[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; the present invention relates to pharmaceutical compositions of T. and methods of administering the same. The administration of the composition results in a lower dose of absorbed radiation per gram of tissue in the human patient's body, including kidney, gastrointestinal tract, left colon, liver, rectum, red bone marrow, spleen, lacrimal gland, and salivary gland.

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, all of 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 comprising 177 Lu-PSMA I&T. 177 Lu-PSMA I&T solutions and / or their kits can be used for prostate cancer radionuclide ligand therapy (PRLT). This disclosure also relates to methods of administering to a human patient in need a composition comprising 177 Lu-PSMA I&T. 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-PSMA-617 and 177 Lu-PSMA I&T are small molecule inhibitors of PSMA, and due to the low toxicity of the inhibitors, they are highly 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 improved formulations of 177 Lu-PSMA I&T that can be administered to a patient, which minimize the radiation of undesired cumulative absorbed dose to healthy organ tissues of the patient that are not targeted for treating cancer (e.g., prostate cancer). 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 and methods of administration that provide a lower cumulative absorbed dose of radiation on a per-administration basis are provided herein. Also provided herein are improved 177 Lu-PSMA I&T compositions and methods of administration that provide a lower cumulative absorbed dose of radiation to key individual organs (e.g., kidneys, lacrimal glands, salivary glands, and liver) and / or on a per-administration basis. Importantly, the improved compositions and methods described herein surprisingly allow for longer treatment cycles and / or lower cumulative absorbed dose radiation levels compared to the prior art. SUMMARY OF THE INVENTION

[0007] Particularly provided herein are compositions comprising 177 Lu-PSMA I&T and methods of administering the compositions to a human patient in need thereof.

[0008] The compositions, methods, and kits described herein comprise 177Lu-PSMA I&T having a radiochemical purity ≥95% and a molar ratio of PSMA I&T to 177Lu of 3.0:1.0 to 8.0:1.0 and / or 4.4:1.0 to 7.6:1.0, suitable for administration to a human patient. This is highly surprising and unexpected because initial tests indicated that this example was not feasible and a molar ratio of at least 11.0:1.0 or greater of PSMA I&T to 177Lu was required to maintain a radiochemical purity ≥95% for 72 hours or longer. Indeed, according to initial expectations, any material 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 material would be further unacceptable for a human patient at 24 hours, 48 hours, 72 hours, or 96 hours after formation. See the PSMA:Lu-177 (mol / mol) chart below, which shows the projected radiochemical formation that is not suitable when the formulation is below 11.0:1.0.

[0009]

[0010] However, using the unique parameters described herein, there are provided herein compositions, methods, and kits comprising 177Lu-PSMA I&T having a radiochemical purity ≥95% suitable for administration to a human patient and a molar ratio of PSMA I&T to 177Lu of 3.0:1.0 to 8.0:1.0 and / or 4.4:1.0 to 7.6:1.0, wherein the composition is stable for 72 hours or longer.

[0011] In another embodiment, the compositions, methods, and kits described herein comprise 177Lu-PSMA I&T having a radiochemical purity ≥95% suitable for administration to a human patient and a PSMA I&T to [177Lu]Lu3+ ratio (in μg:mCi) of from about 0.20 to about 0.60. In another embodiment, the compositions, methods, and kits described herein comprise 177Lu-PSMA I&T having a radiochemical purity ≥95% suitable for administration to a human patient and a PSMA I&T to [177Lu]Lu3+ ratio (in μg:mCi) ≤0.60. This is also highly surprising and unexpected because initial testing indicated that this embodiment was not feasible and a PSMA I&T to [177Lu]Lu3+ ratio (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 predicted radiochemical formation to be inappropriate at a formulation of 0.60 and below.

[0012]

[0013] However, using the unique parameters described herein, there are provided herein compositions, methods, and kits comprising 177Lu-PSMA I&T having a radiochemical purity ≥95% suitable for administration to a human patient 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, wherein the composition is stable for 72 hours or longer.

[0014] In some embodiments, the PSMA I&T of the composition and 177The molar ratio of Lu is from about 1.0:1 to about 8.0:1, about 1.5:1 to about 8.0:1, about 2.0:1 to about 8.0:1, about 2.5:1 to about 8.0:1, about 3.0:1 to about 8.0:1, about 3.5:1 to about 8.0:1, about 4.0:1.0 to about 8.0:1.0, about 4.5:1.0 to about 5.5:1.0 or about 5.0:1.0 to about 6.0:1.0. In some aspects, the PSMA I&T of the composition and 177 The molar ratio of Lu is about 4.0:1.0, about 4.5:1.0, about 5.0:1.0, about 5.5:1.0, about 6.0:1.0, about 6.5:1.0, about 7.0:1.0, about 7.5:1.0 or about 8.0:1.0. In some aspects, the PSMA I&T of the composition and 177 The molar ratio of Lu is from about 5.1:1.0 to about 5.9:1.0, about 5.2:1.0 to about 5.8:1.0, about 5.3:1.0 to about 5.7:1.0 or about 5.4:1.0 to about 5.6:1.0.

[0015] In some embodiments, the composition comprises from about 7.1 GBq to about 7.6 GBq of 177 Lu-PSMA I&T. In some aspects, the composition comprises 7.4 ± 15% GBq of 177 Lu-PSMA I&T, 7.4 ± 10% GBq of 177 Lu-PSMA I&T or 7.4 ± 5% GBq of 177 Lu-PSMA I&T. In one instance, the composition comprises about 7.4 GBq of 177 Lu-PSMA I&T.

[0016] Further provided herein is a method that comprises administering to a human patient in need a composition comprising 177A radiopharmaceutical composition of Lu-PSMA I&T, wherein the absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.2 Gy / GBq to about 0.6 Gy / GBq, about 0.25 Gy / GBq to about 0.55 Gy / GBq, about 0.3 Gy / GBq to about 0.5 Gy / GBq, or about 0.35 Gy / GBq to about 0.45 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the kidney of the human patient is ≤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, ≤0.25 Gy / GBq, ≤0.20 Gy / GBq, or ≤0.15 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.39±0.15 Gy / GBq, about 0.40±0.15 Gy / GBq, about 0.41±0.15 Gy / GBq, about 0.42±0.15 Gy / GBq, about 0.43±0.15 Gy / GBq, about 0.44±0.15 Gy / GBq, or about 0.45±0.15 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the kidney of the human patient is ≤0.39 Gy / GBq, ≤0.40 Gy / GBq, ≤0.41 Gy / GBq, or ≤0.42 Gy / GBq. In some aspects, the standard deviation of the average absorbed radiation dose per gram of tissue in the kidney of the human patient is ≤0.19 Gy / GBq, ≤0.18 Gy / GBq, ≤0.17 Gy / GBq, ≤0.16 Gy / GBq, or ≤0.15 Gy / GBq. In some aspects, the absorbed radiation dose is determined by SPECT imaging, planar imaging, or a combination thereof.

[0017] A method is provided herein, the method comprising administering to a human patient in need thereof a composition comprising 177A radiopharmaceutical composition of Lu-PSMAI&T, wherein the absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is about 0.01 Gy / GBq to about 1.5 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is ≤1.5 Gy / GBq, ≤1.4 Gy / GBq, ≤1.3 Gy / GBq, ≤1.2 Gy / GBq, ≤1.1 Gy / GBq, ≤1.0 Gy / GBq, ≤0.9 Gy / GBq, ≤0.8 Gy / GBq, ≤0.7 Gy / GBq, ≤0.6 Gy / GBq, ≤0.5 Gy / GBq, ≤0.4 Gy / GBq, ≤0.3 Gy / GBq, ≤0.2 Gy / GBq or ≤0.1 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is about 0.01 Gy / GBq, 0.05 Gy / GBq, 0.1 Gy / GBq, 0.2 Gy / GBq, 0.3 Gy / GBq, 0.4 Gy / GBq, 0.5 Gy / GBq, 0.6 Gy / GBq, 0.7 Gy / GBq, 0.8 Gy / GBq, 0.9 Gy / GBq, 1.0 Gy / GBq, 1.1 Gy / GBq, 1.2 Gy / GBq, 1.3 Gy / GBq, 1.4 Gy / GBq or 1.5 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is 0.37±0.36 Gy / GBq, 0.38±0.36 Gy / GBq, 0.39±0.36 Gy / GBq or 0.40±0.36 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is ≤0.40 Gy / GBq, ≤0.50 Gy / GBq, ≤0.60 Gy / GBq, ≤0.70 Gy / GBq, ≤0.80 Gy / GBq, ≤0.90 Gy / GBq or ≤1.0 Gy / GBq. In some aspects, the standard deviation of the average absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is ≤0.37 Gy / GBq. In some aspects, the absorbed radiation dose is determined by SPECT imaging, planar imaging or a combination thereof.

[0018] Further provided herein is a method that comprises administering to a human patient in need a composition comprising 177A radiopharmaceutical composition of Lu-PSMA I&T, wherein the absorbed radiation dose per gram of tissue in the salivary glands of the human patient is from about 0.01 Gy / GBq to about 1.0 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the salivary glands of the human patient is ≤1.0 Gy / GBq, ≤0.9 Gy / GBq, ≤0.8 Gy / GBq, ≤0.7 Gy / GBq, ≤0.6 Gy / GBq, ≤0.5 Gy / GBq, ≤0.4 Gy / GBq, ≤0.3 Gy / GBq, ≤0.2 Gy / GBq or ≤0.1 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the salivary glands of the human patient is from about 0.1 Gy / GBq to about 0.5 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the salivary glands of the human patient is about 0.01 Gy / GBq, 0.05 Gy / GBq, 0.1 Gy / GBq, 0.2 Gy / GBq, 0.3 Gy / GBq, 0.4 Gy / GBq, 0.5 Gy / GBq, 0.6 Gy / GBq, 0.7 Gy / GBq, 0.8 Gy / GBq, 0.9 Gy / GBq or about 1.0 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the salivary glands of the human patient is about 0.17±0.16 Gy / GBq, 0.18±0.16 Gy / GBq, 0.19±0.16 Gy / GBq or 0.20±0.16 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the salivary glands of the human patient is ≤0.18 Gy / GBq, ≤0.19 Gy / GBq, ≤0.20 Gy / GBq, ≤0.21 Gy / GBq, ≤0.22 Gy / GBq, ≤0.23 Gy / GBq, ≤0.24 Gy / GBq, ≤0.25 Gy / GBq, ≤0.26 Gy / GBq, ≤0.27 Gy / GBq, ≤0.28 Gy / GBq, ≤0.29 Gy / GBq or ≤0.30 Gy / GBq. In some embodiments, the standard deviation of the average absorbed radiation dose per gram of tissue in the salivary glands of the human patient is ≤0.25 Gy / GBq, ≤0.24 Gy / GBq, ≤0.23 Gy / GBq, ≤0.22 Gy / GBq, ≤0.21 Gy / GBq, ≤0.20 Gy / GBq, ≤0.19 Gy / GBq, ≤0.18 Gy / GBq, ≤0.17 Gy / GBq or ≤0.16 Gy / GBq. In some aspects, the absorbed radiation dose is determined by SPECT imaging, planar imaging, or a combination thereof.

[0019] Further provided herein is a method that comprises administering to a human patient in need thereof a composition comprising 177A radiopharmaceutical composition of Lu-PSMA I&T, wherein the absorbed radiation dose per gram of tissue in the left colon of the human patient is from about 0.01 Gy / GBq to about 1.6 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the left colon of the human patient is ≤1.6 Gy / GBq, ≤1.5 Gy / GBq, ≤1.4 Gy / GBq, ≤1.3 Gy / GBq, ≤1.2 Gy / GBq, ≤1.1 Gy / GBq, ≤1.0 Gy / GBq, ≤0.9 Gy / GBq, ≤0.8 Gy / GBq, ≤0.7 Gy / GBq, ≤0.6 Gy / GBq, ≤0.5 Gy / GBq, ≤0.4 Gy / GBq, ≤0.3 Gy / GBq, ≤0.2 Gy / GBq or ≤0.1 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the left colon of the human patient is from about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the left colon of the human patient is about 0.01 Gy / GBq, 0.05 Gy / GBq, 0.1 Gy / GBq, 0.2 Gy / GBq Gy / GBq, 0.3 Gy / GBq, 0.4 Gy / GBq, 0.5 Gy / GBq, 0.6 Gy / GBq, 0.7 Gy / GBq, 0.8 Gy / GBq, 0.9 Gy / GBq, 1.0 Gy / GBq, 1.1 Gy / GBq, 1.2 Gy / GBq, 1.3 Gy / GBq, 1.4 Gy / GBq, 1.5 Gy / GBq or about 1.6 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the left colon of the human patient is 0.45±0.31 Gy / GBq, 0.46±0.31 Gy / GBq or 0.47±0.31 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the left colon of the human patient is ≤0.47 Gy / GBq.

[0020] Further provided herein is a method that comprises administering to a human patient in need thereof a composition comprising 177A radiopharmaceutical composition of Lu-PSMA I&T, wherein the absorbed radiation dose per gram of tissue in the rectum of the human patient is about 0.01 Gy / GBq to about 1.5 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the rectum of the human patient is ≤ 1.5 Gy / GBq, ≤ 1.4 Gy / GBq, ≤ 1.3 Gy / GBq, ≤ 1.2 Gy / GBq, ≤ 1.1 Gy / GBq, ≤ 1.0 Gy / GBq, ≤ 0.9 Gy / GBq, ≤ 0.8 Gy / GBq, ≤ 0.7 Gy / GBq, ≤ 0.6 Gy / GBq, ≤ 0.5 Gy / GBq, ≤ 0.4 Gy / GBq, ≤ 0.3 Gy / GBq, ≤ 0.2 Gy / GBq or ≤ 0.1 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the rectum of the human patient is about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the rectum of the human patient is about 0.01 Gy / GBq, 0.05 Gy / GBq, 0.1 Gy / GBq, 0.2 Gy / GBq, 0.3 Gy / GBq, 0.4 Gy / GBq, 0.5 Gy / GBq, 0.6 Gy / GBq, 0.7 Gy / GBq, 0.8 Gy / GBq, 0.9 Gy / GBq, 1.0 Gy / GBq, 1.1 Gy / GBq, 1.2 Gy / GBq, 1.3 Gy / GBq, 1.4 Gy / GBq or about 1.5 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the rectum of the human patient is 0.44 ± 0.30 Gy / GBq. In some aspects, the absorbed radiation dose is determined by SPECT imaging, planar imaging or a combination thereof.

[0021] Also provided herein is a method comprising administering to a human patient in need a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the 177 fraction of the activity of Lu-PSMA I&T in the whole body of the human patient is about 0.5 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some embodiments, the 177 fraction of the activity of Lu-PSMA I&T in the whole body of the human patient is ≤ 0.5, ≤ 0.4, ≤ 0.3, ≤ 0.2 or ≤ 0.1 within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, the 177 fraction of the activity of Lu-PSMA I&T in the whole body of the human patient is about 0.5, 0.4, 0.3, 0.2, 0.1 or less than 0.1 within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, the 177The activity fraction of Lu-PSMA I&T in the whole body of the human patient is about 0.4 or less within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the whole body of the human patient is about 0.4, about 0.3, about 0.2, about 0.1 or less than 0.1 within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the whole body of the human patient is about 0.2 or less within 168 hours after administration of the composition. In some aspects, the administration is by injection. In some aspects, the activity fraction is determined by SPECT imaging, planar image-based dosimetry, or a combination thereof. Further provided herein is a method comprising administering to a human patient in need a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the 177 activity fraction of Lu-PSMA I&T in the kidney of the human patient is about 0.05 or less within 24 hours, 48 hours or 168 hours after administration of the composition.

[0022] Further provided herein is a method comprising administering to a human patient in need a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the 177 activity fraction of Lu-PSMA I&T in the kidney of the human patient is about 0.05 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some embodiments, the 177 activity fraction of Lu-PSMA I&T in the kidney of the human patient is ≤0.05, ≤0.04, ≤0.03, ≤0.02 or ≤0.01 within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMAI&T in the kidney of the human patient is about 0.05, about 0.04, about 0.03, about 0.02, about 0.01 or less than 0.01 within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the kidney of the human patient is ≤0.040 within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the kidney of the human patient is about 0.040 or less, about 0.035 or less or about 0.030 or less within 48 hours or 168 hours after administration of the composition. In some aspects, the177 The activity fraction of Lu-PSMA I&T in the kidney of the human patient is about 0.04, 0.03, 0.02, 0.01 or less than 0.01 within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the kidney of the human patient is about 0.03 or less within 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the kidney of the human patient is about 0.03, 0.02, 0.01 or less than 0.01 within 168 hours after administration of the composition. In some aspects, the administration is by injection. In some aspects, the activity fraction is determined by SPECT imaging, planar imaging or a combination thereof.

[0023] Further provided herein is a method comprising administering to a human patient in need a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the 177 activity fraction of Lu-PSMA I&T in the red bone marrow of the human patient is about 0.08 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some embodiments, the 177 activity fraction of Lu-PSMA I&T in the red bone marrow of the human patient is ≤0.08, ≤0.07, ≤0.06, ≤0.05, ≤0.04, ≤0.03, ≤0.02, ≤0.01 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the red bone marrow of the human patient is about 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01 or less than 0.01 within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the red bone marrow of the human patient is about 0.06 or less within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the red bone marrow of the human patient is about 0.06, 0.05, 0.04, 0.03, 0.02, 0.01 or less than 0.01 within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the red bone marrow of the human patient is about 0.04 or less within 168 hours after administration of the composition. In some aspects, the177 The activity fraction of Lu-PSMA I&T in the red bone marrow of the human patient is about 0.04, 0.03, 0.02, 0.01 or less than 0.01 within 168 hours after administration of the composition. In some aspects, the administration is by injection. In some aspects, the activity fraction is determined by SPECT imaging, planar imaging or a combination thereof.

[0024] Also provided herein is a method comprising administering to a human patient in need thereof a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the 177 activity fraction of Lu-PSMA I&T in the salivary glands of the human patient is about 0.015 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some embodiments, the 177 activity fraction of Lu-PSMA I&T in the salivary glands of the human patient is ≤0.015, ≤0.014, ≤0.013, ≤0.012, ≤0.011, ≤0.010, ≤0.009, ≤0.008, ≤0.007, ≤0.006, ≤0.005, ≤0.004, ≤0.003, ≤0.002, ≤0.001 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the salivary glands of the human patient is about 0.015, 0.014, 0.013, 0.012, 0.011, 0.010, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001 or less than 0.001 within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the salivary glands of the human patient is about 0.007 or less within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the salivary glands of the human patient is about 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001 or less than 0.001 within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the salivary glands of the human patient is about 0.004 or less within 168 hours after administration of the composition. In some aspects, the 177The activity fraction of Lu-PSMA I&T in the salivary glands of the human patient is about 0.004, 0.003, 0.002, 0.001 or less than 0.001 within 168 hours after administration of the composition. In some aspects, the administration is by injection. In some aspects, the activity fraction is determined by SPECT imaging, planar imaging, or a combination thereof.

[0025] Also provided herein is a method comprising administering to a human patient in need thereof a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the 177 activity fraction of Lu-PSMA I&T in the gastrointestinal tract of the human patient is about 0.10 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some embodiments, the 177 activity fraction of Lu-PSMA I&T in the gastrointestinal tract of the human patient is ≤0.10, ≤0.09, ≤0.08, ≤0.07, ≤0.06, ≤0.05, ≤0.04, ≤0.03, ≤0.02, ≤0.01 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, within 24 hours, 48 hours or 168 hours after administration of the composition, the human patient is about 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01 or less than 0.01. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the gastrointestinal tract of the human patient is about 0.10 or less within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the gastrointestinal tract of the human patient is about 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01 or less than 0.01 within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the gastrointestinal tract of the human patient is about 0.05 or less within 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the gastrointestinal tract of the human patient is about 0.05, 0.04, 0.03, 0.02, 0.01 or less than 0.01 within 168 hours after administration of the composition. In some aspects, the administration is by injection. In some aspects, the activity fraction is determined by SPECT imaging, planar imaging, or a combination thereof.

[0026] Further provided herein is a method that includes administering to a human patient in need thereof a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the 177 fraction of the activity of Lu-PSMA I&T in the liver of the human patient is about 0.04 or less within 24 hours, 48 hours, or 168 hours after administering the composition. In some embodiments, the 177 fraction of the activity of Lu-PSMA I&T in the liver of the human patient is ≤0.04, ≤0.03, ≤0.02, ≤0.01, or less within 24 hours, 48 hours, or 168 hours after administering the composition. In some aspects, the 177 fraction of the activity of Lu-PSMA I&T in the liver of the human patient is about 0.04, 0.03, 0.02, 0.01, or less than 0.01 within 24 hours, 48 hours, or 168 hours after administering the composition. In some aspects, the 177 fraction of the activity of Lu-PSMA I&T in the liver of the human patient is about 0.02 or less within 48 hours or 168 hours after administering the composition. In some aspects, the 177 fraction of the activity of Lu-PSMA I&T in the liver of the human patient is about 0.02, 0.01, or less than 0.01 within 48 hours or 168 hours after administering the composition. In some aspects, the 177 fraction of the activity of Lu-PSMA I&T in the liver of the human patient is about 0.01 or less within 168 hours after administering the composition. In some aspects, the administering is by injection. In some aspects, the fraction of activity is determined by SPECT imaging, planar imaging, or a combination thereof.

[0027] Further provided herein is a method that includes administering to a human patient in need thereof a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the 177 fraction of the activity of Lu-PSMA I&T in the spleen of the human patient is about 0.004 or less within 24 hours, 48 hours, or 168 hours after administering the composition. In some embodiments, the 177 fraction of the activity of Lu-PSMA I&T in the spleen of the human patient is ≤0.004, ≤0.003, ≤0.002, ≤0.001, or less within 24 hours, 48 hours, or 168 hours after administering the composition. In some aspects, the 177The activity fraction of Lu-PSMA I&T in the spleen of the human patient is about 0.004, 0.003, 0.002, 0.001 or less than 0.001 within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the spleen of the human patient is about 0.002 or less within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the spleen of the human patient is about 0.002, 0.001 or less than 0.001 within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the spleen of the human patient is about 0.001 or less within 168 hours after administration of the composition. In some aspects, the administration is by injection. In some aspects, the activity fraction is determined by SPECT imaging, planar imaging or a combination thereof.

[0028] Also provided herein is a method that comprises administering to a human patient in need a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the 177 activity fraction of Lu-PSMA I&T in the lacrimal gland of the human patient is about 0.0004 or less within 24 hours, 48 hours or 168 hours after injection of the composition. In some embodiments, the 177 activity fraction of Lu-PSMA I&T in the lacrimal gland of the human patient is ≤0.0004, ≤0.0003, ≤0.0002, ≤0.0001 or less within 24 hours, 48 hours or 168 hours after injection of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the spleen of the human patient is about 0.0004, 0.0003, 0.0002, 0.0001 or less than 0.0001 within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the spleen of the human patient is about 0.0002 or less within 48 hours or 168 hours after administration of the composition. In some aspects, the 177 activity fraction of Lu-PSMA I&T in the spleen of the human patient is about 0.0002, 0.0001 or less than 0.0001 within 48 hours or 168 hours after administration of the composition. In some aspects, the 177The activity fraction of Lu-PSMA I&T in the spleen of the human patient is less than 0.0001 within 168 hours after administration of the composition. In some aspects, the administration is by injection. In some aspects, the activity fraction is determined by SPECT imaging, planar imaging, or a combination thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Various features, aspects, and advantages of the present disclosure will become better understood when the following detailed description is read with reference to the accompanying drawings, in which like characters represent like parts throughout the drawings, and in which:

[0030] Figure 1A The structural formula of precursor PSMA I&T is presented.

[0031] Figure 1B Presents 177 The structural formula of the R isomer of Lu-PSMA I&T.

[0032] Figure 2 Is a flow chart representation of an exemplary method of preparing the disclosed radiopharmaceutical composition.

[0033] Figure 3A Is in one embodiment 177 The flow chart of the synthesis procedure of Lu-PSMA I&T.

[0034] Figure 3B Is in one embodiment 177 The flow chart of the synthesis procedure of Lu-PSMA I&T.

