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

Abstract

This disclosure generally relates to: 177 The present invention relates to a radiopharmaceutical composition comprising Lu-PSMA I&T. The composition is formulated as an injectable solution, and the solution is suitable for administration more than 72 hours after formulation. The composition may contain ascorbic acid and may have a pH of 3.5 to 4.5 in solution. In some examples, the composition is suitable for administration to a human patient in need thereof at least 90 hours after formulation, and the composition has a radiochemical purity of 95% or greater at the time of administration.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. § 119 of U.S. Patent Application No. 63 / 393,777, filed July 29, 2022, and U.S. Patent Application No. 63 / 393,446, filed July 29, 2022, each of which is incorporated by reference in its entirety.

[0002] The present disclosure generally relates to injectable 177 Lu] Lutetium-PSMA I&T ([ 177 Lu]Lu-PSMA I&T or 177 Novel compositions of Lu-PSMA I&T solutions, and 177 Regarding kits containing Lu-PSMA I&T. 177 The Lu-PSMA I&T solution and / or kit thereof can be used for prostate cancer radioligand therapy (PRLT). [Background technology]

[0003] Prostate cancer (PC) is the most frequent non-skin cancer and the second leading cause of cancer death in adult men. In 2020, there were more than 1.4 million new cases of PC, resulting in 375,304 deaths worldwide. Most deaths related to prostate cancer result from progressive disease arising from any combination of lymphatic, hematologic, or adjacent local spread. Most PC patients who die die from metastatic PC, and 90% of these patients have bone metastases. In some cases, surgery and / or chemotherapy may not be available or effective for certain patients, including those with metastatic castration-resistant prostate cancer (mCRPC). Therefore, alternatives are needed for the treatment of prostate cancer.

[0004] Over the past decade, six novel agents have been identified that increase overall survival in patients with metastatic castration-resistant prostate cancer. Patients with symptomatic mCRPC are initially treated with docetaxel. Abiraterone, enzalutamide, cabazitaxel, sipuleucel, and radium-223 increase overall survival in patients who have failed docetaxel. Targeted radionuclide therapy has become an attractive and rapidly evolving treatment option for many different cancers, including lymphoma, melanoma, and neuroendocrine tumors.

[0005] However, no randomized trials have evaluated the agent in patients who have failed to respond to second-line treatment after docetaxel relapse. Therefore, international organizations such as the European Association of Urology (EAU) / European Society for Radiation Therapy and Oncology (ESTRO) have guidelines but no recommendations regarding third-line treatment for mCRPC. There is a clinical need for effective third-line treatments for mCRPC with lower toxicity rates. 177 [Lu]Lu-PSMA-617 is a novel and promising therapeutic option for patients with mCRPC.

[0006] Prostate-specific membrane antigen (PSMA) is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer. PSMA expression levels directly correlate with androgen independence, metastasis, and prostate cancer progression. Therefore, PSMA is a promising molecular target for the diagnosis and therapy of metastatic prostate cancer.

[0007] Lutetium-177( 177 Lu) or yttrium-90 ( 90 Several monoclonal antibodies (mAbs) radiolabeled with Y have shown promising results but have been associated with high rates of hematological toxicity. Therefore, due to side effects, it is prudent to consider small molecule inhibitors of PSMA instead of mAbs. 177 Lu-PSMA-617 and 177Lu-PSMA I&T are small molecule inhibitors of PSMA that are highly desirable for targeted radionuclide therapy due to their low hematotoxicity and nephrotoxicity profiles, resulting in better efficacy and fewer adverse effects.

[0008] 177 Lu is a beta- and gamma-emitting radionuclide that can irradiate tumor cells. 177 Lu has a half-life of 6.7 days and is iodine-131( 131 I) has a lower beta particle emission energy, which indicates that there is a high possibility of fewer side effects. 177 Compositions made by Lu generally have a short shelf life. 177 Previous imaging and therapy formulations using Lu-PSMA have a shelf life of approximately 48 hours. This requires that the compound and final solution be synthesized in-house in close proximity to the site of administration and are generally custom-prepared. This can limit the use of this life-saving cancer treatment to a limited number of geographic locations due to limited resources.

[0009] Has a shelf life of more than 48 hours 177 There remains a need for improved formulations containing Lu-PSMA I&T. The present disclosure provides improved formulations for injection. 177 For Lu-PSMA I&T solution. Summary of the Invention [Means for solving the problem]

[0010] Briefly, therefore, the present disclosure provides: 177 for administration to a human patient in need thereof of a radiopharmaceutical composition comprising Lu-PSMA I&T; 177 The present invention relates to a radiopharmaceutical composition comprising Lu-PSMA I&T. The composition is formulated as an injectable solution, the solution being suitable for administration to a human patient in need thereof more than 48 hours, more than 72 hours, more than 96 hours, or more than 100 hours after formulation.

[0011] The present disclosure provides: 177 Further directed is a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5. In some instances, the composition is suitable for administration to a human patient in need thereof at least 90 hours after formulation, and the composition has a radiochemical purity of 95.0% or greater at the time of administration.

[0012] Another aspect of the present disclosure is a method for preparing a soluble ... 177 Another embodiment of the present disclosure is a reaction composition comprising: Lu, about 463-500 μg / mL of PSMA I&T precursor; 177 A reaction composition comprising Lu, about 463-500 μg / mL of PSMA I&T precursor, about 4 mL of 0.4 M sodium acetate, about 1.6 mL of 0.05 M hydrochloric acid, and about 150 μL of 20% L-ascorbic acid in a total solution of 6-8 mL. 177 In some examples, the reaction composition comprises: 177 Lu activity ≦61 GBq.

[0013] Another aspect of the present disclosure is a method for manufacturing a semiconductor device comprising: 177 In some examples, the reaction composition includes Lu, a PSMA I&T precursor, an ascorbic acid / acetate buffer, hydrochloric acid, and L-ascorbic acid in solution. 177 Lu activity ≦296 GBq.

[0014] The present disclosure provides a radiopharmaceutical composition comprising: 177 Injectable formulation containing Lu-PSMA I&T, ascorbic acid, and ethanol 177 Contains Lu-PSMA I&T solution, 177Further directed to a radiopharmaceutical composition, wherein the Lu-PSMA I&T is of sufficient radioactivity for its intended use, the total amount of ascorbic acid in the solution is about 210-700 mg, the total amount of ethanol in the solution is about 274-706 mg, and the pH of the solution is about 5 or less, and wherein, upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity and experiences a reduction in prostate specific antigen of greater than about 50%.

[0015] The present disclosure provides a radiopharmaceutical composition comprising: 177 An injectable solution comprising Lu-PSMA-I&T, 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). 177 Further of interest is a radiopharmaceutical composition comprising an Lu-PSMA I&T solution, wherein the pH of the solution is from about 3 to about 5, and wherein upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0016] The present disclosure provides a radiopharmaceutical composition comprising: 177 an injectable radiopharmaceutical composition comprising Lu-PSMA I&T, 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; 177 Further of interest is a radiopharmaceutical composition comprising an Lu-PSMA I&T solution, wherein the pH of the solution is from about 3 to about 5, and wherein upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0017] The present disclosure provides: 177 for injection into human patients requiring injection of Lu-PSMA I&T solution 177The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 177Lu-PSMA I&T at which six cycles of 177Lu-PSMA I&T treatment are possible without risk of nephrotoxicity and / or where the six cycles of 177Lu-PSMA I&T treatment provide an average projected dose that is below the absorbed dose limit of 23 Gy. 177 for injection into human patients requiring injection of Lu-PSMA I&T solution 177 The present disclosure also relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection contains a dose of 177Lu-PSMA I&T, and wherein the predicted or actual cumulative renal absorbed dose over six cycles is less than 23 Gy and no nephrotoxicity is observed. 177 for injection into human patients requiring injection of Lu-PSMA I&T solution 177 The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq±0.10 GBq, a dose of 7.4 GBq±0.15 GBq, a dose of 7.4 GBq±0.20 GBq, a dose of 7.4 GBq±0.25 GBq, or a dose of 7.4 GBq±0.30 GBq, at which six cycles of 177Lu-PSMA I&T treatment are possible without risk of nephrotoxicity, and / or the six cycles of 177Lu-PSMA I&T treatment provide a mean predicted dose that is below the absorbed dose limit of 23 Gy, and / or the predicted or actual cumulative renal absorbed dose over six cycles is less than 23 Gy, with no observed nephrotoxicity. 177 for injection into human patients requiring injection of Lu-PSMA I&T solution 177The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.5 GBq±0.10 GBq, a dose of 7.5 GBq±0.15 GBq, a dose of 7.5 GBq±0.20 GBq, a dose of 7.5 GBq±0.25 GBq, or a dose of 7.5 GBq±0.30 GBq, at which six cycles of 177Lu-PSMA I&T treatment are possible without risk of nephrotoxicity, and / or the six cycles of 177Lu-PSMA I&T treatment provide a mean predicted dose that is below the absorbed dose limit of 23 Gy, and / or the predicted or actual cumulative renal absorbed dose over six cycles is less than 23 Gy, with no observed nephrotoxicity. 177 for injection into human patients requiring injection of Lu-PSMA I&T solution 177 The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a 7.4 GBq (mean 7.52±0.16 GBq) dose of 177Lu-PSMA-I&T, at which six cycles of 177Lu-PSMA I&T treatment are possible without risk of nephrotoxicity, and / or the six cycles of 177Lu-PSMA I&T treatment provide a mean predicted dose that is below the absorbed dose limit of 23 Gy, and / or the predicted or actual cumulative renal absorbed dose over six cycles is less than 23 Gy and no nephrotoxicity is observed. 177 for injection into human patients requiring injection of Lu-PSMA I&T solution 177 The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a 7.4 GBq (mean 7.52±0.16 GBq) dose of 177Lu-PSMA-I&T, and wherein six cycles of 177Lu-PSMA I&T treatment provide a mean predicted dose that is less than the absorbed dose limit of 23 Gy, and / or the predicted or actual accumulated renal absorbed dose over six cycles is less than 23 Gy, and no nephrotoxicity is observed. 177 for injection into human patients requiring injection of Lu-PSMA I&T solution 177The present invention further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of 177Lu-PSMA I&T solution, wherein the injection comprises a 7.4 (+ / - 10%) GBq dose of 177Lu-PSMA-I&T, at which six cycles of 177Lu-PSMA I&T treatment are possible without risk of nephrotoxicity, and / or the six cycles of 177Lu-PSMA I&T treatment provide a mean predicted dose that is less than the absorbed dose limit of 23 Gy, and / or the predicted or actual accumulated renal absorbed dose over six cycles is less than 23 Gy and no nephrotoxicity is observed. Note: The term "cumulative" may be interchangeable with "cumulated."

[0018] The present disclosure relates to a method of administering a radiopharmaceutical composition, the method comprising administering the radiopharmaceutical composition to a human patient in need thereof, optionally administering more than 48 hours after formulation, wherein the radiopharmaceutical composition is administered in a dose of 7.4 GBq±0.10 GBq, 7.4 GBq±0.15 GBq, 7.4 GBq±0.20 GBq, 7.4 GBq±0.25 GBq, or 7.4 GBq±0.30 GBq. 177 The present invention further relates to a method comprising comprising Lu-PSMA I&T in a solution comprising a pH of 3.5 to 4.5, the solution optionally comprising ascorbic acid and / or ethanol, the solution optionally comprising a radiochemical purity of greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or greater than 99.5% when administered, at which six cycles of 177Lu-PSMA I&T treatment are possible without risk of nephrotoxicity, and / or the six cycles of 177Lu-PSMA I&T treatment provide a mean predicted dose that is less than the absorbed dose limit of 23 Gy, and / or the predicted or actual accumulated renal absorbed dose over six cycles is less than 23 Gy and no nephrotoxicity is observed.

[0019] The present disclosure provides a method for diagnosing or treating a tumor in a patient in need thereof, the method comprising: 177The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein 20 hours after injection, the radiopharmaceutical composition has an activity of at least 20% IA to 30% IA in the whole body.

[0020] The present disclosure provides a method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity in the kidney of at least 8% IA to 10% IA within 20 hours after injection.

[0021] The present disclosure provides a method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity in the parotid gland of at least 0.7% IA to 1% IA within 20 hours after injection.

[0022] The present disclosure provides a method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity of at least 0.2% IA to 0.5% IA in the patient's lymph node lesions within 20 hours after injection.

[0023] The present disclosure provides a method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity of at least 0.1% IA to 0.4% IA in the patient's bone lesions within 20 hours after injection.

[0024] The present disclosure provides a method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 The present invention further relates to a method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an effective half-life of about 30 to 40 hours in the patient's systemic environment.

[0025] Various refinements of the above-described features exist in connection with various aspects of the present disclosure. Further features may also be incorporated into these various aspects. These refinements and additional features may exist individually or in any combination. For example, various features discussed below in connection with one or more of the illustrated embodiments may be incorporated alone or in any combination into any of the foregoing aspects of the present disclosure. Again, the foregoing brief summary is intended only to familiarize the reader with certain aspects and contexts of the present disclosure without limiting the claimed subject matter.

[0026] The various features, aspects, and advantages of the present disclosure will be better understood when the following detailed description is read in conjunction with the accompanying drawings, in which like characters represent like parts throughout. [Brief explanation of the drawings]

[0027] [Figure 1A] The structural formula of the precursor PSMA I&T is presented. [Figure 1B] The structural formula of the R isomer of 177Lu-PSMA I&T is presented, however, PSMA I&T does not have a specification regarding the enantiomeric purity of the R and S isomers. [Figure 2]FIG. 1 is a flow chart diagram of an exemplary method for preparing the disclosed radiopharmaceutical compositions. [Figure 3A] 1 is a flowchart of the synthesis procedure for 177Lu-PSMA I&T in one embodiment. [Figure 3B] 1 is a flowchart of the synthesis procedure for 177Lu-PSMA I&T in one embodiment. [Figure 4] A drawing of an exemplary product vial is shown. The drug product is delivered in a Type 1 glass, sterile, pyrogen-free glass vial with a fluorine-coated bromobutyl rubber septum. The septum is sealed with a crimped aluminum capsule. The glass vial containing the radiopharmaceutical is kept in a lead-shielded container during transport. The shipping container, including the lead shielding and outer packaging, complies with Type A requirements (IAEA standards). [Figure 5] 1 shows the 177Lu-PSMA I&T radiochemical purity measured by HPLC at different time points. [Figure 6A] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 7±0.1 at 0 and 71 hours after EOS, as detailed in Example 3. [Figure 6B] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 7±0.1 at 0 and 71 hours after EOS, as detailed in Example 3. [Figure 7A] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.4 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 71 hours after EOS, as detailed in Example 3. [Figure 7B] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.4 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 71 hours after EOS, as detailed in Example 3. [Figure 8A]1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 3.5±0.1 at 0 and 90 hours after EOS, as detailed in Example 3. [Figure 8B] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 3.5±0.1 at 0 and 90 hours after EOS, as detailed in Example 3. [Figure 9A] 1 shows HPLC radiochromatograms of a low activity formulation containing 21 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 92 hours after EOS, as detailed in Example 3. [Figure 9B] 1 shows HPLC radiochromatograms of a low activity formulation containing 21 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 92 hours after EOS, as detailed in Example 3. [Figure 10A] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 5±0.1 at 0 and 71 hours after EOS, as detailed in Example 3. [Figure 10B] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 5±0.1 at 0 and 71 hours after EOS, as detailed in Example 3. [Figure 11A] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 93 hours after EOS, as detailed in Example 3. [Figure 11B] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 93 hours after EOS, as detailed in Example 3. [Figure 12A] A summary of the kinetics, effective half-life, and mean absorbed dose (shown as median) in normal organs and tumor lesions is provided for one embodiment of the composition. [Figure 12B] A summary of the kinetics, effective half-life, and mean absorbed dose (shown as median) in normal organs and tumor lesions is provided for one embodiment of the composition. [Figure 12C] A summary of the effective half-life in normal organs and tumor lesions is provided for one embodiment of the composition. [Figure 12D] A summary of the mean absorbed dose (shown as median) in normal organs and tumor lesions is provided for one embodiment of the composition. [Figure 13] Assessment of disease status and treatment decisions at baseline and during treatment are presented. DETAILED DESCRIPTION OF THE INVENTION

[0028] It will be understood that, for simplicity and clarity of illustration, reference numerals have been repeated among the different figures, where appropriate, to indicate corresponding or analogous elements. Additionally, numerous specific details have been set forth in order to provide a thorough understanding of the examples described herein. However, those skilled in the art will understand that the examples described herein may be practiced without these specific details. In other instances, methods, procedures, and components have not been described in detail so as not to obscure the relevant features being described. Additionally, this description should not be considered as limiting the scope of the embodiments described herein. The figures are not necessarily to scale, and the proportions of certain parts may be exaggerated to better illustrate the details and features of the present disclosure.

[0029] Disclosed herein are small molecule inhibitors of PSMA that possess the desirable attributes of large monoclonal antibodies with reduced negative factors such as low permeability and toxicity. 177 Includes Lu-PSMA I&T. 177 Lu-PSMA I&T is a short-lived radiolabeled material from which the product is formulated immediately after final synthesis.

[0030] The headings included herein are for ease of reference only and are not intended to limit the disclosure in any way.

[0031] Additional features and advantages of the present disclosure will be set forth in the description that follows, and in part will be obvious from the description, or may be learned by practice of the principles disclosed herein. The features and advantages of the present disclosure may be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. These and other features of the present disclosure will become more fully apparent from the following 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.

[0032] I. Definition Definitions that apply throughout the above disclosure are presented here. As used herein, the terms "comprising," "having," and "including" are used interchangeably in their open, non-limiting sense. The terms "a," "an," and "the" are understood to encompass plural and singular. Thus, the term "a mixture thereof" also relates to "mixtures thereof."

[0033] In general, provided ranges are intended to include all specific ranges within a given range and combinations of subranges between given ranges. Thus, a range of 1 to 5 specifically includes 1, 2, 3, 4, and 5, as well as subranges such as 2 to 5, 3 to 5, 2 to 3, 2 to 4, and 1 to 4. All ranges and values disclosed herein are inclusive and combinable. For example, any value or point described herein within a range described herein can serve as a minimum or maximum value for deriving subranges, etc.

[0034] As used herein, "about" refers to numerical values, including integers, fractions, percentages, etc., whether explicitly stated or not. The term "about" generally refers to a range of numerical values, e.g., ±0.5-1%, ±1-5%, or ±5-10% of the recited value, that are considered equivalent to (e.g., have the same function or result as) the recited value.

[0035] As used herein, "PSMA" refers to prostate-specific membrane antigen, also known as folate hydrolase I or glutamate carboxypeptidase II, which is a type II transmembrane protein anchored to the cell membrane of prostate epithelial cells. PSMA is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer. PSMA expression level is directly correlated with androgen independence, metastasis, and the progression of prostate cancer. Therefore, PSMA is currently a promising molecular target for the diagnosis and therapy of metastatic prostate cancer.

[0036] As used herein, "lutetium-177" and " 177 Lu" are used interchangeably. 177 Lu is a beta- and gamma-emitting radionuclide with a physical half-life of 6.7 days. It has maximum and average beta particle energies of 0.498 MeV and 0.133 MeV, respectively. 177 The maximum and average soft tissue penetration depths of Lu are 1.7 mm and 0.23 mm, respectively. There are two major gamma emission lines: 113 keV (6% relative abundance) and 208 keV (11% relative abundance).

[0037] As used herein, " 177 "Lu-PSMA-617" refers to a DOTA derivative with a Glu-urea-Lys motif developed at the German Cancer Research Center (DKFZ) Heidelberg, Germany, for the treatment of patients with metastatic prostate cancer.

[0038] As used herein, "[ 177 Lu]Lu-PSMA I&T" and "177 "Lu-PSMA I&T" is used herein 177 Third generation derivatives of Lu-PSMA compounds for imaging and therapy (I&T) 177 This refers to Lu-PSMA. 177 The chemical name of Lu-PSMA I&T is (3S,7S,26R,29R,32R,37R)-29-benzyl-32-(4-hydroxy-3-iodobenzyl)-5,13,20,28,31,34-hexaoxo-37-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-heptaazaheptatriacontane-1,3,7,26,37-pentacarboxylic acid; lutetium-177(III). 177 The chemical structure of Lu-PSMA I&T is provided in Figure 1B.

[0039] The term "half-life" as used herein refers to biological half-life, e.g., the time required for the blood or plasma concentration of a drug to decrease by half. This decrease in drug concentration reflects its excretion or elimination after absorption is complete and distribution reaches an equilibrium or quasi-equilibrium state. The half-life of a drug in blood can be determined graphically from a pharmacokinetic plot of the drug's blood concentration-time plot, typically after intravenous administration to a sample population. Half-life can also be determined using mathematical calculations well known in the art. Furthermore, as used herein, the term "half-life" also includes the "apparent half-life" of a drug. The apparent half-life can be a composite number that accounts for contributions from processes other than elimination, such as absorption, reuptake, or enterohepatic recycling.

[0040] As used herein, "PRLT" refers to prostate radioligand therapy, and "RLT" refers to radioligand therapy. PRLT in this context involves the systemic intravenous administration of specific radiopharmaceuticals consisting of a beta-emitting radionuclide chelated to a small molecule for the purpose of delivering cytotoxic radiation to cancer cells.

[0041] As used herein, the term "CRPC" refers to castration-resistant prostate cancer. In some instances, patients with CRPC may have castrate serum testosterone <50 μg / L or 1.7 nmol / L, as well as one of the following progression patterns: biochemical progression or radiological progression, as defined below.

[0042] As used herein, the term "biochemical progression" refers to three consecutive rises in PSA at one-week intervals, two rises of 50% above the nadir, and a PSA >2 μg / l.

[0043] As used herein, the term "RAC" refers to radioactivity concentration.

[0044] As used herein, the term "radiologic progression" refers to the appearance of new lesions, i.e., either two or more new bone lesions or soft tissue lesions on a bone scan using Response Evaluation Criteria in Solid Tumors (RECIST).

[0045] As used herein, the terms "end of synthesis," "post-formulation," and "end of formulation" are used interchangeably to mean when the process of preparing a composition is complete, which may include quality control by qualified personnel and the time after release of the drug product.

[0046] The term "active agent" or "drug," as used herein, refers to any chemical substance that elicits a biochemical response when administered to a human or animal. A drug may act as a substrate or product of a biochemical reaction, or the drug may interact with a cellular receptor to elicit a physiological response, or the drug may bind to a receptor and block it from eliciting a physiological response.

[0047] The term "adverse event" (AE) is any undesirable medical occurrence in a subject administered an investigational drug, which does not necessarily have a causal relationship to treatment. An AE can be any untoward or unintended sign (e.g., abnormal laboratory finding), symptom, or disease temporarily associated with the use of the drug, whether or not drug-related. This includes any newly occurring event or pre-existing condition that has increased in severity or frequency since administration of the drug.

[0048] The terms "subject" and "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal, including, but not limited to, a human.

[0049] II. Introduction The present disclosure provides: 177 The present disclosure is directed to radiopharmaceutical compositions comprising Lu-PSMA I&T. In some embodiments, the compositions can be formulated as an injectable radiopharmaceutical solution. The present disclosure functions as an antitumor agent for targeted radionuclide therapy. 177 The present invention further relates to high-energy, high-purity, and / or low-toxicity radiopharmaceutical compositions comprising Lu-PSMA I&T.

[0050] The present disclosure is also directed to methods of making radiopharmaceutical compositions.Provided herein are methods of increasing the shelf life of radiopharmaceutical products.

[0051] The present disclosure further relates to properties of radiopharmaceutical compositions and methods of using radiopharmaceutical compositions.

[0052] 177 Lu-PSMA I&T is also known by the following synonyms: 177 Lu]lutetium-PSMA I&T, 177 Lu-ITG-PSMA-1, PSMA-TUM3, 177 Lu-DOTAGA-(Iy)fk(Sub-KuE), or 177Lu-(3S,7S)-29-benzyl-32(3-iodo,4-hydroxy)-benzyl-5,12,20,28,31,34-hexaoxo-37-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-heptaazaheptatriacontane-1,3,7,26,37-pentacarboxylic acid. The molecular formula of the unlabeled precursor is C 63 H 92 IN 11 O 23 ·4TFA·3H2O and has a relative molecular weight of 1498 g / mol.

[0053] Labeled substance 177 Lu-PSMA I&T is a non-carrier-doped lutetium-177 (T 1 / 2 =6.6d) can be labeled with solution. 177 Lu-PSMA I&T is a short-lived radiolabeled material from which the product is formulated immediately after final synthesis. Therefore, there are no specifications or batch analyses of the labeled material. Controls are performed on the labeled drug product.

[0054] Synthesized 177 The Lu-PSMA I&T solution can be formulated in an injection-grade aqueous solution containing a stabilizer such as ascorbic acid. The solution can be sterilized by aseptic filtration through a 0.22 μm filter before being dispensed into multi-dose vials. Administration of the formulated solution can be within 72 hours of completion of synthesis, following quality control by qualified personnel and release of the drug product.

[0055] Ascorbic acid can be used to minimize radioactive degradation of radiolabeled preparations. In addition to ascorbic acid, a dosage formulation pH of 5 or less can stabilize the labeled product against radioactive degradation and extend its shelf life. Thus, in another aspect, the present disclosure further provides a dosage formulation containing ascorbic acid at a pH of 5 or less, which improves the stability of the radiopharmaceutical composition against radioactive degradation and thus improves the shelf life of the composition.

[0056] Stability-enhancing conditions can be applied as early as possible in the manufacturing process. For example, an ascorbic acid solution at a pH of 5 or less can be applied to labeled 177 It can be used in place of water in the purification steps of Lu-PSMA I&T to minimize radiolytic damage.

[0057] The compositions, when administered to a subject, can result in a low hematotoxicity and nephrotoxicity profile, providing better efficacy and fewer adverse effects than monoclonal antibody therapy and other comparable third-line therapies.

[0058] The compositions are improved compositions in that they have a shelf life of greater than 72 hours after formulation. In addition, the improved compositions have a radiochemical purity of greater than 95% at the time of administration. That is, the improved formulations maintain a high level of radiochemical purity for greater than 72 hours after formulation. Thus, the improved formulations 177 It is suitable for administration for up to 24 hours or up to 72 hours longer than other compositions containing Lu-PSMA I&T.

[0059] III. Radiopharmaceutical Compositions The disclosed radiopharmaceutical compositions or formulations comprise: 177 a dose of Lu-PSMA I&T and at least one of a stabilizer, an antioxidant, a pH adjuster, a metal ion chelator, water, or a combination thereof.

[0060] In a specific embodiment, the stabilizer is ethanol. In another embodiment, the antioxidant may be ethanol, ascorbic acid, gentisic acid, or a combination thereof. In another embodiment, the pH adjuster includes, but is not limited to, sodium hydroxide, sodium bicarbonate, hydrochloric acid, or a combination thereof. In yet another embodiment, the chelating agent may be EDTA or DTPA.

