[177Lu] lutetium-PSMA IT compositions, kits, methods of making and methods of use thereof

Abstract

The present disclosure is generally directed to a radiopharmaceutical composition comprising: 177 Lu-PSMA Iamp; t. The composition is formulated as a solution for injection, and the solution is adapted to be administered more than 72 hours after the formulation. The composition may include ascorbic acid and have a pH in solution of from 3.5 to 4.5. In some examples, the composition is suitable for administration to a human patient in need thereof within at least 90 hours after formulation, and the radiochemical purity of the composition upon administration is 95% or higher.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Application No. 63 / 393,777, filed Jul. 29, 2022, and U.S. Application No. 63 / 393,446, filed Jul. 29, 2022, under 35 U.S.C. § 119, the entire contents of each of the U.S. applications being incorporated herein by reference. Technical Field

[0003] The present disclosure generally relates to a novel composition for injection of 177 Lu] lutetium-PSMA I&T ( 177 Lu] Lu-PSMA I&T or 177 Lu-PSMA I&T) solution, and a kit comprising 177 Lu-PSMA I&T. The 177 Lu-PSMA I&T solution and / or its kit can be used for prostate cancer radionuclide therapy (PRLT). Background Art

[0004] Prostate cancer (PC) is the most common non-skin cancer and the second leading cause of cancer death in adult men. In 2020, there were over 1.4 million new cases of PC globally and 375,304 deaths. Most deaths associated with prostate cancer are due to advanced disease, i.e., any combination of lymphatic, hematogenous, or contiguous local spread. Most patients with PC die from metastatic PC, and 90% of these patients have bone metastases. In some cases, surgery and / or chemotherapy may not be applicable or effective for certain patients, including those with metastatic castration-resistant prostate cancer (mCRPC). Therefore, alternative treatments for prostate cancer are needed.

[0005] In the past decade, six new drugs have been found to increase the overall survival of patients with metastatic castration-resistant prostate cancer (mCRPC). Patients with symptomatic mCRPC are initially treated with docetaxel. Abiraterone, enzalutamide, cabazitaxel, sipuleucel, and radium-223 can increase the overall survival of patients who have failed docetaxel treatment. Targeted radionuclide therapy has become an attractive and rapidly evolving treatment option for various cancers such as lymphoma, melanoma, and neuroendocrine tumors.

[0006] However, randomized trials have not evaluated these drugs in patients who relapse after docetaxel treatment and then fail second-line treatment responses. Therefore, international organizations such as the European Association of Urology (EAU) / European Society of Radiotherapy and Oncology (ESTRO) have developed guidelines for the third-line treatment of mCRPC but have not made recommendations. Clinically, an effective third-line treatment for mCRPC with lower toxicity is needed. 177 Lu]Lu-PSMA-617 is a promising new therapy for patients with mCRPC.

[0007] Prostate-specific membrane antigen (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. Therefore, PSMA is a promising molecular target for the diagnosis and treatment of metastatic prostate cancer.

[0008] Some monoclonal antibodies (mAbs) radiolabeled with lutetium-177 ( 177 Lu) or yttrium-90 ( 90 Y) have shown good results; however, the incidence of hematotoxicity is relatively high. Due to the side effects, it is prudent to consider small molecule inhibitors of PSMA as an alternative to mAbs. 177 Lu-PSMA-617 and 177 Lu-PSMA I&T are small molecule inhibitors of PSMA. Due to their low hematotoxicity and nephrotoxicity, they provide better efficacy and fewer adverse reactions and are very suitable for use in targeted radionuclide therapy.

[0009] 177 Lu is a β- and γ-emitting radionuclide that can irradiate tumor cells. 177 The half-life of 131 Lu is 6.7 days and it has a lower β-particle emission energy compared to iodine-131 ( 177 I), indicating a greater likelihood of fewer side effects. Compositions made with 177 Lu usually have a short shelf life. The shelf life of previous imaging and therapy formulations of

[0010] Currently, there is still a need for a composition containing 177An improved formulation of Lu-PSMA I&T with a shelf life of more than 48 hours. This disclosure relates to an improved injectable 177 Lu-PSMA I&T solution. Summary of the Invention

[0011] Thus, in short, this disclosure relates to a radiopharmaceutical composition for administration to a human patient in need, comprising 177 Lu-PSMA I&T. The composition is formulated as a solution for injection, and the solution is suitable for administration to a human patient in need more than 48 hours, more than 72 hours, more than 96 hours, or more than 100 hours after formulation.

[0012] This disclosure further relates to a radiopharmaceutical composition comprising a solution containing 177 Lu-PSMA I&T and ascorbic acid with a pH of 3.5 to 4.5. In some instances, the composition is suitable for administration to a human patient in need within at least 90 hours after formulation, and the radiochemical purity of the composition at the time of administration is 95.0% or higher.

[0013] Another aspect of this disclosure is a reaction composition comprising 177 Lu, ascorbic acid containing PSMA I&T precursor at about 463 μg / mL to 500 μg / mL, and acetate buffer. Another aspect of this disclosure is a reaction composition comprising a total of 6 mL to 8 mL of a solution containing 177 Lu, PSMA I&T precursor at about 463 μg / mL to 500 μg / mL, about 4 ml of 0.4 M sodium acetate, about 1.6 mL of 0.05 M hydrochloric acid, and about 150 μl of 20% L-ascorbic acid. Yet another aspect of this disclosure is a reaction composition comprising 177 Lu, ascorbic acid containing PSMA I&T precursor at about 463 μg / mL to 1000 μg / mL, and acetate buffer. In some instances, the 177 Lu radioactivity of the reaction composition is ≤61 GBq.

[0014] Another aspect of this disclosure is a reaction composition comprising a solution containing 177 Lu, PSMA I&T precursor, ascorbic acid / acetate buffer, hydrochloric acid, and L-ascorbic acid. In some instances, the 177 Lu radioactivity of the reaction composition is ≤296 GBq.

[0015] This disclosure further relates to a radiopharmaceutical composition comprising an injectable 177 Lu-PSMA I&T solution, the solution comprising177 Lu-PSMA I&T, ascorbic acid, and ethanol. Wherein the 177 amount of radioactivity of Lu-PSMA I&T is sufficient for the intended use, wherein the total amount of ascorbic acid in the solution is about 210 - 700 mg, and the total amount of ethanol in the solution is about 274 - 706 mg; wherein the pH of the solution is about 5 or less, wherein after administering the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity, and wherein the prostate-specific antigen decreases by more than about 50%.

[0016] The present disclosure further relates to a radiopharmaceutical composition comprising an injectable 177 solution of Lu-PSMA I&T, the solution comprising an amount of Lu-PSMA-I&T of about 5 μg / ml to about 15 μg / ml, 177 ascorbic acid at a concentration of about 10 mg / ml to about 50 mg / ml, and ethanol at a concentration of about 1% (v / v) to about 10% (v / v), wherein the pH of the solution is between about 3 and about 5, and wherein after administering the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0017] The present disclosure further relates to a radiopharmaceutical composition comprising an injectable 177 solution of Lu-PSMA I&T, the solution comprising an amount of Lu-PSMA-I&T of about 5 μg / ml to about 15 μg / ml, 177 ascorbic acid at a concentration of about 10 mg / ml to about 50 mg / ml, ethanol at a concentration of about 1% (v / v) to about 10% (v / v), and a chelating agent in an amount of about 0.001% to about 0.15% (w / w) of the total weight of the radiopharmaceutical composition, wherein the pH of the solution is between about 3 and about 5, and wherein after administering the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0018] The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of injectable 177 solution of Lu-PSMA I&T, wherein the injection comprises a dose of 177Lu-PSMA-I&T, and wherein it is possible to perform 6 cycles of 177Lu-PSMA I&T treatment at said dose without the risk of nephrotoxicity and / or wherein 6 cycles of 177Lu-PSMA I&T treatment provide an average planned dose below the absorbed dose limit of 23 Gy. The present disclosure also relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of injectable177 Lu-PSMA I&T solution, wherein the injection comprises a dose of 177Lu-PSMA-I&T, and the planned or actual cumulative renal absorbed dose for 6 cycles is less than 23 Gy and no nephrotoxicity is observed. The present disclosure further relates to a radioactive pharmaceutical kit comprising vials, said vials containing at least a single dose for injection into a human patient in need of 177 Lu-PSMA I&T solution, 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 it is possible to perform 6 cycles of 177Lu-PSMA I&T treatment at said dose without the risk of nephrotoxicity and / or wherein 6 cycles of 177Lu-PSMA I&T treatment provide an average planned dose below the absorbed dose limit of 23 Gy and / or the planned or actual cumulative renal absorbed dose for 6 cycles is less than 23 Gy and no nephrotoxicity is observed. The present disclosure further relates to a radioactive pharmaceutical kit comprising vials, said vials containing at least a single dose for injection into a human patient in need of 177 Lu-PSMA I&T solution, 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 it is possible to perform 6 cycles of 177Lu-PSMA I&T treatment at said dose without the risk of nephrotoxicity and / or wherein 6 cycles of 177Lu-PSMA I&T treatment provide an average planned dose below the absorbed dose limit of 23 Gy and / or the planned or actual cumulative renal absorbed dose for 6 cycles is less than 23 Gy and no nephrotoxicity is observed. The present disclosure further relates to a radioactive pharmaceutical kit comprising vials, said vials containing at least a single dose for injection into a human patient in need of 177Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq (average 7.52 ± 0.16 GBq) of 177Lu-PSMA-I&T, and wherein it is possible to perform 6 cycles of 177Lu-PSMA I&T treatment at said dose without risk of nephrotoxicity and / or wherein the 6 cycles of 177Lu-PSMA I&T treatment provide an average planned dose below the absorbed dose limit of 23 Gy and / or the planned or actual cumulative renal absorbed dose for 6 cycles is less than 23 Gy and no nephrotoxicity is observed. The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose for injection into a human patient in need of 177 Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq (average 7.52 ± 0.16 GBq) of 177Lu-PSMA-I&T, wherein the 6 cycles of 177Lu-PSMA I&T treatment provide an average planned dose below the absorbed dose limit of 23 Gy and / or the planned or actual cumulative renal absorbed dose for 6 cycles is less than 23 Gy and no nephrotoxicity is observed. The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose for injection into a human patient in need of 177 Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 (+ / - 10%) GBq of 177Lu-PSMA-I&T, and wherein it is possible to perform 6 cycles of 177Lu-PSMA I&T treatment at said dose without risk of nephrotoxicity and / or wherein the 6 cycles of 177Lu-PSMA I&T treatment provide an average planned dose below the absorbed dose limit of 23 Gy and / or the planned or actual cumulative renal absorbed dose for 6 cycles is less than 23 Gy and no nephrotoxicity is observed. Note: The term "cumulative" may be used in place of "cumulated".

[0019] The present disclosure further relates to a method of administering a radiopharmaceutical composition, the method comprising administering the radiopharmaceutical composition to a patient in need thereof, optionally more than 48 hours after compounding, the radiopharmaceutical composition comprising a pH of 3.5 to 4.5 and containing a dose of 7.4 GBq ± 0.10 GBq, 7.4 GBq ± 0.15 GBq, 7.4 GBq ± 0.20 GBq, 7.4 GBq ± 0.25 GBq or 7.4 GBq ± 0.30 GBq of 177A solution of Lu-PSMA I&T, the solution optionally comprising ascorbic acid and / or ethanol, and the radiochemical purity of the solution at the time of administration optionally exceeding 95%, exceeding 96%, exceeding 97%, exceeding 98%, exceeding 99% or exceeding 99.5%, and wherein it is possible to perform 6 cycles of 177Lu-PSMA I&T treatment at said dose without the risk of nephrotoxicity and / or wherein 6 cycles of 177Lu-PSMA I&T treatment provide an average planned dose below the absorbed dose limit of 23 Gy and / or the planned or actual cumulative renal absorbed dose for 6 cycles is less than 23 Gy and no nephrotoxicity is observed.

[0020] The present disclosure further relates to a method of diagnosing or treating a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein 20 hours after injection, the activity of the radiopharmaceutical composition in the whole body is at least 20% IA to 30% IA.

[0021] The present disclosure further relates to a method of diagnosing a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in the kidney is at least 8% IA to 10% IA.

[0022] The present disclosure further relates to a method of diagnosing a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.7% IA to 1% IA.

[0023] The present disclosure further relates to a method of diagnosing a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesion of the patient is at least 0.2% IA to 0.5% IA.

[0024] The present disclosure further relates to a method for diagnosing tumors in a patient in need thereof, the method comprising administering to the patient a radiopharmaceutical composition by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in the bone lesions of the patient is at least 0.1% IA to 0.4% IA.

[0025] The present disclosure further relates to a method for diagnosing tumors in a patient in need thereof, the method comprising administering to the patient a radiopharmaceutical composition by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the effective half-life of the radiopharmaceutical composition in the whole body of the patient is about 30 hours to 40 hours.

[0026] There are various improvements to the above features related to various aspects of the present disclosure. Other features can also be incorporated into these different aspects. These improvements and additional features can exist individually or in any combination. For example, the various features discussed below with respect to one or more of the illustrated embodiments can be incorporated individually or in any combination into any of the above aspects of the present disclosure. Similarly, the above brief summary is only intended to familiarize the reader with certain aspects and background of the present disclosure and is not limited to the claimed subject matter. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The various features, aspects, and advantages of the present disclosure will be better understood when reading the following detailed description with reference to the accompanying drawings, in which like characters represent like parts throughout the drawings, and in which:

[0028] Figure 1A The structural formula of precursor PSMA I&T is shown.

[0029] Figure 1B Shows 177 The structural formula of the R isomer of Lu-PSMA I&T. However, PSMA I&T does not have a specification for the enantiomeric purity of the R and S isomers.

[0030] Figure 2 is a flow chart of an exemplary method for preparing the disclosed radiopharmaceutical composition.

[0031] Figure 3A is in one embodiment 177 A flow chart of the synthesis procedure of Lu-PSMA I&T.

[0032] Figure 3B is in one embodiment 177Flow chart of the synthesis procedure of Lu-PSMA I&T.

[0033] Figure 4 Figure depicting an example product vial. The drug product is delivered in a Type 1 glass sterile and pyrogen-free glass vial 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 includes lead shielding and the outer packaging meets Class A requirements (IAEA standards).

[0034] Figure 5 Shows the 177 radiochemical purity of Lu-PSMA I&T measured by HPLC at different time points.

[0035] Figure 6A and 6B Shows the HPLC radiochromatograms of high-radioactivity concentration formulations containing 42.5 mg / ml ascorbic acid with a pH of 7 ± 0.1 at 0 hours and 71 hours after EOS, as detailed in Example 3.

[0036] Figure 7A and 7B Shows the HPLC radiochromatograms of high-radioactivity concentration formulations containing 42.4 mg / ml ascorbic acid with a pH of 4.5 ± 0.1 at 0 hours and 71 hours after EOS, as detailed in Example 3.

[0037] Figure 8A and 8B Shows the HPLC radiochromatograms of high-radioactivity concentration formulations containing 42.5 mg / ml ascorbic acid with a pH of 3.5 ± 0.1 at 0 hours and 90 hours after EOS, as detailed in Example 3.

[0038] Figure 9A and 9B Shows the HPLC radiochromatograms of low-radioactivity concentration formulations containing 21 mg / ml ascorbic acid with a pH of 4.5 ± 0.1 at 0 hours and 92 hours after EOS, as detailed in Example 3.

[0039] Figure 10A and 10B Shows the HPLC radiochromatograms of low-radioactivity concentration formulations containing 31 mg / ml ascorbic acid with a pH of 5 ± 0.1 at 0 hours and 71 hours after EOS, as detailed in Example 3.

[0040] Figure 11A and 11BShows the HPLC radiochromatograms of a low-radioactivity concentration formulation containing 31 mg / ml ascorbic acid with a pH of 4.5 ± 0.1 at 0 hours and 93 hours after EOS, as detailed in Example 3.

[0041] Figure 12A and 12B Shows a summary of the kinetics, effective half-life, and mean absorbed dose (expressed as the median) of an embodiment of the composition in normal organs and tumor lesions.

[0042] Figure 12C Shows a summary of the effective half-life of an embodiment of the composition in normal organs and tumor lesions.

[0043] Figure 12D Shows a summary of the mean absorbed dose (expressed as the median) of an embodiment of the composition in normal organs and tumor lesions.

[0044] Figure 13 Shows the disease state assessment and treatment decisions at baseline and during treatment. Detailed Description

[0045] It should be understood that, for simplicity and clarity of illustration, where appropriate, reference numerals have been repeated in different figures to indicate corresponding or similar elements. Additionally, numerous specific details have been set forth to provide a thorough understanding of the examples described herein. However, those skilled in the art will understand that the examples described herein may be practiced without these specific details. In other instances, methods, procedures, and components have not been described in detail so as not to obscure the relevant features being described. Furthermore, the description is not to be regarded as limiting the scope of the embodiments described herein. The figures are not necessarily drawn to scale, and the proportions of certain parts may be exaggerated to better illustrate the details and features of the present disclosure.

[0046] Disclosed herein is a small molecule inhibitor of PSMA that has the desired properties of large monoclonal antibodies while reducing negative impacts 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 from which the product is formulated immediately after synthesis is complete.

[0047] The headings included herein are for reference purposes only and are not intended to limit the present disclosure in any way.

[0048] Additional features and advantages of the present disclosure will be set forth in the following description and to some extent will be apparent from the description, or may be learned by practice of the principles disclosed herein. The features and advantages of the present disclosure may be realized and obtained by means of the instrumentalities and combinations particularly pointed out in the appended claims. These and other features of the present disclosure will become more fully apparent from the following description and the appended claims, or may be learned by practice of the principles set forth herein. All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0049] I. Definitions

[0050] Certain definitions applicable to the entire foregoing disclosure will now be presented. As used herein, the terms "comprising," "having," and "including" are used interchangeably in their open, non-limiting sense. The terms "a / an" and "the" are understood to cover both the plural and the singular. Thus, the term "a mixture thereof" also pertains to "mixtures thereof."

[0051] Generally, the ranges provided are meant to include every specific range and combination of sub-ranges within the given range. Thus, the range of 1 to 5 specifically includes 1, 2, 3, 4, and 5, as well as sub-ranges such as 2 to 5, 3 to 5, 2 to 3, 2 to 4, 1 to 4, etc. All ranges and values disclosed herein are inclusive and combinable. For example, any value or point falling within the ranges described herein can serve as the minimum or maximum for deriving sub-ranges and the like.

[0052] As used herein, "about" refers to a numerical value, including integers, fractions, percentages, etc., whether explicitly stated or not. The term "about" generally refers to a numerical range that would be considered equivalent to the recited value (e.g., having the same function or result), for example, ±0.5% - 1%, ±1% - 5%, or ±5% - 10% of the recited value.

[0053] As used herein, "PSMA" refers to prostate-specific membrane antigen, also known as folate hydrolase I or glutamate carboxypeptidase II, which is a type II transmembrane protein anchored 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 current diagnosis and treatment of metastatic prostate cancer.

[0054] As used herein, "lutetium-177" and "177 "Lu" can be used interchangeably. 177 Lu is a β- and γ-emitting radionuclide with a physical half-life of 6.7 days. Its maximum and average β-particle energies are 0.498 MeV and 0.133 MeV, respectively. 177 The maximum and average soft tissue penetration depths of Lu are 1.7 mm and 0.23 mm, respectively. It has two main γ-emission spectral lines: 113 keV (relative abundance 6%) and 208 keV (relative abundance 11%).

[0055] As used herein, " 177 Lu-PSMA-617" refers to a DOTA derivative of the Glu-urea-Lys motif developed by the German Cancer Research Center (DKFZ) in Heidelberg, Germany, for treating patients with metastatic prostate cancer.

[0056] As used herein, " 177 Lu]Lu-PSMA I&T" and " 177 Lu-PSMA I&T" refer to the 177 Lu-PSMA used herein for imaging and therapy (I&T), 177 the third-generation derivative of the Lu-PSMA compound. 177 The chemical name of Lu-PSMA I&T is (3S,7S,26R,29R,32R,37R)-29-benzyl-32-(4-hydroxy-3-iodobenzyl)-5,13,20,28,31,34-hexaoxo-37-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-heptaazatriacontane-1,3,7,26,37-pentaic acid; lutetium-177(III). 177 The chemical structure of Lu-PSMA I&T is provided in Figure 1B it.

[0057] 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 be reduced by one-half. The reduction in drug concentration reflects the excretion or elimination of the drug after absorption is complete and distribution has reached equilibrium or pseudo-equilibrium. The half-life of a drug in the blood can be determined from the pharmacokinetic profile of a blood concentration-time plot of the drug, typically after intravenous administration to a sample population. The half-life can also be determined using mathematical calculations well known in the art. In addition, 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 takes into account the contributions of other processes in addition to elimination, such as absorption, reuptake, or enterohepatic recirculation.

[0058] As used herein, "PRLT" refers to prostate radio-ligand therapy, and "RLT" refers to radio-ligand 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 for the purpose of delivering cytotoxic radiation to cancer cells.

[0059] As used herein, the term "CRPC" refers to castration-resistant prostate cancer. In one example, a patient with CRPC has a castrate serum testosterone <50 μg / l or 1.7 nmol / l and exhibits one of the following types of progression: biochemical progression or radiological progression, as defined below.

[0060] As used herein, the term "biochemical progression" refers to three consecutive rises in PSA one week apart, resulting in two rises of 50% above the nadir and PSA >2 μg / l.

[0061] As used herein, the term "RAC" refers to radioactivity concentration.

[0062] As used herein, the term "radiological progression" refers to the appearance of new lesions; two or more new bone lesions detected on a bone scan or soft tissue lesions detected using the Response Evaluation Criteria in Solid Tumors (RECIST).

[0063] As used herein, the terms "end of synthesis", "after compounding", and "end of compounding" are used interchangeably and mean the time when the preparation process of the composition has been completed. This can also include the time after quality control and release of the drug product by a qualified person.

[0064] As used herein, the terms "active agent" or "drug" refer to any chemical that elicits a biochemical response when administered to a human or an animal. A drug can act as a substrate or product of a biochemical reaction, or a drug can interact with a cellular receptor and cause a physiological response, or a drug can bind to a receptor and prevent the receptor from causing a physiological response.

[0065] The term "adverse event" (AE) is any adverse medical event in a subject who has received the investigational drug, which is not necessarily causally related to the treatment. An AE can be any adverse or unexpected sign (e.g., abnormal laboratory result), symptom, or disease that is temporally associated with the use of the drug, whether or not it is considered related to the drug. This includes any newly occurring event or a pre-existing condition that has increased in severity or frequency since the administration of the drug.

[0066] 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.

[0067] II. Introduction

[0068] The present disclosure relates to a radiopharmaceutical composition comprising 177 Lu-PSMA I&T. In some embodiments, the composition can be formulated as a radiopharmaceutical solution for injection. The present disclosure further relates to a high-energy, high-purity, and / or low-toxicity radiopharmaceutical composition comprising 177 Lu-PSMA I&T, the radiopharmaceutical composition being an anti-tumor drug for targeted radionuclide therapy.

[0069] The present disclosure also relates to a method for preparing the radiopharmaceutical composition. Methods for increasing the shelf life of radiopharmaceutical products are provided herein.

[0070] The present disclosure further relates to the properties of the radiopharmaceutical composition and methods of using the radiopharmaceutical composition.

[0071] 177 Synonyms of Lu-PSMA I&T are as follows: 177 Lu] lutetium-PSMA I&T, 177 Lu-ITG-PSMA-1, PSMA-TUM3, 177 Lu-DOTAGA-(I-y)fk(Sub-KuE) or 177Lu-(3S,7S)-29-Benzyl-32(3-iodo,4-hydroxy)-benzyl-5,12,20,28,31,34-hexaoxo-37-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-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·3H 2 O, with a relative molecular mass of 1498 g / mol.

[0072] Labeled substance 177 Lu-PSMA I&T can be labeled with a lutetium-177 (T 1 / 2 = 6.6 days) solution without adding a carrier. 177Lu-PSMA I&T is a short-lived radioactive labeled substance, and the product is dispensed immediately after synthesis is completed. Therefore, there are no specifications or batch analysis results for the labeled substance. Control of the labeled drug product is carried out.

[0073] Synthesized 177 Lu-PSMA I&T solution can be formulated in an injection-grade aqueous solution containing stabilizers such as ascorbic acid. The solution can be sterilized by sterile filtration through a 0.22 μm filter before being dispensed into multi-dose vials. The formulated solution can be administered within 72 hours after the synthesis is completed after quality control and release of the drug product by qualified personnel.

[0074] Ascorbic acid can be used to minimize radiolysis of the radioactive labeled preparation. In addition to ascorbic acid, a dosage formulation with a pH of 5 or below can render the labeled product stable against radiolysis and extend its shelf life. Therefore, on the other hand, the present disclosure further provides a dosage formulation containing ascorbic acid with a pH of 5 or below, which enhances the stability of the radiopharmaceutical composition against radiolysis, thereby improving the shelf life of the composition.

[0075] Stability-enhancing conditions can be applied as early as possible during the manufacturing process. For example, an ascorbic acid solution with a pH of 5 or below can be used instead of water in the purification step of labeled 177 Lu-PSMA I&T to minimize radiolysis damage.

[0076] Compared with monoclonal antibody therapy and other comparable third-line therapies, the composition can achieve low blood toxicity and renal toxicity when administered to a subject, thereby providing better effects and fewer adverse reactions.

[0077] The composition is an improved composition because its shelf life after formulation exceeds 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. Therefore, the improved formulation is suitable for administration for up to 24 hours or up to 72 hours longer than other compositions containing 177 Lu-PSMA I&T.

[0078] III. Radiopharmaceutical Composition

[0079] The disclosed radiopharmaceutical composition or formulation comprises 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.

[0080] 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.

[0081] In one embodiment, the pharmaceutical product or radiopharmaceutical composition (or formulation) can be a sterile filtered radiopharmaceutical solution containing an aqueous solution of ascorbic acid containing ethanol and a dose of 177 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 radioactivity for the intended use. Experiments with various doses of the formulation have shown that a 177 Lu-PSMA I&T formulation composition containing about 31 mg / ml of ascorbic acid with a pH of about 4.5 and a radioactivity concentration of about 640 MBq / ml or lower can provide sufficient radiochemical stability for four days. The sufficient radiochemical stability mentioned herein refers to a radiopharmaceutical composition in which the radiochemical purity of 177 Lu-PSMA I&T is at least 95%, 95.5% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater upon administration.

[0082] In one embodiment, the radiopharmaceutical composition is a sterile-filtered radiopharmaceutical solution containing an aqueous solution of ascorbic acid and ethanol with a microdose of 177 Lu-PSMA I&T. In another embodiment, the radiopharmaceutical composition is a sterile-filtered radiopharmaceutical solution containing an aqueous solution of ascorbic acid without ethanol with a microdose of 177 Lu-PSMA I&T. For example, the radiopharmaceutical composition can be a sterile-filtered radiopharmaceutical solution containing an aqueous solution of ascorbic acid and acetate buffer with a microdose of 177 Lu-PSMA I&T, where the buffer contains DTPA (e.g., contains ethanol or is completely ethanol-free). The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk product varies depending on the 177 starting radioactivity of the introduced

[0083] 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.

[0084] A pH of 5 or less can render the radiopharmaceutical composition stable against radiolysis and can extend its shelf life.

