Identification and / or treatment of cancer

Abstract

The present invention relates generally to the identification and / or treatment of cancers and in particular cancers in which gastrin-releasing peptide receptors (GRPR) are expressed. In particular embodiments, the invention relates to the identification and / or treatment of prostate cancer, and in particular of metastatic castration-resistant prostate cancer expressing GRPR.

Description

[0001] Field

[0002] The present invention generally relates to the identification and / or treatment of cancer, and particularly cancers in which gastrin-releasing peptide receptor (GRPR) is expressed. In certain embodiments, the present invention relates to prostate cancer, and particularly the identification and / or treatment of metastatic castration-resistant prostate cancer expressing GRPR.

[0003] Background

[0004] Prostate cancer (PCa) is the second most common malignancy among men worldwide. The American Cancer Society estimates that in 2022 in the United States of America (USA) 268,490 new cases of PCa will be diagnosed, accounting for approximately 27% of all newly estimated cancer cases in men and approximately 14% of all newly estimated cancer cases. The incidence of PCa is age-related, with a rate of 30% in patients aged 40 - 50 years and 50 - 80% in patients 80 years and older. The median age of patients diagnosed with PCa is 67 years, and the median age at death is 81 years. The cause of the disease is unknown; the main risk factors include advanced age, race, and positive family history. Many patients with PCa have indolent disease, in which the serum prostate-specific antigen (PSA) value of the patient is tracked without further treatment. At initial presentation, 74% of patients have local disease, 13% have regional disease, and 7% have metastatic disease, with the remaining 6% classified as unknown. Since 2000, the 5-year relative survival rate for local or regional PCa has exceeded 97%. However, for metastatic (distant) PCa, the 5-year survival rate drops sharply to 30%. Twenty to forty percent of patients will experience elevated PSA levels (biochemical recurrence or failure) within 10 years of primary PCa treatment. Approximately 25 - 35% of patients with recurrent disease have local recurrence, 20 - 25% have metastatic disease, and 45 - 55% have both.

[0005] Gastrin-releasing peptide receptor (GRPR) is a transmembrane G protein-coupled receptor with multiple physiological functions in the gastrointestinal tract and nervous system. By binding to its ligand gastrin-releasing peptide (GRP), its pharmacological activities include stimulating the release of hormones such as gastrin and somatostatin, as well as contraction of gastric and intestinal smooth muscle. Gastrin-releasing peptide receptor expression is upregulated in many human cancers (including PCa, breast cancer, glioma, ovarian cancer, lung cancer, and gastrinoma and gastrointestinal stromal tumors [GIST]), and its normal biological distribution is mainly concentrated in the pancreas and gastrointestinal tract. Although the correlation between GRPR expression and clinical features in PCa (such as Gleason score, disease stage, and PSA level) has been evaluated, the results remain inconclusive. In fact, recent studies have shown that in biochemically recurrent PCa, uptake of gallium-68-labeled GRPR-targeting agents at all PSA levels (68 Ga-RM2)

[0006] Several GRPR-targeted imaging and theranostic agents are under clinical investigation, but none are widely available or have been approved by regulatory agencies to date. Expression of GRPR in PCa has been reported, with expression found in 75 - 100% of analyzed samples. Additionally, clinical studies using GRPR-targeted imaging agents such as 68 Ga-RM2, 68 Ga-NeoB or 68 Ga-SB3 have reported high uptake in primary Pca lesions as well as metastases, and positive / detection rates of 31% to 100% measured in several studies. Clinical treatment studies targeting GRPR have not been reported to date. However, 177 the first-in-human dosimetry study of 177 Lu-RM2 in patients with metastatic castration-resistant prostate cancer (mCRPC) who were ineligible for 177 Lu-PSMA-617 therapy showed that 4.5 GBq of 177 Lu-RM2 was well tolerated by all 4 patients and no side effects were observed. Treatment-related absorbed doses to the tumor were recorded, while rapid clearance from normal organs was observed.

[0007] There is a need to improve patient outcomes in cancers expressing gastrin-releasing peptide receptor (GRPR), including prostate cancer patients, and especially those diagnosed with mCRPC who are ineligible for 177 Lu-PSMA-617 therapy. SUMMARY OF THE INVENTION

[0009] The present inventors have developed a radiolabeled GRPR antagonist for the diagnosis and treatment of prostate cancer. The product is copper-complexed MeCOSar-PEG4-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (Cu-SAR-BBN). Cu-SAR-BBN uses a radioactive form of copper (radionuclide) (copper-64( 64 Cu)) to image cancer using positron emission tomography (PET), and subsequently uses copper-67( 67 Cu) for treatment via internal β-radiation. This "theranostic" approach is well established in neuroendocrine tumors with the following approved products: for imaging or Detectnet TM and for treatment These products consist of DOTA-octreotate, which targets somatostatin receptor-positive lesions, but use different radionuclides (gallium-68 68 Ga] for imaging or 64 Cu and lutetium-177 177 Lu] for therapy). Similarly, prostate-specific membrane antigen (PSMA) targeting agents ( 68 Ga-PSMA-11) and Pluvicto TM ( 177 Lu-PSMA-617) have recently been approved by the USA-FDA as an imaging agent for patient selection and a therapeutic agent for metastatic castration-resistant prostate cancer (mCRPC), respectively. Targeted radionuclide therapy achieves an anti-tumor effect because a higher dose of radiation than that used for diagnostic purposes is administered, and the radionuclides used for therapy impart much higher energy to cellular structures such as deoxyribonucleic acid (DNA), resulting in target cell cytotoxicity. The efficacy of this therapy depends on delivering the highest possible radiation dose to the tumor while sparing normal organs and tissues from damage. This is achieved by highly specific, high-affinity binding to receptors overexpressed on the tumor. A variety of GRPR-targeted radiopharmaceuticals for therapy are disclosed herein. No clinical studies using 67 Cu-labeled products have been reported so far. The inventors have confirmed that 67 Cu has properties similar to 177 Lu; both emit beta minus particles with similar maximum energies (577 keV 30 and 498 keV 31 ) and thus have potentially similar ranges in tissue. In addition, preclinical efficacy studies in tumor-bearing mice have shown that 67 Cu tracers are as effective as 177 Lu tracers.

[0010] Accordingly, a first aspect of the present invention provides a method of treating and diagnosing a patient suffering from cancer expressing GRPR, the method comprising the step of administering an effective amount of a compound of formula (I) complexed to 67 Cu radioisotope or a pharmaceutically acceptable salt thereof:

[0011]

[0012] wherein R is CH3C(O)-;

[0013] ( 67 Cu-SAR-BBN)

[0014] and

[0015] The radiation dose delivered by the radioactive isotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0016] In certain embodiments, cancers expressing GRPR are selected from prostate cancer, breast cancer, glioma, ovarian cancer, lung cancer, and gastrinoma and gastrointestinal stromal tumors (GIST).

[0017] In a second aspect, the present invention provides a method of treating a patient diagnosed with metastatic castration-resistant prostate cancer expressing GRPR, the method comprising administering an effective amount of a compound of formula (I) complexed to 67 a Cu radioactive isotope or a pharmaceutically acceptable salt thereof:

[0018] wherein R is CH3C(O)-;

[0019] ( 67 (64)Cu-SAR-BBN)

[0020] and

[0021] wherein the radiation dose delivered by the radioactive isotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0022] In a third aspect, the present invention further provides a method of treating a patient diagnosed with metastatic castration-resistant prostate cancer expressing GRPR, the patient not being suitable for treatment with 177 Lu-PSMA-617, the method comprising administering an effective amount of a compound of formula (I) complexed to 67 a Cu radioactive isotope or a pharmaceutically acceptable salt thereof:

[0023]

[0024] wherein R is CH3C(O)-;

[0025] ( 67 (64)Cu-SAR-BBN)

[0026] and

[0027] wherein the radiation dose delivered by the radioactive isotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0028] In a fourth aspect, the present invention provides a method of identifying and treating a patient diagnosed with metastatic castration-resistant prostate cancer expressing GRPR, the method comprising the steps of:

[0029] (i) administering an effective amount of a compound complexed to 64A compound of formula (I) of a Cu radioisotope or a pharmaceutically acceptable salt thereof:

[0030]

[0031] wherein R is CH3C(O)-;

[0032] ( 64 (Cu-SAR-BBN)

[0033] and

[0034] wherein the radiation dose delivered by said 64 Cu radioisotope is sufficient to identify one or more lesions associated with said cancer; and

[0035] (ii) Administering an effective amount of a compound of formula (I) of a Cu radioisotope or a pharmaceutically acceptable salt thereof complexed to 67 a Cu radioisotope:

[0036]

[0037] wherein R is CH3C(O)-;

[0038] ( 67 (Cu-SAR-BBN)

[0039] and

[0040] wherein the radiation dose delivered by said 67 Cu radioisotope is sufficient to reduce the size of said one or more lesions associated with said cancer.

