Methods for treating breast cancer

Abstract

The present disclosure is directed to methods of treating breast cancer in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a radiopharmaceutical compound with a GRPR ligand moiety, e.g. [177Lu]Lu-NeoB, in combination with a 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine.

Description

[0001] METHODS FOR TREATING BREAST CANCER

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to methods for treating breast cancer in a subject in need thereof, wherein a therapeutically effective amount of a radiopharmaceutical compound comprising GRPR ligand, e.g. [177Lu]Lu-NeoB, is administered to said subject in combination with fluorouracil or a prodrug for fluorouracil.

[0004] BACKGROUND

[0005] Breast cancer is the most common cancer and the leading cause of cancer death for women worldwide. The global incidence is 85.8 to 91.6 cases per 100,000, whereas mortality rates range from 17.4 to 20.1 deaths per 100,000 (DeSantis et al. Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J Clin; 66(1):31-42 ; Hashim et al. The global decrease in cancer mortality: trends and disparities. Ann Oncol; 27(5):926-33 ; Torre et al. Global Cancer Incidence and Mortality Rates and Trends--An Update. Cancer Epidemiol Biomarkers Prev; 25(1): 16-27; Heer et al. The incidence of breast cancer in Canada 1971-2015: trends in screening-eligible and young-onset age groups. Can J Public Health; 111 (5): 787-793).

[0006] Despite progress in new treatment methods, there is still a need to provide improved clinical treatments of breast cancer.

[0007] SUMMARY

[0008] The present disclosure relates to a method for treating breast cancer in a subject in need thereof by administering to said subject a therapeutically effective amount of a radiopharmaceutical compound in combination with 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine, wherein said radiopharmaceutical compound is a compound of formula (I), or pharmaceutically acceptable salts thereof:

[0009] C-S-P (I) wherein:

[0010] C is a chelating moiety,

[0011] P is a GRP receptor ligand moiety, S is an optional spacer covalently linking C and P, and wherein said radiopharmaceutical compound is labelled with a radionuclide M

[0012] The present disclosure is provided in various aspects as outlined in the following:

[0013] Provided is a method of treating breast cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a radiopharmaceutical compound, in combination with 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine, wherein said radiopharmaceutical compound is a compound of formula (I), or pharmaceutically acceptable salts thereof:

[0014] C-S-P (I) wherein: C is a chelating moiety, S is an optional spacer covalently linking C and P, P is a GRP receptor ligand moiety, and wherein said radiopharmaceutical compound is labelled with a radionuclide M.

[0015] In some embodiments, said 5-fluorouracil or a fluorouracil prodrug is a 5-fluorouracil prodrug.

[0016] In some embodiments, said 5-fluorouracil prodrug is capecitabine.

[0017] In some embodiments, the treatment further comprises administration of a gonadotropinreleasing hormone antagonist (GnRHa). In some embodiments, the GnRHa is goserelin, triptorelin, or leuprolide.

[0018] In some embodiments, M is selected from90Y,131l,121Sn,186Re,188Re,64Cu,67Cu,59Fe,89Sr,198Au,203Hg,212Pb,165Dy,103Ru,149Tb,161Tb,213Bi,166Ho,165Er,169Er,153Sm,177Lu,213Bi,223Ra,225Ac,227Ac,227Th,211At,67Cu,186Re,188Re,161Tb,175Yb,105Rh,166Dy,199Au,44Sc,149Pm,151Pm, i42pr,143Pr76As,111Ag and47Sc.

[0019] In some embodiments, M is177Lu.

[0020] In some embodiments, C is obtained by linking to S or P a chelating agent selected from 1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1 ,4,7,10- tetraazacyclododececane, 1 (glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylentriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triacetic acid (DO3A), triethylenetetramine (TETA), 1 ,4,7-triazacyclononane-1 ,4,7-triacetic acid (NOTA) , NOTAGA, 1-(1 ,3-carboxypropyl)- 4,7-carboxymethyl-1 ,4,7-triazacyclononane (NODAGA), NODASA, NODAPA, and 1 ,4- bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1 ,4-diazepine (AAZTA, e.g. AAZTA5).

[0021] In some embodiments, C is of the following formula,

[0022] In some embodiments, P is of the general formula

[0023] DPhe-GIn-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-i (CH2N)-Pro-NH2 and NH-CH(CH2-CH(CHs)2)2 or Z is wherein X is NH and R2 is (CH2-CH(CHs)2 and R1 is the same as R2 or (CH2N)-Pro-NH2.

[0024] In some embodiments, P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2. In some embodiments, the compound of Formula (I) is a compound of Formula (II) wherein C and P are as defined in any one of Claim 1 and 12-15, and wherein the chelating moiety C is complexed with a radionuclide M. In some embodiments, the radiopharmaceutical compound is M-NeoB of the following formula (III).

[0025] (HI), or pharmaceutically acceptable salts thereof, wherein M is a radionuclide, for example M is177Lu.

[0026] In some embodiments, said subject has ER positive, HER-2 negative (ER+ / HER2-) and GRPR- positive (GRPR+) breast cancer. In some embodiments the cancer is metastatic.

[0027] In some embodiments, said subject has been selected from subjects experiencing progression after previous endocrine therapy in combination with a CDK4 / 6 inhibitor.

[0028] In some embodiments, said subject has been selected from subjects experiencing progression after previous endocrine therapy in combination with a CDK4 / 6 inhibitor.

[0029] In some embodiments, the method comprises administering to said subject a therapeutically effective amount of a radiopharmaceutical compound, in combination with a 5-fluorouracil prodrug which is capecitabine, wherein said radiopharmaceutical compound is NeoB of the following formula wherein M is177Lu, and wherein said subject has ER positive, HER-2 negative (ER+ / HER2-) and GRPR-positive (GRPR+) metastatic breast cancer and has been selected from subjects experiencing progression after previous endocrine therapies of which at least one was in combination with a CDK4 / 6 inhibitor

[0030] In some embodiments, said endocrine therapy comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a non-steroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader.

[0031] In some embodiments, said endocrine therapy comprises administering a therapeutically effective amount of a selective ER degrader.

[0032] In some embodiments, said selective ER degrader is fulvestrant.

[0033] In some embodiments, said CDK4 / 6 inhibitor is ribociclib and said endocrine therapy comprises administering a therapeutically effective amount of fulvestrant.

[0034] In some embodiments, said radiopharmaceutical compound is administered 3 to 12 times, 4 to 10 times, 4 to 8 times, 6 times, 10 times, or 12 times.

[0035] In some embodiments, said radiopharmaceutical compound comprises an administration interval of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 or 4 weeks, or 4 weeks.

[0036] In some embodiments, said radiopharmaceutical compound is administered at a dose ranging from 0.925 GBq (25mCi) to 29.6GBq (800 mCi), from 1.48 GBq (40 mCi) to 18.5 GBq (500mCi), from 1.85 GBq (50mCi) to 14.8 GBq (400mCi), from 3.7 GBq (100mCi) to 11.1 GBq(300mCi), about 3.7 GBq (100mCi), about 5.55 GBq (150mCi), about 7.4 GBq (200mCi), about 9.25GBq (250mCi), or about 11.1 GBq (300mCi).

[0037] In some embodiments, said 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, is administered orally at a daily dose of 1000-2500 mg / m2, e.g. about 2000 mg / m2, e.g. in cycles of a period of 15 to 28 days, e.g. each cycle about 21 days including about 14 days of daily administration followed by a period of about 7 days off treatment, and is administered for at least as long as the radiopharmaceutical is administered, and optionally administration of said fluoruracil or fluoruracil prodrug continues until disease progression.

[0038] In some embodiments, said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously every 14-56 days, for 1 to 12 cycles, for example 6 to 12 cycles, at a dose ranging from 3.7 GBq (100mCi) to 11.1 GBq(300mCi), e.g. about 100 mCi, about 150 mCi, or about 200mCi, in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2, for 7 to 21 days per cycle.

[0039] In some embodiments, said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously about every 14-28 days, e.g. about every 21 days, for 1 to 12 cycles, for example 6 to 12 cycles, at a dose of about 3.7 GBq (100mCi) or about 5.55 GBq (150 mCi) in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2 for 7-21 days per cycle, e.g. about 14 days per cycle.

[0040] In some embodiments, said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously about every 35-50 days, e.g. about every 42 days, on odd numbered cycles only of 14-28 day cycles, e.g. about 21 day cycles for 1 to 12 cycles, for example 6 to 12 cycles, at a dose of about 5.55 GBq (150mCi), in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2 for 7-21 days per cycle, e.g. about 14 days per cycle.

[0041] In some embodiments, said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously about every 35-50 days, e.g. about every 42 days, on odd numbered cycles only of 14-28 day cycles, e.g. about 21 day cycles for 1 to 12 cycles, for example 6 to 12 cycles, at a dose of about 7.4 GBq (200mCi), in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 1000 mg / m2 for 7-21 days per cycle, e.g. about 14 days per cycle.

[0042] In some embodiments, said subject is a post-menopausal woman with metastatic breast cancer.

[0043] In some embodiments, said subject is a pre-menopausal or peri-menopausal woman with metastatic breast cancer.

[0044] In some embodiments, said subject has been selected by PET / CT or PET / MRI imaging with the same radiopharmaceutical compound as defined for the treatment, but with an alternate radionuclide suitable for imaging, for example 68-Gallium, 67-Gallium or 64-Copper, e.g. 68- Gallium, based on detection of said radionuclide in the imaging scan at the tumor region, for example, two weeks prior to start of said treatment.

[0045] In some embodiments, said subject has HR positive, HER-2 negative (HR+ / HER2-) and GRPR- positive (GRPR+) breast cancer and is experiencing progression after previous endocrine therapy in combination with a CDK4 / 6 inhibitor, wherein said radiopharmaceutical compound is administered to said subject in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, wherein a first dose of said radiopharmaceutical compound is administered within 3 days, e.g., the same day, as the first dose of 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine,.

[0046] In some embodiments, said 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, is administered orally at a daily dose of about 2000 mg / m2, for example in cycles of a period of about 21 days, each cycle for example including about 14 days of administration followed by a period of about 7 days off treatment, wherein the radiopharmaceutical compound is administered for 6-12 cycles, and 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, is administered for at least as long as the radiopharmaceutical is administered, and optionally administration of 5- fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, continues until disease progression.

[0047] In some embodiments, said radiopharmaceutical compound is M-NeoB of the following formula: wherein M is177Lu.

[0048] In some embodiments, said radiopharmaceutical compound is M-NeoB of the following formula: wherein M is177Lu, and said radiopharmaceutical compound is administered by intravenous infusion at a concentration of 370MBq / mL. In some embodiments, a radiopharmaceutical compound for use in a method of treating breast cancer in a subject in need thereof is provided

[0049] In some embodiments, a use of a radiopharmaceutical compound in the manufacture of a medicament for use in a method of treating breast cancer in a subject in need thereof is provided.

[0050] According to one aspect of the disclosure, the combination of radiopharmaceutical with 5- fluorouracil or a 5-fluorouracil prodrug in the method of treatment of the disclosure has been found to be at least additive or preferably synergistic.

[0051] In some embodiments, provided is a method for treating breast cancer in a subject in need thereof by administering to said subject a therapeutically effective amount of a radiopharmaceutical compound in combination with 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine, wherein said radiopharmaceutical compound is M-NeoB of the following formula: wherein M is177Lu, wherein the subject has HR positive, HER-2 negative (HR+ / HER2-) and GRPR-positive (GRPR+) metastatic breast cancer and is experiencing progression after previous endocrine therapy in combination with a CDK4 / 6 inhibitor.

[0052] BRIEF DESCRIPTION OF THE FIGURES

[0053] Fig. 1 represents the treatment scheme for both screening and treatment parts of the study .

[0054] DETAILED DESCRIPTION

[0055] The present disclosure relates to a method for treating breast cancer in a subject in need thereof by administering a therapeutically effective amount of a radiopharmaceutical compound to said subject in combination with 5-fluorouracil or a 5-fluorouracil prodrug.

[0056] Gastrin-releasing peptide (GRP) is a mammalian bombesin-like peptide that regulates many biological responses mainly in the central and enteric nervous system (Flores et al 2010. GRP acts through specific membrane G-protein coupled bound receptors (GRPR) which are overexpressed by a variety of cancers including breast cancer (Flores et al. 2010).

[0057] The NeoB compound is a new generation bombesin analogue which binds to the GRPR with high affinity (half maximal inhibitory concentration (IC50) 1-2 nM, Nock et a\J. Nucl. Med. 2017; 58(1):75-80) and shows low internalization. The NeoB compound contains in its structure a DOTA metal-chelator which allows for radiolabeling with different radionuclides including gallium-68 (for PET imaging), lutetium-177 (for radionuclide therapy) and other relevant radionuclides, which makes the theranostic use of NeoB possible, without affecting receptor affinity, internalization properties or biodistribution. In non-clinical models, [68Ga]Ga-NeoB and [177Lu]-Lu NeoB have shown high affinity to the GRPR which is over-expressed in breast, prostate, gastrointestinal stromal tumors (GIST) and gliomas (including glioblastoma) (Flores et al. 2010, supra, Morgat et al, J. Nucl. / Wed.2017;58(9):1401-1407), as well as low degree of internalization upon binding to the specific receptor.

[0058] The ability of the radiolabeled compound to target the GRPR expressing tumor has been confirmed in in vivo imaging and biodistribution studies in tumor models. [177Lu]Lu-NeoB is rapidly cleared from the blood, quickly eliminated through the renal system, with no retention in kidneys. Background radioactivity is observed in GRPR-expressing tissues (mostly pancreas), which however decreases overtime, consistently with a GRPR antagonist profile. On the contrary, tumor radioactivity is persistent, with detectable uptake values up to 7 days after injection.

[0059] Use of the radiopharmaceuticals of this disclosure in combination with 5-fluorouracil or a 5- fluorouracil prodrug may provide an improved treatment.

[0060] Endrocrine treatment (including CDK4 / 6i) is successful in providing improved treatment outcome for a number of cancer patients. However, acquired resistance to endocrine therapy with or without CDK4 / 6i remains a challenge, and optimal therapeutic strategy after failure of CDK4 / 6i treatment is still uncertain. In some embodiments, the methods of this disclosure are intended to provide an improved treatment for patients that relapse after such endocrine therapy.

