical composition. An SSE may be the occurrence of either bone-directed radiation therapy for the relief of bone pain, a new symptomatic pathological fracture, spinal cord compression, or tumor-related orthopedic surgery.

[0330] In certain embodiments, patients may have improved time to soft tissue progression (STP) after initiating administration of the radiopharmaceutical composition. STP may include the occurrence of radiographic progression in soft tissue. In another embodiment, patients may have improved time to chemotherapy (TTC) after initiating administration of the radiopharmaceutical composition.

[0331] In certain embodiments, patients may experience improvement in their Quality of Life Questionnaire results after initiating administration of the radiopharmaceutical composition. For example, quality of life (QoL) may be assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). The EORTC QLQ-C30 is a questionnaire of 30 quality of life (QoL) questions developed to assess the QoL of cancer patients. The EORTC QLQ-C30 contains 30 items, 24 of which are summarized into 9 multi-item scales with a scoring range of 0 to 100. [Example]

[0332] The following non-limiting examples are provided for illustrative purposes only and therefore should not be viewed in a limiting sense.

[0333] Analysis procedure The products were then identified by injecting the Lu-PSMA I&T reference and formulated solutions into a liquid chromatography system. Radionuclide identity was determined by gamma-ray energy detection.

[0334] The pH was estimated by pH paper. Radioactivity was measured with a dose calibrator. Radiochemical purity was determined by liquid chromatography and thin layer chromatography with radioactivity detection.

[0335] [ 177The radioactivity of the [Lu]Lu-PSMA I&T was measured by a dose calibrator as the dose was dispensed.

[0336] Bacterial endotoxin content was measured using a PTS tester (PhEur Method D, USP <85> ) was used to measure each batch prior to release. Sterility was measured according to USP standards in accordance with Ph Eur. <71> was determined to be consistent with

[0337] The quality of the analytical procedures used for the drug product, such as specificity, linearity, and reproducibility, was investigated by using known reference standards for unlabeled precursors. All analytical procedures were found to be suitable for their intended use.

[0338] Acceptable limits for radioactivity in drug products have not been established because this varies depending on the individual clinical need as assessed by the healthcare professional responsible for administering the drug product. The radioactivity content must be within 90% to 110% of the stated value at the date and time stated on the label.

[0339] Example 1: 177 Methods for producing Lu-PSMA I&T radiopharmaceutical formulations Several radiopharmaceutical compositions were prepared using the process outlined in Tables 2A and 2B below. The radiolabel was added as a non-carrier-added [ 177

[0013] LuLuCl3 was used. Compositions 1 and 2 are essentially the same. For Composition 3, the pH of the ascorbic acid solution was adjusted to 4.5, the amount of ascorbic acid was reduced, the amount of ethanol was reduced, and the pH of the final radiopharmaceutical composition was adjusted to 4.5. This resulted in Composition 3 having an extended shelf life compared to Compositions 1 and 2.

[0340] The synthesis of 177Lu-PSMA I&T utilizes an automated synthesis module in a controlled environment. 177 Lu] lutetium chloride ([ 177 The labeling solution containing [Lu]LuCl3) is connected to a synthesis cassette containing the other chemical components required for the labeling process.177 The LuCl solution may be transferred to a reaction vessel for radiolabeling and rinsed with the necessary additional amount of 0.04 M HCl solution. 177 The volume varies depending on the Lu activity.

[0341] [ 177 The [Lu]LuCl solution is mixed with a solution of diluted PSMA I&T precursor in 0.4 M sodium acetate buffer in a reaction chamber. The solution is heated in the reactor. After heating, the generated 177 Lu-PSMA I&T is captured on a C18 cartridge preconditioned with water. The cartridge is rinsed with sterile water and the final product is eluted from the C18 cartridge into a bulk vial with 1.5 ml of 50% sterile ethanol. The drug substance is formed in situ and directly formulated into a drug product.

[0342] For final volume adjustment, a formulation matrix containing 50 mg / ml ascorbic acid and ethanol in water for injection is added to the bulk vial. The composition of the final product is fixed and the amount of formulation matrix added is determined by the amount used in the batch. 177 Depends on the radioactivity of Lu.

[0343] The formulation matrix is ​​prepared from a solution of ascorbic acid diluted to a concentration of 50 mg / ml with water for injection. The ethanol concentration is adjusted to 3.8% ± 1.0% (v / v) to match the concentration of the synthetic bulk product, regardless of dilution.

[0344] The synthesis is a one-step labeling process with C18 purification using injection-grade ethanol and water as the only solvents, so there are no residual solvents.

[0345] Radiochemical impurities are quantified by chromatographic methods (HPLC and TLC). Radiochemical purity as determined by HPLC should be 95.0% or greater.

[0346] Depending on the total radioactivity generated, the bulk product is diluted to a fixed radioactivity concentration of approximately 500 MBq / ml.

[0347] The solution is filtered through a 0.22 μm membrane filter into sterile product vials. In addition to patient doses, sample vials are also dispensed from each production batch (chemical QC samples, microbiological QC samples, and reference samples for retention). The final product is dispensed in a Grade A controlled environment. Filter integrity is tested after filtration by performing a bubble point test before product release. Fill weight / volume and radioactivity are verified for dispensed patient vials. This solution can be used for pre-release quality control and after QP release.

[0348] Radioactivity is monitored by a dose calibrator after the labeling process to ensure successful labeling and to verify the dispensed dose during dispensing. [Table 2A]

[0349] Compositions 1-3 obtained from Processes 1-3 are provided below in Table 2B, which provides the composition for each composition for both the 1 ml volume and the 10 ml or 20 ml vial. [Table 2B]

[0350] Example 2: Stability of Radiochemical Compositions 177 The stability of Lu-PSMA I&T Composition 1 was tested and the radiochemical purity and chemical properties were shown to provide sufficient stability for 48 hours from the end of synthesis for samples stored at +5°C, +20°C, and +40°C (Table 3).

[0351] Stability studies were performed with ascorbic acid 31 mg / ml and ethanol 3.8% (v / v) at pH 4.5 [ 177[Lu]Lu-PSMA I&T Composition 3 (Tables 4A-H) 177 [Lu]Lu-PSMA I&T Composition 1 showed improved stability and extended shelf life compared to I&T Composition 1.

[0352] In formulation composition 3, 177 The radiochemical purity and chemical properties (pH, impurities, visual properties) of [Lu]Lu-PSMA I&T were tested in seven batches over a time span of 70-72 hours from the end of synthesis. Stability samples of typical therapeutic dose activity and volume were stored at different conditions encompassing typical storage, shipping, and use of the product, including temperatures ranging from +5°C to +40°C.

[0353] The final radioactivity concentration in the sample solution varied from 497 MBq / ml to 642 MBq / ml at the end of dispensing.

[0354] All stability samples met the established acceptance criteria: in all analyzed samples, the radiochemical purity was 95.7% or greater at 70 or 72 hours after the end of synthesis.