[0041] In a fifth aspect, the present invention provides a method for identifying and treating a patient diagnosed with metastatic castration-resistant prostate cancer expressing GRPR, said patient not being suitable for treatment with 177 Lu-PSMA-617, said method comprising the steps of:

[0042] (i) Administering an effective amount of a compound of formula (I) of a Cu radioisotope or a pharmaceutically acceptable salt thereof complexed to 64 a Cu radioisotope:

[0043]

[0044] wherein R is CH3C(O)-;

[0045] ( 64 (Cu-SAR-BBN)

[0046] and

[0047] wherein the radiation dose delivered by said 64The radiation dose delivered by the Cu radioisotope is sufficient to identify one or more lesions associated with the cancer; and

[0048] (ii) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to 67 a Cu radioisotope:

[0049]

[0050] wherein R is CH3C(O)-;

[0051] ( 67 (Cu-SAR-BBN)

[0052] and

[0053] wherein the radiation dose delivered by the 67 Cu radioisotope is sufficient to reduce the size of the one or more lesions associated with the cancer.

[0054] In certain embodiments and with reference to all aspects, the stereochemistry of the peptide portion of the compound of formula (I) is depicted as follows:

[0055]

[0056] In some embodiments of the present invention, the radiation dose delivered by the 64 Cu radioisotope to identify one or more lesions is between about 100 MBq and about 300 MBq. In certain embodiments, the radiation dose delivered by the 64 Cu radioisotope to identify one or more lesions is about 100 MBq, about 120 MBq, about 140 MBq, about 160 MBq, about 180 MBq, about 200 MBq, about 220 MBq, about 240 MBq, about 260 MBq, about 280 MBq or about 300 MBq.

[0057] In certain embodiments of the present invention, the radiation dose provided by the 67 Cu radioisotope to reduce the size of one or more lesions associated with the cancer is about 4 GBq, about 6 GBq, about 8 GBq, about 10 GBq, about 12 GBq, about 14 GBq, about 16 GBq, about 18 GBq, about 20 GBq, about 22 GBq or about 24 GBq.

[0058] In certain embodiments of the methods for treating cancer as disclosed herein, the compound of formula (I) complexed to the 67 Cu radioisotope is administered once. In other embodiments, the compound complexed to the 67more than once a compound of formula (I) complexed with a Cu radioisotope. In other embodiments, a compound of formula (I) complexed with a 67 Cu radioisotope is administered to the same subject two, three, four, or five times.

[0059] As discussed above, the compounds of formula (I) target the gastrin-releasing peptide receptor (GRPR), which is associated with multiple cancer types. In certain embodiments, the cancer is breast cancer. In other embodiments, the cancer is a specific subset or type of breast cancer. In some embodiments, the breast cancer is associated with the expression of one or more of estrogen, progesterone, or the HER2 receptor.

[0060] Different subtypes of breast cancer exhibit different levels of sensitivity to conventional 18 FDG-PET imaging, which means that 18 the use of FDG-PET imaging may not necessarily identify all breast cancer lesions. For example, when compared to the triple-negative (i.e., ER / PR / HER2 negative) subtype, 18 FDG has lower sensitivity for ER+ / PR+ breast cancer. As Figures 1 to 6 shown, subjects showing metastatic ER+ / PR+ / HER2− clinical progression are imaged by 18 FDG-PET and 64 64Cu-Sar-BBN imaging. Compared to conventional imaging using FDG, combined patient analysis of images taken after administration of 64 64Cu-Sar-BBN shows a higher average total tumor volume, SUV max and total number of lesions. This indicates that the use of 64 64Cu-Sar-BBN can provide a more comprehensive assessment of lesions in a subject. For example, Figure 2 a subject with classical lobular breast cancer with widespread metastases throughout is shown, and the calculated average total tumor volume is four times higher than the tumor volume calculated by 18 FDG imaging. In Figure 4 , fewer than 3 lesions were identified by conventional imaging with FDG, but imaging of the same subject after administration of 64 64Cu-Sar-BBN identified at least 19 lesions.

[0061] On the other hand, the present invention provides a method for predicting a patient's response to treatment with a 67Method for the treatment of cancer with a Cu-complexed compound of formula (I), said method comprising detecting and counting circulating tumor DNA (ctDNA) associated with one or more genes in said patient and correlating the amount of detected ctDNA with the response of the patient to said treatment, wherein said cancer is a cancer expressing GRPR and wherein said one or more genes are selected from BRCA1, BRCA2, RB and p53.

[0062] Method for predicting the response of a patient to treatment with 67 Cu means that a compound of formula (I) may not be administered to the patient 67 Cu, especially when the ctDNA detected in the patient indicates that the induced response will not result in a decrease in the size of one or more lesions of the cancer associated with this group.

[0063] Summary of the drawings

[0064] Figure 1 . Patients with metastatic ER+ / PR+ / HER2-invasive ductal breast cancer whose clinical progression requires restaging are imaged with 18 FDG-PET (A). 200 MBq of 64 Cu-Sar-BBN is administered to the same patient and imaged by PET (B).

[0065] Figure 2 . Patients with metastatic ER+ / PR+ / HER2-classical lobular breast cancer whose clinical progression requires restaging are imaged with 18 FDG-PET (A). 200 MBq of 64 Cu-Sar-BBN is administered to the same patient and imaged by PET (B). Biopsy of the patient shows metastases in the liver. Administration of 64 Cu-Sar-BBN shows a higher SUV by PET imaging than by conventional FDG means max . By 64 The total tumor volume detected by Cu-Sar-BBN is approximately four times higher than that imaged with FDG, strongly indicating that the identification of cancerous lesions can be achieved by 64 Cu-Sar-BBN. The figure also shows that lesions not detected by conventional FDG imaging can be localized with 64 Cu-Sar-BBN.

[0066] Figure 3 . Patients with metastatic ER+ / PR+ / HER2-invasive ductal breast cancer whose clinical progression requires restaging are imaged with 18 FDG-PET (A). 200 MBq of 64Cu-Sar-BBN and imaged by PET (B). Biopsy of the patient showed metastases in the liver. Using 64 Cu-Sar-BBN imaging revealed lesions not detected by conventional FDG imaging.

[0067] Figure 4 . Patients with metastatic ER+ / PR+ / HER2-invasive ductal breast cancer whose clinical progression requires restaging were imaged with 18 FDG-PET (A). 200 MBq of 64 Cu-Sar-BBN was administered to the same patient and imaged by PET (B). Biopsy of the patient showed metastases in the chest wall. By 64 Cu-Sar-BBN, the total tumor volume detected was higher than that by FDG imaging, strongly indicating that the identification of cancerous lesions can be achieved by 64 Cu-Sar-BBN.

[0068] Figure 5 . Patients with metastatic ER+ / PR+ / HER2-classic lobular breast cancer whose clinical progression requires restaging were imaged with 18 FDG-PET (A). 200 MBq of 64 Cu-Sar-BBN was administered to the same patient and imaged by PET (B). Maximum intensity projections and axial slices of the patient after imaging with 18 FDG-PET (C) and 64 Cu-Sar-BBN PET (D) are also provided. Biopsy of the patient showed metastases in the skin. By 64 Cu-Sar-BBN imaging did identify various tumors throughout the patient, while conventional imaging with FDG revealed no tumors. This also strongly indicates that the identification of cancerous lesions can be achieved by 64 Cu-Sar-BBN.

[0069] Figure 6 . Patients with metastatic ER+ / PR+ / HER2-invasive ductal breast cancer whose clinical progression requires restaging were imaged with 18 FDG-PET (A). 200 MBq of 64 Cu-Sar-BBN was administered to the same patient and imaged by PET (B). Biopsy of the patient showed metastases in the pleura. Using 64 Cu-Sar-BBN imaging revealed lesions not detected by conventional FDG imaging.

[0070] Figure 7 . Patients with prostate cancer after radical prostatectomy showed consecutive negative PSMA-PET, as with 68Determined by Ga-PSMA-11 imaging (A). Other imaging modalities, such as bone scan (B) and 18 FDG-PET (C) also failed to identify any recurrent lesions. The patient was administered 200 MBq of 64 Cu-Sar-BBN, and the resulting PET images (D and E) revealed the presence of additional lesions. Imaging with 64 Cu-Sar-BBN revealed lesions not detected by conventional imaging modalities.

[0071] Figure 8 . Prostate cancer patients after radical prostatectomy showed consecutive negative PSMA-PET, as determined by 68 Ga-PSMA-11 imaging (A). Other imaging modalities, such as bone scan (B) also failed to identify any recurrent lesions. The patient was administered 200 MBq of 64 Cu-Sar-BBN, and the resulting PET images (C and D) revealed the presence of additional lesions in the prostate.

[0072] Figure 9 . Prostate cancer patients after radical prostatectomy showed consecutive negative PSMA-PET, as determined by 68 Ga-PSMA-11 imaging (A). The patient was administered 200 MBq of 64 Cu-Sar-BBN, and the resulting PET images (B and C) revealed the presence of additional lesions in the prostate not detected by conventional imaging modalities.

[0073] Figure 10 . Prostate cancer patients after radical prostatectomy showed consecutive negative PSMA-PET, as determined by 68 Ga-PSMA-11 imaging (A and B). The patient was administered 200 MBq of 64 Cu-Sar-BBN, and the resulting PET image (C) revealed the presence of additional lesions not detected by conventional imaging modalities. DETAILED DESCRIPTION OF THE INVENTION

[0075] Throughout this specification and the following claims, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of the stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0076] As used herein, the term "about" or "substantially" refers to an acceptable error range of a particular value as determined by a person of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0077] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For the purposes of this invention, the following terms are defined as follows.