[0085] 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 radiolysis and can extend its shelf life. In yet another embodiment, compared to known 177 radiopharmaceutical compositions of

[0086] The pH of the radiopharmaceutical composition can be in the range of 3.0 to 5.0, 3.0 to 3.5, 3.0 to 3.05, 3.05 to 3.1, 3.0 to 3.1, 3.1 to 3.15, 3.1 to 3.2, 3.15 to 3.2, 3.2 to 3.25, 3.0 to 3.25, 3.2 to 3.3, 3.25 to 3.3, 3.3 to 3.35, 3.3 to 3.4, 3.35 to 3.4, 3.4 to 3.45, 3.4 to 3.5, 3.45 to 3.5, 3.25 to 3.5, 3.5 to 3.55, 3.5 to 3.6, 3.55 to 3.6, 3.6 to 3.65, 3.6 to 3.7, 3.65 to 3.7, 3.7 to 3.75, 3.5 to 3.75, 3.7 to 3.8, 3.75 to 3.8, 3.8 to 3.85, 3.8 to 3.9, 3.85 to 3.9, 3.9 to 3.95, 3.9 to 4.0, 3.95 to 4.0, 3.5 to 4.0, 3.75 to 4.0, 4.0 to 4.05, 4.0 to 4.1, 4.05 to 4.1, 4.1 to 4.15, 4.1 to 4.2, 4.15 to 4.2, 3.5 to 4.2, 4.2 to 4.25, 4.0 to 4.25, 4.2 to 4.3, 4.25 to 4.3, 4.3 to 4.35, 4.3 to 4.4, 4.35 to 4.4, 4.4 to 4.45, 4.4 to 4.5, 4.45 to 4.5, 4.25 to 4.5, 4.0 to 4.5, 4.5 to 4.55, 4.5 to 4.6, 4.55 to 4.6, 4.6 to 4.65, 4.6 to 4.7, 4.65 to 4.7, 4.7 to 4.75, 4.7 to 4.8, 4.75 to 4.8, 4.8 to 4.85, 4.8 to 4.9, 4.85 to 4.9, 4.9 to 4.95, 4.9 to 5.0, 4.95 to 5.0, 4.5 to 5.0 or 4.75 to 5.0. In some instances, the pH of the radiopharmaceutical composition can be adjusted to a final pH of 3.0, 3.5, 4.0, 4.5 or 5.0. In some embodiments, including the pH numbers and ranges listed above, the pH value includes ±0.05, ±0.10, ±0.15, ±0.20 or ±0.25.

[0087] In another embodiment, the 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%.

[0088] In another embodiment, the purity of the radiopharmaceutical composition or formulation is at least about 90%, at least about 95% or at least about 99%, as measured by HPLC, TLC or liquid chromatography. In another embodiment, 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%, as measured by HPLC, TLC or liquid chromatography. In some instances, the radiochemical purity of the radiopharmaceutical composition at the time of administration can be 95.0% or greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater or 99.5% or greater. Figure 5 Shows the radiochemical purity at different pH formulations.

[0089] In another embodiment, the 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.

[0090] In a specific embodiment, the purity of the radiopharmaceutical composition or formulation is at least about 99% as determined by HPLC, TLC or liquid chromatography at 0 hours after EOS. In another specific embodiment, the purity of the radiopharmaceutical composition or formulation is at least about 96.5% as determined by HPLC, TLC or liquid chromatography at 24 hours after EOS, at least about 93% as determined by HPLC, TLC or liquid chromatography at 46 hours after EOS, at least about 95% as determined by HPLC, TLC or liquid chromatography at 67 hours after EOS, at least about 96% as determined by HPLC, TLC or liquid chromatography at 92 hours after EOS.

[0091] In another embodiment, the radioactivity is measured in a dose calibrator. 177 The radioactivity of Lu-PSMA I&T is determined at the time of dispensing the dose.

[0092] In yet another embodiment, 177The radiochemical purity of Lu-PSMA I&T was determined by liquid chromatography and thin layer chromatography with radioactivity detection.

[0093] In one embodiment, the bacterial endotoxin content of each batch was determined using a PTS-tester (Ph Eur method D) before release, and sterility was determined according to the European Pharmacopoeia.

[0094] 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 a specific embodiment, the radiopharmaceutical composition or formulation is stored at a temperature of about 10°C, about +15°C, about +22°C, about +22.5°C, about +25°C or at room temperature.

[0095] Another aspect of the present disclosure provides a radioactive content of about 70% to 130%. The radioactive content of the radiopharmaceutical composition can be about 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%.

[0096] 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%.

[0097] 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 nodes, 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.

[0098] In some embodiments, the low radioactivity concentration (“low RAC”) of the radiopharmaceutical composition can be from about 579 MBq / ml to about 626 MBq / ml. For example, the radiopharmaceutical composition can have a low radioactivity in a 20 ml volume solution, and the low radioactivity can be about 11,580 MBq (313 mCi), about 11,770 MBq (318 mCi), or about 12,520 MBq (338 mCi). 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, or at least about 650 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, or from about 625 MBq / ml to about 650.

[0099] In additional embodiments, the high radioactivity concentration ("high RAC") of the radiopharmaceutical composition can be from about 1,270 MBq / ml to about 1,311 MBq / ml. For example, the radiopharmaceutical composition can have a high radioactivity in a 10 ml volume solution, and the high radioactivity can be about 12,780 MBq (345 mCi), about 12,810 MBq (346 mCi), or about 13,110 MBq (354 mCi). 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.

[0100] (i) 177 Lu-PSMA I&T

[0101] The total amount of 177 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.

[0102] In one embodiment, the mass of the radiopharmaceutical component ( 177 Lu-PSMA I&T) in the drug product is less than about 30 μg, less than about 25 μg, less than about 20 μg, less than about 15 μg, or less than about 10 μg per vial. In yet another embodiment, the mass of the radiopharmaceutical component ( 177 Lu-PSMA I&T) in 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, or about 30 μg of 177 Lu-PSMA I&T.

[0103] In some embodiments, the total amount of 177 Lu-PSMA I&T present in the radiopharmaceutical composition can be in the range of about 1.0 μg / ml to about 3 μg / ml, about 1 μg / ml to about 2 μg / ml, about 1.1 μg / ml to about 2 μg / ml, about 1.1 μg / ml to about 1.5 μg / ml, about 1.1 μg / ml to about 1.4 μg / ml, or about 1.1 μg / ml to about 1.3 μg / ml. In another embodiment, the total amount of 177 Lu-PSMA I&T in the radiopharmaceutical composition can be in the range of about 0.5 μg / ml to about 1.5 μg / ml. In various embodiments, the total amount of 177 Lu-PSMA I&T present in the radiopharmaceutical composition can be about 0.5 μg / ml, about 0.6 μg / ml, about 0.7 μg / ml, about 0.8 μg / ml, about 0.9 μg / ml, about 1.0 μg / ml, about 1.1 μg / ml, about 1.2 μg / ml, about 1.3 μg / ml, about 1.4 μg / ml, about 1.5 μg / ml, about 1.6 μg / ml, about 1.7 μg / ml, or about 1.8 μg / ml.

[0104] In some embodiments, the total amount of 177The total amount of Lu-PSMA I&T can range from about 3.0 μg / ml to about 9.0 μg / ml, from about 3.5 μg / ml to about 8.5 μg / ml, from about 4.0 μg / ml to about 8.0 μg / ml, from about 4.5 μg / ml to about 7.5 μg / ml, from about 5.0 μg / ml to about 7.0 μg / ml, or from about 5.5 μg / ml to about 6.5 μg / ml. In another embodiment, the 177 total amount of Lu-PSMA I&T in the radiopharmaceutical composition can range from about 0.5 μg / ml to about 1.5 μg / ml. In some embodiments, the 177 total amount of 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-PSMA I&T present in the radiopharmaceutical composition can be less than 4.0 μg / ml. In some embodiments, the 177 total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 3.0 μg / ml. In other embodiments, the total amount of 177Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 5.0 μg / ml. In some embodiments, the total amount of 177Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 3.0 μg / ml. In other embodiments, the total amount of 177Lu-PSMA I&T present in the radiopharmaceutical composition can be less than 6.0 μg / ml

[0105] In some embodiments, the 177 total amount of Lu-PSMA I&T in the radiopharmaceutical composition can range from about 9 μg / ml to 20 μg / ml, from 10 μg / ml to 20 μg / ml, from 11 μg / ml to 20 μg / ml, from 11 μg / ml to 15 μg / ml, from 11 μg / ml to 14 μg / ml, or from 11 μg / ml to 13 μg / ml. In another embodiment, the 177 total amount of Lu-PSMA I&T in the radiopharmaceutical composition can range from about 5 μg / ml to about 15 μg / ml. In various embodiments, the 177 total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can be about 5 μg / ml, 6 μg / ml, 7 μg / ml, 8 μg / ml, 9 μg / ml, 10 μg / ml, 11 μg / ml, 12 μg / ml, 13 μg / ml, 14 μg / ml, 15 μg / ml, 16 μg / ml, 17 μg / ml, or 18 μg / ml. The composition can have less than 12 μg / ml or less than 6 μg / ml of Lu-PSMA I&T.

[0106] The 177 radioactivity / volume of Lu-PSMA I&T in the composition can be adjusted according to the dose intensity. In one embodiment, the composition can include 0.5 GBq (13.5 mCi) of 177 Lu-PSMA I&T in 1 ml of solution. In other words, the composition can include 10 GBq (270 mCi) of 177 Lu-PSMA I&T in 20 ml of solution. In another embodiment, the composition can include 1 GBq (27 mCi) of 177 Lu-PSMA I&T in 1 ml of solution. In other words, the composition can include 10 GBq (270 mCi) of 177 Lu-PSMA I&T in 10 ml of solution.

[0107] In one embodiment, the 177 radioactivity concentration of 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-PSMA I&T in the radiopharmaceutical composition is about 5 mCi / ml to about 30 mCi / ml, about 10 mCi / ml to about 20 mCi / ml or about 13 mCi / ml to about 30 mCi / ml. In a specific embodiment, the 177 radioactivity concentration of 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.

[0108] In one embodiment, the 177 radioactivity of Lu-PSMA I&T in the 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 per vial. In another embodiment, the 177The radioactivity of Lu-PSMA I&T is about 10 mCi to about 750 mCi, about 200 mCi to about 600 mCi, about 300 mCi to about 400 mCi per vial. In one specific embodiment, in the radiopharmaceutical composition 177 the radioactivity of Lu-PSMA I&T is about 27 mCi, 150 mCi, about 160 mCi, about 170 mCi, about 180 mCi, about 190 mCi, about 200 mCi, about 250 mCi, about 270 mCi, about 300 mCi, about 313 mCi, about 318 mCi, about 338 mCi, about 345 mCi, about 346 mCi, about 354 mCi, about 360 mCi, about 370 mCi, about 380 mCi, about 390 mCi, about 400 mCi, about 450 mCi, about 500 mCi, about 550 mCi, about 600 mCi or about 700 mCi per vial.

[0109] 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.

[0110] (ii) Antioxidant

[0111] 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 and 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 per ml.

[0112] In one embodiment, the antioxidant can be ascorbic acid. Ascorbic acid can minimize or reduce the radiolysis of the radiolabeled composition.

[0113] In some embodiments, the ascorbic acid present in the radiopharmaceutical composition can be in the range of about 10 mg to about 90 mg, about 10 to about 80 mg, about 10 to about 70 mg, about 10 to about 60 mg, about 10 to about 50 mg, about 20 to about 50 mg, about 30 to about 50 mg, or about 35 to about 45 mg per ml. In another embodiment, the ascorbic acid in the radiopharmaceutical composition can be in the range of about 5 mg to about 50 mg per ml.

[0114] 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 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.

[0115] In yet another embodiment, the concentration of ascorbic acid in the radiopharmaceutical composition can be about 10 mg / ml to about 80 mg / ml, about 10 mg / ml to about 75 mg / ml, about 10 mg / ml to about 70 mg / ml, about 15 mg / ml to about 80 mg / ml, about 15 mg / ml to about 75 mg / ml, about 15 mg / ml to about 70 mg / ml, about 20 mg / ml to about 80 mg / ml, about 20 mg / ml to about 75 mg / ml, or about 20 mg / ml to about 70 mg / ml.

[0116] 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.

[0117] In at least one embodiment, the total amount of ascorbic acid in the radiopharmaceutical composition can be about 31 mg / ml. In a further embodiment, 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, or about 42.5 mg / ml.

[0118] (iii) Stabilizer

[0119] The stabilizer can be separate from the antioxidant. The total amount of stabilizer present in the radiopharmaceutical composition can and will vary. The stabilizer can further be used to limit or reduce radiolytic decomposition. The stabilizer can also act as a vehicle for the composition.

[0120] Stabilizers include but are not limited to ethanol, p-aminobenzoic acid (PABA), dihydroxybenzoic acid (gentisic acid compounds), gentisic acid, cysteine, selenomethionine, ascorbic acid / ascorbate sodium, methionine, or combinations thereof.

[0121] In some embodiments, the stabilizer is ethanol. Ethanol can be present in the pharmaceutical composition at about 0.01% (v / v) to about 10% (v / v), 0.01% (v / v) to 3% (v / v), about 0.5% (v / v) to 1% (v / v), about 1% (v / v) to 2% (v / v), about 2% (v / v) to about 3% (v / v), about 3% (v / v) to 4% (v / v), about 3.5% to 4.5% (v / v), about 4% 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 not be present in the pharmaceutical composition).

[0122] In one embodiment, the total amount of ethanol present in the radiopharmaceutical composition is from about 3% (v / v) to about 8% (v / v), or 2% (v / v) to about 4% (v / v), or about 7% (v / v) to about 8% (v / v). In various embodiments, the total amount of ethanol present in the radiopharmaceutical composition can be about 1% (v / v), about 2% (v / v), about 3% (v / v), about 3.5% (v / v), about 3.8% (v / v), about 4% (v / v), about 4.5% (v / v), about 5% (v / v), about 5.5% (v / v), about 6% (v / v), about 6.5% (v / v), about 7% (v / v), about 7.5% (v / v), about 8% (v / v), about 8.5% (v / v), about 9% (v / v), about 9.5% (v / v) or about 10% (v / v).

[0123] 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).

[0124] 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 120 mg per ml.

[0125] In some embodiments, the total amount of ethanol present in the radiopharmaceutical composition can be in the range of about 20 mg to about 35 mg per ml. In another embodiment, the total amount of ethanol in the radiopharmaceutical composition can be in the range of about 43 mg to about 63 mg per ml.

[0126] In some embodiments, the total amount of ethanol present in the radiopharmaceutical composition can be in the range of about 25 mg to 80 mg, about 30 to 40 mg, about 40 to 50 mg, about 50 to 60 mg, about 60 to 70 mg or about 70 to 80 mg. In another embodiment, the total amount of ethanol in the radiopharmaceutical composition can be in the range of about 30 mg to about 60 mg per ml.

[0127] In another embodiment, 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 yet another embodiment, the ratio of ethanol in the radiopharmaceutical composition can be about 350 mg per 10 ml.

[0128] 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.

[0129] (iv) Metal ion chelator (chelating agent)

[0130] In some embodiments, the present disclosure provides a radiopharmaceutical composition having a microdose of 177 Lu-PSMA I&T solution and at least one metal ion chelator. Suitable chelators can include ethylenediaminetetraacetic acid (EDTA) and its salts, N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid (NTA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid, 1,4,7,10-tetraaza-cyclododecane-N,N',N"-triacetic acid, 1,4,7-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)formic acid, triethylenetetramine-hexaacetic acid, and 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid. In one embodiment, the chelator can be the sodium salt of EDTA.

[0131] In some embodiments, the metal ion chelator can 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; diethylenetriaminepentaacetic acid (DTPA), ethylenedicysteine, bis(aminoethylthiol)formic acid, triethylenetetraminehexaacetic acid, and 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid. In one embodiment, the metal ion chelator can be disodium EDTA. In one embodiment, the metal ion chelator can be DTPA.

[0132] In one embodiment, the amount of chelator present in the radiopharmaceutical composition can range from about 5 μg to 500 μg. In some embodiments, the amount of metal ion chelator present in the radiopharmaceutical composition can range from about 5 μg to 50 μg.

[0133] 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 120 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.

[0134] 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 75 μg / ml, 10 μg / ml to about 25 μg / ml, about 25 μg / ml to about 50 μg / ml, about 50 μg / ml to about 75 μg / ml, or about 75 μg / ml to about 100 μg / ml. 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.

[0135] In another embodiment, the amount of the metal ion chelator in the radiopharmaceutical composition can be from about 0.001% to about 0.20% (w / w), about 0.20% to about 0.40% (w / w), about 0.40% to about 0.60% (w / w), about 0.60% to about 0.80% (w / w), or about 0.80% to about 1.00% (w / w) of such radiopharmaceutical composition. In some embodiments, the amount of the metal ion chelator present in the radiopharmaceutical composition can be about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, or 0.15% (w / w) of the total weight of the radiopharmaceutical composition.

[0136] For example, the amount of disodium EDTA, diethylenetriaminepentaacetic acid (DTPA) or a combination thereof in 1 ml of the composition can be about 10 μg to 15 μg, about 13 μg to 18 μg, about 15 μg to 20 μg, about 20 μg to 25 μg, about 25 μg to 50 μg, about 50 μg to 75 μg or about 75 μg to 150 μg. In some embodiments, the amount of disodium EDTA present can be about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10.5 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg, about 25 μg, about 26 μg, about 27 μg, about 28 μg, about 29 μg, about 30 μg, about 31 μg, about 32 μg, about 33 μg, about 34 μg, about 35 μg, about 36 μg, about 37 μg, about 38 μg, about 39 μg, about 40 μg, about 45 μg, or about 50 μg.

[0137] In at least one example, 1 ml of the composition includes 15.5 μg of disodium EDTA. In another example, 1 ml of the composition includes 21 μg of disodium EDTA.

[0138] (v) pH adjuster

[0139] Suitable pH adjusters include, but are not limited to, any of the following: hydrochloric acid, sodium hydroxide, sodium bicarbonate, or a combination thereof.

[0140] 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 be in the range of 0 mg / ml to about 2 mg / ml. In some embodiments, the amount of HCl can be in the range of 1.6 ml of 0.05M HCl to 2 ml of 0.04M HCl. The amount of HCl in the composition can be varied to adjust the final formulation pH. In various embodiments, the final formulation pH is in the range of pH 3.0 to 5.0. In at least one example, HCl is added to the composition until a final pH of 3.5 ± 0.1 to 4.5 ± 0.1 is reached.

[0141] In one example, the amount of sodium bicarbonate in the composition can be a sufficient amount to control the pH of the composition to between 5.5 and 7.0 prior to the addition of HCl.

[0142] In one example, the amount of NaOH in the composition can be a sufficient amount to control the pH of the composition to be between 5.5 and 7.0 prior to adding HCl.

[0143] (vi) Water

[0144] The composition may further comprise a sufficient amount of water to bring the solution for injection to a desired final volume. For example, water may be added such that the final volume is 1 ml, 10 ml, or 20 ml. The 10 ml or 20 ml solution may be stored in a vial and divided into smaller volumes for administration.

[0145] IV. Process for Preparing a Radiopharmaceutical Composition

[0146] 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 reaction vial at an elevated temperature. For example, the reactor may be heated at a set point of 110 °C, and the maximum temperature reached in the reaction solution is about 95 °C. The radiolabeled product is separated on a C18 cartridge and formulated into the final composition after elution into a bulk vial. The final product is dispensed in a Class A controlled environment.

[0147] 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 may vary, such as the order of preparing the various solutions.

[0148] In one embodiment, step 102 may include preparing four solutions for carrying out the synthesis.. The four solutions may include 0.04 M hydrochloric acid, 0.4 M sodium acetate, 20% (w / w) L-ascorbic acid, and an aqueous solution of PSMA I&T of about 460 μg / ml to about 500 μg / ml. The PSMA I&T precursor may be dissolved in sterile water for injection. For example, depending on the number of doses produced, 120 μg to 600 μg of the precursor may be used in the reaction. In at least one instance, 463 μl / ml of the PSMA I&T precursor may be used to produce the composition.

[0149] In one embodiment, step 104 may include preparing an ascorbic acid solution (dilution buffer). In some instances, the ascorbic acid solution may be a 50 mg / ml ascorbic acid solution. The solution pH may be adjusted to 4.5 ± 0.25. For example, a 50 mg / ml ascorbic acid solution is prepared and the pH of the solution is adjusted to 4.5 with 30% hydrochloric acid. In another instance, the ascorbic acid solution may include 33 mg / ml ascorbic acid / ascorbate sodium (pH is 4.25 ± 0.25) and 0.1 mg / ml DTPA.

[0150] In one embodiment, optional step 106 may include preparing a formulation solution / buffer. The formulation solution is prepared from an injectable solution containing ascorbic acid, absolute ethanol, and injectable water. In one example, the formulation solution is prepared by adding sufficient amounts of the following solutions to a bulk vial: a solution of approximately 50 mg / ml ascorbic acid at pH 4.5 (prepared in step 104), a 30% ethanol solution, and water. The formulation solution may include 31 mg / ml to 42.5 mg / ml ascorbic acid and 3.8% to 7.5% ethanol (v / v%). In some embodiments, the formulation buffer may be adjusted to enable the final composition to have an extended shelf life. In at least one example, the formulation solution contains 31 mg / ml ascorbic acid, 3.8% (v / v) ethanol, and has a pH of 4.5. The formulation buffer is prepared temporarily as part of the synthesis formulation, and a predetermined amount of the formulation buffer is added to the bulk vial as the synthesis formulation.

[0151] In one embodiment, step 108 may include preparing a reaction solution. The reaction solution may include sodium acetate, HCl, and L-ascorbic acid. Alternatively, the reaction solution may include sodium ascorbate. The reaction solution may be prepared in a reactor using the solution prepared in step 102. In one example, the reaction solution may include 4 ml of 0.4 M sodium acetate, a volume of approximately 463 μg / ml of the PSMA I&T solution, and 150 μl of 20% (w / w) L-ascorbic acid. In another example, the reaction solution may include 0.33 M sodium ascorbate (reaction buffer) and a reaction buffer containing 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 be in the range of 3.75 mg / ml to 5.00 mg / ml.

[0152] In one embodiment, step 110 may include preparing 177 Lu. In some embodiments, 177 Lu may be provided in HCl. 177 Lu]LuCl 3 may be provided in 0.04 M or 0.05 M HCl. For example, 40 - 44 GBq / ml of 177 Lu may be provided in 0.04 M HCl. In another example, less than 61 GBq of 177 Lu may be provided in 0.05 M HCl. The 177 Lu]LuCl 3 of 0.04 M or 0.05 M hydrochloric acid may be transferred to the reactor and 177 Lu]LuCl 3The vial can be rinsed with an additional required volume of 0.04 M hydrochloric acid (prepared in step 102) and then also transferred to the reactor.

[0153] The reaction volume can be in the range of 6 ml to 8 ml. The volume can depend on the amount of precursor used.

[0154] In one embodiment, step 112 can include radiolabeling PSMA-I&T with 177 Lu. The reaction mixture can be heated to at most about 75 °C, at most about 80 °C, at most about 85 °C, at most about 90 °C, or at most about 95 °C. In one instance, the set point for heating is 110 °C and the highest temperature actually reached is about 95 °C. The reaction volume can be heated for at most 5 minutes, at most 10 minutes, at most 15 minutes, or at most 20 minutes. In at least one instance, the reaction mixture is heated at a set point of 110 °C for 15 minutes. In at least one additional instance, the reaction mixture is heated at a set point of 75 °C for 10 minutes.

[0155] In one embodiment, optional step 114 can include purifying the reaction mixture. For example, the solution can be run through a cartridge / cartridge containing a hydrophobic reversed-phase silica-based bonded phase. Sep-Pak C18 can be used to purify the composition. In at least one instance, the reaction mixture can pass through a C18 Sep Pak cartridge and the cartridge can be rinsed with water. 177 The Lu-PSMA I&T product remains in the cartridge. In some embodiments, the reaction mixture can not be purified.

[0156] In one embodiment, step 116 can include eluting or diluting the final product. In one instance, 177 Lu-PSMA I&T is diluted to the desired radioactivity concentration with the dilution buffer prepared in step 104. A 1:1 ratio of 1.5 ml of ethanol-water can be used to elute the composition. Then, the cartridge can be rinsed with 8.5 ml of 50 mg / ml ascorbic acid. Then, the formulation solution is added to form the final composition. In at least one instance, 177 Lu-PSMA I&T is eluted from the C18 cartridge with 1.5 ml of 50% (v / v) ethanol, followed by elution with 8.5 ml of 50 mg / ml pH 4.5 ascorbic acid solution (prepared in step 104) into a bulk vial, where it is diluted with the formulation solution / buffer (prepared in step 106, already in the bulk vial). The pH of the resulting solution can be 3.5 to 4.5. In some embodiments, the pH can be adjusted. In one instance, the 50 mg / ml ascorbic acid solution is adjusted to a pH of 3.5 to 4.5. In other instances, the pH is adjusted to 5.0 or lower.

[0157] It is speculated that during this process, stability-enhancing conditions should preferably be applied as early as possible, such as an ascorbic acid solution with a pH of about 5 or lower. 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.

[0158] 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 into single-dose vials through a 0.22 μm sterile filter, and the vials contain an appropriate volume and radioactivity with reference to a specified calibration time. For example, the final composition can be dispensed into doses with an appropriate volume and radioactivity at the time of calibration in an A-level environment through a 0.22 μm sterile filter.

[0159] 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 depends on the 177 starting radioactivity of the Lu introduced and varies. This solution meets the requirements of the European Pharmacopoeia for sterility and bacterial endotoxins, confirming an acceptable manufacturing process from a microbiological perspective.

[0160] Figure 3A An example of a process 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.

[0161] Methods for increasing the shelf life of radiopharmaceutical products containing 177 Lu-PSMA I&T are provided herein. The methods can include adjusting the pH of the composition to 3.5, 3.75, 4.0, 4.25, or 4.5, adjusting the amount of ascorbic acid in the composition, and / or adjusting the radioactivity, so as to increase the shelf life of the composition by 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.25, 2.5, 2.75, or 3 days. For example, the shelf life of the radiopharmaceutical composition can be 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 days. In 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, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 days.

[0162] The target drug formulation according to the present disclosure is shown in Table 1A.

[0163] Table 1A: Target Drug Formulation

[0164]

[0165] V. Stability

[0166] In HPLC analysis, a stable non-radioactive labeled standard can be used to identify the product peak. The formulation solution can be prepared from an injectable solution containing ascorbic acid, a chelating agent (EDTA), absolute ethanol, and water for injection. The formulation matrix can be prepared temporarily as part of the synthetic formulation, and a predetermined amount of the formulation buffer is added to the bulk vial as the synthetic formulation.

[0167] Without being limited to any one theory, the radioactivity, the amount of ascorbic acid, and / or the pH of the solution may all affect the shelf life of the composition. Surprisingly, compared with compositions having a pH of 5 or higher, a high RAC, and / or a combination thereof, a lower concentration of ascorbic acid in the composition (e.g., 31 mg / ml versus 42.5 mg / ml), a pH of 4.5 or lower, a low RAC, and / or a combination thereof can cause the composition to have higher stability and a longer shelf life. For example, this can be seen from Figure 5 this. The shelf life can generally be determined based on the radiochemical purity of the composition after formulation or at the end of synthesis (EOS). The radiochemical purity can be confirmed by HPLC.

[0168] In one or more embodiments, 177 The Lu-PSMA I&T formulation composition containing 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 lower can provide sufficient stability for four days.

