[177Lu] lutetium-PSMA IT composition and dosimetric method thereof, kit, preparation method and use method of [177Lu] lutetium-PSMA IT composition

Abstract

The present disclosure relates to a composition comprising 177 Lu-PSMA Iamp; radiopharmaceutical compositions, methods, and kits of formula (I). A PSMA Iamp of the compositions, methods, and kits; the molar ratio of T to 177 Lu may be from 4.4: 1.0 to 7.6: 1.0. The composition may be formulated as a solution for injection, and the solution is adapted to be administered within at least 72 hours after the formulation. The composition has a radiochemical purity (RCP) of 95% or more, 95.5% or more, 96% or more, 96.5% or more, 97% or more, 97.5% or more, 98.0% or more, 98.5% or more, 99% or more, or 99.5% or more when applied.

Description

[0001] Cross-reference to related applications

[0002] This invention claims priority to the following U.S. Provisional Applications: Serial Nos. 63 / 529,986, 63 / 620,262, 63 / 626,839, 63 / 671,633, 63 / 671,625, 63 / 677,137, and 63 / 677,276, filed on 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 hereby incorporated by reference in their entirety, including all tables, figures, and claims. Technical Field

[0003] This disclosure relates to compositions of 177 Lu] lutetium-PSMA I&T ( 177 Lu] Lu-PSMA I&T or 177 Lu-PSMA I&T) solutions, and kits containing 177 Lu-PSMA I&T. 177 Lu-PSMA I&T solutions and / or their kits can be used for prostate cancer radioligand therapy (PRLT). Background Art

[0004] For adult men, prostate cancer (PC) is the most common non-skin cancer and the second most common cause of cancer death. Overall, increasing the survival rate of patients with metastatic castration-resistant prostate cancer (mCRPC) is challenging, and there is a clinical need for effective treatment methods for mCRPC patients.

[0005] 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&T are small molecule inhibitors of PSMA, and due to the low toxicity of the inhibitors, they are extremely desirable for targeted radionuclide therapy. However, using these small molecule inhibitors that target PSMA with 177 Lu to treat prostate cancer may also cause undesired absorbed doses of radiation to healthy organs.

[0006] There is still a need for compositions containing 177Improved formulations of Lu-PSMA I&T that minimize the radiation of undesired cumulative absorbed dose to healthy organ tissues of a patient, where the healthy organ tissues are not targeted for cancer treatment. Solutions to these and other problems in the art are provided herein by providing improved 177 Lu-PSMA I&T compositions for PC and mCRPC treatment. Additionally, improved 177 Lu-PSMA I&T compositions that provide a lower cumulative absorbed dose of radiation on a per-administration basis are provided herein. SUMMARY OF THE INVENTION

[0007] The compositions provided herein particularly relate to a radiopharmaceutical composition comprising 177 Lu-PSMA I&T for administration to a human patient in need thereof. The composition is formulated as an injectable solution, and the solution is 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 composition is formulated as an injectable solution, and the radiochemical purity of the solution is ≥95% at least 48 hours, at least 72 hours, at least 96 hours, at least 100 hours, or at least 120 hours after formulation.

[0008] The compositions, methods, and kits described herein comprise 177 Lu-PSMA I&T suitable for administration to a human patient, wherein the healthy organs exhibit a reduction in cumulative absorbed dose after administration.

[0009] The compositions, methods, and kits described herein comprise Lu-PSMA I&T having a radiochemical purity ≥95% and a molar ratio of PSMA I&T to 177 Lu of 3.0:1.0 to 8.0:1.0 and / or 4.4:1.0 to 7.6:1.0. This is highly surprising and unexpected because initial tests indicated that this embodiment was not feasible and required at least 11.0:1.0 or greater of PSMA I&T to 177 Lu-PSMA I&T. 177The molar ratio of Lu is maintained at a radiochemical purity ≥ 95% for 72 hours or longer. Indeed, as initially expected, any substance with a ratio below 11.0:1.0 would likely have an unacceptable radiochemical purity (e.g., below 95%) upon formation and would continue to deteriorate, such that any such substance would be further unacceptable for a human patient at 24 hours after formation, 48 hours after formation, 72 hours after formation, or 96 hours after formation. See the PSMA:Lu-177 (mol / mol) chart below, which shows the inappropriate expected radiochemical formation when the formulation is below 11.0:1.0.

[0010]

[0011] However, using the unique parameters described herein, provided herein are compositions, methods, and kits comprising Lu-PSMA I&T having a radiochemical purity ≥ 95% suitable for administration to a human patient and a molar ratio of PSMA I&T to 177 Lu of 3.0:1.0 to 8.0:1.0 and / or 4.4:1.0 to 7.6:1.0, 177 wherein the composition is stable for 72 hours or longer.

[0012] In another embodiment, the compositions, methods, and kits described herein comprise Lu-PSMA I&T having a radiochemical purity ≥ 95% suitable for administration to a human patient and a ratio of PSMA I&T to [177Lu]Lu3+ (in μg:mCi) of from about 0.20 to about 0.60. 177 In another embodiment, the compositions, methods, and kits described herein comprise Lu-PSMA I&T having a radiochemical purity ≥ 95% suitable for administration to a human patient and a ratio of PSMA I&T to [177Lu]Lu3+ (in μg:mCi) ≤ 0.60. 177 This is also highly surprising and unexpected, as initial tests indicated that this embodiment was not feasible and that a ratio of PSMA I&T to [177Lu]Lu3+ (in μg:mCi) of at least 0.70 or greater was required to maintain a radiochemical purity ≥ 95% for 72 hours or longer. See the PSMA:Lu-177 (mol / mol) chart below, which shows the inappropriate expected radiochemical formation when the formulation is 0.60 or below.

[0013]

[0014] However, using the unique parameters described herein, provided herein are compositions, methods, and kits of Lu-PSMA I&T having a radiochemical purity of ≥95% and a PSMA I&T to [177Lu]Lu3+ ratio (in μg:mCi) of from about 0.20 to about 0.64, from about 0.20 to about 0.63, from about 0.20 to about 0.62, from about 0.20 to about 0.61, or from about 0.20 to about 0.60, suitable for administration to a human patient. 177 The compositions, methods, and kits of Lu-PSMA I&T described herein, wherein the compositions are stable for 72 hours or longer.

[0015] The present disclosure further relates to a radiopharmaceutical composition comprising a solution of Lu]Lu-PSMA I&T and ascorbic acid having a pH of 3.0 to 6.0. In some instances, the composition is suitable for administration to a human patient in need thereof for at least 90 hours after compounding, and the composition has a radiochemical purity of 95.0% or higher 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 and not comprise EDTA. In some aspects, the radiopharmaceutical composition may not comprise gentisic acid and / or gentisate (i.e., no gentisic acid and / or gentisate). 177 On the other hand, the present disclosure is a reaction composition comprising a solution of Lu]LuCl3, from about 463 μg / mL to 500 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. On the other hand, the present disclosure is a reaction composition comprising a total of 6 mL to 8 mL of a solution of Lu]LuCl3, from about 463 μg / mL to 500 μg / mL of a 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. On yet another hand, the present disclosure is a reaction composition comprising a solution of Lu, from about 463 μg / mL to 1000 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. In some instances, the Lu radioactivity of the reaction composition is ≤61 GBq.

[0016] On the other hand, the present disclosure is a reaction composition comprising a solution of Lu]LuCl3, from about 463 μg / mL to 500 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. On the other hand, the present disclosure is a reaction composition comprising a total of 6 mL to 8 mL of a solution of Lu]LuCl3, from about 463 μg / mL to 500 μg / mL of a 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. On yet another hand, the present disclosure is a reaction composition comprising a solution of Lu, from about 463 μg / mL to 1000 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. In some instances, the Lu radioactivity of the reaction composition is ≤61 GBq. 177 On the other hand, the present disclosure is a reaction composition comprising a solution of Lu]LuCl3, from about 463 μg / mL to 500 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. On the other hand, the present disclosure is a reaction composition comprising a total of 6 mL to 8 mL of a solution of Lu]LuCl3, from about 463 μg / mL to 500 μg / mL of a 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. On yet another hand, the present disclosure is a reaction composition comprising a solution of Lu, from about 463 μg / mL to 1000 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. In some instances, the Lu radioactivity of the reaction composition is ≤61 GBq. 177 On the other hand, the present disclosure is a reaction composition comprising a solution of Lu]LuCl3, from about 463 μg / mL to 500 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. On the other hand, the present disclosure is a reaction composition comprising a total of 6 mL to 8 mL of a solution of Lu]LuCl3, from about 463 μg / mL to 500 μg / mL of a 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. On yet another hand, the present disclosure is a reaction composition comprising a solution of Lu, from about 463 μg / mL to 1000 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. In some instances, the Lu radioactivity of the reaction composition is ≤61 GBq. 177 On the other hand, the present disclosure is a reaction composition comprising a solution of Lu, from about 463 μg / mL to 1000 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. In some instances, the 177 Lu radioactivity of the reaction composition is ≤61 GBq.

[0017] On the other hand, the present disclosure is a reaction composition comprising a solution of Lu]LuCl3, from about 463 μg / mL to 500 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. On the other hand, the present disclosure is a reaction composition comprising a total of 6 mL to 8 mL of a solution of Lu]LuCl3, from about 463 μg / mL to 500 μg / mL of a 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. On yet another hand, the present disclosure is a reaction composition comprising a solution of Lu, from about 463 μg / mL to 1000 μg / mL of a PSMA I&T precursor, ascorbic acid, and an acetate buffer. In some instances, the Lu radioactivity of the reaction composition is ≤61 GBq. 177A solution of Lu-Lu-, PSMA I&T precursor, ascorbic acid, acetate buffer, hydrochloric acid, and L-ascorbic acid. In some examples, the 177 radioactivity of Lu is ≤296 GBq (i.e., ≤8,000 mCi).

[0018] The present disclosure further relates to a radiopharmaceutical composition comprising an injectable 177 Lu-Lu-PSMA I&T solution, the solution comprising from about 3 μg / ml to about 16 μg / ml of 177 Lu-Lu-PSMA I&T and related substances (i.e., unlabeled PSMA I&T and PSMA I&T labeled with other metals), ascorbic acid at a concentration of from about 25 mg / ml to about 40 mg / ml, and a chelating agent in an amount of from about 0.075 mg / ml to 0.15 mg / ml, wherein the pH of the solution is between about 3 and about 5, wherein the total volume of the composition is about 15 ml, and wherein after administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity. The present disclosure further relates to a radiopharmaceutical composition comprising an injectable 177 Lu-Lu-PSMA I&T solution, the solution comprising from about 1 μg / ml to about 8 μg / ml of 177 Lu-Lu-PSMA I&T and related substances (i.e., unlabeled PSMA I&T and PSMA I&T labeled with other metals), ascorbic acid at a concentration of from about 25 mg / ml to about 40 mg / ml, and a chelating agent in an amount of from about 0.075 mg / ml to 0.15 mg / ml, wherein the pH of the solution is between about 3 and about 5, wherein the total volume of the composition is about 15 ml, and wherein after administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity. The present disclosure further relates to a radiopharmaceutical composition comprising an injectable 177 Lu-Lu-PSMA I&T solution, the solution comprising from about 3 μg / ml to about 10 μg / ml of 177 Lu-Lu-PSMA I&T and related substances (i.e., unlabeled PSMA I&T and PSMA I&T labeled with other metals), ascorbic acid at a concentration of from about 25 mg / ml to about 40 mg / ml, and a chelating agent in an amount of from about 0.075 mg / ml to 0.15 mg / ml, wherein the pH of the solution is between about 3 and about 5, wherein the total volume of the composition is about 15 ml, and wherein after administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0019] The present disclosure further relates to a radiopharmaceutical composition comprising an injectable 177 Lu]Lu-PSMA I&T solution, the solution comprising 177 Lu]Lu-PSMA I&T, ascorbic acid, and ethanol. Wherein the amount of radioactivity of the 177 Lu]Lu-PSMA I&T is sufficient for the intended use, wherein the total amount of ascorbic acid in the solution is about 210 - 700 mg, and the total amount of ethanol in the solution is about 274 - 706 mg; wherein the pH of the solution is about 5 or less, wherein after administering the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity, and wherein prostate-specific antigen decreases by more than about 50%.

[0020] The present disclosure further relates to a radiopharmaceutical composition comprising an injectable 177 Lu]Lu-PSMA I&T solution, the solution comprising from about 3 μg / ml to about 15 μg / ml of 177 Lu]Lu-PSMA-I&T, ascorbic acid at a concentration of from about 10 mg / ml to about 50 mg / ml, and ethanol at a 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%) ethanol, wherein the pH of the solution is between about 3 and about 5, and wherein after administering the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0021] The present disclosure further relates to a radiopharmaceutical composition comprising an injectable 177 Lu]Lu-PSMA I&T solution, the solution comprising from about 3 μg / ml to about 15 μg / ml or from about 3 μg / ml to about 12 μg / ml of 177 Lu]Lu-PSMA I&T; ascorbic acid at a concentration of from about 10 mg / ml to about 50 mg / ml; ethanol at a concentration of from about 0% (v / v) to about 10% (v / v), and a chelating agent in an amount of from about 0.01 mg / ml to about 0.15 mg / ml or about, wherein the pH of the solution is between about 3 and about 5, and wherein after administering the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0022] The present disclosure further relates to a radiopharmaceutical composition, the radiopharmaceutical composition comprising a solution for injection of 177 Lu]Lu-PSMA I&T, the solution comprising from about 4 μg / ml to about 15 μg / ml of 177 Lu]Lu-PSMA I&T and related substances (i.e., unlabeled PSMA I&T and PSMA I&T labeled with other metals), ascorbic acid at a concentration of from about 25 mg / ml to about 40 mg / ml, and a chelating agent in an amount of from about 0.075 mg / ml to 0.15 mg / ml, wherein the pH of the solution is between about 3 and about 5, wherein the total volume of the composition is about 15 ml, and wherein after administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0023] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 177 Lu]Lu-PSMA-I&T, and wherein it is possible to perform 1, 2, 3, 4, 5, 6, 7, 8 or more cycles of 177 Lu]Lu-PSMA I&T treatment without the risk of nephrotoxicity, and / or wherein performing 1, 2, 3, 4, 5, 6, 7, 8 or more cycles of 177 Lu]Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys.

[0024] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 177 Lu]Lu-PSMA-I&T, and wherein 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177 Lu]Lu-PSMA I&T treatment are performed at a dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or wherein performing 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177The Lu]Lu-PSMA I&T treatment provides an average predicted cumulative absorbed dose to the kidneys of ≤23.0 Gy, ≤22.9 Gy, ≤22.8 Gy, ≤22.7 Gy, ≤22.6 Gy, ≤22.5 Gy, ≤22.4 Gy, ≤22.3 Gy, ≤22.2 Gy, ≤22.1 Gy, ≤22.0 Gy, ≤21.9 Gy, ≤21.8 Gy, ≤21.7 Gy, ≤21.6 Gy, ≤21.5 Gy, ≤21.4 Gy, ≤21.3 Gy, ≤21.2 Gy, ≤21.1 Gy, ≤21.0 Gy, ≤20.9 Gy, ≤20.8 Gy, ≤20.7 Gy, ≤20.6 Gy, ≤20.5 Gy, ≤20.4 Gy, ≤20.3 Gy, ≤20.2 Gy, ≤20.1 Gy, ≤20.0 Gy, ≤19.9 Gy, ≤19.8 Gy, ≤19.7 Gy, ≤19.6 Gy, ≤19.5 Gy, ≤19.4 Gy, ≤19.3 Gy, ≤19.2 Gy or ≤19.1 Gy.

[0025] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising vials containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 177 Lu]Lu-PSMA-I&T, and wherein 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177 Lu}Lu-PSMA I&T treatment are possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177 Lu]Lu-PSMAI&T treatment provides an average predicted cumulative absorbed dose to the kidneys of ≤19.2 Gy, ≤19.1 Gy, ≤19.0 Gy, ≤18.9 Gy, ≤18.8 Gy, ≤18.7 Gy, ≤18.6 Gy, ≤18.5 Gy, ≤18.4 Gy, ≤18.3 Gy, ≤18.2 Gy, ≤18.1 Gy, ≤18.0 Gy, ≤17.9 Gy, ≤17.8 Gy, ≤17.7 Gy, ≤17.6 Gy, ≤17.5 Gy, ≤17.4 Gy, ≤17.3 Gy, ≤17.2 Gy, ≤17.1 Gy, ≤17.0 Gy, ≤16.8 Gy, ≤16.7 Gy, ≤16.6 Gy, ≤16.5 Gy, ≤16.4 Gy, ≤16.3 Gy, ≤16.2 Gy, ≤16.1 Gy, ≤16.0 Gy or ≤15.9 Gy.

[0026] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of [177Lu-PSMA-I&T, and wherein it is possible to perform 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177 Lu]Lu-PSMA I&T treatment without the risk of nephrotoxicity, and / or wherein performing 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177 Lu]Lu-PSMA I&T treatment provides an average predicted dose of cumulative absorbed dose to the kidneys of ≤15.8 Gy, ≤15.7 Gy, ≤15.6 Gy, ≤15.5 Gy, ≤15.4 Gy, ≤15.3 Gy, ≤15.2 Gy, ≤15.1 Gy, ≤15.0 Gy, ≤14.9 Gy, ≤14.8 Gy, ≤14.7 Gy, ≤14.6 Gy, ≤14.3 Gy, ≤14.2 Gy, ≤14.1 Gy, ≤14.0 Gy, ≤13.9 Gy, ≤13.8 Gy, ≤13.7 Gy, ≤13.6 Gy, ≤13.5 Gy, ≤13.4 Gy, ≤13.3 Gy, ≤13.2 Gy, ≤13.1 Gy, ≤13.0 Gy, ≤12.9 Gy, ≤12.8 Gy or ≤12.7 Gy.

[0027] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 177 Lu]Lu-PSMA-I&T, and wherein it is possible to perform 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177 Lu]Lu-PSMA I&T treatment without the risk of nephrotoxicity, and / or wherein performing 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177The Lu-PSMA I&T treatment provides an average predicted dose of the cumulative absorbed dose to the kidney of ≤12.6 Gy, ≤12.5 Gy, ≤12.4 Gy, ≤12.3 Gy, ≤12.2 Gy, ≤12.1 Gy, ≤12.0 Gy, ≤11.9 Gy, ≤11.8 Gy, ≤11.7 Gy, ≤11.6 Gy, ≤11.5 Gy, ≤11.4 Gy, ≤11.3 Gy, ≤11.2 Gy, ≤11.1 Gy, ≤11.0 Gy, ≤10.9 Gy, ≤10.8 Gy, ≤10.7 Gy, ≤10.6 Gy, ≤10.5 Gy, ≤10.4 Gy, ≤10.3 Gy, ≤10.2 Gy, ≤10.1 Gy, ≤10.0 Gy, ≤9.9 Gy, ≤9.8 Gy, ≤9.7 Gy, ≤9.6 Gy, or ≤9.5 Gy.

[0028] The present disclosure further relates to a radioactive pharmaceutical kit, the radioactive pharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 177 Lu-PSMA-I&T, and wherein it is possible to perform 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177 Lu-PSMA I&T treatment without the risk of nephrotoxicity, and / or wherein performing 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177 Lu-PSMA I&T treatment provides an average predicted dose of the cumulative absorbed dose to the kidney of ≤9.4 Gy, ≤9.3 Gy, ≤9.2 Gy, ≤9.1 Gy, ≤9.0 Gy, ≤8.9 Gy, ≤8.8 Gy, ≤8.7 Gy, ≤8.6 Gy, ≤8.5 Gy, ≤8.4 Gy, ≤8.3 Gy, ≤8.2 Gy, ≤8.1 Gy, ≤8.0 Gy, ≤7.9 Gy, ≤7.8 Gy, ≤7.7 Gy, ≤7.6 Gy, ≤7.5 Gy, ≤7.3 Gy, ≤7.2 Gy, ≤7.1 Gy, ≤7.0 Gy, ≤6.9 Gy, ≤6.8 Gy, ≤6.7 Gy, ≤6.6 Gy, ≤6.5 Gy, or ≤6.4 Gy.

[0029] The present disclosure further relates to a radioactive pharmaceutical kit, the radioactive pharmaceutical kit comprising a vial containing at least a single dose of 177 Lu]-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 177Lu]Lu-PSMA-I&T, and wherein 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177 Lu]Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles of 177 Lu]Lu-PSMAI&T treatment provides an average predicted dose of cumulative absorbed dose to the kidney of ≤6.3 Gy, ≤6.2 Gy, ≤6.1 Gy, ≤6.0 Gy, ≤5.9 Gy, ≤5.8 Gy, ≤5.7 Gy, ≤5.6 Gy, ≤5.5 Gy, ≤5.4 Gy, ≤5.3 Gy, ≤5.2 Gy, ≤5.1 Gy, ≤5.0 Gy, ≤4.9 Gy, ≤4.8 Gy, ≤4.7 Gy, ≤4.6 Gy, ≤4.5 Gy, ≤4.3 Gy, ≤4.2 Gy, ≤4.1 Gy, ≤4.0 Gy, ≤3.9 Gy, ≤3.8 Gy, ≤3.7 Gy, ≤3.6 Gy, ≤3.5 Gy, ≤3.4 Gy, ≤3.3 Gy or ≤3.2 Gy.

[0030] The present disclosure also relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 177 Lu]Lu-PSMA-I&T, and the predicted or actual cumulative absorbed dose to the kidney at 1, 2, 3, 4, 5, 6, 7, or 8 or more cycles is less than 23 Gy and no nephrotoxicity is observed.

[0031] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises less than 10 mg / ml gentisate, gentisic acid, alternative antioxidant or a combination thereof. In some embodiments, said injection comprises ≤ 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 gentisate, gentisic acid, alternative antioxidant or a combination thereof. In one embodiment, the present disclosure relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection does not comprise gentisate, gentisic acid, alternative antioxidant or a combination thereof.

[0032] The present disclosure further relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises less than 10 mg / ml ascorbate, ascorbic acid, alternative stabilizer or radioprotectant or a combination thereof. In some embodiments, said injection comprises ≤ 40 mg / ml, ≤ 35 mg / ml, ≤ 33 mg / ml, ≤ 31 mg / ml, ≤ 30 mg / ml, ≤ 25 mg / ml, ≤ 20 mg / ml, ≤ 15 mg / ml, ≤ 10 mg / ml, ≤ 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 ascorbate, ascorbic acid, alternative stabilizer or a combination thereof.

[0033] The present disclosure further relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising a vial containing at least a single dose of 177Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises: (1) less than 10 mg / ml gentisate and / or gentisic acid; and (2) less than 10 mg / ml ascorbate and / or ascorbic acid. In some embodiments, said injection comprises: (1) ≤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 gentisate and / or gentisic acid; and, (2) ≤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 ascorbate and / or ascorbic acid.

[0034] The present disclosure further relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising a vial containing at least a single dose of 177Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises: (1) an antioxidant of less than 10 mg / ml; and, (2) a stabilizer of less than 40 mg / ml. In some embodiments, said injection comprises: (1) ≤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 antioxidant; and, (2) ≤40 mg / ml, ≤35 mg / ml, ≤33 mg / ml, ≤31 mg / ml, ≤30 mg / ml, ≤25 mg / ml, ≤20 mg / ml, ≤15 mg / ml, ≤10 mg / ml, ≤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 stabilizer.

[0035] The present disclosure further relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising vials containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 6.8 GBq ± 0.10 GBq, 6.8 GBq ± 0.15 GBq, 6.8 GBq ± 0.20 GBq, 6.8 GBq ± 0.25 GBq or 6.8 GBq ± 0.30 GBq, and wherein 1, 2, 3, 4, 5, 6, 7 or 8 cycles of 177 Lu]Lu-PSMA I&T treatment are possible without risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6, 7 or 8 cycles of 177 Lu]Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidney, and / or the predicted or actual cumulative absorbed dose to the kidney at 1, 2, 3, 4, 5, 6, 7 or 8 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0036] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises 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, and wherein 1, 2, 3, 4, 5, 6, 7 or 8 cycles of 177 Lu]Lu-PSMA I&T treatment can be performed without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6, 7 or 8 cycles of 177 Lu]Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidney, and / or the predicted or actual cumulative absorbed dose to the kidney at 1, 2, 3, 4, 5, 6, 7 or 8 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0037] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.4 GBq (average 7.52 ± 0.16 GBq) of 177 Lu-PSMA-I&T, and wherein 1, 2, 3, 4, 5, 6, 7 or 8 cycles of 177 Lu-PSMA I&T treatment can be performed without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6, 7 or 8 cycles of 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidney, and / or the predicted or actual cumulative absorbed dose to the kidney at 1, 2, 3, 4, 5, 6, 7 or 8 cycles is less than 23 Gy and no nephrotoxicity is observed. The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.4 GBq (average 7.52 ± 0.16 GBq) of 177 Lu-PSMA-I&T, wherein 1, 2, 3, 4, 5, 6, 7 or 8 cycles of 177The Lu-PSMA I&T treatment provides an average predicted dose with a cumulative absorbed dose below 23 Gy to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys is less than 23 Gy at 1, 2, 3, 4, 5, 6, 7, or 8 cycles, and no nephrotoxicity is observed.

[0038] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising vials containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 6.8 GBq ± 10% GBq, 6.8 GBq ± 5% GBq, or 6.8 GBq ± 3% GBq of 177 Lu-PSMA-I&T, and wherein Lu-PSMA I&T treatment for 1, 2, 3, 4, 5, 6, 7, or 8 cycles is possible without the risk of nephrotoxicity, and / or wherein Lu-PSMA I&T treatment for 1, 2, 3, 4, 5, 6, 7, or 8 cycles 177 provides an average predicted dose with a cumulative absorbed dose below 23 Gy to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys is less than 23 Gy at 1, 2, 3, 4, 5, 6, 7, or 8 cycles, and no nephrotoxicity is observed. 177 The Lu-PSMA I&T treatment provides an average predicted dose with a cumulative absorbed dose below 23 Gy to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys is less than 23 Gy at 1, 2, 3, 4, 5, 6, 7, or 8 cycles, and no nephrotoxicity is observed.

[0039] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising vials containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.4 GBq ± 10% GBq, 7.4 GBq ± 5% GBq, or 7.4 GBq ± 3% GBq of 177 Lu-PSMA-I&T, and wherein Lu-PSMA I&T treatment for 1, 2, 3, 4, 5, 6, 7, or 8 cycles is possible without the risk of nephrotoxicity, and / or wherein Lu-PSMA I&T treatment for 1, 2, 3, 4, 5, 6, 7, or 8 cycles 177 provides an average predicted dose with a cumulative absorbed dose below 23 Gy to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys is less than 23 Gy at 1, 2, 3, 4, 5, 6, 7, or 8 cycles, and no nephrotoxicity is observed. 177 The Lu-PSMA I&T treatment provides an average predicted dose with a cumulative absorbed dose below 23 Gy to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys is less than 23 Gy at 1, 2, 3, 4, 5, 6, 7, or 8 cycles, and no nephrotoxicity is observed.

[0040] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.4 (±10%) GBq of 177 Lu-PSMA-I&T, and wherein 6 cycles of 177 Lu-PSMA I&T treatment are possible at said dose without risk of nephrotoxicity, and / or wherein 6 cycles of 177 Lu-PSMA I&T treatment provides an average projected dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or at 6 cycles the projected or actual cumulative absorbed dose to the kidneys is less than 23 Gy and no nephrotoxicity is observed.

[0041] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises 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, and wherein the projected cumulative absorbed dose to the kidneys at 6 cycles will be 20.4 ± 10.2 Gy. The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.5 GBq ± 0.10 GBq, 7.5 GBq ± 0.15 GBq, 7.5 GBq ± 0.20 GBq, 7.5 GBq ± 0.25 GBq or 7.5 GBq ± 0.30 GBq, and wherein the projected cumulative absorbed dose to the kidneys at 6 cycles will be 20.4 ± 10.2 Gy.

[0042] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.1 GBq ± 0.10 GBq, 7.1 GBq ± 0.15 GBq, 7.1 GBq ± 0.20 GBq, 7.1 GBq ± 0.25 GBq or 7.1 GBq ± 0.30 GBq, and wherein the projected cumulative absorbed dose to the kidneys at 6, 7 or 8 cycles will be 20.4 ± 10.2 Gy.

[0043] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 6.8 GBq ± 0.10 GBq, 6.8 GBq ± 0.15 GBq, 6.8 GBq ± 0.20 GBq, 6.8 GBq ± 0.25 GBq or 6.8 GBq ± 0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidneys at 6, 7 or 8 cycles will be 20.4 ± 10.2 Gy.