[0061] General Definitions

[0062] The use of the articles “a”, “an”, and “the” in both the description and claims are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising”, “having”, “being of’, “including”, and “containing” are to be construed as open terms (i.e., meaning “including but not limited to”) unless otherwise noted. Additionally, whenever “comprising” or another open-ended term is used in an embodiment, it is to be understood that the same embodiment can be more narrowly claimed using the intermediate term “consisting essentially of’ or the closed term “consisting of”.

[0063] The term “about” or “ca.” has herein the meaning that the following value may vary for ± 20%, e.g. ± 10%, e.g. ± 5%, e.g. ± 2%, e.g. ± 1%.

[0064] The term "treating" or "treatment" as used herein comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer. Within the meaning of the present disclosure, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and / or reduce the risk of developing or worsening a disease. As used herein in the context the disclosed combination therapy, the term “treatment” encompasses the administration of the radiopharmaceutical compound in combination with capecitabine. Such treatment may comprises one or more administrations of the radiopharmaceutical compound over a determined period.

[0065] As used herein “breast cancer” refers to the most common cancer and the leading cause of cancer death for women worldwide. The term breast cancer also includes its subtypes based on the presence or absence of the ER and progesterone receptor (PgR), and the expression and amplification of HER2: HR-positive and HER2 negative (HR+; ER+, PgR+ and HER2-), HER2- positive (HER2+) and triple-negative (TN; ER-, PR- and HER2-).

[0066] As used herein the term “radiopharmaceutical” or “radiopharmaceutical compound” refers to a pharmaceutical compound which is labelled with a radionuclide element, typically of metallic nature. Such radiopharmaceutical compound has binding affinity to a specific marker on target cells, for example, a receptor or a tumor antigen, and therefore includes a target ligand (or target binding moiety). Radiopharmaceutical compounds are useful as contrast agents in imaging techniques, such as PET scan or MRI scan, or as therapeutics in nuclear medicine, also known as radioligand therapy (RLT).

[0067] “GRPR ligand” as used herein referes to a chemical compound or group which binds to the gastrin-releasing peptide receptor (GRPR). Consistent with the International System of Units, “MBq” is the abbreviation for the unit of radioactivity “megabecquerel.”

[0068] As used herein, “PET” stands for positron-emission tomography.

[0069] As used herein, “MRI” stands for magnetic resonance imaging.

[0070] As used herein, “CT” stands for computed tomography.

[0071] Standard dosing abbreviations are used herein. “QD” means once a day dosing, “BID” means twice a day dosing, “Q3W” , means once every 3 weeks dosing, and “Q6W” means once every 6 weeks dosing.

[0072] The terms “tumor” and “cancer” are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors and benign cancers. The term "cancer" as used herein includes primary malignant cells or tumors (e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original malignancy or tumor) and secondary malignant cells or tumors (e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor).

[0073] As used herein, the phrase “therapeutically effective amount” of a compound refer to an amount of the compound that will elicit a desired therapeutic response in at least a sub-population of subjects, for example, ameliorate the symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0074] The term "subject" or "patient" as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer. Examples of subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non6WO 2021 / 171261 PCT / IB2021 / 051643 human animals. In an embodiment, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancers.

[0075] “Combination therapy” refers to either a therapy comprising administration of a fixed combination in one dosage unit form, or therapies where a radiopharmaceutical compound as disclosed herein and a combination partner, e.g. another drug as explained below, such as 5-fluorouracil or a 5- fluorouracil prodrug, may be administered concurrently or serarately, i.e. separately within time intervals, especially where these time intervals allow that the combination partners and / or combination radiotherapies show a cooperative effect with the radiopharmaceutical compound, e.g. synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration.

[0076] The terms “co-administration” or “combined administration” or the like as utilized herein are also meant to encompass administration of the selected combination partners, e.g. the radiopharmaceutical compound and the 5-fluorouracil or 5-fluorouracil prodrug, to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0077] A ’’prodrug” is a compound that is administered to a subject and converted into the active drug in the subject’s body. This conversion can be by enzymatic or non-enzymatic chemical means. A 5-fluorouracil prodrug is a compound (e.g. capecitabine) that converts into 5-fluorouracil after being administered to a subject.

[0078] In the chemical formulae, the wavy line represents the attachement point of the moiety.

[0079] The radiopharmaceutical compound for use in the combination therapy of the disclosure

[0080] The radiopharmaceutical compound for use in the methods of the disclosure is a compound of formula (I), or pharmaceutically acceptable salts thereof: C-S-P (I) wherein :

[0081] C is a chelating moitey;

[0082] S is an optional spacer covalently linking C and P;

[0083] P is a GRP receptor ligand moiety covalently linked to C, either directly, or indirectly via S, wherein said compound is labelled with a radionuclide M.

[0084] M is selected among the radioactive isotopes useful in nuclear medicine. Examples of such radioactive isotopes include without limitation90Y,131l,121Sn,186Re,188Re,64Cu,67Cu,59Fe,89Sr,198Au,203Hg,212Pb,165Dy,103Ru,149Tb,161Tb,213Bi,166Ho,165Er,169Er,153Sm,177Lu,213Bi,223Ra,225Ac,227Ac,227Th,211At,67Cu,186Re,188Re,161Tb,175Yb,105Rh,166Dy,199Au,44Sc,149Pm,151Pm, i42pr,143Pr,76As,111Ag and47Sc. In some embodiments, M is177Lu.

[0085] In specific embodiments, M is complexed to the chelating moiety.

[0086] Examples of GRP receptor ligand compounds includes RM2, SB3, RM26, BAY-864367, CB- TE2A-AE06, or Pro-BOMB1.

[0087] In preferred embodiments, P is a GRP receptor ligand moiety of the general formula :

[0088] Xaa1-Xaa2 — Xaa3 — Xaa4 — Xaa5 — Xaa6 — Xaa7 — Z; wherein

[0089] Xaa1 is not present or is selected from the group consisting of amino acid residues Asn, Thr, Phe, 3- (2-thienyl) alanine (Thi), 4-chlorophenylalanine (Cpa) , a-naphthylalanine (a-Nal) , - naphthylalanine (P-Nal) , 1 ,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo- tyrosine (o-l-Tyr) , Trp and pentafluorophenylalanine (5-F-Phe) (all as L- or D-isomers) ; e.g. D- Phe,

[0090] Xaa2 is Gin, Asn or His; e.g. Gin,

[0091] Xaa3 is Trp or 1 , 2, 3, 4-tetrahydronorharman-3-carboxylic acid (Tpi); e.g. Trp,

[0092] Xaa4 is Ala, Ser or Vai; e.g. Ala,

[0093] Xaa5 is Vai, Ser or Thr; e.g. Vai,

[0094] Xaa6 is Gly, sarcosine (Sar), D-Ala, or p-Ala; e.g. Gly,

[0095] Xaa7 is His or (3-methyl )histidine (3-Me)His; e.g. His,

[0096] Z is selected from -NHOH, -NHNH2, -NH-alkyl, -N(alkyl)2, and -O-alkyl or Z is wherein X is NH or O and R1 and R2 are the same or different and selected from a proton, an optionally substituted alkyl, an optionally substituted alkyl ether, an aryl, an aryl ether or an alkyl- , halogen, hydroxyl, hydroxyalkyl, amine, amino, amido, or amide substituted aryl or heteroaryl group.

[0097] According to an embodiment, P is DPhe-GIn-Trp-Ala-Val-Gly-His-Z; wherein Z is defined as above.

[0098] According to an embodiment, P is DPhe-GIn-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-i (CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2 or Z is wherein X is NH and R2 is CH(CH2-CH(CHs)2 and R1 is the same as R2 or different (CH2N)- Pro-NH2.

[0099] As used herein, the term “chelating moiety” refers to an organic moiety comprising functional groups that are able to form non-covalent bonds with the radionuclide M and, thereby, form a stable radionuclide complex.

[0100] The chelating moiey in the context of the present disclosure may be obtained by grafting one chelating agent to S or P, said chelating agent may be selected among the following list (which is not limitative): 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1 ,4, 7, 10-tetraazacyclododececane, 1 (glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylentriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triacetic acid (DO3A), triethylenetetramine (TETA), 1 ,4,7-triazacyclononane-1 ,4,7-triacetic acid (NOTA) , NOTAGA, 1-(1 ,3-carboxypropyl)- 4,7-carboxymethyl-1 ,4,7-triazacyclononane (NODAGA), NODASA, NODAPA, and 1 ,4- bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1 ,4-diazepine (AAZTA, e.g. AAZTA5).

[0101] In specific embodiments, the chelating moiety C is of the following formula,

[0102] wherein the wavy bond represents the point of attachment of the chelating agent to the spacer S, or to the GRP receptor ligand P.

[0103] Such chelating moiety are either directly linked to the GRP receptor ligand moiety or connected via a linker molecule or also referred herein as the spacer S. The linking bond(s) is (are) either covalent or non-covalent bond(s) from GRP receptor ligand (and the spacer) and the chelating moiety, in some embodiments the bond(s) is (are) covalent.

[0104] The chelating moity C is typically bonded to the N-terminal end of the above disclosed peptide derivatives formulae, such as DPhe-GIn-Trp-Ala-Val-Gly-His-Z, optionally via the spacer S. In specific embodiments, the spacer S is selected from the group consisting of: a) aryl containing residues of any the formulae: b) dicarboxylic acids, w-aminocarboxylic acids, w-diaminocarboxylic acids or diamines derivatives of any of the following formulae:

[0105] wherein each n represents independently an integer from 0 to 12, for example n = 0, 1 , 2, 3 or 4; c) PEG spacers of various chain lengths, in particular PEG spacers selected from any the following formulae: wherein m is an integer from 1 to 36, for example m = 1 , 2, 3 or 4, and p is an integer from 0 to 5, for example p = 0 or 1 ; d) p-amino acid residues, single or in homologous chains of various chain lengths or heterologous chains of various chain lengths, in particular: ; and / or, e) any combinations of one or more of a, b, c and / or d.

[0106] In some embodiments, the radiopharmaceutical compound for use in the treatment methods of the disclosure is selected from the group consisting of the radiolabelled compounds of the following formulae: wherein C and P are as defined above, and M is a radioactive isotope complexed to the chelating moiety, in some embodiments M is selected from177Lu.

[0107] In some embodiments, the radiopharmaceutical compound for use according to the disclosure is the following compound of Formula (II) wherein C and P are as defined above, and C is complexed to a radionuclide M.

[0108] In some embodiments, the radiopharmaceutical compound for use in the treatment methods is M-NeoB of formula (III):

[0109] wherein M is as defined above, in some embodiments M is177Lu.

[0110] The radiopharmaceutical compound [177Lu]Lu-NeoB refers to the compound of formula (III) wherein M is177Lu. According to an embodiment, the radiopharmaceutical compound is the radiolabeled NeoB2 of formula (IV): wherein M is as defined above, e.g.177Lu.

[0111] According to another specific embodiment, the radiopharmaceutical compound for use according to the disclosure is a compound of formula (I) is ProBOMBI of the following formula (V): which is radiolabelled with M, in some embodiments M is177Lu.

[0112] Some embodiments of the disclosure encompass combination therapy with [177Lu]Lu-NeoB as the radiopharmaceutical compound. The radiopharmaceutical compound is for use in treating breast cancer in a subject in need thereof wherein a therapeutically effective amount of said radiopharmaceutical compound is administered to said subject.

[0113] The single components or their precursor, typically non-labelled NeoB, may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration.

[0114] In specific embodiments, the radiopharmaceutical compound for use in the disclosed combination therapy may be formulated as previously described, for example in W02021 / 052960

[0115] In some embodiments, the combination therapy comprises administering a pharmaceutical composition consisting of:

[0116] (a) a complex formed by

[0117] (ai) radionuclide177Lutetium (177Lu), and

[0118] (aii) NeoB of formula (III):

[0119] (III); and;

[0120] (b) gentisic acid or salts thereof and ascorbic acid or salts thereof;

[0121] (c) optionally, Macrogol 15 Hydroxystearate ;

[0122] (d) acetate buffer;

[0123] (e) water for injection, and

[0124] (f) at least one other pharmaceutically acceptable excipient, for example a sequestering agent, such as DTPA.

[0125] Synthesis of the compounds of formula (I), (II), (III), (IV) and (V)

[0126] The compounds of formula (I), (II), (III), (IV) and (V) can be synthesized using the methods disclosed in the reference “Positron Emission Tomography Imaging of the Gastrin-Releasing Peptide Receptor with a Novel Bombesin Analogue’’ ACS Omega 2019, 4, 1470-1478. Further information on the synthesis of compound of formula (V) may be found in W02021 / 0608051.

[0127] 5-fluorouracil or 5-fluorouracil prodrug as used in the combination therapy

[0128] The method of treating breast cancer in a subject in need thereof includes a step of administering the radiopharmaceutical compound to said subject in combination with 5-fluorouracil or a 5- fluorouracil prodrug , e.g. capecitabine. Capecitabine is converted into 5-fluorouracil by the enzyme thymidine phosphorylase, which is overexpressed in tumor tissues. Capecitabine can be used for oral dosing and is suitable for long-term administration.

[0129] In some embodiments, the method of the disclosure comprises exposing the tumor to be treated to a therapeutically effective amount of 5-fluorouracil or a 5-fluorouracil prodrug. In some embodiments, the 5-fluorouracil prodrug is capecitabine.

[0130] In some embodiments, said 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine, is administered orally at a daily dose of 1000-2500 mg / m2, e.g. about 2000 mg / m2, e.g. in cycles of a period of 15 to 28 days, e.g. each cycle including about 14 days of daily administration followed by a period of about 7 days off treatment, and is administered for at least as long as the radiopharmaceutical is administered, and optionally administration of said fluoruracil or fluoruracil prodrug continues until disease progression.

[0131] In some embodiments, said 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine, is administered orally at a daily dose of about 2000 mg / m2, for 7 to 21 days per cycle.

[0132] In some embodiments, said 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine, is administered orally at a daily dose of about 2000 mg / m2 for about 14 days per cycle.

[0133] In some embodiments, said 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine, is administered for at least as long as the radiopharmaceutical is administered, and optionally administration continues until disease progression.

[0134] In some embodiments, the first dose of said 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine, is administered the same day as the first dose of the radiopharmaceutical.