[0035] Figure 4 Depicts a diagram of an exemplary product vial. The drug product is delivered in a sterile pyrogen-free glass vial of type 1 glass with a fluorine-coated bromobutyl 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 transportation container, including the lead shield and outer packaging, meets the requirements of type A (IAEA standard).

[0036] Figure 5 Shows the 177 Radiochemical purity of Lu-PSMA I&T measured by HPLC at different time points.

[0037] Figure 6A And 6B Shows 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 the examples.

[0038] Figure 7A And 7BShows the HPLC radiochromatogram of a high-radioactivity concentration formulation containing 42.4 mg / ml ascorbic acid at a pH of 4.5 ± 0.1 at 0 hours and 71 hours after EOS, as detailed in the examples.

[0039] Figure 8A and 8B Shows the HPLC radiochromatogram of a high-radioactivity concentration formulation containing 42.5 mg / ml ascorbic acid at a pH of 3.5 ± 0.1 at 0 hours and 90 hours after EOS, as detailed in the examples.

[0040] Figure 9A and 9B Shows the HPLC radiochromatogram of a low-radioactivity concentration formulation containing 21 mg / ml ascorbic acid at a pH of 4.5 ± 0.1 at 0 hours and 92 hours after EOS, as detailed in the examples.

[0041] Figure 10A and 10B Shows the HPLC radiochromatogram of a low-radioactivity concentration formulation containing 31 mg / ml ascorbic acid at a pH of 5 ± 0.1 at 0 hours and 71 hours after EOS, as detailed in the examples.

[0042] Figure 11A and 11B Shows the HPLC radiochromatogram of a low-radioactivity concentration formulation containing 31 mg / ml ascorbic acid at a pH of 4.5 ± 0.1 at 0 hours and 93 hours after EOS, as detailed in the examples.

[0043] Figure 12 Presents examples of the present invention.

[0044] Figure 13 Presents examples of the present invention.

[0045] Figure 14 Shows the maximum intensity projections of the cycle 1 SPECT / CT images acquired at 4 hours, 24 hours, 48 hours, and 168 hours post-injection for one patient (80 - 001).

[0046] Figure 16 Shows the whole-body time-activity curves expressed as the injected activity fraction for each patient imaged in cycle 1. The curve with the slowest clearance belongs to the patient imaged using a superscan.

[0047] Figure 17 Shows the renal time-activity curves expressed as the injected activity fraction for each patient imaged in cycle 1.

[0048] Figure 18Shows the red marrow time-activity curves, expressed as the injected activity fraction, for each patient imaged in Cycle 1. The highest curve is that of the patient (42-030) imaged with a superscan and reflects the higher dose to the marrow due to extensive metastatic disease of the bone.

[0049] Figure 19 Shows the salivary gland time-activity curves, expressed as the injected activity fraction, for each patient imaged in Cycle 1. The salivary glands of patient 12-004 were not within the SPECT field of view.

[0050] Figure 20 Shows the GI tract time-activity curves, expressed as the injected activity fraction, for each patient imaged in Cycle 1. Two patients (80-004 and 25-005) had no significant uptake in the GI tract and are not included here.

[0051] Figure 21 Shows the liver time-activity curves, expressed as the injected activity fraction, for each patient imaged in Cycle 1.

[0052] Figure 22 Shows the spleen time-activity curves, expressed as the injected activity fraction, for each patient imaged in Cycle 1.

[0053] Figure 23 Shows the lacrimal gland time-activity curves, expressed as the injected activity fraction, for each patient imaged in Cycle 1. The lacrimal glands of 5 patients (42-027; 80-018; 66-024; 25-009 and 12-004) were not within the SPECT field of view.

[0054] Figure 24 Shows the mean Cycle 1 time-activity curves for all source organs on a semi-log scale.

[0055] Figure 25 Shows the plasma time-activity curves, expressed as the injected activity fraction per liter, for patients (n = 27) in Cycle 1 on a semi-log scale.

[0056] Figure 26 Presents the plasma time-activity curves, expressed as the injected activity fraction per liter, for patients (n = 15) in Cycle 3.

[0057] Figure 27 Presents an organ depiction for a representative patient. Detailed Description

[0058] It should be understood that, for the sake of brevity and clarity of illustration, reference numerals have been reused in different figures where appropriate to indicate corresponding or analogous 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. Further, 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 some parts may be enlarged to better show details and features of the present disclosure.

[0059] 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 composition disclosed herein comprises 177 Lu-PSMA I&T. 177 Lu-PSMA I&T is a short-lived radiolabeled substance, and the radiolabeled substance formulated product is immediately prepared after the synthesis is completed.

[0060] The headings included herein are for reference purposes only and are not intended to limit the present disclosure in any way.

[0061] 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.

[0062] I. Definitions

[0063] Certain definitions applicable throughout the above 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".

[0064] 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.

[0065] 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 range of numerical values that are considered equivalent to the recited value (e.g., having the same function or result), e.g., ±0.5 - 1%, ±1 - 5%, or ±5 - 10% of the recited value.

[0066] 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.

[0067] As used herein, "lutetium-177" and "177Lu" are used interchangeably. 177Lu is a β-emitting radionuclide and a γ-emitting radionuclide with a physical half-life of 6.7 days. The maximum β-particle energy and average β-particle energy of 177Lu are 0.498 MeV and 0.133 MeV, respectively. The maximum soft tissue penetration depth and average soft tissue penetration depth of 177Lu are 1.7 mm and 0.23 mm, respectively. 177Lu has two major γ-emission lines: 113 keV (6% relative abundance) and 208 keV (11% relative abundance).

[0068] As used herein, "177Lu-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.

[0069] As used herein, "[177Lu]Lu-PSMA I&T" and "177Lu-PSMA I&T" refer to 177Lu-PSMA for imaging and therapy (I&T), a third-generation derivative of a 177Lu-PSMA compound already in use herein. The chemical name of 177Lu-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 chemical structure of 177Lu-PSMA I&T is provided in Figure 1B which is hereby incorporated by reference.

[0070] 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 population of subjects, the half-life of a drug in the blood can be determined graphically from the pharmacokinetic plot of the drug's blood concentration versus time. 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.

[0071] 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 of the compositions and methods described herein can be used for PRLT and / or the treatment of cancer.

[0072] 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 of the compositions and methods described herein can be used for CRPC and / or the treatment of cancer.

[0073] As used herein, the term "biochemical progression" refers to three consecutive elevations of PSA at one-week intervals, resulting in two 50% increases relative to the nadir, and PSA > 2 μg / l.

[0074] As used herein, the term "RAC" refers to the radioactivity concentration.

[0075] 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).

[0076] As used herein, the terms "end of synthesis", "after compounding", and "end of compounding" are used interchangeably to mean 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.

[0077] 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.

[0078] The term "adverse event" (AE) is any adverse medical event that occurs in a subject administered the investigational drug and that does not necessarily have a causal relationship with 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 that has increased in severity or frequency since the administration of the drug.

[0079] 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.

[0080] As used herein, "composition" refers to a radiopharmaceutical composition and vice versa. Thus, "composition" and "radiopharmaceutical composition" can be used interchangeably.

[0081] The term "effective amount" or "effective dose" refers to the amount of a therapy (e.g., radiation provided herein or another active agent as described herein, such as an anti-cancer treatment as described herein) sufficient to achieve the stated purpose or otherwise achieve the effects of administering the therapy. The effective dose can be sufficient to reduce and / or ameliorate the progression, development, recurrence, severity, and / or duration of a given disease, disorder, or condition and / or the symptoms associated therewith. The effective dose can be a "therapeutically effective dose," which refers to the amount sufficient to provide a therapeutic benefit (e.g., reduce or ameliorate the advancement or progression of a given disease, disorder, or condition, reduce or ameliorate the recurrence, development, or onset of a given disease, disorder, or condition, and / or improve or enhance the prophylactic or therapeutic effect of another therapy). The compositions described herein in a therapeutically effective amount can also enhance the therapeutic efficacy of another therapeutic agent.

[0082] 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 radioligand therapy (RLT) described herein. The term "therapy" can 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.

[0083] 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 pre-cancerous 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.

[0084] The term "treating" or "treatment" refers to any indication 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 the 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, halting 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.

[0085] The term "enhancing" refers to an increase or improvement in the function or activity of a protein or cell, or an improvement in the overall health of a patient, after administration of the "treatment" or "therapy" described herein, compared to the protein or cell prior to such administration or exposure.

[0086] 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, intracardiac, and intracranial administration. Administration typically occurs after the onset of a disease, disorder, or medical condition or its symptoms, but in certain cases, it can occur prior to the onset of the disease, disorder, or medical condition or its symptoms (e.g., administering to a patient predisposed to such a disease, disorder, or medical condition). In some embodiments, "intravenous infusion" is used interchangeably with "injection".

[0087] II. Introduction

[0088] The present disclosure relates to a method of administering to a human patient in need a radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein 177 Lu has a low total absorbed radiation dose in the organs of the human patient. What constitutes a low absorbed radiation dose (total dose, fractional dose, or organ-specific dose) can be determined by one of ordinary skill in the art and relative to other compositions in the prior art, and objectively determined by SPECT imaging and / or planar imaging. For example, in some embodiments, for administration as described herein 177The method of Lu-PSMA I&T can be described by a mathematical formula to ensure that the total cumulative dose to the kidneys of patients after all treatments remains below 23 Gy. By providing improved safety and reduced total absorbed radiation dose, the method of the present invention can allow for more treatment cycles in human patients (e.g., while remaining below the 23 Gy limit). Additionally, when the radiopharmaceutical composition is absorbed by the organs of a human patient rather than the target of the composition, such as a malignant tumor, this low absorbed dose can prevent side effects associated with the use of the radiopharmaceutical. In some embodiments, the composition can be formulated as an injectable radiopharmaceutical solution. The present disclosure further relates to 177 a radiopharmaceutical composition of Lu-PSMA I&T that is high energy, high purity, and / or low toxicity, and that functions as an anti-tumor agent for targeted radionuclide therapy.

[0089] The present disclosure also relates to a method of preparing a radiopharmaceutical composition.

[0090] The present disclosure further relates to the properties of the radiopharmaceutical composition and the method of using the radiopharmaceutical composition.

[0091] 177 Lu-PSMA I&T is also known by its synonyms as follows: 177 Lu] lutetium-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.

[0092] The labeled substance 177 Lu-PSMA I&T can be labeled with a non-carrier-added lutetium-177 (T 1 / 2 = 6.6 days) solution. 177 Lu-PSMA I&T is a short-lived radiolabeled substance, and the radiolabeled substance formulated product is immediately prepared after synthesis. Controls are performed on the labeled drug product. In other embodiments,177 Lu-PSMA I&T can be labeled with carrier-added or carrier-free lutetium-177.

[0093] Synthetic 177 The Lu-PSMA I&T solution may be suitable for administration to a human patient in need. Synthetic 177 The Lu-PSMA I&T solution may be formulated in an injectable grade aqueous solution containing a stabilizer such as ascorbic acid. Prior to dispensing the solution into multi-dose vials, the solution may be sterilized by sterile filtration through a 0.22 μm filter. The formulated solution may be administered within 72 hours after the end of synthesis after quality control and release of the drug product by a qualified person. The formulated solution may be administered by injection to a human patient in need within 72 hours after the end of synthesis after quality control and release of the drug product by a qualified person. Alternatively, the formulated solution may be administered by injection to a human patient in need at least 1 week, at least 2 weeks, at least 3 weeks, at least 3.5 weeks, or at least 4 weeks after synthesis after quality control and release of the drug product by a qualified person. In this way, the compositions as described herein may be stable and suitable for administration to a human patient in need for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 1.5 weeks, 2 weeks, 2.5 weeks, 3 weeks, 3.5 weeks, and / or 4.0 weeks. The radiochemical purity of the stable and suitable composition for administration to a human patient in need at the time of administration may be 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.

[0094] Ascorbic acid can be used to minimize radiolytic decomposition of the radiolabeled formulation. In addition to ascorbic acid, a formulation pH of 6.0, 5.5, 5.0 or below can render the labeled product stable from radiolytic decomposition and extend its shelf life. Thus, on the other hand, the present disclosure further provides a formulation having a pH of 6, 5.5, 5 or below containing ascorbic acid, which improves the stability of the radiopharmaceutical composition against radiolytic decomposition, thereby improving the shelf life of the composition.

[0095] Stability enhancing conditions may be applied as early as possible during the manufacturing process. For example, in the labeled 177In the purification step of Lu-PSMA I&T, an ascorbic acid solution with a pH of 6.0, 5.5, 5.0 or below (e.g., pH of 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 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 to replace water to minimize radiolytic damage.

[0096] When the composition is administered to a subject, it can result in a lower profile of hematotoxicity, hepatotoxicity and / or nephrotoxicity, thereby providing better efficacy and fewer side effects than monoclonal antibody therapy and other comparable third-line therapies.

[0097] The composition is an improved composition because its shelf life after formulation is greater than 72 hours. 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 more than 72 hours after formulation. Thus, compared to other compositions containing 177 Lu-PSMA I&T, the improved formulation is suitable for administration up to 24 hours or up to 72 hours or longer.

[0098] III. Composition

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] In one embodiment, the composition is produced as part of a batch size of 4 Ci to 10 Ci. In another embodiment, the composition is produced as part of a batch size of 4 Ci to 15 Ci. In another embodiment, the composition is produced as part of a batch size of 20 Ci to 32 Ci. In yet another embodiment, the composition is produced as part of a batch size of 32 Ci to 64 Ci.

[0104] 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.

[0105] In one specific embodiment, the stabilizer is ethanol. 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).

[0106] In one embodiment, the pharmaceutical product or radiopharmaceutical composition (or formulation) can be a dose of 177A sterile 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.

[0107] In one embodiment, the radiopharmaceutical composition is a sterile filtered radiopharmaceutical solution containing a certain dose of 177 Lu]Lu-PSMA I&T in an aqueous solution of ascorbic acid and ethanol. In another embodiment, the radiopharmaceutical composition is a sterile filtered radiopharmaceutical solution containing a certain dose of 177 Lu]Lu-PSMA I&T in an aqueous solution of ascorbic acid without ethanol. For example, the radiopharmaceutical composition can be a sterile filtered radiopharmaceutical solution containing a certain microdose of 177 Lu]LuPSMA I&T in an aqueous solution of ascorbic acid and acetate buffer containing DTPA (e.g., containing ethanol or in the complete absence of ethanol). The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk product varies according to the 177 starting radioactivity of Lu.

[0108] 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.

[0109] A pH of 6.0 or less can render the radiopharmaceutical composition stable against radiolytic decomposition and can extend its shelf life.

[0110] 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 to about 5 has improved stability and an extended shelf life. In other embodiments, the radiopharmaceutical composition can be free of gentisic acid (i.e., without gentisic acid).

[0111] The pH of the radiopharmaceutical composition can range from 3.0 to 6.0, from 3.0 to 3.5, from 3.0 to 3.05, from 3.05 to 3.1, from 3.0 to 3.1, from 3.1 to 3.15, from 3.1 to 3.2, from 3.15 to 3.2, from 3.2 to 3.25, from 3.0 to 3.25, from 3.2 to 3.3, from 3.25 to 3.3, from 3.3 to 3.35, from 3.3 to 3.4, from 3.35 to 3.4, from 3.4 to 3.45, from 3.4 to 3.5, from 3.45 to 3.5, from 3.25 to 3.5, from 3.5 to 3.55, from 3.5 to 3.6, from 3.55 to 3.6, from 3.6 to 3.65, from 3.6 to 3.7, from 3.65 to 3.7, from 3.7 to 3.75, from 3.5 to 3.75, from 3.7 to 3.8, from 3.75 to 3.8, from 3.8 to 3.85, from 3.8 to 3.9, from 3.85 to 3.9, from 3.9 to 3.95, from 3.9 to 4.0, from 3.95 to 4.0, from 3.5 to 4.0, from 3.75 to 4.0, from 4.0 to 4.05, from 4.0 to 4.1, from 4.05 to 4.1, from 4.1 to 4.15, from 4.1 to 4.2, from 4.15 to 4.2, from 3.5 to 4.2, from 4.2 to 4.25, from 4.0 to 4.25, from 4.2 to 4.3, from 4.25 to 4.3, from 4.3 to 4.35, from 4.3 to 4.4, from 4.35 to 4.4, from 4.4 to 4.45, from 4.4 to 4.5, from 4.45 to 4.5, from 4.25 to 4.5, from 4.0 to 4.5, from 4.5 to 4.55, from 4.5 to 4.6, from 4.55 to 4.6, from 4.6 to 4.65, from 4.6 to 4.7, from 4.65 to 4.7, from 4.7 to 4.75, from 4.7 to 4.8, from 4.75 to 4.8, from 4.8 to 4.85, from 4.8 to 4.9, from 4.85 to 4.9, from 4.9 to 4.95, from 4.9 to 5.0, from 4.95 to 5.0, from 4.5 to 5.0, from 4.75 to 5.0, from 5.0 to 5.1, from 5.05 to 5.1, from 5.1 to 5.15, from 5.1 to 5.2, from 5.15 to 5.2, from 5.2 to 5.25, from 5.0 to 5.25, from 5.2 to 5.3, from 5.25 to 5.3, from 5.3 to 5.35, from 5.3 to 5.4, from 5.35 to 5.4, from 5.4 to 5.45, from 5.4 to 5.5, from 5.45 to 5.5, from 5.25 to 5.5, from 5.0 to 5.5, from 5.5 to 5.55, from 5.5 to 5.6, from 5.55 to 5.6, from 5.6 to 5.65, from 5.6 to 5.7, from 5.65 to 5.7, from 5.7 to 5.75, from 5.7 to 5.8, from 5.75 to 5.8, from 5.8 to 5.85, from 5.8 to 5.9, from 5.85 to 5.9, from 5.9 to 5.95, from 5.9 to 6.0, from 5.95 to 6.0, from 5.5 to 6.0 or from 5.75 to 6.0. 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, 5.0, 5.5 or 6.0.In some embodiments, including the pH values and ranges listed above, the pH value includes ±0.05, ±0.10, ±0.15, ±0.20 or ±0.25.

[0112] In another embodiment, the radiochemical purity of the radiopharmaceutical composition or formulation is at least about 90%, at least about 95% 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%.

[0113] In another embodiment, as measured by HPLC, TLC or liquid chromatography, the radiochemical purity of the radiopharmaceutical composition or formulation is at least about 90%, at least about 95% or at least about 99%. In another embodiment, as measured by HPLC, TLC or liquid chromatography, the purity of the radiopharmaceutical composition or formulation 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 The radiochemical purity at different pH formulations is shown.

[0114] In another embodiment, the radiochemical purity of the radiopharmaceutical composition or formulation is measured by HPLC, TLC or liquid chromatography at any time after the end of synthesis (EOS). In one embodiment, the purity of the radiopharmaceutical composition or formulation is measured by HPLC, TLC or liquid chromatography 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 after EOS.

[0115] In one specific embodiment, the radiochemical purity of the radiopharmaceutical composition or formulation, as measured by HPLC, TLC, or liquid chromatography at 0 hours post - EOS, is at least about 99%. In another specific embodiment, the purity of the radiopharmaceutical composition or formulation, as measured by HPLC, TLC, or liquid chromatography at 24 hours post - EOS, is at least about 96.5%, at 46 hours post - EOS is at least about 93%, at 67 hours post - EOS is at least about 95%, and at 92 hours post - EOS is at least about 96%.

[0116] In another embodiment, radioactivity is measured in a dose calibrator. When dispensing a dose, the 177 radioactivity amount of [Lu]Lu - PSMA I&T is determined.

[0117] 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.

[0118] In one embodiment, the bacterial endotoxin content of each batch is determined using a PTS - tester (Ph Eur method D) before release, and sterility is determined according to the European Pharmacopoeia.

[0119] In one embodiment, the radiopharmaceutical composition or formulation 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 one specific embodiment, the radiopharmaceutical composition or formulation is stored at about + 10°C, about + 15°C, about + 22°C, about + 22.5°C, about + 25°C, or at room temperature.

[0120] Another aspect of the present disclosure provides a radioactive content of about 70% to 130% of the target administered dose. The radioactive content of the radiopharmaceutical composition can be about 70% to 125%, 70% to 120%, 70% to 115%, 70% to 110%, 80% to 130%, 85% to 130%, 90% to 130%, 95% to 130%, 75% to 125%, 75% to 120%, 75% to 115%, 75% to 110%, 80% to 125%, 80% to 120%, 80% to 115%, 80% to 110%, 85% to 125%, 85% to 120%, 85% to 115%, 85% to 110%, 90% to 125%, 90% to 120%, 90% to 115%, or 90% to 110%.

[0121] 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% of the target administered dose.

[0122] 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.

[0123] In some embodiments, the low radioactivity concentration ("low RAC") of the radiopharmaceutical composition at the end of compounding is from about 563 MBq / ml to about 734 MBq / ml. For example, the radiopharmaceutical composition can have a low radioactivity that can be about 11,580 MBq (313 mCi), about 11,770 MBq (318 mCi), or about 12,520 MBq (338 mCi) in a solution having a volume of 15 ml to 20 ml. 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, 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.

[0124] In additional embodiments, the high radioactivity concentration ("high RAC") of the radiopharmaceutical composition at the end of compounding 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.

[0125] (i) 177 Lu]Lu-PSMA I&T

[0126] The total amount of 177 Lu]Lu-PSMA I&T present in the radiopharmaceutical composition can and will vary. Figure 1A and 1B respectively show the precursor PSMA I&T and 177Chemical structure of Lu-PSMA I&T.

[0127] In one embodiment, the mass of the radiopharmaceutical ingredient ( 177 Lu]Lu-PSMA I&T) in each vial of the drug product is less than about 40 μg, less than about 35 μg, less than about 30 μg, less than about 25 μg, less than about 20 μg, less than about 15 μg or less than about 10 μg. In yet another embodiment, the mass of the radiopharmaceutical ingredient ( 177 Lu]Lu-PSMA I&T) in each vial of the drug 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]Lu-PSMA I&T.

[0128] In one embodiment, the total amount of 177 Lu]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 177Both Lu-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 120 μg / dose ± 15%, ± 10%, or ± 5% to about 200 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 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%.

[0129] In another embodiment, the composition described herein comprises 177The composition of Lu]Lu-PSMA I&T may comprise the following PSMA I&T content: 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]Lu-PSMA I&T may comprise the following PSMA I&T content: 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]Lu-PSMA I&T may comprise the following PSMA I&T content: from about 30 μg / dose to about 100 μg / dose, from about 35 μg / dose to about 100 μg / dose, 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 177The composition of [[Lu]]Lu-PSMA I&T may comprise the following PSMA I&T content: from about 45 μg / dose to about 95 μg / dose, 50 μg / dose to about 100 μg / dose, 55 μg / dose to about 95 μg / dose, 60 μg / dose to about 95 μg / dose, 65 μg / dose to about 95 μg / dose, 70 μg / dose to about 95 μg / dose, 75 μg / dose to about 95 μg / dose, 80 μg / dose to about 95 μg / dose, 85 μg / dose to about 95 μg / dose or about 90 μg / dose to about 95 μg / dose. In another embodiment, the composition comprising 177 The composition of [[Lu]]Lu-PSMA I&T may comprise the following PSMA I&T content: from about 40 μg / dose to about 90 μg / dose, about 45 μg / dose to about 90 μg / dose, about 50 μg / dose to about 90 μg / dose, about 55 μg / dose to about 90 μg / dose, about 60 μg / dose to about 90 μg / dose, about 65 μg / dose to about 90 μg / dose, about 70 μg / dose to about 90 μg / dose, about 75 μg / dose to about 90 μg / dose, about 80 μg / dose to about 90 μg / dose or about 85 μg / dose to about 90 μg / dose. In another embodiment, the composition comprising 177 The composition of [[Lu]]Lu-PSMA I&T may comprise the following PSMA I&T content: from about 40 μg / dose to about 85 μg / dose, about 45 μg / dose to about 85 μg / dose, about 50 μg / dose to about 85 μg / dose, about 55 μg / dose to about 85 μg / dose, about 60 μg / dose to about 85 μg / dose, about 65 μg / dose to about 85 μg / dose, about 70 μg / dose to about 85 μg / dose, about 75 μg / dose to about 85 μg / dose, about 80 μg / dose to about 85 μg / dose. In another embodiment, the composition comprising 177 The composition of [[Lu]]Lu-PSMA I&T may comprise the following PSMA I&T content: from about 40 μg / dose to about 80 μg / dose, about 45 μg / dose to about 80 μg / dose, about 50 μg / dose to about 80 μg / dose, about 55 μg / dose to about 80 μg / dose, about 60 μg / dose to about 80 μg / dose, about 65 μg / dose to about 80 μg / dose, about 70 μg / dose to about 80 μg / dose or about 75 μg / dose to about 80 μg / dose. In another embodiment, the composition comprising 177The composition of Lu-Lu-PSMA I&T may comprise the following PSMA I&T contents: 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.