[0044] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises 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, and wherein the predicted cumulative absorbed dose to the kidneys at 6, 7 or 8 cycles will be 20.4 ± 10.2 Gy.

[0045] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises 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, and wherein the predicted cumulative absorbed dose to the kidneys at 6 or 7 cycles will be ≤ 23.00 Gy, ≤ 22.50 Gy, ≤ 22.00 Gy, ≤ 21.50 Gy, ≤ 21.00 Gy, ≤ 20.50 Gy or ≤ 20.40 Gy. The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177A Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.5 GBq ± 0.10 GBq, 7.5 GBq ± 0.15 GBq, 7.5 GBq ± 0.20 GBq, 7.5 GBq ± 0.25 GBq or 7.5 GBq ± 0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney at 6 or 7 cycles will be ≤ 23.00 Gy, ≤ 22.50 Gy, ≤ 22.00 Gy, ≤ 21.50 Gy, ≤ 21.00 Gy, ≤ 20.50 Gy or ≤ 20.40 Gy.

[0046] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 A Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 6.8 GBq ± 0.10 GBq, 6.8 GBq ± 0.15 GBq, 6.8 GBq ± 0.20 GBq, 6.8 GBq ± 0.25 GBq or 6.8 GBq ± 0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney at 6, 7 or 8 cycles will be ≤ 23.00 Gy, ≤ 22.50 Gy, ≤ 22.00 Gy, ≤ 21.50 Gy, ≤ 21.00 Gy, ≤ 20.50 Gy or ≤ 20.40 Gy.

[0047] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 A Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises 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, and wherein the average absorbed dose of the radiopharmaceutical in the kidney of the human patient is about 0.1 Gy / MBq to 1.0 Gy / MBq. The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 A Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.5 GBq ± 0.10 GBq, 7.5 GBq ± 0.15 GBq, 7.5 GBq ± 0.20 GBq, 7.5 GBq ± 0.25 GBq or 7.5 GBq ± 0.30 GBq, and wherein the average absorbed dose of the radiopharmaceutical in the kidney of the human patient is about 0.1 Gy / MBq to 1.0 Gy / MBq.

[0048] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 6.8 GBq ± 0.10 GBq, 6.8 GBq ± 0.15 GBq, 6.8 GBq ± 0.20 GBq, 6.8 GBq ± 0.25 GBq or 6.8 GBq ± 0.30 GBq, and wherein the average absorbed dose of the radiopharmaceutical in the kidneys of the human patient is about 0.1 Gy / MBq to 1.0 Gy / MBq.

[0049] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises 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, and wherein the average whole-body effective dose of the radiopharmaceutical composition is about 0.001 mSv / MBq to 0.1 mSv / MBq. The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.5 GBq ± 0.10 GBq, 7.5 GBq ± 0.15 GBq, 7.5 GBq ± 0.20 GBq, 7.5 GBq ± 0.25 GBq or 7.5 GBq ± 0.30 GBq, and wherein the average whole-body effective dose of the radiopharmaceutical composition is about 0.001 mSv / MBq to 0.1 mSv / MBq.

[0050] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 6.8 GBq ± 0.10 GBq, 6.8 GBq ± 0.15 GBq, 6.8 GBq ± 0.20 GBq, 6.8 GBq ± 0.25 GBq or 6.8 GBq ± 0.30 GBq, and wherein the average whole-body effective dose of the radiopharmaceutical composition is about 0.001 mSv / MBq to 0.1 mSv / MBq.

[0051] The present disclosure further 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 administration, the radiopharmaceutical composition comprising a solution of Lu-PSMA I&T having a pH of 3.5 to 5.0 and containing 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, the solution optionally comprising ascorbic acid and / or ethanol, and the solution optionally having a radiochemical purity of more than 95%, more than 96%, more than 97%, more than 98%, more than 99% or more than 99.5% at the time of administration, and wherein 1, 2, 3, 4, 5, 6 and / or 7 cycles of Lu-PSMA I&T treatment are possible at said dose without risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 and / or 7 cycles of Lu-PSMA I&T treatment provide an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys at 1, 2, 3, 4, 5, 6 and / or 7 cycles is less than 23 Gy and no nephrotoxicity is observed. On the other hand, the radiopharmaceutical composition may comprise radionuclide identification (gamma spectrometry) of the composition, showing gamma-ray energy peaks at 113 ± 2 keV and 208 ± 4 keV, and no other significant peaks with gamma energy > 100 keV are detected. 177 solution of Lu-PSMA I&T, the solution optionally comprising ascorbic acid and / or ethanol, and the solution optionally having a radiochemical purity of more than 95%, more than 96%, more than 97%, more than 98%, more than 99% or more than 99.5% at the time of administration, and wherein 1, 2, 3, 4, 5, 6 and / or 7 cycles of 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 and / or 7 cycles of 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys at 1, 2, 3, 4, 5, 6 and / or 7 cycles is less than 23 Gy and no nephrotoxicity is observed. On the other hand, the radiopharmaceutical composition may comprise radionuclide identification (gamma spectrometry) of the composition, showing gamma-ray energy peaks at 113 ± 2 keV and 208 ± 4 keV, and no other significant peaks with gamma energy > 100 keV are detected.

[0052] The present disclosure further 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 administration, the radiopharmaceutical composition comprising a solution of 177 Lu]Lu-PSMA I&T having a pH of 3.5 to 4.5 and containing a dose of 6.8 GBq ± 0.10 GBq, 6.8 GBq ± 0.15 GBq, 6.8 GBq ± 0.20 GBq, 6.8 GBq ± 0.25 GBq or 6.8 GBq ± 0.30 GBq, the solution optionally comprising ascorbic acid and / or ethanol, and the solution optionally having a radiochemical purity of more than 95%, more than 96%, more than 97%, more than 98%, more than 99% or more than 99.5% at the time of administration, and wherein 1, 2, 3, 4, 5, 6, 7 and / or 8 cycles of 177Lu-Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or in which 1, 2, 3, 4, 5, 6, 7 and / or 8 cycles of 177 Lu-Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys at 1, 2, 3, 4, 5, 6, 7 and / or 8 cycles is less than 23 Gy, and no nephrotoxicity is observed. On the other hand, the radiopharmaceutical composition may comprise radionuclide identification (gamma spectrometry) of the composition, showing gamma-ray energy peaks at 113 ± 2 keV and 208 ± 4 keV, and no other significant peaks with gamma energy > 100 keV are detected.

[0053] The present disclosure further 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 administration, the radiopharmaceutical composition comprising a solution of 177 Lu-Lu-PSMA I&T having a pH of 3.5 to 5.0 and 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, the solution optionally comprising ascorbic acid and / or ethanol, and the solution optionally having a radiochemical purity of more than 95%, more than 96%, more than 97%, more than 98%, more than 99% or more than 99.5% at the time of administration, and in which 1, 2, 3, 4, 5, 6 and / or 7 cycles of 177 Lu-Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or in which 1, 2, 3, 4, 5, 6, 7 and / or 8 cycles of 177 Lu-Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys at 1, 2, 3, 4, 5, 6, 7 and / or 8 cycles is less than 23 Gy, and no nephrotoxicity is observed. On the other hand, the radiopharmaceutical composition may comprise radionuclide identification (gamma spectrometry) of the composition, showing gamma-ray energy peaks at 113 ± 2 keV and 208 ± 4 keV, and no other significant peaks with gamma energy > 100 keV are detected.

[0054] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising a vial containing at least a single dose of 177A Lu-PSMA I&T solution for injection into a human patient in need thereof, wherein the injection comprises 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, and wherein radionuclide identification (γ - spectrometry) of the solution shows γ - ray energy peaks at 113 ± 2 keV and 208 ± 4 keV, and no other significant peaks with γ - energy > 100 keV are detected.

[0055] The present disclosure also relates to a method comprising administering a radiopharmaceutical composition to a human patient in need thereof, the radiopharmaceutical composition comprising 177 Lu-PSMA I&T, the radiopharmaceutical composition providing an average absorbed dose to the kidneys of the patient of 0.41 ± 0.18 Gy / GBq, 0.41 ± 0.17 Gy / GBq, 0.41 ± 0.16 Gy / GBq, 0.41 ± 0.15 Gy / GBq, 0.41 ± 0.14 Gy / GBq, 0.41 ± 0.13 Gy / GBq, 0.41 ± 0.12 Gy / GBq, 0.41 ± 0.11 Gy / GBq, 0.41 ± 0.10 Gy / GBq, 0.41 ± 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, and wherein radionuclide identification (γ - spectrometry) of the solution shows γ - ray energy peaks at 113 ± 2 keV and 208 ± 4 keV, and no other significant peaks with γ - energy > 100 keV are detected. The present disclosure also relates to a method comprising administering a radiopharmaceutical composition to a human patient in need thereof, the radiopharmaceutical composition comprising 177 Lu-PSMA I&T, the radiopharmaceutical composition providing an average absorbed dose to the kidneys of the patient of ≤ 0.70 Gy / GBq, ≤ 0.65 Gy / GBq, ≤ 0.60 Gy / GBq, ≤ 0.55 Gy / GBq, ≤ 0.50 Gy / GBq, ≤ 0.45 Gy / GBq, ≤ 0.40 Gy / GBq, ≤ 0.35 Gy / GBq, ≤ 0.30 Gy / GBq or ≤ 0.25 Gy / GBq.

[0056] The present disclosure also relates to a method comprising administering a radiopharmaceutical composition to a human patient in need thereof, the radiopharmaceutical composition comprising177 Lu-PSMA I&T, the radiopharmaceutical composition provides an average absorbed dose of the salivary glands of the patient of 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. The present disclosure also relates to a method comprising administering to a human patient in need thereof a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, the radiopharmaceutical composition provides an average absorbed dose of the salivary glands of the patient of ≤ 0.30 Gy / GBq, ≤ 0.25 Gy / GBq, ≤ 0.25 Gy / GBq, ≤ 0.20 Gy / GBq, ≤ 0.15 Gy / GBq, ≤ 0.10 Gy / GBq or ≤ 0.05 Gy / GBq.

[0057] The present disclosure also relates to a method comprising administering to a human patient in need thereof a radiopharmaceutical composition comprising 177Lu-PSMA I&T, the radiopharmaceutical composition provides an average absorbed dose of the lacrimal gland of the patient 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 ± 0.30 Gy / GBq, 0.40 ± 0.29 Gy / GBq, 0.40 ± 0.28 Gy / GBq, 0.40 ± 0.27 Gy / GBq, 0.40 ± 0.26 Gy / GBq, 0.40 ± 0.25 Gy / GBq, 0.40 ± 0.24 Gy / GBq, 0.40 ± 0.23 Gy / GBq, 0.40 ± 0.22 Gy / GBq, 0.40 ± 0.21 Gy / GBq, 0.40 ± 0.20 Gy / GBq, 0.40 ± 0.19 Gy / GBq, 0.40 ± 0.18 Gy / GBq, 0.40 ± 0.17 Gy / GBq, 0.40 ± 0.16 Gy / GBq, 0.40 ± 0.15 Gy / GBq, 0.40 ± 0.14 Gy / GBq, 0.40 ± 0.13 Gy / GBq, 0.40 ± 0.12 Gy / GBq, 0.40 ± 0.11 Gy / GBq, 0.40 ± 0.10 Gy / GBq, 0.40 ± 0.09 Gy / GBq, 0.40 ± 0.08 Gy / GBq, 0.40 ± 0.07 Gy / GBq, 0.40 ± 0.06 Gy / GBq, 0.40 ± 0.05 Gy / GBq, 0.40 ± 0.04 Gy / GBq, 0.40 ± 0.03 Gy / GBq, 0.40 ± 0.02 Gy / GBq or 0.40 ± 0.01 Gy / GBq. The present disclosure also relates to a method comprising administering to a human patient in need thereof a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, the radiopharmaceutical composition provides an average absorbed dose of the lacrimal gland of the patient of ≤1.10 Gy / GBq, ≤1.05 Gy / GBq, ≤1.00 Gy / GBq, ≤0.95 Gy / GBq, ≤0.90 Gy / GBq, ≤0.85 Gy / GBq, ≤0.80 Gy / GBq, ≤0.75 Gy / GBq, ≤0.70 Gy / GBq, ≤0.65 Gy / GBq, ≤0.60 Gy / GBq, ≤0.55 Gy / GBq, ≤0.50 Gy / GBq, ≤0.45 Gy / GBq, ≤0.40 Gy / GBq or ≤0.35 Gy / GBq.

[0058] The present disclosure also relates to a method that includes administering a radiopharmaceutical composition to a human patient in need thereof, the radiopharmaceutical composition comprising 177 Lu-PSMA I&T, the radiopharmaceutical composition providing an average absorbed dose to the liver of the patient of 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. The present disclosure also relates to a method that includes administering a radiopharmaceutical composition to a human patient in need thereof, the radiopharmaceutical composition comprising 177 Lu-PSMA I&T, the radiopharmaceutical composition providing an average absorbed dose to the liver of the patient of ≤ 0.10 Gy / GBq, ≤ 0.09 Gy / GBq, ≤ 0.08 Gy / GBq, ≤ 0.07 Gy / GBq, ≤ 0.06 Gy / GBq, ≤ 0.05 Gy / GBq, ≤ 0.04 Gy / GBq, ≤ 0.03 Gy / GBq, ≤ 0.02 Gy / GBq, or ≤ 0.01 Gy / GBq.

[0059] The present disclosure also relates to a method that includes administering a radiopharmaceutical composition to a human patient in need thereof, the radiopharmaceutical composition comprising 177 Lu-PSMA I&T, the radiopharmaceutical composition providing an average absorbed dose to the kidney of the patient of ≤ 0.70 Gy / GBq, an average absorbed dose to the lacrimal gland of the patient of ≤ 1.10 Gy / GBq, and an average absorbed dose to the salivary gland of the patient of ≤ 0.30 Gy / GBq. On the other hand, the present disclosure relates to a method that includes administering a radiopharmaceutical composition to a human patient in need thereof, the radiopharmaceutical composition comprising 177 Lu-PSMA I&T, the radiopharmaceutical composition providing an average absorbed dose to the kidney of the patient of ≤ 0.60 Gy / GBq, an average absorbed dose to the lacrimal gland of the patient of ≤ 1.00 Gy / GBq, and an average absorbed dose to the salivary gland of the patient of ≤ 0.25 Gy / GBq. Additionally, the present disclosure relates to a method that includes administering a radiopharmaceutical composition to a human patient in need thereof, the radiopharmaceutical composition comprising 177Lu-PSMA I&T, the radiopharmaceutical composition provides an average absorbed dose of ≤0.50 Gy / GBq to the kidneys of the patient, an average absorbed dose of ≤0.90 Gy / GBq to the lacrimal glands of the patient, and an average absorbed dose of ≤0.20 Gy / GBq to the salivary glands of the patient.

[0060] The present disclosure further relates to a method for diagnosing or treating a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 5.0, wherein the radiopharmaceutical composition has an activity in the whole body of at least 20% IA to 30% IA at 20 hours after injection.

[0061] The present disclosure further relates to a method for diagnosing a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity in the kidneys of at least 8% IA to 10% IA less than 20 hours after injection.

[0062] The present disclosure further relates to a method for diagnosing a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity in the parotid glands of at least 0.7% IA to 1% IA less than 20 hours after injection.

[0063] The present disclosure further relates to a method for diagnosing a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity in the lymph node lesions of the patient of at least 0.2% IA to 0.5% IA less than 20 hours after injection.

[0064] The present disclosure further relates to a method for diagnosing a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177A solution of Lu-PSMA I&T and ascorbic acid, wherein the radiopharmaceutical composition has an activity of at least 0.1% IA to 0.4% IA in the bone lesions of the patient within less than 20 hours after injection.

[0065] The present disclosure further relates to a method of diagnosing tumors in a patient in need thereof, the method comprising administering to the patient a radiopharmaceutical composition by injection, the radiopharmaceutical composition comprising a solution of Lu-PSMA I&T and ascorbic acid with a pH of 3.5 to 4.5. 177 A solution of Lu-PSMA I&T and ascorbic acid, wherein the radiopharmaceutical composition has an effective half-life of about 30 hours to 40 hours in the patient's whole body.

[0066] There are various improvements to the above features related to various aspects of the present disclosure. Additional features may also be incorporated into these different aspects. These improvements and additional features may exist individually or in any combination. For example, the various features discussed below in connection with one or more of the illustrated embodiments may be incorporated individually or in any combination into any of the above aspects of the present disclosure. Again, the brief overview presented above is only intended to familiarize the reader with certain aspects and background of the present disclosure, and does not limit the claimed subject matter. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] When reading the following detailed description with reference to the accompanying drawings, various features, aspects, and advantages of the present disclosure will become better understood. In the drawings, like characters throughout the drawings denote like parts, and in the drawings:

[0068] Figure 1A The structural formula of precursor PSMA I&T is presented.

[0069] Figure 1B The structural formula of the R isomer of 177 Lu-PSMA I&T is presented. However, PSMA I&T does not specify the enantiomeric purity of the R and S isomers.

[0070] Figure 2 is a flow chart representation of an exemplary method for preparing the disclosed radiopharmaceutical composition.

[0071] Figure 3A is in one embodiment 177 a flow chart of the synthesis procedure of Lu-PSMA I&T.

[0072] Figure 3B is in one embodiment 177 a flow chart of the synthesis procedure of Lu-PSMA I&T.

[0073] Figure 4Figure depicting an example product vial. The pharmaceutical product is delivered in a sterile, pyrogen-free glass vial of type 1 glass with a fluorinated butyl rubber septum. The septum is sealed with a crimped aluminum capsule. During transportation, the glass vial containing the radiopharmaceutical is kept in a lead-shielded container. The shipping container, including the lead hood and outer packaging, meets the requirements of type A (IAEA standard).

[0074] Figure 5 Shows the 177 radiochemical purity of Lu-PSMA I&T measured by HPLC at different time points.

[0075] Figure 6A and 6B Show the HPLC radiochromatograms of high-radioactivity-concentration formulations containing 42.5 mg / ml ascorbic acid at pH 7 ± 0.1 at 0 hours and 71 hours after EOS as detailed in Example 3.

[0076] Figure 7A and 7B Show the HPLC radiochromatograms of high-radioactivity-concentration formulations containing 42.4 mg / ml ascorbic acid at pH 4.5 ± 0.1 at 0 hours and 71 hours after the end of synthesis (“EOS”) as detailed in Example 3.

[0077] Figure 8A and 8B Show the HPLC radiochromatograms of high-radioactivity-concentration formulations containing 42.5 mg / ml ascorbic acid at pH 3.5 ± 0.1 at 0 hours and 90 hours after EOS as detailed in Example 3.

[0078] Figure 9A and 9B Show the HPLC radiochromatograms of low-radioactivity-concentration formulations containing 21 mg / ml ascorbic acid at pH 4.5 ± 0.1 at 0 hours and 92 hours after EOS as detailed in Example 3.

[0079] Figure 10A and 10B Show the HPLC radiochromatograms of low-radioactivity-concentration formulations containing 31 mg / ml ascorbic acid at pH 5 ± 0.1 at 0 hours and 71 hours after EOS as detailed in Example 3.

[0080] Figure 11A and 11B Show the HPLC radiochromatograms of low-radioactivity-concentration formulations containing 31 mg / ml ascorbic acid at pH 4.5 ± 0.1 at 0 hours and 93 hours after EOS as detailed in Example 3.

[0081] Figure 13Presents baseline and on-treatment disease state assessments and treatment decisions.

[0082] Figure 14 Presents the time-activity curves of the organs depicted in all regions of interest (ROIs) in one embodiment. The data (points) represent the mean of 12 analyzed subjects.

[0083] Figure 15 Presents the mean time-integrated activity coefficient (TIAC) and standard deviation (SD) of all depicted regions for the first 6 patients in one embodiment.

[0084] Figure 16 Presents the maximum intensity projection of SPECT / CT images acquired for one subject at 4 hours, 24 hours, 48 hours, and 168 hours post-injection in one embodiment.

[0085] Figure 17 Presents the mean TIAC and SD of all depicted regions for the first 12 patients in one embodiment.

[0086] Figure 18 Presents the SPLASH study design in one embodiment.

[0087] Figure 19 Presents the variation of RCP with radiolabeled pH.

[0088] Figure 20 Presents the variation of RCP with sodium ascorbate concentration (reaction buffer).

[0089] Figure 21 Presents the effect of reaction time and temperature on RCP.

[0090] Figure 22 Presents the variation of RCP with ascorbic acid content (T0 + 3d).

[0091] Figure 23 Presents the variation of CP with ascorbic acid content (T0 + 7d).

[0092] Figure 24 Presents 177 The radio-HPLC chromatogram of the Lu-PSMA I&T composition at formation / generation (i.e., T0), wherein the PSMA content is about 120 μg.

[0093] Figure 25 Presents the variation of RCP with reaction buffer duration.

[0094] Figure 26 Presents embodiments of the present invention.

[0095] Figure 27 Presents an organ depiction of a representative patient.

[0096] Figure 28 Presents the maximum intensity projection of the Cycle 1 SPECT / CT images.

[0097] Figure 29 Presents the whole body time-activity curve expressed as the injected activity fraction for each patient imaged at Cycle 1.

[0098] Figure 30 Presents the renal time-activity curve expressed as the injected activity fraction for each patient imaged at Cycle 1.

[0099] Figure 31 Presents the red marrow time-activity curve expressed as the injected activity fraction for each patient imaged at Cycle 1.

[0100] Figure 32 Presents the salivary gland time-activity curve expressed as the injected activity fraction for each patient imaged at Cycle 1.

[0101] Figure 33 Presents the GI tract time-activity curve expressed as the injected activity fraction for each patient imaged at Cycle 10.

[0102] Figure 34 Presents the liver time-activity curve expressed as the injected activity fraction for each patient imaged at Cycle 1.

[0103] Figure 35 Presents the spleen time-activity curve expressed as the injected activity fraction for each patient imaged at Cycle 1.

[0104] Figure 36 Presents the lacrimal gland time-activity curve expressed as the injected activity fraction for each patient imaged at Cycle 1.

[0105] Figure 37 Presents the Cycle 1 mean time-activity curve for all source organs on a semi-log scale.

[0106] Figure 38 Presents the plasma time-activity curve expressed as the injected activity fraction per liter for patients (n = 27) at Cycle 1 on a semi-log scale.

[0107] Figure 39 Presents the plasma time-activity curve expressed as the injected activity fraction per liter for patients (n = 15) at Cycle 3.

[0108] Figure 40 Presents the pH change over time for the eight formulations prepared in this report.

[0109] Figure 41 Presents the PSMA I&T and related substance concentrations of eight formulations prepared at different pH values at T0, T0 + 72 hours, and T0 + 168 hours (at the time of measurement).

[0110] Figure 42 Presents the HPLC-UV chromatograms of the formulation with an initial pH of 11.4 at (A) release (T0 hours) and (B) expiration (T0 + 72 hours).

[0111] Figure 43 Presents a plot of the RCP of seven formulations at expiration (T0 + 72 hours) versus the pH of the formulations measured at release (T0 hours).

[0112] Figure 44 Presents the RCP values of four formulations maintained for 7 days (T0 + 168 hours) at T0, T0 + 72 hours, and T0 + 168 hours.

[0113] Figure 45 Presents the HPLC-UV chromatograms of the formulation with an initial pH of 13.1 at (A) release (T0 hours) and (B) expiration (T0 + 72 hours), and the formulation with an initial pH of 11.4 at (C) expiration (T0 + 72 hours). (D) HPLC-radiometric chromatogram of the formulation with an initial pH of 13.1 at expiration (T0 + 72 hours).

[0114] Figure 46 Presents the HPLC-UV chromatograms of two formulations at T0 + 168 hours with initial pH values of (A) 3.6, (B) 4.1, (C) 4.5, and (D) 4.9.

[0115] Figure 47 Presents the effect of the molar ratio on the RCP.

[0116] Figure 48 Presents a plot of the RCP of four formulations prepared in this report versus the target DTPA concentration.

[0117] Figure 49 Presents the (A) DTPA content and (B) percentage of free [177Lu]Lu3+ of the formulations prepared in this report at release (T0) and expiration (T0 + 72 hours). The red dashed line in inset B indicates the 1% limit specification in the presence of free [177Lu]Lu3+.

[0118] Figure 50Presents the HPLC-UV chromatograms of formulations with target DTPA concentrations of 0, 10, 75, and 150 ppm at T0 + 72 hours. The relative peak area is calculated by dividing the area of the specified impurity peak by the sum of the areas of all integrated peaks.

[0119] Figure 51 Presents the HPLC-UV chromatogram of the formulation with a target DTPA concentration of 150 ppm at release (T0 hours). Detailed Description

[0120] It should be understood that, for the sake of brevity and clarity of illustration, where appropriate, reference numerals have been reused in different figures to indicate corresponding or similar elements. Additionally, numerous specific details have been set forth to provide a thorough understanding of the examples described herein. However, one of ordinary skill 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. Furthermore, the description should not be regarded as limiting the scope of the embodiments described herein. The figures are not necessarily drawn to scale, and the scale of certain parts may be enlarged to better show the details and features of the present disclosure.

[0121]

[0122] Disclosed herein is a small molecule inhibitor of PSMA, which has the desired properties of a large monoclonal antibody while having reduced negative aspects, such as poor permeability and toxicity. The radiopharmaceutical compositions disclosed herein comprise 177 Lu-PSMA I&T. 177 Lu-PSMA I&T is a short-lived radiolabeled substance and is formulated from the radiolabeled substance immediately after synthesis.

[0123] The headings included herein are for reference purposes only and are not intended to limit the present disclosure in any way.

[0124] Additional features and advantages of the present disclosure will be set forth in the following description, and in part will be obvious from the description, or may be learned by practicing the principles disclosed herein. The features and advantages of the present disclosure may be realized and obtained by means of the instrumentalities and combinations particularly pointed out in the appended claims. These and other features of the present disclosure will become more apparent from the following description and the appended claims, or may be learned by practicing 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.

[0125] I. Definitions

[0126] Certain definitions applicable to the entire foregoing disclosure will now be presented. 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 cover both the plural and the singular. Thus, the term "a mixture thereof" also pertains to "mixtures thereof."

[0127] Generally, the ranges provided are meant to include every specific range within the given range and combinations of sub-ranges between the given ranges. Thus, the range of 1 - 5 specifically includes 1, 2, 3, 4, and 5, as well as sub-ranges such as 2 - 5, 3 - 5, 2 - 3, 2 - 4, 1 - 4, etc. All ranges and values disclosed herein are inclusive and combinable. For example, any value or point described herein that falls within the ranges described herein can be used as the minimum or maximum value to derive sub-ranges, etc.

[0128] As used herein, "about" refers to a numerical value, including integers, fractions, percentages, etc., whether or not explicitly indicated. The term "about" generally refers to a numerical range that a person would consider equivalent to the recited value (e.g., having the same function or result), for example, ±0.5 - 1%, ±1 - 5%, or ±5 - 10% of the recited value.

[0129] 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 that is anchored in the cell membrane of prostate epithelial cells. PSMA is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer. The PSMA expression level is directly related to androgen independence, metastasis, and prostate cancer progression. Thus, PSMA is a promising molecular target for the diagnosis and therapy of metastatic prostate cancer.

[0130] As used herein, "lutetium-177" and " 177 Lu" are used interchangeably. 177 Lu is a β-emitting and γ-emitting radionuclide with a physical half-life of 6.7 days. 177 The maximum β-particle energy and the average β-particle energy of Lu are 0.498 MeV and 0.133 MeV, respectively. 177 The maximum soft tissue penetration depth and the average soft tissue penetration depth of Lu are 1.7 mm and 0.23 mm, respectively. 177 Lu has two major γ-emission lines: 113 keV (6% relative abundance) and 208 keV (11% relative abundance).

[0131] As used herein, " 177 Lu-PSMA-617" refers to a DOTA derivative of the Glu-urea-Lys motif that has been developed at the German Cancer Research Center (DKFZ) in Heidelberg, Germany for the treatment of patients with metastatic prostate cancer.

[0132] As used herein, " 177 Lu]Lu-PSMA I&T" and " 177 Lu-PSMA I&T" are used interchangeably and refer to 177 Lu-PSMA for imaging and therapy (I&T), a third-generation derivative of a 177 Lu-PSMA-compound that has been used herein. 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-heptaazatriacontane-1,3,7,26,37-pentacarboxylic acid; lutetium-177(III). The Figure 1B chemical structure of Lu-PSMA I&T is provided in 177 .