[0061] In one embodiment, the pharmaceutical product or radiopharmaceutical composition (or formulation) is dissolved in an aqueous solution of ascorbic acid containing ethanol. 177 The radiopharmaceutical solution may be a sterile-filtered solution containing a dose of Lu-PSMA I&T. For example, the total amount of ascorbic acid in the solution may be about 25 to about 65 mg / mL, and the total amount of ethanol in the solution may be about 3.8% (v / v) to about 7.5% (v / v). In some embodiments, the total amount of ascorbic acid in the solution is about 21 mg / mL to about 42.5 mg / mL. 177 Lu-PSMA I&T is present in sufficient amounts of radioactivity for its intended use. Experiments conducted with various dosage formulations contain approximately 31 mg / ml ascorbic acid at a pH of approximately 4.5, and radioactivity concentrations of approximately 640 MBq / ml or less. 177 These results suggest that the Lu-PSMA I&T formulation composition can provide sufficient radiochemical stability for 4 days. The sufficient radiochemical stability referred to herein is 177 A radiopharmaceutical composition wherein the radiochemical purity of the Lu-PSMA I&T is at least 95%, 95.5% or more, 96.5% or more, 97.0% or more, 97.5% or more, 98.0% or more, 98.5% or more, 99.0% or more, or 99.5% or more at the time of administration.

[0062] In one embodiment, the radiopharmaceutical composition is provided in microdoses in aqueous ascorbic acid and ethanol solutions. 177 In another embodiment, the radiopharmaceutical composition is a microdosed solution of ascorbic acid in an ethanol-free aqueous solution. 177 A sterile filtered radiopharmaceutical solution containing Lu-PSMA I&T. For example, the radiopharmaceutical composition may be a microdose solution in an acetate buffer containing aqueous ascorbic acid and DTPA (e.g., with or without ethanol). 177 The product is diluted to a standard radioactivity concentration, so that the final volume of the bulk product is the introduced 177Varies depending on the starting activity of Lu.

[0063] One aspect of the present disclosure provides a radiopharmaceutical composition having a pH of about 3 to about 9, about 4 to about 9, about 5 to about 9, about 3 to about 8, about 4 to about 8, about 3 to about 5, or about 5 to about 8. The pH of the radiopharmaceutical composition may be about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, It may be about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, or about 9.

[0064] Having a pH of 5 or less can stabilize the radiopharmaceutical composition against radiolysis and extend its shelf life.

[0065] In one embodiment, the pH of the radiopharmaceutical composition is from about 3 to about 5. This pH range can stabilize the radiopharmaceutical composition against radiolysis and extend its shelf life. In yet another embodiment, a radiopharmaceutical composition containing ascorbic acid and having a pH of from about 3 to about 5 can have a higher pH value and contain gentisic acid. 177 Lu-PSMA I&T has improved stability and extended shelf life compared to known radiopharmaceutical compositions.

[0066] The pH of the radiopharmaceutical composition may be 3.0 to 5.0, 3.0 to 3.5, 3.0 to 3.05, 3.05 to 3.1, 3.0 to 3.1, 3.1 to 3.15, 3.1 to 3.2, 3.15 to 3.2, 3.2 to 3.25, 3.0 to 3.25, 3.2 to 3.3, 3.25 to 3.3, 3.3 to 3.35, 3.3 to 3.4, 3.35 to 3.4, 3.4 to 3.45, 3.4 to 3.5, 3.45 ... 3.5, 3.25~3.5, 3.5~3.55, 3.5~3.6, 3.55~3.6, 3.6~3.65, 3.6~3.7, 3.65~3.7, 3.7~3.75, 3.5~3.75, 3.7~3.8, 3.75~3.8, 3.8~3.85, 3.8~3.9, 3.85~3.9, 3.9~3.95, 3.9~4.0, 3.95~4.0, 3.5~4.0, 3.75 ~4.0, 4.0~4.05, 4.0~4.1, 4.05~4.1, 4.1~4.15, 4.1~4.2, 4.15~4.2, 3.5~4.2, 4.2~4.25, 4.0~4.25, 4.2~4.3, 4.25~4.3, 4.3~4.35, 4.3~4.4, 4.35~4.4, 4.4~4.45, 4.4~4.5, 4.45~4.5, 4.25~4.5, 4.0 The pH of the radiopharmaceutical composition may range from 4.5 to 4.55, 4.5 to 4.6, 4.55 to 4.6, 4.6 to 4.65, 4.6 to 4.7, 4.65 to 4.7, 4.7 to 4.75, 4.7 to 4.8, 4.75 to 4.8, 4.8 to 4.85, 4.8 to 4.9, 4.85 to 4.9, 4.9 to 4.95, 4.9 to 5.0, 4.95 to 5.0, 4.5 to 5.0, or 4.75 to 5.0. In some examples, the pH of the radiopharmaceutical composition may be adjusted to a final pH of 3.0, 3.5, 4.0, 4.5, or 5.0. In some embodiments, including those pH numbers and ranges listed above, the pH value comprises ±0.05, ±0.10, ±0.15, ±0.20, or ±0.25.

[0067] In another embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the radiopharmaceutical composition or formulation has a purity of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%.

[0068] In another embodiment, the radiopharmaceutical composition or formulation has a purity of 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 radiopharmaceutical composition or formulation has a purity of at least about 90.0%, at least about 91.0%, at least about 92.0%, at least about 93.0%, at least about 94.0%, at least about 95.0%, at least about 96.0%, at least about 97.0%, at least about 98.0%, at least about 99.0%, or at least about 99.5% as measured by HPLC, TLC, or liquid chromatography. In some examples, the radiopharmaceutical composition may have a radiochemical purity of 95.0% or greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater upon administration. Figure 5 shows the radiochemical purity in different pH formulations.

[0069] 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, and about 100 hours after EOS.

[0070] In one specific embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 99% as measured by HPLC, TLC, or liquid chromatography at 0 hours after EOS. In another specific embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 96.5% as measured by HPLC, TLC, or liquid chromatography at 24 hours after EOS, at least about 93% as measured by HPLC, TLC, or liquid chromatography at 46 hours after EOS, at least about 95% as measured by HPLC, TLC, or liquid chromatography at 67 hours after EOS, and at least about 96% as measured by HPLC, TLC, or liquid chromatography at 92 hours after EOS.

[0071] In another embodiment, the radioactivity is measured with a dose calibrator. 177 The radioactivity of the Lu-PSMA I&T is determined when the dose is dispensed.

[0072] In yet another embodiment, 177 The radiochemical purity of Lu-PSMA I&T is determined by liquid chromatography and thin layer chromatography with radioactivity detection.

[0073] In one embodiment, bacterial endotoxin content is determined for each batch prior to release using a PTS tester (Ph Eur method D) and sterility is determined according to Ph Eur.

[0074] 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.

[0075] Another embodiment of the present disclosure provides a radioactive content of about 70% to 130%. The radioactive content of the radiopharmaceutical composition may 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%.

[0076] 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%.

[0077] Another aspect of the present disclosure provides a radiopharmaceutical composition having a mean systemic effective dose of about 23±20 Gy (3.3 Gy / GBq), and mean absorbed organ doses of about 26±20 Gy (3.4 Gy / GBq), 24±16 Gy (3.2 Gy / GBq), 8.5±4.7 Gy (1.28 Gy / GBq), and 13±7.4 Gy (1.7 Gy / GBq) for bone metastases, lymph node metastases, liver metastases, and lung metastases, respectively.

[0078] In some embodiments, the radiopharmaceutical composition may have a low radioactivity concentration ("low RAC") of about 579 MBq / ml to about 626 MBq / ml. For example, the radiopharmaceutical composition may have a low radioactivity of about 11,580 MBq (313 mCi), about 11,770 MBq (318 mCi), or about 12,520 MBq (338 mCi) in a 20 ml volume of solution. In other embodiments, the radiopharmaceutical composition may have a low radioactivity concentration of at least about 550 MBq / ml, at least about 560 MBq / ml, at least about 570 MBq / ml, at least about 580 MBq / ml, at least about 590 MBq / ml, at least about 600 MBq / ml, at least about 610 MBq / ml, at least about 620 MBq / ml, at least about 630 MBq / ml, at least about 640 MBq / ml, or at least about 650 MBq / ml. In still other embodiments, the radiopharmaceutical composition may have a low radioactivity concentration of about 550 MBq / ml to about 575 MBq / ml, about 575 MBq / ml to about 600 MBq / ml, about 600 MBq / ml to about 625 MBq / ml, or about 625 MBq / ml to about 650 MBq / ml.

[0079] In additional embodiments, the radiopharmaceutical composition may have a high radioactivity concentration ("high RAC") of about 1,270 MBq / ml to about 1,311 MBq / ml. For example, the radiopharmaceutical composition may have a high radioactivity that may be about 12,780 MBq (345 mCi), about 12,810 MBq (346 mCi), or about 13,110 MBq (354 mCi) in a 10 ml volume of solution. In other embodiments, the radiopharmaceutical composition is at least about 1,100 MBq / ml, at least about 1,110 MBq / ml, at least about 1,120 MBq / ml, at least about 1,130 MBq / ml, at least about 1,140 MBq / ml, at least about 1,150 MBq / ml, at least about 1,160 MBq / ml, at least about 1,170 MBq / ml, at least about 1,180 MBq / ml, at least about 1,190 MBq / ml, at least about 1,200 MBq / ml, at least about 1,210 MBq / ml, at least about 1,220 MBq / ml, at least about 1,230 MBq / ml, at least about 1,240 MBq / ml, at least about 1,250 MBq / ml, at least about 1,260 MBq / ml, at least about 1,270 MBq / ml, at least about 1,280 MBq / ml, at least about 1,300 MBq / ml, at least about 1,310 MBq / ml, at least about 1,320 MBq / ml, at least about 1,330 MBq / ml, at least about 1,340 MBq / ml, at least about 1,350 MBq / ml, at least about 1,360 MBq / ml, at least about 1,370 MBq / ml, at least about 1,380 MBq / ml, at least about 1,390 MBq / ml, at least about 1,400 MBq / ml, at least about 1,410 MBq / ml, at least about 1,420 MBq / ml, at least about 1,430 MBq / ml, at least about 1,440 MBq / ml, at least about 1,450 MBq / ml, at least about 1,46 The radioactive material may have a high radioactivity concentration of 20 MBq / ml, at least about 1,230 MBq / ml, at least about 1,240 MBq / ml, at least about 1,250 MBq / ml, at least about 1,260 MBq / ml, at least about 1,270 MBq / ml, at least about 1,280 MBq / ml, at least about 1,290 MBq / ml, at least about 1,300 MBq / ml, at least about 1,310 MBq / ml, at least about 1,320 MBq / ml, at least about 1,330 MBq / ml, at least about 1,340 MBq / ml, or at least about 1,350 MBq / ml. In still other embodiments, the radiopharmaceutical composition may have a high radioactivity concentration of about 1,000 MBq / ml to about 1,400 MBq / ml, about 1,050 MBq / ml to about 1,350 MBq / ml, about 1,100 MBq / ml to about 1,300 MBq / ml, about 1,150 MBq / ml to about 1,250 MBq / ml, about 1,200 MBq / ml to about 1,300 MBq / ml, about 1,250 MBq / ml to about 1,350 MBq / ml, or about 1,250 MBq / ml to about 1,300 MBq / ml.

[0080] (i) 177 Lu-PSMA I&T present in the radiopharmaceutical composition 177The total amount of Lu-PSMA I&T can and will vary. Figures 1A and 1B show the precursor PSMA I&T and 177 The chemical structure of Lu-PSMA I&T is shown.

[0081] In one embodiment, the radiopharmaceutical component ( 177 In yet another embodiment, the mass of the radiopharmaceutical component (Lu-PSMA I&T) in the drug product is less than about 30 μg, less than about 25 μg, less than about 20 μg, less than about 15 μg, or less than about 10 μg per vial. 177 The mass of Lu-PSMA I&T) is about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, or about 10 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 17.2 μg, about 18 μg, 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 per vial. 177 Lu-PSMA I&T.

[0082] In some embodiments, present in the radiopharmaceutical composition 177 The total amount of Lu-PSMA I&T can be in the range of about 1.0 μg / ml to about 3 μg / ml, about 1 μg / ml to about 2 μg / ml, about 1.1 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. 177 The total amount of Lu-PSMA I&T can range from about 0.5 μg / ml to about 1.5 μg / ml. In various embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can range from about 0.5 μg / ml to about 1.5 μg / ml. 177The total amount of Lu-PSMA I&T can be about 0.5 μg / ml, about 0.6 μg / ml, about 0.7 μg / ml, about 0.8 μg / ml, about 0.9 μg / ml, about 1.0 μg / ml, about 1.1 μg / ml, about 1.2 μg / ml, about 1.3 μg / ml, about 1.4 μg / ml, about 1.5 μg / ml, about 1.6 μg / ml, about 1.7 μg / ml, or about 1.8 μg / ml.

[0083] In some embodiments, present in the radiopharmaceutical composition 177 The total amount of Lu-PSMA I&T can be in the range of about 3.0 μg / ml to about 9.0 μg / ml, about 3.5 μg / ml to about 8.5 μg / ml, about 4.0 μg / ml to about 8.0 μg / ml, about 4.5 μg / ml to about 7.5 μg / ml, about 5.0 μg / ml to about 7.0 μg / ml, or about 5.5 μg / ml to about 6.5 μg / ml. In another embodiment, the total amount of Lu-PSMA I&T in the radiopharmaceutical composition can be in the range of about 3.0 μg / ml to about 9.0 μg / ml, about 3.5 μg / ml to about 8.5 μg / ml, about 4.0 μg / ml to about 8.0 μg / ml, about 4.5 μg / ml to about 7.5 μg / ml, about 5.0 μg / ml to about 7.0 μg / ml, or about 5.5 μg / ml to about 6.5 μg / ml. 177 The total amount of Lu-PSMA I&T may range from about 0.5 μg / ml to about 1.5 μg / ml. In some embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition may range from about 0.5 μg / ml to about 1.5 μg / ml. 177 The total amount of Lu-PSMA I&T may be less than 3.0 μg / ml. In other embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 3.0 μg / ml. 177 The total amount of Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 4.0 μg / ml. 177 The total amount of Lu-PSMA I&T may be less than 3.0 μg / ml. In other embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 3.0 μg / ml. 177 The total amount of Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 5.0 μg / ml. 177 The total amount of Lu-PSMA I&T may be less than 3.0 μg / ml. In other embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 3.0 μg / ml. 177 The total amount of Lu-PSMA I&T can be less than 6.0 μg / ml.

[0084] In some embodiments, present in the radiopharmaceutical composition 177The total amount of Lu-PSMA I&T can be in the range of about 9 μg / ml to 20 μg / ml, 10 μg / ml to 20 μg / ml, 11 μg / ml to 20 μg / ml, 11 μg / ml to 15 μg / ml, 11 μg / ml to 14 μg / ml, or 11 μg / ml to 13 μg / ml. 177 The total amount of Lu-PSMA I&T can range from about 5 μg / ml to about 15 μg / ml. In various embodiments, the total amount of Lu-PSMA I&T present in the radiopharmaceutical composition can range from about 5 μg / ml to about 15 μg / ml. 177 The total amount of Lu-PSMA I&T can be about 5 μg / ml, 6 μg / ml, 7 μg / ml, 8 μg / ml, 9 μg / ml, 10 μg / ml, 11 μg / ml, 12 μg / ml, 13 μg / ml, 14 μg / ml, 15 μg / ml, 16 μg / ml, 17 μg / ml, or 18 μg / ml. The composition can have less than 12 μg / ml, or less than 6 μg / ml of Lu-PSMA I&T.

[0085] In the composition 177 The radioactivity / volume of Lu-PSMA I&T can be adjusted according to dose strength. In one embodiment, the composition contains 0.5 GBq (13.5 mCi) in 1 ml of solution. 177 In other words, the composition may contain 10 GBq (270 mCi) of Lu-PSMA I&T in a 20 ml solution. 177 In another embodiment, the composition may contain 1 GBq (27 mCi) of Lu-PSMA I&T in 1 ml of solution. 177 In other words, the composition may contain 10 GBq (270 mCi) of Lu-PSMA I&T in a 10 ml solution. 177 Lu-PSMA I&T may be included.

[0086] In one embodiment, in the radiopharmaceutical composition 177 The radioactivity concentration of the Lu-PSMA I&T is less than about 50 mCi / ml, less than about 45 mCi / ml, less than about 40 mCi / ml, less than about 35 mCi / ml, less than about 30 mCi / ml, less than about 25 mCi / ml, less than about 20 mCi / ml, or less than about 15 mCi / ml. 177The radioactivity concentration of Lu-PSMA I&T is about 5 mCi / ml to about 30 mCi / ml, about 10 mCi / ml to about 20 mCi / ml, or about 13 mCi / ml to about 30 mCi / ml. 177 The radioactivity concentration of Lu-PSMA I&T is about 5 mCi / ml, about 10 mCi / ml, about 13.5 mCi / ml, about 15 mCi / ml, about 20 mCi / ml, about 27 mCi / ml, about 30 mCi / ml, about 30 mCi / ml, about 35 mCi / ml or about 40 mCi / ml.

[0087] In one embodiment, in the radiopharmaceutical composition 177 The radioactivity of the Lu-PSMA I&T is less than about 500 mCi, less than about 450 mCi, less than about 400 mCi, less than about 350 mCi, less than about 300 mCi, less than about 250 mCi, or less than about 200 mCi per vial. 177 The radioactivity of Lu-PSMA I&T is about 10 mCi to about 750 mCi, about 200 mCi to about 600 mCi, or about 300 mCi to about 400 mCi per vial. 177 The radioactivity of Lu-PSMA I&T is about 27mCi, 150mCi, about 160mCi, about 170mCi, about 180mCi, about 190mCi, about 200mCi, about 250mCi, about 270mCi, about 300mCi, about 313mCi, about 318mCi, about 338mCi, about 345mCi, about 346mCi, about 354mCi, about 360mCi, about 370mCi, about 380mCi, about 390mCi, about 400mCi, about 450mCi, about 500mCi, about 550mCi, about 600mCi, or about 700mCi per vial.

[0088] In yet another embodiment, 177 The Lu-PSMA I&T drug product has a standard radioactivity concentration of about 12 mCi / ml or about 32 mCi / ml at the end of manufacturing. In one embodiment, 177 Lu-PSMA I&T drug products have a standard radioactivity concentration of about 13.5 mCi / ml or about 27 mCi / ml at the end of manufacture.

[0089] (ii) antioxidants The antioxidant may act as a buffering agent and / or stabilizer. The total amount of antioxidant in the radiopharmaceutical composition can vary and will vary. Examples of suitable antioxidants include, but are not limited to, ascorbic acid or gentisic acid. The amount of antioxidant in the composition can range from about 10 mg / ml to 90 mg / ml, about 15 mg / ml to 85 mg / ml, about 20 mg / ml to 80 mg / ml, about 25 mg / ml to 75 mg / ml, about 30 mg / ml to 70 mg / ml, about 35 mg / ml to 65 mg / ml, about 40 mg / ml to 60 mg / ml, or about 45 mg / ml to 55 mg / ml. Alternatively stated, the amount of antioxidant in the composition can range from about 10 mg to 90 mg, about 15 mg to 85 mg, about 20 mg to 80 mg, about 25 mg to 75 mg, about 30 mg to 70 mg, about 35 mg to 65 mg, about 40 mg to 60 mg, or about 45 mg to 55 mg per ml.

[0090] In certain embodiments, the antioxidant can be ascorbic acid, which can minimize or reduce radiodegradation of the radiolabeled composition.

[0091] In some embodiments, the amount of ascorbic acid present in the radiopharmaceutical composition may 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, hi other embodiments, the amount of ascorbic acid present in the radiopharmaceutical composition may be in the range of about 5 mg to about 50 mg per ml.

[0092] In various embodiments, the ascorbic acid present in the radiopharmaceutical composition may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 31 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 40.5 mg, about 41 mg, about 41.5 mg, about 42 mg, about 42.5 mg, about 43 mg, about 43.5 mg, about 44 mg, about 44.5 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg per ml. For example, the amount of ascorbic acid in 1 ml of the composition can be about 25 mg to 30 mg, about 30 mg to 35 mg, about 35 mg to 40 mg, or about 40 mg to 45 mg.

[0093] In yet another embodiment, the concentration of ascorbic acid in the radiopharmaceutical composition can be from about 10 mg / ml to about 80 mg / ml, from about 10 mg / ml to about 75 mg / ml, from about 10 mg / ml to about 70 mg / ml, from about 15 mg / ml to about 80 mg / ml, from about 15 mg / ml to about 75 mg / ml, from about 15 mg / ml to about 70 mg / ml, from about 20 mg / ml to about 80 mg / ml, from about 20 mg / ml to about 75 mg / ml, or from about 20 mg / ml to about 70 mg / ml.

[0094] 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.

[0095] In at least one embodiment, the total amount of ascorbic acid in the radiopharmaceutical composition may be about 31 mg / ml, hi further embodiments, the total amount of ascorbic acid in the radiopharmaceutical composition may be about 15 mg / ml, about 21 mg / ml, about 25 mg / ml, about 31 mg / ml, or about 42.5 mg / ml.

[0096] (iii) stabilizers The stabilizer may be separate from the antioxidant. The total amount of stabilizer present in the radiopharmaceutical composition can and will vary. Stabilizers may also be used to limit or reduce radiolysis. The stabilizer may also function as a vehicle for the composition.

[0097] Stabilizers include, but are not limited to, ethanol, para-aminobenzoic acid (PABA), dihydroxybenzoic acid (gentisic acid compound), gentisic acid, cysteine, selenomethionine, ascorbic acid / sodium ascorbate, methionine, or combinations thereof.

[0098] In some embodiments, the stabilizer is ethanol. Ethanol may be present in the pharmaceutical composition at a concentration of about 0.01% (v / v) to about 10% (v / v), 0.01% (v / v) to 3% (v / v), about 0.5% (v / v) to 1% (v / v), about 1% (v / v) to 2% (v / v), about 2% (v / v) to about 3% (v / v), about 3% (v / v) to 4% (v / v), or about 3.5% to 4.5% (v / v). ethanol may be present at about 4% to 5% (v / v), about 4.5% to 5.5% (v / v), about 5% to 6% (v / v), about 5.5% to 6.5% (v / v), about 6% to 7% (v / v), about 6.5% to 7.5% (v / v), or about 7% to 8% (v / v). In some embodiments, the pharmaceutical composition comprises zero (0.00% v / v) ethanol (i.e., ethanol may be absent from the pharmaceutical composition).

[0099] In one embodiment, the total amount of ethanol present in the radiopharmaceutical composition is from about 3% (v / v) to about 8% (v / v), or from 2% (v / v) to about 4% (v / v), or from about 7% (v / v) to about 8% (v / v). In various embodiments, the total amount of ethanol present in the radiopharmaceutical composition can be about 1% (v / v), about 2% (v / v), about 3% (v / v), about 3.5% (v / v), about 3.8% (v / v), about 4% (v / v), about 4.5% (v / v), about 5% (v / v), about 5.5% (v / v), about 6% (v / v), about 6.5% (v / v), about 7% (v / v), about 7.5% (v / v), about 8% (v / v), about 8.5% (v / v), about 9% (v / v), about 9.5% (v / v), or about 10% (v / v).

[0100] In at least one example, the radiopharmaceutical composition comprises 3.8% (v / v) ethanol, hi another example, the radiopharmaceutical composition comprises 7.5% (v / v).

[0101] Alternatively stated, the total amount of ethanol present in the radiopharmaceutical composition can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg per ml.

[0102] In some embodiments, the total amount of ethanol present in the radiopharmaceutical composition may range from about 20 mg to about 35 mg per ml, hi other embodiments, the total amount of ethanol in the radiopharmaceutical composition may range from about 43 mg to about 63 mg per ml.

[0103] In some embodiments, the total amount of ethanol present in the radiopharmaceutical composition may range from about 25 mg to about 80 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, or about 70 mg to about 80 mg per ml. In other embodiments, the total amount of ethanol in the radiopharmaceutical composition may range from about 30 mg to about 60 mg per ml.

[0104] In further embodiments, the proportion of ethanol in the radiopharmaceutical composition may be about 300 mg per 10 ml, or about 30 mg / ml. In another embodiment, the proportion of ethanol in the radiopharmaceutical composition may be about 200 mg per 10 ml. In yet another embodiment, the proportion of ethanol in the radiopharmaceutical composition may be about 350 mg per 10 ml.

[0105] Alternatively, the amount of ethanol in the composition can range from about 35 μl / ml to about 75 μl / ml. For example, the amount of ethanol in 1 ml of the composition can be about 35 μl to 40 μl, about 40 μl to 45 μl, about 45 μl to 50 μl, about 50 μl to 55 μl, about 55 μl to 60 μl, about 60 μl to 65 μl, about 65 μl to 70 μl, or about 70 μl to 75 μl. In at least one example, 1 ml of the composition contains 37.5 μl (29.5 mg) of ethanol. In another example, 1 ml of the composition contains 75 μl (58.9 mg) of ethanol.

[0106] (iv) Metal ion chelating agents (chelating agents) In some embodiments, the present disclosure provides a method for the preparation of microdoses. 177A radiopharmaceutical composition is provided having an Lu-PSMA I&T solution and at least one metal ion chelating agent. Suitable chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts, N-(hydroxyethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid (NIA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid, 1,4,7-tris(carboxymethyl)-10-(2'-hydroxy ... Examples of chelating agents include (dipropyl)-1,4,7,10-tetraazocyclodecane, 1,4,7-triazacyclonane-N,N',N"-triacetic acid, 1,4,8,11-tetraazacyclotetra-decane-N,N',N",N'''-tetraacetic acid, diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine, bis(aminoethanethiol)carboxylic acid, triethylenetetramine-hexaacetic acid, and 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid. In one embodiment, the chelating agent can be the sodium salt of EDTA.

[0107] In some embodiments, the metal ion chelator is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA) and its salts, N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid (NIA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid, 1,4,7,10-tetraaza-cyclododecane-N,N',N"-triacetic acid, 1,4,7,10-tetraaza-cyclododecane-N,N',N"-triacetic acid, 1,4,7-tris(carboxymethyl)-10-( 2'-hydroxypropyl)-1,4,7,10-tetraazocyclodecane, 1,4,7-triazacyclonane-N,N',N"-triacetic acid, 1,4,8,11-tetraazacyclotetra-decane-N,N',N",N"'-tetraacetic acid, diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine, bis(aminoethanethiol)carboxylic acid, triethylenetetramine-hexaacetic acid, and 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid. In one embodiment, the metal ion chelator can be disodium EDTA. In one embodiment, the metal ion chelator can be DPTA.

[0108] In one embodiment, the amount of chelating agent present in the radiopharmaceutical composition may range from about 5 μg to 500 μg, hi some embodiments, the amount of metal ion chelating agent present in the radiopharmaceutical composition may range from about 5 μg to 50 μg.