[0169] The radiochemical purity of a composition having a low radioactivity concentration (e.g., 588.5 MBq / ml), pH 4.5, and 31 mg / ml ascorbic acid is 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. The radiochemical purity of a composition having a low radioactivity concentration (e.g., 626 MBq / ml), pH 5.0, and 31 mg / ml ascorbic acid is 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. The radiochemical purity of a composition having a low radioactivity concentration (e.g., 579 MBq / ml), pH 4.5, and 21 mg / ml ascorbic acid is 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. The radiochemical purity of a composition having a high radioactivity concentration (e.g., 1,278 MBq / ml), pH 4.5, and 42.5 mg / ml ascorbic acid is 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.

[0170] The radiopharmaceutical composition can be stored at a temperature within 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.

[0171] 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.

[0172] In one embodiment, the radiopharmaceutical composition is stored at about 22.5°C. In another embodiment, the radiopharmaceutical composition is stored at room temperature.

[0173] VI. Specific Radiopharmaceutical Compositions

[0174] In some embodiments, the pharmaceutical product is a sterile-filtered radiopharmaceutical solution containing a microdose of 177 aqueous solution of ascorbic acid at 42.5 mg / ml containing 7.5% (v / v) or 59 mg / ml ethanol of Lu-PSMA I&T solution. The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk product varies depending on the starting radioactivity introduced. The composition of the final product is described in Table 1B ( 177 Lu-PSMA I&T Composition 1):

[0175] Table 1B. Composition of the Final Product a ( 177 Lu-PSMA I&T Composition 1)

[0176] Component Quantity Function <![CDATA 177 Lu-PSMAI&T]]> <![CDATA[Appropriate amount b > API Ethanol 7.5%(v / v) Vehicle / stabilizer (radiolysis) Ascorbic acid 42.5mg Stabilizer (radiolysis) Disodium EDTA 21μg Metal ion chelator Sodium bicarbonate* Appropriate amount pH regulator Sodium hydroxide* Appropriate amount pH regulator WFI (Water for Injection) Up to 1ml Vehicle

[0177] a The maximum volume per vial is 10 ml

[0178] b Sufficient radioactivity for the intended use

[0179] In yet another embodiment, the pharmaceutical product is a sterile-filtered radiopharmaceutical solution containing a microdose of 177 aqueous solution of ascorbic acid at 31 mg / ml containing 3.8% (v / v) or 30 mg / ml ethanol of Lu-PSMA I&T solution, with a pH of approximately 4.5. The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk product varies depending on the starting radioactivity introduced. The composition is described in Table 1C below ( 177 Lu-PSMA I&T Composition 2):

[0180] Table 1C. Composition of the Final Product * ( 177 Lu-PSMA I&T Composition 3)

[0181]

[0182] * The maximum volume per vial is 20 ml

[0183] ** Sufficient radioactivity for the intended use

[0184] VII. Preparation of the Pharmaceutical Product

[0185] The pharmaceutical product can be delivered in a Type 1 glass sterile and pyrogen-free vial 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 includes lead shielding and the outer packaging meets Class A requirements (IAEA standards). Figure 4 Figure depicting the product vial that can be used in this example.

[0186] In one embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 10 ml to about 20 ml, about 20 ml to about 30 ml, about 30 ml to about 40 ml, about 40 ml to about 50 ml, about 50 ml to about 60 ml, about 60 ml to about 70 ml, about 70 ml to about 80 ml, about 80 ml to about 90 ml, or about 90 ml to about 100 ml. In a specific embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 1 ml, about 5 ml, about 7 ml, about 8 ml, about 9 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, or about 30 ml.

[0187] In a specific embodiment, the final volume in the dose vial is adjusted to 7 ml to 10 ml or 15 ml to 20 ml in order to provide the required radioactivity at the infusion date and time.

[0188] In another embodiment, 177 Lu-PSMA I&T injection is supplied in single-dose vials or multi-dose vials. For example, a radiopharmaceutical kit is provided herein, which includes vials 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.

[0189] 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.

[0190] In some embodiments, the radiochemical purity of the radiopharmaceutical composition should be ≥95% so that 177 the Lu-PSMA I&T is sufficient to be administered to a patient. The combined radiochemical impurities in the composition can be ≤5%. In various embodiments, the radiopharmaceutical composition can have a certain chemical purity such that the Lu-PSMA I&T is present in the composition at a concentration of less than about 12 μg / ml, less than about 11 μg / ml, less than about 10 μg / ml, less than about 9 μg / ml, less than about 8 μg / ml, less than about 7 μg / ml, less than about 6 μg / ml, less than about 5 μg / ml, less than about 4 μg / ml, less than about 3 μg / ml, less than about 2 μg / ml, or less than about 1 μg / ml.

[0191] In some embodiments, the radiopharmaceutical composition can have a certain amount of colloid with a radioactivity less than about 5%, a radioactivity less than about 4.5%, a radioactivity less than about 4%, a radioactivity less than about 3.5%, a radioactivity less than about 3%, a radioactivity less than about 2.5%, a radioactivity less than about 2%, a radioactivity less than about 1.5%, a radioactivity less than about 1%, a radioactivity less than about 0.5%, a radioactivity less than about 0.3%, a radioactivity less than about 0.2%, or a radioactivity less than about 0.1% 177 Lu. In some embodiments, the radiopharmaceutical composition administered to a 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% colloid 177 Lu.

[0192] 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 of bacterial endotoxin or no bacterial endotoxin.

[0193] 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 other embodiments, the radiochemical purity of the composition is suitable for injection and suitable for administration to a patient in need more than 72 hours, more than 96 hours, 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 greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater. For example, the radiochemical purity of the radiopharmaceutical composition can exceed 95% at 46 to 48 hours after compounding, the radiochemical purity of the radiopharmaceutical composition can exceed 96% at 46 to 48 hours after compounding, the radiochemical purity of the radiopharmaceutical composition can exceed 97% at 46 to 48 hours after compounding, the radiochemical purity of the radiopharmaceutical composition can exceed 95% at 69 to 72 hours after compounding, the radiochemical purity of the radiopharmaceutical composition can exceed 96% at 69 to 72 hours after compounding, the radiochemical purity of the radiopharmaceutical composition can exceed 97% at 69 to 72 hours after compounding, the radiochemical purity of the radiopharmaceutical composition can exceed 95% at 90 to 93 hours after compounding, the radiochemical purity of the radiopharmaceutical composition can exceed 96% at 90 to 93 hours after compounding, and / or the radiochemical purity of the radiopharmaceutical composition can exceed 97% at 90 to 93 hours after compounding.

[0194] In some instances, the radiochemical purity of the composition can be in the range of about 99.0% to about 99.4% at 0 hours after EOS. In various embodiments, the radiochemical purity of the composition can be in the range of about 96.5% to about 98.7% at 19 - 25 hours after EOS. In other instances, the radiochemical purity of the composition can be in the range of about 93.3% to about 98.0% at 44 - 47 hours after EOS. In additional instances, the radiochemical purity of the composition can be in the range of about 91.2% to about 97.4% at 69 - 71 hours after EOS. In some instances, the radiochemical purity of the composition can be in the range of about 94.5% to about 97.0% at 90 - 93 hours after EOS.

[0195] In another embodiment, 177The Lu-PSMA I&T injection is supplied in single-dose vials or multi-dose vials.

[0196] In yet another embodiment, a patient in need of radioligand therapy during treatment receives a single intravenous radioactive dose at the start of a treatment cycle. The treatment cycle is from 1 week 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.

[0197] In one embodiment, the volume of the patient dose is calculated based on the radioactive dose to be administered.

[0198] In another embodiment, 177 The Lu-PSMA I&T is slowly injected via the intravenous (IV) route over approximately 10 minutes and is subsequently infused with 500 - 1000 mL of Ringer's solution or saline solution. When the total blood volume exceeds 5,000 mL, an additional injection of 7 mL is insignificant. The dose is administered once every 6 weeks for 4 cycles.

[0199] In yet another embodiment, a patient in need of radioligand therapy during treatment receives a single intravenous radioactive dose at the start of a treatment cycle. The treatment cycle is from 1 week 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.

[0200] In one embodiment, the volume of the patient dose is calculated based on the radioactive dose to be administered.

[0201] VIII. Method for diagnosing or treating prostate cancer

[0202] Methods for diagnosing or treating tumors in patients in need are provided herein. The methods may include administering a radiopharmaceutical composition by injection, the radiopharmaceutical composition comprising a solution containing 177Lu-PSMA I&T and ascorbic acid with a pH of 3.5 to 4.5. After administration, the radiopharmaceutical composition may have Figure 12A - 12D one or more of the kinetic properties shown in

[0203] Figure 12AShows the kinetics of the radiopharmaceutical composition in normal organs (including the whole body, kidneys, and parotid glands) over 60 hours. In one embodiment, within less than 20 hours after injection, the activity of the radiopharmaceutical composition can be about 30% IA to 100% IA, 30% IA to 40% IA, 40% IA to 50% IA, 50% IA to 60%, 60% IA to 70% IA, 70% IA to 80% IA, 80% IA to 90% IA, or 90% IA to 100% IA. IA In certain embodiments, 20 hours after injection, the activity of the radiopharmaceutical composition in the whole body can be at least 20% IA to 30% IA, 20% IA to 21% IA, 21% IA to 22% IA, 22% IA to 23% IA, 23% IA to 24% IA, 24% IA to 25% IA, 25% IA to 26% IA, 26% IA to 27% IA, 27% IA to 28% IA, 28% IA to 29% IA, or 29% IA to 30% IA. In certain embodiments, 40 hours after injection, the activity of the radiopharmaceutical composition in the whole body can be at least 10% IA to 20% IA, 11% IA to 11% IA, 11% IA to 12% IA, 12% IA to 13% IA, 13% IA to 14% IA, 14% IA to 15% IA, 15% IA to 16% IA, 16% IA to 17% IA, 17% IA to 18% IA, 18% IA to 19% IA, 11% IA to 12% IA. In certain embodiments, 60 hours after injection, the activity of the radiopharmaceutical composition in the whole body can be at least 5% IA to 10% IA, 5% IA to 6% IA, 6% IA to 7% IA, 7% IA to 8% IA, 8% IA to 9% IA, or 9% IA to 10% IA.

[0204] In one embodiment, within less than 20 hours after injection, the activity of the radiopharmaceutical composition in the kidneys can be at least 8% IA to 10% IA, 8% IA to 8.5% IA, 8.5% IA to 9% IA, 9% IA to 9.5% IA, or 9.5% IA to 10% IA. In some embodiments, 20 hours after injection, the activity of the radiopharmaceutical composition in the kidneys can be at least 3% IA to 8% IA, 3% IA to 4% IA, 4% IA to 5% IA, 5% IA to 6% IA, 6% IA to 7% IA, or 7% IA to 8% IA. In some embodiments, 40 hours after injection, the activity of the radiopharmaceutical composition in the kidneys can be at least 1% IA to 5% IA, 1% IA to 2% IA, 2% IA to 3% IA, 3% IA to 4% IA, or 4% IA to 5% IA. In some embodiments, 60 hours after injection, the activity of the radiopharmaceutical composition in the kidneys can be at least 1% IA to 5% IA, 1% IA to 2% IA, 2% IA to 3% IA, 3% IA to 4% IA, or 4% IA to 5% IA.

[0205] In another embodiment, less than 20 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland can be at least 0.7% IA to 1.0% IA, 0.7% IA to 0.8% IA, 0.8% IA to 0.9% IA, or 0.9% IA to 1.0% IA. In some embodiments, 20 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland can be at least 0.3% IA to 0.8% IA, 0.3% IA to 0.4% IA, 0.4% IA to 0.5% IA, 0.5% IA to 0.6% IA, 0.6% IA to 0.7% IA, or 0.7% IA to 0.8% IA. In some embodiments, 40 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.2% IA to 0.5% IA, 0.2% IA to 0.3% IA, 0.3% IA to 0.4% IA, or 0.4% IA to 0.5% IA. In some embodiments, 60 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.1% IA to 0.3% IA, 0.1% IA to 0.15% IA, 0.15% IA to 0.2% IA, 0.2% IA to 0.25% IA, 0.25% IA to 0.3% IA.

[0206] Figure 12BShows the kinetics of the radiopharmaceutical composition in tumor lesions (including lymph node lesions and bone lesions) within 60 hours. In additional embodiments, within less than 20 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesions of a patient can be at least 0.2% IA to 0.5% IA, 0.2% IA to 0.3% IA, 0.3% IA to 0.4% IA, or 0.4% IA to 0.5% IA. In some embodiments, at 20 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesions can be at least 0.1% IA to 0.3% IA, 0.1% IA to 0.15% IA, 0.15% IA to 0.2% IA, 0.2% IA to 0.25% IA, 0.25% IA to 0.3% IA. In some embodiments, at 40 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesions is at least 0.08% IA to 0.2% IA, 0.08% IA to 0.1% IA, 0.1% IA to 0.12% IA, 0.12% IA to 0.14% IA, 0.14% IA to 0.16% IA, 0.16% IA to 0.18% IA, 0.18% IA to 0.2% IA. In some embodiments, at 60 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesions is at least 0.05% IA to 0.1% IA, 0.06% IA to 0.06% IA, 0.06% IA to 0.07% IA, 0.07% IA to 0.08% IA, 0.08% IA to 0.09% IA, or 0.09% IA to 0.1% IA.

[0207] In yet another embodiment, less than 20 hours after injection, the activity of the radiopharmaceutical composition in the bone lesion of the patient can be at least 0.1% IA to 0.4% IA, 0.1% IA to 0.2% IA, 0.2% IA to 0.3% IA, or 0.3% IA to 0.4% IA. In some embodiments, 20 hours after injection, the activity of the radiopharmaceutical composition in the bone lesion can be at least 0.1% IA to 0.2% IA, 0.1% IA to 0.12% IA, 0.12% IA to 0.14% IA, 0.14% IA to 0.16% IA, 0.16% IA to 0.18% IA, 0.18% IA to 0.2% IA. In some embodiments, 40 hours after injection, the activity of the radiopharmaceutical composition in the bone lesion can be at least 0.05% IA to 0.1% IA, 0.06% IA to 0.06% IA, 0.06% IA to 0.07% IA, 0.07% IA to 0.08% IA, 0.08% IA to 0.09% IA, or 0.09% IA to 0.1% IA. In some embodiments, 60 hours after injection, the activity of the radiopharmaceutical composition in the bone lesion is at least 0.02% IA to 0.05% IA, 0.02% IA to 0.03% IA, 0.03% IA to 0.04% IA, or 0.04% IA to 0.05% IA.

[0208] Figure 12C The effective half-life of the radiopharmaceutical composition in both normal organs and tumor lesions is shown. In one embodiment, the effective half-life of the radiopharmaceutical composition in the patient's whole body can be about 30 hours to 40 hours, 30 hours to 32 hours, 32 hours to 34 hours, 34 hours to 36 hours, 36 hours to 38 hours, or 38 hours to 40 hours. In some embodiments, the effective half-life of the radiopharmaceutical composition in the patient's kidney can be about 25 hours to 35 hours, 25 hours to 27 hours, 27 hours to 29 hours, 29 hours to 31 hours, 31 hours to 33 hours, or 33 hours to 35 hours. In some embodiments, the effective half-life of the radiopharmaceutical composition in the patient's parotid gland can be about 20 hours to 30 hours, 20 hours to 22 hours, 22 hours to 24 hours, 24 hours to 26 hours, 26 hours to 28 hours, or 28 hours to 30 hours. In some embodiments, the effective half-life of the radiopharmaceutical composition in the patient's bone lesion can be about 45 hours to 55 hours, 45 hours to 47 hours, 47 hours to 49 hours, 49 hours to 51 hours, 51 hours to 53 hours, or 53 hours to 55 hours. In some embodiments, the effective half-life of the radiopharmaceutical composition in the patient's lymph node lesion can be about 35 hours to 45 hours, 35 hours to 37 hours, 37 hours to 39 hours, 39 hours to 41 hours, 41 hours to 43 hours, or 43 hours to 45 hours.

[0209] Figure 12D Shows the average absorbed dose of the radiopharmaceutical composition in normal organs and tumor lesions. In one embodiment, the average absorbed dose of the radiopharmaceutical in the whole body of the patient is about 0.01 mGy / MBq to 0.5 mGy / MBq, 0.01 mGy / MBq to 0.05 mGy / MBq, 0.05 mGy / MBq to 0.1 mGy / MBq, 0.1 mGy / MBq to 0.2 mGy / MBq, 0.2 mGy / MBq to 0.3 mGy / MBq, 0.3 mGy / MBq to 0.4 mGy / MBq or 0.4 mGy / MBq to 0.5 mGy / MBq. In one embodiment, the average absorbed dose of the radiopharmaceutical composition in the kidneys of the patient can be about 0.5 mGy / MBq to 1.0 mGy / MBq, 0.5 mGy / MBq to 0.6 mGy / MBq, 0.6 mGy / MBq to 0.7 mGy / MBq, 0.7 mGy / MBq to 0.8 mGy / MBq, 0.8 mGy / MBq to 0.9 mGy / MBq, 0.9 mGy / MBq to 1.0 mGy / MBq. In some embodiments, the average absorbed dose of the radiopharmaceutical composition in the parotid glands of the patient can be about 1 mGy / MBq to 1.5 mGy / MBq, 1.0 mGy / MBq to 1.1 mGy / MBq, 1.1 mGy / MBq to 1.2 mGy / MBq, 1.2 mGy / MBq to 1.3 mGy / MBq, 1.3 mGy / MBq to 1.4 mGy / MBq or 1.4 mGy / MBq to 1.5 mGy / MBq. In some embodiments, the average absorbed dose of the radiopharmaceutical composition in the bone lesions of the patient can be about 2.5 mGy / MBq to 3.5 mGy / MBq, 2.5 mGy / MBq to 2.7 mGy / MBq, 2.7 mGy / MBq to 2.9 mGy / MBq, 2.9 mGy / MBq to 3.1 mGy / MBq, 3.1 mGy / MBq to 3.3 mGy / MBq or 3.3 mGy / MBq to 3.5 mGy / MBq. In some embodiments, the average absorbed dose of the radiopharmaceutical composition in the lymph node lesions of the patient can be about 3.5 mGy / MBq to 4.5 mGy / MBq, 3.5 mGy / MBq to 3.7 mGy / MBq, 3.7 mGy / MBq to 3.9 mGy / MBq, 3.9 mGy / MBq to 4.1 mGy / MBq, 4.1 mGy / MBq to 4.3 mGy / MBq or 4.3 mGy / MBq to 4.5 mGy / MBq.

[0210] Treatment aimed at eradicating the primary tumor (usually by surgery or radiation) is not successful in approximately 30% of men, who develop recurrent disease, typically first presenting as an elevation in plasma prostate-specific antigen (PSA), followed by metastases to distant sites (Stephenson et al., Journal of Clinical Oncology, 2005; 23:8253-61). Given that the proliferation and survival of prostate cancer cells depend on the androgen receptor (AR), the standard treatment for patients with recurrent disease is androgen deprivation therapy (ADT) with gonadotropin-releasing hormone analogs (GnRHa) with or without antiandrogens.

[0211] The outcomes of treatment with ADT are generally predictable: a decline in PSA, followed by tumor regression, a period of stability during which the tumor does not proliferate, and PSA stability, followed by an increase in PSA and regrowth, which is defined as castration-resistant disease. Almost all men with progressive prostate cancer will eventually develop castration-resistant disease. The development of prostate cancer in the setting of castrate testosterone levels indicates a transition to a lethal disease stage. Docetaxel combined with prednisone, cabazitaxel combined with prednisone, enzalutamide, and abiraterone combined with prednisone have become the standard of care based on National Comprehensive Cancer Network (NCCN) guidelines for men with metastatic castration-resistant prostate cancer (mCRPC) (Mohler et al., NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, (Version 2.2019). JNCCN.org; 17(5), 479-505).

[0212] Abiraterone, enzalutamide, and docetaxel combined with prednisone are all suitable for patients with mCRPC as first-line treatment, while cabazitaxel combined with prednisone is only suitable for mCRPC patients who have progressed after docetaxel treatment. George et al. reported the ranking of treatments for mCRPC patients in the real clinical setting in the United States (George et al., 2020). In the United States, a higher proportion of patients received androgen receptor axis-targeted therapies (ARATs, namely abiraterone and enzalutamide) as first-line treatment compared with docetaxel; similarly, a higher proportion of mCRPC patients received alternative ARATs as second-line treatment (enzalutamide after abiraterone, or vice versa).

[0213] Targeted radionuclide therapy has emerged as an attractive option for many different cancers, including lymphoma, melanoma, and neuroendocrine tumors (Kraeber-Bodéré et al., Semin Oncol, 2014, 41, 613-22; Mier et al., J Nucl Med, 2014, 55, 9-14; Bodei et al., Eur J Nucl Med Mol Imaging, 2015, 42, 5-19). Prostate-specific membrane antigen (PSMA) is a key target for radionuclide diagnosis and therapy of PC. PSMA is normally expressed in prostate cells as well as in some extraprostatic tissues, but its overexpression in prostate cancer cells makes it an attractive target for therapeutic agents and has the potential to limit systemic toxicity (Silver et al., Clin Cancer Res. January 1997; 3(1): 81-5. PMID: 9815541). Preliminary clinical experience with PSMA-based radionuclide therapy of PC using 131 I-labeled PSMA has shown that in all prostate cancer patients treated, PSA decreased by >50% in 60% of patients, with mild hematotoxicity (Zechmann et al., Eur J Nucl Med Mol Imaging 2014, 41, 1280-92).

[0214] IX. Administration

[0215] Also provided herein are methods of administering a radiopharmaceutical composition. The radiopharmaceutical composition can be administered by injection to a human patient in need thereof.

[0216] The administration can have approximately six main aspects.

[0217] First, cooling the salivary glands. For 30 minutes before and up to 4 hours after administration of 177 Lu-PSMA I&T, the patient receives ice packs on the parotid and submandibular glands to reduce the risk of radiation damage to the salivary glands. There is no scientific evidence indicating whether cooling the salivary glands is an effective therapy for protecting these glands from radiation; however, it is tolerable and harmless to the patient.

[0218] Second, use a catheter in incontinent patients within the first 48 hours to avoid any contamination.

[0219] Third, 177Lu-PSMA I&T. In cases of impaired renal function (e.g., creatinine within 1.0 - 1.5 UNL), the amount of activity may be reduced to 4.0 - 5.0 GBq. Based on preliminary results, an activity of 7.4 GBq can be administered safely; however, more data are needed to increase the amount of activity.

[0220] Fourth, inject the activity intravenously in the form of a slow bolus (within about 1 - 15 minutes), followed by an injection of 500 - 1000 ml of Ringer's solution or NaCl solution. The patient should be encouraged to urinate as frequently as possible and drink approximately 2 liters of water per day. In patients with dilated non-obstructive nephropathy, the administration of a diuretic may be meaningful.

[0221] Fifth, perform 3 - 5 RLT cycles on average every 5 - 8 weeks, with up to 11 cycles reported in the experience. In cases where PSA continues to increase, after the first two cycles, accompanied by the deterioration of the general condition, the indication for further RLT should be re-evaluated. If PSA decreases to <1.0 μg / l during the treatment cycle, when the SPECT study information after injection is insufficient, PSMA imaging can evaluate the presence of small PSMA-positive metastases after RLT is completed. If the platelets or white blood cells decrease significantly, the time interval between two cycles can be extended.

[0222] Sixth, perform at least one whole-body scan (preferably using SPECT( / CT)) 24 - 48 hours after injection. In patients with diffuse bone and bone marrow metastases and in patients with brain metastases, it is recommended to use corticosteroid therapy (e.g., prednisone 20 mg / day) simultaneously within the first two weeks after administration.

[0223] In some embodiments, the method may include injecting the radiopharmaceutical composition into a patient in need more than 48 hours after compounding. In some instances, the radiopharmaceutical composition may include a solution containing 177 Lu-PSMA I&T and ascorbic acid with a pH of 3.5 to 4.5, and the radiochemical purity of the solution at the time of administration can exceed 96%. In one embodiment, the pH of the solution is about 3.5 to 4.2. The composition may include <6 μg / ml of Lu-PSMA I&T, about 7 μg / ml to about 18 μg / ml of disodium EDTA, about 25 μl / ml to about 45 μl / ml of ethanol, and / or about 15 mg / ml to about 35 mg / ml of ascorbic acid. The radioactivity of the composition may be about 0.5 GBq / ml or about 13.5 mCi / ml, and the radiochemical purity at 44 hours after compounding can be at least 98%, the radiochemical purity at 69 hours after compounding can be at least 97%, and / or the radiochemical purity at 93 hours after compounding can be at least 97%.

[0224] The pharmaceutical composition can be administered as 2 - 11 cycles / treatments every 5 - 8 weeks. In some embodiments, the patient can be administered up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 treatments, and these treatments can be administered once every 4, 5, 6, 7, or 8 weeks. In one example, the patient can be administered up to 4 treatments, and each treatment is administered once every 6 weeks.

[0225] In various embodiments, the patient can be administered a dose of 0.5 GBq to 10 GBq. For example, the standard radioactivity of the radiopharmaceutical composition at expiration can be about 200 mCi, and the standard radioactivity concentration at the end of production is about 27 mCi / mL; thus, the final volume of the dose vial can be adjusted to 7 mL to 10 mL to provide the required amount of radioactivity at the infusion date and time. In at least one example, the patient can be administered a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) per treatment. On the one hand, the patient can be administered a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) per treatment for four, five, six, or more treatments. On the other hand, the patient can be administered a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) per treatment for four or more treatments, five or more, six or more, seven or more, or eight or more treatments. In yet another aspect, the patient can be administered a dose of about 200 mCi (≥7.1 GBq) per treatment for four, five, six, seven, eight, or more treatments.

[0226] After administering the radiopharmaceutical composition to the patient, the patient can 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%.

[0227] The present disclosure further provides a method for treating a patient with mCRPC by administering a radiopharmaceutical composition comprising 177 Lu - PSMA I&T. The method can further comprise imaging the patient using PSMA - PET before administering the radiopharmaceutical composition to record and confirm that the patient is positive for mCRPC. For example, the patient's PSMA - PET scan (e.g., 68 Ga]Ga - PSMA - 11 or 18 F]DCFPyL) can be positive as determined by a central reader.

[0228] Indications and Contraindications

[0229] Use 177 The RLT of Lu-PSMA I&T can be used to treat patients with mCRPC who do not have any other approved treatment options as part of a multidisciplinary team plan.

[0230] In some embodiments, the patient also has histologically or pathologically confirmed adenocarcinoma of the prostate and no dominant small cell component, and has disease progression meeting one or more of the following criteria: a) Serum / plasma PSA progression, defined as two consecutive increases in PSA measured at least 1 week apart exceeding the previous reference value, and a 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 prior treatment with a next-generation androgen receptor (AR)-directed therapy (e.g., abiraterone, enzalutamide, apalutamide, darolutamide). In additional embodiments, the patient may have had effective castration and a serum testosterone level < 50 ng / dL and plans to continue chronic medical or surgical castration. Patients with mCRPC should receive hormonal therapy and chemotherapy and bone-targeted therapy (if indicated).

[0231] In at least one instance, the need to use 177 Patients undergoing RLT with Lu-PSMA I&T may meet the following criteria:

[0232] 1) Based on PSMA-PET or SPECT imaging, mCRPC with PSMA-positive metastatic disease. There are no restrictions on the number or location of metastases (i.e., bone or soft tissue metastases). For example, patients with diffuse bone marrow metastases, perineural metastases, and brain metastases should be used with caution.