[0133] As used herein, the term "half-life" refers to the 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 has reached equilibrium or quasi-equilibrium. Typically, after intravenous administration to a sample population, the half-life of a drug in the blood can be determined graphically from the pharmacokinetic plot of the drug's blood concentration-time profile. The half-life can also be determined using mathematical calculations well known in the art. Additionally, as used herein, the term "half-life" also includes the "apparent half-life" of a drug. The apparent half-life can be a composite number that accounts for the effects of processes other than elimination, such as absorption, reuptake, or enterohepatic recirculation.

[0134] As used herein, "PRLT" refers to prostate radioligand therapy, and "RLT" refers to radioligand therapy. In this context, PRLT involves the systemic intravenous administration of a specific radiopharmaceutical composed of a β-emitting radionuclide chelated to a small molecule, with the aim of delivering cytotoxic radiation to cancer cells. All compositions and methods described herein can be used for PRLT and / or the treatment of cancer.

[0135] As used herein, the term "CRPC" refers to castration-resistant prostate cancer. In one example, a patient with CRPC may have a castrate serum testosterone < 50 μg / l or 1.7 nmol / l plus one of the following types of progression: biochemical progression or radiological progression, as defined below. All compositions and methods described herein can be used for CRPC and / or the treatment of cancer.

[0136] As used herein, the term "biochemical progression" refers to three consecutive increases in PSA spaced one week apart, resulting in two 50% increases relative to the nadir, and PSA > 2 μg / l.

[0137] As used herein, the term "RAC" refers to the radioactivity concentration.

[0138] As used herein, the term "radiological progression" refers to the appearance of new lesions; the detection of two or more new bone lesions on a bone scan or soft tissue lesions using the Response Evaluation Criteria in Solid Tumors (RECIST).

[0139] As used herein, the terms "end of synthesis", "after compounding", and "end of compounding" are used interchangeably to mean the time when the process of preparing the composition has been completed. The term can also include the time after a qualified person has performed quality control and released the drug product.

[0140] As used herein, the term "active agent" or "drug" refers to any chemical that elicits a biochemical reaction when administered to a human or animal. A drug can be used as a substrate or product of a biochemical reaction, or a drug can interact with a cell receptor and elicit a physiological reaction, or a drug can bind to a receptor and block the receptor from eliciting a physiological reaction.

[0141] The term "adverse event" (AE) is any adverse medical event that occurs in a subject who has received the investigational drug and that is not necessarily causally related to the treatment. An AE can be any adverse or unexpected sign (e.g., abnormal laboratory finding), symptom, or disease that is temporally associated with the use of the drug, whether or not it is considered related to the drug. The term includes any newly occurring event or a pre-existing condition whose severity or frequency has increased since the administration of the drug.

[0142] The terms "subject" or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, humans.

[0143] As used herein, "composition" refers to a radiopharmaceutical composition and vice versa. Thus, "composition" and "radiopharmaceutical composition" may be used interchangeably.

[0144] 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 treatment described herein) sufficient to achieve the stated purpose or otherwise achieve the effect of administering the therapy. The effective dose may be sufficient to reduce and / or ameliorate the progression, development, recurrence, severity, and / or duration of a given disease, disorder, or condition and / or its associated symptoms. The effective dose may be a "therapeutically effective dose," which refers to an amount sufficient to provide a therapeutic benefit (e.g., reducing or ameliorating the advancement or progression of a given disease, disorder, or condition, reducing or ameliorating the recurrence, development, or onset of a given disease, disorder, or condition, and / or improving or enhancing the prophylactic or therapeutic effect of another therapy). The compositions described herein in a therapeutically effective amount may also enhance the therapeutic efficacy of another therapeutic agent.

[0145] The terms "therapies," "therapy," and / or "treatment" refer to any regimen, method, and / or agent that can be used to prevent, treat, manage, and / or ameliorate a disease, disorder, or condition or one or more of its symptoms. In certain instances, the term refers to the radiopharmaceutical ligand therapy (RLT) described herein. The term "therapy" may refer to antiviral therapy, antibacterial therapy, antifungal therapy, anti-cancer therapy, biologic therapy, supportive therapy, and / or other therapies useful in treating, managing, preventing, or ameliorating a disease, disorder, or condition or one or more of its symptoms known to those of skill in the art, e.g., medical professionals such as physicians.

[0146] The term "cancer" refers to any physiological condition in a mammal characterized by unregulated cell growth. The cancers described herein include solid tumors and hematological (blood) cancers, including but not limited to mCRPC. "Hematological cancer" refers to any blood-borne cancer and includes, for example, myeloma, lymphoma, and leukemia. "Solid tumor" or "tumor" refers to a lesion and neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues that result in abnormal tissue growth. As used herein, "neoplastic" refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, that results in abnormal tissue growth.

[0147] The term "treating" or "treatment" refers to any sign of success or improvement in the progression, severity, and / or duration of a disease, pathology, or medical condition, including any objective or subjective parameter, such as abatement; remission; alleviation of symptoms or making an injury, pathology, or medical condition more tolerable to the patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; or improving the physical or mental health of the patient. In the context of treating cancer or a tumor, treatment can include slowing the growth of the tumor, stopping the growth of the tumor, shrinking or reducing the size of the tumor, preventing a change in the shape or morphology of the tumor, preventing the spread of the tumor (e.g., preventing metastasis), increasing survival rate and / or reducing the mortality rate.

[0148] The term "enhancing" means that, compared to a protein or cell before administration or exposure to the "treatment" or "therapy" described herein, after such administration, the function or activity of the protein or cell is increased or improved, or the overall health of the patient is improved.

[0149] The term "administering" refers to the act of delivering a pharmaceutical composition or radiopharmaceutical composition described herein into the body of a subject by a parenteral route (including intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration). Administration typically occurs after the onset of a disease, disorder, or medical condition or its symptoms, but in some cases, it can occur before the onset of a disease, disorder, or medical condition or its symptoms (e.g., administering to a patient susceptible to such a disease, disorder, or medical condition). For the intravenous administration route as used herein, "injection" and "intravenous infusion" can be used interchangeably.

[0150] II. Introduction

[0151] The present disclosure relates to a radiopharmaceutical composition comprising 177 Lu-PSMA I&T. In some embodiments, the composition can be formulated as a radiopharmaceutical solution for injection or intravenous infusion. The present disclosure further relates to a radiopharmaceutical composition comprising 177 Lu-PSMA I&T that is high-energy, high-purity, and / or low-toxicity, and acts as an anti-tumor agent for targeted radionuclide therapy.

[0152] The present disclosure also relates to methods for preparing radiopharmaceutical compositions. Methods for increasing the shelf life of radiopharmaceutical products are provided herein.

[0153] The present disclosure further relates to the properties of radiopharmaceutical compositions and methods of using radiopharmaceutical compositions.

[0154] 177 Lu-PSMA I&T is also known by its synonyms as follows: 177Lutetium-PSMA I&T, 177 Lu-ITG-PSMA-1, PSMA-TUM3, 177 Lu-DOTAGA-(I-y)fk(Sub-KuE) or 177 Lu-(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-heptaazatriacontane-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.

[0155] Labeled substance 177 Lutetium-PSMA I&T can be labeled with a lutetium-177 (T 1 / 2 = 6.6 days) solution without carrier addition. 177 Lutetium-PSMA I&T is a short-lived radioactively labeled substance, and the radioactively labeled substance dispensing product is immediately prepared after synthesis. Therefore, there are no specifications or batch analysis results for the labeled substance. Controls are performed on the labeled drug product.

[0156] Synthesized 177 Lutetium-PSMA I&T solution can be formulated in an injectable grade aqueous solution containing a stabilizer (such as ascorbic acid). Before dispensing the solution into vials, the solution can be sterilized by sterile filtration through a 0.22 μm filter. The formulated solution can be administered within 72 hours after the end of synthesis after quality control and release of the drug product. The formulated solution can be administered to a human patient in need by injection or intravenous infusion within 72 hours after the end of synthesis after quality control and release of the drug product.

[0157] Ascorbic acid can be used to minimize radiolytic decomposition of the radioactively labeled preparation. In addition to ascorbic acid, maintaining the pH of the drug product at 5 or below can keep the labeled product stable from radiolytic decomposition and extend its shelf life. Thus, on the other hand, the present disclosure further provides a dose formulation containing ascorbic acid with a pH of 5 or below, which improves the stability of the radiopharmaceutical composition against radiolytic decomposition, thereby improving the shelf life of the composition.

[0158] Stability enhancing conditions can be applied as early as possible during the manufacturing process. For example, in the labeled177 In the purification step of Lu-PSMA I&T, an ascorbic acid solution with a pH of 5 or lower (e.g., pH 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 used instead of water to minimize radiolytic damage.

[0159] When the composition is administered to a subject, it can result in lower blood toxicity and nephrotoxicity characteristics, thereby providing better efficacy and fewer adverse reactions than monoclonal antibody therapy and other comparable third-line therapies.

[0160] The composition is an improved composition because its shelf life after formulation is 72 hours or longer. Additionally, the improved composition has a radiochemical purity greater than 95% upon administration. That is, the improved formulation maintains a high level of radiochemical purity for 72 hours or longer after formulation. Thus, compared to other compositions containing 177 Lu-PSMA I&T, the improved formulation is suitable for administration for up to 24 hours, up to 72 hours, or longer.

[0161] III. Composition

[0162] Disclosed herein in particular is a composition that comprises 177 Lu, PSMA I&T, and one or more optional agents, including buffers and / or solvents. In one embodiment, the composition is suitable for administration to a human patient in need.

[0163] In one embodiment, the radiochemical purity (RCP) of the composition upon administration is 95% or higher. In another embodiment, the radiochemical purity (RCP) of the composition upon administration is 97% or higher. In another embodiment, the radiochemical purity (RCP) of the composition upon administration is 97.5% or higher. In another embodiment, the radiochemical purity (RCP) of the composition upon administration is 98.0% or higher, 98.5% or higher, 99.0% or higher, or 99.5% or higher.

[0164] In one embodiment, the radiochemical purity (RCP) of the composition is 95% or higher 72 hours after production. In another embodiment, the radiochemical purity (RCP) of the composition is 97% or higher 72 hours after production. In another embodiment, the radiochemical purity (RCP) of the composition is 97.5% or higher 72 hours after production. In another embodiment, the radiochemical purity (RCP) of the composition is 98.0% or higher, 98.5% or higher, 99.0% or higher, or 99.5% or higher 72 hours after production. In another embodiment, the radiochemical purity (RCP) of the composition is 90% or higher, 91% or higher, 92% or higher, 93% or higher, 94% or higher, 95% or higher 7 days after production.

[0165] In one embodiment, the radiochemical purity (RCP) of the composition is 96.0% or higher, 96.5% or higher, 97.0% or higher, 97.5% or higher, 98.0% or higher, 98.5% or higher, 99.0% or higher, or 99.5% or higher 7 days after production.

[0166] 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.

[0167] Further disclosed herein is a radiopharmaceutical composition or formulation, the radiopharmaceutical composition or formulation comprising a dose of 177 Lu-PSMA I&T and at least one of the following: a stabilizer, an antioxidant, a pH regulator, a metal ion chelator, water, or a combination thereof.

[0168] In one specific embodiment, the stabilizer is ascorbic acid. In another embodiment, the antioxidant can be ethanol, ascorbic acid, gentisic acid, or a combination thereof. In another embodiment, the pH regulator includes, but is not limited to, sodium hydroxide, sodium bicarbonate, hydrochloric acid, or a combination thereof. In yet another embodiment, the chelator can be EDTA or DTPA. In another specific embodiment, the stabilizer does not contain ethanol (i.e., 0% ethanol, less than 0.5% ethanol, or less than 1.0% ethanol (w / w) in the composition).

[0169] In one embodiment, the pharmaceutical product or radiopharmaceutical composition (or formulation) can be a dose of 177Sterile filtered radiopharmaceutical solution of Lu-PSMA I&T. For example, the total amount of ascorbic acid in the solution can be from about 25 mg / mL to about 65 mg / mL, and the total amount of ethanol in the solution can be from about 3.8% (v / v) to about 7.5% (v / v). In some embodiments, the total amount of ascorbic acid in the solution is from about 21 mg / mL to about 42.5 mg / mL. 177 Lu-PSMA I&T is present in a sufficient amount of radioactivity for the intended use. Experiments with different dose formulations have shown that at a pH of about 4.5 and a radioactivity concentration of about 640 MBq / ml or less, containing about 31 mg / ml of ascorbic acid 177 The Lu-PSMA I&T formulation composition can provide adequate radiochemical stability for four days. The adequate radiochemical stability mentioned herein is a radiopharmaceutical composition, wherein 177 The radiochemical purity of Lu-PSMA I&T at the time of administration is at least 95%, 95.5% or higher, 96.5% or higher, 97.0% or higher, 97.5% or higher, 98.0% or higher, 98.5% or higher, 99.0% or higher or 99.5% or higher.

[0170] In one embodiment, the radiopharmaceutical composition is a sterile filtered radiopharmaceutical solution containing a small amount of Lu-PSMA I&T in an aqueous solution of ascorbic acid and ethanol. 177 In another embodiment, the radiopharmaceutical composition is a sterile filtered radiopharmaceutical solution containing a small amount of Lu-PSMA I&T in an aqueous solution of ascorbic acid without ethanol. 177 For example, the radiopharmaceutical composition can be a sterile filtered radiopharmaceutical solution containing a certain microdose of Lu-PSMA I&T in an aqueous solution of ascorbic acid and DTPA or EDTA (e.g., containing ethanol or in the complete absence of ethanol). 177 The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk product varies according to the starting radioactivity of the Lu introduced. 177 Lu.

[0171] One aspect of the present disclosure provides a radiopharmaceutical composition having a pH of from about 3 to about 9, from about 4 to about 9, from about 5 to about 9, from about 3 to about 8, from about 4 to about 8, from about 3 to about 5, or from about 5 to about 8. The pH of the radiopharmaceutical composition can 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, 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.

[0172] A pH of 5 or less can render the radiopharmaceutical composition stable against radiolytic decomposition and can extend its shelf life.

[0173] In one embodiment, the pH of the radiopharmaceutical composition is from about 3 to about 5. This pH range can render the radiopharmaceutical composition stable against radiolytic decomposition and can extend its shelf life. In yet another embodiment, compared to a known radiopharmaceutical composition of 177 Lu-PSMA I&T having a higher pH value and which can contain gentisic acid, a radiopharmaceutical composition containing ascorbic acid and having a pH of from about 3.5 to about 5 has improved stability and an extended shelf life. In other embodiments, the radiopharmaceutical composition may not contain gentisic acid (i.e., be free of gentisic acid).). In yet another embodiment, a radiopharmaceutical composition containing ascorbic acid and having a pH of from about 4.0 to about 4.5 has improved stability and an extended shelf life

[0174] The pH of the radiopharmaceutical composition can range from 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 to 3.5, 3.25 to 3.5, 3.5 to 3.55, 3.5 to 3.6, 3.55 to 3.6, 3.6 to 3.65, 3.6 to 3.7, 3.65 to 3.7, 3.7 to 3.75, 3.5 to 3.75, 3.7 to 3.8, 3.75 to 3.8, 3.8 to 3.85, 3.8 to 3.9, 3.85 to 3.9, 3.9 to 3.95, 3.9 to 4.0, 3.95 to 4.0, 3.5 to 4.0, 3.75 to 4.0, 4.0 to 4.05, 4.0 to 4.1, 4.05 to 4.1, 4.1 to 4.15, 4.1 to 4.2, 4.15 to 4.2, 3.5 to 4.2, 4.2 to 4.25, 4.0 to 4.25, 4.2 to 4.3, 4.25 to 4.3, 4.3 to 4.35, 4.3 to 4.4, 4.35 to 4.4, 4.4 to 4.45, 4.4 to 4.5, 4.45 to 4.5, 4.25 to 4.5, 4.0 to 4.5, 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 instances, the pH of the radiopharmaceutical composition can be adjusted to a final pH of 3.0, 3.5, 4.0, 4.5 or 5.0. In some embodiments, including the pH values and ranges listed above, the pH values include ±0.05, ±0.10, ±0.15, ±0.20 or ±0.25.

[0175] In another embodiment, the purity of the radiopharmaceutical composition or formulation is at least about 90%, at least about 95%, at least about 97% or at least about 99%. In another embodiment, the purity of the radiopharmaceutical composition or formulation is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 99.5%.

[0176] In another embodiment, the purity of the radiopharmaceutical composition or formulation, as measured by HPLC, TLC, or liquid chromatography, is at least about 90%, at least about 95%, at least about 97%, or at least about 99%. In another embodiment, the purity of the radiopharmaceutical composition or formulation, as measured by HPLC or TLC, is 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%. In some instances, the radiochemical purity of the radiopharmaceutical composition at the time of administration can be 95.0% or higher, 95.5% or higher, 96.0% or higher, 96.5% or higher, 97.0% or higher, 97.5% or higher, 98.0% or higher, 98.5% or higher, 99.0% or higher, or 99.5% or higher. Figure 5 Shows the radiochemical purity of formulations prepared at different pH values.

[0177] 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.

[0178] In a specific embodiment, the purity of the radiopharmaceutical composition or formulation measured by HPLC or TLC at 0 hours after EOS is at least about 99%. In another specific embodiment, the purity of the radiopharmaceutical composition or formulation measured by HPLC or TLC at 24 hours after EOS is at least about 96.5%, at 46 hours after EOS is at least about 93%, at 67 hours after EOS is at least about 95%, and at 92 hours after EOS is at least about 96%.

[0179] In another embodiment, radioactivity is measured in a dose calibrator. 177 The radioactive amount of Lu-PSMA I&T is determined when the dose is dispensed prior to patient administration.

[0180] In yet another embodiment, 177 The radiochemical purity of Lu-PSMA I&T is determined by liquid chromatography and thin layer chromatography with radioactive detection.

[0181] In one embodiment, the bacterial endotoxin content of each batch is determined using a PTS tester (Ph Eur method D or USP <85>) before release, and sterility is determined in accordance with Ph Eur and USP <71>.

[0182] In one embodiment, the radiopharmaceutical composition or formulation is stored at a temperature of from about +5°C to +55°C, +5°C to +40°C, from about +10°C to +35°C or from 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.

[0183] Another aspect of the present disclosure provides a radioactive content of from about 70% to 130%. The radioactive content of the radiopharmaceutical composition can be from about 90% to 125%, 90% to 120%, 90% to 115% or 90% to 110%.

[0184] 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%.

[0185] Another aspect of the present disclosure provides a radiopharmaceutical composition having an average whole body effective dose of about 23 ± 20 Gy (3.3 Gy / GBq) and average absorbed organ doses for bone, lymph node, liver and lung metastases 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), respectively.

[0186] In some embodiments, the low radioactivity concentration (“low RAC”) of the radiopharmaceutical composition can be from about 563 MBq / ml to about 734 MBq / ml. For example, the radiopharmaceutical composition can have low radioactivity, which can 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 solution. In other embodiments, the low radioactivity concentration of the radiopharmaceutical composition can be 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 low radioactivity concentration of the radiopharmaceutical composition can be from about 550 MBq / ml to about 575 MBq / ml, from about 575 MBq / ml to about 600 MBq / ml, from about 600 MBq / ml to about 625 MBq / ml, from about 625 MBq / ml to about 650 MBq / ml, from about 650 MBq / ml to about 675 MBq / ml, from about 675 MBq / ml to about 700 MBq / ml, from about 700 MBq / ml to about 725 MBq / ml, from about 725 MBq / ml to about 750 MBq / ml, or from about 625 MBq / ml to about 650.

[0187] In additional embodiments, the high radioactivity concentration (“high RAC”) of the radiopharmaceutical composition can be from about 1,270 MBq / ml to about 1,311 MBq / ml. For example, the radiopharmaceutical composition can have a high radioactivity that can 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 solution. In other embodiments, the high radioactivity concentration of the radiopharmaceutical composition can be 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, 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 1,290 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 high radioactivity concentration of the radiopharmaceutical composition can be from about 1,000 MBq / ml to about 1,400 MBq / ml, from about 1,050 MBq / ml to about 1,350 MBq / ml, from about 1,100 MBq / ml to about 1,300 MBq / ml, from about 1,150 MBq / ml to about 1,250 MBq / ml, from about 1,200 MBq / ml to about 1,300 MBq / ml, from about 1,250 MBq / ml to about 1,350 MBq / ml, or from about 1,250 MBq / ml to about 1,300 MBq / ml.

[0188] (i) 177 Lu-PSMA I&T

[0189] Present in the radiopharmaceutical composition 177 The total amount of Lu-PSMA I&T can and will vary. Figure 1A and 1B Respectively show the precursor PSMA I&T and 177 The chemical structures of Lu-PSMA I&T.

[0190] In one embodiment, the mass of the radiopharmaceutical ingredient ( 177 Lu-PSMA I&T) in each vial of the pharmaceutical 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. In yet another embodiment, the mass of the radiopharmaceutical ingredient ( 177 Lu-PSMA I&T) in each vial of the pharmaceutical product 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, 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 of 177 Lu-PSMA I&T.

[0191] In one embodiment, the total amount of 177 Lu-PSMA I&T present in the pharmaceutical composition can and will vary. During the labeling process, the PSMA I&T ligand can be labeled with trace metals present to form a chelated trace metal-PSMA I&T complex (i.e., "M-PSMA I&T"). Excess PSMA I&T present during the labeling process may remain unlabeled with 177 Lu or trace metals. The amounts of M-PSMA I&T and unlabeled PSMA I&T in the composition are hereinafter referred to as "related substances" or "RS". Then, the composition can contain both 177Lu-PSMA I&T, M-PSMA I&T, and unlabeled PSMA I&T. In one embodiment, the PSMA content comprising PSMA I&T and related substance (RS) is 250 μg / dose ±15%, ±10%, or ±5%. In another embodiment, the PSMA I&T content is from 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 from 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 from 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 from about 40 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%, from 50 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%, from 60 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%, or from 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 from about 40 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%, from 50 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%, from 60 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%, or from 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 from about 40 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%, from 50 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%, from 60 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%, or from 70 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%.

[0192] In another embodiment, the composition described herein comprises 177The composition of Lu-PSMA I&T may comprise the following PSMA I&T contents: from about 120 μg / dose to about 250 μg / dose, from about 130 μg / dose to about 250 μg / dose, from about 140 μg / dose to about 250 μg / dose, from about 150 μg / dose to about 250 μg / dose, from about 160 μg / dose to about 250 μg / dose, from about 170 μg / dose to about 250 μg / dose, from about 180 μg / dose to about 250 μg / dose, from about 190 μg / dose to about 250 μg / dose, from about 200 μg / dose to about 250 μg / dose, from about 210 μg / dose to about 250 μg / dose, from about 220 μg / dose to about 250 μg / dose, from about 230 μg / dose to about 250 μg / dose or from about 240 μg / dose to about 250 μg / dose. In another embodiment, the composition comprising 177 The composition of Lu-PSMA I&T may comprise the following PSMA I&T contents: from about 100 μg / dose to about 120 μg / dose, from about 105 μg / dose to about 120 μg / dose, from about 110 μg / dose to about 120 μg / dose or from about 115 μg / dose to about 120 μg / dose. In another embodiment, the composition comprising 177 The composition of Lu-PSMA I&T may comprise the following PSMA I&T contents: from about 40 μg / dose to about 100 μg / dose, from about 45 μg / dose to about 100 μg / dose, from about 50 μg / dose to about 100 μg / dose, from about 55 μg / dose to about 100 μg / dose, from about 60 μg / dose to about 100 μg / dose, from about 65 μg / dose to about 100 μg / dose, from about 70 μg / dose to about 100 μg / dose, from about 75 μg / dose to about 100 μg / dose, from about 80 μg / dose to about 100 μg / dose, from about 85 μg / dose to about 100 μg / dose, from about 90 μg / dose to about 100 μg / dose or from about 95 μg / dose to about 100 μg / dose. In another embodiment, the composition comprising 177 The composition of Lu-PSMA I&T may comprise the following PSMA I&T contents: from about 45 μg / dose to about 95 μg / dose, from 50 μg / dose to about 100 μg / dose, from 55 μg / dose to about 95 μg / dose, from 60 μg / dose to about 95 μg / dose, from 65 μg / dose to about 95 μg / dose, from 70 μg / dose to about 95 μg / dose, from 75 μg / dose to about 95 μg / dose, from 80 μg / dose to about 95 μg / dose, from 85 μg / dose to about 95 μg / dose or from about 90 μg / dose to about 95 μg / dose. In another embodiment, the composition comprising 177The composition of Lu-PSMA I&T may comprise the following PSMA I&T content: from about 40 μg / dose to about 90 μg / dose, from about 45 μg / dose to about 90 μg / dose, from about 50 μg / dose to about 90 μg / dose, from about 55 μg / dose to about 90 μg / dose, from about 60 μg / dose to about 90 μg / dose, from about 65 μg / dose to about 90 μg / dose, from about 70 μg / dose to about 90 μg / dose, from about 75 μg / dose to about 90 μg / dose, from about 80 μg / dose to about 90 μg / dose or from about 85 μg / dose to about 90 μg / dose. In another embodiment, the composition comprising 177 The composition of Lu-PSMA I&T may comprise the following PSMA I&T content: from about 40 μg / dose to about 85 μg / dose, from about 45 μg / dose to about 85 μg / dose, from about 50 μg / dose to about 85 μg / dose, from about 55 μg / dose to about 85 μg / dose, from about 60 μg / dose to about 85 μg / dose, from about 65 μg / dose to about 85 μg / dose, from about 70 μg / dose to about 85 μg / dose, from about 75 μg / dose to about 85 μg / dose, from about 80 μg / dose to about 85 μg / dose. In another embodiment, the composition comprising 177 The composition of Lu-PSMA I&T may comprise the following PSMA I&T content: from about 40 μg / dose to about 80 μg / dose, from about 45 μg / dose to about 80 μg / dose, from about 50 μg / dose to about 80 μg / dose, from about 55 μg / dose to about 80 μg / dose, from about 60 μg / dose to about 80 μg / dose, from about 65 μg / dose to about 80 μg / dose, from about 70 μg / dose to about 80 μg / dose or from about 75 μg / dose to about 80 μg / dose. In another embodiment, the composition comprising 177 The composition of Lu-PSMA I&T may comprise the following PSMA I&T content: from about 40 μg / dose to about 75 μg / dose, from about 45 μg / dose to about 75 μg / dose, from about 50 μg / dose to about 75 μg / dose, from about 55 μg / dose to about 75 μg / dose, from about 60 μg / dose to about 75 μg / dose, from about 65 μg / dose to about 75 μg / dose, from about 70 μg / dose to about 75 μg / dose.

[0193] In one embodiment, the amount of PSMA I&T present in the pharmaceutical composition is from about 30 μg to 120 μg / dose, 35 μg to 120 μg / dose, 40 μg to 120 μg / dose, 45 μg to 120 μg / dose, 50 μg to 120 μg / dose, 55 μg to 120 μg / dose, 60 μg to 120 μg / dose, 65 μg to 120 μg / dose, 70 μg to 120 μg / dose, 75 μg to 120 μg / dose, 85 μg to 120 μg / dose, 90 μg to 120 μg / dose, 95 μg to 120 μg / dose, 100 μg to 120 μg / dose, 105 μg to 120 μg / dose, 110 μg to 120 μg / dose or 115 μg to 120 μg / dose. In one embodiment, the amount of PSMA I&T present in the pharmaceutical composition is from about 30 μg to 100 μg / dose, 35 μg to 100 μg / dose, 40 μg to 100 μg / dose, 45 μg to 100 μg / dose, 50 μg to 100 μg / dose, 55 μg to 100 μg / dose, 60 μg to 100 μg / dose, 65 μg to 100 μg / dose, 70 μg to 100 μg / dose, 75 μg to 100 μg / dose, 85 μg to 100 μg / dose or 90 μg to 100 μg / dose. In another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is from about 30 μg to 90 μg / dose, 35 μg to 90 μg / dose, 40 μg to 90 μg / dose, 45 μg to 90 μg / dose, 50 μg to 90 μg / dose, 55 μg to 90 μg / dose, 60 μg to 90 μg / dose, 65 μg to 90 μg / dose, 70 μg to 90 μg / dose, 75 μg to 90 μg / dose or 85 μg to 90 μg / dose. In another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is from about 30 μg to 80 μg / dose, 35 μg to 80 μg / dose, 40 μg to 80 μg / dose, 45 μg to 80 μg / dose, 50 μg to 80 μg / dose, 55 μg to 80 μg / dose, 60 μg to 80 μg / dose, 65 μg to 80 μg / dose, 70 μg to 80 μg / dose or 75 μg to 80 μg / dose. In yet another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is from about 30 μg to 70 μg / dose, 35 μg to 70 μg / dose, 40 μg to 70 μg / dose, 45 μg to 70 μg / dose, 50 μg to 70 μg / dose, 55 μg to 70 μg / dose, 60 μg to 70 μg / dose or 65 μg to 70 μg / dose.