[0109] In some embodiments, the amount of chelating agent present is about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10.5 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg, Approximately 25μg, approximately 26μg, approximately 27μg, approximately 28μg, approximately 29μg, approximately 30μg, approximately 31μg, approximately 32μg, approximately 33μg, approximately 34μg, approximately 35μg, approximately 36μg , about 37μg, about 38μg, about 39μg, about 40μg, about 45μg, about 50μg, about 60μg, about 70μg, about 80μg, about 90μg, about 100μg, about 11 0μg, about 120μg, about 130μg, about 140μg, about 150μg, about 160μg, about 170μg, about 180μg, about 190μg, about 200μg, about 210 μg, approx. 220 μg, approx. 230 μg, approx. 240 μg, approx. 250 μg, approx. 260 μg, approx. 270 μg, approx. 280 μg, approx. 290 μg, approx. 300 μg, approx. 310 μg g, about 320 μg, about 330 μg, about 340 μg, about 350 μg, about 360 μg, about 370 μg, about 380 μg, about 390 μg, about 400 μg, about 410 μg, about 420 μg, about 430 μg, about 440 μg, about 450 μg, about 460 μg, about 470 μg, about 480 μg, about 490 μg, or about 500 μg.

[0110] The concentration of the metal ion chelating agent in the composition may range from about 5 μg / ml to about 500 μg / ml, hi alternative embodiments, the concentration of the chelating agent present in the radiopharmaceutical composition may 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 chelating agent present is about 5 μg / ml, about 6 μg / ml, about 7 μg / ml, about 8 μg / ml, about 9 μg / ml, about 10.5 μg / ml, about 11 μg / ml, about 12 μg / ml, about 13 μg / ml, about 14 μg / ml, about 15 μg / ml, about 16 μg / ml, about 17 μg / ml, about 18 μg / ml, about 19 μg / ml, about 20 μg / ml, about 21 μg / ml, about 22 μg / ml, about It can be 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.

[0111] In other embodiments, the amount of metal ion chelator in the radiopharmaceutical composition can be from about 0.001% to about 0.20% (w / w), from about 0.20% to about 0.40% (w / w), from about 0.40% to about 0.60% (w / w), from about 0.60% to about 0.80% (w / w), or from about 0.80% to about 1.00% (w / w) of the radiopharmaceutical composition. In some embodiments, the amount of metal ion chelator present in the radiopharmaceutical composition may be about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, or 0.15% (w / w) of the total weight of the radiopharmaceutical composition.

[0112] 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.

[0113] In at least one example, 1 ml of the composition contains 15.5 μg of disodium EDTA. In another example, 1 ml of the composition contains 21 μg of disodium EDTA.

[0114] (v) pH adjuster Suitable pH adjusters include, but are not limited to, any one of hydrochloric acid, sodium hydroxide, sodium bicarbonate, or combinations thereof.

[0115] In some embodiments, hydrochloric acid may be used to adjust the pH of the radiopharmaceutical composition. In certain embodiments, the amount of hydrochloric acid in the composition may range from 0 mg / ml to about 2 mg / ml. In some embodiments, the amount of HCl may range from 1.6 ml of 0.05 M HCl to 2 ml of 0.04 M HCl. The amount of HCl in the composition may be varied to adjust the final formulation pH. In various embodiments, the final formulation pH ranges from pH 3.0 to 5.0. In at least one example, HCl is added to the composition to reach a final pH of 3.5±0.1 to 4.5±0.1.

[0116] In some embodiments, the amount of sodium bicarbonate in the composition may be sufficient to control the pH of the composition between 5.5 and 7.0 prior to the addition of HCl.

[0117] In some embodiments, the amount of NaOH in the composition may be sufficient to control the pH of the composition between 5.5 and 7.0 prior to the addition of HCl.

[0118] (vi) Water The composition may further comprise a sufficient amount of water to produce the desired final volume of the injectable solution. For example, water may be added to produce a final volume of 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.

[0119] IV. PROCESSES FOR MAKING RADIOPHARMACEUTICAL COMPOSITIONS The entire manufacturing process is a one-step radiolabeling process using PSMA I&T precursors. Successful labeling depends on temperature, time, and pH. The reaction is carried out in a reactor vial at elevated temperature. For example, the reactor may be heated to a setpoint of 110°C, with the maximum temperature reached in the reaction solution being approximately 95°C. The radiolabeled product is isolated on a C18 cartridge and formulated into the final composition after elution into bulk vials. The final product is dispensed in a Grade A controlled environment.

[0120] 177 The Lu-PSMA I&T composition solution may be prepared using the following method 100, for example, as shown in Figure 2. The order of steps may vary, including the order in which the various solutions are prepared.

[0121] In certain embodiments, step 102 may include preparing four solutions for synthesis. The four solutions may include 0.04 M hydrochloric acid, 0.4 M sodium acetate, 20% (w / w) L-ascorbic acid, and about 460 to about 500 μg / ml of PSMA I&T in water. The PSMA I&T precursor may be dissolved in sterile water for injection. For example, depending on the number of doses to be produced, 120 μg to 600 μg of precursor may be used in the reaction. In at least one example, 463 μl / ml of PSMA I&T precursor may be used to produce the composition.

[0122] In some embodiments, step 104 may include preparing an ascorbic acid solution (dilution buffer). In some examples, the ascorbic acid solution may be a 50 mg / ml ascorbic acid solution. The solution pH may be adjusted to 4.5±0.25. For example, a 50 mg / ml ascorbic acid solution may be prepared and the pH of the solution adjusted to 4.5 using 30% hydrochloric acid. In another example, the ascorbic acid solution may include 33 mg / ml ascorbic acid / sodium ascorbate and 0.1 mg / ml DTPA at a pH of 4.25±0.25.

[0123] In some embodiments, optional step 106 may include preparing a formulation solution / buffer. The formulation solution is prepared from an injection-grade solution containing ascorbic acid, absolute ethanol, and injection-grade water. In one example, the formulation solution is prepared by adding sufficient amounts of the following solutions to a bulk vial: approximately 50 mg / ml ascorbic acid pH 4.5 solution (prepared in step 104), 30% ethanol solution, and water. The formulation solution may contain 31 mg / ml to 42.5 mg / ml ascorbic acid and 3.8% to 7.5% ethanol (v / v%). In some embodiments, the formulation buffer may be adjusted to enable the final composition to have an extended shelf life. In at least one example, the formulation solution contains 31 mg / ml ascorbic acid, 3.8% (v / v) ethanol, and pH 4.5. The formulation buffer is temporarily prepared as part of the synthesis preparation, and a predetermined amount is added to the bulk vial as part of the synthesis preparation.

[0124] In some embodiments, step 108 may include preparing a reaction solution. The reaction solution may include sodium acetate, HCl, and L-ascorbic acid. Alternatively, the reaction solution may include sodium ascorbate. The reaction solution may be prepared in a reactor using the solution prepared in step 102. In one example, the reaction solution may include 4 ml of 0.4 M sodium acetate, a volume of approximately 463 μg / ml PSMA I&T solution, and 150 μl of 20% (w / w) L-ascorbic acid. In another example, the reaction solution may include 0.33 M sodium ascorbate (reaction buffer) and PSMA I&T in a reaction buffer. In some examples, the reaction solution may include 1.6 ml of 0.05 M HCl or 2 ml of 0.04 M HCl (0.08 mmol HCl). The ascorbic acid concentration in the reaction solution may range from 3.75 mg / ml to 5.00 mg / ml.

[0125] In one embodiment, step 110 includes: 177 In some embodiments, the method may include preparing Lu by 177 Lu can be provided in HCl. 177 Lu]LuCl3 can be provided in 0.04M or 0.05M HCl. For example, 40-44 GBq / ml 177 Lu can be provided in 0.04 M HCl. In another example, less than 61 GBq 177 Lu can be provided in 0.05M HCl. 177 Lu]LuCl3 may be transferred to a reactor and 177 The [Lu]LuCl vial may be rinsed with an additional required volume of 0.04 M hydrochloric acid (prepared in step 102), which is then also transferred to the reactor.

[0126] The reaction volume can range from 6 ml to 8 ml. The volume can depend on the amount of precursor used.

[0127] In one embodiment, step 112 includes 177The method may include radiolabeling with Lu. The reaction mixture may be heated to a maximum of about 75°C, a maximum of about 80°C, a maximum of about 85°C, a maximum of about 90°C, or a maximum of about 95°C. In one example, the set point for heating is 110°C, and the actual maximum temperature reached is about 95°C. The reaction volume may be heated for a maximum of 5 minutes, a maximum of 10 minutes, a maximum of 15 minutes, or a maximum of 20 minutes. In at least one example, the reaction mixture is heated at a set point of 110°C for 15 minutes. In at least one additional example, the reaction mixture is heated at a set point of 75°C for 10 minutes.

[0128] In certain embodiments, optional step 114 can include purifying the reaction mixture. For example, the solution can be run through a cassette / cartridge containing a hydrophobic, reversed-phase, silica-based bonded phase. Sep-Pak C18 can be used to purify the composition. In at least one example, the reaction mixture can be passed through a C18 Sep-Pak cartridge, and the cartridge can be rinsed with water. 177 The Lu-PSMA I&T product is retained within the cartridge. In some embodiments, the reaction mixture may not be purified.

[0129] In some embodiments, step 116 may include eluting or diluting the final product. 177 The Lu-PSMA I&T is diluted to the desired radioactivity concentration with the dilution buffer prepared in step 104. The composition may be eluted using 1.5 ml of ethanol-water in a 1:1 ratio. The cassette may then be flushed with 8.5 ml of ascorbic acid 50 mg / ml. A formulation solution may then be added to form the final composition. In at least one example, 177The Lu-PSMA I&T is eluted from the C18 cartridge into a bulk vial using 1.5 ml of 50% (v / v) ethanol, followed by 8.5 ml of the 50 mg / ml pH 4.5 ascorbic acid solution (prepared in step 104), which is then diluted with the formulation solution / buffer (prepared in step 106 and already in the bulk vial). The resulting solution may have a pH of 3.5-4.5. In some embodiments, the pH may be adjusted. In one example, the pH of the 50 mg / ml ascorbic acid solution is adjusted to 3.5-4.5. In another example, the pH is adjusted to 5.0 or below.

[0130] Stability-enhancing conditions, such as an ascorbic acid solution, perhaps at a pH of about 5 or less, should preferably be applied as early in the process as possible. For example, an ascorbic acid solution at a pH of 5 or less may be used in place of water in step 114 to minimize radiolytic damage.

[0131] In some embodiments, in step 118, the final composition may be sterile filtered. The sterile filter may be a 0.22 μm sterile filter. The final product may be passed through a 0.22 μm sterile filter and dispensed into single-dose vials containing the appropriate volume and activity referenced to a predetermined calibration time. For example, the final composition may be passed through a 0.22 μm sterile filter in a Class A environment and dispensed into doses containing the appropriate volume and activity referenced to a calibration time.

[0132] The final composition can be formulated as a solution suitable for injection. The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk composition is the amount of the introduced 177 Varies depending on the starting radioactivity of Lu. This solution meets the sterility and bacterial endotoxin requirements according to the European Pharmacopoeia, which confirms an acceptable manufacturing process from a microbiological point of view.

[0133] Figure 3A provides an example of a process for making a radiopharmaceutical composition by purifying the reaction mixture and formulation solution with ethanol, and Figure 3B provides an example of a process for making a radiopharmaceutical composition without purification and without ethanol.

[0134] 177 Provided herein are methods for increasing the shelf life of a radiopharmaceutical product comprising Lu-PSMA I&T. The methods may include adjusting the pH of the composition to 3.5, 3.75, 4.0, 4.25, or 4.5, adjusting the amount of ascorbic acid in the composition, and / or adjusting the radioactivity to extend the shelf life of the composition by 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.25, 2.5, 2.75, or 3 days. For example, a radiopharmaceutical composition may have a shelf life of 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 days. In certain embodiments, adjusting the pH, radioactivity, and / or ascorbic acid may increase the radiochemical purity of the composition to at least 99%, at least 98.5%, at least 98%, at least 97.5%, at least 97%, at least 96.5%, at least 96%, at least 95.5%, or at least 95% for up to 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 days.

[0135] Targeted pharmaceutical formulations according to the present disclosure are as provided in Table 1A. [Table 1A]

[0136] V. Stability A stable, non-radiolabeled standard can be used to identify the product peak in HPLC analysis. The formulation can be prepared from an injection-grade solution containing ascorbic acid, a chelating agent (EDTA), absolute ethanol, and injection-grade water. The formulation matrix can be temporarily prepared as part of the synthetic preparation, and a predetermined amount is added to a bulk vial as part of the synthetic preparation.

[0137] Without being limited to any one theory, the radioactivity, the amount of ascorbic acid, and / or the pH of the solution may affect the shelf life of the composition. Surprisingly, a lower concentration of ascorbic acid in the composition (e.g., 31 mg / ml versus 42.5 mg / ml), a pH of 4.5 or less, a low RAC, and / or a combination thereof may result in a higher stability profile and a longer shelf life of the composition compared to a composition having a pH of 5 or more, a high RAC, and / or a combination thereof. For example, this can be seen in Figure 5. Shelf life can generally be determined based on the radiochemical purity of the composition after formulation or at the end of synthesis (EOS). Radiochemical purity may be confirmed by HPLC.

[0138] In one or more embodiments, the dosage formulation has a radioactivity concentration of 640 MBq / ml or less, 31 mg / ml ascorbic acid, and a pH of about 4.5. 177 The Lu-PSMA I&T formulation composition can provide sufficient stability for 4 days.

[0139] A composition having a low radioactivity concentration (e.g., 588.5 MBq / ml), pH 4.5, and 31 mg / ml ascorbic acid has a radiochemical purity of 99.1% at 0 hours after EOS, 98.7% at 20 hours after EOS, 98.0% at 44 hours after EOS, 97.4% at 69 hours after EOS, and 97.0% at 93 hours after EOS. A composition having a low radioactivity concentration (e.g., 626 MBq / ml), pH 5.0, and 31 mg / ml ascorbic acid has a radiochemical purity of 99.2% at 0 hours after EOS, 98.4% at 25 hours after EOS, 97.3% at 47 hours after EOS, and 96.5% at 71 hours after EOS. A composition having a low radioactivity concentration (e.g., 579 MBq / ml), pH 4.5, and 21 mg / ml ascorbic acid has a radiochemical purity of 99.4% at 0 hours after EOS, 98.3% at 19 hours after EOS, 97.5% at 46 hours after EOS, 96.8% at 71 hours after EOS, and 96.0% at 92 hours after EOS. A composition having a high radioactivity concentration (e.g., 1,278 MBq / ml), pH 4.5, and 42.5 mg / ml ascorbic acid has a radiochemical purity of 99.4% at 0 hours after EOS, 98.0% at 24 hours after EOS, 96.7% at 46 hours after EOS, 95.3% at 67 hours after EOS, and 95.2% at 71 hours after EOS.

[0140] The radiopharmaceutical composition may be stored at a temperature ranging from 2°C to 40°C, about 2°C to 5°C, about 5°C to 10°C, about 10°C to 15°C, about 15°C to 20°C, about 20°C to 25°C, about 25°C to 30°C, about 30°C to 35°C, or about 35°C to 40°C.

[0141] In certain embodiments, the radiopharmaceutical composition is stored at a temperature of about 5° C. to 40° C., about 10° C. to 35° C., or about 20° C. to 30° C. In a specific embodiment, the radiopharmaceutical composition is stored at a temperature of about 10° C., about 15° C., about 22° C., about 22.5° C., about 25° C., or at room temperature.

[0142] In one embodiment, the radiopharmaceutical composition is stored at about 22.5° C. In another embodiment, the radiopharmaceutical composition is stored at room temperature.

[0143] VI. Specific Radiopharmaceutical Compositions In some embodiments, the pharmaceutical product is a microdose of 42.5 mg / ml of ascorbic acid in water containing 7.5% (v / v) or 59 mg / ml of ethanol. 177 The sterile filtered radiopharmaceutical solution containing Lu-PSMA I&T solution is diluted to a standard radioactivity concentration, and therefore the final volume of the bulk product varies depending on the starting radioactivity introduced. The composition of the final product is listed in Table 1B ( 177 Lu-PSMA I&T composition 1): [Table 1B]

[0144] In yet another embodiment, the pharmaceutical product is a microdose of 31 mg / ml of ascorbic acid in water containing 3.8% (v / v) or 30 mg / ml of ethanol at a pH of about 4.5. 177 A sterile filtered radiopharmaceutical solution containing Lu-PSMA I&T solution. The product is diluted to a standard radioactivity concentration, and therefore the final volume of the bulk product varies depending on the starting radioactivity introduced. The composition is described in Table 1C below ( 177 Lu-PSMA I&T composition 2): [Table 1C]

[0145] VII. Formulating a Pharmaceutical Product The pharmaceutical product may be delivered in a Type 1 glass, sterile, pyrogen-free glass vial with a fluorine-coated bromobutyl rubber septum. The septum is sealed with a crimped aluminum capsule. The glass vial containing the radiopharmaceutical is kept in a lead-shielded container during transport. The shipping container, including the lead shielding and outer packaging, complies with Type A requirements (IAEA standards). Figure 4 shows a drawing of a product vial that may be used in this embodiment.

[0146] 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.

[0147] 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 to provide the amount of radioactivity required for the day and time of injection.

[0148] In another embodiment, 177 Lu-PSMA I&T injection is supplied as a single-dose vial or a multi-dose vial. For example, a single-dose 177 Provided herein is a radiopharmaceutical kit comprising a vial containing the Lu-PSMA I&T injection product composition. In one embodiment, 177The 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. 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.

[0149] In yet another embodiment, 177 The shelf life of the Lu-PSMA I&T injection product composition is about 30 hours to about 90 hours, about 40 hours to about 80 hours, or about 48 hours to about 72 hours. 177 The shelf life of the Lu-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.

[0150] In some embodiments, the radiopharmaceutical composition is prepared in a manner sufficient for administration to a patient. 177 The radiopharmaceutical composition should have a radiochemical purity of 95% or greater for Lu-PSMA I&T. The combined radiochemical impurities in the composition may be 5% or less. In various embodiments, the radiopharmaceutical composition may have a chemical purity such that Lu-PSMA I&T is present in the composition at 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.

[0151] In some embodiments, the radiopharmaceutical composition comprises a colloid in an amount of less than about 5% radioactivity, less than about 4.5% radioactivity, less than about 4% radioactivity, less than about 3.5% radioactivity, less than about 3% radioactivity, less than about 2.5% radioactivity, less than about 2% radioactivity, less than about 1.5% radioactivity, less than about 1% radioactivity, less than about 0.5% radioactivity, less than about 0.3% radioactivity, less than about 0.2% radioactivity, or less than about 0.1% radioactivity. 177 In one embodiment, the radiopharmaceutical composition administered to a human patient in need thereof may have less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% colloidal Lu. 177 Contains Lu.

[0152] In some embodiments, the radiopharmaceutical composition is less than about 17.5 EU / ml, less than about 17 EU / ml, less than about 16.5 EU / ml, less than about 16 EU / ml, less than about 15.5 EU / ml, less than about 15 EU / ml, less than about 14.5 EU / ml, less than about 14 EU / ml, 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, It may have less than about 9 EU / ml, less than about 8.5 EU / ml, less than about 8 EU / ml, less than about 7.5 EU / ml, less than about 7 EU / ml, less than about 6.5 EU / ml, less than about 6 EU / ml, less than about 5.5 EU / ml, less than about 5 EU / ml, less than about 4.5 EU / ml, less than about 4 EU / ml, less than about 3.5 EU / ml, less than about 3 EU / ml, less than about 2.5 EU / ml, less than about 2 EU / ml, less than about 1.5 EU / ml, less than about 1 EU / ml, less than about 0.5 EU / ml, or may have no bacterial endotoxin.

[0153] In certain embodiments, the radiochemical purity of the composition is 95% or greater 1 day, up to 2 days, up to 3 days, up to 4 days, or up to 5 days after formulation. In additional embodiments, the radiochemical purity of the composition is 95% or greater 24 hours, up to 36 hours, up to 48 hours, up to 72 hours, or up to 96 hours after formulation. In further embodiments, the radiochemical purity of the composition is suitable for injection or administration to a patient in need thereof more than 72 hours after formulation, more than 96 hours after formulation, or more than 100 hours after formulation. The radiopharmaceutical composition may have a radiochemical purity of at least 95%, at least 95.5%, at least 96%, at least 96.5%, at least 97%, at least 97.5%, at least 98%, at least 98.5%, or at least 99% 24 hours, 48 hours, 72 hours, and / or 96 hours after formulation. In some examples, the radiopharmaceutical composition may have a radiochemical purity of 95.0% or greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater upon administration. For example, a radiopharmaceutical composition may have greater than 95% radiochemical purity 46-48 hours after formulation, greater than 96% radiochemical purity 46-48 hours after formulation, greater than 97% radiochemical purity 46-48 hours after formulation, greater than 95% radiochemical purity 69-72 hours after formulation, greater than 96% radiochemical purity 69-72 hours after formulation, greater than 97% radiochemical purity 69-72 hours after formulation, greater than 95% radiochemical purity 90-93 hours after formulation, greater than 96% radiochemical purity 90-93 hours after formulation, and / or greater than 97% radiochemical purity 90-93 hours after formulation.

[0154] In some examples, the radiochemical purity of the composition may range from about 99.0% to about 99.4% at 0 hours after EOS. In various embodiments, the radiochemical purity of the composition may range from about 96.5% to about 98.7% at 19 to 25 hours after EOS. In other examples, the radiochemical purity of the composition may range from about 93.3% to about 98.0% at 44 to 47 hours after EOS. In additional examples, the radiochemical purity of the composition may range from about 91.2% to about 97.4% at 69 to 71 hours after EOS. In some examples, the radiochemical purity of the composition may range from about 94.5% to about 97.0% at 90 to 93 hours after EOS.

[0155] In another embodiment, 177 Lu-PSMA I&T Injection is supplied as a single-dose or multi-dose vial.

[0156] In yet another embodiment, patients requiring radioligand therapy during treatment receive a single intravenous radioactive dose at the beginning of a treatment cycle. A treatment cycle is 1 to 10 weeks long. In one embodiment, treatment includes 1 to 6 treatment cycles. In another embodiment, dose reductions or dose escalations are introduced during treatment.

[0157] In one embodiment, the patient dose volume is calculated according to the administered radioactive dose.

[0158] In another embodiment, 177 Lu-PSMA I&T is injected slowly over approximately 10 minutes via intravenous (IV) route, followed by 500-1000 mL of Ringer's solution or saline. If the total blood volume exceeds 5000 mL, an extra 7 mL injection will have no effect. This dose is administered every 6 weeks for 4 cycles.

[0159] In yet another embodiment, patients requiring radioligand therapy during treatment receive a single intravenous radioactive dose at the beginning of a treatment cycle. A treatment cycle is 1 to 10 weeks long. In one embodiment, treatment includes 1 to 6 treatment cycles. In another embodiment, dose reductions or dose escalations are introduced during treatment.

[0160] In one embodiment, the patient dose volume is calculated according to the administered radioactive dose.

[0161] VIII. Methods for diagnosing or treating prostate cancer Provided herein are methods for diagnosing or treating a tumor in a patient in need thereof. The method may comprise administering by injection a radiopharmaceutical composition comprising 177Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5. Following administration, the radiopharmaceutical composition may have one or more of the kinetic characteristics shown in Figures 12A-12D.

[0162] 12A shows the kinetics of a radiopharmaceutical composition in normal organs, including the whole body, kidney, and parotid gland, over a 60-hour period. In certain embodiments, within 20 hours after injection, the radiopharmaceutical composition may have an activity of 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. In some embodiments, 20 hours after injection, the radiopharmaceutical composition may have a systemic activity of 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 some embodiments, 40 hours after injection, the radiopharmaceutical composition may have a systemic activity of 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 some embodiments, 60 hours after injection, the radiopharmaceutical composition may have a systemic activity of 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.

[0163] In certain embodiments, within 20 hours post-injection, the radiopharmaceutical composition may have an activity in the kidney of 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, at 20 hours post-injection, the radiopharmaceutical composition may have an activity in the kidney of 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, at 40 hours post-injection, the radiopharmaceutical composition may have an activity in the kidney of 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 radiopharmaceutical composition may have an activity in the kidney of 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.

[0164] In other embodiments, within 20 hours post-injection, the radiopharmaceutical composition may have an activity in the parotid gland of 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, at 20 hours post-injection, the radiopharmaceutical composition may have an activity in the parotid gland of 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, at 40 hours post-injection, the radiopharmaceutical composition has an activity in the parotid gland of 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 radiopharmaceutical composition has an activity in the parotid gland of 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.

[0165] Figure 12B shows the kinetics of a radiopharmaceutical composition in tumor lesions, including lymph node and bone lesions, over a 60-hour period. In further embodiments, within 20 hours of injection, the radiopharmaceutical composition may have an activity of 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 the patient's lymph node lesions. In some embodiments, 20 hours after injection, the radiopharmaceutical composition may have an activity of 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, or 0.25% IA to 0.3% IA in the lymph node lesions. In some embodiments, 40 hours after injection, the radiopharmaceutical composition has an activity in lymph node lesions of 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, 60 hours after injection, the radiopharmaceutical composition has an activity in lymph node lesions of 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.

[0166] In still further embodiments, within 20 hours post-injection, the radiopharmaceutical composition may have an activity in the patient's bone lesion of 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 post-injection, the radiopharmaceutical composition may have an activity in the bone lesion of 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 radiopharmaceutical composition may have an activity in bone lesions of 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 radiopharmaceutical composition has an activity in bone lesions of 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.

[0167] Figure 12C shows the effective half-life of the radiopharmaceutical composition in both normal organs and tumor lesions. In certain embodiments, the radiopharmaceutical composition may have an effective half-life of about 30 to 40 hours, 30 to 32 hours, 32 to 34 hours, 34 to 36 hours, 36 to 38 hours, or 38 to 40 hours in a patient's whole body. In some embodiments, the effective half-life of the radiopharmaceutical composition may be about 25 to 35 hours, 25 to 27 hours, 27 to 29 hours, 29 to 31 hours, 31 to 33 hours, or 33 to 35 hours in a patient's kidney. In some embodiments, the effective half-life of the radiopharmaceutical composition may be about 20 to 30 hours, 20 to 22 hours, 22 to 24 hours, 24 to 26 hours, 26 to 28 hours, or 28 to 30 hours in a patient's parotid gland. In some embodiments, the effective half-life of the radiopharmaceutical composition may be about 45 to 55 hours, 45 to 47 hours, 47 to 49 hours, 49 to 51 hours, 51 to 53 hours, or 53 to 55 hours in bone lesions of a patient. In some embodiments, the effective half-life of the radiopharmaceutical composition may be about 35 to 45 hours, 35 to 37 hours, 37 to 39 hours, 39 to 41 hours, 41 to 43 hours, or 43 to 45 hours in lymph node lesions of a patient.