[0135] Prior endocrine therapy

[0136] In some embodiments, the subject shows disease progression after prior endocrine therapy in combination with a CDK4 / 6 inhibitor. In some embodiments, said endocrine therapy comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a non-steroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader, in some embodiments, said endocrine therapy comprises administering a therapeutically effective amount of a selective ER degrader.

[0137] In some embodiments, said selective ER degrader is fulvestrant.

[0138] In some embodiments, said CDK4 / 6 inhibitor is ribociclib.

[0139] The combination therapy

[0140] In some embodiments, the method of treating breast cancer in a subject in need thereof comprises administering to said subject a therapeutically effective amount of a radiopharmaceutical compound as described above, e.g. [177Lu]Lu-NeoB, in combination with 5- fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine.

[0141] In some embodiments, the present disclosure is directed to methods of treating breast cancer in a subject in need thereof comprising administering to said subject a therapeutically effective amount of said radiopharmaceutical compound as described above, e.g. [177Lu]Lu-NeoB, in combination with 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine.

[0142] The disclosure also relates to the use of radiopharmaceutical compound in the preparation of a drug for use in treating breast cancer in a subject in need thereof wherein a therapeutically effective amount of said radiopharmaceutical compound, e.g. [177Lu]Lu-NeoB, is administered to said subject in combination, simultaneously, separately or sequentially, with 5-fluorouracil or a 5- fluorouracil prodrug, e.g. capecitabine.

[0143] In various embodiments of the disclosure, the combination therapy comprises jointly (i) administering to a subject in need thereof therapeutically effective amounts of a pharmaceutical composition comprising a radiopharmaceutical compound (e.g. [177Lu]Lu-NeoB); and (ii) administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine.

[0144] As used herein, the term “jointly” means that the therapeutic agents may be given separately within time intervals (e.g. in a chronologically staggered manner, especially a sequence-specific manner in such time intervals) to show a (e.g. synergistic) interaction (i.e. joint therapeutic effect). In various embodiments of the disclosure, a combined administration where the radiopharmaceutical compound (e.g.177Lu-NeoB) and the 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine, is administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic, effect.

[0145] In some embodiments, the radiopharmaceutical compound, e.g., [177Lu]Lu-NeoB, is administered within 3 days, e.g., the same day, as the 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine.

[0146] Administration of the radiopharmaceutical compound may comprise an administration interval of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 or 4 weeks, or 4 weeks.

[0147] In some embodiments, said radiopharmaceutical compound is administered 3 to 12 times, 4 to 10 times, 4 to 8 times, 6 times, 10 times, or 12 times.

[0148] In some embodiments, said radiopharmaceutical compound, e.g, [177Lu]Lu-NeoB is administered at least 6 times, e.g. at least 12 times, to said subject in combination with 5-fluorouracil or a 5- fluorouracil prodrug, e.g. capecitabine, and wherein the administration interval between two administrations of said radiopharmaceutical compound is 3 weeks, and, wherein a first dose of said radiopharmaceutical compound is administered within 3 days, e.g. the same day, as said 5- fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine.

[0149] In some embodiments, said radiopharmaceutical compound, e.g, [177Lu]Lu-NeoB is administered at least 6 times, e.g., at least 12 times, to said subject in combination with 5-fluorouracil or a 5- fluorouracil prodrug, e.g. capecitabine, and wherein the administration interval between two administrations of said radiopharmaceutical compound is 6 weeks, and, wherein a first dose of said radiopharmaceutical compound is administered within 3 days, e.g., the same day, as said 5- fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine

[0150] In some embodiments, said radiopharmaceutical compound, e.g., [177Lu]Lu-NeoB, is administered at each administration at a dose ranging from 0.925 GBq (25mCi) to 29.6GBq (800 mCi), from 1.48 GBq (40 mCi) to 18.5 GBq (500mCi), from 1.85 GBq (50mCi) to 14.8 GBq (400mCi), from 3.7 GBq (100mCi) to 11.1 GBq(300mCi), about 3.7 GBq (100mCi), about 5.55 GBq (150mCi), about 7.4 GBq (200mCi), about 9.25GBq (250mCi), or about 11.1 GBq(300mCi), for example ranging from about 3.7 GBq (100mCi) to about 7.4 GBq (200 mCi). In some embodiments, said radiopharmaceutical compound, e.g., [177Lu]Lu-NeoB, is administered intravenously every 14-56 days, for 1 to 12 cycles, for example 6 to 12 cycles, at a dose ranging from 3.7 GBq (100mCi) to 11.1 GBq(300mCi), e.g. about 100 mCi, about 150 mCi, or about 200mCi, in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2, for 7 to 21 days per cycle.

[0151] In some embodiments, said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously about every14-28 days, e.g. about every 21 days, for 1 to 12 cycles, for example 6 to 12 cycles, at a dose of about 3.7 GBq (100mCi) or about 5.55 GBq (150 mCi) in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2 for 7-21 days per cycle, e.g. about 14 days per cycle.

[0152] In some embodiments, said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously about every 35-50 days, e.g. about every 42 days, on odd numbered cycles only of 14-28 day cycles, e.g. about 21 day cycles for 1 to 12 cycles, for example 6 to 12 cycles, at a dose of about 5.55 GBq (150mCi), in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2 for 7-21 days per cycle, e.g. about 14 days per cycle.

[0153] In some embodiments, said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously about every 35-50 days, e.g. about every 42 days, on odd numbered cycles only of 14-28 day cycles, e.g. about 21 day cycles for 1 to 12 cycles, for example 6 to 12 cycles, at a dose of about 7.4 GBq (200mCi), in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2 for about 7- 21 days per cycle, e.g. 14 days per cycle.

[0154] In some embodiments, the combined effect of the radiopharmaceutical compound (e.g., [177Lu]Lu- NeoB) treatment and said 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, increases the overall survival in subjects to at least 10%, 20%, 30%, 40%, or at least 50% as compared to single 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine.

[0155] “Overal survival” (OS) is defined herein as the time from date of first dose to date of death due to any cause in participants of a clinical study, for example as disclosed in Example 1 . If a participant is not known to have died, then overall survival is censored at the latest date the participant was known to be alive (on or before the cut-off date). The OS distribution will be estimated using the Kaplan-Meier method. In some embodiments, the combined effect of the radiopharmaceutical compound (e.g., [177Lu]Lu- NeoB), treatment and 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, also increases the progression-free survival to at least 10%, 20%, 30%, 40%, or at least 50% as compared to single 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine,.

[0156] The term “Progression-free survival” (PFS), as used herein, is defined as the time from the date of first dose to the date of confirmed progression according to RECIST or death due to any cause. If no PFS event is observed, PFS is censored at the date of the last adequate tumor assessment prior to data cut-off date and start of new anti-neoplastic therapy, whichever comes first. PFS distribution is estimated using the Kaplan-Meier method.

[0157] In certain aspects, the administration of the composition comprising the radiopharmaceutical compound (e.g., [177Lu]Lu-NeoB) to a subject eligible for said treatment can inhibit, delay, and / or reduce tumor growth in the subject. In certain aspects, the growth of the tumor is delayed by at least 50%, 60%, 70% or 80% in comparison to an untreated control subject. In certain aspects, the growth of the tumor is delayed by at least 80% in comparison to an untreated control subject. In certain aspects, the growth of the tumor is delayed by at least 50%, 60%, 70% or 80% in comparison to the predicted growth of the tumor without the treatment. In certain aspects, the growth of the tumor is delayed by at least 80% in comparison to the predicted growth of the tumor without the treatment. Assessment of the volume of the tumor in breast cancer may be determined by using the RECIST criteria for tumor responses (Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst; 92(3):205-16) and the revised RECIST 1.1 guidelines (Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer; 45(2):228-47.).

[0158] In certain aspects, the administration of the composition comprising the radiopharmaceutical compound (e.g., [177Lu]Lu-NeoB) to a subject eligible for said treatment can increase the length of survival of the subject. In certain aspects, the increase in survival is in comparison to an untreated control subject or control subject with alternative treatment, such as 5-fluorouracil or 5- fluorouracil prodrug, e.g. capecitabine, for patients diagnosed with breast cancer. In certain aspects, the increase in survival is in comparison to the predicted length of survival of the subject with the standard of care treatment. In certain aspects, the length of survival is increased by at least 3 times, 4 times, or 5 times the length in comparison to an untreated control subject or a control subject with alternative treatment, such as 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, for patients newly diagnosed with breast cancer. In certain aspects, the length of survival is increased by at least one week, two weeks, one month, two months, three months, six months, one year, two years, or three years in comparison to control subject with alternative treatment, such as 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, for patients diagnosed with breast cancer. In certain aspects, the length of survival is increased by at least one month, two months, or three months in comparison to the predicted length of survival of the subject with the alternative treatment, such as 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, for patients diagnosed with breast cancer.

[0159] In some embodiments, the combined therapeutic effect of the radiopharmaceutical, and 5- fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, shows synergy.

[0160] Methods for selecting a subject for the combination treatment

[0161] In certain embodiments of the disclosure, said breast cancer is GRPR positive disease.

[0162] In specific embodiments, the subject is selected for the treatment by PET / CT or PET / MRI imaging with the same compound as defined for the treatment but wherein M is a alternate radionuclide suitable for imaging i.e. imaging radiopharmaceutical compound, based on detection of said radionuclide in the imaging scan at the tumor region.

[0163] Typical alternate radionuclide suitable for use as contrast agent in imaging include the following:1111 n,133mln,99mTc,94mTc,67Ga,66Ga,68Ga,52Fe,72As,97Ru,203Pb,62Cu,64Cu,61Cu177Lu,86Y,51Cr,52mMn,157Gd,169Yb,172Tm,117mSn,123l,124l,125l,18F, AI18F,152Tb,155Tb,82Rb,89Zr,43Sc,44Sc.

[0164] In some embodiments, the radionuclide suitable for imaging is67Ga ,68Ga or64Cu, e.g.68Ga.

[0165] In some embodiments, the subject is selected by evaluating the [68Ga]Ga-NeoB uptake by PET / CT or PET / MRI scan at the tumor region, e.g. breast region.

[0166] In some embodiments, PET scan with the radiopharmaceutical compound labelled with a suitable radiometal for imaging, e.g. [68Ga]Ga-NeoB, may be performed from 42 days to 1 day prior the first administration of said radiopharmaceutical compound for the combination treatment. Thus, the disclosure also relates to methods for determining whether a human subject having breast cancer can be selected for the combination therapy as disclosed herein, said method comprising the steps of:

[0167] 1. administering an efficient amount of an imaging radiopharmaceutical compound as a contrast agent for imaging the uptake of said radiopharmaceutical compound,

[0168] 2. acquiring an image scan by PET / MRI or PET / CT of said patient, and

[0169] 3. comparing with a control image scan.

[0170] The objective of the above selection method is to select the patient with GRPR-positive tumors, i.e. which patients are better responders to the combination therapy of the present disclosure. GRPR-positive tumors may be advantageously detected by evaluating the uptake of a imaging radiopharmaceutical compound by PET / MRI or PET / CT imaging after injection of said imaging radiopharmaceutical compound as contrast agent.

[0171] As used herein, a good responder is a patient selected from a patient population which shows statistically better response to a treatment as compared to a randomized patient population (i.e. which has not been selected by the selection step of the present method), and / or which shows less side effects to a treatment as compared to a randomized patient population (i.e. which has not been selected by the selection step of the present method).

[0172] In certain aspect, the [68Ga]Ga-NeoB is provided in a kit. The kit may consist of 2 sterile vials as single dose product:

[0173] Vial 1 : NeoB (active ingredient), 50 pg, powder for solution for injection, to be reconstituted with a solution of gallium-68 chloride (68GaCI3) in HCI eluted from a68Ge / 68Ga generator;

[0174] Vial 2: Reaction buffer. Vial 2 is to be added to the reconstituted Vial 1.

[0175] Examples of such kits are disclosed in WO2021053040.

[0176] The volume of [68Ga]Ga-NeoB solution for injection, corresponding to the radioactive dose to be administered, is calculated according to the estimated time of injection, on the basis of the current activity provided by the generator and of physical decay of the radionuclide (half-life = 68 min).

[0177] In some embodiments, the selection of subject is performed from 10 to 18 days, e.g. around 14 days prior to the first administration of the radiopharmaceutical compound. In some embodiments, said imaging radiopharmaceutical is administered at a single intravenous dose from 100 to300 MBq.

[0178] Images of subject’s body are then acquired by PET / MRI or PET / CT imaging and the images are compared with a control image to identify whether the lesions identified by conventional imaging, for example by MRI or CT, are also identified by said imaging radiopharmaceutcal compound uptake, i.e. [68Ga]Ga-NeoB uptake. In some embodiments, PET / MRI or PET / CT imaging is performed from 30 to 120 minutes, e.g. from 60 to 90 minutes after the intravenous administration of said imaging radiopharmaceutical compound to the subject.

[0179] In some embodiments of the method, a subject is selected for the combination therapy of the disclosure fulfils the following condition: at least 10%, e.g. more than 20%, e.g. more than 30%, e.g. more than 40%, e.g. more than 50%, e.g. more than 60%, e.g. more than 70%, e.g. more than 80% of the lesion or lesions as detected by conventional imaging in said subject, for example by MRI or CT, are also identified by the imaging radiopharmaceutical compound uptake, e.g. [68Ga]Ga-NeoB uptake, as determined by PET / MRI or PET / CT imaging in said subject.

[0180] In some embodiments, the term “lesion” refers to measurable tumor lesions according to RECIST 1.1 criteria as defined above.

[0181] In some embodiments, said subject is diagnosed with breast cancer or suffers from recurrent breast cancer.

[0182] As used herein “recurrent” refers to patients who have relapsed after at least one treatment.

[0183] In some embodiments, said subject has ER positive, HER-2 negative (ER+ / HER2-) and GRPR- positive (GRPR+) breast cancer. In some embodiments the cancer is metastatic.

[0184] In some embodiments, said subject has been selected from subjects experiencing progression after previous endocrine therapy in combination with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib, ribociclib or abemaciclib.

[0185] In some embodiments, said subject has been selected from subjects experiencing progression after previous endocrine therapy in combination with a CDK4 / 6 inhibitor,

[0186] “Relapse” in the case of a cancer refers to a return to progressive disease after a period of static or regressive disease. Progressive disease can be measured in ways that would be appropriate for the cancer in question, for example, increase in the number or size of tumors or cancerous lesions.