[0233] 2) After initial hormonal therapy (LH-RH agonist / antagonist). Despite the use of newly developed hormonal therapies (abiraterone / enzalutamide) or the patient may have avoided these drugs, the disease is still progressing, i.e., biochemical and / or radiological progression. Despite the use of chemotherapy (docetaxel and cabazitaxel) or the patient is not suitable for chemotherapy or avoids chemotherapy, the disease is still progressing.

[0234] 3) Unsuitable for 153 Sm-EDTMP or 223 Ra]RaCl 2 or other radiopharmaceuticals that can be used locally for bone-targeted therapy. In patients who do not have a sufficient response to pain relief or pain exacerbation with bone-targeted therapy even with such therapies, the use of 177Lu-PSMA I&T is used for RLT.

[0235] 4) Life expectancy exceeds 4 - 6 months.

[0236] 5) Salvage therapy is determined by the institutional interdisciplinary tumor board.

[0237] In summary, patients with mCRPC should receive hormonal therapy, chemotherapy, and bone-targeted therapy (if indicated). If there are any contraindications to one of the therapies, they should be discussed and documented in the interdisciplinary tumor board.

[0238] The contraindications are as follows:

[0239] (1) WBC ≤ 1 x 10 9 cells / L.

[0240] (2) Hb ≤ 80 g / L. (In the case of symptomatic anemia, red blood cell transfusions should be administered before therapy. Using 177 Lu-PSMA I&T for RLT may have a positive effect on myelosuppression, reducing the need for blood transfusions due to tumor regression in the bone marrow. It should be noted that simple anemia without thrombocytopenia and leukopenia is not a contraindication to RLT.)

[0241] (3) Platelets ≤ 70 x 10 9 cells / L.

[0242] (4) Creatinine > 1.5 UNL; renal failure and creatinine clearance < 30 mL / min

[0243] (5) Absolute obstruction of renal excretion.

[0244] (6) Prior chemotherapy or bone-targeted radionuclide therapy, and external beam irradiation fields extended to the bone marrow (pelvis, spine) if performed during the 4-week period prior to RLT

[0245] (7) ECOG performance status > 2.

[0246] (8) Allergy to any of the active substances or excipients.

[0247] After identifying patients in need, the activity of the radiopharmaceutical composition can be confirmed before administration. 177 The radioactivity of the Lu-PSMA I&T composition can be 6.5 - 7.5 GBq or in the range of 6.0 - 8.0 GBq. In cases of impaired renal function (e.g., creatinine within 1.0 - 1.5 UNL), the radioactivity can be reduced to 4.0 - 5.0 GBq.

[0248] The radiopharmaceutical composition solution can be intravenously injected in the form of a slow bolus (within about 10 - 15 minutes), followed by injection of 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.

[0249] The pharmaceutical composition can be administered as RLT in 2 - 11 cycles every 5 - 8 weeks. In the case of a continuously increasing PSA, after the first two cycles, along with the deterioration of the general condition, the indication for further RLT can be re-evaluated. If the PSA decreases 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. If there is a significant decrease in platelets or white blood cells, the time interval between two cycles can be extended.

[0250] At least one whole-body scan (preferably using 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, corticosteroid therapy (e.g., prednisone 20 mg / day) can be administered concomitantly within the first two weeks after administration of the radiopharmaceutical composition.

[0251] In some embodiments, after administration of the radiopharmaceutical composition, the patient can have an improved radiographic progression-free survival (rPFS). The rPFS of a patient administered the radiopharmaceutical composition can be from about 6 months to about 12 months after the start of administration of the radiopharmaceutical composition. In various embodiments, the rPFS of a patient administered the radiopharmaceutical composition can be at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months after the start of administration of the radiopharmaceutical composition. For example, using 177 treatment of patients with Lu-PSMA I&T can extend the rPFS from 6 months with standard treatment 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 PCWG3 and RECIST 1.1 criteria, as evaluated by a blinded independent central review [BICR]) or death from any cause.

[0252] In one embodiment, a patient may have an improved overall survival (OS) after initiation of administration of a radiopharmaceutical composition. The overall survival of a patient administered the radiopharmaceutical composition may be from about 18 months to about 26 months after initiation of administration of the radiopharmaceutical composition. In various embodiments, the OS of a patient administered the radiopharmaceutical composition may be at least 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, or 26 months after initiation of administration of the radiopharmaceutical composition. For example, treating a patient with 177 Lu-PSMA I&T can extend the OS from 18 months with standard therapy to up to 25 months with the radiopharmaceutical composition.

[0253] In another embodiment, a patient may have an improved second radiographic progression-free survival (rPFS2) after initiation of administration of the radiopharmaceutical composition.

[0254] In some embodiments, a patient may have an improved progression-free survival after initiation of administration of the radiopharmaceutical composition. In additional embodiments, a patient may have an improved second progression-free survival after initiation of administration of the radiopharmaceutical composition. 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.

[0255] In one embodiment, a patient may have an improved PSA 50 response. The PSA 50 response rate may be the response rate of patients achieving a ≥50% reduction in PSA from a baseline PSA assessment.

[0256] In one embodiment, a patient may have an improved time to first symptomatic skeletal event (SSE) after initiation of administration of the radiopharmaceutical composition. An SSE may be the occurrence of bone pain relief with bone-directed radiotherapy, a new symptomatic pathologic fracture, spinal cord compression, or tumor-related orthopedic surgery.

[0257] In one embodiment, a patient may have an improved time to soft tissue progression (STP) after initiation of administration of the radiopharmaceutical composition. STP may include the occurrence of radiographic progression of soft tissue. In another embodiment, a patient may have an improved time to chemotherapy (TTC) after initiation of administration of the radiopharmaceutical composition.

[0258] In one embodiment, a patient may have improved quality of life questionnaire results after initiation of administration of the radiopharmaceutical composition. For example, quality of life (QoL) may be evaluated 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 QoL questions for evaluating the quality of life (QoL) of cancer patients. The EORTC QLQ-C30 contains 30 items, of which 24 are aggregated into nine multi-item scales and scored from 0 to 100.

[0259] Example

[0260] The following non-limiting examples are for illustrative purposes only and should not therefore be considered restrictive.

[0261] Analysis procedures

[0262] The product is identified by subsequently injecting a reference solution and the formulated solution of Lu-PSMA I&T into a liquid chromatography system. The radionuclide identity is determined by gamma-ray energy detection.

[0263] The pH is estimated using pH test strips. The radioactivity is measured in a dose calibrator. The radiochemical purity is determined by liquid chromatography and thin layer chromatography with radioactivity detection.

[0264] Determined by a dose calibrator at the time of dispensing the dose 177 The radioactivity of Lu-PSMA I&T.

[0265] The bacterial endotoxin content of each batch is determined using a PTS-tester (European Pharmacopoeia method D) before release. Sterility is determined according to the European Pharmacopoeia.

[0266] The quality of the analytical procedures for the drug product, such as specificity, linearity, and reproducibility, was investigated by using known reference standards of the unlabeled precursors. All analytical procedures are suitable for their intended use.

[0267] No acceptance criteria for the radioactivity in the formulation are set as this will depend on the individual clinical needs evaluated by the healthcare professional responsible for administering the formulation. At the date and time stated on the label, the radioactive content must be within the range of 90%-110% of the specified value.

[0268] Example 1: Manufacturing 177 Method for preparing a LU-PSMA I&T radiopharmaceutical formulation

[0269] A variety of radiopharmaceutical compositions are produced using the process set forth in Table 2 below. Using 177 Lu]LuCl without a carrier added3 Perform radio - labeling. 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 extends the shelf - life of Composition 3 compared to Compositions 1 and 2.

[0270] 177 The synthesis of Lu - PSMA I&T is carried out in a controlled environment in an automated synthesis module for radio - labeling. A labeling solution containing 177 Lu] lutetium chloride ( 177 LuCl 3 ) is connected to a synthesis cassette containing the other chemical components required for the labeling process. 177 LuCl 3 The solution is transferred to a reactor for radio - labeling and can be rinsed with an additional required amount of 0.04M HCl solution. The volume of the labeling solution varies depending on the 177 Lu radioactivity.

[0271] The 177 LuCl 3 solution is mixed in the reaction chamber with a 0.4M sodium acetate buffer solution containing a diluted PSMA I&T precursor. The solution is heated in the reactor. After heating, the resulting 177 Lu - PSMA I&T is trapped in a pre - treated (ethanol) C18 cartridge. The cartridge is rinsed with sterile water and then the final product is eluted from the C18 cartridge into a bulk vial with 1.5 ml of 50% sterile ethanol. The drug substance is isolated in - situ and directly formulated into a drug product.

[0272] For final volume adjustment, a formulation matrix containing injection - grade water with 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 formulation matrix added depends on the 177 Lu radioactivity used in the batch.

[0273] The formulation matrix is prepared from an injection - grade solution of ascorbic acid diluted to a concentration of 50 mg / ml with injection - grade water. The ethanol concentration is adjusted to 3.8% (v / v) to match the concentration of the synthesized bulk product, regardless of the dilution rate.

[0274] The synthesis is a one - step labeling process, using injection - grade ethanol and water as the only solvents for C18 purification, so there are no residual solvents.

[0275] The radiochemical impurities are quantified by chromatographic methods (HPLC and TLC). The radiochemical purity determined by HPLC must be not less than 95.0%

[0276] The bulk product is diluted to a fixed radioactivity concentration of approximately 500 MBq / ml based on the overall radioactivity generated.

[0277] 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 allocated from each production batch. The final product is dispensed in a Class A controlled environment. After filtration, the integrity of the filter is tested by performing a bubble point test prior to product release. The fill weight / volume and radioactivity of the dispensed patient vials are checked. After pre-release quality control and QP release, the solution is ready for use.

[0278] After the labeling process, the radioactivity is monitored using a dose calibrator to ensure successful labeling, and the dispensed dose is verified during dispensing.

[0279] Table 2A. Radiolabeling process

[0280]

[0281] Table 2B below provides Compositions 1 - 3 obtained from Processes 1 - 3, and this table provides the compositions for both a 1 ml volume and 10 ml or 20 ml vials for each composition.

[0282] Table 2B. 177 Lu - PSMA I&T Compositions 1 - 3.

[0283]

[0284]

[0285] Example 2: Stability of Radiochemical Compositions

[0286] For 177 The stability of Lu - PSMA I&T Composition 1 was tested, and the radiochemical purity and chemical properties indicated that the samples stored at +5 °C, +20 °C, and +40 °C provided sufficient stability within 48 hours after the end of the synthesis time, Table 3.

[0287] The stability study showed that, compared to 177 Lu - PSMA I&T Composition 1, Lu - PSMA I&T Composition 3 (Table 4A - H) with a pH of 4.5 containing 31 mg / ml ascorbic acid and 3.8% (v / v) ethanol 177 had improved stability and an extended shelf life.

[0288] Over a time span of 70 to 72 hours after the end of the synthesis time, for seven batches of Formulation Composition 3177 The radiochemical purity and chemical properties (pH, impurities, visual properties) of Lu-PSMA I&T were tested. Samples of typical therapeutic dose radioactivity and volume were stored under different conditions, which involved typical storage, transportation, and use of the product, including temperatures in the range of +5°C to +40°C.

[0289] At the end of dispensing, the final radioactivity concentration in the sample solution varied in the range of 497 MBq / ml to 642 MBq / ml.

[0290] All stability samples met the set acceptance criteria. The radiochemical purity of all analytical samples was ≥95.7% after 70 hours or 72 hours after the end of synthesis.

[0291] Based on the results, in formulation composition 3 177 the Lu-PSMA I&T solution was insensitive to the different storage conditions tested.

[0292] Table 3. 177 Stability data of Lu-PSMA I&T composition 1.

[0293]

[0294]

[0295] Table 4A. 177 Chemical quality in the validation batch of Lu-PSMA I&T composition 3.

[0296]

[0297]

[0298] The radioactivity measurement of the test sample RT = UV RT of the reference standard ±5%.

[0299] Table 4B 177 Stability data of Lu-PSMA I&T composition 3.

[0300]

[0301]

[0302] The radioactivity measurement of the test sample RT = UV RT of the reference standard ±5%.

[0303] Table 4C 177 Stability data of Lu-PSMA I&T composition 3.

[0304]

[0305] The radioactivity measurement of the test sample RT = the UV RT of the reference standard ± 5%.

[0306] Table 4D 177 Stability data of Lu-PSMA I&T composition 3.

[0307]

[0308] The radioactivity measurement of the test sample RT = the UV RT of the reference standard ± 5%.

[0309] Table 4E. 177 Stability data of Lu-PSMA I&T composition 3.

[0310]

[0311] The radioactivity measurement of the test sample RT = the UV RT of the reference standard ± 5%.

[0312] Table 4F. 177 Stability data of Lu-PSMA I&T composition 3.

[0313]

[0314] The radioactivity measurement of the test sample RT = the UV RT of the reference standard ± 5%.

[0315] Table 4G. 177 Stability data of Lu-PSMA I&T composition 3.

[0316]

[0317] The radioactivity measurement of the test sample RT = the UV RT of the reference standard ± 5%.

[0318] Table 4H 177 Stability data of Lu-PSMA I&T composition 3.

[0319]

[0320]

[0321] The radioactivity measurement of the test sample RT = the UV RT of the reference standard ± 5%.

[0322] 177 The specifications of the Lu-PSMA I&T solution are presented in Table 5 below. All specifications listed, except for the sterility test, are used as release parameters. The sterility test is performed on all batches after release.

[0323] Table 5. 177 Specifications of Lu-PSMA I&T

[0324]

[0325]

[0326] Example 3: In different formulation compositions 177 Radiochemical purity of Lu-PSMA I&T

[0327] This example demonstrates 177 the radiochemical stability of Lu-PSMA I&T in formulation compositions at different pH values. 177 The shelf life of Lu-PSMA I&T is limited by the high radiolytic rate during preparation and storage, causing 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 acceptance limit of 95.0%.

[0328] By using an aqueous solution of 0.1% trifluoroacetic acid (mobile phase A) and an aqueous solution of 0.1% trifluoroacetic acid:acetonitrile (10:90% v / v) (mobile phase B) with a Phenomenex Luna C18 column (3 μm, 150 mm x 4.6 mm) and an isocratic method of 23% mobile phase B at a temperature of 40 °C, the formation of specific radiochemical impurities of Lu-PSMA I&T was observed, with a retention time of approximately 5.2 minutes. The impurity with a retention time of approximately 5.2 minutes described herein is illustrated in the chromatogram in 177 Figure 6A - 11B

[0329] In previously conducted experiments, it was found that reducing the radioactivity concentration of the formulation was insufficient to reduce the formation of the impurity eluting at approximately 5.2 minutes and maintain 177 the radiochemical stability of the Lu-PSMA I&T solution above 95.0% for 72 hours.

[0330] In this example, six experiments were conducted in which Lu-PSMA I&T was prepared in formulation compositions with different ascorbic acid concentrations, pH values, and radioactivity concentrations. The details of the product formulations are described in Table 6. 177 ​​​

[0331] Table 6. 177 Evaluation of Lu-PSMA I&T Formulation Composition

[0332]

[0333]

[0334] 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 monitored by HPLC up to 71 - 93 hours after radiolabeling. All solutions were stored at 22.5 °C.

[0335] Figure 5 The results of radiochemical purity analysis determined by HPLC at different time points are shown.

[0336] Figure 6A and Figure 6B show the HPLC radiochromatograms of Experiment 1 at 0 hour and 71 hours after EOS, respectively.

[0337] Figure 7A and Figure 7B show the HPLC radiochromatograms of Experiment 2 at 0 hour and 71 hours after EOS, respectively.

[0338] Figure 8A and Figure 8B show the HPLC radiochromatograms of Experiment 3 at 0 hour and 90 hours after EOS, respectively.

[0339] Figure 9A and Figure 9B show the HPLC radiochromatograms of Experiment 4 at 0 hour and 92 hours after EOS, respectively.

[0340] Figure 10A and Figure 10B show the HPLC radiochromatograms of Experiment 5 at 0 hour and 71 hours after EOS, respectively.

[0341] Figure 11A and Figure 11B show the HPLC radiochromatograms of Experiment 6 at 0 hour and 93 hours after EOS, respectively.

[0342] Tables 7 - 12 provide the radiochemical stability results for each experiment at different time points.

[0343] Table 7. Experiment 1

[0344]

[0345] Table 8. Experiment 2

[0346]

[0347] Table 9. Experiment 3

[0348]

[0349] Table 10. Experiment 4

[0350]

[0351] Table 11. Experiment 5

[0352]

[0353] Table 12. Experiment 6

[0354]

[0355] In the examples, the pH of the formulation composition has a significant 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 Figure 6A - 11B shown. In the high RAC solution, the rate of decline of radiochemical purity over time at pH 4.5 is one-half that at pH 7.

[0356] Lowering the formulation pH further to 3.5 does not result in a significant improvement in radiochemical stability compared to the pH 4.5 solution. The ascorbic acid solution at pH 4.5, which is close to the pKa value of ascorbic acid, may already contain a sufficient number of protons to act as 177 an inhibitor of the radiolytic decomposition of Lu-PSMA I&T and reduce the formation of radiochemical impurities eluting at approximately 5.2 minutes.

[0357] Incorporating a solution with a pH of 4.5 into the lower RAC formulation further improves 177 the radiochemical stability of Lu-PSMA I&T. In the lower RAC formulation, the effect of changing the formulation pH from 5 to 4.5 on radiochemical stability is similar to the effect of increasing the ascorbic acid concentration from 21 mg / ml to 31 mg / ml on radiochemical stability.

[0358] 10 ml of high RAC containing 42.5 mg / ml ascorbic acid 177The radiochemical purity of the Lu-PSMA I&T formulation composition is at least about 99% at 0 hours post-EOS and at least about 93.3% at 46 hours post-EOS, as measured by HPLC. When the pH of the formulation is increased from pH 4.5, the radiochemical purity decreases.

[0359] 20 ml of low RAC containing 31 mg / ml ascorbic acid 177 The radiochemical purity of the Lu-PSMA I&T formulation is at least about 99.1% at 0 hours post-EOS, as measured by HPLC. The low RAC with a pH of 4.5 compared to a pH of 5 177 The rate of decline of the radiochemical purity of the Lu-PSMA-I&T formulation over time is slower.

[0360] The results show that compared to formulation compositions with a pH above 5, formulation compositions with a pH of 5 or below can significantly reduce the formation of radiochemical impurities eluting at about 5.2 minutes and thus improve 177 the radiochemical stability of Lu-PSMA I&T. In addition, by incorporating a lower solution RAC, the 177 radiochemical stability of Lu-PSMA I&T can be further improved. In the examples, 177 the Lu-PSMA I&T solution shows the highest radiochemical stability at a low RAC solution of pH 4.5 and an ascorbic acid concentration of 31 mg / ml. This formulation is considered to be a preferred composition for minimizing the formation of radiochemical impurities and maintaining 177 the radiochemical stability of Lu-PSMA I&T above 95.0% for 72 hours or longer.

[0361] Example 4: Use 177 Lu-PSMA-617 and 177 the efficacy of treatment with both Lu-PSMA-I&T compared to third-line treatment

[0362] 177 Dosimetry of Lu-PSMA I&T

[0363] 177 There is no significant difference between Lu-PSMA I&T and 177 the estimated absorbed dose of Lu-PSMA-617. 177 The specific known dosimetry of Lu-PSMAI&T is as follows.

[0364] For normal organs, the mean whole-body effective dose for all cycles was 0.41 ± 0.18 Sv (0.06 Sv / GBq). The mean absorbed organ dose for the kidneys was 5.3 ± 1.6 Gy (0.72 Gy / GBq); for the liver it was 0.89 ± 0.42 Gy (0.12 Gy / GBq); and for the parotid glands it was 4.0 ± 1.1 Gy (0.55 Gy / GBq), for the submandibular glands it was 4.8 ± 2.8 Gy (0.64 Gy / GBq), and for the lacrimal glands it was 27 ± 10 Gy (3.8 Gy / GBq).

[0365] When comparing the absorbed doses of normal organs with respect to the number of cycles, no substantial differences were observed (Table 13). The mean organ masses on which these absorbed dose estimates were based were 1.595 ± 307 g for the liver (range, 1,165 - 2,373 g), 153 ± 29.9 g for the kidneys (range, 88.4 - 218.7 g), 19.1 ± 5.7 g for the parotid glands (range, 8.0 - 35.6 g), 8.2 ± 1.9 g for the submandibular glands (range, 4.2 - 14.3 g), and 0.45 ± 0.12 g for the lacrimal glands (range, 0.25 - 0.78 g). For paired organs, the masses of both sides were added.

[0366] For tumor lesions, all lesions received a mean dose of 23 ± 20 Gy (3.3 Gy / GBq) per cycle. The mean absorbed doses for bone metastases, lymph node metastases, liver metastases, and lung metastases were 26 ± 20 Gy (3.4 Gy / GBq), 24 ± 16 Gy (3.2 Gy / GBq), 8.5 ± 4.7 Gy (1.28 Gy / GBq), and 13 ± 7.4 Gy (1.7 Gy / GBq), respectively.

[0367] The corresponding absorbed dose values (mean, SD, and range) per GBq for normal organs and tumor lesions are presented separately in the following table.

[0368] Table 13. Whole-body effective dose (in Sv / GBq) and absorbed dose of normal organs (in Gy / GBq).

[0369]

[0370]

[0371] Table 14. Absorbed dose of tumor lesions (in Gy / GBq)

[0372] Cycles studied All metastases Bone metastases Lymph node metastases Liver metastases Lung metastases Overall (n) 93 74 8 8 3 Mean ± SD 3.2±2.6 3.4±2.7 3.2±2.2 1.2±0.67 1.75±0.92 Range 0.22-12.03 0.22-12.03 1.63-8.46 0.47-2.59 0.94-2.68 First cycle (n) 41 33 5 2 1 Mean ± SD 3.5±2.9 3.8±3.1 2.6±0.89 1.7 2.7 Range 0.22-12.03 0.22-12.03 1.63-3.76 0.85-2.59 Second cycle (n) 26 21 2 2 1 Mean ± SD 3.3±2.5 3.4±2.4 5.2 0.94 1.3 Range 0.70-8.46 1.03-9.59 1.98-8.46 0.70-1.17 Third cycle (n) 14 10 1 2 1 Mean ± SD 2.7±2.3 3.2±2.5 2.6 0.95 0.94 Range 0.94-7.99 1.11-7.99 18.87 0.47-1.42 Fourth cycle (n) 12 10 2 Mean ± SD 2.4±2.2 2.7±2.3 1.13 Range 0.74-7.60 1.04-7.60 0.74-1.51

[0373] The absorbed dose showed a clear downward trend with increasing cycle number. The average absorbed dose per lesion was 26 ± 21 Gy (3.5 Gy / GBq) in the first cycle, 24 ± 19 Gy (3.3 Gy / GBq) in the second cycle, 20 ± 18 Gy (2.7 Gy / GBq) in the third cycle, and 18 ± 17 Gy (2.4 Gy / GBq) in the fourth cycle. A similar trend can be seen in the bone metastasis subgroup. Due to the small number of samples, no reliable comparison can be made for lymph node metastasis, liver metastasis, and lung metastasis. 177 The effective half-life and average absorbed dose of Lu-PSMA I&T are shown in the table below.

[0374] 177 Lu-PSMA RLT (study includes 177 Lu-PSMA-617 and 177 Lu-PSMA I&T (both) was more effective than third-line treatment and caused fewer adverse reactions. Twelve studies including 669 patients reported 177 Lu-PSMA RLT. Overall, 44% of patients received 177 The maximum decrease in PSA after Lu-PSMA RLT treatment was ≥50%. 177 Lu-PSMA-617 and Imaging and Therapy (I&T) 177 Treatment with Lu-PSMA was associated with primarily transient adverse effects. Sixteen studies (including 1338 patients) reported third-line treatment. Overall, 21% of patients had a best PSA decline of ≥50% after third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, 10% to 23% of patients discontinued treatment due to adverse reactions. 177 Lu-PSMA RLT gave a higher frequency of best PSA decline ≥ 50% (mean 44% vs. 22%, p = 0.0002, t-test). 177 Lu-PSMA RLT resulted in a higher frequency of objective responses (31 of 109 patients vs. 43 of 275 patients overall, p = 0.004, χ2 test). 177 The median survival after Lu-PSMA RLT was longer, but the difference was not statistically significant (mean 14 months vs. 12 months, p = 0.32, t-test). 177 Adverse events leading to treatment discontinuation were more frequent in third-line therapy compared with Lu-PSMA RLT (22 of 66 patients vs. 0 of 469 patients, p < 0.001, χ2 test).

[0375] The purpose of this Investigational Medicinal Product Dossier (IMPD) is to177 Lu-PSMA I&T provides a scientific and ethical platform for useful treatment to initially conduct its application, preferably under an academic center and a controlled research protocol. Except for 177 Lu-PSMA-617, there are no other existing guidelines. The information in this IMPD is based on the latest literature and the best available experience in nuclear medicine centers that have been treating PC patients in this manner.

[0376] The synthesis is a one-step labeling process using injection-grade ethanol and water as the only solvents. Therefore, there are no residual solvents. Radiochemical impurities are quantified by chromatographic methods (HPLC and TLC). The radiochemical purity can be not less than 95.0%.

[0377] Example 5: Comparison 177 A multicenter, open-label, randomized phase 3 trial comparing the safety and efficacy of Lu-PSMA I&T

[0378] A multicenter, open-label, randomized phase 3 trial comparing the safety and efficacy of a composition containing Lu-PSMA I&T versus hormone therapy was conducted in patients with metastatic castration-resistant prostate cancer. 177 A multicenter, open-label, randomized phase 3 trial comparing the safety and efficacy of a composition containing Lu-PSMA I&T versus hormone therapy.

[0379] This study aimed to identify and characterize the safety and efficacy of using 177 Lu-PSMA I&T to treat adult male human patients (males) with metastatic castration-resistant prostate cancer (mCRPC) whose disease was progressing despite receiving a course of standard-of-care hormone therapy.

[0380] 177 Lu-PSMA I&T is a radiotherapeutic agent that specifically targets the prostate-specific membrane antigen protein expressed on metastatic prostate cancer cells.

[0381] In this study, 177 Lu-PSMA I&T is provided as a sterile, filtered radiopharmaceutical solution containing an aqueous solution of ascorbic acid and ethanol containing a microdose of 177 Lu-PSMA I&T.

[0382] Based on the investigator's independent medical judgment, patients randomly assigned to receive standard-of-care hormone therapy for mCRPC will receive abiraterone acetate in combination with prednisone or enzalutamide.

[0383] Abiraterone acetate in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) or metastatic high-risk castration-sensitive prostate cancer (mCSPC). Abiraterone acetate is converted in vivo to abiraterone, an inhibitor of androgen biosynthesis that inhibits 17α-hydroxylase / C17,20-lyase (CYP17). This enzyme is expressed in testicular tumor tissue, adrenal tumor tissue, and prostate tumor tissue and is essential for androgen biosynthesis.

[0384] Enzalutamide is an androgen receptor inhibitor indicated for the treatment of patients with CRPC or mCSPC (metastatic castration-sensitive prostate cancer). Studies have shown that enzalutamide competitively inhibits the binding of androgens to the androgen receptor and thereby inhibits nuclear translocation of the androgen receptor and its interaction with DNA.