[0355] Based on the results, the formulation composition 3 177 The Lu-PSMA I&T solution was stable under the different storage conditions tested. [Table 3] [Table 4A] [Table 4B] [Table 65] [Table 4D] [Table 4E] [Table 4F] [Table 4G] [Table 4H] [Table 4I] [Table 4J]

[0356] [ 177 The specifications for the [Lu]Lu-PSMA I&T solution are shown below in Table 5. The listed specifications were used as release parameters, with the exception of sterility testing, which was tested on all batches after release. [Table 5-1]

[0357] Example 3: In different formulation compositions 177 Radiochemical purity of Lu-PSMA I&T This example demonstrates the effectiveness of the hydroxybenzoates in formulations at different pH values. 177 1 shows the radiochemical stability of Lu-PSMA I&T. 177 The shelf life of Lu-PSMA I&T is limited by its high radioactive degradation rate during preparation and storage. 177 This leads to the degradation of Lu-PSMA I&T and the formation of radiochemical impurities. 177 The radiochemical purity of the Lu-PSMA I&T solution will fall below the acceptable limit of 95.0%.

[0358] 177Formation of a specific radiochemical impurity of Lu-PSMA I&T has been observed with a retention time of approximately 5.2 minutes by HPLC on a Phenomenex Luna C18 column (3 μm, 150 mm × 4.6 mm) using an isocratic method of 0.1% trifluoroacetic acid in water (mobile phase A) and 0.1% trifluoroacetic acid:acetonitrile (10:90% v / v) in water (mobile phase B) and 23% mobile phase B at a temperature of 40° C. The impurity referred to herein as having a retention time of approximately 5.2 minutes is illustrated in the chromatograms of Figures 6A-11B.

[0359] In previous experiments, lowering the radioactivity concentration of the formulation was sufficient to reduce the formation of an impurity that elutes at approximately 5.2 minutes, [ 177 The radiochemical stability of the [Lu]Lu-PSMA I&T solution was maintained above 95.0% over 72 hours.

[0360] In this example, different formulation compositions with various ascorbic acid concentrations, pH, and radioactivity concentrations were used. 177 Six experiments were performed in which [Lu]Lu-PSMA I&T was prepared. Product formulation details are listed in Table 6. [Table 6-1]

[0361] High radioactivity concentrations (high RAC) in the sample solutions were 1278 MBq / ml, 1281 MBq / ml, and 1311 MBq / ml when measured at the end of the production run. Low radioactivity concentrations (low RAC) in the sample solutions were 579 MBq / ml, 589 MBq / ml, and 626 MBq / ml when measured at the end of the production run. Radiochemical purity of each solution was followed by HPLC up to 71–93 h after radiolabeling. All solutions were stored at 22.5°C.

[0362] FIG. 5 shows the results of the radiochemical purity analysis at different time points as determined by HPLC.

[0363] Figures 6A and 6B show the HPLC radiochromatograms of Experiment 1 at 0 and 71 hours after EOS, respectively.

[0364] Figures 7A and 7B show the HPLC radiochromatograms of Experiment 2 at 0 and 71 hours after EOS, respectively.

[0365] Figures 8A and 8B show the HPLC radiochromatograms of Experiment 3 at 0 and 90 hours after EOS, respectively.

[0366] Figures 9A and 9B show the HPLC radiochromatograms of Experiment 4 at 0 and 92 hours after EOS, respectively.

[0367] Figures 10A and 10B show the HPLC radiochromatograms of Experiment 5 at 0 and 71 hours after EOS, respectively.

[0368] Figures 11A and 11B show the HPLC radiochromatograms of Experiment 6 at 0 and 93 hours after EOS, respectively.

[0369] The radiochemical stability results for each experiment at different time points are provided in Tables 5-10. [Table 5-2] [Table 6-2] [Table 7] [Table 8] [Table 9] [Table 10]

[0370] In the examples, the pH of the formulation composition was as illustrated in Figures 6A to 11B. 177 This had a significant impact on the radiochemical stability of Lu-PSMA I&T, more specifically on the formation of a radiochemical impurity that eluted at approximately 5.2 min. In high RAC solutions, the decrease in radiochemical purity over time at pH 4.5 was two times slower than at pH 7.

[0371] Further reduction of the formulation pH to 3.5 did not show any measurable improvement in radiochemical stability compared to the pH 4.5 solution. Although the pH 4.5 ascorbic acid solution is close to the pKa value of ascorbic acid, 177 It is possible that the protons already possess a sufficient amount to act as an inhibitor to the radiolysis of the Lu-PSMA I&T and reduce the formation of a radiochemical impurity that elutes at approximately 5.2 minutes.

[0372] By incorporating a pH 4.5 solution into a lower RAC formulation, 177 The radiochemical stability of Lu-PSMA I&T was further improved. In the lower RAC formulations, changing the formulation pH from 5 to 4.5 had a similar effect on radiochemical stability as increasing the ascorbic acid concentration from 21 mg / ml to 31 mg / ml.

[0373] 10 ml of high RAC containing 42.5 mg / ml ascorbic acid as measured by HPLC 177 The radiochemical purity of the Lu-PSMA I&T formulation composition is at least about 99% at 0 hours post-EOS and at least about 93.3% at 46 hours post-EOS. As the pH of the formulation increases from pH 4.5, the radiochemical purity decreases.

[0374] 20 ml of low RAC containing 31 mg / ml ascorbic acid as measured by HPLC 177 The radiochemical purity of the Lu-PSMA I&T formulation is at least about 99.1% at 0 hours after EOS. The rate at which radiochemical purity decreases over time is significantly greater at low RAC with a pH of 4.5 compared to a pH of 5.177 slower for the Lu-PSMA-I&T formulation.

[0375] The results show that formulation compositions with a pH of 5 or less can substantially reduce the formation of the radiochemical impurity eluting at about 5.2 minutes, and therefore, compared to formulation compositions with a pH greater than 5. 177 This indicates that the radiochemical stability of Lu-PSMA I&T can be improved. 177 The radiochemical stability of Lu-PSMA I&T can be further improved by incorporating a lower solution RAC. 177 The Lu-PSMA I&T solution showed the highest radiochemical stability in a low RAC solution at pH 4.5 and an ascorbic acid concentration of 31 mg / ml. This formulation minimized the formation of radiochemical impurities. 177 This is believed to be a preferred composition for maintaining the radiochemical stability of Lu-PSMA I&T at greater than 95.0% for 72 hours or more.

[0376] Example 4: Compared to third-line treatment 177 Lu-PSMA-617 and 177 Efficacy of combined Lu-PSMA-I&T treatment 177 Dosimetry of Lu-PSMA I&T 177 Lu-PSMA I&T and 177 There were no significant differences in absorbed dose estimates between Lu-PSMA-617 and Lu-PSMA-617. 177 Specific known dosimetry for Lu-PSMA I&T is presented below.

[0377] For normal organs, the mean total-body effective dose for all cycles was 0.41 ± 0.18 Sv (0.06 Sv / GBq). Mean absorbed organ doses were 5.3 ± 1.6 Gy (0.72 Gy / GBq) for the kidneys, 0.89 ± 0.42 Gy (0.12 Gy / GBq) for the liver, 4.0 ± 1.1 Gy (0.55 Gy / GBq) for the parotid gland, 4.8 ± 2.8 Gy (0.64 Gy / GBq) for the submandibular gland, and 27 ± 10 Gy (3.8 Gy / GBq) for the lacrimal gland.

[0378] No substantial differences were observed when comparing absorbed doses to normal organs with respect to cycle number (Table 13). The mean organ masses underlying these absorbed dose estimates were 1.595 ± 307 g (range, 1,165–2,373 g) for the liver, 153 ± 29.9 g (range, 88.4–218.7 g) for the kidney, 19.1 ± 5.7 g (range, 8.0–35.6 g) for the parotid gland, 8.2 ± 1.9 g (range, 4.2–14.3 g) for the submandibular gland, and 0.45 ± 0.12 g (range, 0.25–0.78 g) for the lacrimal gland. For paired organs, masses from both sides were summed.