[0187] In some embodiments, “endocrine therapy” comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a non-steroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader, in some embodiments, said endocrine therapy comprises administering a therapeutically effective amount of a selective ER degrader. In some embodiments, endocrine therapy comprises administering a therapeutically effective amount of fulvestrant or an aromatase inhibitor.

[0188] “Neoadjuvant therapy” is therapy given before another therapy. “Adjuvant therapy” is therapy given after another therapy. For example, if an aromatase inhibitor is given to a breast cancer patient before surgical removal of a breast cancer tumor, the aromatase inhibitor is being administered as neoadjuvant therapy to the surgery. As a further example, if an aromatase inhibitor is given to a breast cancer patient after surgical removal of a breast cancer tumor, the aromatase inhibitor is being administered as adjuvant therapy to the surgery.

[0189] In some embodiments, said subject is a post-menopausal woman with metastatic breast cancer.

[0190] In some embodiments, said subject is a pre-menopausal or peri-menopausal woman with metastatic breast cancer.

[0191] In some embodiments, the subject has metastatic breast cancer.

[0192] Hereinafter, further aspects of the combination therapy of the present disclosure are described in more details and specifically with reference to examples, which however are not intended to limit the present disclosure.

[0193] EXAMPLES

[0194] Example 1 : Clinical study for treating breast cancer subjects

[0195] Provided herein is a protocol example describing a Phase l / ll open label trial of [177Lu]Lu-NeoB in combination with capecitabine in adult patients with ER-positive, HER-2 negative and GRPR- positive metastatic breast cancer after progression on previous endocrine therapy in combination with a CDK4 / 6 inhibitor. The synopsis is shown in table 1.

[0196] Table 1. Synopsis

[0197] Trial Design:

[0198] This is a Phase l / ll, multicenter, open-label study with a dose escalation part (Phase I) followed by a dose optimization part (Phase II) assessing [177Lu]Lu-NeoB in combination with capecitabine for the treatment of adult post-menopausal (and pre / peri-menopausal, in the Phase II part only) women and men with GRPR-positive, ER-positive, HER-2 negative mBC after progression on previous endocrine therapy in combination with a CDK4 / 6L

[0199] Brief Summary:

[0200] Endocrine therapy (ET) is the foundation of treatment for patients with breast cancer driven by expression of estrogen receptor (ER) and / or progesterone receptor (PR). Treatment patterns in advanced hormone receptor positive (HR+) breast cancer (BC) were substantially transformed with cyclin-dependent kinase 4 / 6 (CDK4 / 6i) (e.g. palbociclib, ribociclib or abemaciclib) approvals. These compounds in combination with endocrine therapy (ET) (Al or fulvestrant) represent the current gold standard of care for first- and second- line treatment of patients with HR+ / human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC) leading to improved outcomes.

[0201] Despite remarkable clinical results with the use of CDK4 / 6i, breast cancer patients will experience progression of disease requiring alternative treatment options. The optimal sequence of therapy after progression on CDK4 / 6i has not been established and it depends on multiple factors, including previous regimens, mutational profile, comorbidities, patient preference or disease burden. Thus, new targeted treatment modalities are needed for treatment of patients with endocrine-resistant mBC.

[0202] The purpose of this phase l / ll study is to determine the recommended doses and regimens of [177Lu]Lu-NeoB in combination with capecitabine (and a gonadotropin releasing hormone agonist (GnRha) for pre / peri-menopausal women in the Phase II part only and men, if applicable) in adult participants with ER+ / HER2-, gastrin releasing peptide receptor positive (GRPR+) mBC after progression on CDK4 / 6i-based therapy, and to evaluate preliminary efficacy across two different dose levels and regimens. The study comprises of two parts: the phase I, dose escalation part, followed by the phase II, dose optimization part. During screening, study participants will receive the radioligand imaging agent [68Ga]Ga-NeoB for a positron emission tomography (PET) / computed tomography (CT) or PET / magnetic resonance imaging (MRI). An additional [68Ga]Ga-NeoB for PET / CT or PET / MRI will be administered after their last administration of [177Lu]Lu-NeoB for phase II participants only. During the treatment period participants will be required to attend a site visit approximately every 3 weeks for the first 9 months and every 6 weeks thereafter, on the first day of every cycle (defined as a period of 3 weeks) or every other cycle, respectively, to undergo study treatment administration or dispensing, dosimetry and safety assessments. Tumor assessments are performed every 9 weeks until month 18, every 12 weeks until month 36 and as clinically indicated thereafter, until disease progression. After study treatment discontinuation, participants will be followed up for safety for 8 weeks after their last study treatment administration. Beyond the initial 8 weeks of safety follow-up, all participants will be followed up, for a total of 5 years from their last [177Lu]Lu-NeoB administration, or until death, lost to followup, participant / guardian’s or investigator’s decision or withdrawal of consent (WoC).

[0203] The end of study is defined as the date of the last visit, scheduled procedure or follow up (or date of death, participant / guardian’s or investigator’s decision, WoC or lost to follow up, whichever occurs first) of the last participant in the study globally, or at 5 years from the last [177Lu]Lu-NeoB administration to the last study participant, whichever occurs last.

[0204] Treatment of interest

[0205] This study includes [177Lu]Lu-NeoB and capecitabine as study treatment and [68Ga]Ga-NeoB as an imaging agent. Participants will receive [177Lu]Lu-NeoB in combination with capecitabine (and a GnRHa, where applicable, as per local clinical practice for pre- / peri-menopausal women in the phase II part only, and in men).

[0206] The NeoB peptide is a new generation bombesin analogue which binds to the GRPR with high affinity (half maximal inhibitory concentration (IC50) 1-2 nM) and showing low internalization. It contains a dodecane tretraacetic acid (DOTA) metal-chelator which allows for radiolabeling with different radionuclides including gallium-68 (for PET imaging), and lutetium-177 (for radionuclide therapy) without affecting receptor affinity, internalization properties or biodistribution. These features may mean that [68Ga]Ga-NeoB and [177Lu]Lu-NeoB is a promising theranostic pair. [68Ga]Ga-NeoB is a PET imaging agent investigated as a selection tool for [177Lu]Lu-NeoB treatment in patients with tumors overexpressing GRPR, including mBC patients. [68Ga]Ga- NeoB has shown favorable technical and diagnostic performance to identify GRPR-expressing malignancies, both in preclinical and in clinical studies, with good image quality that allows easy interpretation.

[0207] [177Lu]Lu-NeoB has shown high affinity to the GRPR and its ability to target the GRPR expressing tumor has been confirmed in in vivo imaging and biodistribution studies in tumor models. [177Lu]Lu-NeoB is rapidly cleared from the blood, quickly eliminated through the renal system, with no retention in kidneys. [177Lu]Lu-NeoB is currently being evaluated as a single agent in an ongoing phase l / lla, open-label, multi-center study (EUDRACT no. 2018-004727-37 ) which evaluates the safety, tolerability, whole-body distribution, radiation dosimetry and antitumor activity of [177Lu]Lu-NeoB administered in patients with advanced solid tumors known to overexpress GRPR who have no therapeutic available options. Data show that [177Lu]Lu-NeoB has shown a good tolerability and safety profile and a favorable biodistribution with low uptake in organs considered to be at risk due to GRPR-expression, such as the pancreas, or due to radioligand therapy (RLT), such as the red marrow, and the route of excretion, such as the kidneys.

[0208] Capecitabine is an oral fluoropyrimidine carbamate that is converted to 5-fluorouracil (5-FU) preferentially in tumor tissue through exploitation of high intratumoral concentrations of thymidine phosphorylase. It is one of the most frequent chemotherapy treatment choices for HR+ / HER2- mBC patients post-CDK4 / 6i failure from 2nd line and beyond as reflected in real word data. It is also considered to be a potent radiosensitizer. The synergistic combination of chemotherapy and radionuclides has the potential to enhance efficacy.

[0209] Number of Participants:

[0210] This study will enroll a total of between 36 and 58 participants, depending on the applicable scenario. In the phase I part, about 18 participants will be either enrolled or randomized (as applicable). In the phase II part, between 28 and 40 participants will be randomized, depending on the applicable scenario.

[0211] Key Inclusion criteria:

[0212] • Participant is female or male adult > 18 years old at the time of informed consent(s).

[0213] • Participant has a histologically and / or cytologically documented diagnosis of ER+ breast cancer (ER expression >10% of tumor cell nuclei stain (regardless of PgR expression) (based on the most recently analyzed tissue sample tested by a local laboratory). • Participant has HER2- breast cancer defined as a negative in situ hybridization test (ISH) or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative ISH (e.g., FISH, CISH, or SISH) (based on the most recently analyzed tissue sample tested by a local laboratory) is required.

[0214] • Participant received no more than three prior endocrine therapy / ies (single agent or in combination with targeted therapy) regimen / s in the metastatic setting of which at least one included endocrine therapy in combination with a CDK4 / 6L In addition:

[0215] • in case of confirmed presence of deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation, the participant may also have received a PARP inhibitor-based therapy.

[0216] • In case of HER2-low breast cancer, the participant may also have received Enhertu®.

[0217] •Note: disease progression while on adjuvant ET (with or without CDK4 / 6i) or within 12 months of completing adjuvant endocrine therapy (with or without CDK4 / 6i), will be considered a line of therapy.

[0218] • Participant has metastatic breast cancer with radiologically confirmed progression of disease after the most recent therapy

[0219] • Participant must have measurable disease, i.e. , at least one measurable lesion as per RECIST 1.1. (a lesion at a previously irradiated site may only be counted as a target lesion if there is a clear sign of progression since the irradiation) as per local assessment.

[0220] • Participant has at least one target lesion [as per RECIST 1.1 and based on the baseline contrast-enhanced CT (or MRI)] with [68Ga]Ga-NeoB uptake above the liver at PET / CT or PET / MRI, as per local reading. In addition:

[0221] • Participant with liver or lung disease involvement must show [68Ga]Ga-NeoB uptake above the liver as follows:

[0222] • If there is liver disease involvement (in the absence of lung involvement), in > 50% of all CT measurable liver lesions (RECIST 1.1)

[0223] • If there is lung disease involvement (in the absence of liver involvement), in > 50% of all CT measurable lung lesions (RECIST 1.1)

[0224] • Participants with both liver and lung disease involvement must show [68Ga]Ga-NeoB uptake above the liver in > 50% of all CT measurable lesions either in liver or lung (RECIST 1.1) and in at least one measurable lesion in the remaining organ (lung or liver)

[0225] • Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0226] • Participant has adequate bone marrow and organ function as defined by laboratory (as assessed by local laboratory). • For Phase I part only : Female participant must be in postmenopausal status at the time of starting study treatment.

[0227] • For Phase II part only

[0228] • Female participant is post-menopausal as per criteria above at the time of starting study treatment.

[0229] • Female participant is pre / peri-menopausal at the time of starting study treatment.

[0230] Key Exclusion criteria

[0231] •Participant with symptomatic visceral disease or any disease burden that are at risk of lifethreatening complications as per the investigator’s judgment.

[0232] • Participant has received prior treatment with chemotherapy in the metastatic setting (allowed in neoadjuvant / adjuvant setting, unless progression or recurrence occurred during or within 12 months after completion of adjuvant chemotherapy).

[0233] • Participant has received prior treatment with capecitabine

[0234] • Participant has inflammatory breast cancer at screening.

[0235] •Participant has any other concurrent severe and / or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate participant participation in the clinical study or compromise compliance with the protocol

[0236] • History or current diagnosis of impaired cardiac function, clinically significant cardiac disease or ECG abnormalities

[0237] • Participant is currently receiving brivudine which cannot be discontinued at least 4-week prior to start of capecitabine therapy.

[0238] • Participant is currently receiving NEP inhibitors (i.e. , Entresto®) and images for dosimetry assessments cannot be acquired for this participant.

[0239] • Participant with known deficiency or family history of deficiency of dihydropyrimidine dehydrogenase.

[0240] • Sexually active male participants unwilling to:

[0241] • remain abstinent (refrain from sexual intercourse) or

[0242] • use a condom, while taking study treatment and for at least 4 months after the last administration of [177Lu]Lu-NeoB, or 3 months after the last dose of capecitabine (or as per locally prescribing information) whichever is longer, in addition to the highly effective method used by the partner who is a female of child-bearing potential.

[0243] • For Phase II part only • Pregnant or breast-feeding women

[0244] • Women of childbearing potential

[0245] Treatment Groups:

[0246] •The screening period of 42 days is followed by the treatment period until disease progression, discontinuation of study treatment due to any other reason such as unacceptable toxicity, symptomatic deterioration, WoC, lost to follow up, investigator decision or death, whichever occurs first. The post treatment follow up period comprises the safety follow up for 8 weeks after treatment discontinuation and the long term safety and survival follow up for up to 5 years from the date of the participant's last dose of [177Lu]Lu-NeoB

[0247] • During screening, each participant will receive [68Ga]Ga-NeoB for PET / CT or PET / MRI imaging to confirm eligibility. Additionally, within 4-8 weeks from the last administration of [177Lu]Lu-NeoB, another administration of [68Ga]Ga-NeoB for PET / CT or PET / MRI will be performed, in the phase II part only.

[0248] • In the phase I part, participants will receive [177Lu]Lu-NeoB at a starting dose of 150mCi + / - 10% (iv infusion) Q6W in combination with capecitabine (tablet, 1000 mg / m2 twice daily for 14 consecutive days followed by 7 days off treatment). If dose escalation is supported, then two higher dose levels of [177Lu]Lu-NeoB in combination with capecitabine are planned to be explored, in a randomized way: 200mCi Q6W and 100mCi Q3W. These correspond to the same total dose given in a 6 weeks timeframe but exploring a different dose fractionation.