[0385] A. Study Objectives and Endpoints

[0386] The primary objective of this study was to prospectively evaluate 177 the efficacy of Lu-PSMA I&T compared to standard-of-care hormonal therapy in improving radiographic progression-free survival (rPFS) (as determined by RECIST 1.1 modified by PCWG3) in men with metastatic castration-resistant prostate cancer (mCRPC). The endpoint for this objective was time to radiographic progression as assessed by blinded independent central review as determined by Prostate Cancer Working Group 3 (PCWG3) criteria.

[0387] The secondary objectives were to evaluate 177 whether Lu-PSMA I&T improves overall survival (OS) in patients with mCRPC compared to patients receiving standard-of-care hormonal therapy. The endpoint for this objective was time to death from randomization for any reason.

[0388] Other secondary objectives and endpoints included:

[0389] · Objective : To evaluate improvement in overall survival (OS) in men with mCRPC treated with 177 Lu-PSMA I&T compared to hormonal therapy; Endpoint : Time to second radiographic progression as determined by RECIST 1.1 of PCWG3 or BICR (blinded independent central review) from randomization to crossover.

[0390] · Objective : To evaluate the change in time to second radiographic progression in patients who crossover from the standard-of-care hormonal therapy group to the 177 Lu-PSMA I&T treatment group; Endpoint: Time to second radiographic progression as determined by RECIST 1.1 by PCWG3 or BICR following randomization and crossover.

[0391] · Objective : Identification 177 Change in progression-free survival (PFS, composite) following Lu-PSMA I&T compared to following standard-of-care hormonal therapy; Endpoint : Time from randomization to progression (PFS, composite) based on the following events (whichever comes first): PCWG3 or RECIST progression, clinical / symptomatic progression and / or pain progression, or death due to any cause as determined by the investigator.

[0392] · Objective : Identification 177 Change in progression-free survival 2 (PFS2, composite) following Lu-PSMA I&T compared to following standard-of-care hormonal therapy; Endpoint : Time from randomization to second progression (PFS, composite) based on the following events (whichever comes first): PCWG3 or RECIST progression, clinical / symptomatic progression and / or pain progression, or death due to any cause as determined by the investigator,

[0393] · Objective : Assessment 177 Change in PSA50 (response rate of patients with ≥50% decrease in PSA from baseline) response rate following Lu-PSMA I&T compared to following standard-of-care hormonal therapy; Endpoint : PSA50 response rate, defined as a confirmed ≥50% decrease in PSA from baseline,

[0394] · Objective : Determination 177 Effect of Lu-PSMA I&T on skeletal symptoms compared to standard-of-care hormonal therapy; Endpoint : Time from randomization to first symptomatic skeletal event (skeletal event-free survival),

[0395] · Objective : Determination 177 Effect of Lu-PSMA I&T on radiographic soft tissue progression compared to standard-of-care hormonal therapy; Endpoint : Time from randomization to radiographic soft tissue progression (rSTP) as measured by RECIST 1.1 by BICR,

[0396] · Objective : Assessment 177 Change in chemotherapy use following Lu-PSMA I&T compared to following standard-of-care hormonal therapy;Endpoint : Time from randomization to first use of chemotherapy, and

[0397] · Objective : Evaluate 177 The impact of Lu-PSMA I&T radioligand therapy on quality of life compared to hormonal therapy; Endpoint : Quality of life improvement based on the EORTC QLQ-C30 questionnaire.

[0398] The exploratory objectives and endpoints are:

[0399] · Objective : Evaluate 177 Any differences in objective response rate and disease control rate between Lu-PSMA I&T and standard-of-care hormonal therapy; Endpoint : Objective response rate and disease control rate (DCR = complete / partial response and disease stabilization) based on PCWG3 criteria,

[0400] · Objective : Evaluate 177 The change in time to PSA progression after Lu-PSMA I&T radioligand therapy compared to after standard-of-care; Endpoint : Time from randomization to PSA progression (defined as a ≥25% increase in PSA from the post-treatment nadir), and

[0401] · Objective : Evaluate 177 The duration of response (DoR) of patients achieving a complete or partial response after Lu-PSMA I&T radioligand therapy compared to after hormonal therapy; Endpoint : Time from complete or partial response to radiographic progression.

[0402] B. Study design

[0403] (i) Overview and rationale

[0404] This is an open-label, randomized, multi-center phase 3 study comparing 177 Lu-PSMA I&T radioligand therapy with hormonal therapy in men with mCRPC who have previously received androgen receptor (AR)-directed therapy. Based on the NCCN guidelines, the hormonal therapy regimen in this study is enzalutamide or abiraterone in combination with prednisone. For patients randomized to receive standard of care, the specific regimen will be selected based on the transition from the patient's previous ADRT. Based on published literature, 177 Lu-PSMA I&T radioligand therapy has encouraging anti-tumor activity and favorable safety characteristics in men with mCRPC.

[0405] This study consists of a screening period, a treatment period, and a post-treatment follow-up period. This study uses a 2:1 random assignment to the following treatment groups: (1) 177 Lu-PSMA I&T radioligand therapy, or (2) standard-of-care hormone therapy. The standard-of-care hormone treatment options are abiraterone in combination with prednisone or enzalutamide, and the specific choice is based on the investigator's clinical judgment. Patients randomly assigned to the hormone therapy group will be able to choose to cross over to the radioligand therapy group after radiographic progression is recorded.

[0406] Patients will undergo safety and efficacy follow-up according to the schedule of activities and will continue to receive study treatment until documented radiographic progression (as evaluated by blinded independent central review (BICR)) or unacceptable toxicity occurs. Patients who stop treatment due to documented radiographic progression will enter the long-term follow-up period. Patients who stop treatment before documented radiographic progression will continue to receive the planned quarterly disease assessments until documented radiographic progression.

[0407] In addition, a substudy will be conducted according to this protocol in patients randomly assigned to receive 177 Lu-PSMA I&T radioligand therapy to evaluate pharmacokinetics and dosimetry (as discussed in Example 6).

[0408] Due to the nature of the treatment, the investigators, study personnel, and patients will be aware of the characteristics of the test and control treatments. Blinding is not feasible for this study. For patients with disease progression, after the investigator determines disease progression, and for patients without disease progression, after the study is completed, the blinded radiographic images will be read and interpreted immediately by a panel of up to three trained independent radiologists without access to clinical information or treatment group to evaluate the overall response rate of the treatment.

[0409] The severity of AEs and SAEs will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 based on the subject's symptoms. For AEs not defined in the current version of CTCAE, the severity should be evaluated according to the following scale:

[0410] · Grade 1 = Mild: Transient or mild discomfort, unrestricted activity, no medical intervention / therapy required

[0411] · Grade 2 = Moderate: Mild to moderate activity restriction, may require some assistance, no or minimal medical intervention / therapy required

[0412] · Grade 3 = Severe: Activity is significantly limited, usually requires some assistance, requires medical intervention / therapy, and may require hospitalization.

[0413] · Grade 4 = Life-threatening: Activity is extremely limited, requires substantial assistance, requires extensive medical intervention / therapy, and may require hospitalization or palliative care.

[0414] · Grade 5 = Death: The event results in death.

[0415] It is very important to distinguish between severe and serious SAE. Severity is a measure of intensity, while seriousness is defined by the criteria outlined in Section 10.3. An AE of severe intensity may not be considered serious. Seriousness rather than severity serves as a guide for defining regulatory obligations.

[0416] (ii) Selection of primary endpoint

[0417] Metastatic castration-resistant prostate cancer is generally considered to be an advanced stage in the natural progression of prostate cancer. Although mCRPC is usually associated with a poor prognosis, many patients experience a slower disease progression, and thus the overall survival ranges widely, with approximately 15% of men with mCRPC surviving more than 5 years (Moreira et al., Clin Genitourin Cancer, 2017; 15(1): 60 - 66).

[0418] Considering the relatively wide range of overall survival in men with mCRPC, this study selected radiographic progression-free survival determined by RECIST 1.1 (soft tissue lesion status) and Prostate Cancer Working Group 3 (PCWG3) criteria (bone lesion status) evaluated by blinded independent central review as the primary endpoint. Overall survival is a secondary endpoint of this study, and patients will be followed up for overall survival for 5 years after inclusion.

[0419] (iii) Study results

[0420] The primary efficacy outcome is radiographic progression-free survival. Once radiographic progression is confirmed by BIRC, the study treatment will be stopped. Then, patients will enter the follow-up period of the trial to evaluate overall survival during the 5-year follow-up period starting from the date of inclusion in this study.

[0421] Safety will be evaluated by assessing the following safety parameters until the end of treatment and the 1-month follow-up period: adverse events, vital signs, changes in concomitant medications / therapies, changes in physical examinations, and clinical laboratory measurements.

[0422] C. Patient selection

[0423] (i) Study population

[0424] The study population will include patients with mCRPC with disease progression based on the RECIST 1.1 criteria modified by PCWG3.

[0425] (ii) Inclusion criteria include:

[0426] 1. Males 18 years of age or older.

[0427] 2. Histologically or pathologically confirmed adenocarcinoma of the prostate without a dominant small cell component.

[0428] 3. Disease progression meeting one or more of the following criteria:

[0429] a. Serum / plasma PSA progression, defined as two consecutive increases in PSA measured at least 1 week apart exceeding the previous reference value, with a minimum starting value > 2 ng / mL.

[0430] b. Progression of measurable disease (RECIST 1.1) or the presence of at least two new bone lesions (PCWG3 criteria).

[0431] 4. Prior treatment with next-generation androgen receptor (AR)-directed therapies (e.g., abiraterone, enzalutamide, apalutamide, darolutamide).

[0432] a. Must have received no more than one prior AR-directed therapy.

[0433] b. Must have been administered an ARAT (abiraterone, enzalutamide, darolutamide, or apalutamide) in a castration-sensitive or castration-resistant setting.

[0434] c. Must have had disease progression while receiving an ARAT.

[0435] 5. Positive PSMA-PET scan (e.g., 68 Ga]Ga-PSMA-11 or 18 F]DCFPyL), as determined by a central reader.

[0436] 6. Effective castration, serum testosterone level < 50 ng / dL, and planned continuation of chronic medical or surgical castration.

[0437] 7. HIV patients who are healthy and at low risk for acquired immunodeficiency syndrome-related outcomes may participate in the study at the discretion of the investigator.

[0438] 8. Patients with HBV and HCV may also participate if their symptoms are adequately controlled.

[0439] 9. Life expectancy of at least 6 months as assessed by the investigator.

[0440] 10. Willing to receive ARAT therapy determined by the researcher.

[0441] (iii) Exclusion criteria include:

[0442] 1. Have received treatment with radioligand therapy (including other lutetium-labeled compounds).

[0443] 2. Have received treatment with radium-223 (Xofigo) within the past 12 weeks.

[0444] 3. Have received chemotherapy (docetaxel or cabazitaxel) for hormone-sensitive or hormone-resistant prostate cancer.

[0445] 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 2.

[0446] 5. Patients with known HRR (haploid relative risk) gene mutations who have not previously received olaparib or rucaparib treatment.

[0447] 6. Concurrent receipt of other cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.

[0448] 7. Organ and bone marrow dysfunction, manifested as:

[0449] a. Hemoglobin < 8 g / dL.

[0450] b. Absolute neutrophil count < 1.5 x 109 / L.

[0451] c. Platelet count < 100 x 109 / L.

[0452] d. AST / SGOT and / or ALT / SGPT > 3.0 x ULN (where: "AST" is aspartate aminotransferase, "SGOT" is serum glutamic-oxaloacetic transaminase, "SGPT" is serum glutamic-pyruvic transaminase, and "ALT" is alanine aminotransferase).

[0453] e. Total bilirubin > 2 x ULN (upper limit of normal), unless the patient has known Gilbert's syndrome, in which case it can be 3 x ULN.

[0454] f. Creatinine clearance (CrCl) < 50 mL / min based on the Cockcroft-Gault equation.

[0455] g. Albumin ≥ 2.75 g / dL

[0456] 8. Patients who received blood transfusions only to meet the eligibility criteria for this study.

[0457] 9. Have used the study treatment drug within the last 4 weeks before the start of the study treatment, or plan to receive the study treatment drug during the study period.

[0458] 10. Known CNS metastases, unless they have received therapy, are asymptomatic and neurologically stable.

[0459] 11. Patients receiving zoledronic acid bone-targeted therapy must have received a stable dose for 4 weeks before randomization.

[0460] 12. Patients with active severe heart disease

[0461] 13. Participants with symptomatic spinal cord compression or clinical / radiological findings indicating impending spinal cord compression.

[0462] 14. Patients with a superscan on baseline bone scan as determined by the investigator.

[0463] 15. Active malignancies other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer.

[0464] 16. Have used granulocyte colony-stimulating factor (G-CSF) to treat persistent neutropenia after standard of care treatment.

[0465] 17. Participants with active Covid19. Recovered patients can also be included in the study after complete recovery (asymptomatic for at least 28 days before receiving the study drug and negative for Covid test within 72 hours).

[0466] D. Study Product Dose, Route of Administration, and Schedules of Administration

[0467] (i) 177 Lu-PSMA I&T

[0468] This medicinal product is a sterile, filtered radioactive drug solution containing a microdose formulated in an aqueous solution containing ascorbic acid and ethanol 177 Lu-PSMA I&T. The standard activity of this product at expiration is approximately 200 mCi, and the standard concentration at the end of production is approximately 27 mCi / mL; therefore, the final volume of the dose vial is adjusted to 7.0 mL to 10.0 mL to provide the required amount of radioactivity at the infusion date and time. 177Lu-PSMA I&T injection solution is supplied in single-dose vials as a sterile solution. The septum is sealed with a crimped aluminum cap. The glass vial containing the radiopharmaceutical is kept in a lead-shielded container until use. 177 Lu-PSMA I&T is stored at 25 °C; a deviation between 15 °C and 30 °C is allowed. The expiration date and time of each vial shipped to the clinical site will be noted on the shielding label.

[0469] (ii) Standard of care hormonal therapy

[0470] The standard of care hormonal therapy is:

[0471] · Abiraterone acetate in combination with prednisone: Abiraterone acetate is a CYP 17 inhibitor used in combination with prednisone or methylprednisolone. Prednisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids that are readily absorbed from the gastrointestinal tract.

[0472] · Enzalutamide is an androgen receptor inhibitor.

[0473] (iii) Preparation

[0474] All infusion solutions will be prepared and dispensed by the site prior to administration. The preparation of the solution should be carried out under aseptic conditions, and the final solution should be visually inspected for particulate matter. If an insoluble precipitate is observed, the solution should be discarded.

[0475] 177 The Lu-PSMA I&T injection solution is administered as provided. Before and after administration to the patient, the radioactivity in the vial should be measured in a calibrated dose calibrator. Then, the administered dose is calculated and recorded.

[0476] (iv) Administration and application

[0477] Patients will be randomly assigned in a 2:1 ratio to receive 177 Lu-PSMA I&T radioligand therapy or standard of care hormonal therapy.

[0478] 177 Administration of Lu-PSMA I&T: Patients randomly assigned to receive radioligand therapy will receive a single intravenous injection of a radioactive dose of 200 mCi (7.4 GBq) ± 10% of 177 Lu-PSMA I&T at the start of each treatment cycle.

[0479] Prior to administration of 177 Lu-PSMA I&T, an intravenous line should be established. The site's standard radioligand therapy administration procedure will be used to inject in a slow bolus over a minimum of 10 to 15 minutes 177Lu-PSMA I&T. After 177 the administration of Lu-PSMA I&T, patients should be encouraged to void as frequently as possible and consume two liters of fluid per day for two days.

[0480] Prior to the injection of 177 Lu-PSMA I&T and for up to four hours afterwards, the patient's salivary glands should be cooled by placing ice packs on the parotid and submandibular glands to reduce the risk of radiation damage to the salivary glands.

[0481] Six-week treatment cycles will be used for the injection of 177 Lu-PSMA I&T for four treatment cycles or until radiographic progression of the disease is determined based on the BIRC's assessment of the radiographic images (up to 18 weeks of treatment). Alternatively, eight-week treatment cycles can be used for the injection of 177 Lu-PSMA I&T for six treatment cycles or until radiographic progression of the disease is determined based on the BIRC's assessment of the radiographic images (up to 18 weeks of treatment).

[0482] 177 The dosing cycle of Lu-PSMA I&T can be extended based on the assessment of dose-limiting toxicities experienced by the patient. Dose-limiting toxicities are defined as grade 3 or 4 myelotoxicity or grade 2 or higher salivary gland toxicity. For grade 3 or 4 myelotoxicity, dosing can be resumed when improvement to grade 2 or better is observed. For grade 2 or higher salivary gland toxicity, dosing can be resumed after improvement to grade 1.

[0483] In addition, if dose-limiting toxicities are detected, then 177 the Lu-PSMA I&T dose should be maintained and / or reduced to 160 mCi (5.9 GBq) ± 10%. The following dose maintenance / reduction should be implemented accordingly:

[0484] - For ≥ grade 3 anemia: Maintain the dose until recovery to baseline or ≤ grade 2, and then reduce to 160 mCi (5.9 GBq) in the next cycle

[0485] - For ≥ grade 2 neutropenia: Maintain until recovery to baseline or ≤ grade 1

[0486] - For ≥ grade 2 thrombocytopenia: Maintain until recovery to baseline or ≤ grade 1, and reduce the dose to 160 mCi (5.9 GBq) in the next cycle

[0487] - For ≥ grade 3 non-platelet hematotoxicity: Maintain until recovery to baseline or ≤ grade 2, and reduce the dose to 160 mCi (5.9 GBq) in the next cycle

[0488] In the case of grade 3 or higher acute renal toxicity, the dose should be paused in the next cycle. When it has recovered to baseline or ≤ grade 2, the dose can be resumed, but all remaining doses are reduced to 160 mCi (5.9 GBq).

[0489] If any other grade 3 or higher non-hematological toxicity related to 177 Lu-PSMA I&T as determined by the investigator occurs, the dosing cycle should be extended for an additional six weeks and the dose for the remaining cycles should be reduced to 160 mCi (5.9 GBq). When the toxicity has recovered to grade 2 or lower, the dosing cycle and dose level can be resumed at once every six weeks.

[0490] For all grade 3 and 4 AEs, the patient will only be able to reduce the dose once. If the event persists, the patient will need to permanently discontinue study treatment.

[0491] For grade 2 AEs, only two dose reductions are allowed. If the event persists, the patient will need to permanently discontinue study treatment.

[0492] Abiraterone acetate in combination with prednisone: The dose of abiraterone acetate should be administered according to the package insert. According to the abiraterone package insert, for patients with moderate liver impairment at baseline, the starting dose of abiraterone should be reduced to 250 mg daily. For patients who develop hepatotoxicity during treatment, the use of abiraterone acetate should be paused until recovery. The dose can be reduced to start retreatment. Patients with severe hepatotoxicity should discontinue abiraterone acetate treatment.

[0493] Enzalutamide: The dose of enzalutamide is 160 mg (four 40 mg capsules), administered orally once daily. The capsules should be swallowed whole and can be taken with or without food. According to the enzalutamide package insert, if the patient experiences ≥ grade 3 toxicity or intolerable side effects, dosing should be paused for one week or until the symptoms have improved to ≤ grade 2, and then the same dose or a reduced dose (120 mg or 80 mg) should be resumed as needed.

[0494] (v) Duration of study treatment

[0495] Patients will continue to be treated until radiographic disease progression, clinical / symptomatic progression, unacceptable / uncontrollable toxicity, or the patient refuses to receive further study treatment (i.e., withdraws consent). All patients will be followed up during the period of receiving study treatment and during the follow-up period after completion of study treatment: until death, the study cut-off date (at least 22 weeks after enrollment) or withdrawal of consent, whichever occurs first. The long-term follow-up of all patients will start from enrollment and continue for five years or until death or loss to follow-up.

[0496] E. Study procedures and assessments

[0497] Trial evaluations and time points are summarized in the activity schedules in Tables 15 and 16.

[0498] Table 15. 177 Event schedule for the Lu-PSMA-I&T group.

[0499]

[0500]

[0501] EOT = End of treatment; LTFU = Long-term follow-up; US = Unscheduled

[0502] a Throughout the treatment course, CT / bone scans were performed every 8 weeks until week 24 and, if there was no progression, continued every 12 weeks during LTFU.

[0503] b According to Section 8.5, progression assessments were performed every 12 weeks throughout LTFU until radiographic evidence of disease progression was detected.

[0504] Table 16. Event schedule for the standard-of-care hormone therapy group.

[0505]

[0506]

[0507] EOT = End of treatment; LTFU = Long-term follow-up; US = Unscheduled

[0508] a Throughout the treatment course, CT / bone scans were performed every 8 weeks until week 24 and, if there was no progression, continued every 12 weeks during LTFU.

[0509] b Throughout LTFU, progression assessments were performed every 12 weeks until radiographic evidence of disease progression was detected.

[0510] (i) Clinical evaluation

[0511] Clinical evaluation includes demographics, medical history, physical examination, vital signs, performance status, adverse events, concomitant medications / therapies, tumor assessment, and blinded independent central review (BICR).

[0512] For Performance status , the Eastern Cooperative Oncology Group (ECOG) performance status scale will be used and will be evaluated at screening and at each subsequent outpatient visit as shown in Table 17 below:

[0513] Table 17. Eastern Cooperative Oncology Group (ECOG) Performance Status Scale /

[0514]

[0515] Tumor assessment It will be conducted according to the assessment schedule, regardless of treatment delays due to toxicity. Care must be taken in scheduling tumor assessments to prevent bias due to treatment delays.

[0516] Tumor response will be evaluated in patients by CT imaging plus bone scan at screening and every 8 weeks (±1 week) from the start of treatment until week 24 of the study. Thereafter, for patients who do not show radiographic progression during the 24-week period, CT imaging and bone scan will be performed every 12 weeks (±1 week) until radiographic progression is determined. The schedule of scans will be calendar-based and not based on the start of treatment cycles. Assessments will include CT scans of the chest, abdomen, pelvis, and brain (only if clinically indicated based on symptoms / findings). The bone scans and CT images will be read by the investigator, sub-investigator, or qualified site personnel to assess for radiographic progression. If the investigator determines that the patient's metastatic prostate cancer has progressed, the patient's bone scan and CT images will be immediately sent to the Imaging Core Laboratory (ICL) for review by blinded independent central review (BICR) to confirm radiographic progression, as Figure 13 shown.

[0517] The investigator should not change the treatment until the disease status is confirmed by BICR.

[0518] Blinded Independent Central Review (BICR)

[0519] · Screening: All scan results (CT, bone, and PSMA PET) will be submitted to a third-party Imaging Core Laboratory (ICL) for independent review of patient eligibility (within 3 days of receipt of imaging scan results passing quality assessment). After confirmation by BICR, if all other eligibility criteria are met, the patient can be randomized into the study.

[0520] · Radiographic disease progression: The investigators will evaluate the CT and bone scan results based on the RECIST 1.1 and PCWG3 criteria to assess disease progression. If the investigators determine that disease progression has occurred, a panel BIRC consisting of two independent radiologists qualified to evaluate bone scans and CT images will independently evaluate disease progression according to the RECIST 1.1 and PCWG3 criteria. Confirmation of radiographic disease progression requires agreement between two blinded readers. If the two readers disagree, a third reader will make a ruling. BICR will complete the confirmation of disease progression within 72 hours after receiving the set of images showing radiographic progression provided by the investigators as soon as possible. Before receiving the confirmation of radiographic progression from BICR, the investigators should not make any changes to the clinical management of the patient. Figure 13 Shows the baseline and on-treatment disease status assessments and treatment decisions.

[0521] (ii) Patient-reported outcomes

[0522] Patient-reported outcomes will be determined using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Functional Assessment of Cancer Therapy - Prostate (FACT-P) questionnaire, and the Brief Pain Inventory - Short Form (BPI-SF) questionnaire.

[0523] The EORTC QLQ-C30 is a questionnaire of thirty QoL questions used to evaluate the quality of life (QoL) of cancer patients. The QoL questionnaire has been included as an efficacy endpoint in more than 3,000 phase 3 cancer clinical trials. At baseline, during treatment (as per the event schedule provided in Table 15), and at the end of treatment, patients will be administered the EORTC questionnaire.

[0524] The Functional Assessment of Cancer Therapy - Prostate (FACT-P) is a health-related quality of life questionnaire that has 39 prostate cancer-specific questions that assess the following aspects: physical health, functional health, emotional health, social health, and a prostate cancer subscale that focuses on or is specific to prostate cancer. Higher FACT-P scores correspond to better quality of life. At baseline, during treatment, and at the end of treatment, patients will be administered the FACT-P questionnaire.

[0525] The Brief Pain Inventory - Short Form (BPI-SF) is a short survey used to assess the overall pain and symptoms experienced by participants. At baseline, during treatment, and at the end of treatment, patients will be administered the BPI-SF questionnaire.

[0526] F. Study assessments by visit

[0527] (i) Screening

[0528] The screening must be completed within 28 days before random assignment to the study. The screening visit includes (a) drawing a blood sample and submitting it to the central laboratory to determine PSA levels and baseline clinical laboratory assessments, (b) obtaining CT scans of the brain, chest, abdomen, and pelvis plus a bone scan and submitting them to the BICR within 72 hours to confirm patient eligibility, (c) obtaining a PSMA-PET scan using an FDA-approved radiotracer ( 68 Ga]Ga-PSMA-11 or 18 F]DCFPyL). PSMA-PET positivity is required for trial inclusion. PSMA-PET positivity is defined as uptake of PSMA-PET greater than liver uptake in one or more metastatic lesions of any size in any organ system, (d) recording the medical history, including history of prostate cancer, date of diagnosis, and prior treatments, (e) recording concomitant medications, (f) performing a comprehensive physical examination, (g) performing and recording vital signs and ECOG performance status grade, (h) performing a 12-lead ECG, and (i) if the patient is confirmed eligible for inclusion in the study by the medical monitor, randomizing the patient according to the IVRS system and proceeding to the Cycle 1, Day 1 visit.

[0529] (ii) Day 1 of treatment

[0530] The following assessments will be performed on Day 1 of treatment:

[0531] · Conduct the EORTC QLQ-C30, FACT-P, and BPI-SF questionnaires before treatment to determine the baseline.

[0532] · Record any changes in concomitant medications and any adverse events noted since screening.

[0533] · Perform a brief physical examination

[0534] · Perform and record vital signs and ECOG performance status.

[0535] · Collect blood for clinical laboratory assessments.

[0536] · Administer the study drug in the clinic. For patients in the standard-of-care group included in this study, initiate the standard-of-care hormonal therapy designated by the investigator:

[0537] ○ Abiraterone acetate in combination with prednisone: The initial dose of abiraterone acetate is 1000 mg (four 250-mg tablets), administered once daily. The first dose of abiraterone acetate in combination with prednisone will be administered in the clinic. The time and date of initiation of abiraterone therapy will be recorded.

[0538] ○ Enzalutamide: The initial dose of enzalutamide is 160 mg (four 40-mg capsules), administered once daily. The first dose of enzalutamide will be administered in the clinic. The time and date of initiation of enzalutamide therapy will be recorded.

[0539] · The initial radioactive dose of 200 mCi (7.4 GBq) of 177 Lu-PSMA-I&T infusion should be administered to patients enrolled in the radioligand therapy group within at least 10 to 15 minutes. The 177 dose and time period of the Lu-PSMA-I&T infusion will be recorded.

[0540] · For patients enrolled in 177 Lu-PSMA-I&T, a 12-lead ECG will be performed after the first dose.