[0130] In one embodiment, present in the pharmaceutical composition 177The amount of Lu-PSMA I&T is about 30 μg to 120 μg / vial, 35 μg to 120 μg / vial, 40 μg to 120 μg / vial, 45 μg to 120 μg / vial, 50 μg to 120 μg / vial, 55 μg to 120 μg / vial, 60 μg to 120 μg / vial, 65 μg to 120 μg / vial, 70 μg to 120 μg / vial, 75 μg to 120 μg / vial, 85 μg to 120 μg / vial, 90 μg to 120 μg / vial, 95 μg to 120 μg / vial, 100 μg to 120 μg / vial, 105 μg to 120 μg / vial, 110 μg to 120 μg / vial or 115 μg to 120 μg / vial. In one embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 100 μg / vial, 35 μg to 100 μg / vial, 40 μg to 100 μg / vial, 45 μg to 100 μg / vial, 50 μg to 100 μg / vial, 55 μg to 100 μg / vial, 60 μg to 100 μg / vial, 65 μg to 100 μg / vial, 70 μg to 100 μg / vial, 75 μg to 100 μg / vial, 85 μg to 100 μg / vial or 90 μg to 100 μg / vial. In another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 90 μg / vial, 35 μg to 90 μg / vial, 40 μg to 90 μg / vial, 45 μg to 90 μg / vial, 50 μg to 90 μg / vial, 55 μg to 90 μg / vial, 60 μg to 90 μg / vial, 65 μg to 90 μg / vial, 70 μg to 90 μg / vial, 75 μg to 90 μg / vial or 85 μg to 90 μg / vial. In another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 80 μg / vial, 35 μg to 80 μg / vial, 40 μg to 80 μg / vial, 45 μg to 80 μg / vial, 50 μg to 80 μg / vial, 55 μg to 80 μg / vial, 60 μg to 80 μg / vial, 65 μg to 80 μg / vial, 70 μg to 80 μg / vial or 75 μg to 80 μg / vial. In yet another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 70 μg / vial, 35 μg to 70 μg / vial, 40 μg to 70 μg / vial, 45 μg to 70 μg / vial, 50 μg to 70 μg / vial, 55 μg to 70 μg / vial, 60 μg to 70 μg / vial or 65 μg to 70 μg / vial.

[0131] In one embodiment, the amount of 177The amount of 177 Lu]Lu-PSMA I&T and related substances (RS) is about 30 μg to 100 μg / vial, 35 μg to 100 μg / vial, 40 μg to 100 μg / vial, 45 μg to 100 μg / vial, 50 μg to 100 μg / vial, 55 μg to 100 μg / vial, 60 μg to 100 μg / vial, 65 μg to 100 μg / vial, 70 μg to 100 μg / vial, 75 μg to 100 μg / vial, 85 μg to 100 μg / vial or 90 μg to 100 μg / vial. In another embodiment, the 177 amount of Lu]Lu-PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 30 μg to 90 μg / vial, 35 μg to 90 μg / vial, 40 μg to 90 μg / vial, 45 μg to 90 μg / vial, 50 μg to 90 μg / vial, 55 μg to 90 μg / vial, 60 μg to 90 μg / vial, 65 μg to 90 μg / vial, 70 μg to 90 μg / vial, 75 μg to 90 μg / vial or 85 μg to 90 μg / vial. In another embodiment, the 177 amount of Lu]Lu-PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 30 μg to 80 μg / vial, 35 μg to 80 μg / vial, 40 μg to 80 μg / vial, 45 μg to 80 μg / vial, 50 μg to 80 μg / vial, 55 μg to 80 μg / vial, 60 μg to 80 μg / vial, 65 μg to 80 μg / vial, 70 μg to 80 μg / vial or 75 μg to 80 μg / vial. In yet another embodiment, the 177The amount of

[0132] Lu]Lu-PSMA I&T and related substances (RS) in each vial of the pharmaceutical composition is about 30 μg to 70 μg / vial, 35 μg to 70 μg / vial, 40 μg to 70 μg / vial, 45 μg to 70 μg / vial, 50 μg to 70 μg / vial, 55 μg to 70 μg / vial, 60 μg to 70 μg / vial or 65 μg to 70 μg / vial. 177 In another embodiment, the amount of 177 Lu]Lu-PSMA I&T and related substances (RS) in each vial of the pharmaceutical composition is about 55 μg to 110 μg. In another embodiment, the amount of

[0133] In one embodiment, the amount of 177 Lu]Lu-PSMA I&T and related substances (RS) in each vial of the pharmaceutical composition is about 80 μg to 110 μg. In another embodiment, the amount of 177 Lu]Lu-PSMA I&T and related substances (RS) in each vial of the pharmaceutical composition is about 70 μg to 85 μg. In another embodiment, the amount of 177 Lu]Lu-PSMA I&T and related substances (RS) in each vial of the pharmaceutical composition is about 73 μg to 85 μg. In another embodiment, the amount of 177 Lu]Lu-PSMA I&T and related substances (RS) in each vial of the pharmaceutical composition is about 90 μg to 115 μg. In another embodiment, the amount of 177 Lu]Lu-PSMA I&T and related substances (RS) in each vial of the pharmaceutical composition is about 100 μg to 80 μg.

[0134] In one embodiment, the amount of 177 Lu]Lu-PSMA I&T and related substances (RS) in each vial of the pharmaceutical composition is about 110 μg to 80 μg. In another embodiment, the amount of 177 Lu]Lu-PSMA I&T and related substances (RS) in each vial of the pharmaceutical composition is about 115 μg to 125 μg. In another embodiment, the amount of PSMA I&T and related substances (RS) in each vial of the pharmaceutical composition is about 115 μg to 130 μg.

[0135] In one embodiment, the amount of 177The amount of

[0136] Lu]Lu-PSMA I&T and related substances (RS) 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. 177 In one embodiment, the amount of

[0137] Lu]Lu-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. 177 In one embodiment, the total volume of the vial containing 177 Lu]Lu-PSMA I&T and related substances (RS) is about 5 mL to 30 mL. In another embodiment, the total volume of the vial containing 177 Lu]Lu-PSMA I&T and related substances (RS) is about 10 mL to 20 mL. In another embodiment, the total volume of the vial containing 177 Lu]Lu-PSMA I&T and related substances (RS) is about 15 mL to 20 mL. In another embodiment, the total volume of the vial containing 177 Lu]Lu-PSMA I&T and related substances (RS) is about 15 mL to 17 mL. In another embodiment, the total volume of the vial containing

[0138] Lu]Lu-PSMA I&T and related substances (RS) is about 15 mL. 177 In one embodiment, the concentration of 177 Lu]Lu-PSMA I&T and related substances (RS) per vial is 3 μg / mL to 8 μg / mL. In another embodiment, the concentration of 177 Lu]Lu-PSMA I&T and related substances (RS) per vial is 4 μg / mL to 7 μg / mL. In another embodiment, the concentration of 177 Lu]Lu-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

[0139] Lu]Lu-PSMA I&T and related substances (RS) per vial is 4.8 μg / mL to 6 μg / mL. 177The concentration of Lu]Lu-PSMA I&T and related substances (RS) is 4 μg / mL. In another embodiment, each vial 177 The concentration of Lu]Lu-PSMA I&T and related substances (RS) is 5 μg / mL. In another embodiment, each vial 177 The concentration of Lu]Lu-PSMA I&T and related substances (RS) is 6 μg / mL. In another embodiment, each vial 177 The concentration of Lu]Lu-PSMA I&T and related substances (RS) is 7 μg / mL. In another embodiment, each vial 177 The concentration of Lu]Lu-PSMA I&T and related substances (RS) is 8 μg / mL.

[0140] In one embodiment, the PSMA I&T in the composition and 177 The molar ratio of Lu is from 4.0:1.0 to 12.0:1.0. In another embodiment, the PSMA I&T in the composition and 177 The molar ratio of Lu is from 4.0:1.0 to 12.0:1.0, from 4.0:1.0 to 11.5:1.0, from 4.0:1.0 to 11.0:1.0, from 4.0:1.0 to 10.5:1.0, from 4.0:1.0 to 10.0:1.0, from 4.0:1.0 to 9.5:1.0, from 4.0:1.0 to 9.0:1.0, from 4.0:1.0 to 8.5:1.0, from 4.0:1.0 to 8.0:1.0, from 4.0:1.0 to 7.5:1.0, from 4.0:1.0 to 7.0:1.0, from 4.0:1.0 to 6.5:1.0 or from 4.0:1.0 to 6.0:1.0.

[0141] In one embodiment, the PSMA I&T in the composition and 177 The molar ratio of Lu is from 11.0:1.0 to 12.0:1.0, from 11.1:1.0 to 11.9:1.0, from 11.2:1.0 to 11.8:1.0, from 11.3:1.0 to 11.7:1.0 or from 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, from 10.1:1.0 to 10.9:1.0, from 10.2:1.0 to 10.8:1.0, from 10.3:1.0 to 10.7:1.0 or from 10.4:1.0 to 10.6:1.0.

[0142] In one embodiment, the PSMA I&T in the composition and 177The 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 177 The 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, the 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, the 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.

[0143] In one embodiment, the PSMA I&T in the composition and 177 The molar ratio of Lu is from about 4.0:1.0 to about 4.5:1.0, about 4.5:1.0 to about 5.0:1.0, 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.

[0144] In one embodiment, the PSMA I&T in the composition and177 The molar ratio of Lu is from about 4.0:1.0 to about 4.5:1.0, from about 4.0:1.0 to about 5.0:1.0; from about 4.0:1.0 to about 5.5:1.0, from about 4.0:1.0 to about 6.0:1.0, from about 4.0:1.0 to about 6.5:1.0, from about 4.0:1.0 to about 7.0:1.0, from about 4.0:1.0 to about 7.5:1.0, from about 4.0:1.0 to about 8.0:1.0, from about 4.5:1.0 to about 8.0:1.0, from about 5.0:1.0 to about 8.0:1.0, from about 5.0:1.0 to about 8.0:1.0, from about 5.5:1.0 to about 8.0:1.0, from about 6.0:1.0 to about 8.0:1.0, from about 6.5:1.0 to about 8.0:1.0, from about 7.0:1.0 to about 8.0:1.0 or from about 7.5:1.0 to about 8.0:1.0.

[0145] In some embodiments, the 177 total amount of 177 Lu]Lu-PSMA I&T present in the radiopharmaceutical composition can range from about 1.0 μg / ml to about 3 μg / ml, from about 1 μg / ml to about 2 μg / ml, from about 1.1 μg / ml to about 2 μg / ml, from about 1.1 μg / ml to about 1.5 μg / ml, from about 1.1 μg / ml to about 1.4 μg / ml or from about 1.1 μg / ml to about 1.3 μg / ml. In another embodiment, the 177 total amount of

[0146] In some embodiments, the 177 total amount of177 The total amount of Lu]Lu-PSMA I&T can range from about 0.5 μg / ml to about 1.5 μg / ml.

[0147] In some embodiments, the 177 total amount of Lu]Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 3.0 μg / ml. In other embodiments, the 177 total amount of Lu]Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 4.0 μg / ml. In other embodiments, the 177 total amount of Lu]Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 5.0 μg / ml. In other embodiments, the 177 total amount of Lu]Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 6.0 μg / ml.

[0148] In some embodiments, the 177 total amount of Lu]Lu-PSMA I&T 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]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]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.

[0149] The 177 radioactivity / volume of Lu]Lu-PSMA I&T in the composition can be adjusted according to the dose strength. In one embodiment, the composition can include 0.5 GBq (13.5 mCi) of 177 Lu]Lu-PSMA I&T in 1 ml of solution. In other words, the composition can include 10 GBq (270 mCi) of 177Lu-Lu-PSMA I&T. In another embodiment, the composition can comprise 1 GBq (27 mCi) of 177 Lu-Lu-PSMA I&T in 1 ml of solution. In other words, the composition can comprise 10 GBq (270 mCi) of 177 Lu-Lu-PSMA I&T in 10 ml of solution.

[0150] In one embodiment, the 177 radioactivity concentration of Lu-Lu-PSMA I&T in the radiopharmaceutical composition 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, the 177 radioactivity concentration of Lu-Lu-PSMA I&T in the radiopharmaceutical composition is from about 5 mCi / ml to about 30 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, the 177 radioactivity concentration of Lu-Lu-PSMA I&T in the radiopharmaceutical composition 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.

[0151] In one embodiment, the 177 radioactivity of Lu-Lu-PSMA I&T in each vial of radiopharmaceutical composition 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, the 177 radioactivity of Lu-Lu-PSMA I&T in each vial of radiopharmaceutical composition is from about 10 mCi to about 750 mCi, from about 200 mCi to about 600 mCi, from about 300 mCi to about 400 mCi. In a specific embodiment, the 177The 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, about 400 mCi, about 450 mCi, about 500 mCi, about 550 mCi, about 600 mCi or about 700 mCi.

[0152] In yet another embodiment, 177 The standard radioactivity concentration of the Lu-PSMA I&T drug product at the end of production is about 12 mCi / ml or about 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 about 13.5 mCi / ml or about 27 mCi / ml.

[0153] (ii) Antioxidant

[0154] 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.

[0155] 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.

[0156] In one embodiment, the antioxidant can be ascorbic acid and / or ascorbate. Ascorbic acid and / or ascorbate can minimize or reduce the radiolysis of the radiolabeled composition.

[0157] 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 ascorbic acid or ascorbate.

[0158] 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.

[0159] In yet another embodiment, the concentration of ascorbic acid in the radiopharmaceutical composition can be from about 10 mg / ml to about 80 mg / ml, from about 10 mg / ml to about 75 mg / ml, from about 10 mg / ml to about 70 mg / ml, from about 15 mg / ml to about 80 mg / ml, from about 15 mg / ml to about 75 mg / ml, from about 15 mg / ml to about 70 mg / ml, from about 20 mg / ml to about 80 mg / ml, from about 20 mg / ml to about 75 mg / ml, from about 20 mg / ml to about 70 mg / ml, or from about 20 mg / mL to about 40 mg / mL.

[0160] 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.

[0161] In at least one embodiment, the total amount of ascorbic acid in the radiopharmaceutical composition can be about 31 mg / ml. In another embodiment, the total amount of ascorbic acid in the radiopharmaceutical composition can be about 33 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.

[0162] (iii) Stabilizer

[0163] 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 be further used to limit or reduce radiolysis. The stabilizer can also act as a vehicle for the composition.

[0164] The stabilizer can include, but is not limited to, ethanol, p-aminobenzoic acid (PABA), dihydroxybenzoic acid (gentisate compound), gentisic acid, cysteine, selenomethionine, ascorbic acid / ascorbate sodium, methionine, and / or combinations thereof.

[0165] In some embodiments, the stabilizer is ethanol. Ethanol may 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).

[0166] 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 may 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).

[0167] In another embodiment, there may 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.

[0168] 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).

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] (iv) Metal ion chelator (chelator / chelating agent)

[0175] In some embodiments, the present disclosure provides a radiopharmaceutical composition having a certain dose 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] The concentration of the metal ion chelator in the composition can range from about 5 μg / ml to about 500 μg / ml. In another embodiment, the concentration of the chelator present in the radiopharmaceutical composition can range from about 5 μg / ml to 200 μg / ml, from about 5 μg / ml to 75 μg / ml, from 10 μg / ml to about 25 μg / ml, from about 25 μg / ml to about 50 μg / ml, from about 50 μg / ml to about 75 μg / ml, or from about 75 μg / ml to about 100 μg / ml, 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. In some embodiments, the concentration of the chelator 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.

[0180] In other embodiments, the concentration of the chelator 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.

[0181] In another embodiment, the amount of the metal ion chelator in the radiopharmaceutical composition can be 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.

[0182] For example, the amount of disodium EDTA, diethylenetriamine-pentaacetic acid (DTPA), or a combination thereof in 1 ml of the composition can be about 10 μg to 15 μg, about 13 μg to 18 μg, about 15 μg to 20 μg, about 20 μg to 25 μg, about 25 μg to 50 μg, about 50 μg to 75 μg, or about 75 μg to 150 μg. In some embodiments, the amount of disodium EDTA present can be about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10.5 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg, about 25 μg, about 26 μg, about 27 μg, about 28 μg, about 29 μg, about 30 μg, about 31 μg, about 32 μg, about 33 μg, about 34 μg, about 35 μg, about 36 μg, about 37 μg, about 38 μg, about 39 μg, about 40 μg, about 45 μg, or about 50 μg.

[0183] 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.

[0184] In one embodiment, the content of other trace metals 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.

[0185] (v) pH regulator

[0186] Suitable pH regulators include, but are not limited to, any one of hydrochloric acid, sodium hydroxide, sodium bicarbonate, or a combination thereof.

[0187] 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 can range from 1.6 ml of 0.05 M HCl to 2 ml of 0.04 M HCl. The amount of HCl in the composition can vary to adjust the pH of the final formulation in the production batch. 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. In various embodiments, the pH of the final formulation 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.

[0188] 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 adding HCl.

[0189] 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 adding HCl.

[0190] (vi) Water

[0191] The composition can further include a sufficient amount of water to prepare the desired final volume for an injectable solution. For example, water can be added to make the final volume 1 ml, 10 ml, or 20 ml. The 10 ml or 20 ml solution can be stored in vials and divided into smaller volumes for administration.

[0192] IV. Method for Preparing a Radiopharmaceutical Composition

[0193] 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 to 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.

[0194] 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.

[0195] In one embodiment, step 102 can include preparing four solutions for synthesis. These four solutions can include 0.04 M hydrochloric acid, 0.4 M 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.

[0196] 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 at pH 4.25 ± 0.25 and 0.1 mg / ml DTPA.

[0197] 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 injectable grade water. In one example, the formulation solution is prepared by adding sufficient amounts of the following solutions to a bulk vial: a ~50 mg / ml ascorbic acid pH 4.5 solution (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.

[0198] 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 PSMA I&T solution of approximately 463 μg / ml, 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 ascorbic acid concentration in the reaction solution may range from 3.75 mg / ml to 5.00 mg / ml.

[0199] 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 Lu]LuCl3 vial is rinsed with an additional required volume of 0.04 M hydrochloric acid (prepared in step 102) and then transferred to the reactor.

[0200] The reaction volume can range from 6 ml to 8 ml. The volume can depend on the amount of precursor used.

[0201] In one embodiment, step 112 can include 177 radioactively labeling PSMA-I&T with Lu. The reaction mixture can be heated to up to about 75 °C, up to about 80 °C, up to about 85 °C, up to about 90 °C, or up to about 95 °C. In one example, the heating set point is 110 °C and the actual maximum temperature reached is about 95 °C. The reaction volume can be heated for up to 5 minutes, up to 10 minutes, up to 15 minutes, or up to 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.

[0202] In one embodiment, optional step 114 can include purifying the reaction mixture. For example, the solution can be passed through a cartridge / column containing a hydrophobic, reversed-phase, silica-based bonded phase. Sep-Pak C18 is used to purify the composition. In at least one example, the reaction mixture can be passed 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.

[0203] 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 the desired radioactivity concentration with the dilution buffer prepared in step 104. A 1.5 ml 1:1 ratio ethanol-water wash solution can be used to elute the composition. 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.

[0204] 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.

[0205] 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 a suitable 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 a suitable volume and radioactivity at the calibration time.

[0206] In other embodiments, the reactor can be heated at a set point of 110 °C, and the highest temperature reached in the reaction solution is about 90 °C, about 85 °C, about 80 °C, about 75 °C, or about 70 °C. 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

[0207] Figure 3A An example of a method for preparing a radiopharmaceutical composition by purifying the reaction mixture and the 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.

[0208] An increase in 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 3.5, 3.75, 4.0, 4.25, or 4.5, adjusting the amount of ascorbic acid in the composition, and / or adjusting the radioactivity to 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 a 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, 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 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, 4.25 days, 4.5 days, 4.75 days, or 5 days.

[0209] The targeted drug formulations according to the present disclosure are provided as in Table 1A.

[0210] Table 1A: Targeted drug formulations

[0211]

[0212] a The maximum volume per vial is 10 ml

[0213] b The maximum volume per vial is 20 ml

[0214] c The maximum volume per vial is 15 ml

[0215] In another embodiment, a one-step radiolabeling method carried out in the following steps may be used in the preparation of Composition 4 disclosed in Table 1A above.

[0216] 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 may 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.

[0217] It may be prepared as shown in Figure 2 b(201, 202, 203) 177Lu-PSMA I&T composition solution. The order of steps can be varied, such as the order of preparing various solutions.

[0218] 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 can be dissolved in the reaction buffer, as shown in step 202. For example, 1000 μg to 5000 μg of the precursor can be used in the reaction, depending on the batch size.

[0219] In one embodiment, the 177 amount of 177 Lu]LuCl3 used in radiolabeling (step 204) can range from 50 mCi to 15,200 mCi. The corresponding amount of PSMA I&T used during radiolabeling can range from 0.1 μg / mCi to 0.9 μg / mCi. For example, during radiolabeling, 15,000 mCi of

[0220] In one embodiment, step 203 may include preparing an ascorbic acid solution (dilution buffer). In some instances, the ascorbic acid solution can be a 33 mg / ml ascorbic acid solution. The solution pH can be adjusted to 4.25 ± 0.05, 4.25 ± 0.10, 4.25 ± 0.15, 4.25 ± 0.20, or 4.25 ± 0.25. For example, the ascorbic acid solution can include 33 mg / ml ascorbic acid / sodium ascorbate and 0.1 mg / ml DTPA at pH 4.25 ± 0.25.

[0221] In one embodiment, step 204 may include preparing 177 Lu. In some embodiments, 177 Lu can be provided in HCl. 177 Lu]LuCl3 can be provided in 0.05 M HCl. For example, 2 Ci / ml of 177 Lu can be provided in 0.05 M HCl. The 0.05 M hydrochloric acid containing 177 Lu]LuCl3 can be transferred to the reactor, and the 177 Lu]LuCl3 vial can be rinsed with an additional required volume of 82 mg / mL sodium ascorbate (prepared in step 201) and then also transferred to the reactor.

[0222] The reaction volume can range from 8 ml to 15 ml. The volume can depend on the amount of 177 Lu]LuCl3 used in the radiolabeling reaction.

[0223] In one embodiment, step 204 may include radiolabeling PSMA-I&T with 177 Lu. The reaction mixture may 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 instance, the heating set point is 85 °C and the actual maximum temperature reached is about 75 °C. The reaction volume may 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 instance, the reaction mixture is heated at a set point of 80 °C for 10 minutes. In at least one additional instance, the reaction mixture is heated at a set point of 70 °C for 10 minutes.

[0224] 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 radiolysis damage.

[0225] The final composition may 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 introduced.

[0226] In some embodiments, in step 206, the final composition may be sterile filtered. The sterile filter may be a 0.22 μm sterile filter. The final product may be dispensed through a 0.22 μm sterile filter into single-dose vials containing a suitable volume and radioactivity at a reference specified calibration time. For example, the final composition may be dispensed through a 0.22 μm sterile filter in a Class A environment into doses containing a suitable volume and radioactivity at the calibration time.

[0227] Figure 3B An example of a method for preparing a radiopharmaceutical composition without purification and without using ethanol is provided.

[0228] 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 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 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 or 4 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.

[0229] V. Stability

[0230] 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 synthesis formulation and a predetermined amount added to the bulk vial as part of the synthesis formulation.

[0231] 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 give the composition higher stability characteristics and a longer shelf life. 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.

[0232] In one or more embodiments, a 177Lu-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 can provide sufficient stability for four days.