[0078] As used herein, reference to 177 Lu-PSMA-617 refers to the following compound:

[0079]

[0080] As used herein, in certain embodiments, a patient is not suitable for 177 Lu-PSMA-617 therapy. As used herein, a person skilled in the art can determine such a group of patients based on the following criteria: 68 Ga-PSMA-11 or 18 the uptake of F-DCFPyL in one or more lesions is negative (equal to or lower than the uptake of the liver parenchyma), or any lesion larger than the size criteria is negative [size criteria: organ ≥ 1 cm, lymph node ≥ 2.5 cm, bone (soft tissue component) ≥ 1 cm].

[0081] 68 Ga-PSMA-11 is:

[0082]

[0083] 18 F-DCFPyL is:

[0084]

[0085] In some embodiments, the radiation dose delivered by 67 the Cu radioisotope is between about 6 GBq and about 56 GBq. In some embodiments, the radiation dose delivered by 67 the Cu radioisotope is about 6 GBq, about 10 GBq, or about 14 GBq. In some embodiments, the radiation dose delivered by 67 the Cu radioisotope is more than about 14 GBq. In some embodiments, the radiation dose delivered by 67 the Cu radioisotope is about 20 GBq, about 25 GBq, about 30 GBq, about 35 GBq, about 40 GBq, about 45 GBq, about 50 GBq, or about 55 GBq. In other embodiments, the radiation dose delivered by 67The radiation dose delivered by the Cu radioisotope is the highest dose tolerable by the subject.

[0086] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer expressing GRPR (GRPRmCRPC), and in certain embodiments is progressive GRPRmCRPC, despite prior androgen deprivation therapy and at least enzalutamide and / or abiraterone (or other such androgen receptor pathway inhibitors).

[0087] In another embodiment, the patient is a male subject with a castrate level of serum / plasma testosterone of approximately <50 ng / dL or approximately <1.7 nmol / L.

[0088] In another embodiment, the patient is a male subject who had a prostate-specific antigen (PSA) value of 50 or higher for more than 3 weeks prior to administration of a compound of formula (I) complexed to a 67 Cu radioisotope or a pharmaceutically acceptable salt thereof.

[0089] In another embodiment, relative to a baseline taken prior to each treatment, after one, two, three, or four treatment administration cycles of a compound of formula (I) complexed to a 67 Cu radioisotope or a pharmaceutically acceptable salt thereof, the patient experiences a decrease in the percentage of PSA and / or alkaline phosphatase (ALP) and / or lactate dehydrogenase (LDA) biomarkers.

[0090] In another embodiment, the method comprises administering to the subject an effective amount of a compound of formula (I) complexed to a 67 Cu radioisotope or a pharmaceutically acceptable salt thereof in 1, 2, 3, or 4 treatment cycles.

[0091] In additional embodiments, the method comprises administering to the subject an aqueous formulation of a compound of formula (I) complexed to a 67 Cu radioisotope or a pharmaceutically acceptable salt thereof, with at least 2 administrations, spaced approximately 6 to 14 weeks apart, by intravenous (IV) slow infusion over about 30 minutes to about 60 minutes to provide a dose at the 6 - 14 GBq level. In other embodiments, the method comprises administering to the subject at least 3 times. In other embodiments, the method comprises administering to the subject at least 4 times.

[0092] In one embodiment, the method further comprises performing radioimaging of the subject by PET, SPECT, and / or CT, preferably after each treatment cycle, and preferably by PET using 64 Cu-SAR-BBN.

[0093] In one embodiment, a positive PET and / or CT scan is based on 64 visualization of a 64Cu-SAR-BBN (Formula (I)) PET / CT scan, wherein the 64Cu-SAR-BBN uptake (standardized uptake value [SUV] 64 ) of at least 1 known lesion on a 1-hour positron emission tomography (PET) / computed tomography (CT) scan is higher than the uptake of the gastrointestinal tract. max ) is higher than the uptake of the gastrointestinal tract.

[0094] The inventors believe that, after administration of a 64Cu-complexed compound of Formula (I) according to the above aspects, an image of a subject obtained by PET and / or CT can indicate or at least assist in determining the 64 corresponding dose of the 64Cu-complexed compound of Formula (I) for treating metastatic castration-resistant prostate cancer expressing GRPR. Thus, one benefit of the present invention is that the same BBN-linked compound can be used for a complete diagnostic (identification) treatment regimen by replacing the 64Cu radioisotope with 67 67Cu with 64 67Cu replaced by 67 64Cu.

[0095] Thereby, the inventors also believe that administration of more than one dose (i.e., multiple treatment cycles) of the compounds and formulations described herein for treating metastatic castration-resistant prostate cancer expressing GRPR results in greater accumulation of the radioisotope at the target site. Without wishing to be bound by theory, the inventors believe that using the radiolabeled compounds described herein allows delivery of a greater dose of radiation without increasing the expected adverse reactions. This thus results in greater therapeutic efficacy. The diagnostic (identification) methods previously disclosed herein can be used before or between treatment cycles to evaluate the effectiveness of the treatment.

[0096] Without wishing to be bound by theory, the inventors believe that administering more than one administration dose of the formulations described herein for the treatment of metastatic castration-resistant prostate cancer expressing GRPR results in a higher absorbed radiation dose at the cancer site, which results in greater therapeutic efficacy. This means that repeated administration of a formulation containing a compound of formula (I) complexed with a radioisotope can result in a higher survival rate for the subject when compared to a single administration of the formulations disclosed herein. In one embodiment, the method comprises sequential administration of more than one dose of the compounds described in the first and second aspects. In some embodiments, the sequential doses are administered at intervals of about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks or about 16 weeks (such as at intervals of about 4 to 14 weeks). In one embodiment, the sequential doses are administered at an interval of about 6 weeks. In one embodiment, the total radiation dose delivered to the subject's bone marrow is less than about 2 Gy. In another embodiment, the total radiation dose delivered to the subject's kidneys is less than about 23 Gy.

[0097] The treatment methods of aspects one and two can include administering multiple doses of a 67 Cu complex of a compound of formula (I) and a radioisotope, wherein the doses administered are the same or different. In some embodiments, when administering multiple doses, the second dose and any subsequent doses can be higher than the original dose. In some embodiments, multiple doses are administered, wherein the doses are the same. In another embodiment, multiple doses are administered, wherein the doses are different. Those skilled in the art will understand that since the methods discussed herein incorporate the use of radioisotopes, there is a maximum total radiation dose that can be given to a subject. In some embodiments, multiple doses are administered until the cumulative radiation dose delivered to the subject's kidneys reaches about 23 Gy. In some embodiments, multiple doses are administered until the cumulative radiation dose delivered to the subject's bone marrow reaches about 2 Gy.

[0098] In certain embodiments, 64 / 67 the Cu-complexed compound of formula (I) is administered as an aqueous formulation intended for intravenous (IV) administration. In another embodiment, the aqueous formulation is administered by slow infusion. In a preferred embodiment, the aqueous formulation is administered intravenously by slow infusion, for example, between about 30 - 60 minutes.

[0099] In certain embodiments, 64 the Cu-complexed compound of formula (I) is administered as an aqueous formulation intended for intravenous (IV) slow bolus administration.

[0100] In certain embodiments, 67The Cu-complexed compound of formula (I) is administered as an aqueous formulation intended to be administered by slow intravenous (IV) infusion over about 30 minutes - 60 minutes, and preferably 30 minutes.

[0101] The methods disclosed herein include administering a radioisotope that emits ionizing radiation. Since the kidneys are responsible for blood filtration, the kidneys of a subject to whom a formulation comprising a compound of formula (I) and a radioisotope has been administered are at risk of absorbing unwanted radiation due to the active reabsorption and retention of the radiolabeled compound of formula (I). Prevention of nephrotoxicity can be achieved by co-administering a cationic amino acid that competitively inhibits the reabsorption of the compound of formula (I) (and thereby the radioisotope). In some embodiments, the method of the second aspect further includes administering a formulation comprising one or more amino acids or salts thereof. In some embodiments, the one or more amino acids are in cationic form. In some embodiments, the formulation comprising one or more amino acids comprises lysine or a salt thereof. In other embodiments, the formulation comprising one or more amino acids comprises arginine or a salt thereof. In a preferred embodiment, the method includes administering a formulation comprising lysine and arginine, or salts thereof.

[0102] The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the compounds identified above and includes pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) can be prepared from inorganic acids or organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Suitable organic acids can be selected from organic acids of aliphatic, alicyclic, aromatic, heterocyclic carboxylic and sulfonic acid classes, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, and arylsulfonic acid. Pharmaceutically acceptable salts also include those in which the primary compound acts as an acid and reacts with a suitable base to form, for example, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, and choline salts. Those skilled in the art will further recognize that acid addition salts can be prepared by reaction of the compound with a suitable inorganic or organic acid via any of a large number of known methods. Alternatively, alkali metal salts and alkaline earth metal salts can be prepared by reaction of the compound with a suitable base via various known methods. The following are additional examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate. Additional information on pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case where the reagent is a solid, it is understood by those skilled in the art that the compounds, reagents, and salts of the present invention can exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified general formula.