[0168] 12D shows the mean absorbed dose of the radiopharmaceutical composition in both normal organs and tumor lesions. In certain embodiments, the mean absorbed dose of the radiopharmaceutical 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 the patient's whole body. In some embodiments, the average absorbed dose of the radiopharmaceutical composition may 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, or 0.9 mGy / MBq to 1.0 mGy / MBq in the patient's kidneys. In some embodiments, the average absorbed dose of the radiopharmaceutical composition may be about 1 mGy / MBq to 1.5 mGy / MBq, 1.0 mGy / MBq to 1.1 mGy / MBq, 1.1 mGy / MBq to 1.2 mGy / MBq, 1.2 mGy / MBq to 1.3 mGy / MBq, 1.3 mGy / MBq to 1.4 mGy / MBq, or 1.4 mGy / MBq to 1.5 mGy / MBq in the patient's parotid gland. In some embodiments, the average absorbed dose of the radiopharmaceutical composition may be about 2.5 mGy / MBq to 3.5 mGy / MBq, 2.5 mGy / MBq to 2.7 mGy / MBq, 2.7 mGy / MBq to 2.9 mGy / MBq, 2.9 mGy / MBq to 3.1 mGy / MBq, 3.1 mGy / MBq to 3.3 mGy / MBq, or 3.3 mGy / MBq to 3.5 mGy / MBq in the bone lesion of the patient. In some embodiments, the average absorbed dose of the radiopharmaceutical composition may be about 3.5 mGy / MBq to 4.5 mGy / MBq, 3.5 mGy / MBq to 3.7 mGy / MBq, 3.7 mGy / MBq to 3.9 mGy / MBq, 3.9 mGy / MBq to 4.1 mGy / MBq, 4.1 mGy / MBq to 4.3 mGy / MBq, or 4.3 mGy / MBq to 4.5 mGy / MBq in the patient's lymph node lesions.

[0169] Treatment aimed at eradicating the primary tumor, typically by surgery or radiation, is unsuccessful in approximately 30% of men, who develop recurrent disease, usually manifesting first as elevated plasma prostate-specific antigen (PSA) and then as metastasis to distant sites (Stephenson et al. J Clin Oncol, 2005;23:8253-61). Given that prostate cancer cells depend on the androgen receptor (AR) for their growth and survival, the standard treatment for patients with recurrent disease is androgen deprivation therapy (ADT) with gonadotropin-releasing hormone analogs (GnRHa), with or without antiandrogens.

[0170] Treatment outcomes with ADT are generally predictable: a decline in PSA, followed by tumor regression, a period of PSA stability without tumor growth, followed by an increase in PSA, and regrowth, defined as castration-resistant disease. Nearly all men with advanced prostate cancer eventually develop castration-resistant disease. Progression of prostate cancer despite castrate-level testosterone represents a transition to a lethal disease stage. Docetaxel with prednisone, cabazitaxel with prednisone, enzalutamide, and abiraterone with prednisone are the standard of care for men with metastatic castration-resistant prostate cancer (mCRPC) according to the National Comprehensive Cancer Network (NCCN) guidelines (Mohler et al., NCCN Clinical practice guidelines in oncology. Prostate Cancer, (Version 2. 2019). JNCCN.org; 17(5), 479-505).

[0171] Abiraterone, enzalutamide, and docetaxel with prednisone are all indicated for patients with mCRPC as first-line treatment, whereas cabazitaxel with prednisone is only indicated for patients with mCRPC who have progressed on docetaxel. George et al. reported the treatment sequence for mCRPC patients in a real-world clinical setting in the United States (George et al. 2020). In the United States, a higher proportion of patients receive androgen receptor axis-targeted therapy (ARAT; i.e., abiraterone and enzalutamide) as first-line treatment rather than docetaxel. Similarly, a higher proportion of mCRPC patients receive alternative ARAT (abiraterone followed by enzalutamide, or vice versa) as second-line treatment.

[0172] Targeted radionuclide therapy has become an attractive and emerging treatment option for many different cancers, including lymphoma, melanoma, and neuroendocrine tumors (Kraeber-Bodere et al., Semin Oncol, 2014, 41, 613-22; Mier et al., J Nucl Med, 2014, 55, 9-14; Bodei et al., Eur J Nucl Med Mol Imaging, 2015, 42, 5-19). Prostate-specific membrane antigen (PSMA) is an important target for radionuclide diagnosis and treatment of PC. Although PSMA is normally expressed in prostate cells and some extraprostatic tissues, its overexpression in prostate cancer cells makes it an attractive target for therapeutic agents with the potential to limit systemic toxicity (Silver et al., Clin Cancer Res. 1997 Jan;3(1):81-5. PMID:9815541). 131 Early clinical experience with PSMA-based radionuclide therapy of PC using I-labeled PSMA showed promising results, with a PSA reduction of more than 50% in 60% of all treated prostate cancer patients and mild hematologic toxicity (Zechmann et al., Eur J Nucl Med Mol Imaging, 2014, 41, 1280-92).

[0173] IX. Administration Further provided herein are methods of administering the radiopharmaceutical composition. The radiopharmaceutical composition may be administered by injection to a human patient in need thereof.

[0174] There can be about six main modes of administration.

[0175] First, it cools the salivary glands, reducing the risk of salivary gland radiation damage to the patient. 177 Ice packs are placed on the parotid and submandibular glands 30 minutes before and up to four hours after administration of Lu-PSMA I&T. There is no scientific evidence that cooling the salivary glands is an effective therapy for sparing these glands from radiation, however, it is well tolerated and not harmful to patients.

[0176] Second, use a urinary catheter in incontinent patients within the first 48 hours to avoid any contamination.

[0177] Third, 6.5–7.5 GBq (range: 6.0–8.0 GBq) 177 Lu-PSMA I&T activity. The dose can be reduced to 4.0-5.0 GBq in cases of renal dysfunction (e.g., creatinine within 1.0-1.5 UNL). Preliminary results suggest that 7.4 GBq of activity can be safely administered; however, more data are needed to determine whether the dose should be increased.

[0178] Fourth, the active ingredient is administered intravenously as a slow bolus (over approximately 1 to 15 minutes), followed by 500 to 1000 ml of Ringer's solution or NaCl solution. Patients should be encouraged to urinate as frequently as possible and drink approximately 2 liters of water per day. In patients with dilated non-obstructive renal disease, the administration of diuretics may be beneficial.

[0179] Fifth, with an average of 3 to 5 cycles of RLT every 5 to 8 weeks, up to 11 cycles have been reported. If PSA continues to increase or if performance status worsens after the first two cycles, the indication for further RLT should be reevaluated. If PSA falls below 1.0 μg / L during a therapy cycle, or if post-injection SPECT studies are not sufficiently informative, PSMA imaging can be used to assess the presence of small PSMA-positive metastases after completion of RLT. In the event of a significant decline in platelets or white blood cells, the time interval between two cycles can be extended.

[0180] Sixth, at least one whole-body scan (preferably SPECT( / CT)) should be performed 24–48 hours after injection. Concomitant corticosteroid therapy (e.g., prednisolone 20 mg / day) during the first 2 weeks after administration is recommended for patients with diffuse bone and bone marrow metastases, as well as for patients with brain metastases.

[0181] In some embodiments, the method may include injecting the radiopharmaceutical composition into a patient in need thereof more than 48 hours after formulation. In some examples, the radiopharmaceutical composition comprises: 177 The Lu-PSMA I&T and ascorbic acid may be contained in a solution having a pH of 3.5 to 4.5, and the solution may have a radiochemical purity of greater than 96% when administered. In certain embodiments, the pH of the solution is about 3.5 to 4.2. The composition may contain less than 6 μg / ml of Lu-PSMA I&T, about 7 μg / ml to about 18 μg / ml of disodium EDTA, about 25 μl / ml to about 45 μl / ml of ethanol, and / or about 15 to about 35 mg / ml of ascorbic acid. The composition may have a radioactivity of about 0.5 GBq / ml or about 13.5 mCi / ml and may have a radiochemical purity of at least 98% 44 hours after formulation, at least 97% 69 hours after formulation, and / or at least 97% 93 hours after formulation.

[0182] The pharmaceutical compositions may be administered in 2 to 11 cycles / treatments every 5 to 8 weeks. In some embodiments, a patient may receive up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 treatments, with treatments administered every 4, 5, 6, 7, or 8 weeks. In some examples, a patient may receive up to 4 treatments, with each treatment administered every 6 weeks.

[0183] In various embodiments, a patient may receive a dose of 0.5 GBq to 10 GBq. For example, a radiopharmaceutical composition may contain a standard activity concentration of about 27 mCi / mL at the end of manufacture and a standard activity of about 200 mCi at the expiration date; therefore, the final volume of the dose vial may be adjusted to 7-10 mL to provide the amount of radioactivity required for the day and time of injection. In at least one example, a patient may receive a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) for each treatment. In one aspect, a patient may receive a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) for each of four, five, six, or more treatments. In another aspect, a patient may receive a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) for each of four or more treatments, five or more, six or more, seven or more, or eight or more treatments. In yet another embodiment, the patient may receive 4, 5, 6, 7, 8, or more doses of about 200 mCi (≧7.1 GBq) for each treatment.

[0184] Upon administration of the radiopharmaceutical composition to a patient, the patient may maintain low levels of hematotoxicity and nephrotoxicity, hi some embodiments, the reduction in prostate specific antigen (PSA) is greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, or greater than about 80%.

[0185] 177Further provided herein is a method of treating a patient with mCRPC by administering a radiopharmaceutical composition comprising Lu-PSMA I&T. The method may further include imaging the patient using PSMA-PET prior to administering the radiopharmaceutical composition to document and confirm that the patient is mCRPC positive. For example, the patient may have a PSMA-PET scan (e.g., [ 68 Ga]Ga-PSMA-11 or [ 18 F]DCFPyL) positive.

[0186] Indications and contraindications 177 RLT with Lu-PSMA I&T may be indicated for the treatment of patients with mCRPC who do not have any other approved therapeutic options as planned by a multidisciplinary team.

[0187] In some embodiments, patients also have histologically or pathologically confirmed prostate adenocarcinoma without a predominant small cell component and progressive disease according to one or more of the following criteria: a) progression of serum / plasma PSA, defined as two consecutive increases in PSA relative to the previous reference value, measured at least one week apart with a minimum starting value of >2 ng / mL, or b) measurable disease progression (RECIST 1.1) or the presence of at least two new bone lesions (PCWG3 criteria), and / or have received previous treatment with next-generation androgen receptor (AR)-directed therapy (e.g., abiraterone, enzalutamide, apalutamide, darolutamide). In additional embodiments, patients may have effective castration with serum testosterone levels below 50 ng / dL and may plan to continue chronic medical or surgical castration. mCRPC patients should receive hormonal therapy and chemotherapy, as well as bone-targeted therapy, if indicated.

[0188] In at least one example, 177 Patients requiring RLT using Lu-PSMA I&T may meet the following criteria:

[0189] 1) mCRPC with PSMA-positive metastatic disease based on PSMA-PET or SPECT imaging. There are no restrictions on the number or location of metastases, i.e., bone or soft tissue metastases. For example, attention should be paid to patients with diffuse bone marrow, perineural, and brain metastases.

[0190] 2) After initial hormone therapy (LH-RH agonist / antagonist), patients with progressive disease (i.e., biochemical and / or radiological progression) despite newly developed hormone therapies (abiraterone / enzalutamide) or these medications can be avoided by patients with progressive disease despite chemotherapy (docetaxel and cabazitaxel), or patients who are unsuitable for or avoid chemotherapy.

[0191] 3) due to extraosseous or diffuse bone marrow metastases or avoided by the patient; 153 Sm-EDTMP or [ 223 Ra]RaCl2 or other locally available radiopharmaceuticals for bone-targeted therapy. Even patients who do not adequately respond to bone-targeted therapy for pain relief or pain exacerbation may benefit from such therapy. 177 RLT using Lu-PSMA I&T can be evaluated.

[0192] 4) Life expectancy greater than 4-6 months.

[0193] 5) Salvage therapy decisions made by the institution's interdisciplinary tumor board.

[0194] In summary, patients with mCRPC should receive hormonal therapy and chemotherapy, as well as bone-targeted therapy, when indicated. Contraindications to any of these therapies should be discussed and documented in a multidisciplinary tumor board setting.

[0195] The contraindications are as follows: (1) WBC ≤ 1 × 10 9 / l. (2) Hb≦80g / L. (If symptomatic anemia occurs, red blood cell transfusion is required before treatment.) 177 RLT with Lu-PSMA I&T may have a positive effect on bone marrow depression, reducing the need for transfused blood due to tumor regression in the bone marrow. It should be noted that pure anemia without thrombocytopenia and leukopenia is not a contraindication to RLT. (3) Platelets ≤ 70 × 10 9 / l. (4) Renal failure with creatinine >1.5UNL and creatinine clearance <30mL / min (5) Absolute obstruction in renal excretion. (6) Previous chemotherapy or bone-targeted radionuclide therapy and extended external beam radiation field to bone marrow (pelvis, spine) if administered within 4 weeks before RLT (7) ECOG performance status >2. (8) Hypersensitivity to any of the active substances or excipients.

[0196] After a patient in need thereof has been identified, the activity of the radiopharmaceutical composition may be confirmed prior to administration. 177 The radioactivity of the Lu-PSMA I&T composition can be 6.5-7.5 GBq, or can be in the range of 6.0-8.0 GBq. The radioactivity can be reduced to 4.0-5.0 GBq in cases of renal dysfunction (e.g., creatinine within 1.0-1.5 UNL).

[0197] The radiopharmaceutical composition solution may be infused intravenously as a slow bolus (over approximately 10-15 minutes), followed by 500-1000 ml of Ringer's solution or NaCl solution. Patients may be encouraged to urinate as frequently as possible and to drink approximately 2 liters of water per day. Patients with extensive non-obstructive renal disease may be given diuretics.

[0198] The pharmaceutical composition may be administered as a cycle of 2 to 11 RLTs every 5 to 8 weeks. If PSA continues to increase or if the patient's performance status worsens after the first two cycles, the indication for further RLT may be reevaluated. If PSA falls below 1.0 μg / L during a therapy cycle, or if post-injection SPECT studies are not sufficiently informative, PSMA imaging may be performed to assess the presence of small PSMA-positive metastases after completion of RLT. In the event of a significant decrease in platelets or white blood cells, the time interval between two cycles may be extended.

[0199] At least one whole-body scan (preferably by SPECT / CT) may be performed 24-48 hours after injection. Patients with diffuse bone and bone marrow metastases, as well as patients with brain metastases, may be administered concomitant corticosteroid therapy (e.g., prednisolone 20 mg / day) for the first two weeks after administration of the radiopharmaceutical composition.

[0200] In some embodiments, after administration of the radiopharmaceutical composition, patients may have improved radiographic progression-free survival (rPFS). Patients administered the radiopharmaceutical composition may have an rPFS of about 6 to about 12 months after initiation of administration of the radiopharmaceutical composition. In various embodiments, patients administered the radiopharmaceutical composition may have an rPFS of at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months after initiation of administration of the radiopharmaceutical composition. For example, 177 Treatment of patients with Lu-PSMA I&T may increase rPFS from 6 months with standard therapy to up to 10 months with the radiopharmaceutical composition. Radiographic progression-free survival may be defined as the time from randomization to radiographic progression (using PCWG3 and RECIST 1.1 criteria as assessed by blinded independent central review [BICR]) or death from any cause.

[0201] In certain embodiments, patients may experience improved overall survival (OS) after initiating administration of the radiopharmaceutical composition. Patients administered the radiopharmaceutical composition may have an overall survival of about 18 to about 26 months after initiating administration of the radiopharmaceutical composition. In various embodiments, patients administered the radiopharmaceutical composition may have an OS of at least 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, or 26 months after initiating administration of the radiopharmaceutical composition. For example, 177 Treating patients with Lu-PSMA I&T can increase OS from 18 months with standard therapy to up to 25 months with the radiopharmaceutical composition.

[0202] In another embodiment, the patient may experience an improvement in second radiographic progression-free survival (rPFS 2) after starting administration of the radiopharmaceutical composition.

[0203] In some embodiments, the patient may have an improved progression-free survival after initiating administration of the radiopharmaceutical composition. In additional embodiments, the patient may have an improved second progression-free survival after initiating administration of the radiopharmaceutical composition. The second progression-free survival may be a second occurrence of PCWG3 progression, clinical / symptomatic progression and / or pain progression, or death from any cause.

[0204] In one embodiment, the patient has an improved PSA after starting administration of the radiopharmaceutical composition. 50 May have a response rate. PSA 50 The response rate can be the rate of patients achieving a 50% or greater decrease in PSA from the baseline PSA assessment.

[0205] In certain embodiments, patients may have an improved time to first symptomatic skeletal event (SSE) after starting administration of the radiopharmaceutical composition. An SSE may be the occurrence of either bone-directed radiation therapy for the relief of bone pain, a new symptomatic pathological fracture, spinal cord compression, or tumor-related orthopedic surgery.

[0206] In certain embodiments, patients may have improved time to soft tissue progression (STP) after initiating administration of the radiopharmaceutical composition. STP may include the occurrence of radiographic progression in soft tissue. In another embodiment, patients may have improved time to chemotherapy (TTC) after initiating administration of the radiopharmaceutical composition.

[0207] In certain embodiments, patients may experience improvement in their Quality of Life Questionnaire results after initiating administration of the radiopharmaceutical composition. For example, quality of life (QoL) may be assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). The EORTC QLQ-C30 is a questionnaire of 30 quality of life (QoL) questions developed to assess the QoL of cancer patients. The EORTC QLQ-C30 contains 30 items, 24 of which are summarized into 9 multi-item scales with a scoring range of 0 to 100. [Example]

[0208] The following non-limiting examples are provided for illustrative purposes only and therefore should not be viewed in a limiting sense.

[0209] Analysis procedure The products were then identified by injecting the Lu-PSMA I&T reference and formulated solutions into the chromatography system. Radionuclide identity was determined by gamma energy detection.

[0210] The pH was estimated by pH paper. Radioactivity was measured with a dose calibrator. Radiochemical purity was determined by liquid chromatography and thin layer chromatography with radioactivity detection.

[0211] 177The radioactivity of the Lu-PSMA I&T was determined by a dose calibrator as the dose was dispensed.

[0212] Bacterial endotoxin content was determined for each batch before release using a PTS tester (Ph Eur method D). Sterility was determined according to Ph Eur.

[0213] The quality of the analytical procedures used for the drug product, such as specificity, linearity, and reproducibility, was investigated by using known reference standards for unlabeled precursors. All analytical procedures were found to be suitable for their intended use.

[0214] There are no established acceptance criteria for radioactivity in drug products, as this varies depending on the individual clinical need as assessed by the healthcare professional administering the drug product. The radioactivity content must be within 90% to 110% of the specified value at the date and time indicated on the label.

[0215] Example 1 177 Methods for producing Lu-PSMA I&T radiopharmaceutical formulations Several radiopharmaceutical compositions were prepared using the process outlined below in Table 2. The radiolabel was added as a non-carrier-added [ 177

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

[0216] 177 The synthesis of Lu-PSMA I&T is carried out in an automated synthesis module in a controlled environment, as used for radiolabeling. 177 Lu] lutetium chloride ( 177 The labeling solution containing LuCl3) is connected to a synthesis cassette containing other chemical components required for the labeling process. 177The LuCl solution may be transferred to a reaction vessel for radiolabeling and rinsed with the necessary additional amount of 0.04 M HCl solution. 177 The volume varies depending on the Lu activity.

[0217] 177 The LuCl3 solution is mixed with a solution of diluted PSMA I&T precursor in 0.4 M sodium acetate buffer in a reaction chamber. The solution is heated in the reactor. After heating, the resulting 177 Lu-PSMA I&T is captured on a pre-conditioned (ethanol) C18 cartridge. The cartridge is rinsed with sterile water, and then the final product is eluted from the C18 cartridge with 1.5 ml of 50% sterile ethanol into a bulk vial. The drug substance is isolated in situ and directly formulated into a drug product.

[0218] For final volume adjustment, a formulation matrix containing 50 mg / ml ascorbic acid and ethanol in injection grade water is added to the bulk vial. The composition of the final product is fixed, and the amount of formulation matrix added is determined by the amount used in the batch. 177 Depends on the radioactivity of Lu.

[0219] The formulation matrix is prepared from an injection-grade solution of ascorbic acid diluted to a concentration of 50 mg / ml using injection-grade water. The ethanol concentration is adjusted to 3.8% (v / v) to match the concentration of the synthetic bulk product, regardless of dilution.

[0220] The synthesis is a one-step labeling process with C18 purification using injection-grade ethanol and water as the only solvents, so there are no residual solvents.

[0221] Radiochemical impurities are quantified by chromatographic methods (HPLC and TLC). Radiochemical purity as determined by HPLC should be 95.0% or greater.

[0222] Depending on the total radioactivity generated, the bulk product is diluted to a fixed radioactivity concentration of approximately 500 MBq / ml.

[0223] The solution is filtered through a 0.22 μm membrane filter into sterile product vials. In addition to patient doses, sample vials are also dispensed from each production batch (chemical QC samples, microbiological QC samples, and reference samples for retention). The final product is dispensed in a Grade A controlled environment. Filter integrity is tested after filtration by performing a bubble point test before product release. Fill weight / volume and radioactivity are verified for dispensed patient vials. This solution can be used for pre-release quality control and after QP release.

[0224] Radioactivity is monitored by a dose calibrator after the labeling process to ensure successful labeling and to verify the dispensed dose during dispensing. [Table 2A]

[0225] Compositions 1-3 obtained from Processes 1-3 are provided below in Table 2B, which provides the composition for each composition in both 1 ml volumes and 10 ml or 20 ml vials. [Table 2B]

[0226] Example 2 Stability of radiochemical compositions 177 The stability of Lu-PSMA I&T Composition 1 was tested and radiochemical purity and chemical properties were shown to provide sufficient stability for 48 hours from the end of synthesis for samples stored at +5°C, +20°C, and +40°C (Table 3).

[0227] Stability testing was performed with ascorbic acid 31 mg / ml and ethanol 3.8% (v / v) at pH 4.5.177 Lu-PSMA I&T composition 3 (Tables 4A-H) 177 Lu-PSMA I&T Composition 1 showed improved stability and extended shelf life.

[0228] In formulation composition 3 177 The radiochemical purity and chemical properties (pH, impurities, visual properties) of Lu-PSMA I&T were tested in seven batches over a time span of 70-72 hours from the end of synthesis. Stability samples of typical therapeutic dose activity and volume were stored at different conditions encompassing typical storage, shipping, and use of the product, including temperatures ranging from +5°C to +40°C.

[0229] The final radioactivity concentration in the sample solution varied from 497 MBq / ml to 642 MBq / ml at the end of dispensing.

[0230] All stability samples met the established acceptance criteria: in all analyzed samples, radiochemical purity was 95.7% or greater at 70 or 72 hours after the end of synthesis.

[0231] Based on the results, the formulation composition 3 177 The Lu-PSMA I&T solution was found to be insensitive to the different storage conditions tested. [Table 3] [Table 4A-1] [Table 4A-2] [Table 4B-1] [Table 4B-2] [Table 4C-1] [Table 4C-2] [Table 4D-1] [Table 4D-2] [Table 4E-1] [Table 4E-2] [Table 4F-1] [Table 4F-2] [Table 4G] [Table 4H]

[0232] 177 The specifications for the Lu-PSMA I&T solution are shown below in Table 5. The listed specifications were used as release parameters, with the exception of sterility testing, which was tested on all batches after release. [Table 5]

[0233] Example 3 In different formulation compositions 177 Lu-PSMA I&T radiochemical purity This example demonstrates the effectiveness of the hydroxybenzoates in formulations at different pH values. 177 1 shows the radiochemical stability of Lu-PSMA I&T. 177 The shelf life of Lu-PSMA I&T is limited by its high radioactive degradation rate during preparation and storage. 177This leads to the degradation of Lu-PSMA I&T and the formation of radiochemical impurities. 177 The radiochemical purity of the Lu-PSMA I&T solution would fall below the acceptable limit of 95.0%.

[0234] 177 Formation of a specific radiochemical impurity of Lu-PSMA I&T has been observed with a retention time of approximately 5.2 minutes by HPLC on a Phenomenex Luna C18 column (3 μm, 150 mm × 4.6 mm) using an isocratic method of 0.1% trifluoroacetic acid in water (mobile phase A) and 0.1% trifluoroacetic acid:acetonitrile (10:90% v / v) in water (mobile phase B) and 23% mobile phase B at a temperature of 40° C. The impurity referred to herein as having a retention time of approximately 5.2 minutes is illustrated in the chromatograms of Figures 6A-11B.

[0235] Previous experiments have shown that reducing the radioactivity concentration of the formulation sufficiently reduces the formation of an impurity that elutes at approximately 5.2 minutes. 177 The radiochemical stability of the Lu-PSMA I&T solution was not found to remain above 95.0% over 72 hours.

[0236] In this example, different formulation compositions with varying ascorbic acid concentrations, pH, and radioactivity concentrations were used. 177 Six experiments were performed in which Lu-PSMA I&T was prepared. Product formulation details are listed in Table 6. [Table 6]

[0237] High radioactivity concentrations (high RAC) in the sample solutions were 1278 MBq / ml, 1281 MBq / ml, and 1311 MBq / ml when measured at the end of production. Low radioactivity concentrations (low RAC) in the sample solutions were 579 MBq / ml, 589 MBq / ml, and 626 MBq / ml when measured at the end of production. Radiochemical purity of each solution was followed by HPLC up to 71–93 h after radiolabeling. All solutions were stored at 22.5°C.

[0238] FIG. 5 shows the results of the radiochemical purity analysis at different time points as determined by HPLC.

[0239] Figures 6A and 6B show the HPLC radiochromatograms of Experiment 1 at 0 and 71 hours after EOS, respectively.

[0240] Figures 7A and 7B show the HPLC radiochromatograms of Experiment 2 at 0 and 71 hours after EOS, respectively.

[0241] Figures 8A and 8B show the HPLC radiochromatograms of Experiment 3 at 0 and 90 hours after EOS, respectively.

[0242] Figures 9A and 9B show the HPLC radiochromatograms of Experiment 4 at 0 and 92 hours after EOS, respectively.

[0243] Figures 10A and 10B show the HPLC radiochromatograms of Experiment 5 at 0 and 71 hours after EOS, respectively.

[0244] Figures 11A and 11B show the HPLC radiochromatograms of Experiment 6 at 0 and 93 hours after EOS, respectively.

[0245] The radiochemical stability results for each experiment at different time points are provided in Tables 7-12. [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0246] In the examples, the pH of the formulation composition was as illustrated in Figures 6A to 11B. 177 This had a significant impact on the radiochemical stability of Lu-PSMA I&T, more specifically on the formation of a radiochemical impurity that eluted at approximately 5.2 min. In high RAC solutions, the decrease in radiochemical purity over time at pH 4.5 was two times slower than at pH 7.

[0247] Further reduction of the formulation pH to 3.5 did not show any measurable improvement in radiochemical stability compared to the pH 4.5 solution. Although the pH 4.5 ascorbic acid solution is close to the pKa value of ascorbic acid, 177 It is possible that the protons already possess a sufficient amount to act as an inhibitor to the radiolysis of the Lu-PSMA I&T and reduce the formation of a radiochemical impurity that elutes at approximately 5.2 minutes.