[0379] For tumor lesions, all lesions received a mean dose of 23 ± 20 Gy (3.3 Gy / GBq) per cycle. The mean absorbed doses for bone, lymph node, liver, and lung metastases were 26 ± 20 Gy (3.4 Gy / GBq), 24 ± 16 Gy (3.2 Gy / GBq), 8.5 ± 4.7 Gy (1.28 Gy / GBq), and 13 ± 7.4 Gy (1.7 Gy / GBq).

[0380] The corresponding absorbed dose values ​​per GBq (mean, SD, and range) for normal organs and tumor lesions, respectively, are shown in the table below. [Table 11] [Table 12]

[0381] There is a clear trend toward lower absorbed doses as the number of cycles increases. The mean absorbed dose per lesion was 26 ± 21 Gy (3.5 Gy / GBq) in the first cycle, 24 ± 19 Gy (3.3 Gy / GBq) in the second cycle, 20 ± 18 Gy (2.7 Gy / GBq) in the third cycle, and 18 ± 17 Gy (2.4 Gy / GBq) in the fourth cycle. A similar trend can be seen for the bone metastasis subgroup. Due to the small sample size, reliable comparisons for lymph node, liver, and lung metastases are not possible.177 See the table below for effective half-life and mean absorbed dose of Lu-PSMA I&T.

[0382] 177 Lu-PSMA RLT( 177 Lu-PSMA-617 and 177 Lu-PSMA I&T) had better efficacy and fewer adverse effects than third-line treatment. Twelve studies involving 669 patients 177 reported Lu-PSMA RLT. Overall, 44% of patients 177 After treatment with Lu-PSMA RLT, the maximum PSA reduction was 50% or more. 177 Lu-PSMA-617 and 177 Treatment with Lu-PSMA had mostly transient adverse effects. Sixteen studies, including 1,338 patients, reported on third-line treatment. Overall, 21% of patients achieved a best PSA decline of 50% or more after third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects led to treatment discontinuation in 10% to 23% of patients. 177 Lu-PSMA RLT resulted in a best PSA decline of 50% or more more frequently than third-line treatment (mean 44% vs. 22%, p=0.0002, t-test). 177 Lu-PSMA RLT resulted in objective remission more frequently than third-line treatment (31 of 109 patients vs. 43 of 275 patients overall, p = 0.004, χ test). 177 Median survival after Lu-PSMA RLT was longer than after third-line treatment, but the difference was not statistically significant (mean 12 vs. 14 months, p=0.32, t-test). 177 Lu-PSMA led to treatment discontinuation more frequently for third-line treatment than for RLT (0 of 469 patients vs. 22 of 66 patients, p<0.001, χ2 test).

[0383] The purpose of this Investigational New Drug (IMPD) is to: 177Our goal is to provide a scientific and ethical platform for this useful treatment using Lu-PSMA I&T and to first pursue its application, preferably in academic centers and under controlled clinical trial protocols. 177 With the exception of Lu-PSMA-617, no existing guidelines exist. The information in this IMPD is based on the latest literature and existing best experience from nuclear medicine centers treating PC patients with this modality.

[0384] The synthesis is a one-step labeling process using injection-grade ethanol and water as the only solvents. Therefore, there are no residual solvents. Radiochemical impurities are quantified by chromatographic methods (HPLC and TLC). The radiochemical purity may be less than 95.0%.

[0385] Example 5: 177 A multicenter, open-label, randomized phase 3 study comparing the safety and efficacy of Lu-PSMA I&T Efficacy of hormonal therapy in patients with metastatic castration-resistant prostate cancer 177 A multicenter, open-label, randomized phase 3 study was conducted to compare the safety and efficacy of compositions containing Lu-PSMA I&T.

[0386] This study aims to treat adult male human patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed despite treatment with one course of standard of care hormonal therapy. 177 The aim is to identify and characterize the safety and efficacy of using Lu-PSMA I&T.

[0387] 177 Lu-PSMA I&T is a radiotherapeutic agent that specifically targets the prostate-specific membrane antigen protein expressed on metastatic prostate cancer cells.

[0388] In this study, 177 Lu-PSMA I&T was microdosed in aqueous ascorbic acid and ethanol solutions. 177It is provided as a sterile filtered radiopharmaceutical solution containing Lu-PSMA I&T.

[0389] Patients randomized to be treated with standard-of-care hormonal therapy for mCRPC will be treated with either abiraterone acetate in combination with prednisone or enzalutamide, based on the investigator's independent medical judgment.

[0390] Abiraterone acetate is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) or metastatic high-risk castration-sensitive prostate cancer (mCSPC). Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor that inhibits 17α-hydroxylase / C17,20-lyase (CYP17). This enzyme is expressed in the testes, adrenal glands, and prostate tumor tissue and is required for androgen biosynthesis.

[0391] Enzalutamide is an androgen receptor inhibitor indicated for the treatment of patients with CRPC or mCSPC (metastatic castration-sensitive prostate cancer). Enzalutamide has been shown to competitively inhibit androgen binding to the androgen receptor, thus inhibiting the nuclear translocation of the androgen receptor and its interaction with DNA.

[0392] A. Study Objectives and Endpoints The primary objective of this study was to evaluate the efficacy of rituximab in improving radiographic progression-free survival (rPFS), as determined by PCWG3-modified RECIST 1.1, in men with metastatic castration-resistant prostate cancer (mCRPC) compared with standard-of-care hormonal therapy. 177 To prospectively evaluate the efficacy of Lu-PSMA I&T. The objective endpoint is the time from randomization to radiographic progression as determined by Prostate Cancer Working Group 3 (PCWG3) criteria assessed by blinded independent central review.

[0393] The secondary objective is 177 To evaluate whether Lu-PSMA I&T improves overall survival (OS) in patients with mCRPC compared with patients treated with standard-of-care hormonal therapy, with the objective endpoint being time from randomization to death from any cause.

[0394] Other secondary objectives and endpoints include: ●Purpose: Compared with hormone therapy, 177 To evaluate improvement in overall survival (OS) in men with mCRPC treated with Lu-PSMA I&T, endpoint: time from randomization to second radiographic progression as determined by PCWG3 or RECIST1.1 by BICR (blinded independent central review) after crossover. ●Objective: From the hormone therapy arm of standard treatment 177 For patients who crossed over to the Lu-PSMA I&T treatment arm, evaluate the change in time to second radiographic progression. Endpoint: Time from randomization to second radiographic progression as determined by PCWG3 or RECIST 1.1 by BICR after crossover. ●Objective: Compared with standard hormone therapy, 177 Identify change in progression-free survival (PFS, composite) after Lu-PSMA I&T radioligand therapy, endpoint: time from randomization to progression (PFS, composite) based on PCWG3 or RECIST progression, clinical / symptomatic progression and / or pain progression, or death from any cause as determined by the investigator, whichever occurs first. ●Objective: Compared with standard hormone therapy, 177To identify change in progression-free survival 2 (PFS2, composite) after Lu-PSMA I&T radioligand therapy, endpoint: time from randomization to second progression (PFS, composite) based on PCWG3 or RECIST progression, clinical / symptomatic progression and / or pain progression, or death from any cause as determined by the investigator, whichever occurs first. ●Objective: Compared with standard hormone therapy, 177 To evaluate the change in PSA50 response rate (response rate of patients who achieved a 50% or greater reduction in PSA from baseline) after Lu-PSMA I&T radioligand therapy, endpoint: PSA50 response rate, defined as a confirmed 50% or greater reduction in PSA from baseline. ●Objective: Compared with standard hormone therapy for skeletal symptoms 177 To determine the impact of Lu-PSMA I&T, endpoints: time from randomization to first symptomatic skeletal event (SSE-free survival); Objective: To compare standard of care hormone therapy for radiographic soft tissue progression. 177 Determine the impact of Lu-PSMA I&T, endpoint: time from randomization to radiographic soft tissue progression (rSTP) as determined by RECIST 1.1 by BICR; ●Objective: Compared with standard hormone therapy, 177 Evaluate changes in chemotherapy use after Lu-PSMA I&T, endpoints: time from randomization to first use of chemotherapy, and ●Purpose: For hormone therapy, 177 To evaluate the impact on quality of life after Lu-PSMA I&T radioligand therapy, endpoint: improvement in quality of life based on the EORTC QLQ-C30 questionnaire.