[0194] In one embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 30 μg to 120 μg / dose, 35 μg to 120 μg / dose, 40 μg to 120 μg / dose, 45 μg to 120 μg / dose, 50 μg to 120 μg / dose, 55 μg to 120 μg / dose, 60 μg to 120 μg / dose, 65 μg to 120 μg / dose, 70 μg to 120 μg / dose, 75 μg to 120 μg / dose, 85 μg to 120 μg / dose, 90 μg to 120 μg / dose, 95 μg to 120 μg / dose, 100 μg to 120 μg / dose, 105 μg to 120 μg / dose, 110 μg to 120 μg / dose or 115 μg to 120 μg / 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 / dose, 35 μg to 100 μg / dose, 40 μg to 100 μg / dose, 45 μg to 100 μg / dose, 50 μg to 100 μg / dose, 55 μg to 100 μg / dose, 60 μg to 100 μg / dose, 65 μg to 100 μg / dose, 70 μg to 100 μg / dose, 75 μg to 100 μg / dose, 85 μg to 100 μg / dose or 90 μg to 100 μg / 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 / dose, 35 μg to 90 μg / dose, 40 μg to 90 μg / dose, 45 μg to 90 μg / dose, 50 μg to 90 μg / dose, 55 μg to 90 μg / dose, 60 μg to 90 μg / dose, 65 μg to 90 μg / dose, 70 μg to 90 μg / dose, 75 μg to 90 μg / dose or 85 μg to 90 μg / dose. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 30 μg to 80 μg / dose, 35 μg to 80 μg / dose, 40 μg to 80 μg / dose, 45 μg to 80 μg / dose, 50 μg to 80 μg / dose, 55 μg to 80 μg / dose, 60 μg to 80 μg / dose, 65 μg to 80 μg / dose, 70 μg to 80 μg / dose or 75 μg to 80 μg / dose. In yet another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 30 μg to 70 μg / dose, 35 μg to 70 μg / dose, 40 μg to 70 μg / dose, 45 μg to 70 μg / dose, 50 μg to 70 μg / dose, 55 μg to 70 μg / dose, 60 μg to 70 μg / dose or 65 μg to 70 μg / dose.

[0195] In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is from about 55 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 from about 75 μg to 100 μg per dose.

[0196] In one embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is from 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 from 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 from 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 from 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 from about 100 μg to 80 μg per dose.

[0197] In one embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is from 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 from 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 from about 115 μg to 130 μg per dose

[0198] In one embodiment, the amount of PSMA I&T and related substances (RS) present in each vial of 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. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 80 μg.

[0199] 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.

[0200] In one embodiment, the total volume of the vial containing PSMA I&T and related substances (RS) is about 5 mL to 30 mL. In another embodiment, the total volume of the vial containing PSMA I&T and related substances (RS) is about 10 mL to 20 mL. In another embodiment, the total volume of the vial containing PSMA I&T and related substances (RS) is about 15 mL to 20 mL. In another embodiment, the total volume of the vial containing PSMA I&T and related substances (RS) is about 15 mL to 17 mL. In another embodiment, the total volume of the vial containing PSMA I&T and related substances (RS) is about 15 mL.

[0201] In one embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 3 μg / mL to 8 μg / mL. In another embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 4 μg / mL to 7 μg / mL. In another embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 4.5 μg / mL to 6.5 μg / mL. In another embodiment, the concentration of PSMA I&T and related substances (RS) per vial is 4.8 μg / mL to 6 μg / mL.

[0202] 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.

[0203] In one embodiment, the PSMA I&T in the composition and 177 the molar ratio of Lu is 5.0:1.0 to 12.0:1.0. In another embodiment, the PSMA I&T in the composition and 177The molar ratio of Lu is from 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. In another embodiment, the PSMA I&T in the composition and 177 The molar ratio of Lu is from 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 to 7.7:1.0, 4.0:1.0 to 7.6:1.0, 4.0:1.0 to 7.5:1.0, 4.0:1.0 to 7.4:1.0, 4.0:1.0 to 7.3:1.0, 4.0:1.0 to 7.2:1.0, 4.0:1.0 to 7.1:1.0, 4.0:1.0 to 7.0:1.0, 4.0:1.0 to 6.5:1.0 or 4.0:1.0 to 6.0:1.0.

[0204] In one embodiment, the PSMA I&T in the composition and 177 The molar ratio of Lu at the time of administration is from 3.0:1.0 to 11.0:1.0. In another embodiment, the PSMA I&T in the composition and 177The molar ratio of Lu is from 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.

[0205] In one embodiment, the PSMA I&T in the composition and 177 the molar ratio of Lu at the time of administration is from 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. In another embodiment, the PSMA I&T in the composition and 177 the molar ratio of Lu is from 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.

[0206] In one embodiment, the PSMA I&T in the composition and 177 the molar ratio of Lu is from 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. In another embodiment, the PSMA I&T in the composition and 177 the molar ratio of Lu is from 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. In another embodiment, the PSMA I&T in the composition and 177The molar ratio of Lu is from 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. In another embodiment, PSMA I&T in the composition and 177 The molar ratio of Lu is from 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. In another embodiment, PSMA I&T in the composition and 177 The molar ratio of Lu is from 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 5.7.0:1.0, or 5.4:1.0 to 5.6:1.0. In another embodiment, PSMA I&T in the composition and 177 The molar ratio of Lu is from 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.

[0207] In another embodiment, PSMA I&T in the composition and 177 The molar ratio of Lu is from 4.0:1.0 to 5.0:1.0, from about 4.0:1.0 to about 4.5:1.0, from 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. In one embodiment, PSMA I&T in the composition and 177 The molar ratio of Lu is from about 5.0:1.0 to about 5.5:1.0, from about 5.5:1.0 to about 6.0:1.0, from about 6.0:1.0 to about 6.5:1.0, from about 6.5:1.0 to about 7.0:1.0, from about 7.0:1.0 to about 7.5:1.0, from about 7.5:1.0 to about 8.0:1.0, from about 8.0:1.0 to about 8.5:1.0, from about 8.5:1.0 to about 9.0:1.0, from about 9.0:1.0 to about 9.5:1.0, from about 9.5:1.0 to about 10.0:1.0, from about 10.0:1.0 to about 10.5:1.0, from about 10.5:1.0 to about 11.0:1.0, from about 11.0:1.0 to about 11.5:1.0, or from about 11.5:1.0 to about 12.0:1.0.

[0208] In some embodiments, present in the radiopharmaceutical composition177 The total amount of Lu-PSMA I&T can range from 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. In another embodiment, the 177 total amount of Lu-PSMA I&T in the radiopharmaceutical composition can range from about 0.5 μg / ml to about 1.5 μg / ml. In various embodiments, the 177 total amount of Lu-PSMA I&T present in the radiopharmaceutical composition 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..

[0209] In some embodiments, the 177 total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can range from 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 177 total amount of Lu-PSMA I&T in the radiopharmaceutical composition can range from about 0.5 μg / ml to about 1.5 μg / ml.

[0210] In some embodiments, the 177 total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 2.0 μg / ml. In other embodiments, the 177 total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 4.0 μg / ml. In other embodiments, the 177The total amount of Lu-PSMA I&T can be less than 5.0 μg / ml. In other embodiments, the 177 total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 6.0 μg / ml. In other embodiments, the 177 total amount of Lu-PSMA I&T can be less than 3.0 μg / ml.

[0211] In some embodiments, the 177 total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can range from 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. In another embodiment, the 177 total amount of Lu-PSMA I&T in the radiopharmaceutical composition can range from about 5 μg / ml to about 15 μg / ml. In various embodiments, the 177 total amount of Lu-PSMA I&T present in the radiopharmaceutical composition 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.

[0212] The 177 radioactivity / volume of Lu-PSMA I&T in the composition can be adjusted according to the dose intensity. In one embodiment, the composition can comprise a 1 ml solution containing 0.5 GBq (13.5 mCi) of 177 Lu-PSMA I&T. In other words, the composition can comprise a 20 ml solution containing 10 GBq (270 mCi) of 177 Lu-PSMA I&T. In another embodiment, the composition can comprise a 1 ml solution containing 1 GBq (27 mCi) of 177 Lu-PSMA I&T. In other words, the composition can comprise a 10 ml solution containing 10 GBq (270 mCi) of 177 Lu-PSMA I&T at the time of synthesis.

[0213] In one embodiment, the 177The radiochemical concentration of 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. In another embodiment, in the radiopharmaceutical composition 177 The radiochemical concentration of Lu-PSMA I&T is from about 5 mCi / ml to about 30 mCi / ml, from about 10 mCi / ml to about 20 mCi / ml, from about 10 mCi / ml to about 15 mCi / ml, from about 10 mCi / ml to about 20 mCi / ml, or from about 13 mCi / ml to about 30 mCi / ml. In a specific embodiment, in the radiopharmaceutical composition 177 The radiochemical 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. In another embodiment, in the radiopharmaceutical composition 177 The radiochemical concentration of Lu-PSMA I&T is from about 10 mCi / ml to about 15 mCi / ml, from about 10 mCi / ml to about 20 mCi / ml.

[0214] In one embodiment, in each vial of the radiopharmaceutical composition 177 The radioactivity of 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. In another embodiment, in each vial of the radiopharmaceutical composition 177 The radioactivity of Lu-PSMA I&T is from about 10 mCi to about 400 mCi. In a specific embodiment, in each vial of the radiopharmaceutical composition 177 The radioactivity of Lu-PSMA I&T is about 27 mCi, 150 mCi, about 160 mCi, about 170 mCi, about 180 mCi, about 190 mCi, about 200 mCi, about 250 mCi, about 270 mCi, about 300 mCi, about 313 mCi, about 318 mCi, about 338 mCi, about 345 mCi, about 346 mCi, about 354 mCi, about 360 mCi, about 370 mCi, about 380 mCi, about 390 mCi.

[0215] In yet another embodiment, 177The standard radioactivity concentration of the Lu-PSMA I&T drug product at the end of production is approximately 12 mCi / ml or approximately 32 mCi / ml. In one embodiment, 177 The standard radioactivity concentration of the Lu-PSMA I&T drug product at the end of production is approximately 13.5 mCi / ml or approximately 27 mCi / ml.

[0216] (ii) Antioxidant

[0217] The antioxidant can act as a buffer and / or a stabilizer. The total amount of antioxidant in the radiopharmaceutical composition can 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. In other words, 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 / ml.

[0218] In one embodiment, there can be ≤10 mg / ml, ≤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 antioxidant.

[0219] In one embodiment, the antioxidant can be ascorbic acid and / or ascorbate. Ascorbic acid and / or ascorbate can minimize or reduce the radiolytic decomposition of the radiolabeled composition.

[0220] In some embodiments, the range of ascorbic acid present in the radiopharmaceutical composition can be from about 10 mg to about 50 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, or about 35 mg to about 45 mg per ml. In another embodiment, the range of ascorbic acid in the radiopharmaceutical composition can be from about 5 mg to about 50 mg per ml. In another embodiment, there can be ≤10 mg / ml, ≤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 ascorbic acid or ascorbate.

[0221] In various embodiments, the ascorbic acid 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 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 from 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.

[0222] 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, about 10 mg / ml to about 75 mg / ml, about 10 mg / ml to about 70 mg / ml, about 15 mg / ml to about 80 mg / ml, about 15 mg / ml to about 75 mg / ml, about 15 mg / ml to about 70 mg / ml, about 20 mg / ml to about 80 mg / ml, about 20 mg / ml to about 75 mg / ml, about 25 mg / ml to about 40 mg / ml, about 20 mg / ml to about 80 mg / ml, about 20 mg / ml to about 75 mg / ml, or about 20 mg / ml to about 70 mg / ml.

[0223] 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.

[0224] In at least one embodiment, the total amount of ascorbic acid in the radiopharmaceutical composition can be about 31 mg / ml. In additional embodiments, the total amount of ascorbic acid in the radiopharmaceutical composition can 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.

[0225] (iii) Stabilizer

[0226] The stabilizer can be separated from the antioxidant. The total amount of stabilizer present in the radiopharmaceutical composition can and will vary. The stabilizer can further be used to limit or reduce radiolytic decomposition. The stabilizer can also act as a vehicle for the composition.

[0227] Stabilizers include, but are not limited to, ethanol, para-aminobenzoic acid (PABA), dihydroxybenzoic acid (gentisate compound), gentisic acid, cysteine, selenomethionine, ascorbic acid / sodium ascorbate, methionine, and combinations thereof. In one embodiment, the stabilizer includes ascorbic acid and sodium ascorbate.

[0228] In some embodiments, the stabilizer is ethanol. Ethanol can be present in the pharmaceutical composition at 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), about 3.5% (v / v) to 4.5% (v / v), about 4% (v / v) to 5% (v / v), about 4.5% (v / v) to 5.5% (v / v), about 5% (v / v) to 6% (v / v), about 5.5% (v / v) to 6.5% (v / v), about 6% (v / v) to 7% (v / v), about 6.5% (v / v) to 7.5% (v / v), or about 7% (v / v) to 8% (v / v). In some embodiments, the pharmaceutical composition contains zero (0.00% v / v) ethanol (i.e., ethanol may be absent in the pharmaceutical composition).

[0229] In one embodiment, the total amount of ethanol present in the radiopharmaceutical composition is about 3% (v / v) to about 8% (v / v), or 2% (v / v) to about 4% (v / v), or 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).

[0230] In another embodiment, there can be ≤10 mg / ml, ≤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 gentisic acid or gentisate.

[0231] In at least one instance, the radiopharmaceutical composition comprises 3.8% (v / v) ethanol. In another instance, the radiopharmaceutical composition comprises 7.5% (v / v).

[0232] In other words, 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.

[0233] In some embodiments, the total amount of ethanol present in the radiopharmaceutical composition can range from about 20 mg to about 35 mg per ml. In another embodiment, the total amount of ethanol in the radiopharmaceutical composition can range from about 43 mg to about 63 mg per ml.

[0234] In some embodiments, the total amount of ethanol present in the radiopharmaceutical composition can range from about 25 mg to 80 mg, about 30 mg to 40 mg, about 40 mg to 50 mg, about 50 mg to 60 mg, about 60 mg to 70 mg or about 70 mg to 80 mg per ml. In another embodiment, the total amount of ethanol in the radiopharmaceutical composition can range from about 30 mg to about 60 mg per ml.

[0235] In additional embodiments, the ratio of ethanol in the radiopharmaceutical composition can be about 300 mg per 10 ml or about 30 mg / ml. In another embodiment, the ratio of ethanol in the radiopharmaceutical composition can be about 200 mg per 10 ml. In still another embodiment, the ratio of ethanol in the radiopharmaceutical composition can be about 350 mg per 10 ml.

[0236] In other words, 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 instance, 1 ml of the composition comprises 37.5 μl (29.5 mg) of ethanol. In another instance, 1 ml of the composition comprises 75 μl (58.9 mg) of ethanol.

[0237] (iv) Metal ion chelator (chelator / chelating agent)

[0238] In some embodiments, the present disclosure provides a radiopharmaceutical composition that contains a certain microdose of 177Lu-PSMA I&T solution and at least one metal ion chelator. Suitable chelators may include ethylenediaminetetraacetic acid (EDTA) and its salts, N-(hydroxyethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid (NTA), ethylene-bis(oxyethylenenitrilo)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-tris(carboxymethyl)-10-(2'-hydroxypropyl)-1,4,7,10-tetraazacyclodecane, 1,4,7-triazacyclononane-N,N',N''-triacetic acid, 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid; diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine, bis(aminoethylthiol)carboxylic acid, triethylenetetramine-hexaacetic acid, 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid or combinations thereof. In one embodiment, the chelator may be the sodium salt of EDTA. In one embodiment, the chelator may comprise DTPA and be free of EDTA.

[0239] In some embodiments, the metal ion chelator may be ethylenediaminetetraacetic acid (EDTA) and its salts, N-(hydroxyethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid (NTA), ethylene-bis(oxyethylenenitrilo)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-tris(carboxymethyl)-10-(2'-hydroxypropyl)-1,4,7,10-tetraazacyclodecane, 1,4,7-triazacyclononane-N,N',N''-triacetic acid, 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid; diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine, bis(aminoethylthiol)carboxylic acid, triethylenetetramine-hexaacetic acid and 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid. In one embodiment, the metal ion chelator may be disodium EDTA. In one embodiment, the metal ion chelator may be DPTA.

[0240] In one embodiment, the amount of chelator present in the radiopharmaceutical composition may range from about 5 μg to 500 μg. In some embodiments, the amount of metal ion chelator present in the radiopharmaceutical composition may range from about 5 μg to 50 μg.

[0241] In some embodiments, the amount of chelating agent 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, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 80 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, about 200 μg, about 210 μg, about 220 μg, about 230 μg, about 240 μg, about 250 μg, about 260 μg, about 270 μg, about 280 μg, about 290 μg, about 300 μg, about 310 μg, 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.

[0242] The concentration range of the metal ion chelating agent in the composition can be from about 5 μg / ml to about 500 μg / ml. In another embodiment, the concentration range of the chelating agent present in the radiopharmaceutical composition can be from about 5 μg / ml to about 200 μg / ml. In another embodiment, the concentration range of the chelating agent present in the radiopharmaceutical composition can be from about 5 μg / ml to 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, or 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.

[0243] In some embodiments, the concentration of the chelating agent present can be 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 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 can 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.

[0244] In other embodiments, the concentration of the chelating agent present can be 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, 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.

[0245] In another embodiment, the amount of the metal ion chelator in the radiopharmaceutical composition can be from about 0.001% to about 0.20% (w / w), about 0.20% to about 0.40% (w / w), about 0.40% to about 0.60% (w / w), about 0.60% to about 0.80% (w / w), or about 0.80% to about 1.00% (w / w) of such radiopharmaceutical composition. In some embodiments, the amount of the metal ion chelator present in the radiopharmaceutical composition can be about 0.001% (w / w), 0.002% (w / w), 0.003% (w / w), 0.004% (w / w), 0.005% (w / w), 0.01% (w / w), 0.02% (w / w), 0.03% (w / w), 0.04% (w / w), 0.05% (w / w), 0.06% (w / w), 0.07% (w / w), 0.08% (w / w), 0.09% (w / w), 0.10% (w / w), 0.11% (w / w), 0.12% (w / w), 0.13% (w / w), 0.14% (w / w), or 0.15% (w / w) of the total weight of the radiopharmaceutical composition.

[0246] For example, the amount of disodium EDTA, diethylenetriamine-pentaacetic acid (DTPA), or a combination thereof in 1 ml of the composition can be from 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.

[0247] In at least one instance, 1 ml of the composition comprises 15.5 μg of disodium EDTA. In another instance, 1 ml of the composition comprises 21 μg of disodium EDTA.

[0248] 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, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit. In another embodiment, the Cu metal content in the composition is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit. In another embodiment, the Zn metal content in the composition is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit. In another embodiment, the Pb metal content in the composition is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit. In another embodiment, the Co metal content in the composition is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit. In another embodiment, the Ni metal content in the composition is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit. In another embodiment, the Zn metal content in the composition is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit. In another embodiment, the Cr metal content in the composition is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit. In another embodiment, the Yb metal content in the composition is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit.

[0249] In another embodiment, the composition described herein comprises M-PSMA I&T, where M = Cu, Pb, Co, Fe, Ni, Zn, Cr, and / or Yb, and the total combined 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 composition described herein comprises 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 of Cu-PSMA I&T. In another embodiment, the composition described herein comprises 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 of Pb-PSMA I&T. In another embodiment, the composition described herein comprises 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 of Co-PSMA I&T. In another embodiment, the composition described herein comprises 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 of Fe-PSMA I&T.In another embodiment, the compositions described herein contain 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 contain 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 contain 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 contain 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.

[0250] (v) pH regulator

[0251] Suitable pH regulators include, but are not limited to, any one of hydrochloric acid, sodium hydroxide, sodium bicarbonate, or combinations thereof.

[0252] In some embodiments, hydrochloric acid can be used to adjust the pH of the radiopharmaceutical composition. In one embodiment, the amount of hydrochloric acid in the composition can range from 0 mg / ml to about 2 mg / ml. In some embodiments, the amount of HCl in the production batch can be from 1.6 ml of 0.05 M HCl to 2 ml of 0.04 M HCl. In one embodiment, the activity of the batch is about 10 Ci to 20 Ci. In another embodiment, the activity of the batch is about 16 Ci. The amount of HCl in the composition can 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 instance, HCl is added to the composition until the final pH reaches 3.5 ± 0.1 to 4.5 ± 0.1.

[0253] In one embodiment, the amount of sodium bicarbonate in the composition can be an amount sufficient to control the pH of the composition at 5.5 to 7.0 before the addition of HCl.

[0254] In one embodiment, the amount of NaOH in the composition can be an amount sufficient to control the pH of the composition at 5.5 to 7.0 before the addition of HCl.

[0255] (vi) Water

[0256] The composition can further include a sufficient amount of water to prepare the desired final volume for a solution for injection. For example, water can be added to make the final volume 1 ml, 10 ml, 15 ml, or 20 ml.

[0257] IV. Method for Preparing a Radiopharmaceutical Composition

[0258] The entire manufacturing process is a one-step radiolabeling process using the PSMA I&T precursor. The success of the labeling depends on temperature, time, and pH. The reaction is carried out in a reactor vial at an elevated temperature. For example, the reactor can be heated at a set point of 110 °C and the maximum temperature reached in the reaction solution is about 95 °C. The radiolabeled product is separated on a C18 column and formulated into the final composition after elution into a bulk vial. The final product is dispensed in a Class A controlled environment.

[0259] In another embodiment, the radiolabeling process uses a PSMA I&T precursor and wherein the composition is radiolabeled at a temperature of about 65°C to about 75°C for 5 to 15 minutes. In yet another embodiment, the composition is radiolabeled at a temperature of about 65°C to about 80°C for 5 to 15 minutes. In another embodiment, the composition is radiolabeled at a temperature of about 65°C, about 70°C, about 75°C or about 80°C for 5 to 15 minutes. In another embodiment, the composition is radiolabeled at a temperature of about 70°C to about 80°C for 5 to 15 minutes. In yet another embodiment, the composition is radiolabeled at a temperature of about 75°C to 80°C for 5 to 15 minutes.

[0260] 177 The Lu-PSMA I&T composition solution can be prepared using the following method 100, for example as Figure 2 shown. The order of the steps can vary, such as the order of preparing the various solutions.

[0261] In one embodiment, step 102 can include preparing four solutions for synthesis. These four solutions can include 0.04M hydrochloric acid, 0.4M sodium acetate, 20% (w / w) L-ascorbic acid, and water containing PSMA I&T at about 460 μg / ml to about 500 μg / ml. The PSMA I&T precursor can be dissolved in sterile water for injection. For example, 80 μg to 600 μg of the precursor can be used in the reaction, depending on the dose amount produced. In at least one instance, 463 μl / ml of the PSMA I&T precursor can be used to produce the composition.

[0262] In one embodiment, step 104 can include preparing an ascorbic acid solution (dilution buffer). In some instances, the ascorbic acid solution can be a 50 mg / ml ascorbic acid solution. The solution pH can 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 is prepared and the pH of the solution is adjusted to 4.5 using 30% hydrochloric acid. In another instance, the ascorbic acid solution can include 33 mg / ml ascorbic acid / ascorbate sodium and 0.1 mg / ml DTPA at pH 4.25 ± 0.25.

[0263] In one embodiment, optional step 106 may include preparing a formulation solution / buffer. The formulation solution is prepared from an injectable grade solution containing ascorbic acid, absolute ethanol, and water for injection. In one example, the formulation solution is prepared by adding sufficient amounts of the following solutions to a bulk vial: a solution of approximately 50 mg / ml ascorbic acid at pH 4.5 (prepared in step 104), a 30% ethanol solution, and water. The formulation solution may include 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 prepared temporarily as part of the synthetic formulation and a predetermined amount is added to the bulk vial as part of the synthetic formulation.

[0264] In one embodiment, 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 of the 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 in a reaction buffer (reaction buffer) and PSMA I&T. 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 range of ascorbic acid concentration in the reaction solution may be from 3.75 mg / ml to 5.00 mg / ml.

[0265] In one embodiment, step 110 may include preparing 177 Lu. In some embodiments, 177 Lu may be provided in HCl. 177 Lu]LuCl3 may be provided in 0.04 M or 0.05 M HCl. For example, 177 Lu at 40 - 44 GBq / ml may be provided in 0.04 M HCl. In another example, 177 Lu less than 61 GBq may be provided in 0.05 M HCl. The 0.04 M or 0.05 M hydrochloric acid containing 177 Lu]LuCl3 may be transferred to the reactor, and 177The vial of Lu]LuCl3 is rinsed with an additional required volume of 0.04 M hydrochloric acid (prepared in step 102) and then transferred to a reactor.

[0266] The reaction volume can range from 6 ml to 8 ml. The volume can depend on the amount of precursor used.

[0267] In one embodiment, step 112 can include 177 radioactively labeling PSMA-I&T with Lu. The reaction mixture can be heated to at most about 75 °C, at most about 80 °C, at most about 85 °C, at most about 90 °C, or at most about 95 °C. In one example, the heating set point is 110 °C and the actual maximum temperature reached is about 95 °C. The reaction volume can be heated for at most 5 minutes, at most 10 minutes, at most 15 minutes, or at most 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.

[0268] In one embodiment, optional step 114 can include purifying the reaction mixture. For example, the solution can pass through a cartridge / column containing a hydrophobic, reversed-phase, silica-based bonded phase (e.g., C18 Sep-Pak). In at least one example, the reaction mixture can pass through a C18 Sep Pak column and the column is rinsed with water. 177 The Lu-PSMA I&T product remains in the column. In some embodiments, the reaction mixture may not be purified.

[0269] In one embodiment, step 116 can include eluting or diluting the final product. In one example, the 177 Lu-PSMA I&T is diluted to a desired radioactivity concentration with the dilution buffer prepared in step 104. A 1.5 ml ethanol-water elution composition in a 1:1 ratio can be used. Then the cartridge can be rinsed with 8.5 ml of 50 mg / ml ascorbic acid. Then a formulation solution can be added to form the final composition. In at least one example, 1.5 ml of 50% (v / v) ethanol is used, followed by 8.5 ml of 50 mg / ml pH 4.5 ascorbic acid solution (prepared in step 104) to 177 elute the Lu-PSMA I&T from the C18 column into a bulk vial, where it is diluted with the formulation solution / buffer (prepared in step 106 and already in the bulk vial). The pH of the resulting solution can be from 3.5 to 4.5. In some embodiments, the pH can be adjusted. In one example, the pH of the 50 mg / ml ascorbic acid solution is adjusted to 3.5 to 4.5. In other examples, the pH is adjusted to 5.0 or less.

[0270] It is presumed that the stability-enhancing conditions (such as an ascorbic acid solution with a pH of about 5 or lower) should preferably be applied as early as possible in the process. For example, at step 114, an ascorbic acid solution with a pH of 5 or lower can be used instead of water to minimize radiolytic damage.

[0271] The final composition can be formulated into a solution suitable for injection. The product is diluted to a standard radioactivity concentration, and thus, the final volume of the bulk composition varies according to the 177 starting radioactivity of the Lu introduced. According to the European Pharmacopoeia and the United States Pharmacopoeia, the solution meets the requirements for sterility and bacterial endotoxins, confirming an acceptable preparation process from a microbiological perspective.

[0272] In some embodiments, at step 118, the final composition can be sterile filtered. The sterile filter can be a 0.22 μm sterile filter. The final product can be dispensed through a 0.22 μm sterile filter into single-dose vials containing an appropriate volume and radioactivity at a reference-specified calibration time. For example, the final composition can be dispensed through a 0.22 μm sterile filter into a dose containing an appropriate volume and radioactivity at the calibration time in a Class A environment.

[0273] Figure 3A An example of a method for preparing a radiopharmaceutical composition by purifying a reaction mixture and a formulation solution with ethanol is provided. Figure 3B An example of a method for preparing a radiopharmaceutical composition without purification and without using ethanol is provided.