[0233] A composition having a low radioactivity concentration (e.g., 588.5 MBq / ml), pH 4.5, and 31 mg / ml ascorbic acid has a radiochemical purity of 99.1% at 0 hours post - EOS, 98.7% at 20 hours post - EOS, 98.0% at 44 hours post - EOS, 97.4% at 69 hours post - EOS, and 97.0% at 93 hours post - EOS. A composition having a low radioactivity concentration (e.g., 626 MBq / ml), pH 5.0, and 31 mg / ml ascorbic acid has a radiochemical purity of 99.2% at 0 hours post - EOS, 98.4% at 25 hours post - EOS, 97.3% at 47 hours post - EOS, and 96.5% at 71 hours post - EOS. A composition having a low radioactivity concentration (e.g., 579 MBq / ml), pH 4.5, and 21 mg / ml ascorbic acid has a radiochemical purity of 99.4% at 0 hours post - EOS, 98.3% at 19 hours post - EOS, 97.5% at 46 hours post - EOS, 96.8% at 71 hours post - EOS, and 96.0% at 92 hours post - EOS. A composition having a high radioactivity concentration (e.g., 1,278 MBq / ml), pH 4.5, and 42.5 mg / ml ascorbic acid has a radiochemical purity of 99.4% at 0 hours post - EOS, 98.0% at 24 hours post - EOS, 96.7% at 46 hours post - EOS, 95.3% at 67 hours post - EOS, and 95.2% at 71 hours post - EOS.

[0234] 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.

[0235] 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 a temperature of about 10°C, about 15°C, about 22°C, about 22.5°C, about 25°C, or at room temperature.

[0236] In one embodiment, the radiopharmaceutical composition is stored at about 22.5°C. In another embodiment, the radiopharmaceutical composition is stored at room temperature.

[0237] VI. Specific radiopharmaceutical compositions

[0238] In some embodiments, the pharmaceutical product is a sterile filtered radiopharmaceutical solution containing a dose of 177 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):

[0239] Table 1B: Composition of the final product a ( 177 Lu-PSMA I&T composition 1)

[0240] 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) Vehicle / stabilizer (radiolysis) Ascorbic acid 42.5 mg / ml Stabilizer (radiolysis) EDTA disodium 21 μg / ml Metal ion chelator Sodium bicarbonate* Appropriate amount pH regulator Sodium hydroxide* Appropriate amount pH regulator WFI (Water for Injection) Up to 1 ml Vehicle

[0241] a Maximum volume per vial is 10 ml

[0242] b Sufficient radioactivity for the intended use

[0243] In yet another embodiment, the pharmaceutical product is a sterile filtered radiopharmaceutical solution containing a dose 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 and having a pH of about 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 3):

[0244] Table 1C: Composition of the final product *( 177 Lu-PSMA I&T composition 3)

[0245] Component Amount Function <![CDATA 177 Lu-PSMA I&T]]> Appropriate amount** API Ethanol 3.8%(v / v) Vehicle / stabilizer (radiolysis) Ascorbic acid 31 mg / ml Stabilizer (radiolysis) EDTA disodium 15.5 μg Metal ion chelator 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

[0246] * Maximum volume per vial is 20 ml

[0247] ** Sufficient radioactivity for the intended use

[0248] In yet another embodiment, the pharmaceutical product is in an aqueous solution of 33 mg / ml ascorbic acid containing a dose of 177A sterile filtered radiopharmaceutical solution of 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-PSMA I&T Composition 4):

[0249] Table 1D: Composition of the Final Product*( 177 Lu-PSMA I&T Composition 4)

[0250] Component Amount Function <![CDATA 177 Lu-PSMA I&T]]> Appropriate amount** API PSMA I&T 3 - 8 μg / ml Precursor Ascorbic acid 33 mg / ml Stabilizer (radiolysis) DTPA 0.075 - 0.15 mg / mL Metal ion chelator Hydrochloric acid Appropriate amount pH regulator WFI (Water for Injection) Up to 1 ml Vehicle

[0251] *The maximum volume per vial is 20 ml

[0252] **Sufficient radioactivity for the intended use

[0253] VII. Preparation of the Pharmaceutical Product

[0254] The pharmaceutical product can be delivered in a sterile, pyrogen-free glass vial of Type 1 glass with a fluoropolymer-coated bromobutyl 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 shield and outer packaging, meets Type A requirements (IAEA standards). Figure 4 A figure depicting the product vial that can be used in this example is shown.

[0255] In one embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is from about 10 ml to about 20 ml, about 20 ml to about 30 ml, about 30 ml to about 40 ml, about 40 ml to about 50 ml, about 50 ml to about 60 ml, about 60 ml to about 70 ml, about 70 ml to about 80 ml, about 80 ml to about 90 ml, or about 90 ml to about 100 ml. In a specific embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 1 ml, about 5 ml, about 7 ml, about 8 ml, about 9 ml, about 10 ml, about 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.

[0256] In one embodiment, the volume of the solution containing 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 containing the formulation or radiopharmaceutical composition is about 200 ml, about 225 ml, about 250 ml, about 275 ml, about 300 ml, about 325 ml, about 350 ml, about 375 ml, about 400 ml, about 425 ml, about 450 ml, about 475 ml, about 500 ml, about 525 ml, about 550 ml, about 575 ml, about 600 ml, about 625 ml, about 650 ml, about 675 ml, about 700 ml, about 725 ml, or about 750 ml.

[0257] 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 desired amount of radioactivity at the infusion date and time.

[0258] In another embodiment, 177 Lu-PSMA I&T injection solution is supplied in single-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.

[0259] In yet another embodiment, 177 the shelf life of the 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-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.

[0260] In some embodiments, the radiopharmaceutical composition 177 should have a radiochemical purity of ≥95% for 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 such a chemical purity 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, or less than about 1 μg / ml.

[0261] In some embodiments, the radiopharmaceutical composition can have a certain amount of colloid with radioactivity less than about 5%, radioactivity less than about 4.5%, radioactivity less than about 4%, radioactivity less than about 3.5%, radioactivity less than about 3%, radioactivity less than about 2.5%, radioactivity less than about 2%, radioactivity less than about 1.5%, radioactivity less than about 1%, radioactivity less than about 0.5%, radioactivity less than about 0.3%, radioactivity less than about 0.2%, or radioactivity less than about 0.1% 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 colloid 177 Lu.

[0262] In some embodiments, the radiopharmaceutical composition may 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.

[0263] 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 hours to 48 hours after compounding, greater than 96% from 46 hours to 48 hours after compounding, greater than 97% from 46 hours to 48 hours after compounding, greater than 95% from 69 hours to 72 hours after compounding, greater than 96% from 69 hours to 72 hours after compounding, greater than 97% from 69 to 72 hours after compounding, greater than 95% from 90 hours to 93 hours after compounding, greater than 96% from 90 hours to 93 hours after compounding, and / or greater than 97% from 90 hours to 93 hours after compounding.

[0264] 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% at 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% at 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% at 69 - 71 hours after EOS. In some instances, the range of the radiochemical purity of the composition can be from about 94.5% to about 97.0% at 90 - 93 hours after EOS.

[0265] In another embodiment, 177 The Lu-PSMA I&T injection is supplied in single-dose vials.

[0266] In yet another embodiment, a patient in need of radioligand therapy during treatment receives a single intravenous radioactive dose at the start of the 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.

[0267] In one embodiment, the volume of the patient dose is calculated based on the radioactive dose to be administered.

[0268] In another embodiment, 177 Lu-PSMA I&T is slowly injected via the intravenous (IV) route over approximately 10 minutes, and subsequently 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 inconsequential. The dose is administered once every 6 weeks for 4 cycles.

[0269] In yet another embodiment, a patient in need of radioligand therapy during treatment receives a single intravenous radioactive dose at the start of the 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.

[0270] In one embodiment, the volume of the patient dose is calculated based on the radioactive dose to be administered.

[0271] IX. Administration

[0272] Also provided herein is a method of administering a radiopharmaceutical composition. The radiopharmaceutical composition can be administered by injection to a human patient in need.

[0273] There can be approximately six main aspects of administration.

[0274] First, cool the salivary glands. Thirty minutes before administering 177 Lu-PSMA I&T and up to 4 hours after administering 177 Lu-PSMA I&T, the patient receives ice packs on the parotid and submandibular glands to reduce the risk of radiation damage to the salivary glands. There is no scientific evidence as to whether cooling the salivary glands is an effective therapy for sparing these glands from radiation; however, the cooling of the salivary glands is tolerable and harmless to the patient.

[0275] Second, use a catheter in incontinent patients within the first 48 hours to avoid any contamination.

[0276] Third, 6.5 - 7.5 GBq (range: 6.0 - 8.0 GBq)177 Activity of Lu-PSMA I&T. In 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.

[0277] 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.

[0278] Fifth, 3 - 5 cycles of RLT per 5 - 8 weeks on average, and an experience of up to 11 cycles has been reported. In case of a continuous increase in PSA, after the deterioration of general symptoms in the first two cycles, the indication for additional RLT should be re-evaluated. In case PSA drops to <1.0 μg / l during the therapy cycle, when the post-injection SPECT study is insufficient to provide information, PSMA imaging can be performed after completion of RLT to evaluate the presence of small PSMA-positive metastases. In case of a significant decrease in platelets or white blood cells, the time interval between two cycles can be extended.

[0279] 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., prednisolone 20 mg / day) within the first two weeks after administration.

[0280] 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 Lu-PSMA I&T and ascorbic acid in a solution 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 include <6 μg / ml 177 Lu-PSMA I&T, about 7 μg / ml to about 18 μg / ml disodium EDTA, about 25 μl / ml to about 45 μl / ml ethanol, and / or about 15 mg / ml to about 35 mg / ml ascorbic acid. Alternatively, the composition may include 5 μg / ml 177 Lu-PSMA I&T, about 7 μg / ml to about 18 μg / ml disodium EDTA, about 25 μl / ml to about 45 μl / ml ethanol, and / or about 15 mg / ml to about 35 mg / ml ascorbic acid. 177Lu-PSMA I&T, approximately 0.1 mg / ml DTPA, and approximately 30 mg / ml to approximately 35 mg / ml ascorbic acid. The radioactivity of the composition can be approximately 0.5 GBq / ml or approximately 13.3 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.

[0281] 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 administered once every 6 weeks.

[0282] In various embodiments, the dose can be administered to a patient at a dose of 0.5 GBq / dose / cycle to 10 GBq / dose / cycle 177 Lu-PSMA I&T. For example, the standard radioactivity of the radiopharmaceutical composition at expiration can be approximately 200 mCi, and the standard radioactivity concentration at the end of production is approximately 27 mCi / mL; thus, the final volume of the dose vial can be adjusted to be between 7 mL and 10 mL 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 some embodiments, the dose vial contains 7 mL to 15 mL. In at least one example, for each treatment, a dose of approximately 200 mCi (7.4 GBq ± 0.1 GBq) can be administered to a patient. On the one hand, for four, five, six, seven, or more treatments, a dose of approximately 200 mCi (7.4 GBq ± 0.1 GBq) can be administered to a patient for each 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 approximately 200 mCi (7.4 GBq ± 0.1 GBq) can be administered to a patient for each treatment. In yet another aspect, for four, five, six, seven, eight, or more treatments, a dose of approximately 200 mCi (≥7.1 GBq) can be administered to a patient for each treatment. In another example, a dose of approximately 6.8 GBq ± 0.3 GBq can be administered to a patient for each treatment. On the one hand, for four, five, six, seven, eight, or more treatments, a dose of approximately 6.8 GBq ± 0.3 GBq can be administered to a patient for each treatment.

[0283] In various embodiments, it may be administered to a patient in a dose of from about 0.5 GBq to about 10 GBq, from about 1.0 GBq to about 9.0 GBq, from about 1.5 GBq to about 8.5 GBq, from about 2.0 GBq to about 8.0 GBq, from about 2.5 GBq to about 7.5 GBq or from 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. In various embodiments, it can be from about 0.5 GBq to about 10.0 GBq, from about 0.5 GBq to about 9.5 GBq, from about 0.5 GBq to about 9.0 GBq, from about 0.5 GBq to about 8.5 GBq, from about 0.5 GBq to about 8.0 GBq, from about 0.5 GBq to about 7.5 GBq, from about 1.0 GBq to about 10.0 GBq, from about 1.0 GBq to about 9.5 GBq, from about 1.0 GBq to about 9.0 GBq, from about 1.0 GBq to about 8.5 GBq, from about 1.0 GBq to about 1.0 GBq, from about 1.0 GBq to about 7.5 GBq, from about 1.5 GBq to about 10.0 GBq, from about 1.5 GBq to about 9.5 GBq, from about 1.5 GBq to about 9.0 GBq, from about 1.5 GBq to about 8.5 GBq, from about 1.5 GBq to about 8.0 GBq, from about 1.5 GBq to about 7.5 GBq, from about 2.0 GBq to about 10.0 GBq, from about 2.0 GBq to about 9.5 GBq, from about 2.0 GBq to about 9.0 GBq, from about 2.0 GBq to about 8.5 GBq, from about 2.0 GBq to about 8.0 GBq, from about 2.5 GBq to about 10.0 GBq, from about 2.5 GBq to about 2.5 GBq, from about 2.5 GBq to about 9.0 GBq, from about 2.5 GBq to about 8.5 GBq, from about 2.5 GBq to about 8.0 GBq, from about 2.5 GBq to about 7.5 GBq, from about 3.0 GBq to about 10.0 GBq, from about 3.0 GBq to about 9.5 GBq, from about 3.0 GBq to about 9.0 GBq, from about 3.0 GBq to about 8.5 GBq, from about 3.0 GBq to about 8.0 GBq, from about 3.0 GBq to about 7.5 GBq, from about 3.5 GBq to about 10.0 GBq, from about 3.5 GBq to about 9.5 GBq, from about 3.5 GBq to about 9.0 GBq, from about 3.5 GBq to about 8.5 GBq, from about 3.5 GBq to about 8.0 GBq, from about 3.5 GBq to about 7.5 GBq, from about 0.5 GBq to about 7.5 GBq, from about 0.5 GBq to about 7.4 GBq, from about 1.0 GBq to about 7.4 GBq, from about 1.5 GBq to about 7.4 GBq, from about 2.0 GBq to about 7.4 GBq, from about 2.5 GBq to about 7.4 GBq, from about 3.0 GBq to about 7.4 GBq, from about 3.5 GBq to about 7.A dose of 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 kidney per administration ≤ 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 can be administered to the patient. 177 Lu-PSMA I&T, wherein the total cumulative dose to the patient's kidney per administration ≤ 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.

[0284] In various embodiments, more than 10 treatments can be administered to a patient, and the treatments can be administered every 4, 5, 6, 7, or 8 weeks, provided that 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 a patient, and the treatments can be administered every 4, 5, 6, 7, or 8 weeks, provided that the total cumulative dose to the patient's kidneys remains below 23 gray (Gy) after all treatments.

[0285] In various embodiments, administration 177 of Lu-PSMA I&T results in an absorbed dose per gram of tissue in the patient's kidneys of from 0.2 Gy / MBq to about 0.6 Gy / GBq (i.e., about 0.2 Gy / GBq to about 0.6 Gy / GBq of the administered 177 Lu-PSMA I&T) per gram of tissue. In some additional embodiments, administration 177 of Lu-PSMA I&T results in an absorbed dose in the patient's kidneys that is less than or equal to 0.43 Gy / GBq.

[0286] In some embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose in the patient's kidneys of 0.46 Gy / GBq ± 0.23 Gy / GBq (i.e., 0.46 Gy / GBq of the administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose in the patient's kidneys that is less than or equal to 0.46 Gy / GBq.

[0287] In various embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose in the patient's kidneys of 0.43 Gy / GBq ± 0.18 Gy / GBq (i.e., 0.43 Gy / GBq of the administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose in the patient's kidneys that is less than or equal to 0.43 Gy / GBq.

[0288] In other embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose in the patient's kidneys of 0.41 Gy / GBq ± 0.15 Gy / GBq (i.e., 0.41 Gy / GBq of the administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose in the patient's kidneys that is less than or equal to 0.41 Gy / GBq.

[0289] In various embodiments, administration of 177Lu-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., for 177Lu-PSMA I&T administered at 0.67 Gy / GBq). In some additional embodiments, administration of 177Lu-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.

[0290] In other embodiments, administration of 177Lu-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., for 177Lu-PSMA I&T administered at 0.40 Gy / GBq). In some additional embodiments, administration of 177Lu-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.

[0291] In other embodiments, administration of 177Lu-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., for 177Lu-PSMA I&T administered at 0.10 Gy / GBq). In some additional embodiments, administration of 177Lu-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.

[0292] In various embodiments, administration of 177Lu-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., for 177Lu-PSMA I&T administered at 0.13 Gy / GBq). In some additional embodiments, administration of 177Lu-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.

[0293] In other embodiments, administration of 177Lu-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 177Lu-PSMA I&T administered at 0.18 Gy / GBq). In some additional embodiments, administration of 177Lu-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.

[0294] In various embodiments, administration of 177Lu-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 177Lu-PSMA I&T administered at 0.03 Gy / GBq). In some additional embodiments, administration of 177Lu-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.

[0295] In other embodiments, administration of 177Lu-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 177Lu-PSMA I&T administered at 0.04 Gy / GBq). In some additional embodiments, administration of 177Lu-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.

[0296] 177 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.

[0297]

[0298] where X is the 177 total allowable number of cycles at a given activity of Lu-PSMA I&T, Y is the 177 activity of each dose of Lu-PSMA I&T, Y is the 177 radiation absorbed dose of Lu-PSMA I&T in Gy / GBq, and Z is the activity of 177Lu-PSMA I&T administered in GBq.

[0299] In various embodiments, 1 GBq 177 of Lu-PSMA I&T can be administered to the patient for 53 treatments, 2 GBq 177 of Lu-PSMA I&T for 26 treatments, 3 GBq 177 of Lu-PSMA I&T for 17 treatments, 4 GBq 177 of Lu-PSMA I&T for 13 treatments, 5 GBq 177 of Lu-PSMA I&T for 10 treatments, 6 GBq 177 of Lu-PSMA I&T for 8 treatments, 7 GBq 177 of Lu-PSMA I&T for 7 treatments, 8 GBq 177Lu-PSMA I&T for 6 treatments, administered at 9 GBq 177 Lu-PSMA I&T for 5 treatments, administered at 10 GBq 177 Lu-PSMA I&T for 5 treatments.

[0300] In various embodiments, 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 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 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.

[0301] In various embodiments, 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 6.6 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 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 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.

[0302] In various embodiments, 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 6.7 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 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.

[0303] In various embodiments, 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 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.

[0304] In various embodiments, the present disclosure further relates to a radiopharmaceutical kit, the 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 6.9 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 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 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.

[0305] 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, 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 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.

[0306] 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 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 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.

[0307] 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, 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 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 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.

[0308] 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 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 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 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.

[0309] 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 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 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.

[0310] 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 7.5 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 are carried out at said dose of177 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 6 cycles is less than 23 Gy, and no nephrotoxicity was observed.

[0311] 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, wherein the injection comprises a dose of 7.4 GBq (average 7.52 ± 0.16 GBq) of 177 Lu-PSMA-I&T, and wherein 6 cycles of 177 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 was observed. 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, 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-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 was observed.

[0312] 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, wherein the injection comprises a dose of 6.5 GBq + / - 10% GBq, 6.5 GBq + / - 5% GBq or 6.5 GBq + / - 3% GBq of177 Lu-PSMA-I&T, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu-PSMA I&T treatment are possible at said dose 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.

[0313] 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 6.8 GBq + / - 10% GBq, 6.8 GBq + / - 5% GBq or 6.8 GBq + / - 3% GBq of 177 Lu-PSMA-I&T, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu-PSMA I&T treatment are possible at said dose 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.

[0314] 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 7.4 GBq + / - 10% GBq, 7.4 GBq + / - 5% GBq or 7.4 GBq + / - 3% GBq of 177 Lu-PSMA-I&T, and wherein 1, 2, 3, 4, 5, 6 or 7 cycles of 177 Lu-PSMA I&T treatment are possible at said dose without the risk of nephrotoxicity, and / or wherein 1, 2, 3, 4, 5, 6 or 7 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 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.

[0315] 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 (+ / - 10%) GBq of 177 Lu-PSMA-I&T, and wherein 6 cycles of 177 Lu-PSMA I&T treatment is possible without the risk of nephrotoxicity, and / or wherein 6 cycles of 177 Lu-PSMAI&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.

[0316] 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.

[0317] In some embodiments, the present disclosure includes a kit comprising a predetermined amount of a composition comprising 177 Lu-PSMA I&T. In another embodiment, PSMA I&T is combined with 177The molar ratio of Lu is from 5.0:1.0 to 12.0:1.0. In another embodiment, the composition is suitable for administration to a human patient in need thereof.

[0318] When administering the radiopharmaceutical composition to a patient, the patient may maintain low levels of hematotoxicity and nephrotoxicity. 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%.

[0319] Also provided herein is a method for treating a patient with mCRPC by administering a radiopharmaceutical composition comprising 177 Lu-PSMA I&T. The method may further comprise imaging the patient using PSMA-PET prior to 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.

[0320] In one embodiment, provided herein is a method for imaging the cancer of a human patient. In another embodiment, the method further comprises administering to the 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.

[0321] The absorbed radiation dose from the administered composition can be measured by SPECT / CT imaging, planar imaging or a combination thereof or by other techniques known to those of ordinary skill in the art. The anatomical coverage of the imaging can extend from the salivary glands of the human patient to the pelvis.

[0322] After administration of one of the compositions provided herein, the absorbed radiation dose per gram of tissue in the kidney of a human patient can be from about 0.2 Gy / GBq to about 0.6 Gy / GBq, from about 0.25 Gy / GBq to about 0.55 Gy / GBq, from about 0.3 Gy / GBq to about 0.5 Gy / GBq, or from about 0.35 Gy / GBq to about 0.45 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the kidney of a human patient can be ≤ 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, ≤ 0.25 Gy / GBq, ≤ 0.20 Gy / GBq, or ≤ 0.15 Gy / GBq.

[0323] The PSMA I&T in the composition and 177 the molar ratio of Lu can be from about 4.0:1 to about 8.0:1, such as from about 4.5:1 to about 5.5:1 or from about 5.0:1 to about 6.0:1. In some aspects, the PSMA I&T of the composition and 177 the molar ratio of Lu is about 4.0:1, about 4.1:1, about 4.2:1, about 4.3:1, about 4.4:1, about 4.5:1, about 4.6:1, about 4.7:1, about 4.8:1, about 4.9:1, about 5.0:1, about 5.1:1, about 5.2:1, about 5.3:1, about 5.4:1, about 5.5:1, about 5.6:1, about 5.7:1, about 5.8:1, about 5.9:1, about 6.0:1, about 6.1:1, about 6.2:1, about 6.3:1, about 6.4:1, about 6.5:1, about 6.6:1, about 6.7:1, about 6.8:1, about 6.9:1, about 7.0:1, about 7.1:1, about 7.2:1, about 7.3:1, about 7.4:1, about 7.5:1, about 7.6:1, about 7.7:1, about 7.8:1, about 7.9:1, or about 8.0:1. In some aspects, the PSMA I&T of the composition and 177 the molar ratio of Lu is from about 5.1:1.0 to about 5.9:1.0, from about 5.2:1.0 to about 5.8:1.0, from about 5.3:1.0 to about 5.7:1.0, or from about 5.4:1.0 to about 5.6:1.0.

[0324] The composition can comprise from about 7.1 GBq to about 7.6 GBq of 177 Lu-PSMA I&T. For example, the composition can comprise about 7.1 GBq, about 7.2 GBq, about 7.3 GBq, about 7.4 GBq, about 7.5 GBq, or about 7.6 GBq of 177Lu-PSMA I&T. In some specific embodiments, the composition may comprise 7.4 ± 15% GBq of 177 Lu-PSMA I&T, 7.4 ± 10% GBq of 177 Lu-PSMA I&T or 7.4 ± 5% GBq of 177 Lu-PSMA I&T.

[0325] In some aspects, the average absorbed radiation dose per gram of tissue in the kidney of a human patient may be about 0.39 ± 0.15 Gy / GBq, about 0.40 ± 0.15 Gy / GBq, about 0.41 ± 0.15 Gy / GBq, about 0.42 ± 0.15 Gy / GBq, about 0.43 ± 0.15 Gy / GBq or about 0.45 ± 0.15 Gy / GBq. In some additional aspects, the average absorbed radiation dose per gram of tissue in the kidney of a human patient may be ≤ 0.39 Gy / GBq, ≤ 0.40 Gy / GBq, ≤ 0.41 Gy / GBq or ≤ 0.42 Gy / GBq.