[0541] (iii) Treatment in the study

[0542] 177 Lu-PSMA I&T: Patients randomly assigned to the radioligand therapy group in this study will receive 177 Lu-PSMA I&T infusion with a 6-week infusion cycle and a dose of 200 mCi (7.4 GBq) until radiographic progression is confirmed by BICR or until the patient experiences toxicity requiring discontinuation of treatment or withdraws their consent to participate in the study. Patients in this study can be given up to 4 cycles of 177 Lu-PSMA I&T infusion.

[0543] Abiraterone and enzalutamide standard care group: Patients randomly assigned to the standard care group and receiving abiraterone or enzalutamide treatment will be treated daily with the standard care dose regimen of these drugs according to their prescription information. Patients in this treatment group will continue with standard care treatment until radiographic progression is confirmed by BICR or until the patient experiences toxicity requiring discontinuation of treatment or withdraws their consent to participate in the study.

[0544] (iv) Continuous assessment

[0545] For patients randomly receiving 177 Lu-PSMA I&T and patients receiving abiraterone or enzalutamide standard care, all enrolled patients will be continuously assessed every 4 weeks.

[0546] (v) Progression assessment

[0547] All patients included in the study will be evaluated starting at 8 weeks + 1 week from initial treatment and continuing until week 24, and then every 12 weeks thereafter until radiographic evidence of disease progression is found. The evaluation consists of: (i) obtaining chest, abdominal, and pelvic CTs and bone scans and submitting them to the ICL (Imaging Core Laboratory) for BICR evaluation, and (ii) obtaining plasma samples for PSA and other clinical laboratory evaluations.

[0548] (vi) End-of-treatment visit

[0549] The end-of-treatment (EOT) visit will be conducted one month (±7 days) after the last infusion of 177 Lu-PSMA I&T. Patients receiving abiraterone acetate or enzalutamide may continue their daily treatment until the EOT visit. The following evaluations will be performed: administering the EORTC QLQ-C30, FACT-P, and BPI-SF questionnaires; recording any changes in concomitant medications; recording any adverse events found since screening; performing a brief physical examination; performing and recording vital signs and ECOG performance status; and collecting blood for clinical laboratory evaluations, including PSA and other clinical laboratory evaluations.

[0550] (vii) Crossover

[0551] Patients in the standard-of-care hormone therapy group may crossover to receive 177 Lu-PSMA I&T based on the following criteria:

[0552] · Must have documented radiographic progression confirmed by BICR per RECIST 1.1 modified by PCWG3 during treatment with standard-of-care hormone therapy

[0553] · Must not have started any other anti-cancer drugs or therapies.

[0554] · Participants with organ and bone marrow dysfunction (as defined below) will not be eligible for crossover:

[0555] ○ Absolute neutrophil count < 1.5 x 109 / L

[0556] ○ Platelet count < 100 x 109 / L.

[0557] ○ Hemoglobin < 8 g / dL.

[0558] ○ AST / SGOT and / or ALT / SGPT > 3.0 x ULN.

[0559] ○ Total bilirubin > 2 x ULN, unless the patient has known Gilbert's syndrome, in which case it may be 3 x ULN.

[0560] ○ Based on the Cockcroft-Gault equation, creatinine clearance (CrCl) < 50 mL / min.

[0561] ○ Albumin ≥ 2.75 g / dL

[0562] If a patient does not meet the eligibility for crossover, they should complete the end-of-study visit and enter long-term follow-up.

[0563] (viii) Long-term follow-up

[0564] Long-term patient follow-up will continue for up to 5 years after the initial treatment in this study, or until the patient dies or is lost to follow-up. The following information will be collected:

[0565] · Survival status, development of symptomatic disease progression, initiation of any new systemic anticancer therapy, progression of the first subsequent therapy, and medical resource utilization every 4 months.

[0566] · Additionally, if a patient discontinues study treatment prior to documented disease progression, a CT of the chest, abdomen, and pelvis plus a bone scan should be obtained every 12 weeks and submitted to the BICR to assess disease progression until radiographic disease progression is documented.

[0567] G. Statistical considerations and analysis plan

[0568] (i) Sample size

[0569] Assume that 177 treatment of patients with Lu-PSMA I&T will increase the radiographic progression-free survival (rPFS) from 6 months in the standard-of-care group to 10 months. Therefore, under the alternative hypothesis, it is reasonable to expect the target hazard ratio (HR) for this Phase 3 study to be 0.60. Using a 2:1 randomization, at an overall significance level of α = 0.05 and using a two-sided log-rank test, 237 progression events in the two treatment groups will provide 95% power to detect a statistically significant treatment effect. Considering the expected cumulative rate and follow-up time, these 237 progression events will occur in an estimated 269 patients.

[0570] Also assume that 177 treatment of patients with LuPSMA I&T will extend the overall survival (OS) from 18 months in the standard-of-care group to 25 months. Therefore, under the alternative hypothesis, it is reasonable to expect the target hazard ratio (HR) for this Phase 3 study to be 0.70.

[0571] Using a larger HR (associated with OS) and a 2:1 randomization, 352 events in the two treatment groups estimated will provide 95% power to detect a statistically significant treatment effect at an overall significance level of α = 0.0, using a two-sided log-rank test. Given the expected cumulative rate and follow-up time, these 352 deaths will occur in an estimated 400 patients.

[0572] (ii) Planned interim analyses

[0573] Two interim analyses and one final analysis will be conducted on the secondary outcome variable overall survival (OS). The first interim analysis will be conducted after approximately 25% (90 deaths) have been observed, and the second interim analysis will be conducted after approximately 75% (264 deaths) have been observed. The final analysis will be conducted after all 352 planned deaths have been observed. The first OS interim analysis is expected to be conducted when all 237 progression events have been observed in the primary endpoint analysis.

[0574] The interim and final analyses of OS will be conducted using a two-sided log-rank test at a nominal significance level adjusted using the standard O'Brien-Fleming spending function for α. The nominal significance level for the first interim analysis of OS will be α = 0.0006, the nominal significance level for the second interim analysis will be α = 0.0151, and the final analysis will use a nominal significance level of α = 0.047. These p-values satisfy the cumulative α = 0.05 O'Brien-Fleming spending function.

[0575] If in any of the interim analyses, the test for OS reaches the nominal significance level, this study will be considered positive and, after review and approval by the Data Monitoring Committee (DMC), patient recruitment can be stopped.

[0576] (iii) Analysis populations

[0577] This study plans to enroll a total of 400 patients.

[0578] · Intention-to-treat (ITT) population: All randomized patients are classified according to the treatment group to which they were randomized, regardless of the treatment actually received.

[0579] · Safety population: All treated patients are classified according to the treatment actually received, regardless of randomization.

[0580] · Cross-over population: All patients in the ITT population, but where the analysis utilizes patients who crossed over from standard care treatment to 177Information on Lu-PSMA I&T treatment. This will be used for the final OS analysis.

[0581] Other efficacy datasets may be defined in the SAP (Statistical Analysis Plan) (per protocol, evaluable, etc.), but the primary analysis of efficacy will be for the ITT population.

[0582] (iv) Efficacy analysis

[0583] The primary efficacy analysis will use the ITT population. Unless otherwise stated, the analysis of secondary endpoints will be based on data collected during the randomly assigned treatment period.

[0584] a. Radiographic progression-free survival

[0585] rPFS is the time from random assignment to the first documentation of radiographic progressive disease or death from any cause. The rPFS time of any living patients without radiographic documentation of progression or any patients who initiate other anti-cancer systemic therapies will be reviewed at the last evaluable disease assessment date of the study. The rPFS time of patients without an evaluable disease assessment in the study will be reviewed at random assignment. The frequency of rPFS will be approximately every 8 weeks from the first treatment to week 24, and then every 12 weeks.

[0586] The Kaplan-Meier product-limit method will be used to estimate the distribution of rPFS times. The median rPFS time and two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate the HR and its two-sided 95% CI (confidence interval).

[0587] b. Overall survival

[0588] OS time is the time from random assignment to death from any cause. OS will be followed up for 5 years after study inclusion, or until death or loss to follow-up. Patient data in the standard care group will not be reviewed at crossover.

[0589] The Kaplan-Meier product-limit method will be used to estimate the distribution of OS times. The median OS time and two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate the hazard ratio and its two-sided 95% CI.

[0590] If a sufficient proportion of patients crossover to 177For Lu-PSMA-I&T, a supplementary analysis can be conducted. This analysis will utilize the Rank Preserving Structural Failure Time (RPSFT) (Robins et al. 1991) method.

[0591] c. Second radiographic progression-free survival

[0592] rPFS2 is the time from randomization to the second recorded radiographic disease progression or death from any cause. rPFS2 is defined as the time from randomization to the second radiographic progression (using the PCWG3 criteria evaluated by blinded independent central review [BICR]) or death of a participant who crossed over from the standard-of-care hormonal therapy group to 177 the time of death of a participant receiving Lu-PSMA I&T.

[0593] The Kaplan-Meier product-limit method will be used to estimate the distribution of rPFS2 times. The median rPFS2 time and two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis to compare treatment effects. The Cox proportional hazards model will be used to estimate the HR and its two-sided 95% CI.

[0594] d. Progression-free survival

[0595] Progression is defined as the first occurrence of PCWG3 progression, clinical / symptomatic progression, and / or pain progression, or death from any cause. The time to progression will be evaluated for all patients. Any patient without a recorded progression or any patient who starts receiving other anticancer systemic therapies will be reviewed at the last evaluable disease assessment date of the study.

[0596] The Kaplan-Meier product-limit method will also be used to estimate the distribution of PFS. The median PFS time and two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis to compare treatment effects. The Cox proportional hazards model will be used to estimate the HR (hazard ratio) and its two-sided 95% CI.

[0597] If a sufficient proportion of patients cross over to 177 Lu-PSMA-I&T, a supplementary analysis can be conducted. This analysis will utilize the rank preserving structural failure time method.

[0598] e. Second progression-free survival

[0599] Progression-free survival 2 is the time from randomization to progression based on the following events, whichever occurs first: RECIST 1.1 progression, PCWG3 progression, clinical / symptomatic progression, and / or pain progression, or death from any cause as evaluated by the investigator.

[0600] The Kaplan - Meier product - limit method will also be used to estimate the distribution of PFS2. The median PFS2 time and the two - sided 95% CI will be estimated for each treatment group. The log - rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate the HR and its two - sided 95% CI.

[0601] If a sufficient proportion of patients cross over to 177 Lu - PSMA I&T, a supplementary analysis can be conducted. This analysis will utilize the rank - preserving structural failure time method.

[0602] f. PSA50 response rate

[0603] PSA50 is defined as the response rate of patients who achieve a ≥50% reduction in PSA from the baseline PSA assessment. The PSA50 and the corresponding exact 95% CI will be calculated for each treatment group. Additionally, the difference in response rates and the 95% CI will also be determined. 177 The primary test for treatment effect between Lu - PSMA I&T and standard of care is the Cochran - Mantel - Haenszel (CMH) general association chi - square test, controlling for random assignment stratification. The relative risk and the two - sided 95% CI will be calculated.

[0604] g. Time to the first symptomatic skeletal event

[0605] The time to the first symptomatic skeletal event (or SSE - free survival) is defined as the occurrence of bone - directed radiotherapy for pain relief, new symptomatic pathologic fracture, spinal cord compression, or tumor - related orthopedic surgery. The time to SSE will be evaluated for all patients. Any patient with an unrecorded event or who starts other systemic anti - cancer therapies will be reviewed at the last evaluable disease assessment date of the study.

[0606] The Kaplan - Meier product - limit method will also be used to estimate the distribution of SSE. The median SSE time and the two - sided 95% CI will be estimated for each treatment group. The log - rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate the HR and its two - sided 95% CI.

[0607] If a sufficient proportion of patients cross over to 177 Lu - PSMA I&T, a supplementary analysis can be conducted. This analysis will utilize the rank - preserving structural failure time method.

[0608] h. Time to soft - tissue progression

[0609] The time to first radiographic soft tissue progression (STP) is defined as the occurrence of radiographic progression in soft tissue as detected by RECIST 1.1 as modified by PCWG3. The time to STP will be evaluated for all patients. Any patient with an unrecorded event or any patient who starts receiving other anti-cancer systemic therapies will be reviewed at the date of the last evaluable disease assessment in the study.

[0610] The distribution of STP will also be estimated using the Kaplan-Meier product limit method. The median STP time and bilateral 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis to compare treatment effects. The Cox proportional hazards model will be used to estimate the HR and its bilateral 95% CI.

[0611] If a sufficient proportion of patients cross over to 177 Lu-PSMA I&T, a supplementary analysis can be conducted. This analysis will utilize the rank-preserving structural failure time method.

[0612] i. Time to chemotherapy

[0613] The time to chemotherapy (TTC) is defined as the time from randomization to the start of chemotherapy or death (whichever occurs first). The time to chemotherapy will be evaluated for all patients. Any patient with an unrecorded event or any patient who starts receiving other anti-cancer systemic therapies will be reviewed at the date of the last evaluable disease assessment in the study.

[0614] The distribution of TTC will also be estimated using the Kaplan-Meier product limit method. The median TTC time and bilateral 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis to compare treatment effects. The Cox proportional hazards model will be used to estimate the HR and its bilateral 95% CI.

[0615] If a sufficient proportion of patients cross over to 177Lu-PSMA I&T, a supplementary analysis can be conducted. This analysis will utilize the rank-preserving structural failure time method.

[0616] j. Quality of life

[0617] The EORTC QLQ-C30 is a questionnaire of 30 QoL questions used to evaluate the QoL of cancer patients. It has been translated into 81 languages (including English and Mandarin Chinese) and validated. Version 3.0 of the QLQ-C30 will be used in this Phase 3 study. In over 3,000 Phase 3 cancer clinical trials, the QoL questionnaire has been used as an efficacy endpoint.

[0618] Patients will be given the EORTC questionnaire at baseline, on Day 8 of each cycle, and at EOT. Many statistical techniques for analyzing QoL data are presented in the literature. The statistical methods to be used will be included in the SAP.

[0619] k. Objective response rate

[0620] The objective response rate (ORR) of the treatment regimen will be evaluated according to RECIST version 1.1, and the best overall response will be classified as CR, PR, stable disease, progressive disease (PD), and not evaluable (NE). The ORR is defined as the proportion of patients achieving CR or PR. CT and bone scan results (if applicable) at baseline and during the study will be reviewed by independent radiologists at the central imaging laboratory to determine objective response, response date, and progression.

[0621] The ORR in each treatment group will be calculated along with the corresponding exact 95% CI. Additionally, the difference in response rates and the 95% CI will also be determined. 177 The primary test for treatment effect between Lu-PSMA I&T and standard of care is the Cochran-Mantel-Haenszel (CMH) general association chi-square test, controlling for random assignment stratification. The relative risk and two-sided 95% CI will be calculated.

[0622] Further analysis of the ORR can be performed using cross-groups.

[0623] l. Disease control rate

[0624] The disease control rate (DCR) of the treatment regimen will be evaluated according to RECIST version 1.1, and the best overall response will be classified as CR (complete response), PR (partial response), stable disease, progressive disease (PD), and not evaluable (NE). The DCR is defined as the proportion of patients achieving disease control.

[0625] The DCR in each treatment group will be calculated along with the corresponding exact 95% CI. Additionally, the difference in response rates and the 95% CI will also be determined. 177 The primary test for treatment effect between Lu-PSMA I&T and standard of care is the Cochran-Mantel-Haenszel (CMH) general association chi-square test, controlling for random assignment stratification. The relative risk and two-sided 95% CI will be calculated.

[0626] Further analysis of the DRR can be performed using cross-groups.

[0627] m. Duration of response

[0628] Among patients who achieve the best objective response of CR or PR, DoR is the time from the first observation of CR or PR (whichever occurs first) to the first documented disease progression. The DoR of any patient without documented progression or any patient who starts receiving other anti-cancer systemic therapies will be reviewed at the last evaluable disease assessment date of the study.

[0629] The distribution of DoR will also be estimated using the Kaplan-Meier product-limit method. The median DoR time and two-sided 95% CI for each treatment group will be estimated. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate the HR and its two-sided 95% CI.

[0630] If a sufficient proportion of patients cross over to 177 Lu-PSMA I&T, a supplementary analysis can be conducted. This analysis will utilize the rank-preserving structural failure time method.

[0631] n. Time to PSA progression

[0632] Time to PSA progression is evaluated as an increase in PSA of ≥25% from the post-treatment nadir or baseline PSA (if no nadir) at the last evaluable disease assessment date of the study. The time to PSA progression of any patient without documented progression or any patient who starts receiving other anti-cancer systemic therapies will be reviewed at the last evaluable disease assessment date of the study.

[0633] The distribution of time to PSA progression will also be estimated using the Kaplan-Meier product-limit method. The median time to PSA progression and two-sided 95% CI for each treatment group will be estimated. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate the HR and its two-sided 95% CI.

[0634] If a sufficient proportion of patients cross over to 177 Lu-PSMA I&T, a supplementary analysis can be conducted. This analysis will utilize the rank-preserving structural failure time method.

[0635] (vi) Clinical laboratory assessments

[0636] Clinical laboratory results can be collected from pre-treatment to 28 days after the last dose of any study therapy. All clinically significant laboratory abnormalities, i.e., tests that cause treatment modification and / or require intervention, can be recorded as AEs.

[0637] H. End of trial

[0638] Patients may continue to receive study treatment until disease progression confirmed by BICR, unacceptable toxicity, or withdrawal of consent. Patients who discontinue study treatment may enter a long-term follow-up period and continue to be studied until death, loss to follow-up, or withdrawal of consent (whichever occurs first).

[0639] With an estimated cumulative duration of 12 - 24 months, it is assumed that follow-up of human patients can be at least approximately 34 weeks after the Last Patient In (LPI) for the primary endpoint of radiographic progression-free survival to 5 years after LPI for the secondary endpoint of OS. This corresponds to an expected total study duration of approximately 6 - 7 years.

[0640] Example 6: Pharmacokinetics and Dosimetry Substudy

[0641] A. Objectives

[0642] The objective of this study is to evaluate the plasma pharmacokinetics and dosimetry of 177 Lu-PSMA I&T radioligand therapy in 30 patients.

[0643] This substudy aims to evaluate 177 the plasma pharmacokinetic profile and dosimetry of Lu-PSMA I&T radioligand therapy over 4 treatment cycles.

[0644] B. Study Design and Patient Population

[0645] Table 18 provides the representative batch certifications of each batch of 177 Lu-PSMA I&T used in the study.

[0646] Table 18: 177 Representative Certifications of Analyses of Lu-PSMA I&T

[0647]

[0648]

[0649] 177 The plasma pharmacokinetic profile and radiation absorbed dose of Lu-PSMA I&T radioligand therapy will be evaluated in a subgroup of 30 patients who will participate in the study of Example 5. This subgroup of 30 patients will undergo the same screening procedures as the main protocol of Example 5 in order to be randomly assigned to the study according to the same inclusion / exclusion criteria as in Example 5 and will follow the following additional inclusion criteria:

[0650] Inclusion Criteria

[0651] · Inclusion in the main study (Example 5).

[0652] · Separate informed consent for participation in the sub-study.

[0653] · Willingness to undergo planar imaging and / or SPECT / CT imaging at 4 hours, 24 hours, 48 hours, and 6 - 8 days after each 177 Lu-PSMA I&T treatment cycle (main study cycles 1 - 6).

[0654] Exclusion criteria

[0655] · Unable to perform SPECT / CT imaging as required by the sub-study protocol.

[0656] C. Methods

[0657] Plasma pharmacokinetic profiles for the group of 30 patients included in this study will be determined by obtaining plasma samples at approximately 1 hour, 4 hours, 24 hours, 48 hours, and 6 - 8 days before and after each infusion of 177 Lu-PSMA I&T. The completion time of the Lu-PSMA I&T infusion and the actual time of sample collection will be recorded. The radioactivity in the plasma samples will be measured using a calibrated well counter, and the percentage of the injected dose will be calculated after correcting for 177 the 6.647-day radioactive decay half-life of Lu. 177 177

[0658] Planar whole-body scintigraphic images will be obtained at approximately 4 hours, 24 hours, 48 hours, and 6 - 8 days after each infusion of 177 Lu-PSMA I&T. SPECT / CT images of the upper abdomen, kidneys, and salivary glands will be obtained at approximately 24 hours and 6 - 8 days after each infusion of 177 Lu-PSMA I&T. The actual start time and date of all scintigraphic imaging will be recorded on the CRF.

[0659] The imaging data will be submitted to the core imaging laboratory for processing. For tumor dosimetry calculations, regions of interest (ROIs) will be selected that have negligible overlap with lesions of high physiological uptake or other positive scintigraphic findings. Background ROIs will be obtained from outside the body. At least ROIs of the whole body, kidneys, liver, parotid glands, submandibular glands, and lacrimal glands will be selected, as well as tumor ROIs and ROIs of other organs showing significant uptake of 177 Lu-PSMA I&T.

[0660] After administration / infusion of a certain dose of 177After the Lu-PSMA I&T solution, human patients can undergo single photon emission computed tomography (SPECT) / computed tomography (CT) imaging, for example, at four time points (4 hours, 24 hours, 48 hours, 168 hours). The image data can be analyzed to calculate the time integrated activity coefficient (TIAC) for each organ of interest and / or organs where the 177Lu-PSMA I&T activity is significantly higher than the background and meaningful (including the kidneys, bladder, liver, lumbar vertebrae L2-L4, lacrimal glands, salivary glands, intestines, whole body, and combinations thereof). To calculate the organ dose specific to the subject, the organ level TIAC data can be input into the Organ Level Internal Dose Assessment (OLINDA) 2.2.3 and the resulting organ doses and the whole body effective dose for each target organ (e.g., the kidneys) can be tabulated and averaged.

[0661] D. Schedule of activities specific to the pharmacokinetics and radiodosimetry sub-studies

[0662] (i) Screening

[0663] · Verify compliance with inclusion / exclusion criteria

[0664] · Obtain informed consent for participation in the sub-study

[0665] (ii) 177 Lu-PSMA I&T infusion cycles 1-4

[0666] · As shown in Table 19, obtain plasma samples approximately 1 hour, 4 hours, 24 hours, and 48 hours, and at 6 - 8 days before and after each 177 Lu-PSMA I&T infusion is completed.

[0667] · At each infusion 177 Obtain planar whole body scintigraphy images approximately 4 hours, 24 hours, and 48 hours, and at 6 - 8 days after each

[0668] · At each infusion 177 Obtain SPECT / CT images approximately 24 hours and at 6 - 8 days after each

[0669] Table 19. Sampling time point schedule.

[0670]

[0671] E. Statistical methods

[0672] (i) Pharmacokinetic parameters

[0673] The following PK parameters of the whole blood radioactivity count from 177 Lu-PSMA-I&T infusion will be appropriately determined:

[0674] ·AUC 0-24；0-last : Area under the curve of the whole blood radioactivity count time curve (0 hours to 24 hours, 0 to last), calculated using the trapezoidal rule

[0675] ·AUC 0-∞ : Area under the curve of the whole blood radioactivity count time curve starting from AUC 0-24 or AUC 0-last + Area under the curve estimated by Cp n / k el where:

[0676] Cp n = The last observed whole blood radioactivity count at time n

[0677] k el = Elimination rate constant, calculated based on the log-linear terminal portion of the whole blood radioactivity count time curve

[0678] ·C max : The maximum observed whole blood radioactivity count

[0679] ·T max : Time to C max

[0680] ·k el : Elimination rate constant, calculated based on the log-linear terminal portion of the whole blood radioactivity count time curve

[0681] ·t 1 / 2 : Apparent elimination half-life, calculated as ln2 / k el

[0682] ·CL: Total body clearance following extravascular administration at steady state, calculated as dose / AUC 0-24

[0683] ·V d : Volume of distribution

[0684] (ii) 177 Lu-PSMA I&T infusion radioactivity count

[0685] ·C(t): The radioactivity count measured at time = t will be tabulated by time and for each patient. Whole blood radioactivity counts below the limit of quantification are considered zero (0).

[0686] (iii) Area under the curve

[0687] Unless otherwise stated, the following characteristics will be calculated for all complete curves:

[0688] ·AUC 0-24，0-last : The area under the whole blood radioactivity count C(t) after administration will be calculated using the trapezoidal rule.

[0689] All references cited herein are hereby incorporated by reference. The foregoing has been provided primarily for purposes of illustration. 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 substituted in various ways without departing from the spirit and scope of the invention.

[0690] Example 7: Regarding the 177 Comparative study on extending the product expiration date of Lu-PSMA I&T from 48 hours to 74 hours

[0691] The purpose of this study was to 177 extend the expiration date of the Lu-PSMA I&T injection from 48 hours to 72 hours. The 72-hour expiration was achieved by modifying the drug product components, by 177 reducing the strength of Lu-PSMA I&T from 1 GBq / mL to 0.5 GBq / mL and maintaining a more stringent pH in the range of 4 to 5 for the formulated drug product. The total patient dose remained unchanged at 7.4 GBq 177 of Lu-PSMA I&T. To deliver the desired radioactive dose, the volume of the drug was increased from 8 - 10 mL to 15 - 20 mL. Accordingly, the primary container closure system was changed from a 10 mL vial to a 20 mL vial while maintaining the same glass quality, the same elastomeric closure, and the same aluminum crimp seal (Table 20).

[0692] In this study, the stability of "Drug Product B" was investigated and the result was an extension of the 177 expiration date of the Lu-PSMA I&T injection of "Drug Product A".

[0693] A. Description and composition of the drug product

[0694] Table 20. Description of the drug product

[0695]

[0696] Table 20 provides 177The qualitative and quantitative composition of Lu-PSMA I&T injection, which has been compositionally changed to increase the shelf life by reducing the strength (radioactivity concentration) from 1 GBq / mL to 0.5 to 0.6 GBq / mL using a more stringent pH and increasing the fill volume to - 20 mL / vial. The number of vials per batch was adjusted to produce the dose quantity required for therapeutic administration. Table 21 provides 177 The qualitative and quantitative composition of the drug product of Lu-PSMA I&T.

[0697] Table 21. 177 The qualitative and quantitative composition of the drug product of Lu-PSMA I&T

[0698]

[0699]

[0700] * North American medical institutions stipulate that the maximum adult dose is 2,000 mg / day, so 700 mg is acceptable.

[0701] ** 177 The recommended dose of Lu-PSMA I&T is 7.4 GBq (200 mCi) / administration. Depending on the actual radioactivity intensity of each batch, the volume dispensed into 20 mL vials may vary between approximately 15 - 20 mL.

[0702] *** The updated pH range is within the range of other FDA-approved USP-grade injectable solutions (e.g., 5% dextrose injection solution).

[0703] The changes associated with the extended shelf life did not change the properties, quality, or purity of any of the components in the drug substance or drug product. It did change the strength of the API in the final drug product, established a narrower pH control range, and modified the concentrations of the two main excipients, ascorbic acid and ethanol. These changes were made to extend the shelf life of the drug product.

[0704] In the context of these changes associated with the extended shelf life, the batch size was scaled proportionally to provide the quantity of therapy doses, plus the overage required to provide quality control test samples for microbial and chemical testing and reserve samples for each batch. In this context, all components and excipients were scaled based on the measured quantity of the radioactive Lu-177 precursor labeling solution.

[0705] B. Manufacturing method

[0706] This extended shelf-life study does not involve any substantial changes to the manufacturing method, equipment, or reagents used. The re-formulated product is formulated to a lower radioactivity concentration (intensity), more stringent pH limits are applied, and the same excipients are used, but the intensity is different from the original formulation. Since the manufacturing chemistry of the drug substance remains unchanged, these changes only apply to the formulation of the final drug product solution.