[0395] Exploratory objectives and endpoints are: ●Objective: Compared with standard hormone therapy, 177To evaluate the difference in objective response rate and disease control rate using Lu-PSMA I&T, endpoints: objective response rate and disease control rate (DCR = complete / partial response and stable disease) based on PCWG3 criteria. ●Objective: Compared with standard treatment, 177 To evaluate the change in time to PSA progression after Lu-PSMA I&T radioligand therapy, endpoints: time from randomization to PSA progression, defined as a PSA rise of 25% or more from post-treatment nadir; and ●Purpose: Compared with hormone therapy, 177 To evaluate the duration of response (DoR) in patients achieving a complete or partial response after Lu-PSMA I&T radioligand therapy, endpoint: time from complete or partial response to radiographic progression.

[0396] B. Research design (i) Overview and Rationale This compared with hormone therapy in men with mCRPC who had previously been treated with androgen receptor (AR)-directed therapy. 177 This is an open-label, randomized, multicenter, phase 3 study of Lu-PSMA I&T radioligand therapy. The hormone therapy regimen for this study is enzalutamide or abiraterone with prednisone based on NCCN guidelines. The selection of a specific regimen will be based on patients' switch from previous ADRT for patients randomized to receive standard of care. Based on published literature, 177 Lu-PSMA I&T radioligand therapy promotes antitumor activity and is associated with a favorable safety profile in men with mCRPC.

[0397] The study will consist of a screening phase, a treatment phase, and a post-treatment follow-up phase. The study will use a 2:1 randomization to the following treatment groups: (1) 177Lu-PSMA I&T radioligand therapy, or (2) standard of care hormone therapy. Standard of care hormone therapy options are abiraterone in combination with prednisone or enzalutamide, with the specific choice based on the investigator's clinical judgment. Patients randomized to the hormone therapy arm will have the option to cross over to the radioligand therapy arm upon documentation of radiographic progression.

[0398] Patients will be followed for safety and efficacy according to the activity schedule and will continue on study treatment until documented radiographic progression as assessed by blinded independent central review (BICR) or the development of unacceptable toxicity. Patients who discontinue treatment due to documented radiographic progression will enter a long-term follow-up phase. Patients who discontinue treatment prior to documented radiographic progression will continue scheduled disease assessments every 3 months until documented radiographic progression.

[0399] Additionally, to assess pharmacokinetics and radioactivity (as discussed in Example 4 above), 177 A substudy will be conducted under this protocol in patients randomized to receive Lu-PSMA I&T radioligand therapy.

[0400] Due to the nature of the treatments, the identities of the test and control treatments will be known to the investigators, study staff, and patients. Blinding of this study is not feasible. Immediately after the investigator's determination of progressive disease for progressing patients, and after study completion for non-progressing patients, blinded radiographs will be read and interpreted by a panel of up to three independent trained radiologists without access to clinical information or treatment group to assess overall response to treatment.

[0401] The severity of AEs and SAEs will be graded based on the subject's symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. AEs not defined in the current version of the CTCAE should be rated for severity according to the following scale: Grade 1 = Mild: Transient or mild discomfort, no activity limitation, no medical intervention / therapy required Grade 2 = Moderate: Mild to moderate activity limitation, some assistance may be required, no or minimal medical intervention / therapy required Grade 3 = Severe: Significant limitation of activity, usually requiring some assistance, medical intervention / therapy required, hospitalization possible Grade 4 = Life-threatening: Extreme limitation of activity, significant assistance required, significant medical intervention / therapy required, hospitalization or hospice care possible Grade 5 = Death: Death occurs as a result of the event

[0402] It is important to distinguish between serious and severe AEs. Severity is a measure of intensity, while seriousness is defined by the criteria outlined in Section 10.3. AEs of severe intensity may not be considered serious. Severity, unlike severity, serves as a guide for defining regulatory obligations.

[0403] (ii) Selection of the primary endpoint Metastatic castration-resistant prostate cancer is generally considered a late stage in the natural progression of prostate cancer. mCRPC is usually associated with an unfavorable prognosis, but many patients experience more indolent disease progression, resulting in a wide range of overall survival, with approximately 15% of men with mCRPC surviving beyond 5 years (Moreira et al., Clin Genitourin Cancer, 2017;15(1):60-66).

[0404] Given the relatively wide range of overall survival in men with mCRPC, radiographic progression-free survival using RECIST 1.1 (soft tissue disease status) and Prostate Cancer Working Group 3 (PCWG3) criteria (bone disease status), as assessed by blinded independent central review, was selected as the primary endpoint for this study. Overall survival is a secondary endpoint of the study, and patients will be followed for overall survival for 5 years after enrollment.

[0405] (iii) Research outcomes The primary efficacy outcome is radiographic progression-free survival. If radiographic progression is confirmed by BIRC, study treatment will be discontinued. Patients then enter the follow-up phase of the trial, and overall survival will be assessed over a 5-year follow-up period from the date of study enrollment.

[0406] Safety will be assessed at the end of treatment and up to a 1-month follow-up period by evaluating safety parameters such as adverse events, vital signs, changes in concomitant medications / therapies, changes in physical examination, and clinical laboratory measurements.