[0248] By incorporating a pH 4.5 solution into a lower RAC formulation, 177 The radiochemical stability of Lu-PSMA I&T was further improved. In the lower RAC formulations, changing the formulation pH from 5 to 4.5 had a similar effect on radiochemical stability as increasing the ascorbic acid concentration from 21 mg / ml to 31 mg / ml.

[0249] 10 ml of high RAC containing 42.5 mg / ml ascorbic acid as measured by HPLC 177The radiochemical purity of the Lu-PSMA I&T formulation composition is at least about 99% at 0 hours EOS and at least about 93.3% at 46 hours EOS. As the pH of the formulation increases from pH 4.5, the radiochemical purity decreases.

[0250] 20 ml of low RAC containing 31 mg / ml ascorbic acid as measured by HPLC 177 The radiochemical purity of the Lu-PSMA I&T formulation is at least about 99.1% at 0 hours after EOS. The rate at which radiochemical purity decreases over time is significantly lower at a low RAC with a pH of 4.5 compared to a pH of 5. 177 slower for the Lu-PSMA-I&T formulation.

[0251] The results show that formulation compositions with a pH of 5 or less can substantially reduce the formation of the radiochemical impurity eluting at about 5.2 minutes, and therefore, compared to formulation compositions with a pH greater than 5. 177 This indicates that the radiochemical stability of Lu-PSMA I&T can be improved. 177 The radiochemical stability of Lu-PSMA I&T can be further improved by incorporating a lower solution RAC. 177 The Lu-PSMA I&T solution showed the highest radiochemical stability in a low RAC solution at pH 4.5 and an ascorbic acid concentration of 31 mg / ml. This formulation minimized the formation of radiochemical impurities. 177 This is believed to be a preferred composition for maintaining the radiochemical stability of Lu-PSMA I&T at greater than 95.0% for 72 hours or more.

[0252] Example 4 Compared with third-line treatment 177 Lu-PSMA-617 and 177 Efficacy of combined Lu-PSMA-I&T treatment 177 Dosimetry of Lu-PSMA I&T 177 Lu-PSMA I&T and 177There were no significant differences in absorbed dose estimates between Lu-PSMA-617 and Lu-PSMA-617. 177 Specific known quantity measurements of Lu-PSMA I&T are provided below.

[0253] For normal organs, the mean systemic effective dose across all cycles was 0.41 ± 0.18 Sv (0.06 Sv / GBq). Mean absorbed organ doses were 5.3 ± 1.6 Gy (0.72 Gy / GBq) for the kidney, 0.89 ± 0.42 Gy (0.12 Gy / GBq) for the liver, 4.0 ± 1.1 Gy (0.55 Gy / GBq) for the parotid gland, 4.8 ± 2.8 Gy (0.64 Gy / GBq) for the submandibular gland, and 27 ± 10 Gy (3.8 Gy / GBq) for the lacrimal gland.

[0254] No substantial differences were observed when comparing absorbed doses in normal organs with respect to cycle number (Table 13). The mean organ masses underlying these absorbed dose estimates were 1.595 ± 307 g (range, 1,165–2,373 g) for the liver, 153 ± 29.9 g (range, 88.4–218.7 g) for the kidney, 19.1 ± 5.7 g (range, 8.0–35.6 g) for the parotid gland, 8.2 ± 1.9 g (range, 4.2–14.3 g) for the submandibular gland, and 0.45 ± 0.12 g (range, 0.25–0.78 g) for the lacrimal gland. For paired organs, masses from both sides were summed.

[0255] For tumor lesions, all lesions received a mean dose of 23 ± 20 Gy (3.3 Gy / GBq) per cycle. The mean absorbed doses for bone, lymph node, liver, and lung metastases were 26 ± 20 Gy (3.4 Gy / GBq), 24 ± 16 Gy (3.2 Gy / GBq), 8.5 ± 4.7 Gy (1.28 Gy / GBq), and 13 ± 7.4 Gy (1.7 Gy / GBq).

[0256] The corresponding absorbed dose values per GBq (mean, SD, and range) for normal organs and tumor lesions, respectively, are shown in the tables below. [Table 13] [Table 14]

[0257] There is a clear trend toward lower absorbed doses as the number of cycles increases. The mean absorbed dose per lesion was 26 ± 21 Gy (3.5 Gy / GBq) in the first cycle, 24 ± 19 Gy (3.3 Gy / GBq) in the second cycle, 20 ± 18 Gy (2.7 Gy / GBq) in the third cycle, and 18 ± 17 Gy (2.4 Gy / GBq) in the fourth cycle. A similar trend can be seen for the bone metastasis subgroup. Due to the small sample size, reliable comparisons for lymph node, liver, and lung metastases are not possible. 177 See the table below for effective half-lives and mean absorbed doses of Lu-PSMA I&T.

[0258] 177 Lu-PSMA RLT( 177 Lu-PSMA-617 and 177 Lu-PSMA I&T) had better efficacy and fewer adverse effects than third-line treatment. Twelve studies involving 669 patients 177 reported Lu-PSMA RLT. Overall, 44% of patients 177 After treatment with Lu-PSMA RLT, the maximum PSA reduction was 50% or more. 177 Lu-PSMA-617 and 177 Treatment with Lu-PSMA had mostly transient adverse effects. Sixteen studies, including 1,338 patients, reported on third-line treatment. Overall, 21% of patients achieved a best PSA decline of 50% or more after third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects led to treatment discontinuation in 10% to 23% of patients. 177 Lu-PSMA RLT resulted in a best PSA decline of 50% or more more frequently than third-line treatment (mean 44% vs. 22%, p=0.0002, t-test). 177Lu-PSMA RLT resulted in objective remission more frequently than third-line treatment (43 of 275 patients overall vs. 31 of 109 patients, p = 0.004, χ test). 177 Median survival after Lu-PSMA RLT was longer than after third-line treatment, but the difference was not statistically significant (mean 12 vs. 14 months, p=0.32, t-test). 177 Lu-PSMA led to treatment discontinuation more frequently for third-line treatment than for RLT (0 of 469 patients vs. 22 of 66 patients, p<0.001, χ2 test).

[0259] The purpose of this Investigational New Drug (IMPD) is to: 177 Our goal is to provide a scientific and ethical platform for this useful treatment using Lu-PSMA I&T and to first pursue its application, preferably in academic centers and under controlled clinical trial protocols. 177 With the exception of Lu-PSMA-617, no existing guidelines exist. The information in this IMPD is based on the latest literature and existing best experience from nuclear medicine centers treating PC patients with this modality.

[0260] 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 should not be less than 95.0%.

[0261] Example 5 177 A multicenter, open-label, randomized phase 3 study comparing the safety and efficacy of Lu-PSMA I&T Efficacy of hormonal therapy in patients with metastatic castration-resistant prostate cancer 177 A multicenter, open-label, randomized phase 3 study was conducted to compare the safety and efficacy of compositions containing Lu-PSMA I&T.

[0262] This study aims to treat adult male human patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed despite treatment with one course of standard of care hormonal therapy. 177 The aim is to identify and characterize the safety and efficacy of using Lu-PSMA I&T.

[0263] 177 Lu-PSMA I&T is a radiotherapeutic agent that specifically targets the prostate-specific membrane antigen protein expressed on metastatic prostate cancer cells.

[0264] In this study, 177 Lu-PSMA I&T was microdosed in aqueous ascorbic acid and ethanol solutions. 177 It is provided as a sterile filtered radiopharmaceutical solution containing Lu-PSMA I&T.

[0265] Patients randomized to be treated with standard-of-care hormonal therapy for mCRPC will be treated with either abiraterone acetate in combination with prednisone or enzalutamide, based on the investigator's independent medical judgment.

[0266] Abiraterone acetate is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) or metastatic high-risk castration-sensitive prostate cancer (mCSPC). Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor that inhibits 17α-hydroxylase / C17,20-lyase (CYP17). This enzyme is expressed in the testes, adrenal glands, and prostate tumor tissue and is required for androgen biosynthesis.

[0267] Enzalutamide is an androgen receptor inhibitor indicated for the treatment of patients with CRPC or mCSPC (metastatic castration-sensitive prostate cancer). Enzalutamide has been shown to competitively inhibit androgen binding to the androgen receptor, thus inhibiting the nuclear translocation of the androgen receptor and its interaction with DNA.

[0268] A. Study Objectives and Endpoints The primary objective of this study was to evaluate the efficacy of EGFR-1000 for improving radiographic progression-free survival (rPFS), as measured by PCWG3-modified RECIST 1.1, in men with metastatic castration-resistant prostate cancer (mCRPC), compared with standard-of-care hormonal therapy. 177 To prospectively evaluate the efficacy of Lu-PSMA I&T, the objective endpoint of which is the time from randomization to radiographic progression as determined by Prostate Cancer Working Group 3 (PCWG3) criteria assessed by blinded independent central review.

[0269] The secondary objective is 177 To evaluate whether Lu-PSMA I&T improves overall survival (OS) in patients with mCRPC compared with patients treated with standard-of-care hormonal therapy, with the objective endpoint being time from randomization to death from any cause.

[0270] Other secondary objectives and endpoints include: Purpose: Compared with hormone therapy, 177 To evaluate improvement in overall survival (OS) in men with mCRPC treated with Lu-PSMA I&T, endpoint: time from randomization to second radiographic progression as determined by PCWG3 or RECIST1.1 by BICR (blinded independent central review) after crossover. Objective: From the standard of care hormone therapy arm 177 For patients who crossed over to the Lu-PSMA I&T treatment arm, evaluate the change in time to second radiographic progression. Endpoint: Time from randomization to second radiographic progression as determined by PCWG3 or RECIST 1.1 by BICR after crossover. Objective: Compared with standard hormone therapy, 177Identify change in progression-free survival (PFS, composite) after Lu-PSMA I&T radioligand therapy, endpoint: time from randomization to progression (PFS, composite) based on PCWG3 or RECIST progression, clinical / symptomatic progression and / or pain progression, or death from any cause as determined by the investigator, whichever occurs first. Objective: Compared with standard hormone therapy, 177 To identify change in progression-free survival 2 (PFS2, composite) after Lu-PSMA I&T radioligand therapy, endpoint: time from randomization to second progression (PFS, composite) based on PCWG3 or RECIST progression, clinical / symptomatic progression and / or pain progression, or death from any cause as determined by the investigator, whichever occurs first. Objective: Compared with standard hormone therapy, 177 To evaluate the change in PSA50 response rate (response rate of patients who achieved a 50% or greater reduction in PSA from baseline) after Lu-PSMA I&T radioligand therapy, endpoint: PSA50 response rate, defined as a confirmed 50% or greater reduction in PSA from baseline. Objective: To compare standard hormone therapy for skeletal symptoms 177 To determine the impact of Lu-PSMA I&T, endpoints: time from randomization to first symptomatic skeletal event (SSE-free survival); Objective: To compare standard of care hormone therapy for radiographic soft tissue progression. 177 Determine the impact of Lu-PSMA I&T, endpoint: time from randomization to radiographic soft tissue progression (rSTP) as determined by RECIST 1.1 with BICR; Objective: Compared with standard hormone therapy, 177 Evaluate changes in chemotherapy use after Lu-PSMA I&T, endpoints: time from randomization to first use of chemotherapy, and Purpose: For hormone therapy, 177To evaluate the impact on quality of life after Lu-PSMA I&T radioligand therapy, endpoint: improvement in quality of life based on the EORTC QLQ-C30 questionnaire.

[0271] Exploratory objectives and endpoints are: Objective: Compared with standard hormone therapy, 177 To evaluate the difference in objective response rate and disease control rate using Lu-PSMA I&T, endpoints: objective response rate and disease control rate (DCR = complete / partial response and stable disease) based on PCWG3 criteria. Objective: Compared with standard treatment, 177 To evaluate the change in time to PSA progression after Lu-PSMA I&T radioligand therapy, endpoints: time from randomization to PSA progression, defined as a PSA rise of 25% or more from post-treatment nadir; and Purpose: Compared with hormone therapy, 177 To evaluate the duration of response (DoR) in patients achieving a complete or partial response after Lu-PSMA I&T radioligand therapy, endpoint: time from complete or partial response to radiographic progression.

[0272] B. Research design (i) Overview and Rationale This compared with hormone therapy in men with mCRPC who had previously been treated with androgen receptor (AR)-directed therapy. 177 This is an open-label, randomized, multicenter, phase 3 study of Lu-PSMA I&T radioligand therapy. The hormone therapy regimen for this study is enzalutamide or abiraterone with prednisone based on NCCN guidelines. The selection of a specific regimen will be based on patients' switch from previous ADRT for patients randomized to receive standard of care. Based on published literature, 177 Lu-PSMA I&T radioligand therapy promotes antitumor activity and is associated with a favorable safety profile in men with mCRPC.

[0273] This study will consist of a screening phase, a treatment phase, and a post-treatment follow-up phase. The study will employ a 2:1 randomization to the following treatment groups: (1) 177 Lu-PSMA I&T radioligand therapy, or (2) standard of care hormone therapy. Standard of care hormone therapy options are abiraterone in combination with prednisone or enzalutamide, with the specific choice based on the investigator's clinical judgment. Patients randomized to the hormone therapy arm will have the option to cross over to the radioligand therapy arm upon documentation of radiographic progression.

[0274] Patients will be followed for safety and efficacy according to the activity schedule and will continue on study treatment until documented radiographic progression as assessed by blinded independent central review (BICR) or the development of unacceptable toxicity. Patients who discontinue treatment due to documented radiographic progression will enter the long-term follow-up phase. Patients who discontinue treatment before documented radiographic progression will continue scheduled disease assessments every 3 months until documented radiographic progression.

[0275] Additionally, to assess pharmacokinetics and radioactivity (as discussed in Example 6), 177 A substudy will be conducted under this protocol in patients randomized to receive Lu-PSMA I&T radioligand therapy.

[0276] Due to the nature of the treatments, the identities of the test and control treatments will be known to the investigators, study staff, and patients. Blinding of this study is not feasible. Immediately after the investigator's determination of progressive disease for progressing patients, and after study completion for non-progressing patients, blinded radiographs will be read and interpreted by a panel of up to three independent trained radiologists without access to clinical information or treatment group to assess overall response to treatment.

[0277] The severity of AEs and SAEs will be graded based on the subject's symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. AEs not defined in the current version of the CTCAE should be rated for severity according to the following scale: Grade 1 = Mild: Transient or mild discomfort, no activity limitations, no medical intervention / therapy required Grade 2 = Moderate: Mild to moderate limitation of activity, some assistance may be needed, medical intervention / therapy is unnecessary or minimal Grade 3 = Severe: Significant limitation of activity, usually requires some assistance, requires medical intervention / therapy, can be hospitalized Grade 4 = Life-threatening: Extreme limitation of activity, significant assistance required, significant medical intervention / therapy required, hospitalization or hospice care possible Grade 5 = Death: Death due to the event

[0278] It is important to distinguish between serious and severe AEs. Severity is a measure of intensity, while seriousness is defined by the criteria outlined in Section 10.3. AEs of severe intensity may not be considered serious. Severity, unlike severity, serves as a guide for defining regulatory obligations.

[0279] (ii) Selection of the primary endpoint Metastatic castration-resistant prostate cancer is generally considered a late stage in the natural progression of prostate cancer. mCRPC is usually associated with an unfavorable prognosis, but many patients experience more indolent disease progression, resulting in a wide range of overall survival, with approximately 15% of men with mCRPC surviving beyond 5 years (Moreira et al., Clin Genitourin Cancer, 2017;15(1):60-66).

[0280] Given the relatively wide range of overall survival in men with mCRPC, radiographic progression-free survival using RECIST 1.1 (soft tissue disease status) and Prostate Cancer Working Group 3 (PCWG3) criteria (bone disease status), as assessed by blinded independent central review, was selected as the primary endpoint for this study. Overall survival is a secondary endpoint of the study, and patients will be followed for overall survival for 5 years after enrollment.

[0281] (iii) Research outcomes The primary efficacy outcome is radiographic progression-free survival. If radiographic progression is confirmed by BIRC, study treatment will be discontinued. Patients then enter the follow-up phase of the trial, and overall survival will be assessed over a 5-year follow-up period from the date of study enrollment.

[0282] Safety will be assessed at the end of treatment and up to a 1-month follow-up period by evaluating safety parameters such as adverse events, vital signs, changes in concomitant medications / therapies, changes in physical examination, and clinical laboratory measurements.

[0283] C. Patient Selection (i) Study population The study population will include patients with mCRPC who have progressive disease based on PCWG3-modified RECIST 1.1 criteria. (ii) Inclusion criteria include: 1. Men aged 18 or over. 2. Histologically or pathologically confirmed prostate adenocarcinoma without a predominant small cell component. 3. Progressive disease according to one or more of the following criteria: a. Progression of serum / plasma PSA defined as two consecutive increases in PSA relative to the previous reference value measured at least 1 week apart with a minimum starting value of >2 ng / mL. b. Measurable disease progression (RECIST 1.1) or presence of at least two new bone lesions (PCWG3 criteria) 4. Previous treatment with next-generation androgen receptor (AR)-directed therapy (e.g., abiraterone, enzalutamide, apalutamide, darolutamide). a. Requires one prior AR-directed therapy. b. Requires prior administration of an ARAT (e.g., abiraterone, enzalutamide, darolutamide, or apalutamide) in the castration-sensitive or castration-resistant setting. c. Must have progressed during ARAT. 5. Measure the PSMA-PET scan (e.g., [ 68 Ga]Ga-PSMA-11 or [ 18 F]DCFPyL) positive. 6. Effective castration with serum testosterone levels less than 50 ng / dL and plans to continue chronic medical or surgical castration. 7. HIV patients who are healthy and at low risk for acquired immune deficiency syndrome-related outcomes may participate in this study at the investigator's discretion. 8. Patients with HBV and HCV may also participate if their symptoms are well controlled. 9. Life expectancy of at least 6 months as assessed by the investigator. 10. Willingness to start ARAT therapy as determined by the investigator. (iii) Exclusion criteria include: 1. Previous treatment with radioligand therapy, including other lutetium-labeled compounds. 2. Previous treatment with radium-223 (Xofigo) within the past 12 weeks. 3. Previous chemotherapy treatment for castration-sensitive or castration-resistant prostate cancer (docetaxel or cabazitaxel). 4.Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 2. 5. Patients with known HRR (haploid relative risk) gene mutations who have not been previously treated with olaparib or rucaparib. 6. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy. 7. Poor organ and bone marrow function as evidenced by: Hemoglobin <8g / dL. b. Absolute neutrophil count <1.5 × 109 / L. c. Platelet count <100×109 / L. d. AST / SGOT and / or ALT / SGPT > 3.0 x ULN (where "AST" is aspartate aminotransferase, "SGOT" is serum glutamic-oxaloacetic transaminase, "SGPT" is serum glutamic-pyruvic transaminase, and "ALT" is alanine aminotransferase). e. Total bilirubin >2xULN (upper limit of normal), can be 3xULN unless the patient has known Gilbert syndrome. f. Creatinine clearance (CrCl) <50 mL / min based on the Cockcroft-Gault formula. g. Albumin ≥ 2.75 g / dL 8. Patients who received a blood transfusion for the sole purpose of meeting eligibility for this study. 9. Use of any investigational medication within the last 4 weeks prior to the start of study treatment or scheduled to be received during the study period. 10. Known CNS metastases that are asymptomatic and neurologically stable unless receiving therapy. 11. Patients receiving zoledronic acid for bone-targeted therapy must be on a stable dose for 4 weeks prior to randomization. 12.Patients with significant active heart disease 13. Participant with symptomatic spinal cord compression or clinical / radiological findings indicating impending spinal cord compression. 14. Patients with a superscan visible on the baseline bone scan as determined by the investigator. 15. Active malignancies other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer. 16. Previous use of G-CSF (granulocyte colony-stimulating factor) for persistent neutropenia after standard therapy. 17. Participants with active Covid 19. Recovered patients may be included if they have fully recovered (asymptomatic for at least 28 days prior to study medication administration and a negative Covid test within 72 hours).

[0284] D. Investigational Product Dosage, Route of Administration, and Dosing Schedule (i) 177 Lu-PSMA I&T The pharmaceutical product is a microdose formulated in an aqueous solution containing ascorbic acid and ethanol. 177 This is a sterile-filtered radiopharmaceutical solution containing Lu-PSMA I&T. The product contains a standard concentration of approximately 27 mCi / mL at the end of manufacture and a standard activity of approximately 200 mCi at the expiration date; therefore, the final volume of the dose vial is adjusted to 7.0-10.0 mL to provide the required amount of radioactivity for the day and time of injection. 177 Lu-PSMA I&T Injection is supplied as a sterile solution in a single-dose vial. The septum is sealed with a crimped aluminum cap. The glass vial containing the radiopharmaceutical is kept in a lead-shielded container until use. 177 Lu-PSMA I&T is stored at 25°C, with excursions between 15°C and 30°C permitted. The sealed label contains an expiration date for each vial shipped to the clinical site.

[0285] (ii) Standard-of-care hormone therapy Standard hormone therapy is as follows: Abiraterone acetate with prednisone: Abiraterone acetate is a CYP17 inhibitor used in combination with prednisone or methylprednisone. Prednisone is a glucocorticoid. Glucocorticoids are corticosteroids that are readily absorbed from the gastrointestinal tract. Enzalutamide is an androgen receptor inhibitor.

[0286] (iii) Preparation All infusion solutions will be prepared and dispensed on-site prior to administration. Solution preparation should be performed under sterile conditions, and the final solution should be visually inspected for particulate matter. If an insoluble precipitate is observed, the solution should be discarded.

[0287] 177 Lu-PSMA I&T injection solution is administered as supplied. The radioactivity in the vial must be measured with a calibrated radiation dose calibrator before and after administration to the patient. The administered dose must then be calculated and recorded.

[0288] Medication and Administration The patient 177 Patients will be randomized 2:1 to receive either Lu-PSMA I&T radioligand therapy or standard of care hormone therapy.

[0289] 177 Lu-PSMA I&T Administration: Patients randomized to receive radioligand therapy received 200mCi (7.4GBq) ± 10% at the start of each treatment cycle. 177 They will receive a single intravenous radioactive dose of Lu-PSMA I&T.

[0290] 177 An intravenous line must be established prior to administration of Lu-PSMA I&T. 177 Lu-PSMA I&T will be injected intravenously as a slow bolus over a minimum of 10-15 minutes using the local standard radioligand therapy administration procedure. 177 Patients should be encouraged to urinate as frequently as possible and drink 2 liters of fluids per day for 2 days after Lu-PSMA I&T administration.

[0291] Cooling the patient's salivary glands reduces the risk of salivary gland radiation damage. 177This should be done by placing ice packs on the parotid and submandibular glands 30 minutes before and up to 4 hours after injection of Lu-PSMA I&T.

[0292] A 6-week treatment cycle 177 It will be used for injection of four treatment cycles of Lu-PSMA I&T or until radiographic progression of the disease is determined based on BIRC assessment of radiographic images (maximum 18 weeks of treatment). Alternatively, an 8-week treatment cycle will be used. 177 It may be used for injection of 6 treatment cycles of Lu-PSMA I&T or until radiographic progression of disease is determined based on BIRC assessment of radiographic images (maximum 18 weeks of treatment).

[0293] 177 The dosing cycle of Lu-PSMA I&T may be extended based on the assessment of dose-limiting toxicity experienced by the patient. Dose-limiting toxicity is defined as Grade 3 or 4 bone marrow toxicity or Grade 2 or higher salivary gland toxicity. For Grade 3 or 4 bone marrow toxicity, dosing may be resumed when improvement to Grade 2 or lower is observed. For Grade 2 or higher salivary gland toxicity, dosing may be resumed upon improvement to Grade 1 toxicity.

[0294] In addition, if dose-limiting toxicity is observed, 177 The Lu-PSMA I&T dose should be maintained and / or reduced to 160 mCi (5.9 GBq) ± 10%. The following dose retention / reduction should be implemented accordingly: - For Grade ≥ 3 anemia, hold dose until return to baseline or Grade ≤ 2, then reduce to 160 mCi (5.9 GBq) in the next cycle - Grade ≥ 2 neutropenia: maintain until return to baseline or Grade ≤ 1 -If thrombocytopenia is Grade 2 or greater, maintain until return to baseline or Grade ≤1, then reduce dose to 160 mCi (5.9 GBq) in the next cycle - In case of Grade ≥ 3 non-platelet hematologic toxicity, maintain until return to baseline or Grade ≤ 2, then reduce dose to 160 mCi (5.9 GBq) in the next cycle

[0295] In the event of Grade 3 or greater acute nephrotoxicity, the dose should be held for the next cycle. The dose may be restored upon return to baseline or Grade ≤2, or reduced to 160 mCi (5.9 GBq) for all remaining doses.

[0296] Modifications to extend the dosing cycle by an additional 6 weeks and reduce the dose to 160 mCi (5.9 GBq) for the remaining cycles were considered, as determined by the investigator. 177 Should be initiated for any other Grade 3 or higher non-hematologic toxicity associated with Lu-PSMA I&T. Dosing cycles and dose levels may be resumed every 6 weeks when toxicity returns to Grade 2 or lower.

[0297] For all grade 3 and 4 AEs, patients will only be allowed one dose reduction. If the event persists, patients will be required to permanently discontinue study treatment.

[0298] Only two dose reductions are permitted for grade 2 AEs. If the event persists, the patient will be required to permanently discontinue study treatment.

[0299] Abiraterone acetate with prednisone: The dose of abiraterone acetate should be administered according to the package insert. Per the abiraterone package insert, the starting dose of abiraterone should be reduced to 250 mg daily for patients with baseline moderate hepatic impairment. For patients who develop hepatotoxicity during treatment, abiraterone acetate should be discontinued until recovery. Retreatment may be initiated at a reduced dose. Abiraterone acetate treatment should be discontinued for patients who develop severe hepatotoxicity.

[0300] Enzalutamide: The dose of enzalutamide is 160 mg (four 40 mg capsules) administered orally once daily. The capsules should be swallowed whole and can be taken with or without food. According to the enzalutamide package insert, if a patient experiences Grade 3 or higher toxicity or intolerable side effects, dosing should be discontinued for 1 week or until symptoms improve to Grade 2 or lower, and then resumed at the same dose or at a reduced dose (120 mg or 80 mg) as needed.

[0301] (v) Duration of study treatment Patients will be treated until radiographic progressive disease, clinical / symptomatic progression, unacceptable / unmanageable toxicity, or patient refusal to further study treatment (i.e., withdrawal of consent). All patients will be followed during study treatment and during a follow-up period after completion of study treatment until death, the study cut-off date (minimum 22 weeks after enrollment), or withdrawal of consent, whichever occurs first. Long-term follow-up for all patients will be for 5 years from enrollment or until death or loss to follow-up.

[0302] E. Study Procedures and Assessment The activity schedules in Tables 15 and 16 summarize the study assessments and time points. [Table 15] [Table 16]

[0303] (i) Clinical evaluation Clinical assessments included demographics, medical history, physical examination, vital signs, performance status, adverse events, concomitant medications / therapies, tumor assessment, and blinded independent central review (BICR).