[0707] pH is the only updated critical step. The pH of the final drug product solution is controlled within a narrower range of 4.0 to 5.0 from 5.0 to 8.0. This is achieved by the controlled addition of hydrochloric acid.

[0708] During the specified shelf life, the stability of the product was evaluated at storage temperatures of 2°C - 40°C. Additionally, microbial bioburden studies were conducted on three other batches of 177 Lu-PSMA I&T injection. All batches met the pre-determined acceptance criteria at the extended 72-hour time point. The product composition changed, with the target intensity decreasing from -1 GBq / mL to 0.5 to 0.6 GBq / mL. The pH range was also controlled within a narrower range of 4.0 to 5.0 from 5.0 to 8.0, and due to the lower formulation intensity, the dispensed volume increased from 10 mL / vial to 20 mL / vial. Additionally, the intensities of ascorbic acid and ethanol also decreased. This lower-intensity product was subjected to process validation studies to confirm that a 72-hour shelf life had been achieved.

[0709] Media fill studies were successfully conducted on three test batches to support aseptic filling operations corresponding to the change in drug product volume (increase) and vial size.

[0710] The excipients used in the drug product formulation did not change and remained (ethanol, ascorbic acid, and water for injection). In the case of the change in the drug product formulation, no new impurities were generated or existing impurities increased. Only the concentration / volume of the existing formulation was adjusted to achieve a larger volume.

[0711] Table 22 below lists the test and acceptance criteria for Drug Product A and Drug Product B.

[0712] Table 22. 177 Test and acceptance criteria for Lu-PSMA-I&T injection Drug Product A and Drug Product B.

[0713]

[0714] *Dose = The maximum volume administered per dose is defined as 10 mL (200 mCi) for the original formulation and 20 mL (200 mCi) for the new formulation

[0715] **There is no change in the sterilizing filter.

[0716] ***The sterility test samples start after release.

[0717] C. Analytical procedures

[0718] Due to the decrease in the product strength (radioactivity concentration) (per mL), the sample injection volume for some drug product tests increased from 50 μL to 100 μL. Due to this change, the following method validation studies were conducted:

[0719] ·Determination of colloidal impurities in Lu-177-PSMA injection by TLC

[0720] ·Bioburden - microbial growth

[0721] ·Endotoxin test

[0722] ·Sterility test

[0723] ·Determination of ethanol by gas chromatography

[0724] The decrease in strength (radioactivity concentration) causes a slowdown in the radiolytic decomposition rate, such that at 72 hours after the end of synthesis, the radiochemical purity remains above 95%. In fact, this does not cause the formation of any new impurities or an increase in existing impurities

[0725] D. Container closure system

[0726] The vials in the primary container closure system were changed from 10 mL glass pharmaceutical grade injection vials to 20 mL vials with the same pharmaceutical grade and neck finish. It is sealed with the current fluorine-coated bromobutyl elastomeric closure and secured in place with a top-opening aluminum crimp. There are no changes to the elastomeric closure or the crimp (Table 23).

[0727] Table 23. Comparison of container closures for drug product A and drug product B

[0728]

[0729] E. Stability

[0730] Over a time span of 72 hours after the end of the synthesis time, the radiochemical purity and chemical properties (including pH, impurities, and visual properties) of the 0.5 GBq / mL 177 Lu PSMA-I&T injection solution were tested on three process validation and four separate stability batches. All batches utilized 177 the Lu precursor labeling solution. For all batches 177Stability samples of the Lu-PSMA-I&T injection drug product were stored at room temperature, with selected samples also stored inverted, and some samples stored at elevated temperatures. Initial testing was typically completed within 7 hours after the end of synthesis, and stability indicating tests were repeated at 24 hours, 48 hours, and 72 hours after EOS. For samples formulated at an activity of -0.5 GBq / mL, no deviations from the specification acceptance criteria were observed in samples tested up to and including 72 hours. Based on these supportive stability data, a shelf life of 72 hours after the end of synthesis was designated. Table 24 provides the variation in the shelf life of the drug product.

[0731] Table 24. Comparison of the shelf life of Drug Product A and Drug Product B

[0732] Attribute Drug product A Drug product B Shelf life (expiry) 48 hours after synthesis completion 72 hours after synthesis completion

[0733] F. Conclusions

[0734] The 72-hour expiry was achieved by modifying the drug product formulation by reducing the activity of 177 Lu PSMA I&T from 1 GBq / mL to 0.5 GBq / mL and maintaining the formulated drug product at a more stringent pH in the range of 4 to 5.

[0735] All references cited herein are hereby incorporated by reference. The foregoing has been provided primarily for purposes of illustration. 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 substituted in various ways without departing from the spirit and scope of the invention.

[0736] Numerous examples are provided herein to enhance understanding of the disclosure. A specific set of statements is provided below.

[0737] Statement 1: A radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the composition is formulated as a solution for injection and the solution is suitable for administration more than 72 hours after formulation.

[0738] Statement 2: The radiopharmaceutical composition according to Statement 1, wherein the solution is suitable for administration up to 3 days after formulation.

[0739] Statement 3: The radiopharmaceutical composition according to Statement 1, wherein the solution is suitable for administration up to 4 days after formulation.

[0740] Statement 4: The radiopharmaceutical composition according to Statement 1, further comprising an antioxidant.

[0741] Claim 5: The radiopharmaceutical composition according to Claim 4, wherein the antioxidant is ascorbic acid.

[0742] Claim 6: The radiopharmaceutical composition according to Claim 5, wherein the solution contains 21 mg / ml to 31 mg / ml of ascorbic acid.

[0743] Claim 7: The radiopharmaceutical composition according to Claim 5, wherein the solution contains 42.5 mg / ml of ascorbic acid.

[0744] Claim 8: The radiopharmaceutical composition according to Claim 1, wherein the solution further contains hydrochloric acid.

[0745] Claim 9: The radiopharmaceutical composition according to Claim 1, wherein the solution contains 1.7 mg / ml to 34 mg / ml of hydrochloric acid.

[0746] Claim 10: The radiopharmaceutical composition according to Claim 1, wherein the pH of the solution is 4.5 or less.

[0747] Claim 11: The radiopharmaceutical composition according to Claim 1, wherein the pH of the solution is 5 or less.

[0748] Claim 12: The radiopharmaceutical composition according to Claim 1, wherein the radioactivity of the solution is less than 635 MBq / ml.

[0749] Claim 13: The radiopharmaceutical composition according to Claim 12, wherein the radioactivity of the solution is 579 MBq / ml to 626 MBq / ml.

[0750] Claim 14: The radiopharmaceutical composition according to Claim 1, wherein the radiochemical purity of the solution exceeds 95% at 46 to 48 hours after compounding.

[0751] Claim 15: The radiopharmaceutical composition according to Claim 14, wherein the radiochemical purity of the solution exceeds 96% at 46 to 48 hours after compounding.

[0752] Claim 16: The radiopharmaceutical composition according to Claim 14, wherein the radiochemical purity of the solution exceeds 97% at 46 to 48 hours after compounding.

[0753] Claim 17: The radiopharmaceutical composition according to Claim 1, wherein the radiochemical purity of the solution exceeds 95% at 69 to 71 hours after compounding.

[0754] Claim 18: The radiopharmaceutical composition according to Claim 17, wherein the radiochemical purity of the solution exceeds 96% at 69 to 71 hours after compounding.

[0755] Statement 19: The radiopharmaceutical composition according to Statement 17, wherein the radiochemical purity of the solution exceeds 97% at 69 to 71 hours after compounding.

[0756] Statement 20: The radiopharmaceutical composition according to Statement 1, wherein the radiochemical purity of the solution exceeds 95% at 90 to 93 hours after compounding.

[0757] Statement 21: The radiopharmaceutical composition according to Statement 20, wherein the radiochemical purity of the solution exceeds 96% at 90 to 93 hours after compounding.

[0758] Statement 22: The radiopharmaceutical composition according to Statement 20, wherein the radiochemical purity of the solution exceeds 97% at 90 to 93 hours after compounding.

[0759] Statement 23: The radiopharmaceutical composition according to Statement 1, wherein the solution contains less than 6 μg / ml of Lu-PSMA I&T.

[0760] Statement 24: The radiopharmaceutical composition according to Statement 1, which further comprises a metal ion chelator.

[0761] Statement 25: The radiopharmaceutical composition according to Statement 24, wherein the metal ion chelator is disodium EDTA.

[0762] Statement 26: The radiopharmaceutical composition according to Statement 25, wherein the solution contains approximately 15.5 μg / ml of disodium EDTA.

[0763] Statement 27: The radiopharmaceutical composition according to Statement 1, which further comprises a stabilizer.

[0764] Statement 28: The radiopharmaceutical composition according to Statement 27, wherein the stabilizer is ethanol. The stabilizer of the radiopharmaceutical composition according to Statement 27 is not ethanol.

[0765] Statement 29: The radiopharmaceutical composition according to Statement 28, wherein the solution contains approximately 37.5 μl / ml of ethanol.

[0766] Statement 30: The radiopharmaceutical composition according to Statement 1, which further comprises 31 mg / ml of ascorbic acid and a certain amount of hydrochloric acid, the amount being adjusted such that the pH of the solution is 4.5.

[0767] Statement 31: The radiopharmaceutical composition according to Statement 30, which further comprises 15.5 μg / ml of disodium EDTA and 37.5 μL / ml of ethanol.

[0768] Claim 32: The radiopharmaceutical composition according to Claim 30 or 31, further comprising a sufficient amount of sodium bicarbonate and NaOH to control the pH at 4.5.

[0769] Claim 33: The radiopharmaceutical composition according to Claim 30, wherein the radioactivity of the solution is 588.5 MBq / ml.

[0770] Claim 34: The radiopharmaceutical composition according to Claim 30, wherein the radiochemical purity of the solution 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.

[0771] Claim 35: A radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the composition is suitable for administration to a human patient in need thereof within at least 90 hours after compounding, and wherein the radiochemical purity of the composition at the time of administration is 95% or higher.

[0772] Claim 36: The radiopharmaceutical composition according to Claim 35, wherein the composition comprises <6 μg of Lu-PSMA I&T per mL of solution.

[0773] Claim 37: The radiopharmaceutical composition according to Claim 35, wherein the composition comprises about 13 μg to about 18 μg of disodium EDTA per mL of solution.

[0774] Claim 38: The radiopharmaceutical composition according to Claim 35, wherein the composition comprises about 35 μL to about 40 μL of ethanol per mL of solution.

[0775] Claim 39: The radiopharmaceutical composition according to Claim 35, wherein the radioactivity of the composition is about 0.5 GBq or about 13.5 mCi per mL of solution.

[0776] Claim 40: The radiopharmaceutical composition according to Claim 35, wherein the composition comprises about 31 mg / ml of ascorbic acid.

[0777] Claim 41: The radiopharmaceutical composition according to Claim 35, wherein the composition comprises about 21 mg / ml to about 31 mg / ml of ascorbic acid.

[0778] Claim 42: The radiopharmaceutical composition according to Claim 35, wherein the composition comprises about 31 mg / ml to about 42.5 mg / ml of ascorbic acid.

[0779] Claim 43: A radiopharmaceutical composition comprising a total of 6 mL to 8 mL of a solution containing 177 Lu, approximately 463 μg / mL of PSMA I&T precursor, approximately 4 ml of 0.4 M sodium acetate, approximately 1.6 mL of 0.05 M hydrochloric acid, approximately 150 μl of a 20% L-ascorbic acid solution, and having a specific activity of the radiopharmaceutical composition ≤ 61 GBq.

[0780] Claim 44: The radiopharmaceutical composition according to Claim 43, wherein the pH of the ascorbic acid is 4.5.

[0781] Claim 45: The radiopharmaceutical composition according to Claim 43, further comprising 1.5 ml of ethanol-water in a 1:1 (v / v) ratio.

[0782] Claim 46: A radiopharmaceutical composition comprising a solution containing 177 Lu-PSMA I&T and ascorbic acid with a pH of 4.5, wherein the composition is suitable for administration to a human patient in need within at least 93 hours after compounding, and wherein the radiochemical purity of the composition at the time of administration is 97.0% or higher.

[0783] Claim 47: A radiopharmaceutical composition comprising a solution containing 177 Lu-PSMA I&T and ascorbic acid with a pH of 4.5, wherein the composition is suitable for administration to a human patient in need within at least 92 hours after compounding, and wherein the radiochemical purity of the composition at the time of administration is 96.0% or higher.

[0784] Claim 48: A radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the composition is formulated as a solution suitable for injection and the pH of the solution is 4.5.

[0785] Claim 49: A radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the composition is formulated as a solution suitable for injection and the radiochemical purity of the solution exceeds 96% after more than 48 hours of compounding.

[0786] Claim 50: A radiopharmaceutical composition comprising 177 Lu-PSMA I&T, wherein the composition is formulated as a solution suitable for injection and the radiochemical purity of the solution exceeds 96% after more than 71 hours of compounding.

[0787] Claim 51: A radiopharmaceutical composition according to any one of the preceding claims, wherein after administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity; and wherein the prostate-specific antigen decreases by more than about 50%.

[0788] Claim 52: A method of preparing 177 Lu-PSMA I&T, the method comprising heating the composition according to Claim 43 to at most 95 °C for 15 minutes.

[0789] Claim 53: The method according to Claim 52, further comprising adjusting the pH of the solution to 3.5 to 4.5.

[0790] Claim 54: A method of administering a radiopharmaceutical solution, the method comprising injecting the radiopharmaceutical solution more than 48 hours after compounding, wherein the radiopharmaceutical solution comprises 177 Lu-PSMA I&T.

[0791] Claim 55: A method of administering a radiopharmaceutical solution, the method comprising injecting the radiopharmaceutical solution comprising 177 Lu-PSMA I&T, wherein the pH of the solution is 4.5.

[0792] Claim 56: A method of administering a radiopharmaceutical solution, the method comprising injecting the radiopharmaceutical solution comprising 177 Lu-PSMA I&T, wherein the radiochemical purity of the solution is more than 96% more than 48 hours after compounding.

[0793] Claim 57: A method of administering a radiopharmaceutical solution, the method comprising injecting the radiopharmaceutical solution comprising 177 Lu-PSMA I&T, wherein the radiochemical purity of the solution is more than 96% more than 71 hours after compounding.

[0794] Claim 58: A radiopharmaceutical composition comprising a solution containing 177 Lu-PSMA I&T with a pH of 3.5 to 4.5, about 31 mg / ml ascorbic acid, about 13 μg / ml to about 18 μg / ml disodium EDTA, and about 35 μl / ml to about 40 μl / ml ethanol, wherein the solution is suitable for administration more than 48 hours after compounding, and the radiochemical purity of the solution at the time of administration is more than 96%.

[0795] Claim 59: A method of administering a radiopharmaceutical composition, the method comprising injecting the radiopharmaceutical composition into a patient in need thereof more than 48 hours after compounding, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the solution has a radiochemical purity of more than 96% at the time of administration.

[0796] Claim 60: The method according to claim 59, wherein the pH is 3.5 to 4.2.

[0797] Claim 61: The claim according to claim 59, wherein the composition comprises <6 μg of Lu-PSMA I&T per mL of solution.

[0798] Claim 62: The method according to claim 59, wherein the composition comprises about 13 μg to about 18 μg of disodium EDTA per mL of solution.

[0799] Claim 63: The method according to claim 59, wherein the composition comprises about 35 μL to about 40 μL of ethanol per mL of solution.

[0800] Claim 64: The method according to claim 59, wherein the radioactivity of the composition is about 0.5 GBq or about 13.5 mCi per mL of solution.

[0801] Claim 65: The method according to claim 59, wherein the composition comprises about 31 mg / ml of ascorbic acid.

[0802] Claim 66: The method according to claim 59, wherein the radiochemical purity of the solution 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.

[0803] Claim 67: The method according to claim 59, wherein after administering the composition to the patient, the patient maintains low levels of hematotoxicity and nephrotoxicity, and wherein the prostate-specific antigen decreases by more than about 50%.

[0804] Claim 68: A method of treating a patient in need thereof suffering from mCRP, the method comprising: administering a radiopharmaceutical composition more than 48 hours after compounding, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the solution has a radiochemical purity of more than 96% at the time of administration.

[0805] Claim 69: The method according to Claim 68, further comprising imaging the patient using PSMA-PET before administering the radiopharmaceutical composition to record and confirm that the patient is positive for mCRPC.

[0806] Claim 70: The method according to Claim 68, wherein the patient has an improved radiographic progression-free survival (rPFS).

[0807] Claim 71: The method according to Claim 70, wherein the rPFS of the patient is about 6 months to 12 months.

[0808] Claim 72: The method according to Claim 68, wherein the patient has an improved overall survival (OS).

[0809] Claim 73: The method according to Claim 72, wherein the OS of the patient is about 18 months to 25 months.

[0810] Claim 74: The method according to Claim 68, wherein the patient has an improved second radiographic progression-free survival (rPFS2).

[0811] Claim 75: The method according to Claim 68, wherein the patient has an improved progression-free survival.

[0812] Claim 76: The method according to Claim 68, wherein the patient has an improved second progression-free survival.

[0813] Claim 77: The method according to Claim 68, wherein the patient has an improved PSA 50 response rate.

[0814] Claim 78: The method according to Claim 68, wherein the patient has an improved time to the first symptomatic skeletal event (SSE).

[0815] Claim 79: The method according to Claim 68, wherein the patient has an improved time to soft tissue progression (STP).

[0816] Claim 80: The method according to Claim 68, wherein the patient has an improved time to chemotherapy (TTC).

[0817] Claim 81: The method according to Claim 68, wherein the patient has an improved result of the Quality of Life Questionnaire.

[0818] Claim 82: The method according to Claim 68, wherein the pH is 3.5 to 4.2.

[0819] Claim 83: The method according to claim 68, wherein the composition comprises < 6 μg of Lu-PSMA-I&T per mL of solution.

[0820] Claim 84: The method according to claim 68, wherein the composition comprises about 13 μg to about 18 μg of disodium EDTA per mL of solution, about 35 μL to about 40 μL of ethanol per mL of solution, and about 31 mg / ml of ascorbic acid.

[0821] Claim 85: The method according to claim 68, wherein the radioactivity of the composition is about 0.5 GBq or about 13.5 mCi per mL of solution.

[0822] Claim 86: The method according to claim 68, wherein the radiochemical purity of the solution is at least 98% at 44 hours after formulation, at least 97% at 69 hours after formulation, and / or at least 97% at 93 hours after formulation.

[0823] Claim 87: The method according to claim 68, wherein after administering the composition to a patient, the patient maintains low levels of hematotoxicity and nephrotoxicity, and wherein prostate-specific antigen decreases by more than about 50%.

[0824] Claim 88: The radiopharmaceutical composition according to claim 68, wherein the radioactivity of the composition is 1,270 MBq / ml to about 1,311 MBq / ml.

[0825] Claim 89: A radiopharmaceutical composition comprising a solution containing 177 Lu-PSMA I&T, about 31 mg / ml to about 42.5 mg / ml of ascorbic acid, about 8 μg / ml to about 21 μg / ml of disodium EDTA, and about 35 μl / ml to about 75 μl / ml of ethanol, wherein the radiochemical purity of the solution exceeds 95% at the time of administration.

[0826] Claim 90: The radiopharmaceutical composition according to claim 89, wherein the high radioactivity of the composition is about 1,278 MBq / ml to about 1,311 MBq / ml.

[0827] Claim 91: The radiopharmaceutical composition according to claim 89, wherein the low radioactivity of the composition is about 579 MBq / ml to about 626 MBq / ml.

[0828] Claim 92: The radiopharmaceutical composition according to claim 89, wherein Lu-PSMA I&T is present in the composition at a concentration of less than about 12 μg / ml.

[0829] Claim 93: The radiopharmaceutical composition according to Claim 89, wherein the composition has a certain amount of colloid with a radioactivity less than about 5%. 177 Lu.

[0830] Claim 94: The radiopharmaceutical composition according to Claim 89, wherein the composition has less than about 17.5 EU / ml of endotoxin.

[0831] Claim 95: The radiopharmaceutical composition according to Claim 89, wherein the composition has a shelf life of more than 24 hours after compounding.

[0832] Claim 96: The radiopharmaceutical composition according to Claim 95, wherein the composition has a shelf life of more than 48 hours after compounding.

[0833] Claim 97: The radiopharmaceutical composition according to Claim 96, wherein the composition has a shelf life of more than 72 hours after compounding.

[0834] Claim 98: A radiopharmaceutical composition comprising 177 Lu-PSMA I&T solution for injection.

[0835] Claim 99: The radiopharmaceutical composition according to Claim 98, wherein the 177 Lu-PSMA I&T solution for injection comprises 177 Lu-PSMA I&T, ascorbic acid and ethanol, wherein the 177 Lu-PSMA I&T has a sufficient radioactivity for the intended use, wherein the total amount of ascorbic acid in the solution is about 210 - 700 mg, and the total amount of ethanol in the solution is about 274 - 706 mg, wherein the pH of the solution is about 5 or below, wherein after administering the composition to a subject, the subject maintains a low level of blood toxicity and renal toxicity; and wherein the prostate-specific antigen decreases by more than about 50%.

[0836] Claim 100: The radiopharmaceutical composition according to Claim 98, wherein the 177 Lu-PSMA I&T solution for injection comprises: 177 Lu-PSMA-I&T, the 177The amount of Lu-PSMA-I&T is from about 5 μg / ml to about 15 μg / ml; ascorbic acid, the concentration of the ascorbic acid is from about 10 mg / ml to about 50 mg / ml; and ethanol, the concentration of the ethanol is from about 1% (v / v) to about 10% (v / v), wherein the pH of the solution is between about 3 and about 5, and wherein after administering the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0837] Claim 101: The radiopharmaceutical composition according to Claim 100, wherein the radioactivity of the composition is less than about 300 mCi.

[0838] Claim 102: The radiopharmaceutical composition according to Claim 100, wherein the composition comprises ethanol in an amount of about 1% (v / v), about 2% (v / v), about 3% (v / v), about 3.5% (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).

[0839] Claim 103: The radiopharmaceutical composition according to Claim 100, wherein the composition comprises ascorbic acid at a concentration of 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 or about 80 mg / ml.

[0840] Claim 104: The radiopharmaceutical composition according to Claim 100, wherein the radioactivity content of the composition is from about 70% to about 130%.

[0841] Claim 105: The radiopharmaceutical composition according to Claim 104, wherein the composition provides an average whole body effective dose of about 23 ± 20 Gy (3.3 Gy / GBq) after administration in a subject in need thereof.

[0842] Claim 106: The radiopharmaceutical composition according to Claim 100, wherein the composition is sterile.

[0843] Claim 107: The radiopharmaceutical composition according to Claim 100, wherein the volume of the composition is from about 1 ml to about 50 ml.

[0844] Claim 108: The radiopharmaceutical composition according to Claim 100, wherein the radiochemical purity of the composition is at least 97%, as measured by HPLC at 0 hours after EOS.

[0845] Claim 109: The radiopharmaceutical composition according to Claim 98, wherein the 177 Lu-PSMA I&T solution for injection comprises: 177 Lu-PSMA-I&T, the 177 amount of Lu-PSMA-I&T is from about 5 μg / ml to about 15 μg / ml; ascorbic acid, the concentration of the ascorbic acid is from about 10 mg / ml to about 50 mg / ml; ethanol, the concentration of the ethanol is from about 1% (v / v) to about 10% (v / v); and a chelating agent, the amount of the chelating agent accounts for about 0.001% to about 0.15% (w / w) of the total weight of the radiopharmaceutical composition, wherein the pH of the solution is between about 3 and about 5, and wherein after administering the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0846] Claim 110: The radiopharmaceutical composition according to Claim 109, wherein the radioactivity of the composition is less than about 500 mCi.

[0847] Claim 111: The radiopharmaceutical composition according to Claim 109, wherein the composition comprises ethanol in an amount of about 1% (v / v), about 2% (v / v), about 3% (v / v), about 3.5% (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).

[0848] Claim 112: The radiopharmaceutical composition according to Claim 109, wherein the composition comprises ascorbic acid at a concentration of 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 or about 80 mg / ml.

[0849] Claim 113: The radiopharmaceutical composition according to Claim 109, wherein the chelating agent is present in an amount of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14% or about 0.15% (w / w) of the total weight of the radiopharmaceutical composition.

[0850] Claim 114: The radiopharmaceutical composition according to Claim 109, wherein the radioactive content of the composition is about 70% to about 130%.

[0851] Claim 115: The radiopharmaceutical composition according to Claim 109, wherein the composition provides an average whole-body effective dose of about 23 ± 20 Gy (3.3 Gy / GBq) after administration in a subject in need thereof.

[0852] Claim 116: The radiopharmaceutical composition according to Claim 109, wherein the composition is sterile.

[0853] Claim 117: The radiopharmaceutical composition according to Claim 109, wherein the volume of the composition is about 1 ml to about 50 ml.

[0854] Claim 118: The radiopharmaceutical composition according to Claim 109, wherein the radiochemical purity of the composition is at least 97%, as measured by HPLC at 0 hours after EOS.

[0855] Claim 119: A radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need thereof, wherein the dose for injection is 7.4 GBq ± 0.1 GBq.

[0856] Claim 120: The radiopharmaceutical kit according to Claim 119, wherein the vial is a Type 1 glass sterile and pyrogen-free glass vial with a fluorine-coated bromobutyl rubber septum.

[0857] Claim 121: The radiopharmaceutical kit according to Claim 120, wherein the septum is sealed with a crimped aluminum capsule.

[0858] Claim 122: The radiopharmaceutical kit according to Claim 119, further comprising a lead-shielded transport container, wherein the glass vial is stored in the lead-shielded container during transportation.

[0859] Claim 123: The radiopharmaceutical kit according to Claim 122, wherein the lead-shielded transport container meets the Class A requirements (IAEA standard).

[0860] Claim 124: The radiopharmaceutical kit according to Claim 119, wherein the vial contains multiple doses.

[0861] Claim 125: The radiopharmaceutical kit according to Claim 119, wherein the 177 volume of the Lu-PSMA I&T solution is about 10 ml to about 20 ml, about 20 ml to about 30 ml, about 30 ml to about 40 ml, about 40 ml to about 50 ml, about 50 ml to about 60 ml, about 60 ml to about 70 ml, about 70 ml to about 80 ml, about 80 ml to about 90 ml, or about 90 ml to about 100 ml.

[0862] Claim 126: The radiopharmaceutical kit according to Claim 119, wherein the 177 strength of the Lu-PSMA I&T solution 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.

[0863] Claim 127: The radiopharmaceutical kit according to Claim 119, wherein the 177 Lu-PSMA I&T solution is suitable for administration to a human patient in need after more than 72 hours, more than 96 hours, or more than 100 hours after compounding.

[0864] Claim 128: The radiopharmaceutical kit according to Claim 119, wherein the 177 pH of the Lu-PSMA I&T solution is from 3.5 to 4.5.

[0865] Claim 129: A method of diagnosing or treating a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition by injection, the radiopharmaceutical composition comprising a solution containing 177 Lu-PSMA I&T and ascorbic acid with a pH of from 3.5 to 4.5, wherein at 20 hours after injection, the activity of the radiopharmaceutical composition in the whole body is at least 20% IA to 30% IA.