[0326] In some aspects, the standard deviation of the average absorbed radiation dose per gram of tissue in the kidney of a human patient may be ≤ 0.19 Gy / GBq, ≤ 0.18 Gy / GBq, ≤ 0.17 Gy / GBq, ≤ 0.16 Gy / GBq or ≤ 0.15 Gy / GBq.

[0327] The absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient may be from about 0.01 Gy / GBq to about 1.5 Gy / GBq, such as from about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient may be ≤ 1.5 Gy / GBq, ≤ 1.4 Gy / GBq, ≤ 1.3 Gy / GBq, ≤ 1.2 Gy / GBq, ≤ 1.1 Gy / GBq, ≤ 1.0 Gy / GBq, ≤ 0.9 Gy / GBq, ≤ 0.8 Gy / GBq, ≤ 0.7 Gy / GBq, ≤ 0.6 Gy / GBq, ≤ 0.5 Gy / GBq, ≤ 0.4 Gy / GBq, ≤ 0.3 Gy / GBq, ≤ 0.2 Gy / GBq or ≤ 0.1 Gy / GBq. The absorbed radiation dose can be measured by SPECT / CT imaging, planar imaging or a combination thereof or by other techniques known to those of ordinary skill in the art.

[0328] In some embodiments, the absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient can be about 0.01 Gy / GBq, about 0.05 Gy / GBq, about 0.1 Gy / GBq, about 0.2 Gy / GBq, about 0.3 Gy / GBq, about 0.4 Gy / GBq, about 0.5 Gy / GBq, about 0.6 Gy / GBq, about 0.7 Gy / GBq, about 0.8 Gy / GBq, about 0.9 Gy / GBq, about 1.0 Gy / GBq, about 1.1 Gy / GBq, about 1.2 Gy / GBq, about 1.3 Gy / GBq, about 1.4 Gy / GBq, or about 1.5 Gy / GBq.

[0329] In some embodiments, the average absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient can be 0.37 ± 0.36 Gy / GBq, 0.38 ± 0.36 Gy / GBq, 0.39 ± 0.36 Gy / GBq, or 0.40 ± 0.36 Gy / GBq. In some embodiments, the average absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient can be ≤ 1.5 Gy / GBq, ≤ 1.4 Gy / GBq, ≤ 1.3 Gy / GBq, ≤ 1.2 Gy / GBq, ≤ 1.1 Gy / GBq, ≤ 1.0 Gy / GBq, ≤ 0.9 Gy / GBq, ≤ 0.8 Gy / GBq, ≤ 0.7 Gy / GBq, ≤ 0.6 Gy / GBq, ≤ 0.5 Gy / GBq, ≤ 0.4 Gy / GBq, ≤ 0.3 Gy / GBq, ≤ 0.2 Gy / GBq, or ≤ 0.1 Gy / GBq. In some additional embodiments, the standard deviation of the average absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient can be ≤ 0.40 Gy / GBq, ≤ 0.39 Gy / GBq, ≤ 0.38 Gy / GBq, ≤ 0.37 Gy / GBq, ≤ 0.36 Gy / GBq, ≤ 0.35 Gy / GB, ≤ 0.34 Gy / GBq, ≤ 0.33 Gy / GBq, ≤ 0.32 Gy / GBq, ≤ 0.31 Gy / GBq, or ≤ 0.30 Gy / GBq.

[0330] After administering the composition, the absorbed radiation dose per gram of tissue in the salivary gland of a human patient can be from about 0.01 Gy / GBq to about 1.0 Gy / GBq, such as from about 0.1 Gy / GBq to about 0.5 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the salivary gland of a human patient can be ≤ 1.0 Gy / GBq, ≤ 0.9 Gy / GBq, ≤ 0.8 Gy / GBq, ≤ 0.7 Gy / GBq, ≤ 0.6 Gy / GBq, ≤ 0.5 Gy / GBq, ≤ 0.4 Gy / GBq, ≤ 0.3 Gy / GBq, ≤ 0.2 Gy / GBq, or ≤ 0.1 Gy / GBq.

[0331] In some embodiments, the absorbed radiation dose per gram of tissue in the salivary glands of a human patient can be about 0.01 Gy / GBq, about 0.05 Gy / GBq, about 0.1 Gy / GBq, about 0.2 Gy / GBq, about 0.3 Gy / GBq, about 0.4 Gy / GBq, about 0.5 Gy / GBq, about 0.6 Gy / GBq, about 0.7 Gy / GBq, about 0.8 Gy / GBq, about 0.9 Gy / GBq, or about 1.0 Gy / GBq.

[0332] In some embodiments, the average absorbed radiation dose per gram of tissue in the salivary glands of a human patient can be about 0.17 ± 0.16 Gy / GBq, about 0.18 ± 0.16 Gy / GBq, about 0.19 ± 0.16 Gy / GBq, or about 0.20 ± 0.16 Gy / GBq. In some additional embodiments, the average absorbed radiation dose per gram of tissue in the salivary glands of a human patient can be ≤ 0.18 Gy / GBq, ≤ 0.19 Gy / GBq, ≤ 0.20 Gy / GBq, ≤ 0.21 Gy / GBq, ≤ 0.22 Gy / GBq, ≤ 0.23 Gy / GBq, ≤ 0.24 Gy / GBq, ≤ 0.25 Gy / GBq, ≤ 0.26 Gy / GBq, ≤ 0.27 Gy / GBq, ≤ 0.28 Gy / GBq, ≤ 0.29 Gy / GBq, or ≤ 0.30 Gy / GBq.

[0333] In some embodiments, the standard deviation of the average absorbed radiation dose per gram of tissue in the salivary glands of a human patient can be ≤ 0.25 Gy / GBq, ≤ 0.24 Gy / GBq, ≤ 0.23 Gy / GBq, ≤ 0.22 Gy / GBq, ≤ 0.21 Gy / GBq, ≤ 0.20 Gy / GBq, ≤ 0.19 Gy / GBq, ≤ 0.18 Gy / GBq, ≤ 0.17 Gy / GBq, or ≤ 0.16 Gy / GBq.

[0334] After administration of the composition, the absorbed radiation dose per gram of tissue in the left colon of a human patient can be from about 0.01 Gy / GBq to about 1.6 Gy / GBq, such as from about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the left colon of a human patient can be ≤ 1.6 Gy / GBq, ≤ 1.5 Gy / GBq, ≤ 1.4 Gy / GBq, ≤ 1.3 Gy / GBq, ≤ 1.2 Gy / GBq, ≤ 1.1 Gy / GBq, ≤ 1.0 Gy / GBq, ≤ 0.9 Gy / GBq, ≤ 0.8 Gy / GBq, ≤ 0.7 Gy / GBq, ≤ 0.6 Gy / GBq, ≤ 0.5 Gy / GBq, ≤ 0.4 Gy / GBq, ≤ 0.3 Gy / GBq, ≤ 0.2 Gy / GBq, or ≤ 0.1 Gy / GBq.

[0335] In some embodiments, the absorbed radiation dose per gram of tissue in the left colon of a human patient can be about 0.01 Gy / GBq, about 0.05 Gy / GBq, about 0.1 Gy / GBq, about 0.2 Gy / GBq, about 0.3 Gy / GBq, about 0.4 Gy / GBq, about 0.5 Gy / GBq, about 0.6 Gy / GBq, about 0.7 Gy / GBq, about 0.8 Gy / GBq, about 0.9 Gy / GBq, about 1.0 Gy / GBq, about 1.1 Gy / GBq, about 1.2 Gy / GBq, about 1.3 Gy / GBq, about 1.4 Gy / GBq, about 1.5 Gy / GBq, or about 1.6 Gy / GBq.

[0336] In some embodiments, the average absorbed radiation dose per gram of tissue in the left colon of a human patient can be 0.45 ± 0.31 Gy / GBq, 0.46 ± 0.31 Gy / GBq, or 0.47 ± 0.31 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the left colon of a human patient can be ≤ 0.50 Gy / GBq, ≤ 0.49 Gy / GBq, ≤ 0.48 Gy / GBq, ≤ 0.47 Gy / GBq, ≤ 0.46 Gy / GBq, ≤ 0.45 Gy / GBq, ≤ 0.44 Gy / GBq, ≤ 0.43 Gy / GBq, ≤ 0.42 Gy / GBq, ≤ 0.41 Gy / GBq, or ≤ 0.40 Gy / GBq.

[0337] After administering the composition, the absorbed radiation dose per gram of tissue in the rectum of a human patient can be from about 0.01 Gy / GBq to about 1.5 Gy / GBq, such as from about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the rectum of a human patient can be ≤ 1.5 Gy / GBq, ≤ 1.4 Gy / GBq, ≤ 1.3 Gy / GBq, ≤ 1.2 Gy / GBq, ≤ 1.1 Gy / GBq, ≤ 1.0 Gy / GBq, ≤ 0.9 Gy / GBq, ≤ 0.8 Gy / GBq, ≤ 0.7 Gy / GBq, ≤ 0.6 Gy / GBq, ≤ 0.5 Gy / GBq, ≤ 0.4 Gy / GBq, ≤ 0.3 Gy / GBq, ≤ 0.2 Gy / GBq, or ≤ 0.1 Gy / GBq.

[0338] In some embodiments, the absorbed radiation dose per gram of tissue in the rectum of a human patient can be about 0.01 Gy / GBq, about 0.05 Gy / GBq, about 0.1 Gy / GBq, about 0.2 Gy / GBq, about 0.3 Gy / GBq, about 0.4 Gy / GBq, about 0.5 Gy / GBq, about 0.6 Gy / GBq, about 0.7 Gy / GBq, about 0.8 Gy / GBq, about 0.9 Gy / GBq, about 1.0 Gy / GBq, about 1.1 Gy / GBq, about 1.2 Gy / GBq, about 1.3 Gy / GBq, about 1.4 Gy / GBq, or about 1.5 Gy / GBq.

[0339] In some embodiments, the average absorbed radiation dose per gram of tissue in the rectum of a human patient can be 0.50 ± 0.30 Gy / GBq, 0.49 ± 0.30 Gy / GBq, 0.48 ± 0.30 Gy / GBq, 0.47 ± 0.30 Gy / GBq, 0.46 ± 0.30 Gy / GBq, 0.45 ± 0.30 Gy / GBq, 0.44 ± 0.30 Gy / GBq, 0.43 ± 0.30 Gy / GBq, 0.42 ± 0.30 Gy / GBq, 0.41 ± 0.30 Gy / GBq, or 0.40 ± 0.30 Gy / GBq.

[0340] After administering the composition, 177 The activity fraction of Lu-PSMA I&T in the whole body of a human patient can be about 0.5 or less within 24 hours, 48 hours, or 168 hours after administering the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the whole body of a human patient can be ≤ 0.5, ≤ 0.4, ≤ 0.3, ≤ 0.2, or ≤ 0.1 within 24 hours, 48 hours, or 168 hours after administering the composition. The activity from administering the composition can be measured by SPECT / CT imaging, planar imaging, or a combination thereof or by other techniques known to those of ordinary skill in the art. The anatomical coverage of the imaging can extend from the salivary glands to the pelvis of the human patient.

[0341] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the whole body of a human patient can be about 0.5, about 0.4, about 0.3, about 0.2, about 0.1, or less than about 0.1 within 24 hours, 48 hours, or 168 hours after administering the composition.

[0342] In some aspects, 177 The activity fraction of Lu-PSMA I&T in the whole body of a human patient can be about 0.4 or less within 48 hours or 168 hours after administering the composition. For example, 177The activity fraction of Lu-PSMA I&T in the whole body of a human patient can be about 0.4, about 0.3, about 0.2, about 0.1, or less than 0.1 within 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the whole body of a human patient can be ≤0.4, ≤0.3, ≤0.2, or ≤0.1 within 48 hours or 168 hours after administration of the composition.

[0343] In some aspects, the 177 activity fraction of Lu-PSMA I&T in the whole body of the human patient is about 0.2 or less within 168 hours after administration of the composition.

[0344] After administration of the composition, 177 the activity fraction of Lu-PSMA I&T in the kidneys of a human patient can be about 0.05 or less, such as about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01, within 24 hours, 48 hours, or 168 hours after administration of the composition. In some embodiments, 177 the activity fraction of Lu-PSMA I&T in the kidneys of a human patient can be ≤0.05, ≤0.04, ≤0.03, ≤0.02, ≤0.01, or less within 24 hours, 48 hours, or 168 hours after administration of the composition.

[0345] In some embodiments, 177 the activity fraction of Lu-PSMA I&T in the kidneys of a human patient can be ≤0.040, ≤0.03, ≤0.02, ≤0.01 within 48 hours or 168 hours after administration of the composition. In some aspects, 177 the activity fraction of Lu-PSMA I&T in the kidneys of a human patient can be about 0.040, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 48 hours or 168 hours after administration of the composition.

[0346] In some embodiments, 177 the activity fraction of Lu-PSMA I&T in the kidneys of a human patient is about 0.03 or less, such as about 0.03, about 0.02, about 0.01, or less than about 0.01, within 168 hours after administration of the composition.

[0347] After administration of the composition, 177 the activity fraction of Lu-PSMA I&T in the red bone marrow of a human patient can be about 0.08 or less within 24 hours, 48 hours, or 168 hours after administration of the composition. In some embodiments, 177The activity fraction of Lu-PSMA I&T in the red bone marrow of human patients can be ≤0.08, ≤0.07, ≤0.06, ≤0.05, ≤0.04, ≤0.03, ≤0.02, ≤0.01 or less within 24 hours, 48 hours or 168 hours after administration of the composition.

[0348] In some aspects, 177 The activity fraction of Lu-PSMA I&T in the red bone marrow of human patients can be about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01 or less than about 0.01 within 24 hours, 48 hours or 168 hours after administration of the composition.

[0349] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the red bone marrow of human patients can be about 0.06 or less within 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the red bone marrow of human patients can be about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01 or less than about 0.01 within 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the red bone marrow of human patients can be ≤0.06, ≤0.05, ≤0.04, ≤0.03, ≤0.02, ≤0.01 or less within 48 hours or 168 hours after administration of the composition.

[0350] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the red bone marrow of human patients can be about 0.04 or less within 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the red bone marrow of human patients can be about 0.04, about 0.03, about 0.02, about 0.01 or less than 0.01 within 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the red bone marrow of human patients can be ≤0.04, ≤0.03, ≤0.02, ≤0.01 or less within 168 hours after administration of the composition.

[0351] After administration of the composition, 177 The activity fraction of Lu-PSMA I&T in the salivary glands of human patients can be about 0.015 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, 177The activity fraction of Lu-PSMA I&T in the salivary glands of human patients can be ≤0.015, ≤0.014, ≤0.013, ≤0.012, ≤0.011, ≤0.010, ≤0.009, ≤0.008, ≤0.007, ≤0.006, ≤0.005, ≤0.004, ≤0.003, ≤0.002, ≤0.001 or less within 24 hours, 48 hours, or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the salivary glands of human patients can be about 0.015, about 0.014, about 0.013, about 0.012, about 0.011, about 0.010, about 0.009, about 0.008, about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, about 0.001 or less than about 0.001 within 24 hours, 48 hours, or 168 hours after administration of the composition.

[0352] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the salivary glands of human patients can be about 0.007 or less within 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the salivary glands of human patients can be about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, about 0.001 or less than about 0.001 within 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the salivary glands of human patients can be ≤0.007, ≤0.006, ≤0.005, ≤0.004, ≤0.003, ≤0.002, ≤0.001 or less within 48 hours or 168 hours after administration of the composition.

[0353] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the salivary glands of human patients can be about 0.004 or less within 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the salivary glands of human patients can be about 0.004, about 0.003, about 0.002, about 0.001 or less than about 0.001 within 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the salivary glands of human patients can be ≤0.004, ≤0.003, ≤0.002, ≤0.001 or less within 168 hours after administration of the composition.

[0354] After administration of the composition, 177 The activity fraction of Lu-PSMA I&T in the gastrointestinal tract of human patients can be about 0.10 or less within 24 hours, 48 hours, or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the gastrointestinal tract of human patients can be about 0.10, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 24 hours, 48 hours, or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the gastrointestinal tract of human patients can be ≤0.10, ≤0.09, ≤0.08, ≤0.07, ≤0.06, ≤0.05, ≤0.04, ≤0.03, ≤0.02, ≤0.01, or less within 24 hours, 48 hours, or 168 hours after administration of the composition.

[0355] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the gastrointestinal tract of human patients can be about 0.10 or less within 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the gastrointestinal tract of human patients can be about 0.10, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the gastrointestinal tract of human patients can be ≤0.10, ≤0.09, ≤0.08, ≤0.07, ≤0.06, ≤0.05, ≤0.04, ≤0.03, ≤0.02, ≤0.01, or less within 48 hours or 168 hours after administration of the composition.

[0356] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the gastrointestinal tract of human patients can be about 0.05 or less within 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the gastrointestinal tract of human patients can be about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 168 hours after administration of the composition. In some aspects, 177The activity fraction of Lu-PSMA I&T in the gastrointestinal tract of human patients can be ≤0.05, ≤0.04, ≤0.03, ≤0.02, ≤0.01 or less within 168 hours after administration of the composition.

[0357] After administration of the composition, 177 The activity fraction of Lu-PSMA I&T in the liver of human patients can be about 0.04 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the liver of human patients can be about 0.04, about 0.03, about 0.02, about 0.01 or less than about 0.01 within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the liver of human patients can be ≤0.04, ≤0.03, ≤0.02, ≤0.01 or less within 24 hours, 48 hours or 168 hours after administration of the composition.

[0358] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the liver of human patients can be about 0.02, about 0.01 or less than 0.01 within 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the liver of human patients can be ≤0.02, ≤0.01 or less within 48 hours or 168 hours after administration of the composition.

[0359] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the liver of human patients can be about 0.01 or less within 168 hours after administration of the composition.

[0360] After administration of the composition, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients can be about 0.004 or less within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients can be about 0.004, about 0.003, about 0.002, about 0.001 or less than about 0.001 within 24 hours, 48 hours or 168 hours after administration of the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients can be ≤0.004, ≤0.003, ≤0.002, ≤0.001 or less within 24 hours, 48 hours or 168 hours after administration of the composition.

[0361] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients can be about 0.002 or less within 48 hours or 168 hours after administering the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients can be about 0.002, about 0.001, or less than about 0.001 within 48 hours or 168 hours after administering the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients can be ≤0.002, ≤0.001, or less within 48 hours or 168 hours after administering the composition.

[0362] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients is about 0.001 or less within 168 hours after administering the composition.

[0363] After administering the composition, 177 The activity fraction of Lu-PSMA I&T in the lacrimal gland of human patients can be about 0.0004 or less at 24 hours, 48 hours, or 168 hours after injecting the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients can be about 0.0004, about 0.0003, about 0.0002, about 0.0001, or less than about 0.0001 at 24 hours, 48 hours, or 168 hours after administering the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the lacrimal gland of human patients can be ≤0.0004, ≤0.0003, ≤0.0002, ≤0.0001, or less at 24 hours, 48 hours, or 168 hours after injecting the composition.

[0364] In some embodiments, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients can be about 0.0002 or less within 48 hours or 168 hours after administering the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients can be about 0.0002, about 0.0001, or less than about 0.0001 within 48 hours or 168 hours after administering the composition. In some aspects, 177 The activity fraction of Lu-PSMA I&T in the spleen of human patients can be ≤0.0002, ≤0.0001, or less within 48 hours or 168 hours after administering the composition.

[0365] In some embodiments, 177The activity fraction of Lu-PSMA I&T in the spleen of human patients can be less than 0.0001 within 168 hours after administration of the composition.

[0366] Indications and contraindications

[0367] RLT with 177Lu-PSMA I&T can be indicated for the treatment of patients with mCRPC who do not have any other approved therapy options planned by a multidisciplinary team.

[0368] 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, 3.0:1.0 to 12.0:1.0, 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, 1.5:1.0 to 8.0:1.0, 2.0:1.0 to 8.0:1.0, 2.5:1.0 to 8.0:1.0, 3.0:1.0 to 8.0:1.0, 3.5:1.0 to 8.0:1.0 or 4.0:1.0 to 8.0:1.0. In another embodiment, the molar ratio of PSMA I&T to 177 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, the molar ratio of PSMA I&T to 177 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, the molar ratio of PSMA I&T to 177The 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, the molar ratio of PSMA I&T to 177 The 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. PSMA I&T and 177The molar ratio of Lu can be 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 177 The 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. The molar ratio of PSMA I&T to 177The 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. The molar ratio of PSMA I&T to 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.

[0369] The molar ratio of PSMA I&T to 177 The 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. The molar ratio of PSMA I&T to 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. The molar ratio of PSMA I&T to 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. The molar ratio of PSMA I&T to 177The molar ratio of Lu can be from 8.0:1.0 to 9.0:1.0, from 8.1:1.0 to 8.9:1.0, from 8.2:1.0 to 8.8:1.0, from 8.3:1.0 to 8.7:1.0, or from 8.4:1.0 to 8.6:1.0. PSMA I&T and 177 The molar ratio of Lu can be 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. PSMA I&T and 177 The molar ratio of Lu can be 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 7.8:1.0, from 7.3:1.0 to 7.7:1.0, or from 7.4:1.0 to 6.6:1.0. PSMA I&T and 177 The molar ratio of Lu can be from 5.0:1.0 to 6.0:1.0, from 5.1:1.0 to 5.9:1.0, from 5.2:1.0 to 5.8:1.0, from 5.3:1.0 to 5.7.0:1.0, or from 5.4:1.0 to 5.6:1.0. PSMA I&T and 177 The molar ratio of Lu can be from 4.4:1.0 to 5:0:1.0, from 4.5:1.0 to 5:0:1.0, from 4.6:1.0 to 5:0:1.0, from 4.7:1.0 to 5:0:1.0, from 4.8:1. to 5:0:1.0, or from 4.9:1. to 5:0:1.0.

[0370] PSMA I&T and 177 The molar ratio of Lu can be 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.

[0371] In another embodiment, in the compositions, kits, and methods described herein, the PSMA I&T to [177Lu]Lu3+ ratio (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 PSMA I&T to [177Lu]Lu3+ ratio (in μg:mCi) can be 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. 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 0.21 to about 0.59, from about 0.22 to about 0.58, from about 0.23 to about 0.57, from about 0.24 to about 0.56, from about 0.25 to about 0.55, from about 0.26 to about 0.54, from about 0.27 to about 0.53, from about 0.28 to about 0.52, from about 0.29 to about 0.51, from about 0.30 to about 0.50, from about 0.31 to about 0.49, from about 0.32 to about 0.48, from about 0.33 to about 0.47, from about 0.34 to about 0.46, from about 0.35 to about 0.45, from about 0.36 to about 0.44, from about 0.37 to about 0.43, from about 0.38 to about 0.42, from about 0.39 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 0.50 to about 0.64, from about 0.50 to about 0.63, from about 0.50 to about 0.62, from about 0.50 to about 0.61, from about 0.50 to about 0.60, from about 0.50 to about 0.59, from about 0.50 to about 0.58, from about 0.50 to about 0.57, from about 0.50 to about 0.56, from about 0.50 to about 0.55, from about 0.50 to about 0.54, from about 0.50 to about 0.53, from about 0.50 to about 0.52, or from 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, about 0.30 to about 0.63, about 0.30 to about 0.62, about 0.30 to about 0.61, about 0.30 to about 0.60, about 0.30 to about 0.59, about 0.30 to about 0.58, about 0.30 to about 0.57, about 0.30 to about 0.56, about 0.30 to about 0.55, about 0.30 to about 0.54, about 0.30 to about 0.53, about 0.30 to about 0.52, about 0.30 to about 0.51, about 0.30 to about 0.50, about 0.30 to about 0.49, about 0.30 to about 0.48, about 0.30 to about 0.47, about 0.30 to about 0.46, about 0.30 to about 0.45, about 0.30 to about 0.44, about 0.30 to about 0.43, about 0.30 to about 0.42, about 0.30 to about 0.41, about 0.30 to about 0.40, about 0.30 to about 0.39, about 0.30 to about 0.38, about 0.30 to about 0.37, about 0.30 to about 0.36, about 0.30 to about 0.35, about 0.30 to about 0.34, about 0.30 to about 0.33, about 0.30 to about 0.32, or about 0.30 to about 0.31.In another embodiment, 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.