[0304] Performance status will be assessed at screening and all subsequent clinical visits using the Eastern Cooperative Oncology Group (ECOG) performance status scale, as shown in Table 17 below. [Table 17]

[0305] Tumor assessments will be performed according to the assessment calendar regardless of treatment delays resulting from toxicity. Care must be taken in scheduling tumor assessments to avoid introducing bias based on treatment delays.

[0306] Patients will be evaluated for tumor response by CT imaging and bone scans at screening and every 8 weeks (± 1 week) from the start of treatment until week 24 of the study. Thereafter, patients without radiographic progression during the 24-week period will undergo CT imaging and bone scans every 12 weeks (± 1 week) until radiographic progression is determined. Scan scheduling will be based on a calendar rather than the start of a treatment cycle. Evaluations will include CT scans of the chest, abdomen, pelvis, and brain (only if clinically indicated based on symptoms / findings). The investigator, subinvestigator, or qualified site personnel will read the bone scans and CT images and assess whether radiographic progression is present. If the investigator determines that a patient's metastatic prostate cancer is progressing, the patient's bone scans and CT images will be immediately sent to the Imaging Core Laboratory (ICL) for review by a blinded independent central review (BICR), as shown in Figure 13, to confirm radiographic progression.

[0307] Investigators must not change treatment until confirmation of disease status is received from BICR.

[0308] Blinded Independent Central Review (BICR) Screening: All scans (CT, bone, and PSMA PET) will be submitted to a third-party Imaging Core Laboratory (ICL) for independent review of patient eligibility (within 3 days of receipt of imaging scans that pass quality assessment). After review by the ICL, patients may be randomized into the study if all other eligibility criteria are met. Radiographic disease progression: The investigator will evaluate CT scans and bone scans to assess disease progression based on RECIST 1.1 and PCWG3 criteria. If the investigator determines that disease progression has occurred, the BIRC, consisting of a panel of two independent radiologists qualified to evaluate bone scans and CT scans, will independently assess disease progression according to RECIST 1.1 and PCWG3 criteria. Confirmation of radiographic disease progression requires agreement between two blinded readers. If there is no agreement between the two readers, a third reader will be utilized. The BICR will complete confirmation of disease progression, preferably within 72 hours of receipt of an image set from the investigator showing radiographic progression. The investigator should not initiate changes to the patient's clinical management before receiving BICR confirmation of radiographic progression. Figure 13 presents baseline and on-treatment disease status assessments and treatment decisions.

[0309] (ii) Patient-reported outcomes Patient-reported outcomes will be determined using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Functional Assessment of Cancer Therapy - Prostate (FACT-P) questionnaire, and the Brief Pain Inventory-Short Form (BPI-SF) questionnaire.

[0310] The EORTC QLQ-C30 is a questionnaire of 30 quality of life (QoL) questions developed to assess the QoL of cancer patients. QoL questionnaires have been included in over 3,000 phase 3 cancer clinical trials as an efficacy endpoint. The EORTC questionnaire will be administered to patients at baseline, during treatment as provided in the timeline of events in Table 15, and at the end of treatment.

[0311] The Functional Assessment of Cancer Therapy-Prostate (FACT-P) is a health-related quality of life questionnaire that includes 39 prostate cancer-specific questions assessing physical well-being, functional well-being, emotional well-being, social well-being, and additional concerns or prostate cancer subscales specific to prostate cancer. Higher FACT-P scores correspond to better quality of life. The FACT-P questionnaire will be administered to patients at baseline, during treatment, and at the end of treatment.

[0312] The Brief Pain Inventory-Short Form (BPI-SF) is a short survey to assess the overall pain and symptoms experienced by participants. The BPI-SF questionnaire will be administered to patients at baseline, during treatment, and at the end of treatment.

[0313] F. Study evaluation by visit (i) Screening Screening must be completed within 28 days prior to randomization into the study. The screening visit includes (a) obtaining a blood sample and submitting it to a central laboratory for determination of PSA level and baseline clinical laboratory evaluations; (b) obtaining a CT and bone scan of the brain, chest, abdomen, and pelvis and submitting it to BICR within 72 hours to confirm patient eligibility; and (c) using an FDA-approved radiotracer ([ 68 Ga]Ga-PSMA-11 or [ 18The study included obtaining a PSMA-PET scan with [F]DCFPyL. A positive PSMA-PET result was required for inclusion in the trial. PSMA-PET positivity was defined as PSMA-PET uptake greater than liver uptake in one or more metastatic lesions of any size in any organ system. The study also included (d) recording a medical history, including prostate cancer history, date of diagnosis, and previous treatments; (e) recording concomitant medications; (f) conducting a complete physical examination; (g) performing and recording vital signs and ECOG performance status grade; (h) performing a 12-lead ECG; and (i) if the medical monitor confirmed the patient was eligible for enrollment in the study, randomizing the patient according to the IVRS system and proceeding to the Cycle 1 Day 1 visit.

[0314] (ii) Day 1 of treatment The following assessments will be performed on Day 1 of treatment: EORTC QLQ-C30, FACT-P, and BPI-SF questionnaires will be administered before treatment to determine the baseline. Any changes to concomitant medications and any adverse events noted since screening will be recorded. Conducting an abbreviated physical examination ·Perform and record vital signs and ECOG performance status. ·Draw blood for clinical laboratory evaluation. Study medication will be administered in the clinic. For patients enrolled in the standard of care arm of the study, investigator-assigned standard of care hormone therapy will be initiated: Abiraterone acetate with prednisone: The initial dose of abiraterone acetate is 1000 mg (four 250 mg tablets) administered once daily. The first dose of abiraterone acetate with prednisone will be administered in the clinic. The date and time of initiation of abiraterone therapy will be recorded. Enzalutamide: The initial dose of enzalutamide is 160 mg (four 40 mg capsules) administered once daily. The first dose of enzalutamide will be administered in the clinic. The date and time of initiation of enzalutamide therapy will be recorded. Patients enrolled in the radioligand therapy arm received a minimum of 200 mCi (7.4 GBq) of radioligand infused over 10-15 minutes. 177 An initial radioactive dose of Lu-PSMA-I&T should be administered. 177 The dose and duration of Lu-PSMA-I&T infusion will be recorded. · 177 For patients enrolled in Lu-PSMA-I&T, a 12-lead ECG will be performed after the first dose.

[0315] (iii) investigational treatment 177 Lu-PSMA I&T: Patients randomized to the radioligand therapy arm of the study will receive 200 mCi (7.4 GBq) in 6-week infusion cycles until radiographic progression confirmed by BICR, or until the patient experiences toxicity requiring discontinuation of treatment or withdraws consent to participate in the study. 177 In this study, patients will receive up to four cycles of Lu-PSMA I&T infusions. 177 Lu-PSMA I&T injections can be performed.

[0316] Abiraterone and Enzalutamide Standard of Care Arm: Patients randomized to standard of care and treated with either abiraterone or enzalutamide will be treated daily with the standard of care dosing regimen of these agents according to their prescribing information. Patients in this arm will continue to receive standard of care until radiographic progression is confirmed by BICR, or until the patient experiences toxicity requiring discontinuation of treatment or withdraws consent to participate in the study.

[0317] (iv) Ongoing evaluation Ongoing evaluation is 177It will be conducted every four weeks for all patients enrolled in the study, including patients randomized to receive Lu-PSMA I&T and patients receiving standard of care with abiraterone or enzalutamide.

[0318] (v) Progress evaluation Evaluations will be performed for all patients enrolled in the study, beginning 8 weeks + 1 week after first treatment and continuing for 24 weeks, then every 12 weeks until radiographic evidence of disease progression is observed. Evaluations will consist of (i) obtaining CT chest, abdominal, and pelvic images and bone scans and submitting them to the ICL (Imaging Core Laboratory) for evaluation for BICR, and (ii) obtaining plasma samples for PSA and other clinical laboratory evaluations.

[0319] (vi) End-of-treatment visit End of treatment (EOT) visits are 177 It will be performed 1 month (± 7 days) after the last infusion of Lu-PSMA I&T. Patients receiving abiraterone acetate or enzalutamide will be able to continue receiving daily treatment until the EOT visit. The following assessments will be performed: administer EORTC QLQ-C30, FACT-P, and BPI-SF questionnaires; record any changes to concomitant medications; record any adverse events noted at the time of screening; perform an abbreviated physical examination; perform and record vital signs and ECOG performance status; and obtain blood for clinical laboratory evaluations, including PSA and other clinical laboratory evaluations.

[0320] (vii) Crossover Patients in the standard of care hormone therapy arm were selected based on the following criteria: 177 May cross over to receive Lu-PSMA I&T: Patients must have documented radiographic progression by PCWG3-modified RECIST 1.1 with BICR while on standard-of-care hormonal therapy - Patients must not have started any other anti-cancer medications or therapies. Participants with inadequate organ and bone marrow function as defined below are not eligible for crossover: Absolute neutrophil count <1.5×109 / L ·Platelet count <100×109 / L. Hemoglobin <8g / dL. AST / SGOT and / or ALT / SGPT>3.0×ULN. Total bilirubin >2×ULN, can be 3×ULN unless the patient has known Gilbert syndrome. · Creatinine clearance (CrCl) <50 mL / min based on the Cockcroft-Gault formula. Albumin level ≥ 2.75g / dL

[0321] If a patient is not eligible for crossover, they should instead complete the end-of-study visit and proceed to long-term follow-up.

[0322] (viii) Long-term follow-up Long-term patient follow-up will continue for up to 5 years after initial treatment in this study, or until patient death or loss to follow-up. The following information will be collected: Survival status, onset of symptomatic disease progression, initiation of any new symptomatic anticancer therapy, progression during first subsequent therapy, and healthcare resource utilization every 4 months. Additionally, if a patient discontinues study treatment before documented disease progression, a CT scan of the chest, abdomen, and pelvis and a bone scan will be obtained and a BICR will be submitted every 12 weeks to assess disease progression until documentation of radiographic progression.

[0323] G. Statistical Considerations and Analysis Plan (i) Sample size 177Treatment of patients with Lu-PSMA I&T is hypothesized to increase radiographic progression-free survival (rPFS) from 6 months to 10 months compared with standard treatment. Therefore, a target hazard ratio (HR) under the alternative hypothesis of 0.60 is reasonable to expect from this phase 3 study. Using a 2:1 randomization, an estimated 237 progression events across both treatment arms would provide 95% power to detect a statistically significant treatment effect using a two-sided log-rank test at an overall significance level of α = 0.05. Given the expected enrollment rate and follow-up time, these 237 progression events would occur in an estimated 269 patients.

[0324] Also, 177 Treatment of patients with LuPSMA I&T is hypothesized to increase overall survival (OS) from 18 months to 25 months compared with standard treatment. Therefore, a target hazard ratio (HR) of 0.70 under the alternative hypothesis is reasonable to expect in this phase 3 study.

[0325] Taking advantage of the larger HR (related to OS) and the 2:1 randomization, an estimated 352 events across both treatment arms would provide 95% power to detect a statistically significant treatment effect using a two-sided log-rank test at an overall significance level of α = 0.0. Given the expected enrollment rate and follow-up time, these 352 deaths would occur in an estimated 400 patients.

[0326] (ii) Planned interim analysis The secondary outcome variable, overall survival (OS), will undergo two interim and final analyses. The first interim analysis will be performed after approximately 25% (90) of deaths have been observed, and the second interim analysis will be performed after approximately 75% (264) of deaths have been observed. The final analysis will then be performed after all 352 planned deaths have been observed. The first interim analysis of OS is expected to be performed when all 237 progression events have been observed for the primary endpoint analysis.

[0327] Interim and final analyses of OS will be performed using a two-sided log-rank test at an adjusted nominal significance level utilizing the standard O'Brien-Fleming consumption function for α. The first interim analysis will have α = 0.0006, the second interim analysis will have α = 0.0151, and the final analysis of OS will use a nominal significance level of α = 0.047. These p-values satisfy the O'Brien-Fleming consumption function for a cumulative α = 0.05.

[0328] If the OS trial meets the nominal significance level at any of the interim analyses, the study will be considered positive and patient enrollment may be stopped after review and approval by the Data Monitoring Committee (DMC).

[0329] (iii) Analysis population A total of 400 patients are planned for the study. Intention-to-treat (ITT) population: all randomized patients classified according to the randomized treatment arm, regardless of the treatment they actually received. · Safety population: all treated patients, classified according to the treatment actually received, regardless of random assignment. Crossover population: This is an ITT population, but the analysis uses information on patients who are currently on treatment with standard of care. 177 Crossover to Lu-PSMA I&T was performed, which will be used for the final OS analysis.

[0330] Other efficacy data sets (per protocol, evaluable, etc.) may be defined in the SAP (Statistical Analysis Plan), but the primary analysis of efficacy will be performed on the ITT population.

[0331] (iv) Effectiveness analysis The primary efficacy analysis will use the intention-to-treat population. Unless otherwise specified, analyses of secondary endpoints will be based on data collected during the randomized treatment period.

[0332] aRadiographic progression-free survival rPFS is the time from randomization to first documented radiographic progressive disease or death from any cause. rPFS times for surviving patients without documented radiographic progression or for patients who initiate other anti-cancer systemic therapy will be censored at the date of the last evaluable disease assessment during the study. rPFS times for patients without evaluable disease assessment during the study will be censored at the time of randomization. rPFS frequency will be approximately every 8 weeks from the time of first treatment until week 24, then every 12 weeks thereafter.

[0333] The distribution of rPFS time will be estimated using the Kaplan-Meier product limit estimation method. The median rPFS time with two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate HRs and their two-sided 95% CIs (confidence intervals).

[0334] b. Overall survival OS time is from randomization to death from any cause. OS will be followed up for 5 years from study enrollment, or until death or loss to follow-up. Patient data in the standard treatment group will not be censored at the time of crossover.

[0335] The distribution of OS time will be estimated using the Kaplan-Meier product limit estimation method. Median OS time with two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. Cox proportional hazards models will be used to estimate hazard ratios and their two-sided 95% CIs.

[0336] A sufficient proportion of patients 177If crossed over to Lu-PSMA I&T, a supplemental analysis may be performed utilizing Rank Preserving Structural Failure Time (RPSFT) (Robins et al 1991) methodology.

[0337] c. Second radiographic progression-free survival rPFS2 is the time from randomization to second documented radiographic progressive disease or death from any cause. rPFS2 is the time from randomization to second documented radiographic progression (using PCWG3 criteria assessed by blinded independent central review [BICR]) or death from the standard of care hormone therapy arm. 177 Defined as time to death for participants who crossed over to treatment with Lu-PSMA I&T.

[0338] The distribution of rPFS2 time will be estimated using the Kaplan-Meier product limit estimation method. The median rPFS2 time with two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate HRs and their two-sided 95% CIs.

[0339] d.Progression-free survival Progression will be defined as the first occurrence of PCWG3 progression, clinical / symptomatic progression and / or pain progression, or death from any cause. Time to progression will be assessed for all patients. Any patient without documented progression or who initiates other anti-cancer systemic therapy will be censored at the date of the last evaluable disease assessment during the study.

[0340] The distribution of PFS will also be estimated using the Kaplan-Meier product limit estimation method. Median PFS times with two-sided 95% CIs will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. Cox proportional hazards models will be used to estimate hazard ratios (HRs) and their two-sided 95% CIs.

[0341] A sufficient proportion of patients 177 If crossed over to Lu-PSMA I&T, a supplemental analysis may be performed, which will utilize a rank-preserving structural failure time methodology.

[0342] e. Second progression-free survival Progression-free survival2 is the time from randomization to progression based on whichever of the following events occurs first: RECIST 1.1 progression, PCWG 3 progression, clinical / symptomatic progression and / or pain progression, or death from any cause as determined by the investigator.

[0343] The distribution of PFS2 will also be estimated using the Kaplan-Meier product limit estimation method. Median PFS2 time with two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate HRs and their two-sided 95% CIs.

[0344] A sufficient proportion of patients 177 If crossed over to Lu-PSMA I&T, a supplemental analysis may be performed, which will utilize a rank-preserving structural failure time methodology.

[0345] f.PSA50 response rate PSA50 is defined as the response rate of patients achieving a 50% or greater reduction in PSA from the baseline PSA assessment. PSA50 for each treatment arm will be calculated along with the corresponding exact 95% CI. In addition, the difference in response rates along with the 95% CI will be determined.177 The primary test of treatment effect between Lu-PSMA I&T and standard of care will be the Cochran-Mantel-Haenszel (CMH) general association chi-square test, controlling for randomization stratification. Relative risks with two-sided 95% CIs will be calculated.

[0346] g. Time to first symptomatic skeletal event Time to first symptomatic skeletal event (or SSE-free survival) is defined as the occurrence of any of the following: bone-directed radiation therapy for the palliation of bone pain, a new symptomatic pathological fracture, spinal cord compression, or tumor-related orthopedic surgery. Time to SSE will be assessed for all patients. Any patient without a documented event or who initiates other anticancer systemic therapy will be censored at the date of the last evaluable disease assessment during the study.

[0347] The distribution of SSE will also be estimated using the Kaplan-Meier product limit estimation method. The median time to SSE with two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate HRs and their two-sided 95% CIs.

[0348] A sufficient proportion of patients 177 If crossed over to Lu-PSMA I&T, a supplemental analysis may be performed, which will utilize a rank-preserving structural failure time methodology.

[0349] h. Time to soft tissue progression Time to first radiographic soft tissue progression (STP) is defined as the occurrence of radiographic progression in soft tissue as determined by PCWG3-modified RECIST 1.1. Time to STP will be assessed for all patients. Any patient without a documented event or who initiates other anti-cancer systemic therapy will be censored at the date of the last evaluable disease assessment during the study.

[0350] The distribution of STP will also be estimated using the Kaplan-Meier product limit estimation method. The median STP time with two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate HRs and their two-sided 95% CIs.

[0351] A sufficient proportion of patients 177 If crossed over to Lu-PSMA I&T, a supplemental analysis may be performed, which will utilize a rank-preserving structural failure time methodology.

[0352] i. Time to chemotherapy Time to chemotherapy (TTC) is defined as the time from randomization to initiation of chemotherapy or death, whichever occurs first. Time to chemotherapy will be assessed for all patients. Any patient without a documented event or who initiates other anti-cancer systemic therapy will be censored at the date of their last evaluable disease assessment during the study.

[0353] The distribution of TTC will also be estimated using the Kaplan-Meier product limit estimation method. Median TTC times with two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate HRs and their two-sided 95% CIs.

[0354] If a sufficient proportion of patients cross over to 177Lu-PSMA I&T, a supplemental analysis may be performed that will utilize a rank-preserving structural failure time methodology.

[0355] j. Quality of life The EORTC QLQ-C30 is a questionnaire of 30 QoL questions developed to assess the quality of life (QoL) of cancer patients. It has been translated and validated into 81 languages, including English and Mandarin. This phase 3 study will use version 3.0 of the QLQ-C30. QoL questionnaires have been used as efficacy endpoints in over 3,000 phase 3 cancer clinical trials.

[0356] The EORTC questionnaire will be administered to patients at baseline, day 8 of each cycle, and at EOT. There are numerous statistical techniques presented in the literature for analyzing QoL data. The statistical methods used will be included in the SAP.

[0357] k. Objective response rate Objective response rate (ORR) to protocol treatment will be assessed by RECIST version 1.1, with best overall response classified as CR, PR, stable disease, progressive disease (PD), and not evaluable (NE). ORR is defined as the proportion of patients achieving either CR or PR. Baseline and on-study CT scans, and bone scans, if applicable, will be reviewed by an independent radiologist at a central imaging laboratory to determine objective response rate, date of response, and progression.

[0358] The ORR for each treatment arm will be calculated along with the corresponding exact 95% CI. Additionally, the difference in response rates along with the 95% CI will be determined. 177 The primary test of treatment effect between Lu-PSMA I&T and standard of care will be a Cochran-Mantel-Haenszel (CMH) general association chi-square test, controlling for randomization stratification. Relative risks with two-sided 95% CIs will be calculated.

[0359] Further analysis of ORR may be performed using a crossover population.

[0360] l.Disease control rate Disease control rate (DCR) to protocol treatment will be assessed by RECIST version 1.1, and best overall response will be classified as CR (complete response), PR (partial response), stable disease, progressive disease (PD), and not evaluable (NE). DCR is defined as the proportion of patients who achieve disease control.

[0361] The DCR for each treatment arm will be calculated along with the corresponding exact 95% CI. Additionally, the difference in response rates along with the 95% CI will be determined. 177 The primary test of treatment effect between Lu-PSMA I&T and standard of care will be a Cochran-Mantel-Haenszel (CMH) general association chi-square test, controlling for randomization stratification. Relative risks with two-sided 95% CIs will be calculated.

[0362] Further analysis of the DRR can be performed using a crossover population.

[0363] m. Duration of response For patients who achieve a best objective response rate of CR or PR, the DoR is the time from the first observation of CR or PR (whichever status occurs first) to the first documented progressive disease. The DoR for any patient without documented progression or who initiates other anticancer systemic therapy will be censored at the date of the last evaluable disease assessment during the study.

[0364] The distribution of DoR will also be estimated using the Kaplan-Meier product limit estimation method. Median DoR time with two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate HRs and their two-sided 95% CIs.

[0365] A sufficient proportion of patients 177If crossed over to Lu-PSMA I&T, a supplemental analysis may be performed, which will utilize a rank-preserving structural failure time methodology.

[0366] n.Time to PSA progression Time to PSA progression, as assessed by a PSA rise of 25% or more from post-treatment nadir, or by baseline PSA assessment if there is no nadir. Time to PSA progression for any patient without documented progression or who initiates other anti-cancer systemic therapy will be censored at the date of the last evaluable disease assessment during the study.

[0367] The distribution of time to PSA progression will also be estimated using the Kaplan-Meier product limit estimation method. The median time to PSA progression with two-sided 95% CI will be estimated for each treatment group. The log-rank test will be used as the primary analysis for comparing treatment effects. The Cox proportional hazards model will be used to estimate HRs and their two-sided 95% CIs.

[0368] A sufficient proportion of patients 177 If crossed over to Lu-PSMA I&T, a supplemental analysis may be performed, which will utilize a rank-preserving structural failure time methodology.

[0369] (vi) Clinical and laboratory evaluation Clinical laboratory results may be collected prior to treatment up to 28 days after the last dose of study therapy. All clinically significant laboratory abnormalities, i.e., tests that modify treatment and / or require intervention, may be recorded as AEs.

[0370] H. Termination of the Clinical Trial Patients may continue on study treatment until BICR-confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients who discontinue study treatment may enter the long-term follow-up phase and continue in the study until death, loss to follow-up, or withdrawal of consent, whichever occurs first.

[0371] The estimated enrollment period is 12-24 months, and it is assumed that human patients may be followed for a minimum of approximately 34 weeks beyond the Last Patient In (LPI) for the primary endpoint of radiographic progression-free survival and up to 5 years beyond the LPI for the secondary endpoint of OS, corresponding to a total expected study period of approximately 6-7 years.

[0372] Example 6 Pharmacokinetic and radiation dosimetry substudies A.Purpose The purpose of this study was to 177 Objective: To evaluate the plasma pharmacokinetics and radiation dosimetry of Lu-PSMA I&T radioligand therapy.

[0373] This substudy spanned four treatment cycles 177 It is designed to evaluate the plasma pharmacokinetic profile and radiation dosimetry of Lu-PSMA I&T radioligand therapy.

[0374] B. Study Design and Patient Population Used in the study 177 A representative batch certificate for a batch of Lu-PSMA I&T is presented in Table 18. [Table 18]

[0375] 177 The plasma pharmacokinetic profile and radiation absorbed dose of Lu-PSMA I&T radioligand therapy will be evaluated in a subset of 30 enrolled patients participating in the study of Example 5. The subset of 30 patients will undergo the same screening procedures as the main protocol of Example 5 in order to be randomized into the study, following the same inclusion / exclusion criteria of Example 5, with the following additional enrollment criteria: Inclusion criteria Enrollment in the main study (Example 5). Separate informed consent to participate in the substudy. ·each 177 Willingness to undergo planar imaging and / or SPECT / CT imaging 4 hours, 24 hours, 48 hours, and 6-8 days after the Lu-PSMA I&T treatment cycle (main study cycles 1-6). Exclusion criteria Unable to undergo SPECT / CT imaging as required by the substudy protocol.

[0376] C. Method Plasma pharmacokinetic profiles were obtained for each of the 30 patients enrolled in this study. 177 This will be determined by obtaining plasma samples before completion of the Lu-PSMA I&T infusion and approximately 1, 4, 24, and 48 hours and 6-8 days later. 177 The time of completion of Lu-PSMA I&T infusion and the actual time of sample collection will be recorded. Radioactivity in the plasma samples will be assayed using a calibrated well counter. 177 The percentage of injected dose is calculated after correcting for the radioactive decay half-life of Lu, 6.647 days.

[0377] Planar whole-body scintigraphy images were obtained from each 177 SPECT / CT images of the upper abdomen, kidneys, and salivary glands will be obtained approximately 4, 24, and 48 hours and 6-8 days after completion of Lu-PSMA I&T infusion. 177 Scintigraphy will be obtained approximately 24 hours and 6-8 days after Lu-PSMA I&T infusion. The actual start time and date of all scintigraphy imaging will be recorded on the CRF.

[0378] Imaging data will be submitted to the core imaging lab for processing. Regions of interest (ROIs) showing high physiological uptake on scintigraphy or negligible overlap with other positive lesions will be selected for tumor burden calculations. Background ROIs will be drawn from outside the body. At a minimum, the whole body, kidney, liver, parotid, submandibular, and lacrimal glands, and tumor ROIs will be included.177 ROIs will be selected for other organs that show significant uptake of Lu-PSMA I&T.

[0379] A certain dose 177 After administration / infusion of the Lu-PSMA I&T solution, human patient(s) may undergo single-photon emission computed tomography (SPECT) / computed tomography (CT) imaging, for example, at four time points (4 hours, 24 hours, 48 hours, and 168 hours). Image data may be analyzed to calculate the time-integrated activity index (TIAC) using significant and meaningful Lu-PSMA I&T activity above background in each organ of interest, and / or including the kidney, bladder, liver, lumbar vertebrae L2-L4, lacrimal gland, salivary gland, intestine, whole body, and combinations thereof. To calculate subject-specific organ doses, organ-level TIAC data may be entered into Organ Level Internal Dose Assessment (OLINDA 2.2.3), and the resulting organ doses and whole body effective doses for each target organ (e.g., kidney) may be collated and averaged. D. Schedule of Activities Specific to the Pharmacokinetic and Dosimetry Substudy (i) Screening Ensure inclusion / exclusion criteria are met Obtain informed consent to participate in the substudy (ii) 177 Lu-PSMA I&T Infusion Cycles 1-4 As shown in Table 19, each 177 Plasma samples will be obtained before completion of the Lu-PSMA I&T infusion and approximately 1, 4, 24, and 48 hours and 6-8 days later. ·each 177 Planar whole-body scintigraphy images are obtained approximately 4, 24, and 48 hours and 6-8 days after completion of Lu-PSMA I&T infusion. ·each 177 SPECT / CT images will be obtained approximately 24 hours and 6-8 days after completion of the Lu-PSMA I&T infusion. [Table 19]

[0380] E. Statistical methods (i) Pharmacokinetic parameters 177 The following PK parameters derived from whole blood radioactivity counts of Lu-PSMA-I&T infusion will be determined as needed: AUC 0-24;0-last : Area under the whole blood radioactivity count time curve (0-24 hours, 0-end) calculated using the trapezoidal rule AUC 0-∞ :AUC 0-24 or AUC 0-last Area under the whole blood radioactivity count time curve (calculated by using the trapezoidal rule) + Cp n / k el The area under the curve estimated by Cp n = last observed whole blood radioactivity count at time n k el = elimination rate constant calculated from the log-linear terminal portion of the whole blood radioactive count time curve C max : Maximum observed whole blood radioactivity count T max :C max Time until ·k el = elimination rate constant calculated from the log-linear terminal portion of the whole blood radioactive count time curve ·t 1 / 2 :ln2 / k el The apparent elimination half-life was calculated as ·CL: Dose / AUC 0-24 Systemic clearance for extravascular administration at steady state, calculated as ·V d :Volume of distribution (ii) 177 Lu-PSMA I&T injection radiation count C(t): Radiocounts measured at time = t were tabulated for each patient and time. Whole blood radiocounts below the limit of quantification were treated as zero (0).