[0274] Provided herein is for increasing the inclusion of 177Method for the shelf life of a radiopharmaceutical product of Lu-PSMA I&T. The method can 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 so as to increase the shelf life of the composition by 0.25 days, 0.5 days, 0.75 days, 1 day, 1.25 days, 1.5 days, 2 days, 2.25 days, 2.5 days, 2.75 days, or 3 days. For example, the shelf life of the radiopharmaceutical composition can be 1 day, 1.5 days, 2 days, 2.25 days, 2.5 days, 2.75 days, 3 days, 3.25 days, 3.5 days, 3.75 days, 4 days, 4.25 days, 4.5 days, 4.75 days, or 5 days. In one embodiment, adjusting the pH, radioactivity, and / or ascorbic acid can 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 day, 1.5 days, 2 days, 2.25 days, 2.5 days, 2.75 days, 3 days, 3.25 days, 3.5 days, 3.75 days, 4 days, 4.25 days, 4.5 days, 4.75 days, or 5 days.

[0275] The target drug formulation according to the present disclosure is as provided in Table 1A.

[0276] Table 1A: Target Drug Formulation

[0277]

[0278] In another embodiment, the composition 4 disclosed in Table 1A above can be prepared using a one-step radiolabeling method carried out in the following steps.

[0279] The success of the labeling depends on temperature, time, and pH. The reaction is carried out in a reactor vial at an elevated temperature. For example, the reactor can be preheated at a set point of 100 °C for 5 minutes and then reduced to 85 °C to achieve a reaction temperature of about 75 °C for 10 minutes. The radiolabeled product is formulated into the final composition, sterile filtered, and dispensed in a Class A controlled environment.

[0280] 177 The Lu-PSMA I&T composition solution can be prepared as Figure 2 shown in b(201, 202, 203). The order of the steps can vary, such as the order of preparing the various solutions.

[0281] In one embodiment, step 201 may include preparing a reaction buffer for synthesis. The solution may include an aqueous solution of sodium ascorbate at 82 mg / mL with a pH > 5. The PSMA I&T precursor may be dissolved in the reaction buffer, as shown in step 202. For example, 1000 μg to 5000 μg of the precursor may be used in the reaction, depending on the batch size.

[0282] In one embodiment, the amount of 177 Lu]LuCl3 used in the radiolabeling (step 204) may range from 50 mCi to 15,200 mCi. The corresponding amount of PSMA I&T used during the radiolabeling may range from 0.1 μg / mCi to 0.9 μg / mCi. For example, during the radiolabeling, 15,000 mCi of 177 Lu]LuCl3 and 4200 μg of PSMA I&T are added to the reactor.

[0283] In one embodiment, step 203 may include preparing an ascorbic acid solution (dilution buffer). In some instances, the ascorbic acid solution may be a 33 mg / ml ascorbic acid solution. The solution pH may 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 may include 33 mg / ml ascorbic acid / sodium ascorbate and 0.1 mg / ml DTPA at pH 4.25 ± 0.25.

[0284] In one embodiment, step 204 may include preparing 177 Lu. In some embodiments, 177 Lu may be provided in HCl. 177 Lu]LuCl3 may be provided in 0.05 M HCl. For example, 2 Ci / ml of 177 Lu may be provided in 0.05 M HCl. The 0.05 M hydrochloric acid containing 177 Lu]LuCl3 may be transferred to the reactor, and the 177 Lu]LuCl3 vial may be rinsed with an additional required volume of 82 mg / mL sodium ascorbate (prepared in step 201) and then transferred to the reactor.

[0285] The reaction volume may range from 8 ml to 15 ml. The volume may depend on the amount of 177 Lu]LuCl3 used in the radiolabeling reaction.

[0286] In one embodiment, step 204 may include using 177Lu radioactively labeled PSMA-I&T. The reaction mixture can be heated to at most about 70 °C, at most about 75 °C, at most about 80 °C, at most about 85 °C, at most about 90 °C or at most about 95 °C. In one example, the heating set point is 85 °C and the actual maximum temperature reached is about 75 °C. The reaction volume can be heated for at most 5 minutes, at most 10 minutes, at most 15 minutes, at most 20 minutes, at most 25 minutes, at most 30 minutes, at most 35 minutes, at most 40 minutes or at most 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.

[0287] It is contemplated that stability enhancing conditions such as an ascorbic acid solution with a pH of about 5 or lower should preferably be applied as early as possible in the process. For example, in step 205, an ascorbic acid solution with a pH of 5 or lower can be used instead of water to minimize radiolytic damage.

[0288] 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 varies according to the 177 starting radioactivity of the Lu.

[0289] In some embodiments, in step 206, the final composition can be sterile filtered. The sterile filter can be a 0.22 μm sterile filter. The final product can be dispensed through a 0.22 μm sterile filter into single-dose vials containing the appropriate volume and radioactivity at a reference specified calibration time. For example, the final composition can be dispensed through a 0.22 μm sterile filter in a Class A environment into doses containing the appropriate volume and radioactivity at calibration time.

[0290] Figure 3B An example of a method for preparing a radiopharmaceutical composition without purification and without using ethanol is provided.

[0291] Provided herein for increasing the inclusion of 177Method for the shelf life of a radiopharmaceutical product of Lu-PSMA I&T. The method 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 increase the shelf life of the composition by 0.25 days, 0.5 days, 0.75 days, 1 day, 1.25 days, 1.5 days, 2 days, 2.25 days, 2.5 days, 2.75 days or 3 days. For example, the shelf life of the radiopharmaceutical composition may be 1 day, 1.5 days, 2 days, 2.25 days, 2.5 days, 2.75 days, 3 days, 3.25 days, 3.5 days, 3.75 days or 4 days. In one embodiment, 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 day, 1.5 days, 2 days, 2.25 days, 2.5 days, 2.75 days, 3 days, 3.25 days, 3.5 days, 3.75 days, 4 days.

[0292] V. Stability

[0293] In HPLC analysis, a stable non-radiolabeled standard can be used to identify the product peak. The formulation can be prepared from an injectable grade solution containing ascorbic acid, a chelating agent (EDTA, DTPA or a combination thereof), optionally dehydrated ethanol and water for injection. The formulation matrix can be prepared temporarily as part of the synthetic formulation and a predetermined amount added to the bulk vial as part of the synthetic formulation.

[0294] Without being limited to any one theory, radioactivity, the amount of ascorbic acid and / or the pH of the solution may affect the shelf life of the composition. Surprisingly, compared to compositions having a pH of 5 or higher, high RAC and / or a combination thereof, a lower concentration of ascorbic acid (e.g., 31 mg / ml vs. 42.5 mg / ml) in the composition (pH 4.5 or lower, low RAC and / or a combination thereof) can confer higher stability characteristics and a longer shelf life to the composition. 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 expiration of the composition. The radiochemical purity can be confirmed by HPLC.

[0295] In one or more embodiments, a Lu-PSMA I&T formulation composition having 31 mg / ml of ascorbic acid and a pH of about 4.5 in a dose formulation with a radioactivity concentration of 640 MBq / ml or less 177 can provide sufficient stability for four days.

[0296] In one embodiment, the composition has a low radioactivity concentration (e.g., 588.5 MBq / ml), a pH of 4.5, and 31 mg / ml of ascorbic acid. It 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. The composition with a low radioactivity concentration (e.g., 626 MBq / ml), a pH of 5.0, and 31 mg / ml of 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. The composition with a low radioactivity concentration (e.g., 579 MBq / ml), a pH of 4.5, and 21 mg / ml of 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. The composition with a high radioactivity concentration (e.g., 1,278 MBq / ml), a pH of 4.5, and 42.5 mg / ml of 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.

[0297] The radiopharmaceutical composition can be stored at a temperature in the range of 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.

[0298] In one embodiment, 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 about 10°C, about 15°C, about 22°C, about 22.5°C, about 25°C, or at room temperature.

[0299] In one embodiment, the radiopharmaceutical composition is stored at about 22.5°C. In another embodiment, the radiopharmaceutical composition is stored at room temperature.

[0300] VI. Specific radiopharmaceutical compositions

[0301] In some embodiments, the pharmaceutical product is a sterile-filtered radiopharmaceutical solution containing a microdose of 177 Lu]Lu-PSMA I&T solution in an aqueous solution of 42.5 mg / ml ascorbic acid containing 7.5% (v / v) or 59 mg / ml ethanol. The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk product varies according to the starting radioactivity introduced. The composition of the final product is described in Table 1B ( 177 Lu-PSMA I&T Composition 1):

[0302] Table 1B: Composition of the final product a ( 177 Lu-PSMA I&T Composition 1)

[0303] Component Amount Function <![CDATA 177 Lu-PSMA I&T]]> <![CDATA[Appropriate amount b > API PSMA I&T 5 - 12 μg / ml Precursor Ethanol 7.5%(v / v) Stabilizer (radiolysis) Ascorbic acid 42.5 mg Stabilizer (radiolysis) Disodium EDTA 21 μg Metal scavenger Sodium bicarbonate * Appropriate amount pH regulator Sodium hydroxide * Appropriate amount pH regulator WFI (Water for Injection) Up to 1 ml Vehicle

[0304] a Maximum volume per vial is 10 ml

[0305] b Sufficient radioactivity for the intended use

[0306] In yet another embodiment, the pharmaceutical product is a sterile-filtered radiopharmaceutical solution containing a microdose of 177 Lu-PSMA I&T solution in an aqueous solution of 31 mg / ml ascorbic acid containing 3.8% (v / v) or 30 mg / ml ethanol, with a pH of approximately 4.5. The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk product varies according to the starting radioactivity introduced. The composition is described in Table 1C below ( 177 Lu-PSMA I&T Composition 2):

[0307] Table 1C: Composition of the final product*( 177 Lu]Lu-PSMA I&T Composition 2)

[0308] Component Amount Function <![CDATA 177 Lu-PSMA I&T]]> Appropriate amount ** API PSMA I&T 45 - 120 μg Ethanol 3.8%(v / v) Stabilizer (radiolysis) Ascorbic acid 31 mg / ml Stabilizer (radiolysis) Disodium EDTA 15.5 μg Metal scavenger Sodium bicarbonate Appropriate amount pH regulator Sodium hydroxide Appropriate amount pH regulator Hydrochloric acid Appropriate amount pH regulator WFI (Water for Injection) Up to 1 ml Vehicle

[0309] * Maximum volume per vial is 20 ml

[0310] ** Sufficient radioactivity for the intended use

[0311] In yet another embodiment, the pharmaceutical product contains a small amount of 177A radiopharmaceutical solution of [[Lu]]Lu-PSMA I&T with a pH of approximately 4.25. The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk product varies according to the starting radioactivity introduced. The composition is described in Table 1D below ( 177 [[Lu]]Lu-PSMA I&T Composition 3):

[0312] Table 1D: Composition of the Final Product* ( 177 [[Lu]]Lu-PSMA I&T Composition 3)

[0313]

[0314]

[0315] * Maximum volume per vial is 15 ml

[0316] ** Sufficient radioactivity for the intended use

[0317] VII. Preparation of the Pharmaceutical Product

[0318] The pharmaceutical product can be delivered in a sterile, pyrogen-free glass vial of Type 1 glass with a fluoropolymer-coated butyl rubber septum. The septum is sealed with a crimped aluminum seal. During transportation, the glass vial containing the radiopharmaceutical is kept in a lead-shielded container. The shipping container, including the lead shield and outer packaging, meets the requirements of Type A (IAEA standard). Figure 4 A figure depicting the product vial that can be used in this example.

[0319] In one embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is from about 10 ml to about 20 ml, from about 20 ml to about 30 ml, from about 30 ml to about 40 ml, from about 40 ml to about 50 ml, from about 50 ml to about 60 ml, from about 60 ml to about 70 ml, from about 70 ml to about 80 ml, from about 80 ml to about 90 ml, or from 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.

[0320] In one embodiment, the volume of the solution comprising the formulation or radiopharmaceutical composition is from about 100 ml to about 200 ml, from about 200 ml to about 300 ml, from about 300 ml to about 400 ml, from about 400 ml to about 500 ml, from about 500 ml to about 600 ml, from about 600 ml to about 700 ml, from about 700 ml to about 800 ml, from about 800 ml to about 900 ml or from about 900 ml to about 1000 ml. In a specific embodiment, the volume of the solution comprising 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.

[0321] In a specific embodiment, the final volume in the dose vial is adjusted to be between 7 ml and 10 ml, between 10 ml and 15 ml or between 15 ml and 20 ml in order to provide the required amount of radioactivity at the infusion date and time.

[0322] In another embodiment, 177 Lu-PSMA I&T injection is supplied in single-dose vials or multi-dose vials. For example, a radiopharmaceutical kit is provided herein, the radiopharmaceutical kit comprising a vial containing a single dose of 177 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, 177 the 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.

[0323] In yet another embodiment, 177 the shelf life of the Lu]Lu-PSMA I&T injection product composition is from about 30 hours to about 90 hours, from about 40 hours to about 80 hours, or from about 48 hours to about 72 hours. In a specific embodiment, 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.

[0324] In some embodiments, the radiopharmaceutical composition 177 should have a radiochemical purity of ≥95% for Lu]Lu-PSMA I&T to be sufficient for administration to a patient. The combined radiochemical impurities in the composition can be <5%. In various embodiments, the radiopharmaceutical composition can have a chemical purity such that 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.

[0325] In some embodiments, the radiopharmaceutical composition can have an amount of radioactivity less than about 5%, less than about 4.5%, less than about 4%, less than about 3.5%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.5%, less than about 1%, less than about 0.5%, less than about 0.3%, less than about 0.2%, or less than about 0.1% of colloidal 177 Lu. In one embodiment, the radiopharmaceutical composition administered to a human patient in need contains less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% of colloidal 177 Lu.

[0326] In some embodiments, the radiopharmaceutical composition can have 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, 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 no bacterial endotoxin.

[0327] In one embodiment, the radiochemical purity of the composition is ≥95% at 1 day, at most 2 days, at most 3 days, at most 4 days, or at most 5 days after compounding. In additional embodiments, the radiochemical purity of the composition is ≥95% at 24 hours, at most 36 hours, at most 48 hours, at most 72 hours, or at most 96 hours after compounding. In additional embodiments, the radiochemical purity of the composition is suitable for injection and suitable for administration to a patient in need more than 72 hours after compounding, more than 96 hours after compounding, or more than 100 hours after compounding. The radiochemical purity of the radiopharmaceutical composition at 24 hours, 48 hours, 72 hours, and / or 96 hours after compounding can be 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%. In some instances, the radiochemical purity of the radiopharmaceutical composition at the time of administration can be 95.0% or higher, 95.5% or higher, 96.0% or higher, 96.5% or higher, 97.0% or higher, 97.5% or higher, 98.0% or higher, 98.5% or higher, 99.0% or higher, or 99.5% or higher. For example, the radiochemical purity of the radiopharmaceutical composition can be greater than 95% from 46 to 48 hours after compounding, greater than 96% from 46 to 48 hours after compounding, greater than 97% from 46 to 48 hours after compounding, greater than 95% from 69 to 72 hours after compounding, greater than 96% from 69 to 72 hours after compounding, greater than 97% from 69 to 72 hours after compounding, greater than 95% from 90 to 93 hours after compounding, greater than 96% from 90 to 93 hours after compounding, and / or greater than 97% from 90 to 93 hours after compounding.

[0328] In some instances, the range of the radiochemical purity of the composition can be from about 99.0% to about 99.4% at 0 hours after EOS. In various embodiments, the range of the radiochemical purity of the composition can be from about 96.5% to about 98.7% from 19 - 25 hours after EOS. In other instances, the range of the radiochemical purity of the composition can be from about 93.3% to about 98.0% from 44 - 47 hours after EOS. In additional instances, the range of the radiochemical purity of the composition can be from about 91.2% to about 97.4% from 69 - 71 hours after EOS. In some instances, the range of the radiochemical purity of the composition at 90 - 93 hours after EOS can be from about 95% to about 97.0%.

[0329] In another embodiment, 177The Lu]Lu-PSMA I&T injection is supplied in single-dose vials or multi-dose vials.

[0330] In yet another embodiment, a patient in need of radioligand therapy during treatment receives a single intravenous radioactive dose at the start of a treatment cycle. The treatment cycle is from 1 to 10 weeks. In one embodiment, the treatment comprises 1 to 6 treatment cycles. In another embodiment, a dose reduction or dose increase is introduced during treatment.

[0331] In one embodiment, the volume of the patient dose is calculated based on the radioactive dose to be administered.

[0332] In another embodiment, 177 Lu]Lu-PSMA I&T is slowly infused via the intravenous (IV) route over approximately 10 minutes, and then 500 - 1000 mL of Ringer's solution or saline solution is infused. When the total blood volume exceeds 5,000 mL, an additional 7 mL injection is insignificant. The dose is administered once every 6 weeks for 4 cycles.

[0333] In yet another embodiment, a patient in need of radioligand therapy during treatment receives a single intravenous radioactive dose at the start of a treatment cycle. The treatment cycle is from 1 to 10 weeks. In one embodiment, the treatment comprises 1 - 6 treatment cycles. In another embodiment, a dose reduction or dose increase is introduced during treatment.

[0334] In one embodiment, the volume of the patient dose is calculated based on the radioactive dose to be administered.

[0335] VIII. Methods of diagnosing or treating prostate cancer

[0336] Methods are provided herein for diagnosing or treating tumors in a patient in need thereof. The methods can comprise administering a radiopharmaceutical composition by injection, the radiopharmaceutical composition comprising a solution having a pH of 3.5 to 4.5 and containing 177 Lu-PSMA I&T and ascorbic acid.

[0337] In some embodiments, the average absorbed dose of the radiopharmaceutical composition in the kidneys of the patient can be from about 0.1 mGy / MBq to 0.5 mGy / MBq, from about 0.5 mGy / MBq to 1.0 mGy / MBq, 0.5 mGy / MBq to 0.6 mGy / MBq, 0.6 mGy / MBq to 0.7 mGy / MBq, 0.7 mGy / MBq to 0.8 mGy / MBq, 0.8 mGy / MBq to 0.9 mGy / MBq, 0.9 mGy / MBq to 1.0 mGy / MBq, 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, 1.5 mGy / MBq to 2.5 mGy / MBq, 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, 3.3 mGy / MBq to 3.5 mGy / MBq or 3.5 mGy / MBq to 4.5 mGy / MBq. In some embodiments, the average absorbed dose of the radiopharmaceutical composition in the parotid glands of the patient can be from 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 some embodiments, the average absorbed dose of the radiopharmaceutical composition in the bone lesions of the patient can be from 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 some embodiments, the average absorbed dose of the radiopharmaceutical composition in the lymph node lesions of the patient can be from 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.

[0338] Therapies aimed at eradicating the primary tumor, usually surgery or radiotherapy, are unsuccessful in approximately 30% of men, who develop recurrent disease, which typically first presents as an elevation in plasma prostate-specific antigen (PSA), followed by metastasis to distant sites (Stephenson et al., Journal of Clinical Oncology (J Clin Oncol), 2005; 23:8253-61). Given that the proliferation and survival of prostate cancer cells are dependent on the androgen receptor (AR), the standard treatment for patients with recurrent disease is androgen deprivation therapy (ADT) using gonadotropin-releasing hormone analogs (GnRHa), with or without anti-androgens.

[0339] The treatment outcomes of ADT are generally predictable: PSA declines, followed by tumor regression, a stable period during which the tumor no longer proliferates and PSA stabilizes; subsequently PSA rises and regrowth is defined as castration-resistant disease. Nearly all men with progressive prostate cancer will eventually develop castration-resistant disease. Despite testosterone levels being castrated, progression of prostate cancer represents a transition to a fatal disease stage. Docetaxel with prednisone, cabazitaxel with prednisone, enzalutamide, and abiraterone with prednisone have become the standard of care for men with metastatic castration-resistant prostate cancer (mCRPC) based on 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).

[0340] Abiraterone, enzalutamide, and docetaxel with prednisone are all suitable for patients with mCRPC as first-line treatment, while cabazitaxel with prednisone is only suitable for mCRPC patients who progress under docetaxel treatment. George et al. reported the treatment sequencing for mCRPC patients in the real clinical setting in the United States (George et al., 2020). In the United States, a higher proportion of patients received androgen receptor axis-targeted therapies (ARATs, i.e., abiraterone and enzalutamide) as first-line treatment compared to docetaxel; similarly, a higher proportion of mCRPC patients received alternative ARATs as second-line treatment (receiving enzalutamide after abiraterone treatment and vice versa).

[0341] Targeted radionuclide therapy is an emerging treatment option for many different cancers, including lymphoma, melanoma, and neuroendocrine tumors (Kraeber-Bodéré 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 a key target for radionuclide diagnosis and therapy of PC. PSMA is normally expressed in prostate cells as well as in some extraprostatic tissues, but 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., January 1997; 3(1):81-5. PMID:9815541). The initial clinical experience with PSMA-based radionuclide therapy of PC using 131 I-labeled PSMA showed that in all prostate cancer patients treated, 60% of patients had a PSA decline >50% and had mild hematotoxicity, which is a promising result (Zechmann et al., Eur J Nucl Med Mol Imaging, 2014, 41, 1280-92).

[0342] IX. Administration

[0343] Methods of administering a radiopharmaceutical composition are further provided herein. The radiopharmaceutical composition can be administered to a human patient in need thereof by injection or infusion.

[0344] There can be approximately six major aspects of administration.

[0345] First, cool the salivary glands. Thirty minutes before administration of 177 Lu-PSMA I&T and up to 4 hours after administration of 177 Lu-PSMA I&T, the patient receives ice packs on the parotid and submandibular glands to reduce the risk of salivary gland radiation damage. There is no scientific evidence indicating whether cooling the salivary glands is an effective therapy for sparing these glands from radiation; however, cooling the salivary glands is tolerable and harmless to the patient.

[0346] Second, use a urinary catheter in incontinent patients within the first 48 hours to avoid any contamination.

[0347] Third, 6.5 - 7.5 GBq (range: 6.0 - 8.0 GBq) 177Activity of Lu-PSMA I&T. In the case of impaired renal function (e.g., creatinine within 1.0 - 1.5 UNL), the activity amount can be reduced to 4.0 - 5.0 GBq. According to preliminary results, an activity of 7.4 GBq can be administered safely; however, more data are needed to increase the activity amount.

[0348] Fourth, the activity is intravenously infused in the form of a slow bolus (over about 1 - 15 minutes), followed by 500 - 1000 ml of Ringer's solution or NaCl solution. The patient should be encouraged to urinate as frequently as possible and drink about 2 liters of water per day. In patients with dilated non-obstructive nephropathy, the administration of diuretics can be meaningful.

[0349] Fifth, 3 - 5 cycles of RLT per 5 - 8 weeks on average, and an experience of up to 11 cycles has been reported. In the case of a continuously increasing PSA, after the general condition deteriorates in the first two cycles, the indication for additional RLT should be re-evaluated. In the case where PSA drops to <1.0 μg / l during the therapy cycle, when the post-injection SPECT study does not provide sufficient information, PSMA imaging can evaluate the presence of small PSMA-positive metastases after the completion of RLT. In the case of a significant decrease in platelets or white blood cells, the time interval between two cycles can be extended.

[0350] Sixth, at least one whole-body scan is performed 24 - 48 hours after injection (preferably with SPECT( / CT). In patients with diffuse bone and bone marrow metastases and in patients with brain metastases, it is advisable to accompany corticosteroid therapy (e.g., prednisone 20 mg / day) within the first two weeks after administration.

[0351] In some embodiments, the method may include injecting the radiopharmaceutical composition into a patient in need more than 48 hours after compounding. In some instances, the radiopharmaceutical composition may include a solution containing 177 Lu-PSMA I&T and ascorbic acid with a pH of 3.5 to 4.5, and when administered, the radiochemical purity of the solution can be greater than 96%. In one embodiment, the pH of the solution is about 3.5 to 4.2. The composition may contain <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 mg / ml to about 35 mg / ml of ascorbic acid. The radioactivity of the composition can be about 0.5 GBq / ml or about 13.5 mCi / ml, and the radiochemical purity is at least 98% at 44 hours after compounding, at least 97% at 69 hours after compounding, and / or at least 97% at 93 hours after compounding.

[0352] The pharmaceutical composition can be administered at 2 - 11 cycles / treatment every 5 - 8 weeks. In some embodiments, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 treatments can be administered to a patient, and the treatment can be administered once every 4, 5, 6, 7, or 8 weeks. In one example, up to 4 treatments can be administered to a patient, with the treatment being administered once every 6 weeks.

[0353] In various embodiments, it can be administered to a patient at a dose of 0.5 GBq to 10 GBq per dose cycle 177 Lu-PSMA I&T. For example, the standard radioactivity of the radiopharmaceutical composition at the time of administration can be about 200 mCi, and the standard radioactivity concentration at the end of production is about 27 mCi / mL; thus, the final volume of the dose vial can be adjusted to be between 7 and 15 mL in order to provide the required amount of radioactivity at the infusion date and time. In some embodiments, the dose vial contains 10 mL to 20 mL. In at least one example, a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) can be administered to a patient per treatment. On the one hand, for four, five, six, seven, or more treatments, a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) can be administered to a patient per treatment. On the other hand, for four or more treatments, five or more, six or more, seven or more, or eight or more treatments, a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) can be administered to a patient per treatment. On yet another hand, for four, five, six, seven, eight, or more treatments, a dose of about 200 mCi (≥7.1 GBq) can be administered to a patient per treatment. In another example, a dose of about 6.8 GBq ± 0.3 GBq can be administered to a patient per treatment. On the one hand, for four, five, six, seven, eight, or more treatments, a dose of about 6.8 GBq ± 0.3 GBq can be administered to a patient per treatment.

[0354] In various embodiments, it can be administered to a patient at 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, wherein the total cumulative dose to the patient's kidneys per administration is ≤ 3.9 Gy, ≤ 3.8 Gy, ≤ 3.7 Gy, ≤ 3.6 Gy, ≤ 3.5 Gy, ≤ 3.4 Gy, ≤ 3.3 Gy, ≤ 3.2 Gy, ≤ 3.1 Gy, ≤ 3.0 Gy, ≤ 2.9 Gy, ≤ 2.8 Gy, ≤ 2.7 Gy, ≤ 2.6 Gy, ≤ 2.5 Gy or ≤ 2.4 Gy, and wherein for one, two, three, four, five, six, seven, eight or more treatments (i.e., treatment cycles), a certain dose is administered to the patient per treatment. For four, five, six, seven, eight or more treatments (i.e., treatment cycles). In various embodiments, it can be from 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 1.0 GBq, about 1.0 GBq to about 7.5 GBq, about 1.5 GBq to about 10.0 GBq, about 1.5 GBq to about 9.5 GBq, about 1.5 GBq to about 9.0 GBq, about 1.5 GBq to about 8.5 GBq, about 1.5 GBq to about 8.0 GBq, about 1.5 GBq to about 7.5 GBq, about 2.0 GBq to about 10.0 GBq, about 2.0 GBq to about 9.5 GBq, about 2.0 GBq to about 9.0 GBq, about 2.0 GBq to about 8.5 GBq, about 2.0 GBq to about 8.0 GBq, about 2.5 GBq to about 10.0 GBq, about 2.5 GBq to about 2.5 GBq, about 2.5 GBq to about 9.0 GBq, about 2.5 GBq to about 8.5 GBq, about 2.5 GBq to about 8.0 GBq, about 2.5 GBq to about 7.5 GBq, about 3.0 GBq to about 10.0 GBq, about 3.0 GBq to about 9.5 GBq, about 3.0 GBq to about 9.0 GBq, about 3.0 GBq to about 8.5 GBq, about 3.0 GBq to about 8.0 GBq, about 3.0 GBq to about 7.5 GBq, about 3.5 GBq to about 10.0 GBq, about 3.5 GBq to about 9.5 GBq, about 3.5 GBq to about 9.0 GBq, about 3.5 GBq to about 8.5 GBq, about 3.5 GBq to about 8.0 GBq, about 3.5 GBq to about 7.5 GBq, about 0.5 GBq to about 7.5 GBq, about 0.5 GBq to about 7.4 GBq, about 1.0 GBq to about 7.4 GBq, about 1.5 GBq to about 7.4 GBq, about 2.0 GBq to about 7.4 GBq, about 2.5 GBq to about 7.A dose of 4 GBq, from about 3.0 GBq to about 7.4 GBq, from about 3.5 GBq to about 7.4 GBq, from about 4.0 GBq to about 7.4 GBq, from about 4.5 GBq to about 7.4 GBq, from about 5.0 GBq to about 7.4 GBq, from about 5.5 GBq to about 7.4 GBq, from about 6.0 GBq to about 7.4 GBq, from about 6.5 GBq to about 7.4 GBq, from about 6.6 GBq to about 7.4 GBq, from about 6.7 GBq to about 7.4 GBq, from about 6.8 GBq to about 7.4 GBq, from about 6.9 GBq to about 7.4 GBq, from about 7.0 GBq to about 7.4 GBq, from about 7.1 GBq to about 7.4 GBq, from about 7.2 GBq to about 7.4 GBq, or from about 7.3 GBq to about 7.4 GBq is administered to a patient. 177 Lu-PSMA I&T, wherein the total cumulative dose to the patient's kidneys per administration is ≤ 3.9 Gy, ≤ 3.8 Gy, ≤ 3.7 Gy, ≤ 3.6 Gy, ≤ 3.5 Gy, ≤ 3.4 Gy, ≤ 3.3 Gy, ≤ 3.2 Gy, ≤ 3.1 Gy, ≤ 3.0 Gy, ≤ 2.9 Gy, ≤ 2.8 Gy, ≤ 2.7 Gy, ≤ 2.6 Gy, ≤ 2.5 Gy, or ≤ 2.4 Gy, and wherein for one, two, three, four, five, six, seven, eight, or more treatments (i.e., treatment cycles), a certain dose can be administered to the patient per treatment. In various other embodiments, a dose from about 0.5 GBq to about 6.8 GBq, from about 1.0 GBq to about 6.8 GBq, from about 1.5 GBq to about 6.8 GBq, from about 2.0 GBq to about 6.8 GBq, from about 2.5 GBq to about 6.8 GBq, from about 3.0 GBq to about 6.8 GBq, from about 3.5 GBq to about 6.8 GBq, from about 4.0 GBq to about 6.8 GBq, from about 4.5 GBq to about 6.8 GBq, from about 5.0 GBq to about 6.8 GBq, from about 5.5 GBq to about 6.8 GBq, from about 6.0 GBq to about 6.8 GBq, from about 6.1 GBq to about 6.8 GBq, from about 6.2 GBq to about 6.8 GBq, from about 6.3 GBq to about 6.8 GBq, from about 6.4 GBq to about 6.8 GBq, from about 6.5 GBq to about 6.8 GBq, from about 6.6 GBq to about 6.8 GBq, or from about 6.7 GBq to about 7.4 GBq is administered to the patient 177Lu-PSMA I&T, wherein the total cumulative dose to the patient's kidneys per administration is ≤ 3.9 Gy, ≤ 3.8 Gy, ≤ 3.7 Gy, ≤ 3.6 Gy, ≤ 3.5 Gy, ≤ 3.4 Gy, ≤ 3.3 Gy, ≤ 3.2 Gy, ≤ 3.1 Gy, ≤ 3.0 Gy, ≤ 2.9 Gy, ≤ 2.8 Gy, ≤ 2.7 Gy, ≤ 2.6 Gy, ≤ 2.5 Gy or ≤ 2.4 Gy, and wherein for one, two, three, four, five, six, seven, eight or more treatments (i.e., treatment cycles), a certain dose can be administered to the patient per treatment.