[0407] C. Patient Selection (i) Study population The study population will include patients with mCRPC who have progressive disease based on PCWG3-modified RECIST 1.1 criteria. (ii) Inclusion criteria include: 1. Men over 18 years of age. 2. Histologically or pathologically confirmed prostate adenocarcinoma without a predominant small cell component. 3. Progressive disease according to one or more of the following criteria: a. Progression of serum / plasma PSA defined as two consecutive increases in PSA relative to the previous reference value measured at least 1 week apart with a minimum starting value of >2 ng / mL. b. Measurable disease progression (RECIST 1.1) or presence of at least two new bone lesions (PCWG3 criteria) 4. Previous treatment with next-generation androgen receptor (AR)-directed therapy (e.g., abiraterone, enzalutamide, apalutamide, darolutamide). a. Requires one prior AR-directed therapy. b. Requires prior administration of an ARAT (e.g., abiraterone, enzalutamide, darolutamide, or apalutamide) in the castration-sensitive or castration-resistant setting. c. Must have progressed during ARAT. 5. PSMA-PET scan (e.g., [ 68 Ga]Ga-PSMA-11 or [ 18 F]DCFPyL) positive. 6. Effective castration with serum testosterone levels less than 50 ng / dL and plans to continue chronic medical or surgical castration. 7. HIV patients who are healthy and at low risk for acquired immune deficiency syndrome-related outcomes may participate in this study at the investigator's discretion. 8. Patients with HBV and HCV may also participate if their symptoms are well controlled. 9. Life expectancy of at least 6 months as assessed by the investigator. 10. Willingness to start ARAT therapy as determined by the investigator. (iii) Exclusion criteria include: 1. Previous treatment with radioligand therapy, including other lutetium-labeled compounds. 2. Previous treatment with radium-223 (Xofigo) within the past 12 weeks. 3. Previous chemotherapy treatment for castration-sensitive or castration-resistant prostate cancer (docetaxel or cabazitaxel). 4.Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 2. 5. Patients with known HRR (haploid relative risk) gene mutations who have not been previously treated with olaparib or rucaparib. 6. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy. 7. Poor organ and bone marrow function as evidenced by: Hemoglobin <8g / dL. b. Absolute neutrophil count <1.5 × 109 / L. c. Platelet count <100×109 / L. d. AST / SGOT and / or ALT / SGPT > 3.0 x ULN (where "AST" is aspartate aminotransferase, "SGOT" is serum glutamic-oxaloacetic transaminase, "SGPT" is serum glutamic-pyruvic transaminase, and "ALT" is alanine aminotransferase). e. Total bilirubin >2xULN (upper limit of normal), can be 3xULN unless the patient has known Gilbert syndrome. f. Creatinine clearance (CrCl) <50 mL / min based on the Cockcroft-Gault formula. g. Albumin ≥ 2.75 g / dL 8. Patients who received a blood transfusion for the sole purpose of meeting eligibility for this study. 9. Use of any investigational medication within the last 4 weeks prior to the start of study treatment or scheduled to be received during the study period. 10. Known CNS metastases who are asymptomatic and neurologically stable unless receiving therapy. 11. Patients receiving zoledronic acid for bone-targeted therapy must be on a stable dose for 4 weeks prior to randomization. 12.Patients with significant active heart disease 13. Participant with symptomatic spinal cord compression or clinical / radiological findings indicating impending spinal cord compression. 14. Patients with a superscan visible on the baseline bone scan as adjudicated by the investigator. 15. Active malignancies other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer. 16. Previous use of G-CSF (granulocyte colony-stimulating factor) for persistent neutropenia after standard therapy. 17. Participants with active Covid 19. Recovered patients may be included if they have fully recovered (asymptomatic for at least 28 days prior to study medication administration and a negative Covid test within 72 hours).

[0408] D. Investigational Product Dosage, Route of Administration, and Dosing Schedule (i) 177 Lu-PSMA I&T The pharmaceutical product is a microdose formulated in an aqueous solution containing ascorbic acid and ethanol. 177 This is a sterile-filtered radiopharmaceutical solution containing Lu-PSMA I&T. The product contains a standard concentration of approximately 27 mCi / mL at the end of manufacture and a standard activity of approximately 200 mCi at the end of the expiration date; therefore, the final volume of the dose vial is adjusted to 7.0-10.0 mL to provide the required amount of radioactivity for the date and time of injection. 177 Lu-PSMA I&T Injection is supplied as a sterile solution in a single-dose vial. The septum is sealed with a crimped aluminum cap. The glass vial containing the radiopharmaceutical is kept in a lead-shielded container until use. 177 Lu-PSMA I&T is stored at 25°C, with excursions between 15°C and 30°C permitted. The sealed label contains the expiration date for each vial shipped to the clinical site.

[0409] (ii) Standard-of-care hormone therapy Standard hormone therapy is as follows: Abiraterone acetate with prednisone: Abiraterone acetate is a CYP17 inhibitor used in combination with prednisone or methylprednisone. Prednisone is a glucocorticoid. Glucocorticoids are corticosteroids that are readily absorbed from the gastrointestinal tract. ●Enzalutamide is an androgen receptor inhibitor.

[0410] (iii) Preparation All infusion solutions will be prepared and dispensed on-site prior to administration. Solution preparation should be performed under sterile conditions, and the final solution should be visually inspected for particulate matter. If an insoluble precipitate is observed, the solution should be discarded.

[0411] 177 Lu-PSMA I&T Injection Solution is administered as supplied. The radioactivity in the vial must be measured with a calibrated radiation dose calibrator before and after administration to the patient. The administered dose must then be calculated and recorded.

[0412] Medication and Administration The patient 177 Patients will be randomized 2:1 to receive either Lu-PSMA I&T radioligand therapy or standard of care hormone therapy.

[0413] 177 Lu-PSMA I&T Administration: Patients randomized to receive radioligand therapy received 200mCi (7.4GBq) ± 10% at the start of each treatment cycle. 177 They will receive a single intravenous radioactive dose of Lu-PSMA I&T.

[0414] 177 An intravenous line must be established prior to administration of Lu-PSMA I&T. 177 Lu-PSMA I&T will be injected intravenously as a slow bolus over a minimum of 10-15 minutes using the local standard radioligand therapy administration procedure. 177 Patients should be encouraged to urinate as frequently as possible and drink 2 liters of fluids per day for 2 days after Lu-PSMA I&T administration.

[0415] Cooling the patient's salivary glands reduces the risk of salivary gland radiation damage. 177This should be done by placing ice packs on the parotid and submandibular glands 30 minutes before and up to 4 hours after injection of Lu-PSMA I&T.

[0416] A 6-week treatment cycle 177 It will be used for injection of four treatment cycles of Lu-PSMA I&T or until radiographic progression of disease is determined based on BIRC assessment of radiographic images (maximum 18 weeks of treatment). Alternatively, an 8-week treatment cycle will be used. 177 It may be used for injection of 6 treatment cycles of Lu-PSMA I&T or until radiographic progression of disease is determined based on BIRC assessment of radiographic images (maximum 18 weeks of treatment).

[0417] 177 The dosing cycle of Lu-PSMA I&T may be extended based on the assessment of dose-limiting toxicity experienced by the patient. Dose-limiting toxicity is defined as Grade 3 or 4 bone marrow toxicity or Grade 2 or higher salivary gland toxicity. For Grade 3 or 4 bone marrow toxicity, dosing may be resumed when improvement to Grade 2 or lower is observed. For Grade 2 or higher salivary gland toxicity, dosing may be resumed upon improvement to Grade 1 toxicity.

[0418] In addition, if dose-limiting toxicity is observed, 177 The Lu-PSMA I&T dose should be maintained and / or reduced to 160 mCi (5.9 GBq) ± 10%. The following dose retention / reduction should be implemented accordingly: - For Grade ≥ 3 anemia, hold dose until return to baseline or Grade ≤ 2, then reduce to 160 mCi (5.9 GBq) in the next cycle - Grade ≥ 2 neutropenia: maintain until return to baseline or Grade ≤ 1 -If thrombocytopenia is Grade 2 or greater, maintain until return to baseline or Grade ≤1, then reduce dose to 160 mCi (5.9 GBq) in the next cycle - In case of Grade ≥ 3 non-platelet hematologic toxicity, maintain until return to baseline or Grade ≤ 2, then reduce dose to 160 mCi (5.9 GBq) in the next cycle

[0419] In the event of Grade 3 or greater acute nephrotoxicity, the dose should be held for the next cycle. The dose may be restored upon return to baseline or Grade ≤2, or reduced to 160 mCi (5.9 GBq) for all remaining doses.