[0381] (iii) Area under the curve Unless otherwise specified, the following features will be calculated for every complete profile: AUC 0-24,0-last : The area under the whole blood radiocounts C(t) from the dose will be calculated by use of the trapezoidal rule.

[0382] All references cited herein are incorporated herein by reference. The foregoing is provided primarily for illustrative purposes. It will be readily apparent to those skilled in the art that additional agents may be included, and that the components, additives, proportions, 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 present invention.

[0383] Example 7 177 Comparative study to extend the product shelf life of Lu-PSMA I&T from 48 to 74 hours The purpose of this study is to 177 The aim was to extend the expiration date of Lu-PSMA I&T injection from 48 hours to 74 hours. The 72-hour expiration date was achieved by modifying the drug product composition. 177 This was achieved by reducing the strength of the Lu-PSMA I&T from 1 GBq / mL to 0.5 GBq / mL and maintaining the formulated drug product at a more restrictive pH in the range of 4 to 5. The total patient dose remained unchanged, at 7.4 GBq. 177 The Lu-PSMA I&T remained the same. To deliver the desired radioactive dose, the drug volume was increased from 8–10 mL to 15–20 mL. Therefore, the primary container closure system was changed to 10 mL–20 mL vials while maintaining the same glass quality, the same elastomeric closure, and the same aluminum crimp seal (Table 20).

[0384] In this study, the stability of "Drug Product B" was tested and the stability of "Drug Product A" 177 This resulted in an extended shelf life of Lu-PSMA I&T injections. A. Drug Product Description and Composition [Table 20]

[0385] Table 20 shows the formulation of the 500mg HCl solution, which underwent a formulation change to increase shelf life, achieved by reducing the strength (radioactivity concentration) from 1 GBq / mL to 0.5-0.6 GBq / mL, using a more stringent pH, and increasing the fill volume to 20 mL / vial. 177 The quantitative and qualitative composition of Lu-PSMA I&T injection is listed below. The number of vials produced per batch was adjusted to produce the number of doses required for therapeutic administration. 177 The qualitative and quantitative composition of Lu-PSMA I&T drug product is provided in Table 21. [Table 21-1] [Table 21-2]

[0386] The changes associated with the expiration date extension did not alter the identity, quality, or purity of the drug substance or any component of the drug product. The strength of the API in the final drug product was changed, a narrower control range for pH was established, and the concentrations of two key excipients, ascorbic acid and ethanol, were modified. These changes were made to extend the expiration date of the drug product.

[0387] With these changes related to the expiration date extension, batch sizes were scaled to accommodate the number of therapeutic doses plus the excess amounts needed to provide quality control test samples for both microbiological and chemical testing, and to provide reserve samples for each batch. In this context, all components and excipients were scaled relative to the measured amount of radioactive Lu-177 receptor-labeled solution.

[0388] B. Manufacturing Process No substantive changes were made to the manufacturing process, equipment, or reagents used in this expiration date extension study. The reformulated product was formulated to a lower radioactivity concentration (strength), stricter pH limits were applied, and the same excipients were used, but at a different strength than the original formulation. Because the manufacturing chemistry of the drug substance remained unchanged, changes were applied only to the formulation of the final drug product solution.

[0389] The pH was the only critical step that was updated. The pH of the final drug product solution was controlled from 5.0-8.0 to a narrower range of 4.0-5.0. This was achieved by the controlled addition of hydrochloric acid.

[0390] Product stability was evaluated over the allocated shelf life at storage temperatures ranging from 2°C to 40°C. In addition, microbial bioburden testing was performed. 177 Three other batches of Lu-PSMA I&T injection were tested. All batches met the predetermined acceptance criteria by the extended 72-hour expiration time point. The product formulation was modified, lowering the target strength from 1 GBq / mL to 0.5-0.6 GBq / mL. The pH range was again controlled from 5.0-8.0 to a narrower range of 4.0-5.0, and due to the lower strength formulation, the dispense volume was increased to 10-20 mL / vial. In addition, the strength of the ascorbic acid and ethanol was reduced. Process validation testing was performed on this lower strength product, confirming that the 72-hour expiration time point was achieved.

[0391] To assist the aseptic filling operation in accommodating changes (increases) in drug product volume and changes in vial size, a media fill study was successfully conducted on three test batches.

[0392] The excipients utilized in the drug product formulation remained unchanged (ethanol, ascorbic acid, and water for injection). The change in drug product composition did not result in the creation of any new impurities or an increase in existing impurities. Only the concentrations / volumes of existing excipients were adjusted to achieve the larger volume.

[0393] Table 22 below lists the tests and pass / fail criteria for Drug Product A and Drug Product B. [Table 22]

[0394] C. Analytical Procedures Due to a decrease in product strength (radioactivity concentration) (per mL), the sample injection volume was increased to 50 μL-100 μL for some drug product tests. Due to this change, the following method validation studies were performed: Determination of colloidal impurities in Lu-177-PSMA injection by TLC Bioburden - microbial growth Endotoxin test Sterility testing Determination of ethanol by gas chromatography

[0395] The decrease in intensity (radioactivity concentration) slowed the rate of radiolysis, and the radiochemical purity remained above 95% 72 hours after the end of the synthesis, without virtually generating new impurities or increasing existing ones.

[0396] D. Container Closure System The vials in the primary container closure system were changed from 10 mL glass pharmaceutical-grade injection vials to 20 mL vials of the same pharmaceutical grade and neck finish. They were sealed with the current fluorine-coated bromobutyl elastomer closures held in place with open-top aluminum crimps. Neither the elastomer closures nor the crimps were changed (Table 23). [Table 23]

[0397] E. Stability 0.5GBq / mL 177The radiochemical purity and chemical properties (including pH, impurities, and visual properties) of Lu PSMA-I&T injection solution were tested in three process validation and four separate stability batches over a 72-hour time span from the end of synthesis. 177 Lu precursor labeling solution was utilized. 177 Stability samples from all batches of Lu-PSMA-I&T injectable drug product were stored at room temperature, with selected samples also stored upside down and some samples stored at elevated temperatures. Initial testing was generally completed within 7 hours after completion of synthesis, and stability-indicating testing was repeated at 24, 48, and 72 hours after EOS. For samples formulated at 0.5 GBq / mL strength, no deviations from specification acceptance criteria were observed for samples tested up to and including 72 hours. Based on these supportive stability data, an expiration date of 72 hours after completion of synthesis was assigned. The evolution of the drug product's shelf life is provided in Table 24. [Table 24]

[0398] F. Conclusion The 72-hour expiration date can be achieved by modifying the drug product formulation. 177 This was achieved by reducing the strength of the Lu-PSMA I&T from 1 GBq / mL to 0.5 GBq / mL and maintaining the formulated drug product at a more restrictive pH in the range of 4-5.

[0399] All references cited herein are incorporated herein by reference. The foregoing is provided primarily for illustrative purposes. It will be readily apparent to those skilled in the art that additional agents may be included, and that the components, additives, proportions, 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 present invention.

[0400] A number of examples are provided herein to facilitate understanding of the present disclosure. A specific set of statements is as follows:

[0401] Statement 1: A radiopharmaceutical composition comprising: 177 A radiopharmaceutical composition comprising 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.

[0402] Statement 2: A radiopharmaceutical composition according to statement 1, wherein the solution is suitable for administration up to 3 days after formulation.

[0403] Statement 3: A radiopharmaceutical composition according to statement 1, wherein the solution is suitable for administration up to 4 days after formulation.

[0404] Statement 4: The radiopharmaceutical composition according to statement 1, further comprising an antioxidant.

[0405] Statement 5: The radiopharmaceutical composition according to statement 4, wherein the antioxidant is ascorbic acid.

[0406] Statement 6: The radiopharmaceutical composition according to statement 5, wherein the solution comprises 21 mg / ml to 31 mg / ml of ascorbic acid.

[0407] Statement 7: A radiopharmaceutical composition according to statement 5, wherein the solution comprises 42.5 mg / ml ascorbic acid.

[0408] Statement 8: The radiopharmaceutical composition according to statement 1, wherein the solution further comprises hydrochloric acid.

[0409] Statement 9: The radiopharmaceutical composition according to statement 1, wherein the solution comprises 1.7 mg / ml to 34 mg / ml of hydrochloric acid.

[0410] Statement 10: A radiopharmaceutical composition according to statement 1, wherein the solution has a pH of 4.5 or less.

[0411] Statement 11: A radiopharmaceutical composition according to statement 1, wherein the solution has a pH of 5 or less.

[0412] Statement 12: A radiopharmaceutical composition according to statement 1, wherein the solution has a radioactivity of less than 635 MBq / ml.

[0413] Statement 13: The radiopharmaceutical composition according to statement 12, wherein the solution has a radioactivity of 579 MBq / ml to 626 MBq / ml.

[0414] Statement 14: A radiopharmaceutical composition according to Statement 1, wherein the solution has a radiochemical purity of greater than 95% 46-48 hours after formulation.

[0415] Statement 15: The radiopharmaceutical composition of statement 14, wherein the solution has a radiochemical purity of greater than 96% 46-48 hours after formulation.

[0416] Statement 16: The radiopharmaceutical composition of statement 14, wherein the solution has a radiochemical purity of greater than 97% 46-48 hours after formulation.

[0417] Statement 17: A radiopharmaceutical composition according to Statement 1, wherein the solution has a radiochemical purity of greater than 95% 69-71 hours after formulation.

[0418] Statement 18: The radiopharmaceutical composition of Statement 17, wherein the solution has a radiochemical purity of greater than 96% 69-71 hours after formulation.

[0419] Statement 19: The radiopharmaceutical composition of Statement 17, wherein the solution has a radiochemical purity of greater than 97% 69-71 hours after formulation.

[0420] Statement 20: The radiopharmaceutical composition of Statement 1, wherein the solution has a radiochemical purity of greater than 95% 90-93 hours after formulation.

[0421] Statement 21: The radiopharmaceutical composition of Statement 20, wherein the solution has a radiochemical purity of greater than 96% 90-93 hours after formulation.

[0422] Statement 22: The radiopharmaceutical composition of Statement 20, wherein the solution has a radiochemical purity of greater than 97% 90-93 hours after formulation.

[0423] Statement 23: The radiopharmaceutical composition according to statement 1, wherein the solution comprises less than 6 μg / ml of Lu-PSMA I&T.

[0424] Statement 24: The radiopharmaceutical composition of statement 1, further comprising a metal ion chelator.

[0425] Statement 25: The radiopharmaceutical composition according to statement 24, wherein the metal ion chelator is disodium EDTA.

[0426] Statement 26: The radiopharmaceutical composition of statement 25, wherein the solution comprises about 15.5 μg / ml disodium EDTA.

[0427] Statement 27: The radiopharmaceutical composition according to statement 1, further comprising a stabilizer.

[0428] Statement 28: A radiopharmaceutical composition according to statement 27, wherein the stabilizing agent is ethanol. A radiopharmaceutical composition according to statement 27, wherein the stabilizing agent is not ethanol.

[0429] Statement 29: The radiopharmaceutical composition of statement 28, wherein the solution comprises about 37.5 μl / ml of ethanol.

[0430] Statement 30: A radiopharmaceutical composition according to statement 1, further comprising 31 mg / ml ascorbic acid and an amount of hydrochloric acid adjusted so that the solution has a pH of 4.5.

[0431] Statement 31: A radiopharmaceutical composition according to statement 30, further comprising 15.5 μg / ml disodium EDTA and 37.5 μL / ml ethanol.

[0432] Statement 32: A radiopharmaceutical composition according to statement 31, further comprising sodium bicarbonate and NaOH in amounts sufficient to control the pH at 4.5.

[0433] Statement 33: A radiopharmaceutical composition according to statement 30, wherein the solution has a radioactivity of 588.5 MBq / ml.

[0434] Statement 34: The radiopharmaceutical composition of Statement 30, wherein the solution has a radiochemical purity of at least 98% after 44 hours from formulation, at least 97% after 69 hours from formulation, and / or at least 97% after 93 hours from formulation.

[0435] Statement 35: A radiopharmaceutical composition comprising: 177 1. A radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the composition is suitable for administration to a human patient in need thereof at least 90 hours after formulation, and wherein the composition has a radiochemical purity of 95% or greater at the time of administration.

[0436] Statement 36: The radiopharmaceutical composition of Statement 35, wherein the composition comprises less than 6 μg of Lu-PSMA I&T per mL of solution.

[0437] Statement 37: The radiopharmaceutical composition of statement 35, wherein the composition comprises about 13 μg to about 18 μg of disodium EDTA per mL of solution.

[0438] Statement 38: The radiopharmaceutical composition of statement 35, wherein the composition comprises about 35 μL to about 40 μL of ethanol per mL of solution.

[0439] Statement 39: The radiopharmaceutical composition of statement 35, wherein the composition contains about 0.5 GBq or about 13.5 mCi of radioactivity per mL of solution.

[0440] Statement 40: The radiopharmaceutical composition of statement 35, wherein the composition comprises about 31 mg / ml ascorbic acid.

[0441] Statement 41: The radiopharmaceutical composition of statement 35, wherein the composition comprises from about 21 mg / ml to about 31 mg / ml of ascorbic acid.

[0442] Statement 42: The radiopharmaceutical composition of statement 35, wherein the composition comprises from about 31 mg / ml to about 42.5 mg / ml of ascorbic acid.

[0443] Statement 43: A radiopharmaceutical composition comprising: 177 1. A radiopharmaceutical composition comprising 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 20% L-ascorbic acid, and a specific activity of 61 GBq or less in a total volume of 6 to 8 mL of solution.

[0444] Statement 44: The radiopharmaceutical composition according to statement 43, wherein the ascorbic acid has a pH of 4.5.

[0445] Statement 45: A radiopharmaceutical composition according to statement 43, further comprising 1.5 ml of ethanol-water in a 1:1 (v / v) ratio.

[0446] Statement 46: A radiopharmaceutical composition comprising: 1771. A radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 4.5, wherein the composition is suitable for administration to a human patient in need thereof at least 93 hours after formulation, and wherein the composition has a radiochemical purity of 97.0% or greater at the time of administration.

[0447] Statement 47: A radiopharmaceutical composition comprising: 177 1. A radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 4.5, wherein the composition is suitable for administration to a human patient in need thereof at least 92 hours after formulation, and wherein the composition has a radiochemical purity of 96.0% or greater at the time of administration.

[0448] Statement 48: A radiopharmaceutical composition comprising: 177 A radiopharmaceutical composition comprising Lu-PSMA I&T, wherein the composition is formulated as a solution suitable for injection, and wherein the solution has a pH of 4.5.

[0449] Statement 49: A radiopharmaceutical composition comprising: 177 1. A radiopharmaceutical composition comprising Lu-PSMA I&T, wherein the composition is formulated as a solution suitable for injection, and wherein the solution has a radiochemical purity of greater than 96% more than 48 hours after formulation.

[0450] Statement 50: A radiopharmaceutical composition comprising: 177 1. A radiopharmaceutical composition comprising Lu-PSMA I&T, wherein the composition is formulated as a solution suitable for injection, and wherein the solution has a radiochemical purity of greater than 96% after more than 71 hours from formulation.

[0451] Statement 51: A radiopharmaceutical composition according to any of the preceding statements, wherein upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity and experiences a reduction in prostate specific antigen of greater than about 50%.

[0452] Statement 52: 177A method for preparing Lu-PSMA I&T, comprising heating the composition of statement 43 to a maximum of 95°C for 15 minutes.

[0453] Statement 53: The method of statement 52, further comprising adjusting the solution pH to 3.5 to 4.5.

[0454] Statement 54: A method of administering a radiopharmaceutical solution, the method comprising injecting the radiopharmaceutical solution more than 48 hours after formulation, wherein the radiopharmaceutical solution comprises: 177 A method comprising Lu-PSMA I&T.

[0455] Statement 55: A method of administering a radiopharmaceutical solution, the method comprising: 177 1. A method comprising injecting a radiopharmaceutical solution comprising Lu-PSMA I&T, wherein the solution has a pH of 4.5.

[0456] Statement 56: A method of administering a radiopharmaceutical solution, the method comprising: 177 1. A method comprising injecting a radiopharmaceutical solution comprising Lu-PSMA I&T, wherein the solution has a radiochemical purity of greater than 96% greater than 48 hours after formulation.

[0457] Statement 57: A method of administering a radiopharmaceutical solution, the method comprising: 177 1. A method comprising injecting a radiopharmaceutical solution comprising Lu-PSMA I&T, wherein the solution has a radiochemical purity of greater than 96% after more than 71 hours from formulation.

[0458] Statement 58: A radiopharmaceutical composition comprising: 1771. A radiopharmaceutical composition comprising 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 in a solution having a pH of 3.5 to 4.5, wherein the solution is suitable for administration more than 48 hours from formulation and has a radiochemical purity of greater than 96% when administered.

[0459] Statement 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 formulation, wherein the radiopharmaceutical composition 177 A method comprising Lu-PSMA I&T and ascorbic acid in a solution having a pH of 3.5 to 4.5, the solution having a radiochemical purity of greater than 96% when administered.

[0460] Statement 60: The method according to statement 59, wherein the pH is 3.5 to 4.2.

[0461] Statement 61: The method of claim 59, wherein the composition comprises less than 6 μg of Lu-PSMA I&T per mL of solution.

[0462] Statement 62: The method of statement 59, wherein the composition comprises about 13 μg to about 18 μg of disodium EDTA per mL of solution.

[0463] Statement 63: The method of statement 59, wherein the composition comprises about 35 μL to about 40 μL of ethanol per mL of solution.

[0464] Statement 64: The method of statement 59, wherein the composition contains about 0.5 GBq or about 13.5 mCi of radioactivity per mL of solution.

[0465] Statement 65: The method of statement 59, wherein the composition comprises about 31 mg / ml of ascorbic acid.

[0466] Statement 66: The method of statement 59, wherein the solution has a radiochemical purity of at least 98% after 44 hours from formulation, at least 97% after 69 hours from formulation, and / or at least 97% after 93 hours from formulation.

[0467] Statement 67: The method of statement 59, wherein upon administration of the composition to a patient, the patient maintains low levels of hematotoxicity and nephrotoxicity and experiences a reduction in prostate specific antigen of greater than about 50%.

[0468] Statement 68: A method of treating a patient having mCRP in need thereof, wherein the method is administered more than 48 hours after formulation. 177 1. A method comprising administering a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in a solution having a pH of 3.5 to 4.5, wherein the solution has a radiochemical purity of greater than 96% when administered.

[0469] STATEMENT 69: The method of statement 68, further comprising imaging the patient using PSMA-PET prior to administering the radiopharmaceutical composition to document and confirm that the patient is mCRPC positive.

[0470] STATEMENT 70: The method of statement 68, wherein the patient has improved radiographic progression-free survival (rPFS).

[0471] Statement 71: The method of statement 70, wherein the patient has an rPFS of about 6 months to 12 months.

[0472] Statement 72: The method of statement 68, wherein the patient has improved overall survival (OS).

[0473] Statement 73: The method of statement 72, wherein the patient has an OS of about 18 months to 25 months.

[0474] STATEMENT 74: The method of statement 68, wherein the patient has improved second radiographic progression-free survival (rPFS 2).

[0475] STATEMENT 75: The method of statement 68, wherein the patient has improved progression-free survival.

[0476] STATEMENT 76: The method of statement 68, wherein the patient has improved second progression-free survival.

[0477] Statement 77: Patients should have improved PSA 50 69. The method of statement 68, having a response rate.

[0478] Statement 78: The method of statement 68, wherein the patient has an improved time to first symptomatic skeletal event (SSE).

[0479] Statement 79: The method of statement 68, wherein the patient has improved time to soft tissue progression (STP).

[0480] Statement 80: The method of statement 68, wherein the patient has an improved time to chemotherapy (TTC).

[0481] Statement 81: The method of statement 68, wherein the patient has improved results on a quality of life questionnaire.

[0482] Statement 82: The method according to statement 68, wherein the pH is 3.5 to 4.2.

[0483] Statement 83: The method of statement 68, wherein the composition contains less than 6 μg of Lu-PSMA-I&T per mL of solution.

[0484] Statement 84: The method of statement 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.

[0485] Statement 85: The method of statement 68, wherein the composition contains about 0.5 GBq or about 13.5 mCi of radioactivity per mL of solution.

[0486] Statement 86: The method of statement 68, wherein the solution has a radiochemical purity of at least 98% after 44 hours from formulation, at least 97% after 69 hours from formulation, and / or at least 97% after 93 hours from formulation.

[0487] Statement 87: The method of statement 68, wherein upon administration of the composition to a patient, the patient maintains low levels of hematotoxicity and nephrotoxicity and experiences a reduction in prostate specific antigen of greater than about 50%.

[0488] Statement 88: The radiopharmaceutical composition of statement 68, wherein the composition has a radioactivity of 1,270 MBq / ml to about 1,311 MBq / ml.

[0489] Statement 89: A radiopharmaceutical composition comprising: 177 1. A radiopharmaceutical composition comprising Lu-PSMA I&T, about 31 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 in a solution having a pH of 3.5 to 4.5, wherein the solution has a radiochemical purity of greater than 95% when administered.

[0490] Statement 90: The radiopharmaceutical composition of statement 89, wherein the composition has a high radioactivity of about 1,278 MBq / ml to about 1,311 MBq / ml.

[0491] Statement 91: The radiopharmaceutical composition of statement 89, wherein the composition has a low radioactivity of about 579 MBq / ml to about 626 MBq / ml.

[0492] Statement 92: The radiopharmaceutical composition of statement 89, wherein the Lu-PSMA I&T is present in the composition at a concentration of less than about 12 μg / ml.

[0493] Statement 93: The composition contains colloidal radioactivity in an amount of less than about 5%. 177 89. The radiopharmaceutical composition according to statement 89, comprising Lu.

[0494] Statement 94: The radiopharmaceutical composition of statement 89, wherein the composition has less than about 17.5 EU / ml bacterial endotoxin.

[0495] Statement 95: The radiopharmaceutical composition of statement 89, wherein the composition has a shelf life of greater than 24 hours after formulation.

[0496] Statement 96: The radiopharmaceutical composition of statement 95, wherein the composition has a shelf life of greater than 48 hours after formulation.

[0497] Statement 97: The radiopharmaceutical composition of statement 96, wherein the composition has a shelf life of greater than 72 hours after formulation.

[0498] Statement 98: Injectable 177 A radiopharmaceutical composition comprising a Lu-PSMA I&T solution.

[0499] Statement 99: Injectable 177 Lu-PSMA I&T solution 177 Lu-PSMA I&T, ascorbic acid, and ethanol, 17799. The radiopharmaceutical composition of statement 98, wherein the Lu-PSMA I&T is of sufficient radioactivity for its intended use, the total amount of ascorbic acid in the solution is about 210-700 mg, the total amount of ethanol in the solution is about 274-706 mg, the pH of the solution is about 5 or less, and wherein, upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity and experiences a reduction in prostate specific antigen of greater than about 50%.

[0500] Statement 100: Injectable 177 The Lu-PSMA I&T solution is administered in an amount of about 5 μg / ml to about 15 μg / ml. 177 99. The radiopharmaceutical composition of claim 98, comprising Lu-PSMA-I&T, 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 about 3 to about 5, and wherein, upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0501] Statement 101: The radiopharmaceutical composition of statement 100, wherein the composition has a radioactivity of less than about 300 mCi.

[0502] Statement 102: The radiopharmaceutical composition of statement 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).

[0503] Statement 103: The radiopharmaceutical composition of statement 100, wherein the composition comprises ascorbic acid in 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.

[0504] Statement 104: The radiopharmaceutical composition of statement 100, wherein the composition has a radioactivity content of about 70% to about 130%.

[0505] Statement 105: The radiopharmaceutical composition of statement 104, wherein the composition provides a mean systemic effective dose of about 23±20 Gy (3.3 Gy / GBq) after administration to a subject in need thereof.

[0506] Statement 106: The radiopharmaceutical composition of statement 100, wherein the composition is sterile.

[0507] Statement 107: The radiopharmaceutical composition of statement 100, wherein the composition has a volume of from about 1 ml to about 50 ml.

[0508] Statement 108: The radiopharmaceutical composition of statement 100, wherein the composition has a radiochemical purity of at least 97% as measured by HPLC at 0 hours EOS.

[0509] Statement 109: Injectable 177 The Lu-PSMA I&T solution is administered in an amount of about 5 μg / ml to about 15 μg / ml. 17799. The radiopharmaceutical composition of claim 98, comprising Lu-PSMA-I&T, 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 at a concentration 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 about 3 to about 5, and wherein, upon administration of the composition to a subject, the subject maintains low levels of hematotoxicity and nephrotoxicity.

[0510] Statement 110: The radiopharmaceutical composition of statement 109, wherein the composition has a radioactivity of less than about 500 mCi.

[0511] Statement 111: The radiopharmaceutical composition of statement 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).

[0512] Statement 112: The radiopharmaceutical composition of statement 109, wherein the composition comprises ascorbic acid in 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.

[0513] Statement 113: The radiopharmaceutical composition of statement 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.

[0514] Statement 114: The radiopharmaceutical composition of statement 109, wherein the composition has a radioactivity content of about 70% to about 130%.

[0515] Statement 115: The radiopharmaceutical composition of statement 109, wherein the composition provides a mean systemic effective dose of about 23±20 Gy (3.3 Gy / GBq) after administration to a subject in need thereof.

[0516] Statement 116: The radiopharmaceutical composition of statement 109, wherein the composition is sterile.

[0517] Statement 117: The radiopharmaceutical composition of statement 109, wherein the composition has a volume of from about 1 ml to about 50 ml.

[0518] STATEMENT 118: A radiopharmaceutical composition according to statement 109, wherein the composition has a radiochemical purity of at least 97% as measured by HPLC at 0 hours EOS.