[0355] In various embodiments, more than 10 treatments can be administered to the patient, and the treatments can be administered every 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks, as long as the total cumulative dose to the patient's kidneys remains below 23 gray (Gy) after all treatments. For example, 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 can be administered to the patient, and the treatments can be administered every 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks, as long as the total cumulative dose to the patient's kidneys remains below 23 gray (Gy) after all treatments.

[0356] In some embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the patient's kidneys of 0.46 Gy / GBq ± 0.23 Gy / GBq (i.e., the 177 Lu-PSMA I&T administered at 0.46 Gy / GBq). In some additional embodiments, administering 177 Lu-PSMA I&T results in an absorbed dose to the patient's kidneys that is less than or equal to 0.46 Gy / GBq.

[0357] In various embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the patient's kidneys of 0.43 Gy / GBq ± 0.05 Gy / GBq (i.e., the 177 Lu]Lu-PSMA I&T administered at 0.43 Gy / GBq). In some additional embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the patient's kidneys that is less than or equal to 0.43 Gy / GBq.

[0358] In other embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the patient's kidneys of 0.41 Gy / GBq ± 0.15 Gy / GBq (i.e., the 177Lu]Lu-PSMA I&T). In some additional embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the kidneys of the patient that is less than or equal to 0.41 Gy / GBq.

[0359] In various embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the lacrimal glands of the patient of 0.67 Gy / GBq ± 0.33 Gy / GBq (i.e., the administered 177 Lu]Lu-PSMA I&T at 0.67 Gy / GBq). In some additional embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the lacrimal glands of the patient that is less than or equal to 0.67 Gy / GBq.

[0360] In other embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the lacrimal glands of the patient of 0.40 Gy / GBq ± 0.37 Gy / GBq (i.e., the administered 177 Lu]Lu-PSMA I&T at 0.40 Gy / GBq). In some additional embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the lacrimal glands of the patient that is less than or equal to 0.40 Gy / GBq.

[0361] In other embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the salivary glands of the patient of 0.10 Gy / GBq ± 0.06 Gy / GBq (i.e., the administered 177 Lu]Lu-PSMA I&T at 0.10 Gy / GBq). In some additional embodiments, administering 177 Lu-PSMA I&T results in an absorbed dose to the salivary glands of the patient that is less than or equal to 0.10 Gy / GBq.

[0362] In various embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the salivary glands of the patient of 0.13 Gy / GBq ± 0.08 Gy / GBq (i.e., the administered 177 Lu]Lu-PSMA I&T at 0.13 Gy / GBq). In some additional embodiments, administering 177 Lu]Lu-PSMA I&T results in an absorbed dose to the salivary glands of the patient that is less than or equal to 0.13 Gy / GBq.

[0363] In other embodiments, administering 177Lu]Lu-PSMA I&T results in an absorbed dose to the salivary glands of the patient of 0.18 Gy / GBq ± 0.16 Gy / GBq (i.e., for the administered 177 Lu]Lu-PSMA I&T of 0.18 Gy / GBq). In some additional embodiments, administration of 177 Lu]Lu-PSMA I&T results in an absorbed dose to the salivary glands of the patient that is less than or equal to 0.18 Gy / GBq.

[0364] In various embodiments, administration of 177 Lu]Lu-PSMA I&T results in an absorbed dose to the liver of the patient of 0.03 Gy / GBq ± 0.02 Gy / GBq (i.e., for the administered 177 Lu]Lu-PSMA I&T of 0.03 Gy / GBq). In some additional embodiments, administration of 177 Lu]Lu-PSMA I&T results in an absorbed dose to the liver of the patient that is less than or equal to 0.03 Gy / GBq.

[0365] In other embodiments, administration of 177 Lu]Lu-PSMA I&T results in an absorbed dose to the liver of the patient of 0.04 Gy / GBq ± 0.02 Gy / GBq (i.e., for the administered 177 Lu-PSMA I&T of 0.04 Gy / GBq). In some additional embodiments, administration of 177 Lu-PSMA I&T results in an absorbed dose to the liver of the patient that is less than or equal to 0.04 Gy / GBq.

[0366] 177 The administration of Lu-PSMA I&T can be described by a mathematical formula to ensure that the total cumulative dose to the kidneys of the patient remains below 23 Gy after all treatments. An example formula is shown below to determine the allowable number of cycles.

[0367]

[0368] Where X is the total allowable number of cycles at a given activity of 177 Lu-PSMA I&T, Y is the activity of each dose of 177 Lu-PSMA I&T, Y is the absorbed radiation dose of the administered 177 Lu-PSMA I&T in Gy / MBq, and Z is the activity of the administered 177 Lu-PSMA I&T in MBq.

[0369] In various embodiments, 1 GBq can be administered to the patient 177Lu-PSMA I&T was administered at 2 GBq for 53 treatments 177 Lu-PSMA I&T was administered at 3 GBq for 26 treatments 177 Lu-PSMA I&T was administered at 4 GBq for 17 treatments 177 Lu-PSMA I&T was administered at 5 GBq for 13 treatments 177 Lu-PSMA I&T was administered at 6 GBq for 10 treatments 177 Lu-PSMA I&T was administered at 7 GBq for 8 treatments 177 Lu-PSMA I&T was administered at 8 GBq for 7 treatments 177 Lu-PSMA I&T was administered at 9 GBq for 6 treatments 177 Lu-PSMA I&T was administered at 10 GBq for 5 treatments 177 Lu-PSMA I&T was administered for 5 treatments.

[0370] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need thereof, wherein the injection comprises 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, and wherein 1, 2, 3, 4, 5, 6, or 7 cycles of 177 Lu-PSMA I&T treatment are possible without risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6, or 7 cycles of 177 Lu-PSMA I&T treatment provides an average projected dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the projected or actual cumulative absorbed dose to the kidneys at 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0371] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of 177Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 6.6 GBq ± 0.10 GBq, 6.6 GBq ± 0.15 GBq, 6.6 GBq ± 0.20 GBq, 6.6 GBq ± 0.25 GBq or 6.6 GBq ± 0.30 GBq, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles are carried out at said dose of 177 Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 cycles are carried out of 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys at 1, 2, 3, 4, 5, 6 or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0372] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 6.7 GBq ± 0.10 GBq, 6.7 GBq ± 0.15 GBq, 6.7 GBq ± 0.20 GBq, 6.7 GBq ± 0.25 GBq or 6.7 GBq ± 0.30 GBq, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles are carried out at said dose of 177 Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 cycles are carried out of 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys at 1, 2, 3, 4, 5, 6 or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0373] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising a vial containing at least a single dose of 177Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 6.8 GBq ± 0.10 GBq, 6.8 GBq ± 0.15 GBq, 6.8 GBq ± 0.20 GBq, 6.8 GBq ± 0.25 GBq or 6.8 GBq ± 0.30 GBq, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys at 1, 2, 3, 4, 5, 6 or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0374] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising vials containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 6.9 GBq ± 0.10 GBq, 6.9 GBq ± 0.15 GBq, 6.9 GBq ± 0.20 GBq, 6.9 GBq ± 0.25 GBq or 6.9 GBq ± 0.30 GBq, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys at 1, 2, 3, 4, 5, 6 or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0375] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising vials containing at least a single dose of 177Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 7.0 GBq ± 0.10 GBq, 7.0 GBq ± 0.15 GBq, 7.0 GBq ± 0.20 GBq, 7.0 GBq ± 0.25 GBq or 7.0 GBq ± 0.30 GBq, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles are carried out at said dose 177 Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 cycles are carried out 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidney, and / or the predicted or actual cumulative absorbed dose to the kidney at 1, 2, 3, 4, 5, 6 or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0376] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 7.1 GBq ± 0.10 GBq, 7.1 GBq ± 0.15 GBq, 7.1 GBq ± 0.20 GBq, 7.1 GBq ± 0.25 GBq or 7.1 GBq ± 0.30 GBq, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles are carried out at said dose 177 Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 cycles are carried out 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidney, and / or the predicted or actual cumulative absorbed dose to the kidney at 1, 2, 3, 4, 5, 6 or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0377] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising a vial containing at least a single dose of 177Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 7.2 GBq ± 0.10 GBq, 7.2 GBq ± 0.15 GBq, 7.2 GBq ± 0.20 GBq, 7.2 GBq ± 0.25 GBq or 7.2 GBq ± 0.30 GBq, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles are performed at said dose 177 Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 cycles are performed 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidney, and / or the predicted or actual cumulative absorbed dose to the kidney at 1, 2, 3, 4, 5, 6 or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0378] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 7.3 GBq ± 0.10 GBq, 7.3 GBq ± 0.15 GBq, 7.3 GBq ± 0.20 GBq, 7.3 GBq ± 0.25 GBq or 7.3 GBq ± 0.30 GBq, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles are performed at said dose 177 Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 cycles are performed 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidney, and / or the predicted or actual cumulative absorbed dose to the kidney at 1, 2, 3, 4, 5, 6 or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0379] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit, said radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises 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, and wherein 6 cycles are performed at said dose177 Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or in which 1, 2, 3, 4, 5, 6, or 7 cycles of 177 Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys at 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0380] In various embodiments, the present disclosure further relates to a radioactive pharmaceutical kit, the radioactive pharmaceutical kit comprising vials containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.5 GBq ± 0.10 GBq, 7.5 GBq ± 0.15 GBq, 7.5 GBq ± 0.20 GBq, 7.5 GBq ± 0.25 Gbq, or 7.5 GBq ± 0.30 GBq, and wherein 1, 2, 3, 4, 5, 6, or 7 cycles of 177 Lu]Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or in which 1, 2, 3, 4, 5, 6, or 7 cycles of 177 Lu]Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or the predicted or actual cumulative absorbed dose to the kidneys at 6 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0381] In various embodiments, the present disclosure further relates to a radioactive pharmaceutical kit, the radioactive pharmaceutical kit comprising vials containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.4 GBq (average 7.52 ± 0.16 GBq) of 177 Lu]Lu-PSMA-I&T, and wherein 6 cycles of 177 Lu]Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or in which 1, 2, 3, 4, 5, 6, or 7 cycles of 177Lu-Lu-PSMA I&T therapy provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or a predicted or actual cumulative absorbed dose to the kidneys of less than 23 Gy at 1, 2, 3, 4, 5, 6, or 7 cycles, and no nephrotoxicity is observed. The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.4 GBq (average 7.52 ± 0.16 GBq) of 177 Lu-PSMA-I&T, wherein 1, 2, 3, 4, 5, 6, or 7 cycles of 177 Lu-Lu-PSMA I&T therapy provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or a predicted or actual cumulative absorbed dose to the kidneys of less than 23 Gy at 1, 2, 3, 4, 5, 6, or 7 cycles, and no nephrotoxicity is observed.

[0382] The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 6.5 GBq + / - 10% GBq, 6.5 GBq + / - 5% GBq, or 6.5 GBq + / - 3% dose of 177 Lu-PSMA-I&T, and wherein 1, 2, 3, 4, 5, 6, or 7 cycles of 177 Lu-Lu-PSMA I&T therapy is possible without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6, or 7 cycles of 177 Lu-Lu-PSMA I&T therapy provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or a predicted or actual cumulative absorbed dose to the kidneys of less than 23 Gy at 1, 2, 3, 4, 5, 6, or 7 cycles, and no nephrotoxicity is observed.

[0383] The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 6.8 GBq + / - 10% GBq, 6.8 GBq + / - 5% GBq, or 6.8 GBq + / - 3% dose of177 Lu]Lu-PSMA-I&T, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu]Lu-PSMA I&T treatment can be carried out at said dose without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu]Lu-PSMA I&T treatment provides an average predicted dose below the cumulative absorbed dose of 23 Gy to the kidney, and / or the predicted or actual cumulative absorbed dose to the kidney at 1, 2, 3, 4, 5, 6 or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0384] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising vials containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 7.4 GBq + / - 10% GBq, 7.4 GBq + / - 5% GBq or 7.4 GBq + / - 3% of 177 Lu-PSMA-I&T, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu-PSMA I&T treatment can be carried out at said dose without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu]Lu-PSMA I&T treatment provides an average predicted dose below the cumulative absorbed dose of 23 Gy to the kidney, and / or the predicted or actual cumulative absorbed dose to the kidney at 1, 2, 3, 4, 5, 6 or 7 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0385] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising vials containing at least a single dose of 177 Lu]Lu-PSMA I&T solution for injection into a human patient in need, wherein said injection comprises a dose of 7.4 (+ / - 10%) GBq of 177 Lu]Lu-PSMA-I&T, and wherein 6 cycles of 177 Lu]Lu-PSMA I&T treatment can be carried out at said dose without the risk of nephrotoxicity, and / or wherein 6 cycles of 177The Lu-PSMA I&T treatment provides an average predicted dose of less than 23 Gy of cumulative absorbed dose to the kidneys, and / or a predicted or actual cumulative absorbed dose to the kidneys at 6 cycles of less than 23 Gy, and no renal toxicity was observed.

[0386] The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising vials containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises 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, and wherein the predicted cumulative absorbed dose to the kidneys at 6 cycles will be 20.4 ± 10.2 Gy. The present disclosure further relates to a radiopharmaceutical kit, the radiopharmaceutical kit comprising vials containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need, wherein the injection comprises a dose of 7.5 GBq ± 0.10 GBq, 7.5 GBq ± 0.15 GBq, 7.5 GBq ± 0.20 GBq, 7.5 GBq ± 0.25 GBq or 7.5 GBq ± 0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidneys at 6 cycles will be 20.4 ± 10.2 Gy.

[0387] In some embodiments, the present disclosure includes a kit that includes a predetermined amount of a composition that includes 177 Lu-PSMA I&T. In another embodiment, the molar ratio of PSMA I&T to 177 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.

[0388] When administering the radiopharmaceutical composition to a patient, the patient can maintain low levels of hematotoxicity and renal toxicity. In some embodiments, the prostate-specific antigen (PSA) decreases by more than about 40%, more than about 45%, more than about 50%, more than about 55%, more than about 60%, more than about 65%, more than about 70%, more than about 75% or more than about 80%.

[0389] Further provided herein is by administering a composition comprising 177Method of treating a patient suffering from cancer and / or mCRPC with a radiopharmaceutical composition of Lu-PSMA I&T. The method may further comprise imaging the patient using PSMA-PET before administering the radiopharmaceutical composition to record and confirm that the patient is mCRPC positive. For example, the patient's PSMA-PET scan (e.g., 68 Ga]Ga-PSMA-11 or 18 F]DCFPyL) may be positive as determined by a central reader. In one embodiment, a method of imaging the cancer of its human patient is provided herein. In another embodiment, the method further comprises administering to a human patient a composition comprising 177 Lu-PSMA I&T. In another embodiment, the molar ratio of PSMA I&T to 177 Lu is from 5.0:1.0 to 12.0:1.0.

[0390] Indications and contraindications

[0391] With 177 RLT of Lu-PSMA I&T may be indicated for treating patients suffering from cancer and / or mCRPC who do not have any other approved treatment options planned by a multidisciplinary team. In one embodiment, a method of treating the cancer of a patient in need is provided herein.

[0392] In another embodiment, the method comprises administering to a human patient a composition comprising 177 Lu-PSMA I&T. In another embodiment, the molar ratio of PSMA I&T to 177 Lu is from 1.0:1.0 to 12.0:1.0, from 3.0:1.0 to 12.0:1.0, from 5.0:1.0 to 12.0:1.0. In another embodiment, the molar ratio of PSMA I&T to 177 Lu is from 1.0:1.0 to 8.0:1.0, from 1.5:1.0 to 8.0:1.0, from 2.0:1.0 to 8.0:1.0, from 2.5:1.0 to 8.0:1.0, from 3.0:1.0 to 8.0:1.0, from 3.5:1.0 to 8.0:1.0 or from 4.0:1.0 to 8.0:1.0. In another embodiment, the molar ratio of PSMA I&T to 177The molar ratio of Lu is from 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. In another embodiment, PSMA I&T and 177 The molar ratio of Lu is from 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. In another embodiment, PSMA I&T and 177 The molar ratio of Lu is from 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, 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. In another embodiment, PSMA I&T and 177The molar ratio of Lu is from 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 to 11.0:1.0, 8.8:1.0 to 11.0:1.0, 8.9:1.0 to 11.0:1.0, 9.0:1.0 to 11.0:1.0, 9.1:1.0 to 11.0:1.0, 9.2:1.0 to 11.0:1.0, 9.3:1.0 to 11.0:1.0, 9.4:1.0 to 11.0:1.0, 9.5:1.0 to 11.0:1.0, 9.6:1.0 to 11.0:1.0, 9.7:1.0 to 11.0:1.0, 9.8:1.0 to 11.0:1.0, 9.9:1.0 to 11.0:1.0, 10.0:1.0 to 11.0:1.0, 10.1:1.0 to 11.0:1.0, 10.2:1.0 to 11.0:1.0, 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. The molar ratio of PSMA I&T to 177 The molar ratio of Lu can be from 3.0:1.0 to 12.0:1.0, 3.5:1.0 to 12.0:1.0, 4.0:1.0 to 12.0:1.0, 4.4:1.0 to 12.0:1.0, 4.4:1.0 to 11.5:1.0, 4.4:1.0 to 11.0:1.0, 4.4:1.0 to 10.5:1.0, 4.4:1.0 to 10.0:1.0, 4.4:1.0 to 9.5:1.0, 4.4:1.0 to 9.0:1.0, 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. The molar ratio of PSMA I&T to 177The molar ratio of Lu can be 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, 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. PSMA I&T and 177 The molar ratio of Lu can be 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 10.0:1.0, 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. PSMA I&T and 177 The molar ratio of 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.

[0393] PSMA I&T and 177The molar ratio of 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. PSMA I&T and 177 The molar ratio of 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. PSMA I&T and 177 The molar ratio of 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. PSMA I&T and 177 The molar ratio of 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. PSMA I&T and 177 The molar ratio of 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. PSMA I&T and 177 The molar ratio of 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. PSMA I&T and 177 The molar ratio of 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 5.7.0:1.0 or 5.4:1.0 to 5.6:1.0. PSMA I&T and 177 The molar ratio of 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.

[0394] PSMA I&T and 177The molar ratio of Lu can be from 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 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.

[0395] 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 ≤0.65, ≤0.64, ≤0.63, ≤0.62, ≤0.61, or ≤0.60. 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 from 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. 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 from 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, 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 from 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 PSMA I&T to [177Lu]Lu3+ ratio (in μg:mCi) can be from 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 0.40 to about 0.53, about 0.40 to about 0.52, about 0.40 to about 0.51, about 0.40 to about 0.50, about 0.40 to about 0.49, about 0.40 to about 0.48, about 0.40 to about 0.47, about 0.40 to about 0.46, about 0.40 to about 0.45, about 0.40 to about 0.44, about 0.40 to about 0.43, about 0.40 to about 0.42, about 0.40 to about 0.41. In another embodiment, in the compositions, kits, and methods described herein, the PSMA I&T to [177Lu]Lu3+ ratio (in μg:mCi) can be from 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 0.51, 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 PSMA I&T to [177Lu]Lu3+ ratio (in μg:mCi) can be from about 0.30 to about 0.64, from about 0.30 to about 0.63, from about 0.30 to about 0.62, from about 0.30 to about 0.61, from about 0.30 to about 0.60, from about 0.30 to about 0.59, from about 0.30 to about 0.58, from about 0.30 to about 0.57, from about 0.30 to about 0.56, from about 0.30 to about 0.55, from about 0.30 to about 0.54, from about 0.30 to about 0.53, from about 0.30 to about 0.52, from about 0.30 to about 0.51, from about 0.30 to about 0.50, from about 0.30 to about 0.49, from about 0.30 to about 0.48, from about 0.30 to about 0.47, from about 0.30 to about 0.46, from about 0.30 to about 0.45, from about 0.30 to about 0.44, from about 0.30 to about 0.43, from about 0.30 to about 0.42, from about 0.30 to about 0.41, from about 0.30 to about 0.40, from about 0.30 to about 0.39, from about 0.30 to about 0.38, from about 0.30 to about 0.37, from about 0.30 to about 0.36, from about 0.30 to about 0.35, from about 0.30 to about 0.34, from about 0.30 to about 0.33, from about 0.30 to about 0.32, or from about 0.30 to about 0.31.In another embodiment, in the compositions, kits, and methods described herein, the PSMA I&T to [177Lu]Lu3+ ratio (in μg:mCi) can be from 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 PSMA I&T to [177Lu]Lu3+ ratio (in μg:mCi) can be from about 0.20 to about 0.30.

[0396] In another embodiment, the patient is treatment-naive. In another embodiment, the patient is treatment-experienced.

[0397] 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 part of a regimen. In another embodiment, the pharmaceutical composition administered has a radiochemical purity greater than 95% at the time of administration.

[0398] In one embodiment, the method of treating cancer prolongs the time to disease progression of the cancer in the patient. In another embodiment, the method of treating cancer prolongs 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).

[0399] In some embodiments, the patient also has histologically or pathologically confirmed prostate adenocarcinoma without a major small cell component and has progressive disease according to one or more of the following criteria: a) Serum / plasma PSA progression, defined as two consecutive increases in PSA relative to a previous reference value measured at intervals of at least 1 week, where the minimum starting value > 2 ng / mL; or b) Progression of measurable disease (RECIST 1.1) or the presence of at least two new bone lesions (PCWG3 criteria), and / or has previously received treatment with a next-generation androgen receptor (AR)-directed therapy (e.g., abiraterone, enzalutamide, apalutamide, darolutamide). In additional embodiments, the patient may have effective castration with a serum testosterone level < 50 ng / dL and plans to continue chronic medical or surgical castration. mCRPC patients should undergo hormone therapy, chemotherapy, and bone-targeted therapy if indicated.

[0400] In at least one instance, using 177 Patients in need of RLT with Lu-PSMA I&T may meet the following criteria:

[0401] 1) mCRPC with PSMA-positive metastatic disease based on PSMA-PET or SPECT imaging. There is no limit to the number or location of metastases (i.e., bone or soft tissue metastases). Attention should be paid, for example, to patients with diffuse bone marrow, perineural, and brain metastases.

[0402] 2) After initial hormone therapy (LH-RH agonist / antagonist). Progressive disease, i.e., biochemical and / or radiological progression, despite newly developed hormone therapies (abiraterone / enzalutamide) or these drugs may be avoided by the patient. Progressive disease despite chemotherapy (Docetaxel and Cabazitaxel) or the patient is not suitable for chemotherapy or avoids chemotherapy.

[0403] 3) Not applicable to bone-targeted therapy due to extraosseous metastases or diffuse bone marrow metastases or avoided by the patient 153 Sm-EDTMP or 223 Ra]RaCl2 or other locally available radiopharmaceuticals. In patients with insufficient response to bone-targeted therapy for pain relief or pain exacerbation (even with this therapy), RLT with 177 Lu-PSMA I&T may be evaluated.

[0404] 4) Life expectancy of more than 4 - 6 months.

[0405] 5) Decisions on salvage therapies by the institutional interdisciplinary tumor board.

[0406] In general, mCRPC patients should undergo hormonal therapy, chemotherapy, and bone-targeted therapy if indicated. In the event of any contraindications to one of these therapies, they should be discussed and documented in the interdisciplinary tumor board.

[0407] The contraindications are as follows:

[0408] (1) WBC ≤ 1 x 10 9 / l.

[0409] (2) Hb ≤ 80 g / l. (In the case of symptomatic anemia, red blood cell transfusions should be performed before therapy. RLT with 177 Lu-PSMA I&T can have a positive effect on myelosuppression, with less need for blood transfusions 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.)

[0410] (3) Platelets ≤ 70 x 10 9 / l.

[0411] (4) Creatinine > 1.5 UNL; renal failure with creatinine clearance < 30 ml / min

[0412] (5) Absolute obstruction in renal excretion.

[0413] (6) Prior chemotherapy or bone-targeted radionuclide therapy and external beam irradiation fields extending to the bone marrow (pelvis, spine) if performed during the 4-week period prior to RLT

[0414] (7) ECOG performance status > 2.

[0415] (8) Hypersensitivity to the active substance or any excipient.

[0416] After identifying patients in need, the activity of the radiopharmaceutical composition can be confirmed before administration. 177 The radioactivity of the Lu-PSMA I&T composition can be 6.5 - 7.5 GBq or in the range of 6.0 - 8.0 GBq. In cases of impaired renal function (e.g., creatinine within 1.0 - 1.5 UNL), the radioactivity can be reduced to 4.0 - 5.0 GBq.

[0417] The radiopharmaceutical composition solution can be intravenously infused in the form of a slow bolus (over about 10 - 15 minutes), followed by 500 - 1000 ml of Ringer's solution or NaCl solution. The patient can be encouraged to urinate as frequently as possible and drink about 2 liters of water per day. A diuretic can be administered to patients with dilated non-obstructive nephropathy.

[0418] The pharmaceutical composition can be administered by RLT in 2 - 11 cycles every 5 - 8 weeks. In the case of a continuously increasing PSA, after the deterioration of the general condition in the first two cycles, the indication for additional RLT can be re-evaluated. In the case where the PSA drops to <1.0 μg / l during the therapy cycle, when the post-injection SPECT study is not sufficient to provide information, PSMA imaging can be used to evaluate the presence of small PSMA-positive metastases after the completion of RLT. In the case of a significant decrease in platelets or white blood cells, the time interval between two cycles can be extended.

[0419] At least one whole-body scan (preferably with SPECT / CT) can be performed 24 - 48 hours after injection. In patients with diffuse bone and bone marrow metastases and in patients with brain metastases, concomitant corticosteroid therapy (e.g., prednisone 20 mg / day) can be administered within the first two weeks after the administration of the radiopharmaceutical composition.