[0420] A modification to extend the dosing cycle by an additional 6 weeks and reduce the dose to 160 mCi (5.9 GBq) for the remaining cycles was considered, as determined by the investigator. 177 Lu-PSMA Should be initiated for any other Grade 3 or higher non-hematologic toxicity related to I&T. Dosing cycles and dose levels may be resumed every 6 weeks when toxicity returns to Grade 2 or lower.

[0421] For all grade 3 and 4 AEs, patients will only be allowed one dose reduction. If the event persists, patients will be required to permanently discontinue study treatment.

[0422] Only two dose reductions are permitted for grade 2 AEs. If the event persists, the patient will be required to permanently discontinue study treatment.

[0423] Abiraterone acetate with prednisone: The dose of abiraterone acetate should be administered according to the package insert. Per the abiraterone package insert, the starting dose of abiraterone should be reduced to 250 mg daily for patients with baseline moderate hepatic impairment. For patients who develop hepatotoxicity during treatment, abiraterone acetate should be discontinued until recovery. Retreatment may be initiated at a reduced dose. Abiraterone acetate treatment should be discontinued for patients who develop severe hepatotoxicity.

[0424] Enzalutamide: The dose of enzalutamide is 160 mg (four 40 mg capsules) administered orally once daily. The capsules should be swallowed whole and can be taken with or without food. According to the enzalutamide package insert, if a patient experiences Grade 3 or higher toxicity or intolerable side effects, dosing should be discontinued for 1 week or until symptoms improve to Grade 2 or lower, and then resumed at the same dose or a reduced dose (80 mg or 80 mg) as needed.

[0425] (v) Duration of study treatment Patients will be treated until radiographic progressive disease, clinical / symptomatic progression, unacceptable / unmanageable toxicity, or patient refusal to further study treatment (i.e., withdrawal of consent). All patients will be followed during study treatment and during a follow-up period after completion of study treatment until death, the study cut-off date (minimum 22 weeks after enrollment), or withdrawal of consent, whichever occurs first. Long-term follow-up for all patients will be for 5 years from enrollment or until death or loss to follow-up.

[0426] E. Study Procedures and Assessment The activity schedules in Tables 13 and 14 summarize the study assessments and time points. [Table 13] [Table 14]

[0427] (i) Clinical evaluation Clinical assessments included demographics, medical history, physical examination, vital signs, performance status, adverse events, concomitant medications / therapies, tumor assessment, and blinded independent central review (BICR).

[0428] Performance status will be assessed at screening and all subsequent clinical visits using the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale, as shown in Table 15 below. [Table 15]

[0429] Tumor assessments will be performed according to the assessment calendar regardless of treatment delays resulting from toxicity. Care must be taken in scheduling tumor assessments to avoid introducing bias based on treatment delays.

[0430] Patients will be evaluated for tumor response by CT imaging and bone scans at screening and every 8 weeks (±1 week) from the start of treatment until week 24 of the study. Thereafter, patients without radiographic progression during the 24-week period will undergo CT imaging and bone scans every 12 weeks (±1 week) until radiographic progression is determined. Scan scheduling will be based on a calendar rather than the start of a treatment cycle. Evaluations will include CT scans of the chest, abdomen, pelvis, and brain (only if clinically indicated based on symptoms / findings). The investigator, subinvestigator, or qualified site personnel will read the bone scans and CT images and assess whether radiographic progression is present. If the investigator determines that a patient's metastatic prostate cancer is progressing, the patient's bone scans and CT images will be immediately sent to the Imaging Core Laboratory (ICL) for review by a blinded independent central review (BICR), as shown in Figure 12, to confirm radiographic progression.

[0431] Investigators must not change treatment until confirmation of disease status is received from BICR.

[0432] Blinded Independent Central Review (BICR) Screening: All scans (CT, bone, and PSMA PET) will be submitted to a third-party Imaging Core Laboratory (ICL) for independent review of patient eligibility (within 3 days of receipt of imaging scans that pass quality assessment). After confirmation by the ICL, patients may be randomized into the study if all other eligibility criteria are met. Radiographic Disease Progression: The investigator will evaluate CT scans and bone scans to assess disease progression based on RECIST 1.1 and PCWG3 criteria. If the investigator determines that disease progression has occurred, the BIRC, consisting of a panel of two independent radiologists qualified to evaluate bone scans and CT scans, will independently assess disease progression according to RECIST 1.1 and PCWG3 criteria. Confirmation of radiographic disease progression requires agreement between two blinded readers. If there is no agreement between the two readers, a third reader will be utilized. The BICR will complete confirmation of disease progression, preferably within 72 hours of receipt of an image set from the investigator showing radiographic progression. The investigator should not initiate changes to the patient's clinical management before receiving BICR confirmation of radiographic progression. Figure 12 presents baseline and on-treatment disease status assessments and treatment decisions.

[0433] (ii) Patient-reported outcomes Patient-reported outcomes will be determined using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, and the Brief Pain Inventory-Short Form (BPI-SF) questionnaire.

[0434] The EORTC QLQ-C30 is a questionnaire of 30 quality of life (QoL) questions developed to assess the QoL of cancer patients. QoL questionnaires have been included in over 3,000 phase 3 cancer clinical trials as an efficacy endpoint. The EORTC questionnaire will be administered to patients at baseline, during treatment as provided in the timeline of events in Table 15, and at the end of treatment.

[0435] The Functional Assessment of Cancer Therapy-Prostate (FACT-P) is a health-related quality of life questionnaire that includes 39 prostate cancer-specific questions assessing physical well-being, functional well-being, emotional well-being, social well-being, and additional concerns or prostate cancer subscales specific to prostate cancer. Higher FACT-P scores correspond to better quality of life. The FACT-P questionnaire will be administered to patients at baseline, during treatment, and at the end of treatment.

[0436] The Brief Pain Inventory-Short Form (BPI-SF) is a short survey to assess the overall pain and symptoms experienced by participants. The BPI-SF questionnaire will be administered to patients at baseline, during treatment, and at the end of treatment.

[0437] F. Study evaluation by visit (i) Screening Screening must be completed within 28 days prior to randomization into the study. The screening visit includes (a) obtaining a blood sample and submitting it to a central laboratory for determination of PSA level and baseline clinical laboratory evaluations; (b) obtaining a CT and bone scan of the brain, chest, abdomen, and pelvis and submitting it to BICR within 72 hours to confirm patient eligibility; and (c) using an FDA-approved radiotracer ([ 68 Ga]Ga-PSMA-11 or [ 18The study included obtaining a PSMA-PET scan with [F]DCFPyL. A positive PSMA-PET result was required for inclusion in the trial. PSMA-PET positivity was defined as PSMA-PET uptake greater than liver uptake in one or more metastatic lesions of any size in any organ system. The study also included (d) recording a medical history, including prostate cancer history, date of diagnosis, and previous treatments; (e) recording concomitant medications; (f) conducting a complete physical examination; (g) performing and recording vital signs and ECOG performance status grade; (h) performing a 12-lead ECG; and (i) if the medical monitor confirmed the patient was eligible for enrollment in the study, randomizing the patient according to the IVRS system and proceeding to the Cycle 1 Day 1 visit.