[0249] •If dose escalation from the starting dose is not supported, then lower dose levels will be explored (100mCi Q6W and if shown safe, 100mCi Q3W) in combination with capecitabine. If none of these are shown safe then the study will be terminated

[0250] • In the phase II part, there are four potential scenarios that may apply, depending on the outcome of the phase I part:

[0251] • Scenario 1 (if both higher dose levels in phase I were shown safe) participants will be randomized to either [177Lu]Lu-NeoB 200mCi Q6W or 100mCi Q3W, in combination with capecitabine

[0252] • Scenario 2 (if only one of the two higher dose levels in phase I were shown safe) participants will be randomized to either [177Lu]Lu-NeoB 200mCi Q6W / 100mCi Q3W (whichever was shown safe in phase I) or 150 mCi Q6W, in combination with capecitabine • Scenario 3 (if none of the higher doses in phase I are shown safe): participants will be randomized to either [177Lu]Lu-NeoB 150mCi Q6W or 100mCi Q6W, in combination with capecitabine

[0253] • Scenario 4 (if dose escalation from the starting dose was not supported in phase I and lower investigational dose levels and regimens are shown safe in phase I part): participants will be randomized to either [177Lu]Lu-NeoB 100 mCi Q6W or 100 mCi Q3W, in combination with capecitabine.

[0254] • Treatment duration with [177Lu]Lu-NeoB is 6 administrations for Q6W regimens and 12 administrations for Q3W regimens. Additional [177Lu]Lu-NeoB administrations may be considered based on an individual benefit-risk assessment performed by the Investigator, participant and Sponsor.

[0255] • In each of the scenarios above, capecitabine is given as a tablet, 1000 mg / m2 twice daily for 14 consecutive days followed by 7 days off treatment.

[0256] •Treatment cycles are 21 days. The study participants may receiveup to 12 doses of [177Lu]Lu- NeoB if tolerated, and can be treated with further doses if appropriate.

[0257] •The [177Lu]Lu-NeoB will be dosed on day 1 of each cycle for a 3 week dosing regimen (Q3W), and on day one of odd numbered cycles only for a 6 week dosing regimen (Q6W).

[0258] •Capecitabine will be dosed daily on days 1-14 of each cycle followed by a 7 day break.

[0259] Capecitabine can be dosed until disease progression

[0260] Example 2: Rationale for the study

[0261] Nonclinical Biodistribution and DMPK

[0262] The biodistribution of [177Lu]Lu-NeoB has been evaluated in vivo in healthy mice and in tumorbearing models. NeoB is rapidly cleared from the blood, eliminated through the renal system with no retention in the body. Background radioactivity, observed in GRPR-expressing tissues (mostly pancreas), decreases over time. On the contrary, tumor uptake remains high at all time points evaluated, yielding to increased tumor / background ratios. [177Lu]Lu-NeoB induces cellular damage mainly through free radical formation in GRPR-positive tumor and neighboring cells.

[0263] The NeoB peptide was stable in vitro after incubation at 37°C in plasma and hepatocytes from four different species (mouse, rat, mini-pig, and human). In all tested species, intact NeoB was predominant in the metabolic profile, with only a minor fraction of fragments generated by protease activity, suggesting no hepatic metabolism. In rodents, NeoB showed overall fast elimination through renal and hepatobiliary routes.

[0264] Due to the radio-metabolites detected in human, the metabolism of [175Lu]Lu-NeoB and unlabelled NeoB was further investigated in kidney metabolic fractions (S9 and brush border membrane vesicles (BBMV)) in the presence and absence of protease inhibitors. Results indicated that neprilysin (NEP) is the primary metabolic enzyme in human in vitro (Novartis internal data). Therefore, NEP inhibition could potentially lead to increased [177Lu]Lu-NeoB absorbed doses (exposure).

[0265] Based on the results of in vitro drug-drug interaction (DDI) studies, [177Lu]Lu-NeoB is not considered to have a potential for CYP- or transporter-mediated drug-drug interactions.

[0266] Toxicology

[0267] Non-clinical studies were conducted with the non-radioactive surrogate [175Lu]Lu-NeoB formulation and support the NeoB peptide safety for administration in patients. No adverse effects have been observed in the safety pharmacology studies. Similarly, no signs of toxicity have been reported after either the acute or repeated administrations of [175Lu]Lu-NeoB confirming the safety of the non-radioactive molecule.

[0268] Clinical Experience with [177Lu]Lu-NeoB

[0269] The FIH Phase l / lla open-label, multi-center, NeoRay study (NCT03872778) is currently ongoing to evaluate the safety, tolerability, whole-body distribution, radiation dosimetry and anti-tumor activity of [177Lu]Lu-NeoB administered every 6 weeks in patients with advanced solid tumors known to overexpress GRPR. As of Jun 7th, 2023, [177Lu]Lu-NeoB has been administered to 17 patients as per Table 2. Patients included in the first cohort received a first dose (Cycle 1) of [177Lu]Lu-NeoB of 50 mCi (1.85 GBq). In Dose level (DL) 1 , an intra-patient dose escalation to 150 mCi [177Lu]Lu-NeoB was implemented based on clinical dosimetry in Cycle 1.

[0270] Table 2. Patients enrolled across cohorts in NeoRay Dose Level 1 Dose Level 2 Dose Level 3

[0271] N parents enrolled

[0272] Tumor type 1 Breast cancer 2 Prostate cancer 2 Prostate cancer

[0273] 1 Prostate cancer 2 GIST 6 GIST

[0274] 1 GIST 1 Glioblastoma 1 Glioblastoma cycles completed 2 tor 2 patients t for 3 patients 3 in 3 patients

[0275] 6 for 1 patient 2 for 1 patient 2 in 5 patients

[0276] 3 for 1 patient 1 In 1 patient

[0277] Cut-off date 07- J un-2023

[0278] DL1 (50 mCi in cycle 1 and 150 mCi in subsequent cycles) did not lead to any significant toxicity (no Serious Adverse Events (SAE)). The patient with breast cancer enrolled in this cohort was a 54-year old woman with a stage IV HR+ / HER2+ invasive ductal carcinoma with multiple bone metastasis first diagnosed on May-2018. The patient received prior mastectomy, radiotherapy, and multiple lines of therapies (including palbociclib + ET, trastuzumab, pertuzumab, fulvestrant, capecitabine, and everolimus + exemestane) prior to enrolling in the study. The patient discontinued study treatment after 2 administrations of [177Lu]Lu-NeoB due to disease progression.

[0279] In the second cohort of patients receiving dose level 2 (300 mCi) two out of the 4 enrolled patients experienced dose limiting toxicities (DLTs) (anemia grade 3 in both patients and encephalopathy grade 3 in one). All these events have resolved.

[0280] With the observed incidence of DLTs at dose level 2, a dose de-escalation to 250 mCi (dose level 3) was decided in alignment with the protocol.

[0281] Dose level 3 evaluated 250 mCi in 4 patients initially and treatment was overall well tolerated with the majority of the reported AEs being mild / moderate, with no DLTs and no SAEs reported. Given the overall favorable safety profile of DL 3, a dose re-escalation to 300 mCi for cohort 4 was decided. Only one patient with GBM was enrolled and developed moderate (grade 2) nausea, severe (grade 3) vomiting 5 days after the first dose of study treatment and ‘neurological decline’ (grade 3) (preferred term: nervous system disorder) leading to hospitalization the following day. All the events were considered serious and probably related to [177Lu]Lu-NeoB by the investigator. Neurological decline has met the definition of DLT. Twelve days after the first dose of the study treatment, a new event of grade 2 nausea and grade 3 vomiting developed while the AE of nervous system disorder worsened to grade 4. While the events of nausea and vomiting rapidly resolved the day after, the event of nervous system disorder further worsened to grade 4 despite the increase of the dexamethasone therapy, led to treatment discontinuation and was ongoing at the time of patient’s death due to active euthanasia. Considering that the very first patient treated in this new cohort at 300 mCi experienced a DLT (neurological decline) and taking into account the other 2 patients who experienced DLTs (anemia and encephalopathy) in the prior cohort at 300 mCi (DL 2), the dose was de-escalated as per protocol to 250 mCi (DL 3) and cohort 5 was opened for enrollment. As of Jun 7th, 2023, in cohort 5 with 250 mCi dose (DL 3) a total of 5 patients were enrolled of which 4 were with GIST and 1 patient with prostate cancer indications. None of the patients in cohort 5 experienced any DLT or SAE. Reported AEs were mild or moderate in severity. Laboratory abnormalities of > grade 2 were non clinically significant.

[0282] Across the dose levels assessed, two prolonged disease stabilization were observed in cohort 1 (50 mCi and 150 mCi) (approximately one year in a GIST patient and five months in a prostate cancer patient).

[0283] Out of the 17 treated patients in the study, 4 patients completed treatment, 2 patients discontinued due to AEs, 7 discontinued due to PD, 3 patients discontinued due to investigator / patient decision, and 1 patient is ongoing.

[0284] Preliminary blood-radioactivity pharmacokinetics of [177Lu]Lu-NeoB from NeoRay showed a quick elimination from systemic circulation with a geometric mean elimination half-life of -55-80 h and an average effective half-life of -44 h. Radio-HPLC data shows metabolites in systemic circulation and urine (likely pharmacologically inactive metabolites unable to bind to the receptor) and cumulative excretion of activity indicates that radioactivity is still primarily (> 80% on average) excreted via the kidneys within 24-48 hours. Metabolites will be investigated in plasma.

[0285] Preliminary dosimetry results demonstrate favorable biodistribution with low uptake in organs considered to be at risk due to GRPR-expression, such as the pancreas, or due to RLT, such as the red marrow, and the route of excretion, such as the kidneys. Dose normalized observed mean absorbed doses (rounded to 2 significant digits) from all cohorts in Gy / GBq (± SD, n=13) were 0.10 ± 0.056 (kidneys), 0.018 ± 0.0076 (red marrow), 0.056 ± 0.038 (pancreas), 0.011 ± 0.0041 (testes, n=10), 0.021 ± 0.0094 (ovaries, n=3) and 0.53 ± 0.84 (all tumor lesions, n=28), respectively.

[0286] Given the overall favorable safety profile of DL 3, a dose re-escalation to 300 mCi for cohort 4 was decided. Only one patient with GBM was enrolled and developed moderate (grade 2) nausea, severe (grade 3) vomiting 5 days after the first dose of study treatment and ‘neurological decline’ (grade 3) (PT: nervous system disorder) leading to hospitalization the following day. All the events were considered serious and probably related to [177Lu]Lu-NeoB by the investigator. Neurological decline has met the definition of DLT. Considering that the very first patient treated in this new cohort at 300 mCi experienced a DLT (neurological decline) and taking into account the other 2 patients who experienced DLTs (anemia and encephalopathy) in the prior cohort at 300 mCi (DL 2), the dose was de-escalated as per protocol to 250 mCi (DL 3). As of 29-Jan-2023, recruitment of patients in cohort 5 at 250 mCi was ongoing with 2 additional patients affected by GIST (for a total of 6) having received 1 cycle of [177Lu]Lu-NeoB at this DL and no DLT been reported.

[0287] The generated Phase I dosimetry data displayed a favorable [177Lu]Lu-NeoB organ dosimetry profile with large safety margin compared to EBRT thresholds even at high cumulative activities. Consequently, based on the observed safety and tolerability data in the tested dose levels, the MTD was determined to be 250 mCi every 6 weeks. Novartis with the participating investigators declared Recommended Phase II Dose (RP2D) as 250 mCi and would be further tested in Phase Ila part of the FIH study CAAA603A12101.

[0288] Background on [68Ga]Ga-NeoB

[0289] [68Ga]Ga-NeoB is a PET imaging agent investigated as a selection tool for [177Lu]Lu-NeoB treatment in patients with tumors overexpressing GRPR, including mBC patients. [68Ga]Ga- NeoB has shown favorable technical and diagnostic performance to identify GRPR-expressing malignancies, both in preclinical and in clinical studies, with good image quality that allows easy interpretation. Its diagnostic performance has been assessed in two completed clinical trials:

[0290] • MITIGATE (NCT02931929), a Phase l / lla clinical trial evaluated the safety, biodistribution, dosimetry and preliminary diagnostic performance of [68Ga]Ga-NeoB in subjects with advanced, tyrosine-kinase-inhibitor-pretreated GIST. [68Ga]Ga-NeoB was well tolerated in all 9 participants, with a good safety profile (single injection of [68Ga]Ga-NeoB at 3 MBq / kg body weight with a minimum of 150 and a maximum of 250 MBq was administered). Radiation exposure was low, due to a rapid renal and blood clearance. Biodistribution showed a high [68Ga]Ga-NeoB uptake in the pancreas, followed by the kidneys and the liver. A fast, visually moderate-to-high tumorspecific uptake in GRPR expressing lesions was identified.

[0291] • NeoFIND (NCT03724253), a Phase II clinical trial, evaluated the preliminary diagnostic performance of [68Ga]Ga-NeoB in 19 subjects with breast (n=5), prostate (n=5), colorectal (n=5), non-small cell (n=3) and small cell (n= 1 ) lung cancers. The favorable safety profile of [68Ga]Ga- NeoB was confirmed in this study. Results indicated a variable [68Ga]Ga-NeoB uptake in tumor lesions, with the highest number of lesions showing a visually moderate-to-high uptake in breast cancer patients.

[0292] In addition, [68Ga]Ga-NeoB is currently used in the ongoing Phase l / lla NeoRay study (NCT03872778) as an imaging agent to select patients for the treatment with [177Lu]Lu-NeoB. As of Jun 7th, 2023, 50 patients received [68Ga]Ga-NeoB and no safety concerns related to [68Ga]Ga- NeoB have been reported, with an administered dose of 150-250 MBq.

[0293] Background on capecitabine

[0294] Capecitabine is an oral fluoropyrimidine carbamate, a prodrug of 5-fluorouracil (5-Fll) that is converted to 5-Fll preferentially in tumor tissue through exploitation of high intratumoral concentrations of thymidine phosphorylase. This enzyme is overexpressed in tumor tissues compared with normal tissues, thus resulting in the generation of 5-Fll preferentially at the tumor site and decreasing systemic exposure to 5-Fll. (Blum JL, Dieras V, Lo Russo PM, et al (2001) Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer; 92(7): 1759-68). Data from multiple trials in mBC using capecitabine as monotherapy show response rate ranging 15-28%, time-to-progression of 3-5 months and OS of 10-18 months in patients pretreated with prior lines of therapy. (Lee SH, Lee J, Park J, et al (2004) Capecitabine monotherapy in patients with anthracycline- and taxane- pretreated metastatic breast cancer. Med Oncol; 21(3):223-31 ; Roche H, Vahdat LT (2011) Treatment of metastatic breast cancer: second line and beyond. Ann Oncol; 22(5): 1000- 10.)