[0372] In one embodiment, a method of treating cancer in a patient in need thereof is provided herein. 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 5.0:1.0 to 12.0:1.0, such as from about 4.0:1 to about 8.0:1, from about 4.5:1 to about 5.5:1, or from about 5.0:1 to about 6.0:1. In another embodiment, the patient is untreated. In another embodiment, the patient is treated.

[0373] 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 the patient as a regimen. In another embodiment, the administered pharmaceutical composition has a radiochemical purity greater than 95% at the time of administration.

[0374] In one embodiment, a method of treating cancer prolongs the time to disease progression of the cancer in its patients. In another embodiment, a method of treating cancer prolongs the survival of the patient. In another embodiment, a method of treating cancer increases the progression-free survival of the patient. In another embodiment, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0375] In some embodiments, the patient also has prostate adenocarcinoma histologically or pathologically confirmed to have no major small cell component, 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 hormonal therapy, chemotherapy, and bone-targeted therapy if indicated.

[0376] In at least one instance, patients in need of RLT using 177 Lu-PSMA I&T may meet the following criteria:

[0377] 1) mCRPC with PSMA-positive metastatic disease based on PSMA-PET or SPECT imaging. There are no restrictions on the number or location of metastases (i.e., bone or soft tissue metastases). Attention should be paid, for example, to patients with diffuse bone marrow, perineural, and brain metastases.

[0378] 2) After initial hormonal therapy (LH-RH agonist / antagonist). Progressive disease, i.e., biochemical and / or radiological progression, despite newly developed hormonal 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.

[0379] 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 223Ra]RaCl2 or other locally available radiopharmaceuticals. In patients who do not have a sufficient response to bone-targeted therapies for pain relief or pain exacerbation (even with this therapy), RLT with 177 Lu-PSMA I&T may be evaluated.

[0380] 4) Life expectancy of more than 4 - 6 months.

[0381] 5) Decision on salvage therapy by the institutional interdisciplinary tumor board.

[0382] Overall, mCRPC patients should undergo hormonal therapy, chemotherapy, and bone-targeted therapy, if indicated. In the case of any contraindications to one of these therapies, it should be discussed and documented in the interdisciplinary tumor board.

[0383] Contraindications are as follows:

[0384] (1) WBC ≤ 1 x 10 9 / l.

[0385] (2) Hb ≤ 80 g / l. (In the case of symptomatic anemia, red blood cell transfusion should be performed before the therapy. RLT with 177 Lu-PSMA I&T may have a positive effect on myelosuppression, due to tumor regression in the bone marrow, and thus less need for blood transfusion. It should be noted that pure anemia without thrombocytopenia and leukopenia is not a contraindication to RLT.

[0386] (3) Platelets ≤ 70 x 10 9 / l.

[0387] (4) Creatinine > 1.5 UNL; renal failure with creatinine clearance < 30 ml / min

[0388] (5) Absolute obstruction in renal excretion.

[0389] (6) Previous 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

[0390] (7) ECOG performance status > 2.

[0391] (8) Allergy to the active substance or any excipient.

[0392] After identifying patients in need, the activity of the radiopharmaceutical composition can be confirmed before administration. 177The radioactivity of the Lu-PSMA I&T composition can be 6.5 - 7.5 GBq or within the range of 6.0 - 8.0 GBq. In the case of impaired renal function (e.g., creatinine within 1.0 - 1.5 UNL), the radioactivity can be reduced to 4.0 - 5.0 GBq.

[0393] 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. Diuretics can be administered to patients with dilated non-obstructive nephropathy.

[0394] 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 is reduced to <1.0 μg / l during the therapy cycle, when the post-injection SPECT study is insufficient 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.

[0395] 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.

[0396] In some embodiments, after the administration of the radiopharmaceutical composition, the patient can have an improved radiographic progression-free survival (rPFS). The rPFS of the patient after the start of the administration of the radiopharmaceutical composition can be about 6 months to about 12 months. In various embodiments, the rPFS of the patient after the start of the administration of the radiopharmaceutical composition can be at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. 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.

[0397] In one embodiment, after initiating administration of the radiopharmaceutical composition, the patient may have an improved overall survival (OS). The overall survival of a patient receiving the radiopharmaceutical composition may be from about 18 months to about 26 months after initiating administration of the radiopharmaceutical composition. In various embodiments, the OS of a patient receiving 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 initiating 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.

[0398] In another embodiment, after initiating administration of the radiopharmaceutical composition, the patient may have an improved second radiographic progression-free survival (rPFS2).

[0399] In some embodiments, after initiating administration of the radiopharmaceutical composition, the patient may have an improved progression-free survival. In additional embodiments, after initiating 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.

[0400] In one embodiment, after initiating 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.

[0401] In one embodiment, after initiating 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 the relief of bone pain, new symptomatic pathologic fracture, or spinal cord compression.

[0402] In one embodiment, after initiating 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 initiating administration of the radiopharmaceutical composition, the patient may have an improved time to chemotherapy (TTC).

[0403] In one embodiment, after initiating 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 assess QoL in cancer patients. The EORTC QLQ-C30 contains 30 items, 24 of which are grouped into nine multi-item scales scored from 0 to 100.

[0404] Example

[0405] The following non-limiting examples are provided for illustrative purposes only and should not, therefore, be taken as having a limiting significance.

[0406] Example 1: Preparation 177 Method for Preparing a LU-PSMA I&T Radiopharmaceutical Formulation

[0407] · Generate a variety of radiopharmaceutical compositions using the methods outlined in Tables 2A and 2B below. Use non-carrier added 177 Lu]LuCl3 for radiolabeling. 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.

[0408] · 177 The synthesis of Lu-PSMA I&T utilizes an automated synthesis module in a controlled environment. Connect a labeling solution containing 177 Lu] lutetium chloride ( 177 Lu]LuCl3) to a synthesis cassette containing the other chemical components required for the labeling process. Transfer the 177 LuCl3 solution to a reactor for radiolabeling and it can be rinsed with an additional required amount of 0.04M HCl solution. The volume of the labeling solution varies according to the 177 radioactivity of the Lu.

[0409] · Mix the 177 Lu]Lu Cl3 solution in the reaction chamber with a solution of 0.4M sodium acetate buffer containing a diluted PSMA I&T precursor. Heat the solution in the reactor. After heating, the resulting 177Lu-PSMA I&T is retained on a C18 column pre-conditioned with water. The column is rinsed with sterile water and the final product is eluted from the C18 column with 1.5 ml of a 50% sterile ethanol-water mixture into a bulk vial. The drug substance is formed in situ and directly formulated into a drug product.

[0410] · 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 177 radioactivity of Lu used in the batch.

[0411] · The formulation matrix is prepared from an ascorbic acid solution diluted to a concentration of 50 mg / ml with water for injection. The ethanol concentration is adjusted to 3.8% ± 1.0% (v / v) to match the concentration of the synthetic bulk product, regardless of the required dilution.

[0412] · The synthesis is a one-step labeling process with C18 purification using injection-grade ethanol and water as the only solvents, so there are no residual solvents.

[0413] · Radiochemical impurities are quantified by chromatographic methods (HPLC and TLC). The radiochemical purity determined by HPLC must be not less than 95.0%.

[0414] · Depending on the total radioactivity generated, the bulk product is diluted to a fixed radioactivity concentration of approximately 500 MBq / ml.

[0415] · The solution is filtered through a 0.22 μm membrane filter into sterile product vials. In addition to the patient dose, sample vials (chemical QC samples, microbial QC samples, and reference samples for retention) are dispensed from each production batch. The final product is dispensed in a Class A controlled environment. The integrity of the filter is tested by a bubble point test before product release after filtration. The fill weight / volume and radioactivity of the dispensed patient vials are checked. The solution is ready for use after pre-release quality control and QP release.

[0416] · Radioactivity is monitored with a dose calibrator after the labeling process to ensure successful labeling and to verify the dispensed dose during dispensing.

[0417] Table 2A: Radiolabeling process

[0418]

[0419] · Compositions 1 - 3 obtained from Processes 1 - 3 are provided in Table 2B below, which gives the composition for a 1 ml volume and for 10 ml or 20 ml vials for each composition.

[0420] Table 2B: 177 Lu]Lu-PSMA I&T Compositions 1-3.

[0421]

[0422]

[0423] Example 2: Stability of the Radiochemical Composition

[0424] · The stability of 177 Lu-PSMA I&T Composition 1 was tested and the radiochemical purity and chemical characteristics were shown for samples stored at +5 °C, +20 °C and +40 °C to provide adequate stability for 48 hours from the end of synthesis time, Table 3.

[0425] · The stability study showed that, compared with 177 Lu]Lu-PSMA I&T Composition 1, 177 Lu]Lu-PSMA I&T Composition 3 (Tables 4A-4H) containing 31 mg / ml of ascorbic acid at pH 4.5 and 3.8% (v / v) ethanol had improved stability and an extended shelf life.

[0426] · The radiochemical purity and chemical characteristics (pH, impurities, visual characteristics) of 177 Lu]Lu-PSMA I&T in Formulation Composition 3 were tested in seven batches over a time span from 70 hours to 72 hours from the end of synthesis time. Stability samples of 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.

[0427] · At the end of dispensing, the final radioactive concentration in the sample solution varied from 497 MBq / ml to 642 MBq / ml.

[0428] · 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.

[0429] · Based on the results, 177 the Lu-PSMA I&T solution in Formulation Composition 3 was stable under the different storage conditions tested.

[0430] Table 3: 177 Stability data for Lu-PSMA I&T Composition 1.

[0431]

[0432] Table 4A: 177 Chemical quality in the validation batch of Lu-PSMA I&T composition 3.

[0433]

[0434]

[0435] The radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0436] Table 4B: 177 Stability data of Lu-PSMA I&T composition 3.

[0437]

[0438]

[0439] The 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.

[0440]

[0441]

[0442] The radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0443] Table 4D: 177 Stability data of Lu-PSMA I&T composition 3.

[0444]

[0445]

[0446] The radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0447] Table 4E: 177 Stability data of Lu-PSMA I&T composition 3.

[0448]

[0449]

[0450] The radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0451] Table 4F: 177 Stability data of Lu-PSMA I&T composition 3

[0452]

[0453]

[0454] The radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0455] Table 4G: 177 Stability data of Lu-PSMA I&T composition 3

[0456]

[0457]

[0458] The radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0459] Table 4H: 177 Stability data of Lu-PSMA I&T composition 3

[0460]

[0461]

[0462] The radiation measurement of the test sample RT = UV RT of the reference standard ± 5%.

[0463] Table 4I - Release data from the commercial scale development batches of composition 4

[0464]

[0465] Table 4J – Stability data from composition 4

[0466]

[0467] · 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.

[0468] Table 5: 177 Specifications of Lu]Lu-PSMA I&T

[0469]

[0470]

[0471] Example 3: 177 Radiochemical Purity of Lu-PSMA I&T in Different Formulation Combinations

[0472] · The examples demonstrated 177 the radiochemical stability of Lu-PSMA I&T in formulation combinations 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%.

[0473] · By HPLC with a Phenomenex Luna C18 column (3μm, 150mm x 4.6mm), using 0.1% aqueous trifluoroacetic acid (mobile phase A) and 0.1% aqueous trifluoroacetic acid:acetonitrile (10:90% v / v) (mobile phase B) and an isocratic method with 23% mobile phase B at a temperature of 40°C, the formation of a specific radiochemical impurity of Lu-PSMA I&T with a retention time of approximately 5.2 minutes has been observed. 177 Lu-PSMA I&T Figures 6A - 11B The impurity with a retention time of approximately 5.2 minutes mentioned herein is illustrated in the chromatogram in

[0474] · In previously conducted experiments, reducing the formulation radioactivity concentration was sufficient to reduce the formation of the impurity eluting at approximately 5.2 minutes and maintain 177 the radiochemical stability of the Lu]Lu-PSMA I&T solution above 95.0% for 72 hours.

[0475] · In this example, six experiments were conducted in which Lu]Lu-PSMA I&T was prepared in different formulation combinations with different ascorbic acid concentrations, pH values, and radioactivity concentrations. 177 The product formulation details are described in Table 6.

[0476] Table 6: Evaluated 177 Lu]Lu-PSMA I&T Formulation Combinations

[0477]

[0478]

[0479] · The high radioactivity concentration (high RAC) in the sample solution measured at the end of production was 1278 MBq / ml, 1281 MBq / ml, and 1311 MBq / ml. The low radioactivity concentration (low RAC) in the sample solution measured at the end of production was 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.

[0480] · Figure 5 The results of the radiochemical purity analysis at different time points determined by HPLC are shown.

[0481] · Figure 6A and Figure 6B show the HPLC radiochromatograms of Experiment 1 at 0 hours and 71 hours after EOS, respectively.

[0482] · Figure 7A and Figure 7B show the HPLC radiochromatograms of Experiment 2 at 0 hours and 71 hours after EOS, respectively.

[0483] · Figure 8A and Figure 8B show the HPLC radiochromatograms of Experiment 3 at 0 hours and 90 hours after EOS, respectively.

[0484] · Figure 9A and Figure 9B show the HPLC radiochromatograms of Experiment 4 at 0 hours and 92 hours after EOS, respectively.

[0485] · Figure 10A and Figure 10B show the HPLC radiochromatograms of Experiment 5 at 0 hours and 71 hours after EOS, respectively.

[0486] · Figure 11A and Figure 11B show the HPLC radiochromatograms of Experiment 6 at 0 hours and 93 hours after EOS, respectively.

[0487] · The radiochemical stability results at different time points for each experiment are provided in Tables 5 - 10.

[0488] Table 5: Experiment 1

[0489]

[0490] Table 6: Experiment 2

[0491]

[0492] Table 7: Experiment 3

[0493]

[0494] Table 8: Experiment 4

[0495]

[0496] Table 9: Experiment 5

[0497]

[0498] Table 10: Experiment 6

[0499]

[0500] · In the examples, the pH of the formulation composition has a considerable effect 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 illustrated in Figures 6A - 11B . 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.

[0501] · 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.

[0502] · 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.

[0503] · 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.

[0504] · 20 ml of low RAC containing 31 mg / ml of ascorbic acid, as measured by HPLC 177 The radiochemical purity of the Lu-PSMA I&T formulation is at least about 99.1% at 0 hours post-EOS. The low RAC at pH 4.5 has a slower rate of decrease in radiochemical purity over time compared to pH 5 177 The radiochemical purity of the Lu-PSMA-I&T formulation decreases more slowly over time.

[0505] · Results demonstrate that formulation compositions at pH 5 or lower can significantly reduce the formation of radiochemical impurities eluting at approximately 5.2 minutes and thus enhance the radiochemical stability of Lu-PSMA I&T compared to formulation compositions with a pH higher than 5. Additionally 177 the radiochemical stability of Lu-PSMA I&T can be further improved by incorporating low solution RAC. In the examples 177 the Lu-PSMA I&T solution shows the highest radiochemical stability in a low RAC solution at pH 4.5 and ascorbic acid concentration of 31 mg / ml. This formulation is considered to be a preferred composition that minimizes the formation of radiochemical impurities and maintains 177 the radiochemical stability of Lu-PSMA I&T above 95.0% for 72 hours or longer. 177

[0506] Example 4 - Results of Dosimetry Study

[0507] This example presents the biodistribution, dosimetry, and pharmacokinetic (PK) results of a PK / dosimetry sub-study conducted as part of a Phase III trial. Twenty-seven (27) patients were administered a target activity of 7.4 ± 10% GBq of 177 Lu-PSMA-I&T and underwent single photon emission computed tomography (SPECT) / computed tomography (CT) imaging at four time points (4 hours, 24 hours, 48 hours, and 168 hours). The image data was analyzed to calculate the time-activity curve (TAC) and subsequently the time-integrated activity coefficient (TIAC) in each organ of interest and in organs showing significant and meaningful 177 Lu-PSMA-I&T activity. Organ-level internal dose assessment (OLINDA 2.2.3) was used to calculate the organ and whole-body absorbed radiation doses for each patient.

[0508] Additionally, for PK assessment, whole blood samples were collected at six time points (pre-infusion, 1 hour, 4 hours, 24 hours, 48 hours, and 168 hours) and processed to extract plasma. All plasma samples were subjected to local gamma counting for pharmacokinetic analysis. ​

[0509] For 177 The organs with a medium or higher absorbed dose for Lu-PSMA-I&T are the organs involved in the elimination of the radioligand and / or the organs expressing PSMA, i.e., the kidneys (0.41 ± 0.15 Gy / GBq), the bladder (0.41 ± 0.05 Gy / GBq), the salivary and lacrimal glands (0.19 ± 0.16 Gy / GBq and 0.40 ± 0.36 Gy / GBq, respectively), and some parts of the gastrointestinal (GI) tract (left colon, 0.47 ± 0.31 Gy / GBq and rectum, 0.44 ± 0.30 Gy / GBq).

[0510] The mean absorbed radiation dose to the red bone marrow was 0.08 ± 0.12 Gy / GBq. The relatively high variability in the marrow absorbed dose was attributed to some patients having diffuse metastatic disease within the bone, resulting in increased bone uptake and thus a higher estimated marrow absorbed dose. Additionally, in some patients, the presence of metastases in the lumbar spine L2-L4 (the region used for marrow dosimetry imaging) potentially led to an overestimation of the marrow dose.

[0511] The whole-body time-activity curve was fitted with a biexponential equation, and the distribution half-life was 2.16 ± 1.30 hours and the elimination half-life was 46.29 ± 23.83 hours.

[0512] PK evaluation based on plasma radioactivity concentration data showed that the mean distribution half-life was 1.89 ± 0.34 hours and the mean elimination half-life was 14.7 ± 10.1 hours.

[0513] A patient subgroup (16 / 27) underwent imaging after both the first and third treatment cycles to evaluate the organ doses after multiple treatment cycles. By comparing the organ absorbed doses between cycle 1 and cycle 3 in these 16 patients, it was observed that the normal organ absorbed doses remained similar between the two cycles. This finding supports the validity of estimating the cumulative organ absorbed radiation dose by extrapolation from cycle 1 data.

[0514] Introduction

[0515] This is a phase 3, open-label, multicenter, randomized trial evaluating 177 the safety and efficacy of Lu-PSMA-I&T radioligand therapy compared to hormone therapy in men with metastatic castration-resistant prostate cancer (mCRPC). 177 Lu-PSMA-I&T is a radiotherapeutic agent that specifically targets prostate-specific membrane antigen (PSMA) expressed on both primary and metastatic prostate cancer cells.

[0516] Substudies were conducted to evaluate 177PK and dosimetry of Lu-PSMA-I&T, where patients underwent PK sampling and SPECT / CT imaging after the first and third 177 Lu-PSMA I&T infusions.

[0517] Methods

[0518] Data collection

[0519] All participating sites underwent a rigorous site setup process during which all dose calibrators, scanners, and gamma counters used in the sub-study were calibrated. Sites were only allowed to enroll patients in the sub-study after all site setup processes were completed and approved by Invicro. After administration of targeted 7.4 ± 10% GBq 177 Lu-PSMA-I&T in cycle 1, patients underwent SPECT / CT imaging, where anatomical coverage typically extended from the salivary glands to the pelvis. SPECT / CT imaging was performed at four time points: 4 hours, 24 hours, 48 hours, and 168 hours post-injection. Additionally, a subgroup of patients imaged in cycle 1 (16 out of 27) were also imaged in cycle 3 (Table 2).

[0520] Table 2: SPECT imaging time points obtained in cycle 3

[0521]

[0522]

[0523] Standardize image acquisition and reconstruction protocols across all imaging time points and patients at each site. Additionally, each site always used the same SPECT / CT scanner throughout the study to ensure consistency.

[0524] Generally, raw projection data were acquired into a 128x128 matrix using a step-and-shoot acquisition mode with medium energy general purpose (MEGP) collimation, with 60 projections acquired per detector (180-degree rotation per detector), 20 seconds per projection, where the acquisition zoom was 1.0, and a 20% (±10%) energy window centered at 208 keV.

[0525] A low-dose CT scan was performed prior to starting the SPECT scan for attenuation correction. Sites were instructed to use institutional standard parameters to obtain the low-dose CT. Institutional standard reconstruction parameters were used. A 20% (±10%) scatter window centered at 170 keV was required to apply scatter correction.

[0526] PK plasma samples were collected prior to infusion, at 1 hour, 4 hours, 24 hours, 48 hours, and 168 hours, and counted for radioactivity. Blood samples were first centrifuged to extract plasma, and then the radioactivity in the plasma was counted in a gamma counter.

[0527] For a detailed overview of site qualification and establishment and data collection procedures, refer to the Technical Operations Manual (TOM).

[0528] Image analysis methods

[0529] The imaging data was analyzed using Invicro's VivoQuant software, a validated software used in a 21 CFR §11 compliant workflow. The general quantification method is based on the principles detailed in MIRD pamphlets No. 16, 23, and 26, as appropriate.

[0530] The SPECT images were calibrated in Becquerel (Bq) using a calibration factor derived from a known activity source, which was measured during site establishment with the same acquisition and reconstruction parameters used for patient imaging. Patient-specific calibration factors were also derived at each clinical time point after acquisition of the patient's SPECT / CT. As a quality control measure, if the patient-specific calibration factor differed from the site establishment calibration factor by more than 10%, the study was conducted.

[0531] The volumes of interest (VOIs) (kidney, bladder, liver, lumbar vertebrae L2-L4, lacrimal gland, salivary glands [parotid and submandibular glands], and whole body) were delineated on each data set by trained image analysts. The GI tract and spleen were only delineated in a patient subgroup where these organs showed visible uptake. Organs were segmented by drawing the entire outline of the organ or by placing spheres in representative regions of the organ and then multiplying by the effective mass of the organ (based on the patient's height and weight). The segmentation method for each organ is specified in Table 3 and was applied consistently to each patient.

[0532] Table 14: Organ VOIs and delineation methods

[0533] Organ Method Bladder CT and SPECT uptake Liver Sphere-based CT Spleen Sphere-based CT Kidney SPECT uptake L2 - L4 CT Salivary gland SPECT uptake GI tract SPECT uptake Lacrimal gland SPECT uptake

[0534] Plasma quantitative analysis

[0535] Collect whole blood samples as detailed in the protocol Schedule of Events, i.e., pre-injection and then at 1 hour, 4 hours, 24 hours, 48 hours, and 168 hours post-injection. First, centrifuge the samples to separate the plasma, and then measure the radioactivity in the plasma using a gamma counter. Subsequently, fit the plasma concentration with a biexponential function to derive result parameters such as the half-life and clearance rate of the radiopharmaceutical in the plasma.

[0536] Normal organ dosimetry analysis

[0537] The clearance rate of the radiopharmaceutical is derived from appropriate fitting of the data of the TAC of each organ. Depending on the shape of the TAC, the data is fitted with the sum of one, two, or three exponentials or using the rising and falling model. The fitting is performed using in-house Python software. The TIAC is calculated by analytical integration of the curve fitting extrapolated to infinity. If no appropriate fit is found, the area under the curve (AUC) is estimated using the imaging measurement results and the sum of the trapezoidal integrals of the physical decay from the last time point forward (for organs, the injected activity fraction is set to zero at t = 0, and for the whole body, it is set to 1). The whole body TAC is obtained by imaging the body. The residual activity is determined by subtracting the cumulative organ TIAC from the whole body TIAC.

[0538] The organ TIAC is input into OLINDA 2.2.3 to calculate the organ and whole body absorbed doses using the International Commission on Radiological Protection (ICRP)-103 weighting factors. The ICRP-89 derived male phantom is used for dose assessment. The patient's effective mass is used to measure the organs and body weights defined by ICRP-89 based on height and mass. 4 Assuming a voiding interval of 4 hours, the voiding bladder model implemented in OLINDA is used to determine the bladder TIAC. The Human Alimentary Tract model (HAT model) described in ICRP 100 and implemented in OLINDA is used to calculate the doses to the small intestine, right colon, left colon, and rectum of patients showing clearance through the GI tract. The fraction of injected activity cleared through the GI tract (fIA) is determined by taking the peak fIA in the GI tract at all imaging time points. The red marrow dose assessment is obtained by segmenting the lumbar vertebrae L2-L4 as seen on the CT. It is assumed that the red marrow mass in L2-L4 is 6.7% of the total red marrow mass.