[0420] In some embodiments, after the administration of the radiopharmaceutical composition, the patient can have an improved radiographic progression-free survival (rPFS). The rPFS of a patient receiving the radiopharmaceutical composition can be about 6 months to about 12 months after the start of the administration of the radiopharmaceutical composition. In various embodiments, the rPFS of a patient receiving the radiopharmaceutical composition can be at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months after the start of the administration of the radiopharmaceutical composition. For example, 177 treating patients with Lu-PSMA I&T can increase the rPFS from 6 months with standard of care to up to 10 months with the radiopharmaceutical composition. The radiographic progression-free survival can be defined as the time from randomization to radiographic progression (using the PCWG3 and RECIST 1.1 criteria, as evaluated by blinded independent central review [BICR]) or death from any cause.

[0421] In one embodiment, after initiation of administration of the radiopharmaceutical composition, the patient may have an improved overall survival (OS). The overall survival of a patient administered the radiopharmaceutical composition may be from about 18 months to about 26 months after initiation of administration of the radiopharmaceutical composition. In various embodiments, the OS of a patient administered the radiopharmaceutical composition may be at least 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, or 26 months after initiation of administration of the radiopharmaceutical composition. For example, treating a patient with 177 Lu-PSMA I&T can increase the OS from 18 months with standard of care to up to 25 months with the radiopharmaceutical composition.

[0422] In another embodiment, after initiation of administration of the radiopharmaceutical composition, the patient may have an improved second radiographic progression-free survival (rPFS2).

[0423] In some embodiments, after initiation of administration of the radiopharmaceutical composition, the patient may have an improved progression-free survival. In additional embodiments, after initiation of administration of the radiopharmaceutical composition, the patient may have an improved second progression-free survival. The second progression-free survival may be the second occurrence of PCWG3 progression, clinical / symptomatic progression, and / or pain progression or death from any cause.

[0424] In one embodiment, after initiation of administration of the radiopharmaceutical composition, the patient may have an improved PSA 50 response rate. The PSA 50 response rate may be the response rate of patients achieving a ≥50% reduction in PSA relative to baseline PSA assessment.

[0425] In one embodiment, after initiation of administration of the radiopharmaceutical composition, the patient may have an improved time to first symptomatic skeletal event (SSE). SSE may be the result of bone-directed radiotherapy or tumor-related orthopedic surgery for relief of bone pain, new symptomatic pathologic fracture, or spinal cord compression.

[0426] In one embodiment, after initiation of administration of the radiopharmaceutical composition, the patient may have an improved time to soft tissue progression (STP). STP may include radiographic progression in soft tissue. In another embodiment, after initiation of administration of the radiopharmaceutical composition, the patient may have an improved time to chemotherapy (TTC).

[0427] In one embodiment, after initiation of administration of the radiopharmaceutical composition, the patient may have improved results on a quality of life questionnaire. For example, quality of life (QoL) can 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 thirty quality of life (QoL) questions developed to evaluate QoL in cancer patients. The EORTC QLQ-C30 contains 30 items, 24 of which are aggregated into nine multi-item scales scored from 0 to 100.

[0428] Example

[0429] The following non-limiting examples are provided for illustrative purposes only and should not therefore be taken as having a limiting significance.

[0430] Analysis procedure

[0431] Subsequently, reference solutions and formulated solutions of Lu-PSMA I&T are injected into a liquid chromatography system for product identification. Radionuclide identity is determined by gamma-ray energy detection.

[0432] pH is estimated by pH paper. Radioactivity is measured in a dose calibrator. Radiochemical purity is determined by liquid chromatography radioactivity detection and thin layer chromatography.

[0433] 177 The radioactivity of [Lu]Lu-PSMA I&T is determined by a dose calibrator at the time of dispensing the dose.

[0434] The bacterial endotoxin content of each batch is determined using a PTS-tester (Ph. Eur. method D, USP <85>) before release. Sterility is determined according to Ph. Eur. and USP <71>.

[0435] The quality (e.g., specificity, linearity, and reproducibility) of the analytical procedures used for the drug product was studied by using reference standards of known unlabeled precursors. All analytical procedures were found to meet their intended use.

[0436] No acceptable criteria for radioactivity in the formulation are set as this will vary according to the individual clinical needs assessed by the healthcare professional responsible for administering the formulation. At the date and time stated on the label, the radioactivity content must be within 90%-110% of the stated value.

[0437] Example 1: Preparation 177 Method for preparing a LU-PSMA I&T radiopharmaceutical formulation

[0438] ​Multiple radiopharmaceutical compositions are produced using the methods outlined in Tables 2A and 2B below. Radiolabeling is performed using non-carrier-added 177 Lu]LuCl3. Compositions 1 and 2 are substantially the same. In Composition 3, the pH of the ascorbic acid solution is adjusted to 4.5, the amount of ascorbic acid is reduced, the amount of ethanol is reduced, and the pH of the final radiopharmaceutical composition is adjusted to 4.5. This gives Composition 3 an extended shelf life compared to Compositions 1 and 2.

[0439] 177 The synthesis of 177 Lu]-PSMA I&T is carried out using an automated synthesis module in a controlled environment. A labeling solution containing 177 Lu] lutetium chloride ( 177 Lu]LuCl3) is connected to a synthesis cassette containing the other chemical components required for the labeling process. The 177 LuCl3 solution is transferred to a reactor for radiolabeling and can be rinsed with an additional required amount of 0.04M HCl solution. The volume of the labeling solution varies according to the

[0440] radioactivity of 177 Lu. 177 The

[0441] Lu]-PSMA I&T is formed in situ and directly formulated into a drug product. 177 To achieve final volume adjustment, a formulation matrix of water for injection containing 50 mg / ml ascorbic acid and ethanol is added to the bulk vial. The composition of the final product is fixed, and the amount of the added formulation matrix depends on the

[0442] radioactivity of

[0443] Lu used in the batch.

[0444] Quantify radiochemical impurities by chromatographic methods (HPLC and TLC). The radiochemical purity determined by HPLC must be not less than 95.0%.

[0445] Dilute the bulk product to a fixed radioactivity concentration of approximately 500 MBq / ml according to the total radioactivity generated.

[0446] Filter the solution through a 0.22 μm membrane filter into sterile product vials. In addition to the patient dose, sample vials (chemical QC samples, microbiological QC samples, and reference samples for retention) are allocated from each production batch. The final product is dispensed in a Class A controlled environment. Test the integrity of the filter by performing a bubble point test before product release after filtration. Check the fill weight / volume and radioactivity of the dispensed patient vials. The solution is ready for use after pre-release quality control and QP release.

[0447] Monitor the radioactivity with a dose calibrator after the labeling process to ensure successful labeling and verify the dispensed dose during dispensing.

[0448] Table 2A: Radiolabeling process

[0449]

[0450] Compositions 1 - 3 obtained from Processes 1 - 3 are provided in Table 2B below, which provides the composition for a 1 ml volume and for 10 ml or 20 ml vials of each composition.

[0451] Table 2B: 177 Lu]Lu-PSMA I&T Compositions 1 - 3.

[0452]

[0453]

[0454] Example 2: Stability of radiochemical compositions

[0455] Tested 177 the stability of Lu-PSMA I&T Composition 1, and the radiochemical purity and chemical characteristics are shown for samples stored at +5 °C, +20 °C, and +40 °C to provide adequate stability for 48 hours from the end of synthesis, Table 3.

[0456] The stability study showed that compared with 177 Lu]Lu-PSMA I&T Composition 1, 177The Lu-Lu-PSMA I&T composition 3 (Tables 4A - 4H) has improved stability and an extended shelf life.

[0457] Within the time span of 70 to 72 hours from the end time of synthesis, the radiochemical purity and chemical characteristics (pH, impurities, visual characteristics) of Lu-Lu-PSMA I&T in the formulated composition 3 were tested in seven batches. Stability samples with typical therapeutic dose radioactivity and volume were stored under different conditions covering typical storage, transportation, and use of the product, including temperatures ranging from +5°C to +40°C. 177 The Lu-Lu-PSMA I&T composition 3 (Tables 4A - 4H) has improved stability and an extended shelf life.

[0458] At the end of dispensing, the final radioactivity concentration in the sample solution varied from 497 MBq / ml to 642 MBq / ml.

[0459] All stability samples met the set acceptance criteria. In all analyzed samples, the radiochemical purity was ≥95.7% after 70 hours or 72 hours after the end of synthesis time.

[0460] Based on the results, the Lu-Lu-PSMA I&T solution in the formulated composition 3 was stable under the different storage conditions tested. 177 The Lu-Lu-PSMA I&T solution in the formulated composition 3 was stable under the different storage conditions tested.

[0461] Table 3: 177 Stability data of Lu-Lu-PSMA I&T composition 1.

[0462]

[0463]

[0464] Table 4A: 177 Chemical quality in the validation batch of Lu-Lu-PSMA I&T composition 3.

[0465]

[0466]

[0467] The radiation measurement of the test sample RT = UV RT of the reference standard ±5%.

[0468] Table 4B: 177 Stability data of Lu-Lu-PSMA I&T composition 3.

[0469]

[0470]

[0471] Radiation measurement of the test sample RT = UV RT of the reference standard ± 5%. Table 4C: 177 Stability data of Lu-PSMA I&T composition 3.

[0472]

[0473]

[0474] Radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0475] Table 4D: 177 Stability data of Lu-PSMA I&T composition 3.

[0476]

[0477] Radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0478] Table 4E: 177 Stability data of Lu-PSMA I&T composition 3.

[0479]

[0480] Radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0481] Table 4F: 177 Stability data of Lu-PSMA I&T composition 3.

[0482]

[0483]

[0484] Radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0485] Table 4G: 177 Stability data of Lu-PSMA I&T composition 3.

[0486]

[0487]

[0488] Radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0489] Table 4H:177 Stability data of Lu-PSMA I&T Composition 3.

[0490]

[0491]

[0492] The radiometric measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0493] Table 4I - Release data from a commercial-scale development batch of Composition 4

[0494]

[0495]

[0496] Table 4J – Stability data from Composition 4

[0497]

[0498] 177 The specifications of the [Lu]Lu-PSMA I&T solution are presented in Table 5 below. The listed specifications are used as release parameters, except for the sterility test. After release, the sterility of all batches is tested.

[0499] Table 5: 177 Specifications of [Lu]Lu-PSMA I&T

[0500]

[0501]

[0502] Example 3: 177 Radiochemical purity of Lu-PSMA I&T in different formulation compositions

[0503] The example demonstrates 177 the radiochemical stability of Lu-PSMA I&T in formulation compositions at different pH values. 177 The shelf life of Lu-PSMA I&T is limited by the high radiolytic decomposition rate during preparation and storage, resulting in 177 the decomposition of Lu-PSMA I&T and the formation of radiochemical impurities. This ultimately causes 177 the radiochemical purity of the Lu-PSMA I&T solution to drop below the acceptable limit of 95.0%.

[0504] ​By HPLC with a Phenomenex Luna C18 column (3 μm, 150 mm x 4.6 mm), using an isocratic method with 0.1% aqueous trifluoroacetic acid (mobile phase A) and 0.1% aqueous trifluoroacetic acid:acetonitrile (10:90% v / v) (mobile phase B) and 23% mobile phase B at a temperature of 40 °C, a retention time of approximately 5.2 minutes has been observed for 177 the formation of specific radiochemical impurities of Lu-PSMA I&T. In Figures 6A - 11B the chromatogram in shows the impurity with a retention time of approximately 5.2 minutes as mentioned herein.

[0505] In previous experiments, reducing the radioactivity concentration of the formulation was sufficient to reduce the formation of the impurity eluting at approximately 5.2 minutes and to maintain the radiochemical stability of the 177 Lu]Lu-PSMA I&T solution above 95.0% for 72 hours.

[0506] In this example, six experiments were conducted in which 177 Lu]Lu-PSMA I&T was prepared in different formulation compositions with different ascorbic acid concentrations, pH, and radioactivity concentrations. The product formulation details are described in Table 6.

[0507] Table 6: The 177 Lu]Lu-PSMA I&T formulation compositions evaluated

[0508]

[0509]

[0510] The high radioactivity concentrations (high RAC) in the sample solutions measured at the end of production were 1278 MBq / ml, 1281 MBq / ml, and 1311 MBq / ml. The low radioactivity concentrations (low RAC) in the sample solutions measured at the end of production were 579 MBq / ml, 589 MBq / ml, and 626 MBq / ml. The radiochemical purity of each solution was tracked by HPLC up to 71 - 93 hours after radiolabeling. All solutions were stored at 22.5 °C.

[0511] Figure 5 The results of the radiochemical purity analysis at different time points determined by HPLC are shown.

[0512] Figure 6A and Figure 6B show the HPLC radiochromatograms of Experiment 1 at 0 hours and 71 hours after EOS, respectively.

[0513] Figure 7A andFigure 7B The HPLC radiochromatograms of Experiment 2 at 0 hours and 71 hours after EOS are shown respectively.

[0514] Figure 8A and Figure 8B The HPLC radiochromatograms of Experiment 3 at 0 hours and 90 hours after EOS are shown respectively.

[0515] Figure 9A and Figure 9B The HPLC radiochromatograms of Experiment 4 at 0 hours and 92 hours after EOS are shown respectively.

[0516] Figure 10A and Figure 10B The HPLC radiochromatograms of Experiment 5 at 0 hours and 71 hours after EOS are shown respectively.

[0517] Figure 11A and Figure 11B The HPLC radiochromatograms of Experiment 6 at 0 hours and 93 hours after EOS are shown respectively.

[0518] The radiochemical stability results of each experiment at different time points are provided in Table 5 - 10.

[0519] Table 5: Experiment 1

[0520]

[0521] Table 6: Experiment 2

[0522]

[0523] Table 7: Experiment 3

[0524]

[0525] Table 8: Experiment 4

[0526]

[0527] Table 9: Experiment 5

[0528]

[0529] Table 10: Experiment 6

[0530]

[0531] In the examples, the pH of the formulation composition has a considerable impact on 177 the radiochemical stability of Lu - PSMA I&T, and more specifically on the formation of radiochemical impurities eluting at approximately 5.2 minutes, as shown in Figures 6A - 11BAs exemplified. In the high RAC solution, the decrease in radiochemical purity over time at pH 4.5 is 1 / 2 of the decrease in radiochemical purity over time at pH 7.

[0532] Compared to the pH 4.5 solution, further reducing the formulation pH to 3.5 did not show a measurable improvement in radiochemical stability. It is possible that the ascorbic acid solution at pH 4.5, which is close to the pKa value of ascorbic acid, already has a sufficient amount of protons to act as an inhibitor against 177 the radiolytic decomposition of Lu-PSMA I&T and reduce the formation of radiochemical impurities eluting at approximately 5.2 minutes.

[0533] Incorporating a solution with a pH of 4.5 into the lower RAC formulation further improved 177 the radiochemical stability of Lu-PSMA I&T. In the lower RAC formulation, 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.

[0534] As measured by HPLC, the radiochemical purity of a 10 ml high RAC 177 Lu-PSMA I&T formulation composition containing 42.5 mg / ml ascorbic acid was at least about 99% at 0 hours after EOS and at least about 93.3% at 46 hours after EOS. The radiochemical purity decreased as the pH of the formulation increased from pH 4.5.

[0535] As measured by HPLC, the radiochemical purity of a 20 ml low RAC 177 Lu-PSMA I&T formulation containing 31 mg / ml ascorbic acid was at least about 99.1% at 0 hours after EOS. Compared to a pH of 5, the rate of decrease in the radiochemical purity of the low RAC 177 Lu-PSMA-I&T formulation over time was slower.

[0536] The results demonstrate that, compared to formulation compositions with a pH higher than 5, formulation compositions with a pH of 5 or lower can significantly reduce the formation of radiochemical impurities eluting at approximately 5.2 minutes and thus enhance 177 the radiochemical stability of Lu-PSMA I&T. Additionally, 177 the radiochemical stability of Lu-PSMA I&T can be further improved by incorporating a low solution RAC. In the examples, 177The Lu-PSMA I&T solution shows the highest radiochemical stability in a low RAC solution at pH 4.5 with an ascorbic acid concentration of 31 mg / ml. This formulation is considered to minimize the formation of radiochemical impurities and maintain 177 a preferred composition with the radiochemical stability of Lu-PSMA I&T maintained above 95.0% for 72 hours or longer.

[0537] Example 4: Compared with third-line treatment, the efficacy of treatment using 177 Lu-PSMA-617 and 177 both Lu-PSMA-I&T

[0538] 177 Dosimetry of Lu-PSMA I&T

[0539] 177 There is not much difference in the absorbed dose estimates between Lu-PSMA I&T and 177 Lu-PSMA-617. 177 The specific known dosimetry of Lu-PSMA I&T is shown below.

[0540] For normal organs, the mean whole-body effective dose for all cycles is 0.41 ± 0.18 Sv (0.06 Sv / GBq). The mean absorbed organ dose for the kidneys is 5.3 ± 1.6 Gy (0.72 Gy / GBq); for the liver, it is 0.89 ± 0.42 Gy (0.12 Gy / GBq); for the parotid glands, it is 4.0 ± 1.1 Gy (0.55 Gy / GBq), for the submandibular glands, it is 4.8 ± 2.8 Gy (0.64 Gy / GBq), and for the lacrimal glands, it is 27 ± 10 Gy (3.8 Gy / GBq).

[0541] When comparing the absorbed doses of normal organs with the number of cycles, no substantial differences were observed (Table 13). The mean organ masses on which these absorbed dose estimates are based are: liver 1.595 ± 307 g (range 1,165 - 2,373 g), kidneys 153 ± 29.9 g (range 88.4 - 218.7 g), parotid glands 19.1 ± 5.7 g (range 8.0 - 35.6 g), submandibular 8.2 ± 1.9 g (range 4.2 - 14.3 g), and lacrimal glands 0.45 ± 0.12 g (range 0.25 - 0.78 g). For paired organs, the masses of both sides were added.

[0542] For tumor lesions, the mean dose received per cycle for all lesions was 23 ± 20 Gy (3.3 Gy / GBq). 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), respectively.

[0543] The corresponding absorbed dose / GBq values (mean, SD, and range) for normal organs and tumor lesions are presented separately in the table below.

[0544] Table 11: Whole body effective dose (in Sv / GBq) and absorbed dose in normal organs (in Gy / GBq).

[0545]

[0546]

[0547] Table 12: Absorbed dose in tumor lesions (in Gy / GBq)

[0548] Investigation period All metastases Bone metastases Lymph node metastases Liver metastases Lung metastases Total (n) 93 74 8 8 3 Mean ± SD 3.2±2.6 3.4±2.7 3.2±2.2 1.2±0.67 1.75±0.92 Range 0.22-12.03 0.22-12.03 1.63-8.46 0.47-2.59 0.94-2.68 First cycle (n) 41 33 5 2 1 Mean ± SD 3.5±2.9 3.8±3.1 2.6±0.89 1.7 2.7 Range 0.22-12.03 0.22-12.03 1.63-3.76 0.85-2.59 Second cycle (n) 26 21 2 2 1 Mean ± SD 3.3±2.5 3.4±2.4 5.2 0.94 1.3 Range 0.70-8.46 1.03-9.59 1.98-8.46 0.70-1.17 Third cycle (n) 14 10 1 2 1 Mean ± SD 2.7±2.3 3.2±2.5 2.6 0.95 0.94 Range 0.94-7.99 1.11-7.99 18.87 0.47-1.42 Fourth cycle (n) 12 10 2 Mean ± SD 2.4±2.2 2.7±2.3 1.13 Range 0.74-7.60 1.04-7.60 0.74-1.51

[0549] With the increase in the number of cycles, the absorbed dose showed an obvious downward trend. 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 could be seen in the subgroup of bone metastases. Due to the small number of samples, reliable comparisons could not be made for lymph node, liver, and lung metastases. 177 The effective half-life and mean absorbed dose of Lu-PSMA I&T are shown in the table below.

[0550] 177 Lu-PSMARLT (the study included 177 Lu-PSMA-617 and 177 Lu-PSMA I&T both) had better efficacy and fewer adverse reactions than third-line treatment. Twelve studies including 669 patients reported 177 Lu-PSMA RLT. Overall, 44% of the patients had a maximum PSA decline ≥ 50% after receiving 177 Lu-PSMARLT treatment. For imaging and therapy (I&T), 177 Lu-PSMA-617 and 177Treatment with Lu-PSMA has mainly transient adverse reactions. Sixteen studies including 1,338 patients reported third-line treatment. Overall, 21% of patients had a best decline in PSA ≥ 50% after third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, 10% to 23% of patients discontinued treatment due to adverse reactions. Compared with third-line treatment, 177 the frequency of best PSA decline ≥ 50% was higher with Lu-PSMA RLT (mean 44% vs 22%, p = 0.0002, t-test). Compared with third-line treatment, 177 the objective response was higher with Lu-PSMA RLT (31 out of 109 patients overall vs 43 out of 275 patients, P = 0.004, χ2 test). Compared with after third-line treatment, 177 the median survival was longer after Lu-PSMA RLT, but the difference was not statistically significant (mean 14 months vs 12 months, p = 0.32, t-test). Compared with 177 Lu-PSMA RLT, adverse reactions with third-line treatment led to a higher frequency of treatment discontinuation (22 out of 66 patients vs 0 out of 469 patients, p < 0.001, χ2 test).

[0551] The purpose of this Investigational Medicinal Product Dossier (IMPD) is to provide a scientific and ethical platform for this useful treatment with 177 Lu-PSMA I&T to initially conduct its application, preferably in academic centers and under a controlled research protocol. Except for 177 Lu-PSMA-617, there are no other guidelines currently. The information in this IMPD is based on the latest literature and the best available experience in nuclear medicine centers that have been treating PC patients in this manner.

[0552] Synthesis is a one-step labeling process using only injection-grade ethanol and water as solvents. Therefore, there are no residual solvents. Radiochemical impurities are quantified by chromatographic methods (HPLC and TLC). The radiochemical purity can be not less than 95.0%.

[0553] Example 5: Comparison 177 A multicenter, open-label, randomized phase 3 trial comparing the safety and efficacy of Lu-PSMA I&T

[0554] A multicenter, open-label, randomized phase 3 trial compared the safety and efficacy of a composition containing 177 Lu-PSMA I&T with hormone therapy in patients with metastatic castration-resistant prostate cancer.

[0555] This study aimed to identify and characterize the use of 177The safety and efficacy of Lu-PSMA I&T in adult male human patients (males) with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed after a course of standard-of-care hormonal therapy.

[0556] 177 Lu-PSMA I&T is a radiotherapeutic agent that specifically targets the prostate-specific membrane antigen protein expressed on metastatic prostate cancer cells.

[0557] In this study, 177 Lu-PSMA I&T is provided as a sterile, filtered radiopharmaceutical solution that contains a microdose of 177 Lu-PSMA I&T in an aqueous solution of ascorbic acid and ethanol.

[0558] Patients randomized according to the standard-of-care hormonal therapy for mCRPC will receive treatment with abiraterone acetate and prednisone or enzalutamide based on the independent medical judgment of the investigator.

[0559] The combination of abiraterone acetate and prednisone is indicated 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, which is an androgen biosynthesis inhibitor that inhibits 17α-hydroxylase / C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostate tumor tissues and is essential for androgen biosynthesis.

[0560] Enzalutamide is an androgen receptor inhibitor indicated for the treatment of patients with CRPC or mCSPC (metastatic castration-sensitive prostate cancer). It has been shown that enzalutamide competitively inhibits the binding of androgens to the androgen receptor and thus inhibits nuclear translocation of the androgen receptor and its interaction with DNA.

[0561] A. Study Objectives and Endpoints

[0562] The primary objective of this study is to prospectively evaluate the improved efficacy of Lu-PSMA I&T in terms of radiographic progression-free survival (rPFS) in males with metastatic castration-resistant prostate cancer (mCRPC) compared to standard-of-care hormonal therapy, as determined by PCWG3-modified RECIST 1.1. The endpoint for this objective is the time from randomization to radiographic progression, as determined by Prostate Cancer Working Group 3 (PCWG3) criteria and evaluated by blinded independent central review. 177 The secondary objectives are to evaluate, compared to patients receiving standard hormonal therapy,

[0563] 177Does Lu-PSMA I&T improve overall survival (OS) in patients with mCRPC? The endpoint for this objective is the time from randomization to death from any cause.

[0564] Other secondary objectives and endpoints include:

[0565] ● Objective : To evaluate the improvement in overall survival (OS) in men with mCRPC receiving 177 Lu-PSMA I&T compared to hormone therapy; Endpoint : Time from randomization to second radiographic progression after crossover, as determined by BICR (Blinded Independent Central Review) using PCWG3 or RECIST 1.1.

[0566] ● Objective : To evaluate the change in time to second radiographic progression in patients crossing over from the standard-of-care hormone therapy group to the 177 Lu-PSMA I&T treatment group; Endpoint : Time from randomization to second radiographic progression after crossover, as determined by BICR using PCWG3 or RECIST 1.1,

[0567] ● Objective : To identify the change in progression-free survival (PFS, composite) after 177 Lu-PSMA I&T radioligand therapy compared to standard-of-care hormone therapy; Endpoint : Time from randomization to progression (PFS, composite) based on the following events (whichever comes first): PCWG3 or RECIST progression, clinical / symptomatic progression, and / or pain progression, or death from any cause as determined by the investigator.

[0568] ● Objective : To identify the change in progression-free survival 2 (PFS2, composite) after 177 Lu-PSMA I&T radioligand therapy compared to standard-of-care hormone therapy; Endpoint : Time from randomization to second progression (PFS, composite) based on the following events (whichever comes first): PCWG3 or RECIST progression, clinical / symptomatic progression, and / or pain progression, or death from any cause as determined by the investigator,

[0569] ● Objective : To evaluate the change in PSA50 (response rate of patients with ≥50% reduction in PSA from baseline) response rate after 177 Lu-PSMA I&T radioligand therapy compared to standard-of-care hormone therapy; Endpoint: PSA50 response rate, defined as a confirmed reduction in PSA from baseline of ≥50%,

[0570] ● Objective : To determine the impact of Lu-PSMA I&T on skeletal symptoms compared to standard of care hormonal therapy; 177 Lu-PSMA I&T on skeletal symptoms; Endpoint : Time from randomization to the first asymptomatic skeletal event (skeletal symptom-free survival),

[0571] ● Objective : To determine the impact of Lu-PSMA I&T on radiographic soft tissue progression compared to standard of care hormonal therapy; 177 Lu-PSMA I&T on radiographic soft tissue progression; Endpoint : Time from randomization to radiographic soft tissue progression (rSTP), as determined by BICR per RECIST 1.1,

[0572] ● Objective : To evaluate the change in the use of chemotherapy after 177 Lu-PSMA I&T compared to standard of care hormonal therapy; Endpoint : Time from randomization to the first use of chemotherapy, and

[0573] ● Objective : To evaluate the impact of 177 Lu-PSMA I&T radioligand therapy on quality of life of hormonal therapy; Endpoint : Improvement in quality of life based on the EORTC QLQ-C30 questionnaire.

[0574] Exploratory objectives and endpoints are:

[0575] ● Objective : To evaluate any differences in objective response rate and disease control rate of 177 Lu-PSMA I&T compared to standard of care hormonal therapy; Endpoint : Objective response rate and disease control rate (DCR = complete / partial response and stable disease) based on PCWG3 criteria,

[0576] ● Objective : To evaluate the change in time to PSA progression after 177 Lu-PSMA I&T radioligand therapy compared to standard of care; Endpoint : Time from randomization to PSA progression, defined as a ≥25% increase in PSA from the post-treatment nadir, and

[0577] ● Objective : To evaluate compared to hormonal therapy, in 177Duration of response (DoR) in patients who achieved a complete or partial response after Lu-PSMA I&T radioligand therapy; Endpoint : Time from complete or partial response to radiographic progression.

[0578] B. Study design

[0579] (i) Overview and rationale

[0580] This is an open-label, randomized, multi-center phase 3 study comparing Lu-PSMA I&T radioligand therapy with hormonal therapy in men with mCRPC who have previously received androgen receptor (AR)-directed therapy. Based on the NCCN guidelines, the hormonal therapy regimens in this study are enzalutamide or abiraterone with prednisone. For patients randomized to receive standard of care, the specific treatment regimen will be selected based on the switch of the patient's previous ADRT. Based on the published literature, 177 Lu-PSMA I&T radioligand therapy has encouraging anti-tumor activity and favorable safety characteristics in men with mCRPC. 177 The study consists of a screening period, a treatment period, and a post-treatment follow-up period. The study uses a 2:1 randomization method and is divided into the following treatment groups: (1)

[0581] Lu-PSMA I&T radioligand therapy, or (2) standard of care hormonal therapy. The standard of care hormonal treatment options are abiraterone with prednisone or enzalutamide, and the specific selection is based on the investigator's clinical judgment. Patients randomized to the hormonal therapy group will be selected to cross over to the radiographic ligand therapy group after radiographic progression is recorded. 177 Patients will undergo safety and efficacy follow-up according to the activity schedule and will continue to receive study treatment until documented radiographic progression as evaluated by blinded independent central review (BICR) or unacceptable toxicity occurs. Patients who discontinue treatment due to documented radiographic progression will enter the long-term follow-up period. Patients who discontinue treatment before documented radiographic progression will continue to receive planned disease assessments every three months until documented radiographic progression.