[0866] Claim 130: The method according to Claim 129, wherein at 40 hours after injection, the activity of the radiopharmaceutical composition in the whole body is at least 10% IA to 20% IA.

[0867] Claim 131: The method according to Claim 129, wherein at 60 hours after injection, the activity of the radiopharmaceutical composition in the whole body is at least 5% IA to 10% IA.

[0868] Claim 132: A method of diagnosing a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution containing 177 Lu-PSMA I&T and ascorbic acid with a pH of from 3.5 to 4.5, wherein at less than 20 hours after injection, the activity of the radiopharmaceutical composition in the kidney is at least 8% IA to 10% IA.

[0869] Claim 133: The method according to Claim 132, wherein at 20 hours after injection, the activity of the radiopharmaceutical composition in the kidney is at least 3% IA to 8% IA.

[0870] Claim 134: The method according to Claim 132, wherein at 40 hours after injection, the activity of the radiopharmaceutical composition in the kidney is at least 1% IA to 5% IA.

[0871] Claim 135: The method according to Claim 132, wherein at 60 hours after injection, the activity of the radiopharmaceutical composition in the kidney is at least 1% IA to 5% IA.

[0872] Claim 136: A method of diagnosing a tumor in a patient in need thereof, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution containing 177Solution of Lu-PSMA I&T and ascorbic acid, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.7% IA to 1% IA.

[0873] Claim 137: The method according to claim 136, wherein 20 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.3% IA to 0.8% IA.

[0874] Claim 138: The method according to claim 136, wherein 40 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.2% IA to 0.5% IA.

[0875] Claim 139: The method according to claim 136, wherein 60 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.1% IA to 0.3% IA.

[0876] Claim 140: A method for diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient by injection a radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesions of the patient is at least 0.2% IA to 0.5% IA.

[0877] Claim 141: The method according to claim 140, wherein 20 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesions is at least 0.1% IA to 0.3% IA.

[0878] Claim 142: The method according to claim 140, wherein 40 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesions is at least 0.08% IA to 0.2% IA.

[0879] Claim 143: The method according to claim 140, wherein 60 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesions is at least 0.05% IA to 0.1% IA.

[0880] Claim 144: A method for diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient by injection a radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in the bone lesions of the patient is at least 0.1% IA to 0.4% IA.

[0881] Claim 145: The method according to claim 144, wherein at 20 hours after injection, the activity of the radiopharmaceutical composition in the bone lesion is at least 0.1% IA to 0.2% IA.

[0882] Claim 145: The method according to claim 144, wherein at 40 hours after injection, the activity of the radiopharmaceutical composition in the bone lesion is at least 0.05% IA to 0.1% IA.

[0883] Claim 146: The method according to claim 144, wherein at 60 hours after injection, the activity of the radiopharmaceutical composition in the bone lesion is at least 0.02% IA to 0.05% IA.

[0884] Claim 147: A method for diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient by injection a radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the effective half-life of the radiopharmaceutical composition in the whole body of the patient is about 30 hours to 40 hours.

[0885] Claim 148: The method according to claim 147, wherein the effective half-life of the radiopharmaceutical composition in the kidneys of the patient is about 25 hours to 35 hours.

[0886] Claim 149: The method according to claim 147, wherein the effective half-life of the radiopharmaceutical composition in the parotid glands of the patient is about 20 hours to 30 hours.

[0887] Claim 150: The method according to claim 147, wherein the effective half-life of the radiopharmaceutical composition in the bone lesion of the patient is about 45 hours to 55 hours.

[0888] Claim 151: The method according to claim 147, wherein the effective half-life of the radiopharmaceutical composition in the lymph node lesion of the patient is about 35 hours to 45 hours.

[0889] Claim 152: A method for diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient by injection a radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the average absorbed dose of the radiopharmaceutical in the whole body of the patient is about 0.01 mGy / MBq to 0.5 mGy / MBq.

[0890] Claim 153: The method according to Claim 152, wherein the average absorbed dose of the radiopharmaceutical composition in the kidneys of the patient is from about 0.5 mGy / MBq to 1.0 mGy / MBq.

[0891] Claim 154: The method according to Claim 152, wherein the average absorbed dose of the radiopharmaceutical composition in the parotid glands of the patient is from about 1 mGy / MBq to 1.5 mGy / MBq.

[0892] Claim 155: The method according to Claim 152, wherein the average absorbed dose of the radiopharmaceutical composition in the bone lesions of the patient is from about 2.5 mGy / MBq to 3.5 mGy / MBq.

[0893] Claim 156: The method according to Claim 152, wherein the average absorbed dose of the radiopharmaceutical composition in the lymph node lesions of the patient is from about 3.5 mGy / MBq to 4.5 mGy / MBq.

[0894] Claim 157: A radiopharmaceutical kit comprising a vial containing at least a single dose of 177 Lu-PSMA I&T solution for injection into a human patient in need thereof, wherein the dose for injection is ≥ 7.1 GBq.

Claims

1. A radiopharmaceutical composition comprising a solution of 177 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the composition is suitable for administration to a human patient in need thereof for at least 90 hours after compounding, and wherein the radiochemical purity of the composition at the time of administration is 95% or higher.

2. The radiopharmaceutical composition according to claim 1, wherein the pH is 3.5 to 4.

2.

3. The radiopharmaceutical composition according to claim 2, wherein the pH is 3.5 to 4.

0.

4. The radiopharmaceutical composition according to claim 1, wherein the composition contains <6 μg / mL solution of Lu-PSMA I&T.

5. The radiopharmaceutical composition according to claim 1, wherein the composition contains about 13 μg / mL to about 18 μg / mL of disodium EDTA per mL of solution.

6. The radiopharmaceutical composition according to claim 1, wherein the composition contains about 35 μL / mL to about 40 μL / mL of ethanol per mL of solution.

7. The radiopharmaceutical composition according to claim 1, wherein the composition does not include ethanol.

8. The radiopharmaceutical composition according to claim 1, wherein the radioactivity of the composition is about 0.5 GBq / mL or about 13.5 mCi / mL of solution.

9. The radiopharmaceutical composition according to claim 1, wherein the composition contains about 31 mg / mL of ascorbic acid.

10. The radiopharmaceutical composition according to claim 1, wherein the composition contains about 21 mg / mL to about 31 mg / mL of ascorbic acid.

11. The radiopharmaceutical composition according to claim 1, wherein the composition contains about 31 mg / mL to about 42.5 mg / mL of ascorbic acid.

12. A radiopharmaceutical composition comprising a total of 6 mL to 8 mL of a solution containing 177 Lu, about 463 μg / mL of PSMA I&T precursor, about 4 mL of 0.4 M sodium acetate, about 1.6 mL of 0.05 M hydrochloric acid, about 150 μL of a 20% L-ascorbic acid solution, and the specific activity of the radiopharmaceutical composition is ≤ 61 GBq.

13. The radiopharmaceutical composition according to claim 11, wherein the pH of the ascorbic acid is 3.5 to 4.

5.

14. The radiopharmaceutical composition according to claim 11, wherein the pH of the solution is 3.5 to 4.

5.

15. The radiopharmaceutical composition according to claim 11, which further comprises 1.5 mL of ethanol-water in a 1:1 (v / v) ratio.

16. A method of administering a radiopharmaceutical composition, the method comprising injecting the radiopharmaceutical composition into a patient in need thereof more than 48 hours after compounding, the radiopharmaceutical composition comprising a solution of 177 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the solution has a radiochemical purity of more than 96% at the time of administration.

17. The method according to claim 16, wherein the pH is 3.5 to 4.

2.

18. The method according to claim 16, wherein the composition contains <6 μg / mL solution of Lu-PSMA I&T.

19. The method according to claim 16, wherein the composition contains about 13 μg / mL to about 18 μg / mL of disodium EDTA per mL of solution.

20. The method according to claim 16, wherein the composition contains about 35 μL / mL to about 40 μL / mL of ethanol per mL of solution.

21. The method according to claim 16, wherein the radioactivity of the composition is about 0.5 GBq / mL or about 13.5 mCi / mL of solution.

22. The method according to claim 16, wherein the composition contains about 31 mg / mL of ascorbic acid.

23. The method according to claim 16, wherein the radiochemical purity of the solution 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.

24. The method according to claim 16, wherein after administering the composition to a patient, the patient maintains low levels of hematotoxicity and nephrotoxicity, and wherein the prostate-specific antigen decreases by more than about 50%.

25. A method of treating a patient in need of treatment for mCRP, the method comprising: Administering a radiopharmaceutical composition more than 48 hours after compounding, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the radiochemical purity of the solution at the time of administration is greater than 96%.

26. The method according to claim 25, further comprising imaging the patient using PSMA-PET prior to administering the radiopharmaceutical composition to record and confirm that the patient is positive for mCRPC.

27. The method according to claim 25, wherein the patient has an improved radiographic progression-free survival (rPFS).

28. The method according to claim 27, wherein the rPFS of the patient is from about 6 months to 12 months.

29. The method according to claim 25, wherein the patient has an improved overall survival (OS).

30. The method according to claim 29, wherein the OS of the patient is from about 18 months to 25 months.

31. The method according to claim 25, wherein the patient has an improved second radiographic progression-free survival (rPFS2).

32. The method according to claim 25, wherein the patient has an improved progression-free survival.

33. The method according to claim 25, wherein the patient has an improved second progression-free survival.

34. The method according to claim 25, wherein the patient has an improved PSA50 response rate.

35. The method according to claim 25, wherein the patient has an improved time to the first symptomatic skeletal event (SSE).

36. The method according to claim 25, wherein the patient has an improved time to soft tissue progression (STP).

37. The method according to claim 25, wherein the patient has an improved time to chemotherapy (TTC).

38. The method according to claim 25, wherein the patient has an improved result of the Quality of Life Questionnaire.

39. The method according to claim 25, wherein the pH is from 3.5 to 4.

2.

40. The method according to claim 25, wherein the composition comprises <6 μg of Lu-PSMA I&T per mL of solution.

41. The method according to claim 25, wherein the composition comprises from about 13 μg to about 18 μg of disodium EDTA per mL of solution, from about 35 μL to about 40 μL of ethanol per mL of solution, and about 31 mg / ml of ascorbic acid.

42. The method according to claim 25, wherein the radioactivity of the composition is about 0.5 GBq or about 13.5 mCi per mL of solution.

43. The method according to claim 25, wherein the radiochemical purity of the solution 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.

44. The method according to claim 25, wherein after administering the composition to a patient, the patient maintains low levels of hematotoxicity and nephrotoxicity, and wherein the prostate-specific antigen decreases by more than about 50%.

45. A radiopharmaceutical composition comprising a solution of 177 177 Lu-PSMA I&T, about 31 mg / ml ascorbic acid, about 13 μg / ml to about 18 μg / ml disodium EDTA, and about 35 μl / ml to about 40 μl / ml ethanol, wherein the solution is suitable for administration more than 48 hours after compounding, and the radiochemical purity of the solution at the time of administration is more than 96%.

46. A radiopharmaceutical composition comprising 177 Lu-PSMA I&T and ascorbic acid, wherein the composition is formulated as a solution for injection having a pH of 3.5 to 4.5, and the solution is suitable for administration more than 48 hours after formulation.

47. The radiopharmaceutical composition according to claim 46, wherein the solution is suitable for administration within at most 3 days after compounding.

48. The radiopharmaceutical composition according to claim 46, wherein the solution is suitable for administration within at most 4 days after compounding.

49. The radiopharmaceutical composition according to claim 46, wherein the solution contains 21 mg / ml to 31 mg / ml of ascorbic acid.

50. The radiopharmaceutical composition according to claim 46, wherein the solution contains 42.5 mg / ml of ascorbic acid.

51. The radiopharmaceutical composition according to claim 46, wherein the solution further contains hydrochloric acid.

52. The radiopharmaceutical composition according to claim 46, wherein the solution contains 1.7 mg / ml to 34 mg / ml of hydrochloric acid.

53. The radiopharmaceutical composition according to claim 46, wherein the pH of the solution is 3.5 to 4.

2.

54. The radiopharmaceutical composition according to claim 46, wherein the pH of the solution is 3.5 to 4.

0.

55. The radiopharmaceutical composition according to claim 46, wherein the radioactivity of the solution is less than 635 MBq / ml.

56. The radiopharmaceutical composition according to claim 55, wherein the radioactivity of the solution is about 579 MBq / ml to about 626 MBq / ml.

57. The radiopharmaceutical composition according to claim 46, wherein the radiochemical purity of the solution exceeds 95% at 46 to 48 hours after compounding.

58. The radiopharmaceutical composition according to claim 57, wherein the radiochemical purity of the solution exceeds 96% at 46 to 48 hours after compounding.

59. The radiopharmaceutical composition according to claim 57, wherein the radiochemical purity of the solution exceeds 97% at 46 to 48 hours after compounding.

60. The radiopharmaceutical composition according to claim 46, wherein the radiochemical purity of the solution exceeds 95% at 69 to 71 hours after compounding.

61. The radiopharmaceutical composition according to claim 60, wherein the radiochemical purity of the solution exceeds 96% at 69 to 71 hours after compounding.

62. The radiopharmaceutical composition according to claim 60, wherein the radiochemical purity of the solution exceeds 97% at 69 to 71 hours after compounding.

63. The radiopharmaceutical composition according to claim 46, wherein the radiochemical purity of the solution exceeds 95% at 90 to 93 hours after compounding.

64. The radiopharmaceutical composition according to claim 63, wherein the radiochemical purity of the solution is more than 96% at 90 to 93 hours after compounding.

65. The radiopharmaceutical composition according to claim 63, wherein the radiochemical purity of the solution is more than 97% at 90 to 93 hours after compounding.

66. The radiopharmaceutical composition according to claim 46, wherein the solution contains less than 6 μg / ml of Lu-PSMA I&T.

67. The radiopharmaceutical composition according to claim 46, which further comprises a metal ion chelator.

68. The radiopharmaceutical composition according to claim 67, wherein the metal ion chelator is disodium EDTA.

69. The radiopharmaceutical composition according to claim 68, wherein the solution contains about 15.5 μg / ml of disodium EDTA.

70. The radiopharmaceutical composition according to claim 46, which further comprises a stabilizer.

71. The radiopharmaceutical composition according to claim 70, wherein the stabilizer is ethanol.

72. The radiopharmaceutical composition according to claim 71, wherein the solution contains about 37.5 μl / ml of ethanol.

73. The radiopharmaceutical composition according to claim 46, which further comprises 31 mg / ml of ascorbic acid and a certain amount of hydrochloric acid, the amount being adjusted such that the pH of the solution is 3.5 to 4.

5.

74. The radiopharmaceutical composition according to claim 73, which further comprises 10.5 μg / ml of disodium EDTA and 37.5 μL / ml of ethanol.

75. The radiopharmaceutical composition according to claim 73, which further comprises sufficient sodium bicarbonate and NaOH to control the pH at 4.

5.

76. The radiopharmaceutical composition according to claim 75, wherein the radioactivity of the solution is 588.5 MBq / ml.

77. The radiopharmaceutical composition according to claim 73, wherein the radiochemical purity of the solution 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.

78. The radiopharmaceutical composition according to claim 46, wherein after administering the composition to a patient, the patient maintains a low level of blood toxicity and renal toxicity, and wherein the prostate-specific antigen decreases by more than about 50%.

79. The radiopharmaceutical composition according to claim 46, wherein the radioactivity of the composition is 1,270 MBq / ml to about 1,311 MBq / ml.

80. A radiopharmaceutical composition comprising a solution of 177 177 Lu-PSMA I&T, about 31 mg / ml to about 42.5 mg / ml ascorbic acid, about 8 μg / ml to about 21 μg / ml disodium EDTA, and about 35 μl / ml to about 75 μl / ml ethanol, wherein the radiochemical purity of the solution at the time of administration exceeds 95%.

81. The radiopharmaceutical composition according to claim 80, wherein the high radioactivity of the composition is about 1,278 MBq / ml to about 1,311 MBq / ml.

82. The radiopharmaceutical composition according to claim 80, wherein the low radioactivity of the composition is about 579 MBq / ml to about 626 MBq / ml.

83. The radiopharmaceutical composition according to claim 80, wherein Lu-PSMA I&T is present in the composition at a concentration of less than about 12 μg / ml.

84. The radiopharmaceutical composition according to claim 80, wherein the composition has an amount of colloid with a radioactivity less than about 5% 177 Lu.

85. The radiopharmaceutical composition according to claim 80, wherein the composition has less than about 17.5 EU / ml of bacterial endotoxin.

86. The radiopharmaceutical composition according to claim 80, wherein the composition has a shelf life of more than 24 hours after compounding.

87. The radiopharmaceutical composition according to claim 86, wherein the composition has a shelf life of more than 48 hours after compounding.

88. The radiopharmaceutical composition according to claim 87, wherein the composition has a shelf life of more than 72 hours after compounding.

89. A radiopharmaceutical composition comprising: For injection 177 Lu-PSMA I&T solution, said solution comprising 177 Lu-PSMA I&T, ascorbic acid and ethanol; wherein said 177 Lu-PSMA I&T is used at a sufficient radioactivity for the intended use; wherein the total amount of ascorbic acid in the solution is about 210 - 700 mg, and the total amount of ethanol in the solution is about 274 - 706 mg; wherein the pH of the solution is about 5 or less; wherein after administering the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity; and wherein prostate-specific antigen decreases by more than about 50%.

90. A radiopharmaceutical composition comprising 177 a Lu-PSMA I&T solution for injection, said solution comprising: (a) 177 Lu-PSMA-I&T, the 177 amount of Lu-PSMA-I&T is from about 5 μg / ml to about 15 μg / ml; (b) ascorbic acid, the concentration of the ascorbic acid being about 10 mg / ml to about 50 mg / ml; and (c) ethanol, the concentration of the ethanol being about 1% (v / v) to about 10% (v / v); wherein the pH of the solution is between about 3 and about 5; and wherein after administering the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

91. The radiopharmaceutical composition according to claim 90, wherein the radioactivity of the composition is less than about 300 mCi.

92. The radiopharmaceutical composition according to claim 90, wherein the composition comprises ethanol in an amount of about 1% (v / v), about 2% (v / v), about 3% (v / v), about 3.5% (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).

93. The radiopharmaceutical composition according to claim 90, wherein the composition comprises ascorbic acid at a concentration of 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 or about 80 mg / ml.

94. The radiopharmaceutical composition according to claim 90, wherein the radioactive content of the composition is from about 70% to about 130%.

95. The radiopharmaceutical composition according to claim 94, wherein the composition provides an average whole body effective dose of about 23 ± 20 Gy (3.3 Gy / GBq) after administration in a subject in need thereof.

96. The radiopharmaceutical composition according to claim 90, wherein the composition is sterile.

97. The radiopharmaceutical composition according to claim 90, wherein the volume of the composition is from about 1 ml to about 50 ml.

98. The radiopharmaceutical composition according to claim 90, wherein the radiochemical purity of the composition is at least 97%, as measured by HPLC at 0 hours post - EOS.

99. A radiopharmaceutical composition comprising a 177 Lu-PSMA I&T solution for injection, said solution comprising: (a) 177 Lu-PSMA I&T, wherein 177 the amount of Lu-PSMA I&T is from about 5 μg / ml to about 15 μg / ml; (b) Ascorbic acid, wherein the concentration of the ascorbic acid is from about 10 mg / ml to about 50 mg / ml; (c) Ethanol, wherein the concentration of the ethanol is from about 1% (v / v) to about 10% (v / v); and (d) A chelating agent, wherein the amount of the chelating agent accounts for about 0.001% to about 0.15% (w / w) of the total weight of the radiopharmaceutical composition; wherein the pH of the solution is between about 3 and about 5; and wherein after administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

100. The radiopharmaceutical composition according to claim 99, wherein the radioactivity of the composition is less than about 500 mCi.

101. The radiopharmaceutical composition according to claim 99, wherein the composition comprises ethanol in an amount of about 1% (v / v), about 2% (v / v), about 3% (v / v), about 3.5% (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).

102. The radiopharmaceutical composition according to claim 99, wherein the composition comprises ascorbic acid at a concentration of 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 or about 80 mg / ml.

103. The radiopharmaceutical composition according to claim 99, wherein the chelating agent is present in an amount of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14% or about 0.15% (w / w) of the total weight of the radiopharmaceutical composition.

104. The radiopharmaceutical composition according to claim 99, wherein the radioactivity content of the composition is about 70% to about 130%.

105. The radiopharmaceutical composition according to claim 99, wherein the composition provides an average whole body effective dose of about 23 ± 20 Gy (3.3 Gy / GBq) after administration in a subject in need thereof.

106. The radiopharmaceutical composition according to claim 99, wherein the composition is sterile.

107. The radiopharmaceutical composition according to claim 99, wherein the volume of the composition is about 1 ml to about 50 ml.

108. The radiopharmaceutical composition according to claim 99, wherein the radiochemical purity of the composition is at least 97%, as measured by HPLC at 0 hours after EOS.

109. A radiopharmaceutical kit, comprising: A vial containing at least a single dose for injection into a human patient in need of 177 Lu-PSMA I&T solution, wherein the injected dose is 7.4 GBq ± 0.1 GBq.

110. The radiopharmaceutical kit according to claim 109, wherein the vial is a type 1 glass sterile and pyrogen-free glass vial with a fluorine-coated bromobutyl rubber septum.

111. The radiopharmaceutical kit according to claim 110, wherein the septum is sealed with a crimped aluminum capsule.

112. The radiopharmaceutical kit according to claim 109, further comprising a lead-shielded transport container, wherein the glass vial is stored in the lead-shielded container during transportation.

113. The radiopharmaceutical kit according to claim 112, wherein the lead-shielded transport container meets the requirements of Class A (IAEA standard).

114. The radiopharmaceutical kit according to claim 109, wherein the vial contains multiple doses.

115. The radiopharmaceutical kit according to claim 109, wherein the 177 volume of the Lu-PSMA I&T solution is about 10 ml to about 20 ml, about 20 ml to about 30 ml, about 30 ml to about 40 ml, about 40 ml to about 50 ml, about 50 ml to about 60 ml, about 60 ml to about 70 ml, about 70 ml to about 80 ml, about 80 ml to about 90 ml or about 90 ml to about 100 ml.

116. The radiopharmaceutical kit according to claim 109, wherein the 177 intensity of the Lu-PSMA I&T solution 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.

117. The radiopharmaceutical kit according to claim 109, wherein the 177 Lu-PSMA I&T solution is suitable for administration to a human patient in need thereof more than 72 hours after compounding, more than 96 hours after compounding, or more than 100 hours after compounding.

118. The radiopharmaceutical kit according to claim 109, wherein the 177 pH of the Lu-PSMA I&T solution is 3.5 to 4.

5.

119. A method for diagnosing or treating tumors in a patient in need thereof, the method comprising administering a radiopharmaceutical composition by injection, the radiopharmaceutical composition comprising a solution of 177 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein 20 hours after injection, the activity of the radiopharmaceutical composition in the whole body is at least 20% IA to 30% IA.

120. The method according to claim 119, wherein at 40 hours after injection, the activity of the radiopharmaceutical composition in the whole body is at least 10% IA to 20% IA.

121. The method according to claim 119, wherein at 60 hours after injection, the activity of the radiopharmaceutical composition in the whole body is at least 5% IA to 10% IA.

122. A method for diagnosing tumors in a patient in need, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in the kidneys is at least 8% IA to 10% IA.

123. The method according to claim 122, wherein at 20 hours after injection, the activity of the radiopharmaceutical composition in the kidney is at least 3% IA to 8% IA.

124. The method according to claim 122, wherein at 40 hours after injection, the activity of the radiopharmaceutical composition in the kidney is at least 1% IA to 5% IA.

125. The method according to claim 122, wherein at 60 hours after injection, the activity of the radiopharmaceutical composition in the kidney is at least 1% IA to 5% IA.

126. A method for diagnosing tumors in a patient in need, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.7% IA to 1% IA.

127. The method according to claim 126, wherein at 20 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.3% IA to 0.8% IA.

128. The method according to claim 126, wherein at 40 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.2% IA to 0.5% IA.

129. The method according to claim 126, wherein at 60 hours after injection, the activity of the radiopharmaceutical composition in the parotid gland is at least 0.1% IA to 0.3% IA.

130. A method for diagnosing tumors in a patient in need, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in lymph node lesions of the patient is at least 0.2% IA to 0.5% IA.

131. The method according to claim 130, wherein at 20 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesion is at least 0.1% IA to 0.3% IA.

132. The method according to claim 130, wherein at 40 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesion is at least 0.08% IA to 0.2% IA.

133. The method according to claim 130, wherein at 60 hours after injection, the activity of the radiopharmaceutical composition in the lymph node lesion is at least 0.05% IA to 0.1% IA.

134. A method for diagnosing tumors in a patient in need, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein less than 20 hours after injection, the activity of the radiopharmaceutical composition in the bone lesions of the patient is at least 0.1% IA to 0.4% IA.

135. The method according to claim 134, wherein at 20 hours after injection, the activity of the radiopharmaceutical composition in the bone lesion is at least 0.1% IA to 0.2% IA.

136. The method according to claim 134, wherein at 40 hours after injection, the activity of the radiopharmaceutical composition in the bone lesion is at least 0.05% IA to 0.1% IA.

137. The method according to claim 134, wherein at 60 hours after injection, the activity of the radiopharmaceutical composition in the bone lesion is at least 0.02% IA to 0.05% IA.

138. A method for diagnosing tumors in a patient in need, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 177 Lu-PSMA I&T and ascorbic acid having a pH of 3.5 to 4.5, wherein the effective half-life of the radiopharmaceutical composition in the patient's whole body is about 30 hours to 40 hours.

139. The method according to claim 138, wherein the effective half-life of the radiopharmaceutical composition in the kidney of the patient is about 25 hours to 35 hours.

140. The method according to claim 138, wherein the effective half-life of the radiopharmaceutical composition in the parotid gland of the patient is about 20 hours to 30 hours.

141. The method according to claim 138, wherein the effective half-life of the radiopharmaceutical composition in the bone lesion of the patient is about 45 hours to 55 hours.

142. The method according to claim 138, wherein the effective half-life of the radiopharmaceutical composition in the lymph node lesion of the patient is about 35 hours to 45 hours.

143. A method for diagnosing tumors in a patient in need, the method comprising administering a radiopharmaceutical composition to the patient by injection, the radiopharmaceutical composition comprising a solution of 177 Lu-PSMA I&T and ascorbic acid with a pH of 3.5 to 4.5, wherein the average absorbed dose of the radiopharmaceutical in the whole body of the patient is about 0.01 mGy / MBq to 0.5 mGy / MBq.

144. The method according to claim 143, wherein the average absorbed dose of the radiopharmaceutical composition in the kidney of the patient is about 0.5 mGy / MBq to 1.0 mGy / MBq.

145. The method according to claim 143, wherein the average absorbed dose of the radiopharmaceutical composition in the parotid gland of the patient is about 1 mGy / MBq to 1.5 mGy / MBq.

146. The method according to claim 143, wherein the average absorbed dose of the radiopharmaceutical composition in the bone lesion of the patient is about 2.5 mGy / MBq to 3.5 mGy / MBq.

147. The method according to claim 143, wherein the average absorbed dose of the radiopharmaceutical composition in the lymph node lesion of the patient is about 3.5 mGy / MBq to 4.5 mGy / MBq.

148. A radiopharmaceutical kit, comprising: A vial containing at least a single dose for injection into a human patient in need of 177 a Lu-PSMA I&T solution, wherein the dose for injection ≥ 7.1 GBq.

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