[0103] The compound preparation of the present invention for injection comprises a pharmaceutically acceptable sterile aqueous solution. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. The preparation may also contain excipients such as preservatives, wetting agents, emulsifying agents and dispersing agents. By including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenolsorbic acid, etc., prevention of microbial action can be ensured. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form can be achieved by including agents that delay absorption such as aluminum monostearate and gelatin. The injectable preparation can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use. The pharmaceutical preparation may further contain a pH control agent. Examples of suitable pH control agents include hydrochloric acid, sodium hydroxide, etc. Confirmation of the preferred pH range (where appropriate) and suitable excipients is routine in the art, for example as described in Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press).

[0104] The preparation of the present invention as disclosed herein can be provided in a pharmaceutically acceptable carrier or diluent. As will be understood by those skilled in the art, the choice of pharmaceutically acceptable carrier or diluent will depend on the route of administration and the nature of the condition to be treated and the subject. Those skilled in the art can readily determine a particular carrier or diluent and the route of administration. The carrier or diluent and the route of administration should be carefully selected so as to ensure the activity of the compound of formula (I) when it reaches the site of action.

[0105] Pharmaceutical forms suitable for injection include sterile injectable solutions or dispersions and sterile powders for the preparation of sterile injectable solutions. Such forms should be stable under the conditions of manufacture and storage and should be protected against reduction, oxidation and microbial contamination. For injection, the compositions of the present invention can be formulated in an aqueous solution, suitably in a physiologically compatible buffer such as Hanks' solution, Ringer's solution or physiological saline buffer.

[0106] For the treatment of metastatic castration-resistant prostate cancer expressing GRPR, the compound of formula (I) is combined with 67Cu radioisotope complexation. The inventors have found that the sarcophagine fragment of formula (I) has a strong affinity for copper isotopes and is capable of complexing and retaining the radioisotope for a time sufficient for therapeutic purposes even after administration to a subject. The 67 Cu radioisotope has a half-life of approximately 60 hours and undergoes β decay, making the isotope suitable for local radiotherapy. Since 67 the decay of the Cu radioisotope is accompanied by γ radiation, the treatment of a subject with a compound of formula (I) complexed with 67 Cu can be monitored and imaged by single photon emission computed tomography (SPECT). In one embodiment, a method for treating a subject in need thereof by administering a compound of formula (I) complexed with 67 Cu includes monitoring and / or imaging by SPECT. Other imaging techniques, such as MRI and CT, can also be used during the treatment. In a preferred embodiment, the method for treatment includes imaging by SPECT and / or CT.

[0107] For the purpose of radioimaging, the delivered radiation dose should be sufficient to provide an image of sufficient quality without administering an excessive amount to the patient. For the purpose of radioimaging, the radiation dose to be administered (and subsequently the amount of the radiolabeled compound of formula (I) complexed with the 64 Cu radioisotope) can be determined based on the body weight of the subject. For the purpose of treatment, the radiation dose to be administered and delivered to the subject by the 67 Cu radioisotope can be determined based on the body weight of the subject and the image quality obtained by radioimaging after administering a compound of formula (I) complexed with the 64 Cu radioisotope. In some embodiments, the radiolabeled compound of formula (I) complexed with the 64 Cu radioisotope is used to simulate the distribution of the corresponding compound of formula (I) complexed with the 67 Cu radioisotope.

[0108] The units of radioactivity enumerated herein are given in gray (Gy) or becquerel (Bq). It will be understood that known conversion factors can be used to convert the radiation dose from one unit to another, and other units of the amount of radioactivity not explicitly enumerated herein can also be used.

[0109] As used herein, the terms "treating" or "treatment" and grammatical equivalents refer to any and all uses that address the cancer, prevent, delay or defer the establishment of a disease, or otherwise prevent, impede, delay or reverse disease progression. Thus, the terms "treatment" and the like should be considered in their broadest context. For example, treatment does not necessarily mean that the patient is treated until completely recovered. When a disease presents or is characterized by multiple symptoms, treatment or prevention does not necessarily need to address, prevent, impede, delay or reverse all of the stated symptoms, but can prevent, impede, delay or reverse one or more of the stated symptoms.

[0110] As used herein, the term "cancer" broadly encompasses neoplastic diseases characterized by abnormal cell growth with the potential to invade or spread to other parts of the body. Cancers can be benign, which do not spread to other parts of the body. Cancers can be malignant, meaning that cancer cells can spread through the circulatory system or the lymphatic system. The term as used herein includes all malignant (i.e., cancerous) disease states. Cancers can exist as tumors.

[0111] As used herein, the term "tumor" refers to any malignant cancerous or pre-cancerous cell growth. The term specifically relates to solid tumors or carcinomas. When cancer is present in the prostate, the cancer is referred to as "prostate cancer", which is typically characterized by elevated and / or increased serum prostate-specific antigen (PSA) levels, overexpression of the PSMA membrane protein. A subject may have prostate cancer, wherein the cancer is a primary cancer and is distributed in the prostate. Prostate cancer can metastasize and spread to other parts of the subject. A subject may also have recurrent prostate cancer, which is characterized by an increase in PSA within 10 years of treatment of the primary prostate cancer.

[0112] Treatment or imaging with 64 Cu / 67 Cu-Sar-BBN of other types of GRPR-expressing cancers includes prostate cancer, breast cancer, glioma, ovarian cancer, lung cancer, and gastrinoma and gastrointestinal stromal tumors (GIST).

[0113] There are multiple forms of prostate cancer, each characterized by the location of the cancer, the cell types involved in the cancer (i.e., histology), and the level of prostate-specific antigen (PSA) in the patient. Prostate cancer can also be described by the stage and / or grade of the cancer, e.g., according to the Gleason score, the size and / or location of the tumor, the presence of one or more tumors in the lymph nodes, and the degree of metastasis. One form of prostate cancer includes metastatic castration-resistant prostate cancer (mCRPC). Recorded progressive mCRPC is based on at least one or more of the following criteria:

[0114] a. Serum / plasma prostate-specific antigen (PSA) progression, defined as two consecutive increases in PSA compared to a previous reference value measured at least 1 week earlier. The minimum value is 2.0 ng / mL;

[0115] b. Soft tissue progression, defined as an increase in the sum of diameters (SOD) of all target lesions (short axis for nodular lesions and long axis for non-nodular lesions) of ≥20% or the appearance of one or more new lesions based on the smallest SOD since the start of the last treatment for metastatic cancer (excluding hormone therapy); and

[0116] c. Bone disease progression: disease assessable by bone scan or new (one or more) bone lesions;

[0117] d. They express GRPR (positive 64 Cu-SAR-BBN scan) and meet one of the above criteria defining GRPR-positive mCRPC.

[0118] There are also multiple forms of breast cancer, which are characterized based on whether the cancer is invasive or non-invasive, the location of the cancer, and the presence / sensitivity of certain receptors on the cancer cells. For example, non-invasive breast cancer has abnormal cells contained within the mammary ducts (ductal type) or lobules (lobular type) of the breast and has not spread to the surrounding tissues, while the invasive form of the same cancer has spread to the surrounding tissues. The types of breast cancer can be classified based on the receptors present on the cancer cells. For example, hormone receptor-positive breast cancer shows sensitivity to estrogen and / or progesterone, while HER2-positive breast cancer shows an increase in the human epidermal growth factor receptor 2 (HER2) on the cell surface. Breast cancer can also be classified based on whether the cancer is contained within the lymph nodes or has spread to the lymph nodes or more distant parts of the body.

[0119] The methods disclosed herein for treating cancer include treating breast cancer that expresses GRPR, which can be further characterized according to the subtypes discussed above.

[0120] As used herein, the term "patient" refers to a mammal and includes humans, primates, domestic animals (e.g., sheep, pigs, cows, horses, donkeys), laboratory test animals (e.g., mice, rabbits, rats, guinea pigs), sport and performing animals (e.g., horses, livestock, dogs, cats), companion animals (e.g., dogs, cats), and captive wild animals. Preferably, the mammal is a human or a laboratory test animal. Even more preferably, the mammal is male.

[0121] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to achieve a beneficial or desired clinical outcome. The effective amount can be administered in one or more administrations. For the purpose of radioimaging, the effective amount is sufficient to display an image of the localization of the compound of formula (I) administered to a subject due to detection of decay products of a radioisotope complexed with the compound. For therapeutic purposes, the effective amount is typically sufficient to alleviate, ameliorate, stabilize, reverse, slow down and / or delay the progression of cancer.

[0122] Radiographic progression-free survival (rPFS) is defined as the time from the date of the first 67 Cu-SAR-BBN treatment to radiographic progression on a bone scan or radiographic soft tissue progression or death from any cause (whichever comes first). rPFS will be presented as Kaplan-Meier curves and summary statistics (median and rPFS at 6, 9, and 12 months). In certain embodiments, the method provides an rPFS of greater than 6 months to greater than 5 years.