[0539] To evaluate potential changes in tracer kinetics and uptake after multiple treatment cycles, 16 out of 27 patients included in the dosimetry sub-study were imaged at both Cycle 1 and Cycle 3. Among them, at Cycle 3, three patients were imaged at all 4 time points, and an additional 13 patients were imaged at only one or two time points (24 hours, 48 hours, or both 24 hours and 48 hours) (Table 2). For these 13 patients, the TACs obtained at Cycle 1 were used for each source organ and converted to normalized activity values measured at Cycle 3. For patients imaged at two time points, the average scaling factor between the two time points was preferably used to scale the TACs. If the two time points yielded significantly different scaling factors, the more conservative time point was preferred, provided that the resulting dose estimates were reasonable.

[0540] Data acquisition quality control

[0541] Use a 177 Lu reference standard to control the quantitative accuracy of each SPECT image. Before scanning the patients, a reference standard was prepared by injecting 100 μCi (taken from the patient dose vial) into a 100 mL saline bag. Subsequently, the radioactivity of the saline bag was imaged immediately after each imaging time point using the same acquisition and reconstruction parameters. The number of counts in the image attributable to the reference standard activity was measured, and the calibration factor was obtained by dividing the number of counts by the known activity in the reference standard at the time of imaging. For all images acquired with the same SPECT / CT system, this calibration factor was expected to be the same (difference < 10% compared to the value determined at the site establishment). For patients with a calibration factor that differed by more than 10% compared to the site establishment, an investigation was initiated to determine the cause of this change, and if the change reflected differences in patient data acquisition and / or reconstruction.

[0542] Use the same 177 Lu reference standard to perform quality control on plasma samples for gamma counting by measuring 0.5 ml in 100 mL of the saline bag. For each patient, triplicates were prepared and measured immediately before counting all plasma samples. Long-lived isotopes were also counted to ensure that the protocol was correctly followed at each site. Similar to the imaging standard, when the gamma counter efficiency factor differed by more than 10% compared to the gamma counter efficiency factor at the site establishment, a study was initiated to determine the cause of this change, and if the change reflected differences in data acquisition.

[0543] Results

[0544] All twenty-seven (27) patients included in the sub-study had SPECT / CT images acquired at the first cycle for dosimetry purposes. Sixteen of the 27 patients were imaged additionally at Cycle 3. The activities injected into each patient at Cycle 1 and Cycle 3 are shown in Table 15.

[0545] Table 15:

[0546] Patient ID Cycle 1 (GBq) Cycle 3 (GBq) 12-004 7.93 7.97 25-005 7.58 7.51 25-007 7.56 7.44 25-008 7.21 7.35 25-009 7.71 7.72 37-013 7.42 Not applicable 37-015 7.49 7.53 37-016 7.46 7.50 37-017 7.59 7.53 37-019 7.35 7.40 37-020 7.19 7.37 37-022 7.48 Not applicable 37-023 7.53 Not applicable 42-027 7.56 Not applicable 42-028 7.62 Not applicable 42-030 7.56 Not applicable 62-032 7.48 Not applicable 66-024 7.26 Not applicable 80-001 7.67 Not applicable 80-004 7.52 7.22 80-007 7.54 7.14 80-018 7.31 7.16 80-019 7.43 7.58 80-020 7.39 7.42 80-022 7.32 7.48 80-023 7.44 Not applicable 80-024 7.49 Not applicable Average value 7.48 7.46 SD 0.16 0.20

[0547] The dosimetry analysis included all acquired and / or evaluable imaging. Patient 37-016 did not have SPECT / CT imaging at the 168-hour time point, and thus the results were based on only 3 time points for this patient. For Patient 12-004, the 48-hour scan presented unrealistic high values (the whole-body injected activity fraction at 48 hours was higher than the whole-body injected activity fractions at 4 hours and 24 hours, although no additional activity was administered to the patient after the initial 177 Lu-PSMA-I&T injection). Additionally, for unknown reasons, the image quality at 48 hours was abnormally poor. Therefore, this time point was excluded from further analysis, and the 4-hour, 24-hour, and 168-hour SPECT images were used for dosimetry.

[0548] Cycle 1 biodistribution

[0549] Based on the image and dosimetry data, physiological uptake of 177 Lu-PSMA-I&T was mainly observed in the kidneys, bladder, lacrimal glands, GI tract, and salivary glands. 177 Lu-PSMA-I&T was excreted mainly via urine, as indicated by the accumulation visible in the bladder. Intestinal uptake was observed in 25 patients, while no significant uptake was found in 2 of the analyzed patients (80-004 and 25-005). The salivary glands of 1 patient (12-004) were outside the SPECT / CT field of view, and the lacrimal glands of 5 patients (12-004, 25-009, 42-027, 80-018, 66-024) were outside the field of view. The Figure 14 distribution of 177 Lu-PSMA-I&T in the patients imaged over time is presented.

[0550] At Figures 17 - 25 the individual time-activity curves for each source organ represented as fIA at different time points are shown. Note: The time-activity curves in these figures are not decay-corrected relative to the injection time.

[0551] All patients showed similar total body clearance, except for patient 42-030 who had a significantly slower clearance rate. This slower clearance rate may be due to the patient's diffuse bone metastatic disease, which was confirmed by exposure measurements taken at the site 24 hours after injection of the investigational product (IP). An ionization chamber (Ludlum 9DP*) was used for the measurements, taken at a distance of 1 meter from the patient. After each cycle, the dose rate for this patient was approximately three times that of two other patients from the same site:

[0552] · Patient 42-027: 7 μSv / hour; 6 μSv / hour; 5 μSv / hour.

[0553] · Patient 42-028: 6 μSv / hour; 8 μSv / hour; 5 μSv / hour.

[0554] · Patient 42-030: 16 μSv / hour; 18 μSv / hour; 17 μSv / hour.

[0555] Given the significant bone involvement, the patient was determined by the site principal investigator (PI) to receive a superscan, which is an exclusion criterion. Consistent with the patient's high bone involvement, the estimated bone marrow uptake was also high, as shown in Figure 18 Therefore, even though dosimetry and PK analysis were performed, the biodistribution and dose values for this patient were removed from all aggregated data (mean, standard deviation, and mean curve) in this report.

[0556] The total body time-activity curve was fitted with a biexponential equation, and the two components were used for the distribution and elimination half-lives. The mean half-lives (excluding patient 42-030) were a distribution half-life of 2.16 ± 1.30 hours and an elimination half-life of 46.29 ± 23.83 hours.

[0557] Regarding the TACs in the individual organs (kidney, liver, spleen, salivary gland, lacrimal gland, GI tract), the distribution among different patients was fairly similar, with some expected variability. Not surprisingly, the variability was more pronounced in the GI tract.

[0558] Figure 15 The mean TACs for all source organs across the analyzed patients (excluding patient 42-030 who received a superscan) were reported. As already observed from the individual profiles, the total body TAC showed an initial rapid clearance rate, with an average activity retention rate of 44% ± 13% at 4 hours (minimum = 24%; maximum = 78%), followed by a second phase characterized by a slower clearance rate.

[0559] The mean TACs in the other organs showed similar behavior, particularly during the elimination phase.

[0560] Cycle 1 Dosimetry

[0561] It is very similar to the biodistribution data, with relatively high absorbed radiation doses per gram of tissue in the organs responsible for tracer elimination, namely the kidneys (0.41 ± 0.15 Gy / GBq), the bladder (0.41 ± 0.05 Gy / GBq), and some parts of the GI tract, namely the left colon (0.47 ± 0.31 Gy / GBq) and the rectum (0.44 ± 0.30 Gy / GBq). The salivary and lacrimal glands also showed moderate absorbed radiation doses (0.19 ± 0.16 Gy / GBq and 0.40 ± 0.36 Gy / GBq, respectively). Note that the salivary glands of patient 12 - 004 were not within the field of view of the scan, so the salivary gland TIAC could not be calculated, and this patient was excluded from the absorbed dose aggregation measure for the salivary glands.

[0562] The mean absorbed dose to the bone marrow was 0.08 ± 0.12 Gy / GBq). The high variability in bone marrow dose was due to some patients having abnormally high bone marrow doses (42 - 027, 62 - 032, 80 - 018, 80 - 024, 37 - 013, 37 - 016). In two of these six patients (42 - 027 and 62 - 032), the high bone marrow dose estimates may have been due to the presence of discrete metastases in the vertebrae, which were segmented to obtain image - based bone marrow dosimetry (L2 - L4). Due to the method of bone marrow dose estimation, the presence of metastatic lesions within the VOI led to an overestimation of the absorbed radiation dose to the bone marrow. In the other four patients, the images showed diffuse bone metastatic disease, resulting in a higher and more diffuse radioactive distribution in the bone tissue and thus higher bone marrow dose estimates. Excluding these six specific cases and the patients who received a superscan, the mean absorbed dose to the red bone marrow for the remaining 20 patients would be 0.02 ± 0.02 Gy / GBq.

[0563] The mean doses to all target organs are reported in Table 16.

[0564] Table 16: Cycle 1 Mean Absorbed Dose Estimates (n = 26)

[0565]

[0566]

[0567] The calibration factors for individual patients were similar to those determined at the time of site establishment (difference < 10%), except for two patients from one site in Cycle 1.

[0568] There were differences in both the calibration factors and the efficiency factors for these two patients (80 - 018 and 80 - 023), differing from the reference values determined at the time of site establishment by approximately +135% and -45% respectively (Table 6). Since the same differences were found in the calibration factors for SPECT and the efficiency factors for the gamma counter, it was concluded that these differences might be due to errors in the measurement results of the standard reference values. After quality control of the acquisition and reconstruction parameters, it was concluded that the whole-body images of these two patients were correctly acquired, and the problem seemed to be limited to the measurement results of the calibration factors. This conclusion was confirmed by the dosimetry results for these two patients, which were entirely within the range of other patients.

[0569] Table 17: SPECT Calibration Factors and Gamma Counter Efficiency Factors from Site 80

[0570]

[0571] Cycle 1 PK Monitoring

[0572] Plasma PK modeling results are reported in Tables 7A and 7B. Plasma data were fitted with a biexponential curve. As Figure 16 shown, plasma concentration decreased over time, with a similar characteristic curve in all patients, initially a faster decline (mean distribution half-life of 1.89 ± 0.34 hours), followed by a slower, prolonged decline. The mean elimination half-life was 14.70 ± 10.10 hours. Patient 42 - 030 exhibited an outlier half-life value of 113.96 hours, which was consistent with the patient's whole-body and bone marrow TACs, where radioactivity was taken up by numerous bone metastases.

[0573] The time to peak concentration always corresponded to the time of the first post-dose blood sample collected one hour after injection. Possibly, although the peak occurred shortly after injection, it was not captured by the sampling schedule applied in this study. Therefore, the peak concentration value reflected the

[0574] value measured at the first sample, rather than the true peak in plasma. Notably, patient 80 - 007 reached the peak at 127 minutes rather than one hour after injection because of a delay in the collection of the first post-dose sample for this patient.

[0575] Although the elimination phase of the plasma characteristic curve seemed to be prolonged in most patients, it should be noted that the concentration levels at later time points were very low. In fact, the clearance rate value (13.06 ± 16.50 liters / hour) indicated that most of the injected dose was cleared from the body quite rapidly. A portion of the injected activity was captured in the tissues and tumors expressing the target, as indicated by the moderate to high distribution volume.

[0576] Table 18: PK Plasma Modeling Results for Cycle 1

[0577]

[0578]

[0579] Table 19: PK Plasma Modeling Results for Cycle 1

[0580] Table 19: PK Plasma Modeling Results for Cycle 1

[0581]

[0582] Table 19: PK Plasma Modeling Results for Cycle 1

[0583]

[0584] Biodistribution and Dosimetry Results for Cycle 3

[0585] A subgroup of 16 out of 27 patients underwent additional dosimetry evaluations during Cycle 3. Of these, three patients received dosimetry based on images taken at four time points, while the remaining patients received dosimetry at only one or two imaging time points.

[0586] Similar to Cycle 1, the highest uptake and organ absorbed radiation doses in Cycle 3 were primarily seen in the kidney, bladder, lacrimal gland, GI tract, and salivary gland.

[0587] For the same patient subgroup, the organ absorbed radiation doses were compared to the mean organ absorbed radiation doses from Cycle 1, as shown in Tables 8A and 8B. The dosimetry estimates obtained during Cycle 3 were very close to the dosimetry estimates from Cycle 1. At this time point, although the kidney had the highest dose (0.49 ± 0.19 Gy / GBq), the estimated absorbed dose values for most organs were similar to or lower than the estimated absorbed dose values from Cycle 1. Although the mean absorbed doses in the kidney and bladder wall were slightly higher in Cycle 3 compared to Cycle 1, this difference remained within the expected variability.

[0588] For the three patients for whom dosimetry for Cycle 3 was calculated using four image time points, the organ absorbed radiation dose values were also within the variability observed in Cycle 1.

[0589] In summary, the dosimetry estimates performed during Cycle 3 support the method of predicting cumulative absorbed dose based on extrapolation from Cycle 1 data in this patient population.

[0590] Table 20: Mean, SD, Minimum, and Maximum Organ Absorbed Radiation Dose Estimates for 16 Patients Imaged in Cycle 1 and Cycle 3

[0591]

[0592]

[0593] a The OLINDA sphere model with assumed dose local deposition was used to calculate the lacrimal gland absorbed dose.

[0594] Table 21: Mean, SD, minimum, and maximum organ absorbed radiation dose estimates for 16 patients imaged in Cycle 1 and Cycle 3

[0595]

[0596] a The OLINDA sphere model with assumed dose local deposition was used to calculate the lacrimal gland absorbed dose.

[0597] Cycle 3 PK Modeling

[0598] In Cycle 3, blood samples were obtained from 15 of the 16 patients. Patient 12 - 004 was only bled at the 24 - hour time point and was thus not included in the plasma PK analysis. Consistent with Cycle 1, the plasma concentration - time courses among patients were similar. The PK parameter ranges obtained in Cycle 3 were similar to those from the Cycle 1 data (Tables 9A and 9B).

[0599] Table 22: Cycle 3 PK plasma modeling results (n = 15)

[0600]

[0601] Table 23: Cycle 3 PK plasma modeling results (n = 15)

[0602]

[0603]

[0604] Conclusion

[0605] Injection 177Bio-distribution, PK, and dosimetry analysis of the patient population of Lu-PSMA-I&T showed that the organs with moderate to high physiological uptake and absorbed dose were mainly the organs involved in the elimination of the radiopharmaceutical and / or the organs expressing PSMA. These organs included the kidneys (0.41 ± 0.15 Gy / GBq), bladder (0.41 ± 0.05 Gy / GBq), salivary and lacrimal glands (0.19 ± 0.16 Gy / GBq and 0.40 ± 0.36 Gy / GBq, respectively), and some parts of the GI tract (left colon, 0.47 ± 0.31 Gy / GBq and rectum, 0.44 ± 0.30 Gy / GBq).

[0606] The average absorbed radiation dose to the red bone marrow was 0.08 ± 0.12 Gy / GBq. The high variability observed for this parameter using an image-based method was attributed to the presence of diffuse bone metastatic disease in some patients, which led to 177 increased bone uptake of Lu-PSMA-I&T and thus a higher absorbed radiation dose in the bone marrow. Additionally, few patients had metastases in the lumbar region (L2-L4), where images for bone marrow dosimetry were available, which potentially led to an overestimation of the absorbed bone marrow dose in these cases.

[0607] The PK results showed that the elimination curves of the radiopharmaceutical in plasma across patients were consistent. Specifically, the plasma kinetics showed a monotonically decreasing trend across all patients and fitted well with a biexponential model.

[0608] Overall, the dosimetry data for the main organs of interest were within the expected range compared to the values published in the literature on Lu-PSMA-I&T 177 derived from various studies using different dosimetry methods.

[0609] Notably, the cycle 3 data showed dosimetry and PK values similar to those from cycle 1. This consistency indicates that the values obtained in cycle 1 can be reliably used to extrapolate the cumulative absorbed dose for subsequent cycles.

[0610] All references cited herein are incorporated herein by reference. The foregoing is provided primarily for illustrative purposes. It will be apparent to those skilled in the art that additional drugs may be included and that the components, additives, ratios, formulation methods, methods of use, and other parameters described herein may be further modified or replaced in various ways without departing from the spirit and scope of the invention.

[0611] Example 5: Evaluation 177 The safety and efficacy of Lu-PSMA-I&T radioligand therapy compared to hormone therapy in men with metastatic castration-resistant prostate cancer (mCRPC)

[0612] Eclipse is an evaluation 177 A phase 3, open-label, multi-center, randomized trial of the safety and efficacy of Lu-PSMA-I&T radioligand therapy compared to hormonal therapy in men with metastatic castration-resistant prostate cancer (mCRPC). 177 Lu-PSMA-I&T is a radiotherapeutic agent that specifically targets prostate-specific membrane antigen (PSMA) expressed on both primary and metastatic prostate cancer cells.

[0613] Sub-studies were conducted to evaluate 177 The PK and dosimetry of Lu-PSMA-I&T, in which patients underwent PK sampling and SPECT / CT imaging after the first and third 177 Lu-PSMA I&T infusions.

[0614] Methods

[0615] Data collection: All participating sites underwent a rigorous site-setting process during which all dose calibrators, scanners, and gamma counters used in the sub-study were calibrated. Sites were only allowed to enroll patients in the sub-study after all site-setting processes were completed and approved by Invicro.

[0616] After administration of targeted 7.4 ± 10% GBq of 177 Lu-PSMA-I&T in cycle 1, patients underwent SPECT / CT imaging, in which anatomical coverage typically extended from the salivary glands to the pelvis. SPECT / CT imaging was performed at four time points: 4 hours, 24 hours, 48 hours, and 168 hours after injection. Additionally, a subgroup of patients imaged in cycle 1 (16 out of 27) was also imaged in cycle 3 (Table 7 in Appendix 1).

[0617] Standardize image acquisition and reconstruction protocols across all imaging time points and patients at each site. Additionally, the same SPECT / CT scanner was used at each site throughout the study to ensure consistency.

[0618] Generally, raw projection data were acquired into a 128x128 matrix using a step-and-shoot acquisition mode with medium-energy general-purpose (MEGP) collimation, with 60 projections acquired per detector (180-degree rotation per detector), 20 seconds per projection, with an acquisition zoom of 1.0, and a 20% (±10%) energy window centered at 208 keV.

[0619] A low-dose CT scan is performed before starting the SPECT scan for attenuation correction. Sites are instructed to use institutional standard parameters to acquire the low-dose CT. Institutional standard reconstruction parameters are used. A scatter correction is applied using a 20% (±10%) scatter window centered at 170 keV.

[0620] PK plasma samples are collected before infusion, at 1 hour, 4 hours, 24 hours, 48 hours, and 168 hours, and counted for radioactivity. Blood samples are centrifuged first to extract plasma, and then the radioactivity in the plasma is counted in a gamma counter.

[0621] For a detailed overview of site eligibility and setup and data collection procedures, refer to the Technical Operations Manual (TOM) (Appendix 2).

[0622] Image analysis methods

[0623] Image preprocessing and segmentation

[0624] The imaging data are analyzed using Invicro's VivoQuant software, a validated software used in a 21 CFR §11 compliant workflow. The general quantification method is based on the principles detailed in MIRD Pamphlet No. 16 1 、No. 23 2 and No. 26 3 (as applicable).

[0625] The SPECT images are calibrated in Becquerel (Bq) using a calibration factor derived from a known activity source, which is measured during site setup using the same acquisition and reconstruction parameters as for patient imaging. Patient-specific calibration factors are also derived at each clinical time point after acquisition of the patient's SPECT / CT. As a quality control measure, if the patient-specific calibration factor differs from the site setup calibration factor by more than 10%, the study is conducted.

[0626] The volumes of interest (VOIs) (kidney, bladder, liver, lumbar vertebrae L2-L4, lacrimal glands, salivary glands [parotid and submandibular glands], and whole body) are delineated by a trained image analyst on each dataset. The GI tract and spleen are only delineated in a patient subgroup where these organs show visible uptake. The organs are segmented by drawing the entire outline of the organ or by placing spheres in representative regions of the organ and then multiplying by the effective mass of the organ (based on the patient's height and weight). 4 The segmentation method for each organ is specified in Table 1 and is applied consistently to each patient.

[0627] At Figure 27The maximum intensity projection (MIP) CT image of a representative patient with segmented regions is shown.

[0628] Table 24: Organ VOIs and depiction methods

[0629]

[0630]

[0631] Plasma quantitative analysis

[0632] Whole blood samples are collected as detailed in the protocol event schedule, i.e., before injection and then at 1 hour, 4 hours, 24 hours, 48 hours, and 168 hours after injection. The samples are first centrifuged to separate the plasma, and then the radioactivity in the plasma is measured using a gamma counter. Subsequently, the plasma concentration is fitted with a double-exponential function to derive result parameters such as the half-life and clearance rate of the radiopharmaceutical in the plasma.

[0633] Normal organ dosimetry analysis

[0634] The clearance rate of the radiopharmaceutical is derived from appropriate fitting of the data of the TAC for each organ. Depending on the shape of the TAC, the data is fitted with the sum of one, two, or three exponentials or using a rising and falling model. The fitting is performed using in-house Python software. The TIAC is calculated by the analytical integration of the curve fitting extrapolated to infinity. If no appropriate fit is found, the area under the curve (AUC) is estimated using the imaging measurement results and the sum of the trapezoidal integrals of the physical decay from the last time point forward (for organs, the injected activity fraction at t = 0 is set to zero, and for the whole body, it is set to 1). The whole-body TAC is obtained by depicting the imaged body. The remaining activity is determined by subtracting the cumulative organ TIAC from the whole-body TIAC.

[0635] The organ TIACs are input into OLINDA 2.2.3 to calculate the organ and whole-body absorbed doses using the International Commission on Radiological Protection (ICRP)-103 weighting factors. The ICRP-89 derived male phantom is used for dose assessment. The patient's effective mass is used to measure the organs and body weights defined by ICRP-89 based on height and mass. 4Assume a voiding interval of 4 hours and use the voiding bladder model implemented in OLINDA to determine bladder TIAC. Use the human alimentary tract model (HAT model) described in ICRP 100 and implemented in OLINDA to calculate the doses to the small intestine, right colon, left colon, and rectum for patients showing clearance through the GI tract. The fraction of injected activity cleared through the GI tract (fIA) is determined by taking the peak fIA in the GI tract at all imaging time points. Red marrow dose assessment is obtained by segmenting lumbar vertebrae L2-L4 as seen on CT. Assume that the red marrow mass in L2-L4 is 6.7% of the total red marrow mass. 5

[0636] Single time point dosimetry analysis for cycle 3

[0637] To evaluate potential changes in tracer kinetics and uptake after multiple treatment cycles, 16 out of 27 patients included in the dosimetry substudy were imaged in both cycle 1 and cycle 3. Among them, in cycle 3, three patients were imaged at all 4 time points, and an additional 13 patients were imaged at only one or two time points (24 hours, 48 hours, or both 24 hours and 48 hours) (Table 7 in Appendix 1). For these 13 patients, the TACs obtained in cycle 1 were used for each source organ and converted to normalized activity values measured in cycle 3. For patients imaged at two time points, the average scaling factor between the two time points was preferably used to scale the TAC. If the two time points yielded significantly different scaling factors, the more conservative time point was preferred, provided that the resulting dose estimates were reasonable.

[0638] Data acquisition quality control

[0639] Use a 177 Lu reference standard with known activity to control the quantitative accuracy of each SPECT image. Before scanning the patient, a reference standard was prepared by injecting 100 μCi (taken from the patient dose vial) into a 100 mL saline bag. Subsequently, the radioactivity of the saline bag was imaged immediately after each imaging time point using the same acquisition and reconstruction parameters. The number of counts in the image attributable to the reference standard activity was measured, and a calibration factor was obtained by dividing the number of counts by the known activity in the reference standard at the time of imaging. For all images acquired with the same SPECT / CT system, this calibration factor was expected to be the same (difference < 10% compared to the value determined at the site establishment). For patients with a calibration factor that differed from the site establishment by more than 10%, an investigation was initiated to determine the cause of this change, and if the change reflected differences in patient data acquisition and / or reconstruction.