[0582] In addition, a sub-study was conducted in patients randomized to receive

[0583] Lu-PSMA I&T radioligand therapy according to the protocol to evaluate pharmacokinetics and radiation dosimetry (as discussed in Example 4 above). 177 Lu-PSMA I&T radioligand therapy to evaluate pharmacokinetics and radiation dosimetry (as discussed in Example 4 above).

[0584] Due to the nature of the treatment, the identity of the test and control treatments will be known to the investigators, research staff, and patients. This study cannot be blinded. For patients with disease progression, after the investigators have determined progressive disease, and for patients without disease progression, after the study has ended, radiographic images will be blindly read and interpreted by a panel of up to three trained independent radiologists to assess the overall response rate to treatment, and the radiologists will not have access to clinical information or treatment groups.

[0585] The severity of AEs and SAEs will be graded based on the symptoms of the subject according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. For AEs not defined in the current version of CTCAE, the severity will be evaluated according to the following criteria:

[0586] ● Grade 1 = Mild: Transient or mild discomfort, no restriction of activity, no medical intervention / therapy required

[0587] ● Grade 2 = Moderate: Mild to moderate restriction of activity, may require some assistance; no or minimal medical intervention / therapy required

[0588] ● Grade 3 = Severe: Marked restriction of activity, usually requires some assistance; medical intervention / therapy required, may require hospitalization

[0589] ● Grade 4 = Life-threatening: Extreme restriction of activity, requires substantial assistance; substantial medical intervention / therapy required, likely hospitalization or hospice

[0590] ● Grade 5 = Death: An event resulting in death

[0591] 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. An AE of severity may not be considered serious. Seriousness, rather than severity, is the guide for defining regulatory obligations.

[0592] (ii) Selection of the primary endpoint

[0593] Metastatic castration-resistant prostate cancer is generally considered to be an advanced stage in the natural progression of prostate cancer. Although mCRPC generally has a poor prognosis, the disease progression of many patients is relatively slow, so the overall survival range is large, and approximately 15% of men with mCRPC survive for more than 5 years (Moreira et al., Clin Genitourin Cancer, 2017; 15(1): 60-66).

[0594] Given the relatively wide range of overall survival in men with mCRPC, this study selected radiographic progression-free survival, as determined by RECIST 1.1 (soft tissue lesion status) and Prostate Cancer Working Group 3 (PCWG3) criteria (bone lesion status) as assessed by blinded independent central review, as the primary endpoint. Overall survival was a secondary endpoint of the study, and patients will be followed for overall survival for 5 years after enrollment.

[0595] (iii) Study Results

[0596] The primary efficacy outcome was radiographic progression-free survival. Once radiographic progression was confirmed by BIRC, study treatment was terminated. Patients then entered the follow-up period of the trial to assess overall survival over a 5-year follow-up period from the date of study enrollment.

[0597] Safety was evaluated by assessing the following safety parameters before the end of treatment and during a 1-month follow-up period: adverse events, vital signs, changes in concomitant medications / therapies, changes in physical examinations, and clinical laboratory measurements.

[0598] C. Patient Selection

[0599] (i) Study Population

[0600] The study population will include patients with mCRPC with progressive disease based on RECIST 1.1 criteria modified for PCWG3.

[0601] (ii) Inclusion criteria included:

[0602] 1. Males 18 years of age or older.

[0603] 2. Histologically or pathologically confirmed adenocarcinoma of the prostate without a major small cell component.

[0604] 3. Progressive disease according to one or more of the following criteria:

[0605] a. Serum / plasma PSA progression was defined as PSA increasing on 2 consecutive occasions from a previous reference value, with a measurement interval of at least 1 week and a minimum starting value >2 ng / mL.

[0606] b. Progression of measurable disease (RECIST 1.1) or the appearance of at least two new bone lesions (PCWG3 criteria)

[0607] 4. Prior treatment with a new generation of androgen receptor (AR)-directed therapy (e.g., abiraterone, enzalutamide, apalutamide, darolutamide).

[0608] a. Must have received no more than one AR-directed therapy previously.

[0609] b. ARAT (abiraterone, enzalutamide, darolutamide or apalutamide) must have been administered in either a castration-sensitive or castration-resistant setting.

[0610] c. Progression must have occurred while on ARAT.

[0611] 5. PSMA-PET scan (e.g., 68 Ga]Ga-PSMA-11 or 18 F]DCFPyL) positive as determined by a central reader.

[0612] 6. Effective castration with serum testosterone level <50 ng / dL and planned continuation of chronic medical or surgical castration.

[0613] 7. HIV patients who are healthy and at low risk for acquired immunodeficiency syndrome-related outcomes may participate at the discretion of the investigator.

[0614] 8. Patients with HBV and HCV may also participate if their symptoms are adequately managed.

[0615] 9. Life expectancy of at least 6 months as assessed by the investigator.

[0616] 10. Willingness to initiate ARAT therapy as determined by the investigator.

[0617] (iii) Exclusion criteria include:

[0618] 1. Prior receipt of radioligand therapy, including other lutetium-labeled compounds.

[0619] 2. Prior receipt of radium-223 (Xofigo) treatment within the past 12 weeks.

[0620] 3. Prior receipt of chemotherapy (docetaxel or cabazitaxel) for castration-sensitive or castration-resistant prostate cancer.

[0621] 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2.

[0622] 5. Patients with known HRR (haploid relative risk) gene mutations who have not previously received olaparib or rucaparib.

[0623] 6. Receiving other cytotoxic chemotherapy, immunotherapy, radioligand therapy or investigational therapy.

[0624] 7. Organ and bone marrow dysfunction manifested as:

[0625] a. Hemoglobin <8 g / dL.

[0626] b. Absolute neutrophil count < 1.5 x 109 / L.

[0627] c. Platelet count < 100 x 109 / L.

[0628] d. AST / SGOT and / or ALT / SGPT > 3.0 x ULN (where: "AST" is aspartate aminotransferase, "SGOT" is serum glutamate-oxaloacetate transaminase, "SGPT" is serum glutamate-pyruvate transaminase, and "ALT" is alanine aminotransferase).

[0629] e. Total bilirubin > 2 x ULN (upper limit of normal), unless the patient has known Gilbert's syndrome, and then it may be 3 x ULN.

[0630] f. Creatinine clearance (CrCl) based on the Cockcroft-Gault equation < 50 mL / min.

[0631] g. Albumin ≥ 2.75 g / dL

[0632] 8. Patients who have received transfusions only for eligibility for this study.

[0633] 9. Have used the study treatment drug within the 4 weeks prior to the start of the study treatment, or plan to use the study treatment drug during the study period.

[0634] 10. Known CNS metastases, unless they have received therapy, are asymptomatic and neurologically stable.

[0635] 11. Patients receiving zoledronic acid bone-targeted therapy must have taken a stable dose for 4 weeks prior to randomization.

[0636] 12. Patients with severe heart disease

[0637] 13. Participants with symptomatic spinal cord compression or clinical / radiological findings indicating impending spinal cord compression.

[0638] 14. Patients with superscan on baseline bone scan, as determined by the investigator.

[0639] 15. Active malignancies other than low-grade non-muscle invasive bladder cancer and non-melanoma skin cancer.

[0640] 16. Persistent neutropenia after previous treatment with G-CSF (granulocyte colony-stimulating factor) for standard of care treatment.

[0641] 17. Participants with active Covid19. Recovered patients can also be included in the study after complete recovery (asymptomatic for at least 28 days before taking the study drug and negative for Covid test within 72 hours).

[0642] D. Dosage, route of administration, and dosing schedule of the study product

[0643] (i) 177 Lu-PSMA I&T

[0644] The pharmaceutical product is a sterile filtered radioactive drug solution containing a microdose of 177 Lu-PSMA I&T formulated in an aqueous solution containing ascorbic acid and ethanol. The standard activity of the product at expiration is approximately 200 mCi, and the standard concentration at the end of production is approximately 27 mCi / mL; therefore, the final volume of the dose vial is adjusted to be between 7.0 mL and 10.0 mL to provide the required amount of radioactivity at the infusion date and time. 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 radioactive drug is kept in a lead-shielded container until use. 177 Lu-PSMA I&T is stored at 25 °C; a temperature deviation between 15 °C - 30 °C is allowed. The expiration date and time of each vial shipped to the clinical site will be noted on the shielding label.

[0645] (ii) Standard of care hormonal therapy

[0646] The standard of care hormonal therapy methods are:

[0647] ● Abiraterone acetate and prednisone: Abiraterone acetate is a CYP 17 inhibitor used in combination with prednisone or methylprednisone. Prednisone is a glucocorticoid. Glucocorticoids are adrenal cortical steroids that are readily absorbed from the gastrointestinal tract.

[0648] ● Enzalutamide is an androgen receptor inhibitor.

[0649] (iii) Preparation

[0650] All infusion solutions will be prepared and dispensed by the site before administration. The preparation of the solution should be carried out under aseptic conditions, and the final solution should be visually inspected for particulate matter. If an insoluble precipitate is observed, the solution should be discarded.

[0651] 177The Lu-PSMA I&T injection solution is administered as supplied. Before and after administration to the patient, the radioactivity in the vial should be measured in a calibrated radiation dose calibrator. The administered dose should then be calculated and recorded.

[0652] (iv) Administration and dosing

[0653] Patients will be randomized 2:1 to receive 177 Lu-PSMA I&T radioligand therapy or standard-of-care hormonal therapy.

[0654] 177 Lu-PSMA I&T administration: Patients randomized to receive radioligand therapy will receive a single intravenous radioactive dose of 200 mCi (7.4 GBq) ± 10% of 177 Lu-PSMA I&T at the start of each treatment cycle.

[0655] An intravenous line should be established before administration of 177 Lu-PSMA I&T. 177 Lu-PSMA I&T will be administered as a slow bolus over at least 10 to 15 minutes according to the site's standard radioligand therapy administration procedure. For 177 two days after Lu-PSMA I&T administration, patients should be encouraged to void as frequently as possible and drink two liters of fluid per day.

[0656] Thirty minutes before injection of 177 Lu-PSMA I&T and up to 4 hours after injection of 177 Lu-PSMA I&T, the patient's salivary glands should be cooled by placing ice packs on the parotid and submandibular glands to reduce the risk of salivary gland radiation damage.

[0657] A six-week treatment cycle will be used for 4 treatment cycles of 177 Lu-PSMA I&T injections, or until radiographic progression of the disease is determined based on BIRC assessment of radiographic images (up to 18 weeks of treatment). Alternatively, an eight-week treatment cycle is used for 6 treatment cycles of 177 Lu-PSMA I&T injections, or until radiographic progression of the disease is determined based on BIRC assessment of radiographic images (up to 18 weeks of treatment).

[0658] 177The dosing cycle of Lu-PSMA I&T can be extended based on the assessment of dose-limiting toxicities that occur in the patient. Dose-limiting toxicities are defined as grade 3 or 4 myelotoxicity or grade 2 or higher salivary gland toxicity. For grade 3 or 4 myelotoxicity, dosing can be resumed when improvement to grade 2 or better is observed. For grade 2 or more severe salivary gland toxicity, dosing can be resumed after the toxicity has improved to grade 1.

[0659] In addition, if a dose-limiting toxicity is identified, 177 the Lu-PSMA I&T dose should be maintained and / or reduced to 160 mCi (5.9 GBq) ± 10%. The following dose maintenance / reduction measures should be carried out accordingly:

[0660] - For ≥ grade 3 anemia: Maintain the dose until recovery to baseline or ≤ grade 2, and then reduce to 160 mCi (5.9 GBq) in the next cycle

[0661] - For ≥ grade 2 neutropenia: Maintain until recovery to baseline or ≤ grade 1

[0662] - For ≥ grade 2 thrombocytopenia: Maintain until recovery to baseline or ≤ grade 1, and reduce the dose in the next cycle to 160 mCi (5.9 GBq)

[0663] - For ≥ grade 3 non-thrombocytopenic hematotoxicity: Maintain until recovery to baseline or ≤ grade 2, and reduce the dose in the next cycle to 160 mCi (5.9 GBq)

[0664] If grade 3 or more severe acute renal toxicity occurs, dosing should be suspended in the next cycle. Dosing can be resumed when recovery to baseline or ≤ grade 2 is achieved, but all remaining doses are reduced to 160 mCi (5.9 GBq).

[0665] For any other grade 3 or higher non-hematological toxicity related to 177 Lu-PSMA I&T as determined by the investigator, the dosing cycle should be extended by an additional six weeks and the dose for the remaining cycles reduced to 160 mCi (5.9 GBq). When the toxicity has recovered to grade 2 or lower, the dosing cycle and dose level can be resumed to once every six weeks.

[0666] For all grade 3 and 4 AEs, the patient will only be able to reduce the dose once. If the event persists, the patient will need to permanently discontinue study treatment.

[0667] For grade 2 AEs, only two dose reductions are allowed. If the event persists, the patient will need to permanently discontinue study treatment.

[0668] Abiraterone acetate and prednisone: The dose of abiraterone acetate should be administered according to the package insert. According to the abiraterone package insert, for patients with baseline moderate liver function impairment, the starting dose of abiraterone should be reduced to 250 mg daily. For patients who develop hepatotoxicity during treatment, the administration of abiraterone acetate should be suspended until recovery. Retreatment can be initiated at a reduced dose. Patients with severe hepatotoxicity should discontinue abiraterone treatment.

[0669] Enzalutamide: The dose of enzalutamide is 160 mg (four 40-mg capsules), taken 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 toxicity or intolerable side effects, dosing should be suspended for one week or until the symptoms improve to ≤ Grade 2, and then resumed at the same dose or a reduced dose (80 or 40 mg) as needed.

[0670] (v) Duration of study treatment

[0671] Patients will receive treatment until radiographic progressive disease, clinical / symptomatic progression, unacceptable / uncontrollable toxicity, or the patient refuses further study treatment (i.e., revokes consent). All patients will be followed during the study treatment period and during the follow-up period after the end of study treatment: until death, the study cut-off date (at least 22 weeks after enrollment) or revocation of consent (whichever occurs first). Long-term follow-up for all patients will begin at enrollment and continue for five years until the patient dies or is lost to follow-up.

[0672] E. Study procedures and assessments

[0673] The activity schedules in Tables 13 and 14 outline the trial assessments and time points.

[0674] Table 13: 177 Event schedule for the Lu-PSMA-I&T arm.

[0675]

[0676]

[0677] EOT = End of treatment; LTFU = Long-term follow-up; US = Unscheduled

[0678] a Throughout the treatment course, CT / bone scans will be performed every 8 weeks until week 24, and then continued every 12 weeks for LTFU if there is no progression.

[0679] bAccording to Section 8.5, during the entire LTFU period, a progression assessment was conducted every 12 weeks until radiographic evidence of disease progression was found.

[0680] Table 14: Event schedule for the standard-of-care hormonal therapy group.

[0681]

[0682] EOT = End of treatment; LTFU = Long-term follow-up; US = Unscheduled

[0683] a During the entire treatment course, CT / bone scans were performed every 8 weeks until week 24, and then continued with LTFU every 12 weeks if there was no progression.

[0684] b During the entire LTFU period, a progression assessment was conducted every 12 weeks until radiographic evidence of disease progression was found.

[0685] (i) Clinical assessment

[0686] Clinical assessment included demographics, medical history, physical examination, vital signs, performance status, adverse events, concomitant medications / treatments, tumor assessment, and blinded independent central review (BICR).

[0687] For Performance status , the Eastern Cooperative Oncology Group (ECOG) performance status scale was used and evaluated at screening and at each subsequent outpatient visit as shown in Table 15 below:

[0688] Table 15: Eastern Cooperative Oncology Group (ECOG) performance status scale /

[0689]

[0690] Tumor assessment was conducted according to the assessment schedule, regardless of treatment delays due to toxicity. Care must be taken when planning tumor assessments to prevent bias due to treatment delays.

[0691] At screening and every 8 weeks (±1 week) after treatment initiation until Week 24 of the study, the patient's tumor response will be evaluated by CT imaging plus bone scan. Thereafter, for patients who do not show radiographic progression within the 24-week period, CT imaging and bone scan will be performed every 12 weeks (±1 week) until radiographic progression is determined. The scan schedule will be calendar-based and not based on the start of the treatment cycle. The evaluations will include CT scans of the chest, abdomen, pelvis, and brain (only when clinically indicated based on symptoms / findings). The investigator, sub-investigator, or qualified site personnel will read the bone scans and CT images to assess whether radiographic progression has occurred. If the investigator determines that the patient's metastatic prostate cancer has progressed, the patient's bone scan and CT images will be immediately transmitted to the Imaging Core Laboratory (ICL) for review by Blinded Independent Central Review (BICR) to confirm radiographic progression, as Figure 13 shown.

[0692] The investigator shall not change the treatment regimen until the disease status confirmation from BICR is received.

[0693] Blinded Independent Central Review (BICR)

[0694] ● 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 passing quality assessment). After confirmation by BICR, if all other eligibility criteria are met, the patient may be randomized into the study.

[0695] ● Radiographic disease progression: The investigator will evaluate CT and bone scans according to RECIST 1.1 and PCWG3 criteria to assess disease progression. If the investigator determines that the disease has progressed, BIRC, consisting of two independent radiologists qualified to evaluate bone scans and CT images, will independently evaluate disease progression according to RECIST 1.1 and PCWG3 criteria. Confirmation of radiographic disease progression requires agreement from two blinded readers. If the two readers disagree, a third reader will adjudicate. BICR will complete the confirmation of disease progression within 72 hours of receipt of the image set showing radiographic progression provided by the investigator, if possible. The investigator shall not make any changes to the patient's clinical management until the radiographic progression confirmation from BICR is received. Figure 13 Presents baseline and on-treatment disease status evaluations and treatment decisions.

[0696] (ii) Patient-reported outcomes

[0697] 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.

[0698] The EORTC QLQ-C30 is a questionnaire of thirty quality of life (QoL) questions developed to assess the QoL of cancer patients. The QoL questionnaire has been included as an efficacy endpoint in over 3,000 cancer phase 3 clinical trials. Patients will be administered the EORTC questionnaire at baseline, during treatment (as provided in the timeline of events in Table 15), and at the end of treatment.

[0699] The Functional Assessment of Cancer Therapy - Prostate (FACT-P) is a health-related quality of life questionnaire that contains 39 prostate cancer-specific questions and assesses the following aspects: physical health, functional health, emotional health, social health, and additional concerns specific to prostate cancer or the prostate cancer subscale. The higher the FACT-P score, the higher the quality of life. Patients will be administered the FACT-P questionnaire at baseline, during treatment, and at the end of treatment.

[0700] The Brief Pain Inventory - Short Form (BPI-SF) is a short survey used to assess the overall pain and symptoms experienced by participants. Patients will be administered the BPI-SF questionnaire at baseline, during treatment, and at the end of treatment.

[0701] F. Study Assessments by Visit

[0702] (i) Screening

[0703] Screening must be completed within 28 days prior to randomization into the study. The screening visit includes (a) drawing a blood sample and submitting it to the central laboratory to determine PSA levels and baseline clinical laboratory assessments, (b) obtaining CT scans of the brain, chest, abdomen, and pelvis, as well as a bone scan, and submitting them to the BICR within 72 hours to confirm patient eligibility, (c) using an FDA-approved radiotracer ( 68 Ga]Ga-PSMA-11 or 18Subjects will undergo PSMA-PET scanning with [F]DCFPyL. Only those with positive PSMA-PET results can participate in the trial. Positive PSMA-PET is defined as PSMA-PET uptake greater than liver uptake in one or more metastatic lesions of any size in any organ system. (d) Record the medical history, including history of prostate cancer, date of diagnosis, and previous treatments; (e) Record concomitant medications; (f) Conduct a comprehensive physical examination; (g) Measure and record vital signs and ECOG performance status; (h) Perform a 12-lead ECG; and (i) If the medical monitor confirms that the patient meets the eligibility criteria for the study, randomize the patient according to the IVRS system and conduct a visit on Day 1 of Cycle 1.

[0704] (ii) Day 1 of treatment

[0705] The following evaluations will be conducted on Day 1 of treatment:

[0706] ● Administer the EORTC QLQ-C30, FACT-P, and BPI-SF questionnaires before treatment to determine the baseline.

[0707] ● Record any changes in concomitant medications and any adverse events noted since screening.

[0708] ● Conduct a brief physical examination

[0709] ● Measure and record vital signs and ECOG performance status.

[0710] ● Collect blood for clinical laboratory evaluations.

[0711] ● Administer the study drug at the clinic. For patients enrolled in the standard-of-care study group, initiate the standard-of-care hormonal therapy designated by the investigator:

[0712] ○ 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 at the clinic. The time and date of initiation of abiraterone therapy will be recorded.

[0713] ○ Enzalutamide: The initial dose of enzalutamide is 160 mg (four 40-mg capsules), administered once daily. The first dose of enzalutamide will be administered at the clinic. The time and date of initiation of enzalutamide therapy will be recorded.

[0714] ● Patients enrolled in the radioligand therapy group should receive an initial radioligand dose of 200 mCi (7.4 GBq) of 177 Lu-PSMA-I&T infused over at least 10 to 15 minutes. The 177 dose and duration of the

[0715] ● Inclusion 177 Patients on Lu-PSMA-I&T will have a 12-lead ECG after the first dose.

[0716] (iii) Treatment in the study

[0717] 177 Lu-PSMA I&T: Patients randomized to the radioligand therapy group will receive 177 a Lu-PSMA I&T infusion for a 6-week cycle at a dose of 200 mCi (7.4 GBq) until radiographic progression is confirmed by BICR, or until the patient develops toxicity requiring treatment termination, or withdraws consent to participate in the study. Patients in this study can receive a maximum of 4 cycles of 177 Lu-PSMA I&T infusions.

[0718] Abiraterone and enzalutamide standard-of-care group: Patients randomized to standard of care and receiving abiraterone or enzalutamide treatment will receive treatment according to their prescription information at the standard-of-care dose regimen daily. Patients in this treatment group will continue to receive standard-of-care treatment until radiographic progression is confirmed by BICR, or until the patient develops toxicity requiring treatment termination, or withdraws consent to participate in the study.

[0719] (iv) Continuous assessment

[0720] For patients randomized to receive 177 Lu-PSMA I&T and patients receiving abiraterone or enzalutamide standard of care, all patients enrolled in the study will have a continuous assessment every 4 weeks.

[0721] (v) Progression assessment

[0722] All patients enrolled in the study will be evaluated starting 8 weeks + 1 week after the first treatment and continuing until week 24, and then every 12 weeks thereafter until radiographic evidence of disease progression is found. The evaluation consists of: (i) obtaining CT images of the chest, abdomen, and pelvis and a bone scan and submitting them to the ICL (Imaging Core Laboratory) for BICR evaluation, and (ii) obtaining plasma samples for PSA and other clinical laboratory evaluations.

[0723] (vi) End-of-treatment visit

[0724] The end-of-treatment (EOT) visit will be conducted at the last infusion 177It will be conducted one month (±7 days) after Lu-PSMA I&T. Patients receiving abiraterone acetate or enzalutamide can continue their daily treatment until the EOT visit. The following assessments will be performed: administer the EORTC QLQ-C30, FACT-P, and BPI-SF questionnaires; record any changes in concomitant medications; record any adverse events noted at screening; perform a brief physical examination; perform and record vital signs and ECOG performance status; and collect blood for clinical laboratory evaluations, including PSA and other clinical laboratory evaluations.

[0725] (vii) Crossover

[0726] Patients in the standard-of-care hormone therapy group may crossover to receive 177 Lu-PSMA I&T based on the following criteria:

[0727] ● While receiving standard-of-care hormone therapy, radiographic progression must be recorded by BICR using RECIST 1.1 modified by PCWG3

[0728] ● Must not have started any other anti-cancer drugs or therapies.

[0729] ● Participants with organ and bone marrow dysfunction (as defined below) will not be eligible for crossover:

[0730] ○ Absolute neutrophil count < 1.5 x 109 / L

[0731] ○ Platelet count < 100 x 109 / L.

[0732] ○ Hemoglobin < 8 g / dL.

[0733] ○ AST / SGOT and / or ALT / SGPT > 3.0 x ULN.

[0734] ○ Total bilirubin > 2 x ULN, unless the patient has known Gilbert syndrome, and then it may be 3 x ULN.

[0735] ○ Creatinine clearance (CrCl) based on the Cockcroft-Gault formula < 50 mL / min.

[0736] ○ Albumin ≥ 2.75 g / dL

[0737] If a patient is not eligible for crossover, they should complete the end-of-study visit and enter long-term follow-up.

[0738] (viii) Long-term follow-up

[0739] Long-term follow-up of patients will continue for up to 5 years after the first treatment in this study, or until the patient dies or is lost to follow-up. The following information will be collected:

[0740] ● Survival status, development of asymptomatic disease progression, initiation of any new systemic anti-cancer therapy, progression of the first subsequent therapy, and healthcare resource utilization every 4 months.

[0741] ● Additionally, if a patient discontinues study treatment prior to documented disease progression, CT of the chest, abdomen, and pelvis and a bone scan are obtained and submitted to the BICR for disease progression assessment every 12 weeks until documented radiographic disease progression.

[0742] G. Statistical Considerations and Analysis Plan

[0743] (i) Sample Size

[0744] It is assumed that for patients 177 Lu-PSMA I&T treatment will extend the radiographic progression-free survival (rPFS) from 6 months in the standard-of-care group to 10 months. Therefore, it is reasonable that the target hazard ratio (HR) for this Phase 3 study is 0.60 under the alternative hypothesis. Using a ...

Claims

1. A composition comprising 177 Lu-PSMA I&T; wherein the molar ratio of PSMA I&T to 177 Lu is from 3.0:1.0 to 8.0:1.0, and the composition is adapted to be administered to a human patient in need within at least 72 hours after compounding.

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

0.

3. The composition according to claim 2, wherein the composition is adapted to be administered to a human patient in need thereof within at least 120 hours after compounding.

4. The composition according to claim 1, wherein the radiochemical purity (RCP) of the composition at the time of administration is 95% or higher.

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

0.

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

0.

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

5.

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

0.

10. The composition according to claim 1, wherein the molar ratio of the PSMA I&T to 177 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 5.7:1.0 or from 5.4:1.0 to 5.6:1.

0.

11. The composition according to claim 1, wherein the molar ratio of the PSMA I&T to 177 Lu is from 4.0:1.0 to 5.0:1.0, from 4.1:1.0 to 4.9:1.0, from 4.2:1.0 to 4.8:1.0, from 4.3:1.0 to 4.7:1.0 or from 4.4:1.0 to 4.6:1.

0.

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

0.

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

14. The composition according to 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. The composition according to claim 1, wherein the Fe metal content is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit.

16. The composition according to claim 1, wherein the Cu metal content is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit.

17. The composition according to claim 1, wherein the Zn metal content is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit.

18. The composition according to claim 1, wherein the Pb metal content is ≤ 0.05 μg / GBq, ≤ 0.03 μg / GBq, ≤ 0.01 μg / GBq or below the detection limit.

19. The composition according to claim 1, wherein the radiochemical purity (RCP) of the composition 72 hours after production is 97.5% or higher.

20. The composition according to claim 1, wherein the radiochemical purity (RCP) of the composition 72 hours after production is 98.0% or higher.

21. The composition according to claim 1, wherein the composition is suitable for human administration for 7 or more treatment cycles.

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

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

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

25. A radiopharmaceutical kit comprising the composition according to claim 1.

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

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

28. A method of treating cancer or reducing the incidence of cancer using a radiochemical composition, the method comprising administering to a human patient in need thereof a radiochemical composition comprising a solution of 177 Lu-PSMA I&T having a pH of 3.5 to 6.0, wherein the molar ratio of PSMA I&T to 177 Lu is from 3.0:1.0 to 8.0:1.0, wherein the radiochemical purity of the solution at the time of administration is greater than 95%, and wherein the composition is suitable for administration to a human patient in need thereof for at least 72 hours after formulation.

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

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

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