[0123] In some embodiments, the effective amount is an amount effective to elicit one of the following:

[0124] Complete Response (CR): All target lesions disappear. The short axis of all pathological lymph nodes must have shrunk to <10 mm. All target lesions disappear. The short axis of any pathological lymph node (whether target or non-target) must have decreased to <10 mm;

[0125] Partial Response (PR): Taking the baseline sum diameter as a reference, the sum of the diameters of the target lesions is reduced by at least 30%.

[0126] The treatment regimen will generally include multiple treatment cycles (e.g., 1, 2, 3, 4, 5, or 6), and the cycles are continued until the condition improves. Again, the optimal number of cycles and the interval between each treatment cycle will depend on many factors, such as the height and weight of the subject, the severity of the condition being treated, the health (or lack thereof) of the subject being treated, and their prior response to radiotherapy and / or the extent of the condition as determined by radioimaging.

[0127] The formulations defined in this specification for use in a treatment method can be administered parenterally, preferably intravenously. In one embodiment, an aqueous formulation containing a radiolabeled compound of formula (I) is administered intravenously by bolus injection or infusion.

[0128] It will be understood that the specific dose of the radiolabeled compound of formula (I) for any particular subject will depend on a variety of factors including, for example, the age, weight and indication of the individual to be treated, the time of administration, the rate of excretion, and the combination with any other treatment or therapy. Single or multiple administrations can be carried out, where the dose level and pattern are selected by the treating physician. The dosing regimen can be adjusted to provide an optimal therapeutic response. For example, a given dose delivering a certain amount of radiation can be calculated as a fraction of the total radiation to be delivered to the subject. The dosing regimen can comprise administering multiple doses of the radiolabeled compound of formula (I), where the doses are the same or different. In some embodiments, the method for treating prostate cancer as described herein can include administering multiple doses of the compound of formula (I) complexed with the copper-67 radioisotope, where the doses are the same. In other embodiments, the method comprises administering multiple doses, where the second and subsequent doses are higher than the first dose administered to the subject. For example, the first dose can deliver a first dose level of approximately 6 GBq, and the second subsequent dose can deliver a dose of approximately 10 GBq. In some embodiments, the dose administered for the purpose of treatment or therapy is determined by prior radiological imaging of the subject, the prior radiological imaging being carried out by administering a compound of formula (I) complexed with 64 a Cu radioisotope in order to localize the cancer site, estimate the amount of the compound retained by the subject (and thus the amount of radioactivity subsequently delivered), and evaluate the nature of the cancer site. The inventors believe that the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for both radiological imaging and radiotherapy represents a method for the diagnosis and treatment of metastatic castration-resistant prostate cancer expressing GRPR.

[0129] That is to say, the method for radiological imaging and treatment of metastatic castration-resistant prostate cancer expressing GRPR, where the compound of formula (I) has different isotopes administered, the methods disclosed herein represent a method for the diagnosis and treatment of such cancers, i.e., a method for treatment and diagnosis (identification). This is because the administration of the compound of formula (I) can also be complexed with a radioisotope that allows radiological imaging of the subject, while administering a compound complexed with 67Compounds of formula (I) complexed with Cu allow the treatment of a subject. The radioimaging allows the visualization (identification) of the location where the compounds of formula (I) accumulate, which location then corresponds to the site of treatment. Without wishing to be bound by theory, the inventors believe that the methods and uses disclosed herein allow for a more effective treatment of metastatic castration-resistant prostate cancer expressing GRPR. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a copper radioisotope enables the delivery of a higher dose of radioactivity in a single dose. Since the compound of formula (I) is specific for the GRPR membrane protein and retains the copper radioisotope for a longer time (when compared to other metal chelators), the radioactivity is delivered more effectively to the cancer site and localized. The compound of formula (I) also shows better clearance from key organs. This in turn reduces any off-target effects of the radioisotope and limits the undesirable damage to healthy tissue attributed to the dissociation and subsequent circulation of the radioisotope. The better clearance and retention of the radiolabeled compound of formula (I) at the targeted cancer site results in an image with higher contrast and subsequently a more reliable diagnostic image. The ability to deliver a more persistent radiation dose by administering a compound of formula (I) complexed with a copper radioisotope also results in an overall more effective treatment since a smaller amount of the compound of formula (I) and the radioisotope is required. In the case of delivering the required radiation in fewer doses, this results in better tolerance of the treatment by the subject.

[0130] The present invention also contemplates combination therapies, wherein a radiolabeled compound of formula (I) as described herein is co-administered with other suitable agents that may facilitate the desired treatment outcome. The term "co-administered" means administered simultaneously or sequentially via the same or different routes in the same formulation or in two different formulations. The term "concomitant" means the administration of more than one formulation, wherein the formulations are administered to the subject simultaneously. The term "simultaneously" means that the active agents are administered substantially at the same time. The term "sequential" administration means a time difference of seconds, minutes, hours or days between the administrations of the agents. The administrations can be carried out in any order.

[0131] Since the methods disclosed herein involve the administration of radioactive isotopes that emit ionizing radiation, co - administration of one or more amino acids with an aqueous formulation comprising a compound of formula (I) radiolabeled as disclosed herein can prevent or limit nephrotoxicity caused by the retention of the radiopharmaceutical. The one or more amino acids co - administered to a subject undergoing treatment for cancer associated with over - expression of the GRPR membrane protein competitively inhibit the re - absorption of the radiolabeled compound of formula (I) by the proximal tubules of the kidney. The inventors believe that limiting the re - uptake of the radiolabeled compound of formula (I) and thus reducing the nephrotoxicity of the subject enables the administration of higher doses of said compound and thus increases the treatment efficiency. The methods for treating cancer as disclosed herein further comprise administering to the subject one or more amino acids or salts thereof. In one embodiment, a formulation comprising one or more amino acids or salts thereof is co - administered with an aqueous formulation comprising a compound of formula (I) complexed with a 67 Cu radioisotope. In one embodiment, the one or more amino acids comprise lysine or a salt thereof. In another embodiment, the one or more amino acids comprise arginine or a salt thereof. In a preferred embodiment, the method for treating cancer further comprises administering lysine and / or arginine, or salts thereof. In a preferred embodiment, the method for treating cancer further comprises administering lysine and arginine, or salts thereof. In a preferred embodiment, the method for treating cancer as disclosed herein further comprises co - administering lysine and arginine or salts thereof and a compound of formula (I) complexed with a 67 Cu radioisotope. In some embodiments, the one or more amino acids, or salts thereof, are administered in the form of an intravenous infusion. In some embodiments, the formulation comprising one or more amino acids comprises L - lysine or a salt thereof. In other embodiments, the formulation comprising one or more amino acids comprises L - arginine or a salt thereof. In some embodiments, the one or more amino acids are present as hydrochloride salts. In some embodiments, the one or more amino acids are each present at a concentration of about 2.5% w / v.

[0132] The method of the present invention may further comprise administering an anti - emetic. In one embodiment, the method of the present invention further comprises administering an anti - emetic to the subject. In some embodiments, the anti - emetic and a compound of formula (I) complexed with 67 Cu are administered simultaneously or prior thereto.

[0133] The treatment methods as disclosed herein comprise administering a formulation comprising a compound of formula (I) complexed with 67 Cu. The formulation may be administered intravenously, for example, by slow intravenous infusion. The treatment methods disclosed herein may comprise a single administration of a formulation comprising a compound of formula (I) complexed with 67Formulations of Cu-complexed compounds of formula (I), or administration of the same or different formulations more than once. In one embodiment, a method for treating cancer comprises administering a dose of an aqueous formulation comprising a compound of formula (I) complexed with 67 Cu. In another embodiment, the method comprises administering two doses of an aqueous formulation comprising a compound of formula (I) complexed with 67 Cu. In another embodiment, the method comprises administering three doses of an aqueous formulation comprising a compound of formula (I) complexed with 67 Cu. In another embodiment, the method comprises administering four doses of an aqueous formulation comprising a compound of formula (I) complexed with 67 Cu. When four doses are administered, 67 the maximum planned cumulative administered activity of Cu-SAR-BBN will not exceed the critical organ dose limits (23 Gy for the kidney and 2 Gy for the bone marrow) over 4 administrations.

[0134] When more than one administration is required, the interval between formulation doses can be between about 6 weeks and about 14 weeks. In one embodiment, the method comprises administering more than one dose of an aqueous formulation comprising a compound of formula (I) complexed with 67 Cu, wherein the dose interval is about 6 weeks. In another embodiment, the method comprises administering more than one dose, wherein the dose interval is about 8 weeks. In another embodiment, the method comprises administering more than one dose, wherein the dose interval is about 10 weeks. In another embodiment, the method comprises administering more than one dose, wherein the dose interval is about 12 weeks. In another embodiment, the method comprises administering more than one dose, wherein the dose interval is about 14 weeks. In some embodiments, the methods for treatment discussed herein comprise administering two or more doses of a formulation comprising a compound of formula (I) complexed with 67 Cu, wherein the time between doses can be the same. In some embodiments, the method comprises administering two or more doses of the formulation, wherein the time between doses is approximately the same, e.g., about 6 weeks between each dose, about 8 weeks between each dose, about 10 weeks between each dose, about 12 weeks between each dose, or about 14 weeks between each dose. In other embodiments, the time between doses can be different, e.g., about 6 weeks between the first and second doses and about 8 weeks between the second and third doses. Other embodiments of the time between different doses are also contemplated, wherein the time between two consecutive doses can be about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks or about 16 weeks.