[0438] (ii) Day 1 of treatment The following assessments will be performed on Day 1 of treatment: ●EORTC QLQ-C30, FACT-P, and BPI-SF questionnaires will be administered before treatment to determine baseline. • Any changes to concomitant medications and any adverse events noted since screening will be recorded. Conducting an abbreviated physical examination •Perform and record vital signs and ECOG performance status. • Drawing blood for clinical laboratory evaluation. Study medication will be administered in the clinic. For patients enrolled in the standard of care arm of the study, investigator-assigned standard of care hormone therapy will be initiated: Abiraterone acetate with prednisone: The initial dose of abiraterone acetate is 1000 mg (four 250 mg tablets) administered once daily. The first dose of abiraterone acetate with prednisone will be administered in the clinic. The date and time of initiation of abiraterone therapy will be recorded. Enzalutamide: The initial dose of enzalutamide is 160 mg (four 40 mg capsules) administered once daily. The first dose of enzalutamide will be administered in the clinic. The date and time of initiation of enzalutamide therapy will be recorded. Patients enrolled in the radioligand therapy arm received a minimum of 200 mCi (7.4 GBq) of radioligand infused over 10-15 minutes. 177 An initial radioactive dose of Lu-PSMA-I&T should be administered. 177 The dose and duration of Lu-PSMA-I&T infusion will be recorded. ● 177 For patients enrolled in Lu-PSMA-I&T, a 12-lead ECG will be performed after the first dose.

[0439] (iii) investigational treatment 177 Lu-PSMA I&T: Patients randomized to the radioligand therapy arm of the study will receive 200 mCi (7.4 GBq) in 6-week infusion cycles until radiographic progression confirmed by BICR, or until the patient experiences toxicity requiring discontinuation of treatment or withdraws consent to participate in the study. 177 In this study, patients will receive up to four cycles of Lu-PSMA I&T infusions. 177 Lu-PSMA I&T injections can be performed.

[0440] Abiraterone and Enzalutamide Standard of Care Arm: Patients randomized to standard of care and treated with either abiraterone or enzalutamide will be treated daily with the standard of care dosing regimen of these agents according to their prescribing information. Patients in this arm will continue to receive standard of care until radiographic progression is confirmed by BICR, or until the patient experiences toxicity requiring discontinuation of treatment or withdraws consent to participate in the study.

[0441] (iv) Ongoing evaluation Ongoing evaluation is 177It will be conducted every four weeks for all patients enrolled in the study, including patients randomized to receive Lu-PSMA I&T and those receiving standard of care with abiraterone or enzalutamide.

[0442] (v) Progress evaluation Evaluations will be performed for all patients enrolled in the study, beginning 8 weeks + 1 week after first treatment and continuing for 24 weeks, then every 12 weeks until radiographic evidence of disease progression is observed. Evaluations will consist of (i) obtaining CT chest, abdominal, and pelvic images and bone scans and submitting them to the ICL (Imaging Core Laboratory) for evaluation for BICR, and (ii) obtaining plasma samples for PSA and other clinical laboratory evaluations.

[0443] (vi) End-of-treatment visit End of treatment (EOT) visits are 177 It will be performed 1 month (± 7 days) after the last infusion of Lu-PSMA I&T. Patients receiving abiraterone acetate or enzalutamide will be able to continue receiving daily treatment until the EOT visit. The following assessments will be performed: administer EORTC QLQ-C30, FACT-P, and BPI-SF questionnaires; record any changes to concomitant medications; record any adverse events noted at the time of screening; perform an abbreviated physical examination; perform and record vital signs and ECOG performance status; and obtain blood for clinical laboratory evaluations, including PSA and other clinical laboratory evaluations.

[0444] (vii) Crossover Patients in the standard of care hormone therapy arm were selected based on the following criteria: 177 May cross over to receive Lu-PSMA I&T: Patients must have documented radiographic progression by PCWG3-modified RECIST 1.1 with BICR while on standard-of-care hormonal therapy. - Patients must not have started any other anti-cancer medications or therapies. Participants with inadequate organ and bone marrow function, as defined below, are not eligible for crossover: Absolute neutrophil count < 1.5 × 109 / L ○Platelet count <100×109 / L. o Hemoglobin <8g / dL. AST / SGOT and / or ALT / SGPT > 3.0 × ULN. Total bilirubin >2x ULN, can be 3x ULN unless the patient has known Gilbert syndrome. Creatinine clearance (CrCl) <50 mL / min based on the Cockcroft-Gault formula. Albumin ≥ 2.75g / dL

[0445] If a patient is not eligible for crossover, they should instead complete the end-of-study visit and proceed to long-term follow-up.

[0446] (viii) Long-term follow-up Long-term patient follow-up will continue for up to 5 years after initial treatment in this study, or until patient death or loss to follow-up. The following information will be collected: • Survival status, onset of symptomatic disease progression, initiation of any new symptomatic anticancer therapy, progression during first subsequent therapy, and healthcare resource utilization every 4 months. Additionally, if a patient discontinues study treatment prior to documented disease progression, a CT scan of the chest, abdomen, and pelvis and a bone scan will be obtained and a BICR will be submitted every 12 weeks until documentation of radiographic progression to assess disease progression.

[0447] G. Statistical Considerations and Analysis Plan (i) Sample size 177Treatment of patients with Lu-PSMA I&T is hypothesized to increase radiographic progression-free survival (rPFS) from 6 months to 10 months compared with standard treatment. Therefore, a target hazard ratio (HR) of 0.60 under the alternative hypothesis is reasonable to expect from this phase 3 study. Utilizing a 2:1 randomization, an estimated 237 progression events across both treatment arms would provide 95% power to detect a statistically significant treatment effect using a two-sided log-rank test at an overall significance level of α = 0.05. Given the expected enrollment rate and follow-up time, these 237 progression events would occur in an estimated 269 patients.

[0448] Also, 177 Treatment of patients with LuPSMA I&T is hypothesized to increase overall survival (OS) from 18 months to 25 months compared with standard treatment. Therefore, a target hazard ratio (HR) of 0.70 under the alternative hypothesis is reasonable to expect in this phase 3 study.

[0449] Taking advantage of the larger HR (related to OS) and the 2:1 randomization, an estimated 352 events across both treatment arms would provide 95% power to detect a statistically significant treatment effect using a two-sided log-rank test at an overall significance level of α = 0.0. Given the expected enrollment rate and follow-up time, these 352 deaths would occur in an estimated 400 patients.

[0450] (ii) Planned interim analysis The secondary outcome variable, overall survival (OS), will undergo two interim and final analyses. The first interim analysis will be performed after approximately 25% (90) of deaths have been observed, and the second interim analysis will be performed after approximately 75% (264) of deaths have been observed. The final analysis will then be performed after all 352 planned deaths have been observed. The first interim analysis of OS is expected to be performed when all 237 progression events have been observed for the primary endpoint analysis.

[0451] Interim and final analyses of OS will be performed using a two-sided log-rank test at an adjusted nominal significance level utilizing the standard O'Brien-Fleming consumption function for α. The first interim analysis will have α = 0.0006, the second interim analysis will have α = 0.0151, and the final analysis of OS will use a nominal significance level of α = 0.047. These p-values ​​satisfy the O'Brien-Fleming consumption function for a cumulative α = 0.05.

[0452] If the OS trial meets the nominal significance level at any of the interim analyses, the study will be considered positive and patient enrollment may be stopped after review and approval by the Data Monitoring Committee (DMC).

[0453] (iii) Analysis population A total of 400 patients are planned for the study. • Intention-to-treat (ITT) population: all randomized patients classified according to the randomized treatment arm, regardless of the treatment they actually received. • Safety population: all treated patients, classified according to the treatment actually received, regardless of random assignment. Crossover population: Although this is an ITT population, the analysis uses information on patients who are currently on treatment with standard therapy. 177 Crossover to Lu-PSMA I&T was performed, which will be used for the final OS analysis.