[0295] PEARL, a phase III randomized study enrolled patients with Al-resistant mBC who were randomized 1 :1 to palbociclib plus exemestane / fulvestrant or capecitabine. In the primary and final analyses palbociclib plus ET was not superior to capecitabine (in the overall population regardless of ESR1 mutational status), with median PFS of 7.4 versus 9.4 months, adjusted hazard ratio (aHR): 1.11 ; 95% Cl: [0.92-1.34]) and mOS of 32.6 versus 30.9 months (aHR 1.00, 95% Cl: [0.82-1.23]). The objective response rate (ORR) among patients randomized to palbociclib + fulvestrant vs capecitabine was 26.7% and 33.3%, respectively. In patients with ESR1 wild-type, ORR was 27.8% for palbociclib plus ET (exemestane or fulvestrant) versus 36.9% for capecitabine (Martin JM, Handorf EA, Montero AJ, et al (2022) Systemic Therapies Following Progression on First-line CDK4 / 6-inhibitor Treatment: Analysis of Real-world Data. Oncologist; 27(6):441-46. Martin M, Zielinski C, Ruiz-Borrego M, et al (2021) Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL. (Ann Oncol; 32(4):488-99). Efficacy results with capecitabine in this study were in alignment with results from the phase II BOLERO-6 study where ER+ / HER2- locally advanced or metastatic BC patients upon Al treatment failure were enrolled to receive everolimus plus exemestane or everolimus monotherapy or capecitabine monotherapy; in this study mPFS was 8.4 months with everolimus plus exemestane vs 6.8 months with everolimus alone (HR, 0.74; 90% Cl, 0.57-0.97) vs 9.6 months with capecitabine (HR, 1.26; 90% Cl, 0.96-1.66); mOS and ORR were 23.1 months, 29.3 months and 25.6 months and 20%, 12% and 23% with everolimus plus exemestane vs everolimus alone vs capecitabine, respectively. (Jerusalem G, de Boer RH, Hurvitz S, et al (2018) Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized Clinical Trial. JAMA Oncol; 4(10):1367-74).

[0296] Capecitabine is one of the most frequent chemotherapy treatment choices for HR+ / HER2- mBC patients post-CDK4 / 6i failure from 2nd line and beyond as reflected in real word data. (Choong GM, Liddell S, Ferre RAL, et al (2022) Clinical management of metastatic hormone receptorpositive, HER2-negative breast cancer (MBC) after CDK 4 / 6 inhibitors: a retrospective singleinstitution study. Breast Cancer Res Treat; 196(1):229-37; Xi J, Oza A, Thomas S, et al (2019) Retrospective Analysis of Treatment Patterns and Effectiveness of Palbociclib and Subsequent Regimens in Metastatic Breast Cancer. J Natl Compr Cane Netw; 17(2):141-147).

[0297] An ad hoc analysis investigating the clinical treatment outcome post ribociclib in patients enrolled in MONALEESA-2 (NCT01958021), MONALEESA-3 (NCT02422615) and MONALEESA-7 (NCT02278120) studies has been conducted. The analysis included a total of 58 and 76 patients treated with capecitabine as post-study treatment anti-neoplastic therapy and whose data was available for assessment of PFS and OS, respectively. Data showed that capecitabine led to a mPFS of 7.6 months and mOS of 23.6 months in these patients.

[0298] Capecitabine offers the benefit of oral dosing and is suitable for long-term administration and generally lacks cumulative toxicity with prolonged use. (O'Shaughnessy JA, Kaufmann M, Siedentopf F, et al (2012) Capecitabine monotherapy: review of studies in first-line HER-2- negative metastatic breast cancer. Oncologist; 17(4):476-84). Multiple phase ll / lll randomized trials in patients with mBC have shown that capecitabine is a safe therapy in the first- and subsequent- lines settings. The most frequent non-hematological adverse events reported were mild or moderate, manageable by treatment interruption and, if necessary, dose reduction and included hand-foot syndrome (HFS) (42-62%), nausea (31-55%), vomiting (24-37 %), hyperbilirubinemia (-22%), diarrhea (20-58%), stomatitis (15-33.8%), constipation, dermatitis, abdominal pain (-15%), fatigue (13-23%) and asthenia (10-35%). Rates of mild or moderate hematological toxicities varied across studies and included anemia (50-70%), leukopenia (-54%), thrombocytopenia (31-27%) and neutropenia (25.6-43%). The predominant treatment- related grade 3 and 4 adverse events were HFS (13-21.6%), diarrhea (10-16%) and nausea (-10%). Severe hematological toxicities were rare. (XELODA®USPI 1998; Pallis AG, Boukovinas I, Ardavanis A, et al (2012) A multicenter randomized phase III trial of vinorelbine / gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane- pretreated women with metastatic breast cancer. Ann Oncol; 23(5): 1164-69).

[0299] Screening

[0300] The study informed consent form (IGF) must be signed and dated before any study specific screening procedures are performed, except for evaluations performed as part of standard of care.

[0301] During the screening period of up to 42 days, participant eligibility will be determined according to the protocol’s pre-defined inclusion and exclusion criteria. All screening assessments should be performed according to the SoA. Each participant will receive an administration of [68Ga]Ga- NeoB during screening to confirm eligibility for treatment with [177Lu]Lu-NeoB. A safety follow-up phone call will occur at 3 (+ / -1) days after [68Ga]Ga-NeoB administration for all participants.

[0302] Participants who meet all eligibility criteria at screening can be enrolled in the study.

[0303] The general dose plan for both screening and treatment period is shown in Fig. 1.

[0304] Treatment period

[0305] 1- Dose escalation part in Phase I

[0306] The dose escalation part will estimate the RDs (recommended doses) and dosing regimen(s) of [177Lu]Lu-NeoB in combination with capecitabine. The general dosing plan is shown in Fig. 1. The starting dose of [177Lu]Lu-NeoB will be 150 mCi (5.55 GBq) Q6W, for 6 administrations, in combination with capecitabine 1000 mg / m2 administered orally (BID, morning and evening; equivalent to 2000 mg / m2 total daily dose) from Day 1 through Day 14 followed by 7 days of treatment pause, in a 21 day (3 weeks) cycle. Approximately six participants will be enrolled at this dose, in order to have at least four evaluable participants for evaluation of DLTs during the DLT period.

[0307] The DLT period is defined as a period of 42 days starting from the day of first [177Lu]Lu-NeoB administration. In addition, for participants in the Q3W dosing regimen, DLT period will continue until 21 days after the second administration of [177Lu]Lu-NeoB.

[0308] Dose evaluation will be made by Investigators and Novartis study personnel. Decisions will be based on a combination of all relevant data available for each dose level evaluated in the ongoing study using overall safety and tolerability information, including DLTs during DLT period, all CTCAE Grade > 2 toxicities, PK, dosimetry and preliminary efficacy data from evaluable participants:

[0309] • If dose escalation is supported, a total of 12 additional participants will be randomized in a 1 :1 ratio into one of two higher dose levels which correspond to the same total dose given in a 6 weeks timeframe, but exploring a different dose fractionation (i.e. different dosing regimen):

[0310] • [177Lu]Lu-NeoB at 200 mCi (7.4 GBq) Q6W for 6 dose administrations + capecitabine 1000 mg / m2 BID Day1-14 in a 21-day (3 week) cycle (i.e. [177Lu]Lu-NeoB dosing every other cycle)

[0311] • [177Lu]Lu-NeoB at 100 mCi (3.7 GBq) Q3W for 12 dose administrations + capecitabine 1000 mg / m2 BID Day1-14 in a 21-day (3 week) cycle

[0312] Participants randomized to either of these 2 dose levels will be followed for DLTs during the DLT period.

[0313] If both these dose levels are considered safe, they will be expanded in the phase II part (scenario 1 below). If at least one dose level is not considered safe, the non-safe dose level will be discontinued and either scenario 2 or 3, as described below, will apply for the phase II part.

[0314] • If dose escalation is NOT supported, a lower dose level of [177Lu]Lu-NeoB at 100 mCi Q6W for 6 administrations in combination with capecitabine 1000 mg / m2 BID Day 1-14 in a 21-day cycle will be assessed in a cohort of 6 participants. If this dose and regimen is safe, a dose escalation to [177Lu]Lu-NeoB 100 mCi Q3W for 12 dose administrations in combination with capecitabine 1000 mg / m2 BID Day 1-14 on a 21-day cycle will be initiated in another cohort of 6 participants.

[0315] If neither [177Lu]Lu-NeoB 100 mCi Q6W nor [177Lu]Lu-NeoB 100 mCi Q3W are safe, the study will be terminated.

[0316] 2- Dose optimization part in Phase II The dose optimization part will evaluate the preliminary anti-tumor activity among two randomized treatment arms of [177Lu]Lu-NeoB in combination with capecitabine.

[0317] Based on the phase I part, one of four different scenarios will be applicable for the phase II part. Scenario 1 : if both the higher doses and dosing regimens in the phase I part (200 mCi Q6W and 100 mCi Q3W) are safe:

[0318] A total of 28 participants will be randomized in a 1 : 1 ratio to one of two treatment arms to have a total of 40 participants (including the 12 participants randomized to the two cohorts evaluating these dose levels in phase I) as follows:

[0319] • [177Lu]Lu-NeoB at 200 mCi Q6W + capecitabine 1000 mg / m2 BID Day1-14 in a 21-day cycle (i.e. [177Lu]Lu-NeoB administration on Day 1 of every other cycle)

[0320] • [177Lu]Lu-NeoB at 100 mCi Q3W + capecitabine 1000 mg / m2 BID Day1-14 in a 21-day cycle

[0321] Scenario 2: only one of the two higher dose and dosing regimen in the phase I part (either 200 mCi Q6W or 100 mCi Q3W) is safe:

[0322] A total of 40 participants will be randomized in a 1 :1 ratio to two treatment arms as follows:

[0323] • Either [177Lu]Lu-NeoB at 200 mCi Q6W or [177Lu]Lu-NeoB at 100 mCi Q3W + capecitabine 1000 mg / m2 BID Day1-14 in a 21-day cycle (whichever was shown safe in phase I)

[0324] • [177Lu]Lu-NeoB at 150 mCi Q6W + capecitabine 1000 mg / m2 BID Day1-14 in a 21-day cycle

[0325] Scenario 3: neither of the higher doses and dosing regimens in phase I (neither 200 mCi Q6W nor 100 mCi Q3W) are safe:

[0326] A total of 40 participants will be randomized in a 1 :1 ratio to two treatment arms as follows:

[0327] • [177Lu]Lu-NeoB at 150 mCi Q6W + capecitabine 1000 mg / m2 BID Day1-14 in a 21-day cycle

[0328] • [177Lu]Lu-NeoB at 100 mCi Q6W + capecitabine 1000 mg / m2 BID Day1-14 in a 21-day cycle

[0329] If dose escalation was NOT supported in the phase I part, [177Lu]Lu-NeoB 100 mCi Q6W and 100 mCi Q3Wwill be investigated, as described above. If these two regimens are considered safe, then scenario 4 will apply:

[0330] Scenario 4:

[0331] A total of 40 participants will be randomized in a 1 :1 ratio across two treatment arms as follow:

[0332] • [177Lu]Lu-NeoB at 100 mCi Q6W + capecitabine 1000 mg / m2 BID Day1-14 in a 21-day cycle

[0333] • [177Lu]Lu-NeoB at 100 mCi Q3W + capecitabine 1000 mg / m2 BID Day1-14 in a 21-day cycle If neither [177Lu]Lu-NeoB 100 mCi Q6W nor [177Lu]Lu-NeoB 100 mCi Q3W are safe (more than 1 participant experiences a DLT), the study will be terminated.

[0334] Scientific rationale for study design

[0335] This is a phase l / ll, randomized, dose escalation and optimization study of [177Lu]Lu-NeoB in combination with capecitabine (and a GnRha for pre / peri-menopausal women in the Phase II part only and men, if applicable) in adult participants with ER+ / HER2-, GRPR+ mBC after progression on CDK4 / 6i-based therapy.

[0336] The study is designed as a Phase I dose escalation part with the purpose of identifying two recommended doses (RD) and dosing regimen(s) of [177Lu]Lu-NeoB in combination with capecitabine based on overall safety and tolerability data . The selected doses / dosing regimen(s) will be further evaluated in the Phase II randomized part for safety and tolerability and assessment of anti-tumoral activity. The ultimate goal of this study is the identification of the optimal dose and dosing regimen of [177Lu]Lu-NeoB in combination with capecitabine which will maximize the benefit-risk ratio for the treatment of the targeted population in future studies.

[0337] Randomization in the phase I and phase II parts is used to minimize selection bias and allow an unbiased evaluation of safety, tolerability and anti-tumoral activity of the different doses / dosing regimens tested.

[0338] An open label study design was selected due to the study treatment modalities of administration and requirements for radioprotection as per local regulations and the non-pivotal stage of the study.

[0339] The study will investigate the combination of [177Lu]Lu-NeoB with capecitabine in the phase I part in postmenopausal women. In the phase II part both pre / perimenopausal (with the addition of a GnRHa e.g. goserelin, triptorelin, or leuprolide if applicable) and postmenopausal participants will be enrolled based on the following considerations:

[0340] • recommended treatment for HR+ / HER2- mBC in pre / perimenopausal and postmenopausal women is generally similar with the exception of addition of GnRHa in pre / perimenopausal women

[0341] • alignment with FDA guidance recommending for inclusion of premenopausal women with adequate estrogen suppression in BC studies

[0342] • enrollment of an appropriately broad population to allow assessment of the doses / dosing regimens of [177Lu]Lu-NeoB in combination with capecitabine across relevant subpopulations. The evidence of high GRPR expression in ER+ breast cancer, the possibility to select patients with GRPR positive tumors using [68Ga]Ga-NeoB PET imaging and the possible synergistic effect of capecitabine with [177Lu]Lu-NeoB, make the combination to be tested in this study a plausible potential targeted treatment modality aiming at improving the prognosis of this patient population.

[0343] Justification for dose

[0344] [177Lu]Lu-NeoB

[0345] The starting dose of [177Lu]Lu-NeoB in the Phase I part (dose escalation) will be 5.55 GBq (150 mCi) every 6 weeks (Q6W). The selection of this dose of [177Lu]Lu-NeoB is based on the totality of data collected to date from the FIH NeoRay study for the treatment of patients with solid tumors overexpressing GRPR with [177Lu]Lu-NeoB as single agent.