[0135] In one embodiment, a method for treating metastatic castration-resistant prostate cancer expressing GRPR comprises administering a dose of a formulation comprising a compound of formula (I) complexed with 67 Cu. In some embodiments, the formulation comprising a compound of formula (I) complexed with 67 Cu is administered more than once, and the formulations administered each time are the same or different. When the formulations are different, the compounds of formula (I) complexed with 67 Cu in each formulation may deliver different doses of radioactivity, such as approximately 6 GBq, approximately 10 GBq, approximately 14 GBq, approximately 18 GBq, approximately 22 GBq, or approximately 24 GBq. In one embodiment, an aqueous formulation of a compound of formula (I) complexed with 67 Cu administered for a method of treating cancer associated with overexpression of the GRPR membrane antigen delivers a radiation dose between approximately 6 GBq and approximately 24 GBq to a subject. In one embodiment, an aqueous formulation of a compound of formula (I) complexed with 67 Cu administered for a method of treating cancer associated with overexpression of the GRPR membrane antigen delivers a radiation dose between approximately 6 GBq and approximately 14 GBq to a subject. In one embodiment, the aqueous formulation delivers a dose of approximately 4 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 6 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 8 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 9 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 10 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 12 GBq. In yet another embodiment, the aqueous formulation delivers a dose of approximately 14 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 16 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 18 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 20 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 22 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 24 GBq.

[0136] Alternatively, by a compound complexed with 67The dose of radioactivity delivered by the Cu-complexed compound of formula (I) is the maximum dose tolerated by an individual subject. Those skilled in the art will understand that the maximum tolerated dose will vary between subjects. The inventors have found that administering a compound of formula (I) complexed with a radioisotope suitable for imaging not only allows visualization of the distribution and uptake of the radiolabeled compound, but also enables the subject to tolerate a given dose. In cases where the subject appears to tolerate the dose well and other physiological measurements (such as liver and kidney function) are satisfactory, this information can be used to determine a higher dose of radiation specific to the subject. In one embodiment, the methods disclosed herein include assessing the subject's tolerance to the Cu-complexed compound of formula (I) and modifying the dose of radioactivity delivered to the subject in subsequent doses. Those skilled in the art will appreciate that a variety of techniques can be used, including nuclear imaging, comparing baseline levels of radiation, and levels after administration of the Cu-complexed compound of formula (I) to determine uptake, comparison of lesion size and number before and after administration, and monitoring of biochemical markers by one or more diagnostic assays of tissue. 67 Cu-complexed compound of formula (I) and modifying the dose of radioactivity delivered to the subject in subsequent doses. Those skilled in the art will understand that a variety of techniques can be used, including nuclear imaging, comparing baseline levels of radiation, and levels after administration of the Cu-complexed compound of formula (I) to determine uptake, comparison of lesion size and number before and after administration, and monitoring of biochemical markers by one or more diagnostic assays of tissue. 67 Cu-complexed compound of formula (I) to determine uptake, comparison of lesion size and number before and after administration, and monitoring of biochemical markers by one or more diagnostic assays of tissue.

[0137] The present invention thus also provides a method for treating metastatic castration-resistant prostate cancer expressing GRPR, wherein the dose of the Cu-complexed compound of formula (I) administered to the subject is specific to the subject and is determined by a combination of imaging and physiological assay techniques. In one embodiment, the dose is determined by administering to the subject a compound of formula (I) complexed with a suitable radioisotope and then imaging the subject for a period of time to obtain one or more images that can be used to determine the suitability of the administered dose for the subject. In some embodiments, the imaging can be performed by one or more techniques such as PET, SPECT, CT, and MRI. Without wishing to be bound by theory, the inventors believe that the methods disclosed herein allow for a more precise and personalized regimen for treating patients with metastatic castration-resistant prostate cancer expressing GRPR and for diagnosing cancer in patients with metastatic castration-resistant prostate cancer expressing GRPR who are not suitable for treatment with 67 Lu-PSMA-617. 177 Lu-PSMA-617.

[0138] In another aspect, the present invention provides a method for predicting a patient's response to treatment with a 67Method for treating cancer with a Cu-complexed compound of formula (I), said method comprising detecting and counting circulating tumor DNA (ctDNA) associated with one or more genes in said patient, and correlating the amount of detected ctDNA with the patient's response to said treatment, wherein said cancer is a cancer expressing GRPR, and wherein said one or more genes are selected from BRCA1, BRCA2, RB and p53.

[0139] In one embodiment, said cancer expressing GRPR is selected from prostate cancer, breast cancer, glioma, ovarian cancer, lung cancer, gastrinoma and gastrointestinal stromal tumor (GIST).

[0140] As used herein, the term "circulating tumor DNA" (ctDNA) refers to DNA fragments released from cancer cells (e.g., tumor cells) of a cancer patient into the blood of said patient via apoptosis, necrosis or active release.

[0141] According to the method for predicting a patient's response to treatment with a Cu-complexed compound of formula (I) as disclosed herein, the patient's ctDNA is obtained and quantified by appropriate means. The nature and amount of ctDNA analyzed will depend on the nature of the patient and the cancer. Once determined, comparison of the nature and amount of ctDNA with a reference value can predict whether the patient is likely (or not likely) to respond to treatment with a Cu-complexed compound of formula (I). 67 Once determined, comparison of the nature and amount of ctDNA with a reference value can predict whether the patient is likely (or not likely) to respond to treatment with a Cu-complexed compound of formula (I). 67 treatment with a Cu-complexed compound of formula (I).

[0142] In certain embodiments, the ctDNA analyzed is related to BRCA1. In other embodiments, the ctDNA analyzed is related to BRCA2. In other embodiments, the ctDNA analyzed is related to RB. In other embodiments, the ctDNA analyzed is related to p53.

[0143] Any reference in this specification to any prior publication (or information derived therefrom) or to any matter known is not, and should not be taken as, an admission or acknowledgment or any form of suggestion that the prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field of endeavor to which this specification pertains.

[0144] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications falling within its spirit and scope. The invention also includes all steps, features, compositions and compounds referred to or indicated in this specification, singly or jointly, and any and all combinations of any two or more of said steps or features. Examples

[0145] The following examples are illustrative of the present disclosure and should not be construed in any way as limiting the general nature of the disclosure of the specification throughout this specification.

[0146] Example 1 - Preparation 64 Cu-SAR-BBN and 67 Cu-SAR-BBN

[0147] The synthesis of SAR-BBN begins with the solid-phase synthesis of a linear 9-amino acid chain (peptide), followed by the coupling of a PEG spacer and a (Boc) 4-5 MeCOSar solution-phase chelator on the resin. The final capping step with Z-L-Ala-OH terminates any peptide chains that did not couple with (Boc) 4-5 MeCOSar. The completed peptide is cleaved from the resin and globally deprotected, purified by reverse-phase high-performance liquid chromatography (RP-HPLC), and the salt is exchanged for acetate.

[0148] Solid-phase peptide synthesis

[0149] Amino acids are added sequentially via a proven chemical sequence that includes: deprotection of the terminal amino group, activation of the carboxyl group of the next amino acid, and subsequent washing of the resulting peptide before starting the next step. The peptide (Boc) 4-5 MeCOSar-(PEG)4-D-Phe-Gln(Trt)-Trp(Boc)-Ala-Val-Gly-His(Trt)-Sta-Leu-Rink Resin is prepared using an 11-cycle method.

[0150] Resin cleavage and global deprotection

[0151] In the presence of a cation scavenger, the resin-bound fully protected SAR-BBN peptide is treated with trifluoroacetic acid to cleave the peptide from the resin and remove all acid-labile protecting groups, namely the Boc group of MeCOSar and the orthogonal protecting groups of the peptide. Subsequently, the solution of the crude product is freeze-dried using the following sequence: the product solution is pre-frozen (-60 °C) as a crust on the inner surface of a round-bottom flask and placed on a vacuum manifold at ambient temperature. The maximum achievable vacuum (0.1 - 0.4 mbar) is applied to the freeze-dryer until the product is confirmed dry by manual inspection of solid ice, typically after 30 to 48 hours. The crude product MeCOSar-(PEG)4-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 is then analyzed by RP-HPLC to confirm the quality of the material and by mass spectrometry to confirm complete deprotection (removal of all Boc groups) of the product.

[0152] Purification

[0153] The crude SAR-BBN is then purified by preparative RP-HPLC as the trifluoroacetate salt. Fractions from each purification run are collected in tubes and analyzed by analytical HPLC; fractions of acceptable purity are combined and freeze-dried under the same conditions.

[0154] Acetate exchange

[0155] The trifluoroacetate form is exchanged to the acetate form by preparative RP-HPLC using an eluent system of ammonium acetate and acetic acid (AcOH) in water / acetonitrile.