[0519] Statement 119: A radiopharmaceutical kit comprising: 177 for injection into human patients requiring injection of Lu-PSMA I&T solution 177 A radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a 7.4 GBq±0.1 GBq dose.

[0520] Statement 120: A radiopharmaceutical kit according to statement 119, wherein the vial is a sterile pyrogen-free glass vial of type 1 glass having a fluorine-coated bromobutyl rubber septum.

[0521] Statement 121: The radiopharmaceutical kit of statement 120, wherein the septum is sealed with a crimped aluminum capsule.

[0522] Statement 122: The radiopharmaceutical kit of statement 119, further comprising a lead-shielded shipping container, wherein the glass vial is maintained within the lead-shielded container during shipping.

[0523] Statement 123: Radiopharmaceutical kits as described in Statement 122, wherein the lead-shielded transport container complies with Type A requirements (IAEA standard).

[0524] Statement 124: The radiopharmaceutical kit of statement 119, wherein the vial contains multiple doses.

[0525] Statement 125: 177 119. The radiopharmaceutical kit of statement 119, wherein the Lu-PSMA I&T solution has a volume of 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.

[0526] Statement 126: 177119. The radiopharmaceutical kit of statement 119, wherein the Lu-PSMA I&T solution has a strength of 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.

[0527] Statement 127: 177 119. The radiopharmaceutical kit of statement 119, wherein the Lu-PSMA I&T solution is suitable for administration to a human patient in need thereof more than 72 hours after formulation, more than 96 hours after formulation, or more than 100 hours after formulation.

[0528] Statement 128: 177 119. The radiopharmaceutical kit of statement 119, wherein the Lu-PSMA I&T solution has a pH of 3.5 to 4.5.

[0529] Statement 129: A method of diagnosing or treating a tumor in a patient in need thereof, the method comprising: 177 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein 20 hours after injection, the radiopharmaceutical composition has an activity of at least 20% IA to 30% IA in the whole body.

[0530] Statement 130: The method of statement 129, wherein 40 hours after injection, the radiopharmaceutical composition has an activity of at least 10% IA to 20% IA in the whole body.

[0531] Statement 131: The method of statement 129, wherein 60 hours after injection, the radiopharmaceutical composition has an activity of at least 5% IA to 10% IA in the whole body.

[0532] Statement 132: A method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity in the kidney of at least 8% IA to 10% IA within 20 hours after injection.

[0533] Statement 133: The method of statement 132, wherein 20 hours after injection, the radiopharmaceutical composition has an activity in the kidney of at least 3% IA to 8% IA.

[0534] Statement 134: The method of statement 132, wherein 40 hours after injection, the radiopharmaceutical composition has an activity in the kidney of at least 1% IA to 5% IA.

[0535] Statement 135: The method of statement 132, wherein 60 hours after injection, the radiopharmaceutical composition has an activity in the kidney of at least 1% IA to 5% IA.

[0536] Statement 136: A method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity in the parotid gland of at least 0.7% IA to 1% IA within 20 hours after injection.

[0537] Statement 137: The method of statement 136, wherein 20 hours after injection, the radiopharmaceutical composition has an activity in the parotid gland of at least 0.3% IA to 0.8% IA.

[0538] Statement 138: The method of statement 136, wherein 40 hours after injection, the radiopharmaceutical composition has an activity in the parotid gland of at least 0.2% IA to 0.5% IA.

[0539] Statement 139: The method of statement 136, wherein 60 hours after injection, the radiopharmaceutical composition has an activity in the parotid gland of at least 0.1% IA to 0.3% IA.

[0540] Statement 140: A method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity of at least 0.2% IA to 0.5% IA in the patient's lymph node lesions within 20 hours of injection.

[0541] Statement 141: The method of statement 140, wherein 20 hours after injection, the radiopharmaceutical composition has an activity of at least 0.1% IA to 0.3% IA in lymph node lesions.

[0542] Statement 142: The method of statement 140, wherein 40 hours after injection, the radiopharmaceutical composition has an activity in lymph node lesions of at least 0.08% IA to 0.2% IA.

[0543] Statement 143: The method of statement 140, wherein 60 hours after injection, the radiopharmaceutical composition has an activity of at least 0.05% IA to 0.1% IA in lymph node lesions.

[0544] Statement 144: A method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 1771. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity of at least 0.1% IA to 0.4% IA in the patient's bone lesion within 20 hours of injection.

[0545] Statement 145: The method of statement 144, wherein 20 hours after injection, the radiopharmaceutical composition has an activity in the bone lesion of at least 0.1% IA to 0.2% IA.

[0546] Statement 145: The method of statement 144, wherein 40 hours after injection, the radiopharmaceutical composition has an activity in the bone lesion of at least 0.05% IA to 0.1% IA.

[0547] Statement 146: The method of statement 144, wherein 60 hours after injection, the radiopharmaceutical composition has an activity in the bone lesion of at least 0.02% IA to 0.05% IA.

[0548] Statement 147: A method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an effective half-life of about 30 to 40 hours in the patient's systemic tissue.

[0549] Statement 148: The method of statement 147, wherein the radiopharmaceutical composition has an effective half-life in the patient's kidney of about 25 hours to about 35 hours.

[0550] Statement 149: The method of statement 147, wherein the radiopharmaceutical composition has an effective half-life of about 20 hours to about 30 hours in the patient's parotid gland.

[0551] Statement 150: The method of statement 147, wherein the effective half-life of the radiopharmaceutical composition is from about 45 hours to about 55 hours in the bone lesion of the patient.

[0552] Statement 151: The method of statement 147, wherein the radiopharmaceutical composition has an effective half-life of about 35 hours to about 45 hours in the patient's lymph node lesion.

[0553] Statement 152: A method of diagnosing a tumor in a patient in need thereof, the method comprising administering to the patient: 177 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the average absorbed dose of the radiopharmaceutical is about 0.01 mGy / MBq to 0.5 mGy / MBq in the patient's whole body.

[0554] Statement 153: The method of statement 152, wherein the mean absorbed dose of the radiopharmaceutical composition is about 0.5 mGy / MBq to 1.0 mGy / MBq in the kidneys of the patient.

[0555] Statement 154: The method of statement 152, wherein the mean absorbed dose of the radiopharmaceutical composition is about 1 mGy / MBq to 1.5 mGy / MBq in the patient's parotid gland.

[0556] Statement 155: The method of statement 152, wherein the mean absorbed dose of the radiopharmaceutical composition is about 2.5 mGy / MBq to 3.5 mGy / MBq in the patient's bone lesion.

[0557] Statement 156: The method of statement 152, wherein the mean absorbed dose of the radiopharmaceutical composition is about 3.5 mGy / MBq to 4.5 mGy / MBq in the patient's lymph node lesions.

[0558] Statement 157: A radiopharmaceutical kit comprising: 177 for injection into human patients requiring injection of Lu-PSMA I&T solution177 A radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection contains a dose of 7.1 GBq or more.

Claims

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

2. 2. The radiopharmaceutical composition of claim 1, wherein the pH is between 3.5 and 4.

2.

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

0.

4. 10. The radiopharmaceutical composition of claim 1, wherein said composition contains less than 6 μg of Lu-PSMA I&T per mL of solution.

5. 10. The radiopharmaceutical composition of claim 1, wherein said composition comprises from about 13 μg to about 18 μg of disodium EDTA per mL of solution.

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

7. The radiopharmaceutical composition of claim 1 , wherein the composition is ethanol-free.

8. 2. The radiopharmaceutical composition of claim 1, wherein the composition contains about 0.5 GBq or about 13.5 mCi of radioactivity per mL of solution.

9. 10. The radiopharmaceutical composition of claim 1, wherein the composition comprises about 31 mg / ml ascorbic acid.

10. 10. The radiopharmaceutical composition of claim 1, wherein said composition comprises from about 21 mg / ml to about 31 mg / ml ascorbic acid.

11. 10. The radiopharmaceutical composition of claim 1, wherein said composition comprises from about 31 mg / ml to about 42.5 mg / ml ascorbic acid.

12. 1. A radiopharmaceutical composition comprising: １７７ 1. A radiopharmaceutical composition comprising: 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 20% L-ascorbic acid, and a specific activity of 61 GBq or less in a total volume of 6 to 8 mL of solution.

13. 12. The radiopharmaceutical composition of claim 11, wherein the ascorbic acid has a pH of 3.5 to 4.

5.

14. 12. The radiopharmaceutical composition of claim 11, wherein the solution has a pH of 3.5 to 4.

5.

15. 12. The radiopharmaceutical composition of claim 11, further comprising 1.5 ml of ethanol-water in a 1:1 (v / v) ratio.

16. 1. A method of administering a radiopharmaceutical composition, said method comprising injecting said radiopharmaceutical composition into a patient in need thereof more than 48 hours after formulation, said radiopharmaceutical composition comprising: １７７ A method comprising comprising Lu-PSMA I&T and ascorbic acid in a solution having a pH of 3.5-4.5, said solution having a radiochemical purity of greater than 96% when administered.

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

2.

18. 17. The method of claim 16, wherein the composition comprises less than 6 μg of Lu-PSMA I&T per mL of solution.

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

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

21. 17. The method of claim 16, wherein the composition comprises about 0.5 GBq or about 13.5 mCi of radioactivity per mL of solution.

22. 17. The method of claim 16, wherein the composition comprises about 31 mg / ml ascorbic acid.

23. 17. The method of claim 16, wherein the solution has a radiochemical purity of at least 98% after 44 hours from formulation, at least 97% after 69 hours from formulation, and / or at least 97% after 93 hours from formulation.

24. 17. The method of claim 16, wherein upon administration of the composition to a patient, the patient maintains low levels of hematologic and nephrotoxicity and experiences a reduction in prostate specific antigen of greater than about 50%.

25. 1. A method of treating a patient having mCRP in need thereof, said method comprising: More than 48 hours after formulation １７７ administering a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in a solution having a pH of 3.5 to 4.5; wherein said solution has a radiochemical purity of greater than 96% when administered.

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

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

28. 28. The method of claim 27, wherein the patient has an rPFS of about 6 to 12 months.

29. 26. The method of claim 25, wherein the patient has improved overall survival (OS).

30. 30. The method of claim 29, wherein the patient has an OS of about 18 to 25 months.

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

32. 26. The method of claim 25, wherein the patient has improved progression-free survival.

33. 26. The method of claim 25, wherein the patient has improved second progression-free survival.

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

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

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

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

38. 26. The method of claim 25, wherein the patient has improved results on a quality of life questionnaire.

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

2.

40. 26. The method of claim 25, wherein the composition comprises less than 6 μg of Lu-PSMA I&T per mL of solution.

41. 26. The method of claim 25, 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.

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

43. 26. The method of claim 25, wherein the solution has a radiochemical purity of at least 98% after 44 hours from formulation, at least 97% after 69 hours from formulation, and / or at least 97% after 93 hours from formulation.

44. 26. The method of claim 25, wherein upon administration of the composition to a patient, the patient maintains low levels of hematologic and nephrotoxicity and experiences a reduction in prostate specific antigen of greater than about 50%.

45. 1. A radiopharmaceutical composition comprising: １７７ 1. A radiopharmaceutical composition comprising 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 in a solution having a pH of 3.5 to 4.5, said solution being suitable for administration more than 48 hours after formulation and having a radiochemical purity of greater than 96% when administered.

46. 1. A radiopharmaceutical composition comprising: １７７ 1. A radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid, said composition formulated as an injectable solution having a pH of 3.5 to 4.5, said solution being suitable for administration more than 48 hours after formulation.

47. 47. The radiopharmaceutical composition of claim 46, wherein the solution is suitable for administration up to 3 days after formulation.

48. 47. The radiopharmaceutical composition of claim 46, wherein the solution is suitable for administration up to 4 days after formulation.

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

50. 47. The radiopharmaceutical composition of claim 46, wherein the solution comprises 42.5 mg / ml ascorbic acid.

51. 47. The radiopharmaceutical composition of claim 46, wherein the solution further comprises hydrochloric acid.

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

53. 47. The radiopharmaceutical composition of claim 46, wherein the solution has a pH of 3.5 to 4.

2.

54. 47. The radiopharmaceutical composition of claim 46, wherein the solution has a pH of 3.5 to 4.

0.

55. 47. The radiopharmaceutical composition of claim 46, wherein the solution has a radioactivity of less than 635 MBq / ml.

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

57. 47. The radiopharmaceutical composition of claim 46, wherein the solution has a radiochemical purity of greater than 95% 46-48 hours after formulation.

58. 58. The radiopharmaceutical composition of claim 57, wherein the solution has a radiochemical purity of greater than 96% 46-48 hours after formulation.

59. 58. The radiopharmaceutical composition of claim 57, wherein the solution has a radiochemical purity of greater than 97% 46-48 hours after formulation.

60. 47. The radiopharmaceutical composition of claim 46, wherein the solution has a radiochemical purity of greater than 95% 69-71 hours after formulation.

61. 61. The radiopharmaceutical composition of claim 60, wherein the solution has a radiochemical purity of greater than 96% 69-71 hours after formulation.

62. 61. The radiopharmaceutical composition of claim 60, wherein the solution has a radiochemical purity of greater than 97% 69-71 hours after formulation.

63. 47. The radiopharmaceutical composition of claim 46, wherein the solution has a radiochemical purity of greater than 95% 90-93 hours after formulation.

64. 64. The radiopharmaceutical composition of claim 63, wherein the solution has a radiochemical purity of greater than 96% 90-93 hours after formulation.

65. 64. The radiopharmaceutical composition of claim 63, wherein the solution has a radiochemical purity of greater than 97% 90-93 hours after formulation.

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

67. 47. The radiopharmaceutical composition of claim 46, further comprising a metal ion chelator.

68. 68. The radiopharmaceutical composition of claim 67, wherein said metal ion chelator is disodium EDTA.

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

70. 47. The radiopharmaceutical composition of claim 46, further comprising a stabilizer.

71. 71. The radiopharmaceutical composition of claim 70, wherein the stabilizing agent is ethanol.

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

73. 47. The radiopharmaceutical composition of claim 46, further comprising 31 mg / ml ascorbic acid and an amount of hydrochloric acid adjusted so that the solution has a pH of 3.5 to 4.

5.

74. 74. The radiopharmaceutical composition of claim 73, further comprising 10.5 μg / mL disodium EDTA and 37.5 μL / mL ethanol.

75. 74. The radiopharmaceutical composition of claim 73, further comprising sodium bicarbonate and NaOH in amounts sufficient to control the pH at 4.

5.

76. 76. The radiopharmaceutical composition of claim 75, wherein the solution has a radioactivity of 588.5 MBq / ml.

77. 74. The radiopharmaceutical composition of claim 73, wherein the solution has a radiochemical purity of at least 98% after 44 hours from formulation, at least 97% after 69 hours from formulation, and / or at least 97% after 93 hours from formulation.

78. 47. The radiopharmaceutical composition of claim 46, wherein upon administration of said composition to a patient, said patient maintains low levels of hematotoxicity and nephrotoxicity and experiences a reduction in prostate specific antigen of greater than about 50%.

79. 47. The radiopharmaceutical composition of claim 46, wherein the composition has a radioactivity of 1,270 MBq / ml to about 1,311 MBq / ml.

80. 1. A radiopharmaceutical composition comprising: １７７ 1. A radiopharmaceutical composition comprising Lu-PSMA I&T, about 31 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 in a solution having a pH of 3.5 to 4.5, said solution having a radiochemical purity of greater than 95% when administered.

81. 81. The radiopharmaceutical composition of claim 80, wherein said composition has a high radioactivity of about 1,278 MBq / ml to about 1,311 MBq / ml.

82. 81. The radiopharmaceutical composition of claim 80, wherein said composition has a low radioactivity of about 579 MBq / ml to about 626 MBq / ml.

83. 81. The radiopharmaceutical composition of claim 80, wherein Lu-PSMA I&T is present in said composition at a concentration of less than about 12 μg / ml.

84. The composition comprises a colloidal solution containing less than about 5% of the radioactivity. １７７ 81. The radiopharmaceutical composition of claim 80, comprising Lu.

85. 81. The radiopharmaceutical composition of claim 80, wherein said composition has less than about 17.5 EU / ml of bacterial endotoxin.

86. 81. The radiopharmaceutical composition of claim 80, wherein the composition has a shelf life of greater than 24 hours after formulation.

87. 87. The radiopharmaceutical composition of claim 86, wherein the composition has a shelf life of greater than 48 hours after formulation.

88. 88. The radiopharmaceutical composition of claim 87, wherein the composition has a shelf life of greater than 72 hours after formulation.

89. 1. A radiopharmaceutical composition comprising: １７７ Injectable formulation containing Lu-PSMA I&T, ascorbic acid, and ethanol １７７ Lu-PSMA I&T solution, The aforementioned １７７ the Lu-PSMA I&T is radioactive in sufficient quantity for its intended use; the total amount of ascorbic acid in the solution is about 210-700 mg, the total amount of ethanol in the solution is about 274-706 mg, and the pH of the solution is about 5 or less; administering the composition to a subject causes the subject to maintain low levels of hematologic and nephrotoxic toxicity; A radiopharmaceutical composition that reduces prostate specific antigen by more than about 50%.

90. For injection １７７ 1. A radiopharmaceutical composition comprising a Lu-PSMA I&T solution, (a) in an amount of about 5 μg / ml to about 15 μg / ml １７７ Lu-PSMA-I&T and (b) ascorbic acid at a concentration of about 10 mg / ml to about 50 mg / ml; (c) ethanol at a concentration of about 1% (v / v) to about 10% (v / v); the pH of the solution is from about 3 to about 5; A radiopharmaceutical composition, wherein upon administration of said composition to a subject, said subject maintains low levels of hematotoxic and nephrotoxic toxicity.

91. 91. The radiopharmaceutical composition of claim 90, wherein said composition has a radioactivity of less than about 300 mCi.

92. 91. The radiopharmaceutical composition of 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. 91. The radiopharmaceutical composition of 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. 91. The radiopharmaceutical composition of claim 90, wherein said composition has a radioactive content of from about 70% to about 130%.

95. 95. The radiopharmaceutical composition of claim 94, wherein the composition provides a mean systemic effective dose of about 23±20 Gy (3.3 Gy / GBq) after administration to a subject in need thereof.

96. 91. The radiopharmaceutical composition of claim 90, wherein the composition is sterile.

97. 91. The radiopharmaceutical composition of claim 90, wherein the composition has a volume of from about 1 ml to about 50 ml.

98. 91. The radiopharmaceutical composition of claim 90, wherein said composition has a radiochemical purity of at least 97% as measured by HPLC at 0 hours EOS.

99. For injection １７７ 1. A radiopharmaceutical composition comprising a Lu-PSMA I&T solution, (a) in an amount of about 5 μg / ml to about 15 μg / ml １７７ Lu-PSMA I&T and (b) ascorbic acid at a concentration of about 10 mg / ml to about 50 mg / ml; (c) ethanol at a concentration of about 1% (v / v) to about 10% (v / v); (d) a chelating agent in an amount of about 0.001% to about 0.15% (w / w) of the total weight of the radiopharmaceutical composition; the pH of the solution is from about 3 to about 5; A radiopharmaceutical composition, wherein upon administration of said composition to a subject, said subject maintains low levels of hematotoxic and nephrotoxic toxicity.

100. 100. The radiopharmaceutical composition of claim 99, wherein the composition has a radioactivity of less than about 500 mCi.

101. 100. The radiopharmaceutical composition of 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. 100. The radiopharmaceutical composition of 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. 100. The radiopharmaceutical composition of 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. 100. The radiopharmaceutical composition of claim 99, wherein said composition has a radioactive content of from about 70% to about 130%.

105. 100. The radiopharmaceutical composition of claim 99, wherein the composition provides a mean systemic effective dose of about 23±20 Gy (3.3 Gy / GBq) after administration to a subject in need thereof.

106. 100. The radiopharmaceutical composition of claim 99, wherein the composition is sterile.

107. 100. The radiopharmaceutical composition of claim 99, wherein the composition has a volume of from about 1 ml to about 50 ml.

108. 100. The radiopharmaceutical composition of claim 99, wherein said composition has a radiochemical purity of at least 97% as measured by HPLC at 0 hours EOS.

109. 1. A radiopharmaceutical kit comprising: １７７ for injection into a human patient in need of an injection of Lu-PSMA I&T solution. １７７ A radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, said injection comprising a 7.4 GBq±0.1 GBq dose.

110. 110. The radiopharmaceutical kit of claim 109, wherein said vial is a sterile pyrogen-free glass vial of type 1 glass with a fluorine-coated bromobutyl rubber septum.

111. 111. The radiopharmaceutical kit of claim 110, wherein the septum is sealed with a crimped aluminum capsule.

112. 110. The radiopharmaceutical kit of claim 109, further comprising a lead-shielded shipping container, wherein said glass vial is maintained within the lead-shielded container during shipping.

113. 113. The radiopharmaceutical kit of claim 112, wherein said lead-shielded shipping container complies with Type A requirements (IAEA standard).

114. 110. The radiopharmaceutical kit of claim 109, wherein the vial contains multiple doses.

115. The aforementioned １７７ 110. The radiopharmaceutical kit of claim 109, wherein the Lu-PSMA I&T solution has a volume of 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 aforementioned １７７ 110. The radiopharmaceutical kit of claim 109, wherein the Lu-PSMA I&T solution has a strength of 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 aforementioned １７７ 110. The radiopharmaceutical kit of claim 109, wherein the Lu-PSMA I&T solution is suitable for administration to a human patient in need thereof more than 72 hours after formulation, more than 96 hours after formulation, or more than 100 hours after formulation.

118. The aforementioned １７７ 110. The radiopharmaceutical kit of claim 109, wherein the Lu-PSMA I&T solution has a pH of 3.5 to 4.

5.

119. 1. A method of diagnosing or treating a tumor in a patient in need thereof, said method comprising: １７７ 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein 20 hours after injection, the radiopharmaceutical composition has an activity of at least 20% IA to 30% IA in the body.

120. 120. The method of claim 119, wherein 40 hours after injection, the radiopharmaceutical composition has an activity in the system of at least 10% IA to 20% IA.

121. 120. The method of claim 119, wherein 60 hours after injection, the radiopharmaceutical composition has an activity in the system of at least 5% IA to 10% IA.

122. 1. A method of diagnosing a tumor in a patient in need thereof, said method comprising administering to said patient: １７７ 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity in the kidney of at least 8% IA to 10% IA within 20 hours after injection.

123. 123. The method of claim 122, wherein 20 hours after injection, the radiopharmaceutical composition has an activity in the kidney of at least 3% IA to 8% IA.

124. 123. The method of claim 122, wherein 40 hours after injection, the radiopharmaceutical composition has an activity in the kidney of at least 1% IA to 5% IA.

125. 123. The method of claim 122, wherein 60 hours after injection, the radiopharmaceutical composition has an activity in the kidney of at least 1% IA to 5% IA.

126. 1. A method of diagnosing a tumor in a patient in need thereof, said method comprising administering to said patient: １７７ 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity of at least 0.7% IA to 1% IA in the parotid gland within 20 hours after injection.

127. 127. The method of claim 126, wherein 20 hours after injection, the radiopharmaceutical composition has an activity in the parotid gland of at least 0.3% IA to 0.8% IA.

128. 127. The method of claim 126, wherein 40 hours after injection, the radiopharmaceutical composition has an activity in the parotid gland of at least 0.2% IA to 0.5% IA.

129. 127. The method of claim 126, wherein 60 hours after injection, the radiopharmaceutical composition has an activity in the parotid gland of at least 0.1% IA to 0.3% IA.

130. 1. A method of diagnosing a tumor in a patient in need thereof, said method comprising administering to said patient: １７７ 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity of at least 0.2% IA to 0.5% IA in lymph node lesions in the patient within 20 hours or less after injection.

131. 131. The method of claim 130, wherein 20 hours after injection, the radiopharmaceutical composition has an activity of at least 0.1% IA to 0.3% IA in the lymph node lesions.

132. 131. The method of claim 130, wherein 40 hours after injection, the radiopharmaceutical composition has an activity of at least 0.08% IA to 0.2% IA in the lymph node lesions.

133. 131. The method of claim 130, wherein 60 hours after injection, the radiopharmaceutical composition has an activity of at least 0.05% IA to 0.1% IA in the lymph node lesions.

134. 1. A method of diagnosing a tumor in a patient in need thereof, said method comprising administering to said patient: １７７ 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an activity of at least 0.1% IA to 0.4% IA in bone lesions in the patient within 20 hours after injection.

135. 135. The method of claim 134, wherein 20 hours after injection, the radiopharmaceutical composition has an activity of at least 0.1% IA to 0.2% IA in the bone lesion.

136. 135. The method of claim 134, wherein 40 hours after injection, the radiopharmaceutical composition has an activity of at least 0.05% IA to 0.1% IA in the bone lesion.

137. 135. The method of claim 134, wherein 60 hours after injection, the radiopharmaceutical composition has an activity of at least 0.02% IA to 0.05% IA in the bone lesion.

138. 1. A method of diagnosing a tumor in a patient in need thereof, said method comprising administering to said patient: １７７ administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the radiopharmaceutical composition has an effective half-life in the patient's systemic tissue of about 30 to 40 hours.

139. 139. The method of claim 138, wherein the effective half-life of the radiopharmaceutical composition is from about 25 hours to about 35 hours in the kidney of the patient.

140. 139. The method of claim 138, wherein the effective half-life of the radiopharmaceutical composition is from about 20 hours to about 30 hours in the patient's parotid gland.

141. 139. The method of claim 138, wherein the effective half-life of the radiopharmaceutical composition is from about 45 hours to about 55 hours in the patient's bone lesion.

142. 139. The method of claim 138, wherein the effective half-life of the radiopharmaceutical composition is from about 35 hours to about 45 hours in the patient's lymph node lesion.

143. 1. A method of diagnosing a tumor in a patient in need thereof, said method comprising administering to said patient: １７７ 1. A method comprising administering by injection a radiopharmaceutical composition comprising Lu-PSMA I&T and ascorbic acid in solution at a pH of 3.5 to 4.5, wherein the average absorbed dose of the radiopharmaceutical is about 0.01 mGy / MBq to 0.5 mGy / MBq in the patient's whole body.

144. 144. The method of claim 143, wherein the average absorbed dose of the radiopharmaceutical composition is about 0.5 mGy / MBq to 1.0 mGy / MBq in the kidneys of the patient.

145. 144. The method of claim 143, wherein the average absorbed dose of the radiopharmaceutical composition is between about 1 mGy / MBq and 1.5 mGy / MBq in the patient's parotid gland.

146. 144. The method of claim 143, wherein the average absorbed dose of the radiopharmaceutical composition is about 2.5 mGy / MBq to 3.5 mGy / MBq in the patient's bone lesion.

147. 144. The method of claim 143, wherein the average absorbed dose of the radiopharmaceutical composition is about 3.5 mGy / MBq to 4.5 mGy / MBq in the patient's lymph node lesions.

148. 1. A radiopharmaceutical kit comprising: １７７ for injection into a human patient in need of an injection of Lu-PSMA I&T solution. １７７ A radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, said injection containing a dose of 7.1 GBq or more.

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