[0346] In this FIH study, patients enrolled in the first dose level received an initial dose of 1.85 GBq (50 mCi, not considered an effective dose) followed by subsequent dose administrations of 150 mCi of [177Lu]Lu-NeoB (based on the Estimated Cumulative Dose established from the dosimetry data obtained in cycle 1), to receive potentially therapeutic doses of the study medication. Subsequent cohorts evaluated higher doses of [177Lu]Lu-NeoB i.e. 250 mCi (9.25 GBq) and 300 mCi (11.1 GBq) Q6W, and 250 mCi has been declared as RP2D for [177Lu]Lu-NeoB as monotherapy to be further investigated in the phase Ila part of the NeoRay study.

[0347] Based on dosimetry data (data cut-off Jun 7th, 2023) from the three investigated dose levels at Cycle 1 (50 mCi, 250 mCi, and 300 mCi), the mean cumulative absorbed doses in kidney, pancreas, red marrow, testes, and ovaries are significantly below external beam radiation therapy (EBRT) thresholds even at the highest investigated dose of 300 mCi, indicating that the risk of radiation related toxicities at this dose from both singular and cumulative administrations is low.

[0348] In this study, a total of six or twelve dose administrations of [177Lu]Lu-Neo for the Q6W and the Q3W dosing regimen are initially foreseen, respectively. Margins for 6 administrations of 11.1 GBq (300 mCi) [177Lu]Lu-NeoB in Neoray (the highest investigated radiation dose thus far) were significantly below external beam radiation therapy (EBRT) thresholds: ~11 -fold for the pancreas (40 Gy EBRT threshold), ~1.7-fold margin for the red marrow (2 Gy EBRT threshold), 1.4-2.1-fold margin for testes and ovaries (1 Gy and 3 Gy EBRT thresholds), and 3.5-fold margin for the kidneys (23 Gy EBRT thresholdcalculations are based on the mean absorbed doses and above mentioned EBRT thresholds. However, since [177Lu]Lu-NeoB is administered in combination with capecitabine in this study and in the absence of clinical data for this combination, the starting dose was lowered to 150 mCi (corresponding to approximately 60 % of the RP2D of [177Lu]Lu-NeoB as monotherapy in the NeoRay study i.e. 250 mCi). Therefore, radio-safety margins are proportionally higher for the starting dose of [177Lu]Lu-NeoB at 150 mCi and the cumulative dose considered to be safe to be administered over at least 6 (or 12, with fractionated doses) administrations with the potential to deliver clinical activity.

[0349] A lower dose of [177Lu]Lu-NeoB at 100 mCi Q6Wwill be evaluated in the phase I part, in case 150 mCi is not deemed safe.

[0350] Given the observed tumor absorbed dose, doses lower than 100 mCi were not considered in this study in order to not further reduce the cumulative absorbed dose delivered to the tumor over the treatment period and thus potentially reduce the likelihood of clinical responses and efficacy.

[0351] On the other hand, in the context of the phase I dose escalation part, a higher dose of [177Lu]Lu- NeoB at 200 mCi (7.4 GBq) Q6W in combination with capecitabine will be investigated, providing the starting dose of 150 mCi Q6W is deemed safe, in this combination.

[0352] Safety review of blood laboratory parameters over time after [177Lu]Lu-NeoB administration in NeoRay showed that there is no trend for decrease or deterioration of hematological parameters. As such a certain recovery period between administrations is not considered necessary. There are no data available suggesting that a higher frequency of administration would aggravate the safety of a single administration, especially since [177Lu]Lu-NeoB related radioactivity is cleared rapidly from the body. Hence, for optimization of the dosing regimen, 100 mCi administered at a shorter interval i.e. Q3W will also be investigated in the Phase I part. The shorter interval will enable administration of sufficient radioactivity amount per single dose to reach a potentially effective cumulative dose in an appropriate timeframe.

[0353] NeoRay is currently enrolling in the phase Ila part at RP2D for [177Lu]Lu-NeoB as monotherapy i.e. 250 mC in a GPRP-positive but otherwise highly heterogenous and heavily pretreated population with different cancer types (e.g., GIST, prostate cancer, breast cancer, and GBM), hence making it challenging to identify early signals of clinical efficacy.

[0354] Based on the observed tumor absorbed dose from NeoRay, 6 administrations for the Q6W regimen and 12 for the Q3W regimen are selected, provided the participant can tolerate the treatment and the disease does not show progression. As patients may continue to derive benefit beyond these planned administrations and to maximize the benefit-risk for each individual participant, the study will allow for additional administrations of [177Lu]Lu-NeoB, if prerequisites are met. This approach is supported by the observed preliminary dosimetry data and radiation safety margins for up to 300 mCi showing that the mean cumulative absorbed dose in all organs at risk would still be below common EBRT thresholds with a positive safety margin. It is, however, important to note that the application of these EBRT limits to RLT is, likely too conservative due to the intrinsic differences between external beam radiation and radionuclide therapy. This includes different dose rates and fractionation (dosing regimen) schemes, an inhomogeneous absorbed dose distribution and potentially different radiobiological mechanisms of cytotoxicity resulting in varying biological effects. In fact, there is growing evidence that a biologically effective dose (BED) of ~40 Gy is safe for the kidneys with Lu- 177 labelled RLTs, with a conversion factor of 1.09 to convert absorbed dose to BED with 177Lu- based RLTs (ffiB L, Cremonesi M, Ferrari M, et al (2008) Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging; 35(10):1847-56LOBj7LOBJ:Schafer H, Mayr S, Buttner-Herold M, et al (2022) Extensive 177Lu-PSMA Radioligand Therapy Can Lead to Radiation Nephropathy with a Renal Thrombotic Microangiopathy Eur Urol; 83(5):385-90LOBJJ).

[0355] Hence at a dose of 100, 150 and 200 mCi there may be minimal concern for radiation-induced toxicities beyond initially planned number of administrations (depending on the regimen), as organs may be able to tolerate higher radiation dose. This approach will enable to assess different cumulative doses on an individual patient level.

[0356] Rationale for choice of combination drug

[0357] During the study [177Lu]Lu-NeoB will be administered in combination with capecitabine, which is considered to be a potent radiosensitizer.

[0358] Capecitabine is an effective treatment for mBC as supported by data from multiple trials showing a response rate of 15-28%, a median time-to progression (mTTP) of 3-5 months and mOS of 10- 18 months in patients pretreated with prior lines of therapy (Lee SH, Lee J, Park J, et al (2004) Capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Med Oncol; 21(3):223-31 ; Roche H, Vahdat LT (2011) Treatment of metastatic breast cancer: second line and beyond. Ann Oncol; 22(5): 1000-10).

[0359] There are a number of mechanisms by which capecitabine in the form of its active metabolite 5- FU could increase radiation sensitivity at the cellular level. The final step of activation of capecitabine into 5-Fll is driven by the action of the tumor-associated angiogenic factor thymidine phosphorylase (TP), which is overexpressed in tumor cells. The enzyme TP appears to be essential for the antitumor activity of capecitabine (Smorenburg CH, Bontenbal M, Verweij J (2001) Capecitabine in breast cancer: current status. Clin Breast Cancer; 1(4):288-93

[0360] ) and in preclinical studies has been shown to be upregulated in irradiated cells, resulting in higher concentrations of 5-Fll in those cells and in a selective synergistic effect between radiotherapy and capecitabine. Such a mechanism may improve the likelihood of capecitabine enhanced radiosensitization due to increased exposure of tumor to the chemotherapeutic agent, which would be anticipated to increase cell killing (De Paoli A, Chiara S, Luppi G, et al (2006) Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol; 17(2):246-51).

[0361] 5-Fll has both DNA-directed and RNA-directed effects. Although both effects can produce cytotoxicity, 5-Fll radiosensitization results from its DNA-directed actions (Lawrence TS, Tepper JE, Blackstock AW (1997) Fluoropyrimidine-Radiation Interactions in Cells and Tumors. Semin Radiat Oncol; 7(4):260-6). In fact, a substantial body of evidence suggests that radiosensitization of 5-Fll is also a result of inhibition of the thymidylate synthase enzyme which causes deleterious consequences for DNA synthesis leading to cell death and to increase in deoxyadenosine triphosphate (dATP), resulting in inhibition of DNA synthesis and accumulation of cells in early S phase. The cell cycle effects seem to be crucial for radiosensitization with 5- Fll, loss of the S-phase checkpoint in cancer cells may provide the molecular basis for selective killing of tumors compared with normal tissues (Shewach DS, Lawrence TS (2007) Antimetabolite radiosensitizers. J Clin Oncol; 25(26):4043-50).

[0362] The use of capecitabine as a radiosensitizer has been widely applied in the clinical setting for the treatment of several cancer types, including pancreatic, rectal and breast cancers combined with EBRT and shown to be effective and safe. When capecitabine is combined with EBRT the range of doses used (1500-1700 mg / m2daily) is lower than the approved dose of 1250 mg / m2BID (De Paoli A, Chiara S, Luppi G, et al (2006) Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol; 17(2):246-51 ; Velenik V, Anderluh F, Oblak I, et al (2006) Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced resectable rectal cancer: prospective phase II trial. Croat Med J; 47(5):693-700; Abrams MJ, Huber KE, Knisely JP, et al (2015) Capecitabine as a Radiosensitizer in Adjuvant Chemoradiotherapy for Pancreatic Cancer: A Retrospective Study. Anticancer Res; 35(12):6901-7; Gaui MF, Amorim G, Arcuri RA, et al (2007) A phase II study of second-line neoadjuvant chemotherapy with capecitabine and radiation therapy for anthracycline-resistant locally advanced breast cancer. Am J Clin Oncol; 30(1 ):78-81 ; Sherry AD, Mayer IA, Ayala-Peacock DN, et al (2020) Combining Adjuvant Radiotherapy With Capecitabine in Chemotherapy-resistant Breast Cancer: Feasibility, Safety, and Toxicity. Clin Breast Cancer; 20(4): 344-52).

[0363] The synergistic combination of chemotherapy and radionuclides has the potential to enhance efficacy. Chemotherapeutic agents often radiosensitize tumors to targeted radionuclide treatment and cytotoxic effects are additive. Chemosensitization with 5-Fll in combination with radiolabeled somatostatin analog (indium-111 octreotide) was shown to be feasible with an acceptable safety profile, and enhanced efficacy of therapy in neuro-endocrine tumors (NETs) (Kong G, Thompson M, Collins M, et al (2014) Assessment of predictors of response and longterm survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT). Eur J Nucl Med Mol Imaging; 41 (10): 1831 -44).

[0364] The use of oral capecitabine (at doses ranging 1500-1650 mg / m2daily) in combination with the radioligand [177Lu]Lu-Octreotate has been evaluated in several studies in gastro- enteropancreatic-neuroendocrine tumors (GEP-NET) patients:

[0365] • the combination was shown to be feasible and safe, considering acute and subacute side effects and did not lead to increased toxicity as compared to the use of RLT alone (van Essen M, Krenning EP, Kam BL, et al (2008) Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging; 35(4):743-8; Claringbold PG, Brayshaw PA, Price RA, et al (2011) Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours. Eur J Nucl Med Mol Imaging; 38(2): 302-11).

[0366] • treatment was efficacious leading to tumor control and stabilization of disease (Objective Response Rate (ORR): ~ 38%, partial response (PR): 24-38% and stable disease (SD): 50-70% (Nicolini S, Bodei L, Bongiovanni A, et al (2021) Combined use of 177Lu- DOTATATE and metronomic capecitabine (Lu-X) in FDG-positive gastro-entero- pancreatic neuroendocrine tumors. Eur J Nucl Med Mol Imaging; 48(10):3260-67; Satapathy S, Mittal BR, Sood A, et al (2021) 177Lu-DOTATATE Plus Radiosensitizing Capecitabine Versus Octreotide Long-Acting Release as First-Line Systemic Therapy in Advanced Grade 1 or 2 Gastroenteropancreatic Neuroendocrine Tumors: A SingleInstitution Experience. JCO Glob Oncol; 7:1167-75).

[0367] • the combination of [177Lu]Lu-Octreotate with capecitabine, temozolomide, or both (CAPTEM) for the treatment of GEP-NETs showed promising tumor response rates (Complete Response (OR): 16%, PR: 41%, SD: 37% and progressive disease: 6%; Claringbold PG, Price RA, Turner JH (2012) Phase l-ll study of radiopeptide 177Lu- octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. Cancer Biother Radiopharm; 27(9):561-9) with no significant increase of the short-term and long-term hematological toxicity.

[0368] Overall, these features support the combination of capecitabine, as radiosensitizer, with radioligand therapy targeting cellular receptors with high sensitivity and specificity. The combination may enhance anti-tumor effects without necessarily causing more adverse events as demonstrated in multiple studies conducted in various solid tumors.

[0369] In addition, based on Investigator's discretion and local clinical practice, GnRhas may be administered to peri / premenopausal women in the phase II part and men for suppression of sex hormones level.

[0370] Rationale for dose selection of capecitabine in combination with [177Lu]Lu-NeoB

[0371] Participants in this study will receive capecitabine 1000 mg / m2BID for 2 weeks followed by 1 week off in combination with [177Lu]Lu-NeoB.

[0372] The original capecitabine approved dose for the treatment of mBC in the US and EU was 1250 mg / m2BID for 2 weeks followed by a one-week rest period in 3-week schedule until progression or unacceptable toxicity (Xeloda® USPi / EU 2022 SmPC). When capecitabine is used as monotherapy at the registered dose 1250 mg / m2for treatment of mBC, frequent dose modifications for management of toxicities occur in approximately 40% of patients (Leonard R, Hennessy BT, Blum JL, et al (2011) Dose-adjusting capecitabine minimizes adverse effects while maintaining efficacy: a retrospective review of capecitabine for metastatic breast cancer. Clin Breast Cancer; 11 (6): 349-56). In Phase Il-Ill studies, 27% to 65% of patients required a 25% dose reduction. The median time to dose reduction is typically less than 2 months (Zielinski C, Gralow J, Martin M (2010) Optimising the dose of capecitabine in metastatic breast cancer: confused, clarified or confirmed? Ann Oncol; 21 (11):2145-52). This high rate of dose modifications led to hypothesize that a lower starting dose might improve tolerability, enabling patients to continue treatment and thus maintain control of disease for longer. Of note, in the US, the capecitabine dose regimen was recently revised to reflect the current clinical practice to reduce starting dose for patients with mBC (i.e., 1000 mg / m2or 1250 mg / m2BID for 2 weeks followed by a one-week rest period in 3-week) (Xeloda® USPI 2022).