[0156] Freeze-drying of bulk material

[0157] The bulk SAR-BBN acetate is freeze-dried under the conditions described above for the crude SAR-BBN. The product is weighed into screw-cap storage bottles, vacuum-sealed and stored refrigerated, and subsequently aliquoted into vials in the desired amounts for radiolabeling.

[0158] is prepared by adding 64 Cu]CuCl2 (1000 - 2000 MBq, 100 - 500 μL, 0.05 M HCl) to SAR-BBN (60 μg) in a solution of 5 mL of sodium phosphate buffer (0.1 M, pH 6.5 - 7.0) containing sodium gentisate (5.7 mg) 64Cu-SAR-BBN. The reaction mixture was incubated at room temperature for 25 minutes and then the reaction mixture was filtered through a 0.22 μm filter into a sterile product vial. The reaction was quenched by adding 10 mL of an aqueous 7.5% ethanol solution containing sodium ascorbate (1.17 g) via a 0.22 μm filter into the sterile product vial. 64 Cu-SAR-BBN was produced with an average radiochemical yield of 84% and a radiochemical purity greater than 95%.

[0159] Cu-SAR-BBN was prepared by adding 64 Cu]CuCl2 (6000 - 12000 MBq, 100 - 500 μL, 0.05 M HCl) to SAR-BBN (120 μg) in 14 mL of a sodium phosphate buffer solution (0.1 M, pH 6.5 - 7.0) containing sodium gentisate (11.4 mg). 67 Cu-SAR-BBN. The reaction mixture was incubated at room temperature for 25 minutes and then the reaction mixture was filtered through a 0.22 μm filter into a sterile product vial. The reaction was quenched by adding 13 mL of an aqueous 8% ethanol solution containing sodium ascorbate (2.27 g) via a 0.22 μm filter into the sterile product vial. 64 Cu-SAR-BBN was produced with an average radiochemical yield of 86% and a radiochemical purity greater than 95%.

[0160] Example 2 - Non-clinical studies

[0161] A number of non-clinical studies were conducted to determine the biodistribution, in vivo safety and tolerance, and tumor imaging and efficacy of SAR-BBN labeled with natural stable Cu( nat Cu), 64 Cu or 67 Cu.

[0162] PCa xenograft mouse models were injected with 64 Cu-Sar-BBN, which showed high uptake and retention of the radiolabeled compound over a 24-hour period (19.6% injected activity (IA) / g at 1 hour post-injection and 7.9% IA / g at 24 hours). In similar preclinical models, these results were favorable compared to other GRPR-targeting ligands.

[0163] 67 Preclinical efficacy data of Cu-SAR-BBN in mice showed statistically significant tumor growth inhibition and improved survival rates compared to the control group in PCa xenograft studies.

[0164] Male and female mice were administered weekly by intravenous (IV) injection for 4 weeks to conduct a repeated dose toxicology study of the compound of formula (I). Abnormal clinical signs were observed only on the injection days in the mice administered nat Cu-Sar-BBN. In male mice treated with 2 mg / kg nat Cu-Sar-BBN, fully reversible microscopic findings were observed, but these findings were not considered adverse, and no other clinical abnormalities, significant changes in body weight or food intake, or effects on hematology, blood biochemistry, or urine analysis were observed. This determined that no adverse event level was observed for both male and female mice for nat Cu-Sar-BBN at 2 mg / kg.

[0165] Example 3– 67 Biodistribution of Cu-SAR-BBN

[0166] The biodistribution of 67 Cu-SAR-BBN was studied in healthy male and female mice. In male (0.79 ± 0.22% IA / g) and female (1.06 ± 0.18% IA / g) mice, effective blood clearance of 67 Cu-SAR-BBN was confirmed at 1 hour, and it further decreased over time. The expression of GRPR in the pancreas led to high initial pancreatic uptake, with the highest cumulative activity at 1 hour in male and female mice (19.43 ± 9.98% IA / g and 22.32 ± 10.54% IA / g, respectively), and more than 75% and 97% of the 67 Cu-SAR-BBN activity in the pancreas was cleared at 4 and 24 hours, respectively. Similar rapid clearance curves were observed in other organs expressing GRPR, particularly the adrenal gland and the stomach. 67 Cu-SAR-BBN showed low uptake in the kidneys of male and female mice, even at 1 hour (3.79 ± 0.542% IA / g and 6.15 ± 0.73% IA / g, respectively), and it further decreased over time, indicating rapid renal clearance. Uptake in the liver and intestine indicated the presence of 67 hepatic-biliary clearance of

[0167] Full dosimetry calculations from the mouse biodistribution study enabled the extrapolation of organ radiation doses for adult males for both 67 therapeutic 64 Cu-SAR-BBN and 67For Cu-SAR-BBN, the maximum absorbed radiation dose is estimated to be 0.109 mGy / MBq for the liver, followed by the bladder wall at 0.641 mGy / MBq. Similarly, for 64 Cu-SAR-BBN, the maximum absorbed radiation doses are estimated to be the bladder wall and the liver, with values of 0.070 mGy / MBq and 0.040 mGy / MBq, respectively. 64 The effective whole-body dose for Cu-SAR-BBN is estimated to be 0.018 mSv / MBq for adult males.

[0168] These results show 64 Cu-SAR-BBN and 67 targeted delivery of Cu-SAR-BBN to the tumor site and show the therapeutic efficacy of the radiolabeled compound in GRPR-expressing cancers in humans.

[0169] Blood data show rapid clearance of blood pool activity and relatively rapid clearance of renal and hepatic activity. These dosimetric results suggest that the red bone marrow may be the dose-limiting organ for 67 Cu-SAR-BBN, with an estimated absorbed dose of 0.023 mGy / MBq. The pancreas was evaluated as the organ with the highest absorbed dose (0.303 mGy / MBq), while the absorbed dose of the kidneys was estimated to be 0.070 mGy / MBq. No clear dose limit for radiotherapy of the pancreas was given in the literature, and the pancreas has not been considered an organ at risk in radiotherapy planning.

[0170] The absorbed doses received from the planned administration activities of 67 Cu-SAR-BBN in this study were estimated for a 2 Gy bone marrow absorbed dose limit (shown in Table 1). To reach the 2 Gy kidney threshold, it has been estimated that an administration activity of 67 ~87 GBq of Cu-SAR-BBN needs to be administered to adult males. The proposed dose levels have a total administration activity range of 6 - 56 GBq, which will result in a total absorbed dose to the bone marrow of 0.138 - 1.288 Gy, which is well below the established limit at all proposed doses.

[0171] Example 4 - Formulation of Sar-BBN

[0172] The 64 Cu-Sar-BBN and 67 Cu-Sar-BBN were formulated as a sterile solution for intravenous (IV) injection suitable for human use.

[0173] The 64 Cu-SAR-BBN and 67Cu-SAR-BBN is stored at room temperature in a sealed, sterile, pyrogen-free glass vial with an expiration time indication on the label. 64 Cu-SAR-BBN and 67 The shelf life of Cu-SAR-BBN is shown on the product label.

[0174] Example 5 – Administration 64 Cu-Sar-BBN for radioimaging

[0175] A dose of 200 MBq of 64 Cu-Sar-BBN is administered to a subject by slow intravenous bolus injection. The subject is imaged by PET / CT, and the images are analyzed to determine the location, size, and volume of any cancerous lesions present, as indicated by the decay products of the 64 Cu radioisotope detected.

[0176] The images of the subject generated as described above are used to determine the suitability of the subject for treatment of cancer (if present) using 67 Cu-Sar-BBN.

[0177] Example 6 – Use of Conventional 18 FDG PET or 64 Cu-Sar-BBN PET for Diagnostic Imaging in Breast Cancer Patients

[0178] FDG is administered to women with metastatic ER+ / PR+ / HER2- breast cancer who require restaging due to clinical progression. Images of each patient are acquired by PET. Cu-Sar-BBN PET (administering 200 MBq of 18 Cu-Sar-BBN by intravenous (IV) injection) is performed within 2 weeks of imaging with 18 FDG. Qualitative interpretation of the PET studies is performed by a board-certified nuclear medicine physician. Quantitative analysis is performed using MIM software (Cleveland). Comparison of the images obtained from each subject after administration of both 64 FDG and 64 Cu-Sar-BBN can be seen in 18 FDG and 64 Cu-Sar-BBN (see Table 1). The figures show that Figures 1 to 6 Cu-Sar-BBN targeting the GRPR receptor localizes lesions in subjects that were not identified during imaging with other modalities. 64 Cu-Sar-BBN

[0179]

[0180] Table 1. In breast cancer patients using 18 FDG and64 Comparison of Imaging of Cu-Sar-BBN

[0181] Example 7 - Use of Conventional 18 FDG PET or 64 Diagnostic Imaging with Cu-Sar-BBN PET

[0182] Four men after radical prostatectomy showed biochemical recurrence with consecutive negative PSMA-PET ( 68 Ga-PSMA-11). The conventionally used imaging modalities including bone scan, CT and in some cases whole-body MRI also failed to identify the site of recurrence. All patients received an average of 200 MBq of 64 Cu]Cu-SAR-BBN intravenously over 60 minutes for uptake. Patients were scanned from 60 - 180 minutes after injection with arms raised from the top of the head to mid-thigh and for two minutes at each bed position. A low-dose CT scan was performed for attenuation correction and anatomical localization. In Figures 7 to 10 the comparison of images obtained from each subject after administration of 18 FDG and 64 Cu-Sar-BBN can be seen. These figures show that 64 Cu-Sar-BBN targeting the GRPR receptor localized lesions in subjects not identified during imaging with other modalities.