[0454] Other efficacy data sets (per protocol, evaluable, etc.) may be defined in the SAP (Statistical Analysis Plan), but the primary analysis of efficacy will be performed on the ITT population.

[0455] (iv) Effectiveness analysis The primary efficacy analysis will use the intention-to-treat population. Unless otherwise specified, analyses of secondary endpoints will be based on data collected during the randomized treatment period.

[0456] aRadiographic progression-free survival rPFS is the time from randomization to first documented radiographic progressive disease or death from any cause. rPFS times for surviving patients without documented radiographic progression or for patients who initiate other anti-cancer systemic therapy will be censored at the date of the last evaluable disease assessment during the study. rPFS times for patients without evaluable disease assessment during the study will be censored at the time of randomization. rPFS frequency will be approximately every 8 weeks from the time of first treatment until week 24, then every 12 weeks thereafter.

[0457] The distribution of rPFS time will be estimated using the Kaplan-Meier product limit estimation method. The median rPFS time with two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate HRs and their two-sided 95% CIs (confidence intervals).

[0458] b. Overall survival OS time is from randomization to death from any cause. OS will be followed up for 5 years from study enrollment, or until death or loss to follow-up. Patient data in the standard treatment group will not be censored at the time of crossover.

[0459] The distribution of OS time will be ...

Claims

1. １７７ A composition comprising Lu-PSMA I&T, wherein the PSMA I&T １７７ Lu molar ratio of 3.0:1.0 to 8.0:1.0, wherein the composition is suitable for administration to a human patient in need thereof for at least 72 hours after formulation.

2. The PSMA I&T １７７ 2. The composition of claim 1, wherein the molar ratio of Lu to Lu is from 4.4:1.0 to 7.6:1.

0.

3. 3. The composition of claim 2, wherein the composition is suitable for administration to a human patient in need thereof for at least 120 hours after formulation.

4. 10. The composition of claim 1, wherein the composition has a radiochemical purity (RCP) of 95% or greater at the time of administration.

5. The composition of claim 1, wherein the pH of the composition is from 3.5 to 6.

0.

6. The composition of claim 1, wherein the pH of the composition is from 3.5 to 5.

0.

7. The composition of claim 1, wherein the pH of the composition is from 3.5 to 4.

5.

8. The PSMA I&T １７７ 2. The composition of claim 1, wherein the molar ratio of Lu to Lu is from 7.0:1.0 to 8.0:1.0, from 7.1:1.0 to 7.9:1.0, from 7.2:1.0 to 7.8:1.0, from 7.3:1.0 to 7.7:1.0, or from 7.4:1.0 to 7.6:1.

0.

9. The PSMA I&T １７７ 2. The composition of claim 1, wherein the molar ratio of Lu to Lu is 6.0:1.0 to 7.0:1.0, 6.1:1.0 to 6.9:1.0, 6.2:1.0 to 6.8:1.0, 6.3:1.0 to 6.7:1.0, or 6.4:1.0 to 6.6:1.

0.

10. The PSMA I&T １７７ 2. The composition of claim 1, wherein the molar ratio of Lu to Lu is from 5.0:1.0 to 6.0:1.0, from 5.1:1.0 to 5.9:1.0, from 5.2:1.0 to 5.8:1.0, from 5.3:1.0 to 5.7.0:1.0, or from 5.4:1.0 to 5.6:1.

0.

11. The PSMA I&T １７７ 2. The composition of claim 1, wherein the molar ratio of Lu to Lu is 4.0:1.0 to 5.0:1.0, 4.1:1.0 to 4.9:1.0, 4.2:1.0 to 4.8:1.0, 4.3:1.0 to 4.7.0:1.0, or 4.4:1.0 to 4.6:1.

0.

12. The PSMA I&T １７７ 2. The composition of claim 1, wherein the molar ratio of Lu to Lu is from 3.0:1.0 to 4.0:1.0, from 3.1:1.0 to 3.9:1.0, from 3.2:1.0 to 3.8:1.0, from 3.3:1.0 to 3.7.0:1.0, or from 3.4:1.0 to 3.6:1.

0.

13. 2. The composition of claim 1, wherein the PSMA I&T content is 30 μg / dose to 110 μg / dose, 30 μg / dose to 100 μg / dose, or 30 μg / dose to 90 μg / dose.

14. 2. The composition of claim 1, wherein the PSMA I&T content is 95 μg / dose ±15%, ±10%, or ±5%, 90 μg / dose ±15%, ±10%, or ±5%, 85 μg / dose ±15%, ±10%, or ±5%, 80 μg / dose ±15%, ±10%, or ±5%, 75 μg / dose ±15%, ±10%, or ±5%, 70 μg / dose ±15%, ±10%, or ±5%, 60 μg / dose ±15%, ±10%, or ±5%, 55 μg / dose ±15%, ±10%, or ±5%, 50 μg / dose ±15%, ±10%, or ±5%, 45 μg / dose ±15%, ±10%, or ±5%, or 40 μg / dose ±15%, ±10%.

15. 10. The composition of claim 1, wherein the Fe metal content is less than or equal to 0.05 μg / GBq, less than or equal to 0.03 μg / GBq, less than or equal to 0.01 μg / GBq, or below the detectable limit.

16. 10. The composition of claim 1, wherein the Cu metal content is less than or equal to 0.05 μg / GBq, less than or equal to 0.03 μg / GBq, less than or equal to 0.01 μg / GBq, or below the detectable limit.

17. 10. The composition of claim 1, wherein the Zn metal content is less than or equal to 0.05 μg / GBq, less than or equal to 0.03 μg / GBq, less than or equal to 0.01 μg / GBq, or below the detectable limit.

18. 10. The composition of claim 1, wherein the Pb metal content is less than or equal to 0.05 μg / GBq, less than or equal to 0.03 μg / GBq, less than or equal to 0.01 μg / GBq, or below the detectable limit.

19. 10. The composition of claim 1, wherein the composition has a radiochemical purity (RCP) of 97.5% or greater 72 hours after production.

20. 10. The composition of claim 1, wherein the composition has a radiochemical purity (RCP) of 98.0% or greater 72 hours after production.

21. 10. The composition of claim 1, wherein the composition is suitable for human administration for seven or more treatment cycles.

22. 10. The composition of claim 1, wherein the solution comprises from about 10 mg / ml to about 50 mg / ml of ascorbic acid.

23. 10. The composition of claim 1, wherein the solution comprises at least 28 mg / ml of ascorbic acid.

24. The composition of claim 1 , wherein the composition further comprises DTPA.

25. A radiopharmaceutical kit comprising the composition of claim 1.

26. 10. A method of treating cancer in a human patient in need thereof, comprising administering to said human patient the composition of claim 1.

27. 10. A method of treating cancer in a human patient in need thereof, comprising administering to said human patient the composition of claim 2.

28. 1. A method of treating or reducing the incidence of cancer using a radioactive chemical composition, said method comprising administering a radioactive chemical composition to a human patient in need thereof, said radioactive chemical composition being in a solution having a pH of 3.5 to 6.

0. １７７ Lu-PSMA I&T, including PSMA I&T １７７ Lu molar ratio is 3.0:1.0 to 8.0:1.0, said solution has a radiochemical purity of greater than 95% when administered, and said composition is suitable for administration to a human patient in need thereof for at least 72 hours after formulation.

29. 29. The method of claim 28, wherein the cancer is prostate cancer.

30. 29. The method of claim 28, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

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