[0640] Use the same 177The Lu reference standard is used to perform quality control on plasma samples counted by gamma counting by measuring 0.5 ml in 100 ml of the saline bag. For each patient, triplicates are prepared and measured immediately before all plasma samples are counted. Long-lived isotopes are also counted to ensure that each site is following the protocol correctly. Similar to the imaging standard, when the gamma counter efficiency factor differs by more than 10% compared to the gamma counter efficiency factor at the time of site establishment, a study is initiated to determine the cause of this change and if the change reflects differences in data acquisition.

[0641] Results

[0642] All twenty-seven (27) patients included in the sub-study had SPECT / CT images acquired for dosimetry purposes in the first cycle. Sixteen of the 27 patients were imaged additionally in cycle 3, as described in section 4.4.1. The activities injected into each patient in cycles 1 and 3 are shown in Table 25.

[0643] Table 25: 177Lu-PSMA-I&T injection activities in cycles 1 and 3

[0644]

[0645]

[0646] The dosimetry analysis included all acquired and / or evaluable imaging. Patient 37-016 did not have SPECT / CT imaging at the 168-hour time point and thus the results were based only on 3 time points for this patient. For patient 12-004, the 48-hour scan presented unrealistic high values (the whole-body injection activity fraction at 48 hours was higher than the whole-body injection activity fractions at 4 hours and 24 hours, although no additional activity was administered to the patient after the initial 177 Lu-PSMA-I&T injection). Additionally, for unknown reasons, the image quality at 48 hours was abnormally poor. Therefore, this time point was excluded from further analysis and 4-hour, 24-hour, and 168-hour SPECT images were used for dosimetry.

[0647] Cycle 1 biodistribution

[0648] Based on the image and dosimetry data, physiological uptake of 177 Lu-PSMA-I&T was mainly observed in the kidneys, bladder, lacrimal glands, GI tract, and salivary glands. 177Lu-PSMA-I&T is excreted mainly via urine, as indicated by the accumulation visible in the bladder. In 25 patients, uptake in the intestine was observed, while no significant uptake was found in 2 of the patients analyzed (80 - 004 and 25 - 005). The salivary glands of 1 patient (12 - 004) were outside the SPECT / CT field of view, and the lacrimal glands of 5 patients (12 - 004, 25 - 009, 42 - 027, 80 - 018, 66 - 024) were outside the field of view. In Figure 27 shows the 177 Lu-PSMA-I&T distribution of the patients imaged over time.

[0649] In Figures 17 - 25 are shown the individual time-activity curves for each source organ expressed as fIA at different time points. Note: The time-activity curves in these figures are not decay-corrected relative to the injection time.

[0650] All patients showed similar whole-body clearance rates, except for patient 42 - 030, who had a significantly slower clearance rate. This slower clearance rate may be due to the patient's diffuse bone metastatic disease, as confirmed by the exposure measurements performed at the site 24 hours after injection of the investigational product (IP). An ionization chamber (Ludlum 9DP*) was used for the measurement, performed at 1 meter from the patient. After each cycle, the dose rate for this patient was approximately three times that of two other patients from the same site:

[0651] Patient 42 - 027: 7 uSv / hour; 6 uSv / hour; 5 uSv / hour.

[0652] Patient 42 - 028: 6 uSv / hour; 8 uSv / hour; 5 uSv / hour.

[0653] Patient 42 - 030: 16 uSv / hour; 18 uSv / hour; 17 uSv / hour.

[0654] Given the significant bone involvement, the patient was determined by the site principal investigator (PI) to receive a superscan, which is an exclusion criterion. Consistent with the patient's high bone involvement, the estimated bone marrow uptake was also high, as Figure 18 shown. Therefore, even though dosimetry and PK analyses were performed, the biodistribution and dose values for this patient were removed from all aggregated data (means, standard deviations, and mean curves) in this report.

[0655] The whole-body time-activity curve was fitted with a biexponential equation, and two components were used for the distribution and elimination half-lives. The mean half-lives (excluding patient 42-030) were a distribution half-life of 2.16 ± 1.30 hours and an elimination half-life of 46.29 ± 23.83 hours.

[0656] Regarding the TAC in individual organs (kidney, liver, spleen, salivary gland, lacrimal gland, GI tract), the distribution among different patients was quite similar, with some expected variability. Not surprisingly, the variability was more pronounced in the GI tract.

[0657] Cycle 1 Dosimetry

[0658] Very similar to the biodistribution data, the absorbed radiation dose per gram of tissue was higher in the organs responsible for tracer elimination, namely the kidney (0.41 ± 0.15 Gy / GBq), bladder (0.41 ± 0.05 Gy / GBq), and some parts of the GI tract, namely the left colon (0.47 ± 0.31 Gy / GBq) and rectum (0.44 ± 0.30 Gy / GBq). The salivary and lacrimal glands also showed moderate absorbed radiation doses (0.19 ± 0.16 Gy / GBq and 0.40 ± 0.36 Gy / GBq, respectively). Note that the salivary gland of patient 12-004 was not within the field of view of the scan, so the salivary gland TIAC could not be calculated, and this patient was excluded from the salivary gland absorbed dose aggregation metric.

[0659] The mean absorbed dose to the bone marrow was 0.08 ± 0.12 Gy / GBq). The high variability in bone marrow dose was due to some patients having abnormally high bone marrow doses (42-027, 62-032, 80-018, 80-024, 37-013, 37-016). In two of these six patients (42-027 and 62-032), the high bone marrow dose estimate was likely due to the presence of isolated metastases in the vertebrae, which were segmented to obtain image-based bone marrow dosimetry (L2-L4). Due to the method of bone marrow dose estimation, the presence of metastatic lesions within the VOI led to an overestimation of the absorbed radiation dose to the bone marrow. In the other four patients, the images showed diffuse bone metastatic disease, resulting in a higher and more diffuse radioactive distribution in the bone tissue and thus a higher bone marrow dose estimate. Excluding these six specific cases and the patients who received a superscan, the mean absorbed dose to the red bone marrow for the remaining 20 patients would be 0.02 ± 0.02 Gy / GBq.

[0660] The mean doses to all target organs are reported in Table 26, and the individual doses are reported in Appendix 1.

[0661] Table 26: Cycle 1 Mean Absorbed Dose Estimates (n = 26)

[0662]

[0663]

[0664] Data quality control results

[0665] The calibration factors for individual patients were similar to those determined at the time of site establishment (difference < 10%), except for two patients from one site in Cycle 1.

[0666] Both the calibration factors and efficiency factors differed for these two patients (80 - 018 and 80 - 023), by approximately +135% and -45% respectively from the reference values determined at the time of site establishment (Table 8 in Appendix 1). Since the same differences were found in the calibration factors for SPECT and the efficiency factors for the gamma counter, it was concluded that these differences were likely due to errors in the measurement of the standard reference values. After quality control of the acquisition and reconstruction parameters, it was concluded that the whole-body images of these two patients were acquired correctly and the problem seemed to be limited to the measurement of the calibration factors. This conclusion was confirmed by the dosimetry results for these two patients, which were entirely within the range of other patients.

[0667] Cycle 1 PK modeling

[0668] Plasma PK modeling results are reported in Table 4, see also Figures 12 - 13 and 14 - 25. Plasma data were fitted with a biexponential curve. Plasma concentration decreased over time, with a similar characteristic curve in all patients, initially a faster decline (mean distribution half-life of 1.89 ± 0.34 hours), followed by a slower, prolonged decline. The mean elimination half-life was 14.70 ± 10.10 hours. Patient 42 - 030 showed an outlier half-life value of 113.96 hours, which was consistent with the whole-body and bone marrow TAC for the patient, where radioactivity was taken up by numerous bone metastases.

[0669] The time to peak concentration always corresponded to the time of the first post-dose blood sample collected one hour after injection. Possibly, although the peak occurred soon after injection, it was not captured by the sampling schedule applied in this study. Therefore, the peak concentration value reflects the value measured at the first sample, rather than the true peak in plasma. It is noteworthy that patient 80 - 007 reached the peak at 127 minutes, rather than one hour after injection, because the collection of the first post-dose sample for this patient was delayed.

[0670] Although the elimination phase of the plasma profile appears to be prolonged in most patients, it should be noted that the concentration levels at later time points are very low. In fact, the clearance value (13.06 ± 16.50 L / hour) indicates that most of the injected dose is cleared from the body rather rapidly. A portion of the injected activity is captured in the tissues and tumors expressing the target, as indicated by the moderate to high distribution volume.

[0671] Table 27: Cycle 1 PK Plasma Modeling Results

[0672]

[0673]

[0674] Cycle 3 Biodistribution and Dosimetry Results

[0675] A subgroup of 16 out of 27 patients underwent additional dosimetry evaluations in Cycle 3. Among them, three patients received dosimetry based on images taken at 4 time points, while the remaining patients received dosimetry only at 1 or 2 imaging time points, as described in Section 4.4.1.

[0676] Similar to Cycle 1, the highest uptake and organ absorbed radiation doses in Cycle 3 were mainly seen in the kidney, bladder, lacrimal gland, GI tract, and salivary gland (individual and aggregated values of TIAC of the target organs are shown in Appendix 1).

[0677] For the same subgroup of patients, the organ absorbed radiation doses were compared with the mean organ absorbed radiation doses from Cycle 1, as shown in Table 5. The dosimetry estimates obtained in Cycle 3 were very close to the dosimetry estimates from Cycle 1. See Figure 26 . At this time point, although the kidney had the highest dose (0.49 ± 0.19 Gy / GBq), for most organs, the estimated absorbed dose values were similar to or lower than the estimated absorbed dose values in Cycle 1. Although the mean absorbed doses in the kidney and bladder wall in Cycle 3 were slightly higher compared to Cycle 1, this difference remained within the expected variability.

[0678] For the three patients who used 4 image time points to calculate the dosimetry in Cycle 3, the organ absorbed radiation dose values were also within the variability observed in Cycle 1.

[0679] In summary, the dosimetry estimates performed in Cycle 3 support the method of predicting the cumulative absorbed dose based on extrapolation from Cycle 1 data in this patient population.

[0680] Table 28: Mean, SD, Minimum, and Maximum Organ Absorbed Radiation Dose Estimates for 16 Patients Imaged in Cycle 1 and Cycle 3

[0681]

[0682]

[0683] PK Modeling in Cycle 3

[0684] In Cycle 3, blood samples were obtained from 15 out of 16 patients. Patient 12-004 was only bled at the 24-hour time point and was therefore not included in the plasma PK analysis. Consistent with Cycle 1, the plasma concentration-time profiles were similar among patients. The range of PK parameters obtained in Cycle 3 was similar to the range of PK parameters from Cycle 1 data (Table 29). See Table 29: PK Plasma Modeling Results in Cycle 3 (n = 15)

[0685]

[0686]

[0687] Conclusion

[0688] Injection 177 Biodistribution, PK, and dosimetry analyses of the patient population of Lu-PSMA-I&T showed that the organs with moderate to high physiological uptake and absorbed dose were mainly the organs involved in the elimination of the radiopharmaceutical and / or the organs expressing PSMA. These organs included the kidneys (0.41 ± 0.15 Gy / GBq), bladder (0.41 ± 0.05 Gy / GBq), salivary and lacrimal glands (0.19 ± 0.16 Gy / GBq and 0.40 ± 0.36 Gy / GBq, respectively), and some parts of the GI tract (left colon, 0.47 ± 0.31 Gy / GBq and rectum, 0.44 ± 0.30 Gy / GBq).

[0689] The mean absorbed radiation dose to the red bone marrow was 0.08 ± 0.12 Gy / GBq. The high variability observed for this parameter using the image-based method was attributed to the presence of diffuse bone metastatic disease in some patients, which led to 177 increased bone uptake of Lu-PSMA-I&T and thus higher absorbed radiation dose in the bone marrow. Additionally, few patients had metastases in the lumbar region (L2-L4), where images were available for bone marrow dosimetry, which potentially led to an overestimation of the absorbed bone marrow dose in these cases.

[0690] The PK results showed that the elimination curves of the radiopharmaceutical in plasma were consistent across patients. Specifically, the plasma kinetics showed a monotonically decreasing trend across all patients and fit well with the biexponential model.

[0691] Overall, compared to those from various studies using different dosimetry methods177 Compared with the values reported in the literature of Lu-PSMA-I&T, the dosimetry data for the main organs of interest are within the expected range.

[0692] Notably, the Cycle 3 data showed dosimetry and PK values similar to those from Cycle 1. This consistency indicates that the values obtained in Cycle 1 can be reliably used to extrapolate the cumulative absorbed dose for subsequent cycles.

[0693] Example 6: Imaging Center Training and Establishment

[0694] Technical Operations Manual Inspection and Gamma Counter Data

[0695] Always ensure consistent scan parameters are used across time points. The same scanner must be used for all evaluations within and across all patients, unless otherwise approved by Invicro or the study sponsor.

[0696] Acquire images according to the trial-specific procedure standards within the protocol activity schedule and according to the protocol activity schedule. Image acquisition and recording should not deviate from the clinical trial protocol; however, the TOM can provide extended information and procedures.

[0697] All SPECT / CT scans and gamma counter data, along with corresponding files, must preferably be submitted to Invicro within 24 hours (but not more than 3 working days) after the final imaging and blood collection time point for each patient per cycle. All gamma counter data must be submitted to Invicro within 24 hours of the final blood collection time point for each patient's cycle.

[0698] Respond to queries generated by Invicro in a timely manner (preferably within 24 hours but not more than 5 days).

[0699] Confirm that all technical experts or other personnel who will perform scans for this protocol are specifically trained on the study-specific acquisition and reconstruction parameters, as well as data submission and query handling procedures.

[0700] Compliance: All site personnel must comply with the guidelines of the International Council for Harmonization E6(R2) on Good Clinical Practice (GCP) when recording acquisitions, archiving images, and submitting image data to Invicro.

[0701] Confidentiality: Prior to submitting image data to Invicro, follow regional privacy practices to identify (i.e., redact) all patient information (name, medical record number, etc.). Submitters should pay particular attention to data that may include protected health information, such as DICOM headers, CT dose reports, image overlays, and screenshots.

[0702] Activity Schedule

[0703] After completion of all training and approval requirements, the imaging center may scan and collect samples from the first patient. After the scan of the first patient is approved, scanning and sample collection of the remaining patients may commence according to the protocol activity schedule summarized in Table 60.

[0704] Table 30: PK Sub-Study Activity Schedule

[0705]

[0706] Image Data Submission Timeline

[0707] All SPEC - MCI scans and gamma counter data and corresponding files must preferably be submitted to Invicro within 24 hours (but no more than 3 working days) after the final imaging and blood collection time point for each patient per cycle.

[0708] Imaging center establishment : Prior to imaging study patients, it will be necessary for the participating imaging center to complete Invicro's establishment procedures. The purpose of these procedures is to ensure that each imaging center participating in the study meets the high-level standards required by Invicro and the study sponsor, provide training on study imaging requirements for technical experts and support staff, evaluate the performance of the imaging equipment to be used in the study, and ensure that the protocol followed for patient imaging is properly established.

[0709] The following procedures are included as part of the establishment.

[0710] Technical Assessment Questionnaire

[0711] The initial step in the establishment process is for the center to complete the Technical Assessment Questionnaire. This form provides Invicro with contact information for key individuals, address information, specific scanner and computer system capabilities, and other specifications necessary for satisfactory completion of the study. Invicro will provide the site and imaging center with

[0712]

[0713] A brief overview of the establishment process.

[0714] Invicro reviews the completed questionnaire for an initial assessment of the imaging center's technical capabilities. If the center meets the technical standards required to perform as a participating center, Invicro will contact the center and inform them of the next steps required to complete the qualification process for the study described in the following paragraphs.

[0715] In certain cases where Invicro has recently collaborated with or is currently collaborating with imaging centers on another study and has collected certain questionnaires, the requirement for the center to complete a new questionnaire may be waived.

[0716] Technical site training

[0717] Training of the imaging centers for this trial will be conducted via teleconference.

[0718] The teleconference training will be between imaging center staff, clinical site staff, and Invicro-established experts. During this session, the overall objectives and rationale of the imaging components of the clinical trial are reviewed. Individual responsibilities for obtaining imaging measurements are discussed, as well as pre-scheduling of the site's communication flow, logistics, and potential issues (e.g., scanner availability, etc.), and questions are raised -

[0719] The imaging center may be required to acquire phantom data and transmit it to Invicro, which will be analyzed and used to evaluate scanner performance. Details regarding phantom preparation, acquisition, and reconstruction will be provided in a separate document _ Please note that if Invicro has recent phantom data from the participating imaging centers on record, acquisition and transmission of phantom data may be waived.

[0720] Additionally, the imaging center will need to establish study-specific protocols in its scanners and may be required to submit screenshots of relevant parameters to Invicro for review and approval.

[0721] Now note that at least one primary staff member (technical expert, physicist, or physician) is responsible for performing the study imaging of IMISE trained by Invicro. It is the responsibility of the imaging center to ensure that all additional personnel are peer-trained by the primary staff member initially trained by Invicro and are supplied with a copy of this TOM and all other study materials. All additional training activities must be recorded, and a copy of the training documentation is provided to the relevant clinical sites. For additional training or questions, please contact Invicro for assistance.

[0722] Approval to scan the first patient: After completion of the technical setup procedure, a 'Scan Approved' notification and a detailed technical site setup report summarizing the approved methods for dose, acquisition, and reconstruction parameters, image archiving, and image transmission are sent to the imaging center, with copies to the clinical site and sponsor-designated personnel. The approval notification and technical report should be archived.

[0723] Now note: This 'Scan Approved' notification indicates that the imaging center is now ready to scan its first study patient only.

[0724] Approval to scan all subsequent patients:After imaging the first study patient, the imaging center will be instructed to transfer these images to Invicro for OC review within 24 hours of acquisition. Once the patient images pass QC, the imaging center and clinical coordinator will be notified by email that they have been approved to proceed with imaging additional patients. Sites will be notified within approximately 5 business days after receipt of the first patient's data (unless there are questions). If the first patient scan does not pass OC review, Invicro will communicate with the imaging and clinical staff regarding how to resolve the issues before proceeding with imaging additional patients.

[0725] All references cited herein are incorporated herein by reference. The foregoing is provided primarily for illustrative purposes. It will be apparent to those skilled in the art that additional drugs may be included and that the components, additives, ratios, formulation methods, methods of use, and other parameters described herein may be further modifie...

Claims

1. A method comprising administering to a human patient in need thereof a radiopharmaceutical 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, the radiochemical purity of the composition is ≥95% within at least 72 hours after manufacture, and wherein the absorbed radiation dose per gram of tissue in the kidney of the human patient is from about 0.2 Gy / GBq to about 0.6 Gy / GBq, from about 0.25 Gy / GBq to about 0.55 Gy / GBq, from about 0.3 Gy / GBq to about 0.5 Gy / GBq or from about 0.35 Gy / GBq to about 0.45 Gy / GBq.

2. The method according to claim 1, wherein the absorbed radiation dose per gram of tissue in the kidney of the human patient is from about 0.25 Gy / GBq to about 0.55 Gy / GBq.

3. The method according to claim 1, wherein the absorbed radiation dose per gram of tissue in the kidney of the human patient is from about 0.3 Gy / GBq to about 0.5 Gy / GBq.

4. The method according to claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.39 ± 0.15 Gy / GBq.

5. The method according to claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.40 ± 0.15 Gy / GBq.

6. The method according to claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.41 ± 0.15 Gy / GBq.

7. The method according to claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.42 ± 0.15 Gy / GBq.

8. The method according to claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.43 ± 0.15 Gy / GBq.

9. The method according to claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.45 ± 0.15 Gy / GBq.

10. The method according to claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is ≤ 0.39 Gy / GBq.

11. The method according to claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is ≤ 0.40 Gy / GBq.

12. The method according to claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is ≤ 0.41 Gy / GBq.

13. The method according to claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is ≤ 0.42 Gy / GBq.

14. The method according to claim 1, wherein the standard deviation of the average absorbed radiation dose per gram of tissue in the kidney of the human patient is ≤ 0.19 Gy / GBq, ≤ 0.18 Gy / GBq, ≤ 0.17 Gy / GBq, ≤ 0.16 Gy / GBq or ≤ 0.15 Gy / GBq.

15. The method according to claim 1, wherein the molar ratio of PSMAI&T of the composition to 177 Lu is from about 4.0:1.0 to about 8.0:1.0, from about 4.4:1.0 to about 7.6:1.0, from about 4.5:1.0 to about 5.5:1.0 or from about 5.0:1.0 to about 6.0:1.

0.

16. The method according to claim 1, wherein the molar ratio of PSMAI&T of the composition to 177 Lu is about 3.0:1, about 3.5:1, about 4.0:1.0, about 4.5:1.0, about 5.0:1.0, about 5.5:1.0, about 6.0:1.0, about 6.5:1.0, about 7.0:1.0, about 7.5:1.0 or about 8.0:1.

0.

17. The method according to claim 1, wherein the molar ratio of PSMAI&T of the composition to 177 Lu is from about 5.1:1.0 to about 5.9:1.0, from about 5.2:1.0 to about 5.8:1.0, from about 5.3:1.0 to about 5.7:1.0, or from about 5.4:1.0 to about 5.6:1.

0.

18. The method according to claim 1, wherein the molar ratio of PSMAI&T of the composition to 177 Lu is from 4.4:1.0 to 7.6:1.

0.

19. The method according to claim 1, wherein the composition comprises from about 7.1 GBq to about 7.6 GBq of 177 Lu-PSMA I&T.

20. The method according to claim 1, wherein the composition comprises 7.4 ± 15% GBq of 177 Lu-PSMA I&T.

21. The method according to claim 1, wherein the composition comprises 7.4 ± 10% GBq of 177 Lu-PSMA I&T.

22. The method according to claim 1, wherein the composition comprises 7.4 ± 5% GBq of 177 Lu-PSMA I&T.

23. The method according to claim 1, wherein the composition comprises about 7.4 GBq of 177 Lu-PSMA I&T.

24. The method according to claim 1, wherein the absorbed radiation dose is determined by SPECT imaging, planar imaging, or a combination thereof.

25. A method comprising administering to a human patient in need thereof a radiopharmaceutical 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, the radiochemical purity of the composition is ≥95% within at least 72 hours after manufacture, and wherein the absorbed radiation dose per gram of tissue in the kidney of the human patient is ≤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, ≤0.25 Gy / GBq, ≤0.20 Gy / GBq or ≤0.15 Gy / GBq.

26. A method comprising administering to a human patient in need thereof a radiopharmaceutical 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, the radiochemical purity of the composition is ≥95% within at least 72 hours after manufacture, and wherein the absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is from about 0.01 Gy / GBq to about 1.5 Gy / GBq.

27. A method comprising administering to a human patient in need thereof a radiopharmaceutical 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, the radiochemical purity of the composition is ≥95% within at least 72 hours after manufacture, and wherein the absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is ≤1.5 Gy / GBq, ≤1.4 Gy / GBq, ≤1.3 Gy / GBq, ≤1.2 Gy / GBq, ≤1.1 Gy / GBq, ≤1.0 Gy / GBq, ≤0.9 Gy / GBq, ≤0.8 Gy / GBq, ≤0.7 Gy / GBq, ≤0.6 Gy / GBq, ≤0.5 Gy / GBq, ≤0.4 Gy / GBq, ≤0.3 Gy / GBq, ≤0.2 Gy / GBq or ≤0.1 Gy / GBq.

28. The method according to claim 27, wherein the molar ratio of PSMA I&T of the composition to 177 Lu is from about 4.0:1.0 to about 8.0:1.0, from about 4.4:1.0 to about 7.6:1.0, from about 4.5:1.0 to about 5.5:1.0 or from about 5.0:1.0 to about 6.0:1.

0.

29. The method according to claim 27, wherein the molar ratio of PSMAI&T of the composition to 177 Lu is from 4.4:1.0 to 7.6:1.

0.

30. The method according to claim 27, wherein the absorbed radiation dose is determined by SPECT imaging, planar imaging, or a combination thereof.

Images