[0183] Example 8 - Eligibility of Subjects for Treatment with 67 Cu-Sar-BBN

[0184] In images of subjects who have received 64 Cu-Sar-BBN as obtained by PET / CT, the subject is considered eligible for treatment with 64 Cu-Sar-BBN because 67 Cu and 64 Cu are a therapeutic pair. 67 Cu-Sar-BBN

[0185] Example 9 - Administration of 67 Sar-BBN for Treatment

[0186] Compound of formula (I) complexed with 67 Cu radioisotope (i.e., 67 Cu-SarBBN) was administered at a dose of 6 GBq to subjects determined to have cancerous lesions associated with GRPR as identified by radioimaging after administration of 64 Cu-Sar-BBN.

[0187] Six weeks after the initial administration, an additional dose of 6 GBq is administered to the same patient.

[0188] After a period of at least two days (i.e., allowing for the elimination of 67 Cu-Sar-BBN), an additional dose of 200 MBq of 64 Cu-Sar-BBN is administered to the subject, and the subject's image is taken by PET / CT. The images taken after the administration of 64 Cu-Sar-BBN (before and after the administration of 67 Cu-Sar-BBN) are used to determine the progression of any lesions present in the subject.

[0189] Example 10 - Determining the efficacy of Sar-BBN efficacy assessment

[0190] Tumor response assessment

[0191] Tumor measurements for disease evaluation are performed using bone scans and CT / MRI, and the response is evaluated according to the PCWG3 (Prostate Cancer Working Group 3) guidelines. When a patient shows evidence of progression by a separate bone scan, a confirmatory scan (i.e., by administering 64 Cu-Sar-BBN and subsequent imaging) is performed and the images are further evaluated.

[0192] Example 11 - Quantitative analysis of scans

[0193] Evaluation 64 Cu-SAR-BBN PET / CT and baseline standard of care images are evaluated to identify the number of detected lesions. Lesion level analysis compares the number of GRPR-expressing lesions seen on the 64 Cu-SAR-BBN PET / CT screening scan with the number of lesions seen on the baseline standard of care images.

[0194] Baseline standard of care images for comparison:

[0195] · CT or MRI scans for soft tissue diseases.

[0196] · Bone scans for bone lesions.

[0197] Example 12 - Detecting and quantifying ctDNA

[0198] Blood is drawn from the patient and Analysis was performed using a circulating tumor cell kit (Janssen Diagnostics, Raritan, NJ). Subsequently, the volume / amount of the measured circulating tumor cells (CTCs) or ctDNA was compared with an expected value, such as that of a healthy patient or a value previously measured for the patient. The CTC count will be reported as:

[0199] · Advantageously, 4 cells or fewer per 7.5 mL of blood.

[0200] · Disadvantageously, if 5 cells or more per 7.5 mL of blood.

[0201] This CTC or ctDNA value was then correlated with prognosis and response to treatment.

Claims

1. A method for treating and diagnosing a patient suffering from a cancer expressing GRPR, said method comprising the step of administering an effective amount of a compound of formula (I) complexed to a 67 Cu radioisotope or a pharmaceutically acceptable salt thereof: wherein R is CH3C(O)-; ( 67 Cu-SAR-BBN and wherein the radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

2. The method according to claim 1, wherein the GRPR-expressing cancer is selected from prostate cancer, breast cancer, glioma, ovarian cancer, lung cancer, gastrinoma, and gastrointestinal stromal tumor (GIST).

3. A method of treating a patient diagnosed with metastatic castration-resistant prostate cancer expressing GRPR, the method comprising the step of administering an effective amount of a compound of formula (I) complexed to a 67 Cu radioisotope or a pharmaceutically acceptable salt thereof: wherein R is CH3C(O)-; ( 67 Cu-SAR-BBN and wherein the radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

4. A method of treating a patient diagnosed with metastatic castration-resistant prostate cancer expressing GRPR, said patient being unsuitable for treatment with 177 Lu-PSMA-617, said method comprising the step of administering an effective amount of a compound of formula (I) complexed to 67 a Cu radioisotope or a pharmaceutically acceptable salt thereof: wherein R is CH3C(O)-; ( 67 Cu-SAR-BBN and wherein the radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

5. A method of identifying and treating a patient diagnosed with a GRPR cancer, the method comprising the steps of: (i) Administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to 64 a Cu radioisotope: wherein R is CH3C(O)-; ( 64 Cu-SAR-BBN and wherein the radiation dose delivered by the 64 Cu radioisotope is sufficient to identify one or more lesions associated with the cancer; and (ii) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to 67 a Cu radioisotope: wherein R is CH3C(O)-; ( 67 Cu-SAR-BBN) and wherein the radiation dose delivered by the 67 Cu radioisotope is sufficient to reduce the size of the one or more lesions associated with the cancer.

6. A method of identifying and treating a patient diagnosed with metastatic castration-resistant prostate cancer expressing GRPR, the method comprising the steps of: (iii) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to 64 a Cu radioisotope: wherein R is CH3C(O)-; ( 64 Cu-SAR-BBN and wherein the radiation dose delivered by the 64 Cu radioisotope is sufficient to identify one or more lesions associated with the cancer; and (iv) Administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to 67 a Cu radioisotope: wherein R is CH3C(O)-; ( 67 Cu-SAR-BBN) and wherein the radiation dose delivered by the 67 Cu radioisotope is sufficient to reduce the size of the one or more lesions associated with the cancer.

7. A method for identifying and treating a patient diagnosed with metastatic castration-resistant prostate cancer expressing GRPR, who is not suitable for 177 treatment with Lu-PSMA-617, the method comprising the following steps: (iii) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to 64 a Cu radioisotope: wherein R is CH3C(O)-; ( 64 Cu-SAR-BBN and wherein the radiation dose delivered by the 64 Cu radioisotope is sufficient to identify one or more lesions associated with the cancer; and (iv) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to 67 a Cu radioisotope: wherein R is CH3C(O)-; ( 67 Cu-SAR-BBN) and wherein the radiation dose delivered by the 67 Cu radioisotope is sufficient to reduce the size of the one or more lesions associated with the cancer.

8. The method according to any one of claims 1 to 7, wherein the stereochemistry of the peptide moiety of the compound of formula (I) is depicted as follows:

9. The method according to claim 5, 6 or 7, wherein the radiation dose delivered by 64 the Cu radioisotope is about 200 MBq.

10. The method according to any one of claims 1 to 9, wherein the patient is 67 administered 1, 2, 3 or 4 times with Cu-SAR-BBN.

11. The method according to claim 10, wherein 67 the maximum planned cumulative administered activity of Cu-SAR-BBN will not exceed the critical organ dose limits (23 Gy for the kidney and 2 Gy for the bone marrow) after 4 administrations.

12. The method according to any one of claims 1 to 11, wherein the patient is a male subject with a castrate level of serum / plasma testosterone of about <50 ng / dL or about <1.7 nmol / L.

13. The method according to claim 3 or 4, wherein the metastatic castration-resistant prostate cancer expressing GRPR (GRPRmCRPC) is progressive GRPRmCRPC despite prior androgen deprivation therapy and at least enzalutamide and / or abiraterone (or other such androgen receptor pathway inhibitors).

14. The method according to any one of claims 1 to 13, wherein, relative to a baseline taken prior to each treatment, after one, two, three or four treatment administration cycles of a compound of formula (I) complexed to a 67 Cu radioisotope or a pharmaceutically acceptable salt thereof, the patient experiences a decrease in the percentage of the PSA and / or alkaline phosphatase (ALP) and / or lactate dehydrogenase (LDA) biomarkers.

15. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope for the treatment of diagnosing a patient suffering from cancer expressing GRPR: wherein R is CH3C(O)-; ( 67 Cu-SAR-BBN wherein the radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

16. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope in the manufacture of a medicament for the treatment or diagnosis of a patient suffering from a cancer expressing GRPR: wherein R is CH3C(O)-; ( 67 Cu-SAR-BBN) wherein the radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

17. A method for predicting a patient's response to treatment of cancer with a compound of formula (I) complexed with 67 Cu, the method comprising detecting and counting circulating tumor DNA (ctDNA) associated with one or more genes in the patient and correlating the amount of detected ctDNA with the patient's response to the treatment, wherein the cancer is a cancer that expresses GRPR, and wherein the one or more genes are selected from BRCA1, BRCA2, RB, and p53.

18. A method for predicting a patient's response to treatment of cancer with a compound of formula (I) complexed with 67 Cu, the method comprising detecting and counting circulating tumor DNA (ctDNA) associated with one or more genes in the patient and correlating the amount of detected ctDNA with the patient's response to the treatment, wherein the cancer is a cancer that expresses GRPR, and wherein the one or more genes are selected from BRCA1, BRCA2, RB, and p53.

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