[0373] Capecitabine has been evaluated as monotherapy or in combination at a lower starting dose of 1000 mg / m2BID for 2 weeks on / 1 week off in prospective Phase II trials and demonstrated a more favorable safety profile with lower incidence of gastrointestinal and hand-foot syndrome (HFS) toxicity, less dose modifications (19-33%) and similar efficacy to the higher dose (Baselga J, Segalla JG, Roche H, et al (2012) Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol; 30(13):1484-91).

[0374] A systematic review and meta-analysis comparing the toxicity profile of standard dose (1250 mg / m2BID) and lower starting dose (1000 mg / m2BID) of capecitabine in breast cancer across 4,833 patients from 34 trials showed that the lower dose has a better safety profile compared to the higher dose. In fact, analysis showed a significantly lower incidence of dose reduction (15.9 vs. 39.0%; P = 0.007), high-grade HFS (12.0 vs. 19.0%; P = 0.01), diarrhea (5.3 vs. 9.1 %; P = 0.01), and neutropenia (1.8 vs. 7.3%; P < 0.01) and all-grade neutropenia (5.8 vs. 25.4%; P = 0.01) in capecitabine 1000 mg / m2BID compared to 1250 mg / m2BID (Nishijima TF, Suzuki M, Muss HB (2016) A comparison of toxicity profiles between the lower and standard dose capecitabine in breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat; 156(2):227-36).

[0375] Evidence supporting the efficacy of capecitabine at 1000 mg / m2BID comes from prospective and retrospective Ph II studies which reported similar overall response and clinical benefit rates and comparable mTTP to those obtained with the higher dose (Zielinski C, Gralow J, Martin M (2010) Optimising the dose of capecitabine in metastatic breast cancer: confused, clarified or confirmed? Ann Oncol; 21 (11):2145-52).

[0376] (

[0377] This tendency is also in alignment with the most recent NCCN guidelines and revised USPI which recommend using 1000-1250 mg / m2 BID when given as monotherapy. Multiple studies showed that capecitabine administered at lower doses (ranging 1500-1700 mg / m2 / day) than 1250 mg / m2BID and at various schedules (metronomic or 2 weeks on / 1 week off) in combination with radiotherapy or radioligand therapy may enhance the therapeutic effect of the combination with no safety concerns of acute or delayed toxicity.

[0378] Capecitabine is an effective and overall well tolerated chemotherapeutic agent for the treatment of breast cancers and it is convenient for patients thanks to oral administration.

[0379] When used in combination with [177Lu]Lu-NeoB there are not known drug-drug interactions which are likely to adversely affect the benefit-risk of this combination. Mild or moderate hematological toxicities reported in patients receiving capecitabine at approved dose may overlap with [177Lu]Lu- NeoB potential myelosuppression which is an identified risk of [177Lu]Lu-NeoB.

[0380] Taking into consideration the toxicity challenges observed with the 1250 mg / m2BID dose of capecitabine, in the context of mitigating the potential risk of overlapping myelotoxicity and exploring capecitabine as a radiosensitizer, the dose of 1000 mg / m2BID for 2 weeks followed by 1 week off treatment will be given in this study in combination with [177Lu]Lu-NeoB.

[0381] Study Treatments

[0382] In this study, the term "investigational drug" refers to the radioligand imaging (RLI) compound [68Ga]Ga-NeoB, and to the RLT compound [177Lu]Lu-NeoB. The term "study treatment" refers to the combination of [177Lu]Lu-NeoB and capecitabine.

[0383] Participants will receive [177Lu]Lu-NeoB in combination with capecitabine, in both the phase I and the phase II parts of the study. GnRHa administration is allowed as per local clinical practice for pre / peri-menopausal participants in the phase II part only and men.

[0384] The [177Lu]Lu-NeoB solution for infusion and the kit for the radiopharmaceutical preparation of [68Ga]Ga-NeoB will be provided centrally by Novartis. Capecitabine and GnRHa (if applicable) will be provided locally by the study site, by the Novartis subsidiary or designee, as commercially available, or centrally by Novartis, in each participating country according to local practices and regulations.

[0385] All dosages prescribed and dispensed to the participant and all dose changes during the study must be recorded on the Dosage Administration Record eCRF. Details on requirements for storage, management and administration of study treatment, instructions for participant numbering, prescribing and dispensing are outlined in the accompanying Pharmacy Manual. A summary of the drugs is shown in Table 3.

[0386] Table 3. Investigational and combination drugs

[0387] [68Ga]Ga-NeoB

[0388] In this study, after radiolabeling with Ga-68, [68Ga]Ga-NeoB serves as a radioactive imaging compound to be used for PET for localization of GRPR positive lesions. It will be used for participant selection during screening and for PET imaging after the last administration of [177Lu]Lu-NeoB.

[0389] [68Ga]Ga-NeoB will be administered intravenously (IV). The optimal recommended activity to be administered will be defined after testing different dose activity ranges in a small group of participants in the phase I part of the study. [177Lu]Lu-NeoB

[0390] Study participants will receive a dose of 3.7 GBq (100 mCi) + / - 10% of [177Lu]Lu-NeoB which will be administered once every 28 days (1 cycle) for 6 cycles.

[0391] Capecitabine

[0392] Capecitabine will be administered at dose of 1000 mg / m2twice daily from Day 1 through 14 of a 21-day cycle (2 weeks on / 1 week off).

[0393] Additional study treatments In addition to the study treatment, pre- and peri-menopausal women in the phase II part of the study and men, may receive appropriate GnRHa treatment for ovarian suppression and reduction of sex hormones as per locally approved prescribing information and / or local clinical practice. The gnRHa treatment can include, for example, goserlin, triptorelin, or leuprolide.

[0394] Treatment Duration

[0395] Participants will receive a single dose of the RLI compound [68Ga]Ga-NeoB at screening ; participants in the phase 11 part only will also receive an additional one after the last administration of [177Lu]Lu-NeoB.

[0396] Participants receiving [177Lu]Lu-NeoB Q6W, will receive up to 6 planned administrations, whereas participants receiving [177Lu]Lu-NeoB Q3W, will receive up to 12 planned administrations.

[0397] More than 6 or 12 administrations of [177Lu]Lu-NeoB, for the Q6W and Q3W regimens respectively, may be given based on benefit-risk evaluation by investigator and in agreement with the Sponsor.

[0398] The maximum duration of treatment with [177Lu]Lu-NeoB in this study will depend on the total doses of [177Lu]Lu-NeoB that each participant in the study will receive.

[0399] Participants will continue receiving capecitabine until disease progression, unacceptable toxicity, death, loss to follow up, participant / guardian’s or investigator’s decision or WoC.

[0400] Dose and treatment schedule

[0401] The dose and treatment schedule is shown in Tables 4 and 5.

[0402] Table 4. Dose and treatment schedule (Phase I part)

[0403] Table 5. Dose and treatment schedule (Phase 2 part)

[0404] Guidelines for dose escalation

[0405] For the purposes of dose escalation decisions, each cohort will consist of approximately 6 newly enrolled participants to have at least four evaluable participants treated at the specified dose / dosing regimen. The first cohort will be treated with the starting dose of [177Lu]Lu-NeoB 150 mCi Q6W.

[0406] Participants must complete a minimum of 42 days of treatment from the first [177Lu]Lu-NeoB administration or 21 days from the second administration in the Q3W dosing regimen (corresponding to DLT (dose limiting toxicity) period) with the minimum safety evaluation and have received at least 90% of the planned [177Lu]Lu-NeoB dose and at least 75% of the planned capecitabine dose or have had a DLT during the DLT period to be considered evaluable for dose escalation decisions. If the subsequent planned dose (second or third for the Q6W or Q3W regimen, respectively), is administered earlier than planned for any reason, DLT period will end the day before this administration. In addition, participants from the Q3W dosing regimen who received their 2nd administration of [177Lu]Lu-NeoB with a delay of more than 7 days will also be excluded from the Dose Determination Set (DDS) unless they have experienced a DLT. Dose decisions will occur when the cohort of participants has met these criteria.

[0407] Dose decisions will be made by Investigators and Novartis study personnel. Decisions will be based on a synthesis of all relevant data available from all dose levels evaluated in the ongoing study using overall safety and tolerability information, including DLTs during DLT period, all CTCAE Grade > 2 toxicities data, PK, dosimetry and preliminary efficacy data from evaluable participants.

[0408] The decision rules to escalate or de-escalate will be guided by the following rules:

[0409] • When a dose escalation is foreseen (i.e. during the evaluation of 150 mCi Q6W or 100mCi Q6W):

[0410] • 0 DLTs: escalate the dose

[0411] • 1 DLT:

[0412] • in 4 or 5 evaluable participants, complete the recruitment up to a minimum of 6 evaluable participants and escalate if no new DLT or de-escalate if new DLTs occurred (if 150 mCi Q6W is being evaluated) or stop the study (if 100 mCi Q6W is being evaluated)

[0413] • in minimum of 6 evaluable participants, escalate the dose

[0414] • > 1 DLT: de-escalate (if 150 mCi Q6W is being evaluated) or stop the study (if 100 mCi Q6W is being evaluated)

[0415] • When NO dose escalation is foreseen (i.e. during the evaluation of 200 mCi Q6W and 100 mCi Q3W):

[0416] • 0-1 DLT: the dose is considered safe

[0417] • > 1 DLT: the dose is not considered safe

[0418] Eligibility screening

[0419] Informed consent must be obtained before any study specific procedures are performed, except for evaluations performed as part of standard of care.

[0420] Procedures conducted as part of the participant’s routine clinical management / standard of care (e.g. blood count) and obtained before signing of the IGF may be utilized for screening or baseline purposes provided the procedures met the protocol-specified criteria and were performed within the timeframe defined in the Schedule of Activities.

[0421] The screening period is up to 6 weeks (42 days) and occurs between participant screening visit (at which informed consent signature occurs) and participant enrollment (when participant eligibility has been confirmed as per inclusion / exclusion criteria). The screening period should be shortened as much as possible. During the screening period, imaging with [68Ga]Ga-NeoB should be performed as soon as possible in order not to delay participant enrollment and as close as possible to the CT or MRI used for tumor assessment (no more than 2 weeks apart). All screened participants receiving [68Ga]Ga-NeoB will be followed for safety before being discharged from the imaging unit at screening and with a dedicated call 3 ± 1 days after administration to assess occurrence of AEs.

[0422] Only participants who meet all eligibility criteria at screening can be enrolled in the study. Participant enrollment and ordering of [177Lu]Lu-NeoB must be performed immediately after all eligibility criteria are verified and the participant is confirmed to be eligible and at least 14 days before the planned administration of [177Lu]Lu-NeoB.

[0423] [68Ga]Ga-NeoB Imaging

[0424] The [68Ga]Ga-NeoB PET scan allows both to assess the expression of the target molecule (GRPR) on the tumor cells to which [177Lu]Lu-NeoB will subsequently bind, and to evaluate the intensity of the expression. In the current study, a baseline PET / CT or PET / RI will be performed , with the purpose ofselecting particpants for treatment with [177Lu]Lu-NeoB. Eligibility will be based on the uptake of [68Ga]Ga-NeoB in tumor lesions, which will be graded using the uptake of the healthy liver as a visual reference. This baseline PET will be performed as close as possible in time to the baseline CT or MRI.

[0425] [68Ga]Ga-NeoB PET / CT or PET / MRI mst be acquired at 120+ / - 30 minutes after the intravenous injection of the radiotracer, scanning from the top of the head to proximal mid thigh (torso with head included), with arms raised whenever possible.

[0426] The coded medical images will be used primarily for analysis as described in this protocol; however, the images may also be used for the development and evaluation of new analysis methods directly related to the area of research that this study covers.

[0427] Incidental findings are beyond the scope of central imaging vendor. If an Investigator / radiologist recognizes any incidental finding in the images during the course of conducting the clinical trial, the Investigator should follow up as part of his / her duty of care to ensure the safety and wellbeing of the participant, as well as compliance with local ethical regulations.

[0428] The dose ranges of [68Ga]Ga-NeoB tested will be 200 MBq (150-250MBq), 300 MBq (270- 333MBq), and 100 MBq (74-130 MBq)

Claims

Claims1 . A method of treating breast cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a radiopharmaceutical compound, in combination with 5-fluorouracil or a 5-fluorouracil prodrug, e.g. capecitabine, wherein said radiopharmaceutical compound is a compound of formula (I), or pharmaceutically acceptable salts thereof:C-S-P (I) wherein: C is a chelating moiety, S is an optional pspacer covalently linking C and P, P is a GRP receptor ligand moiety, and wherein said radiopharmaceutical compound is labelled with a radionuclide M.

2. The method of claim 1 , wherein said 5-fluorouracil or a fluorouracil prodrug is a 5-fluorouracil prodrug.

3. The method of claim 2, wherein said 5-fluorouracil prodrug is capecitabine.

4. The method of any one of claims 1-3, wherein M is selected from90Y,131l,121Sn,186Re,188Re,64Cu,67Cu,59Fe,89Sr,198Au,203Hg,212Pb,165Dy,103Ru,149Tb,161Tb,213Bi,166Ho,165Er,169Er,153Sm,177Lu,213Bi,223Ra,225Ac,227Ac,227Th,211At,67Cu,186Re,188Re,161Tb,175Yb,105Rh,166Dy,199Au,44Sc,149Pm,151Pm,142Pr,143Pr,76As,111Ag and47Sc.

5. The method of any one of claims 1-4, wherein M is177Lu.

6. The method of any one of claims 1-5, wherein C is obtained by linking to S or P a chelating agent selected from 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1 ,4, 7, 10-tetraazacyclododececane,1 (glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylentriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triacetic acid (D03A), triethylenetetramine (TETA), 1 ,4,7-triazacyclononane-1 ,4,7-triacetic acid (NOTA) , NOTAGA, 1-(1 ,3-carboxypropyl)-4,7-carboxymethyl-1 ,4,7-triazacyclononane (NODAGA), NODASA, NODAPA, and 1 ,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6- methylperhydro-1 ,4-diazepine (AAZTA, e.g. AAZTA5).

7. The method of claim 6, wherein C is of the following formula,8. The method of any one of claims 1-7, wherein P is of the general formulaDPhe-GIn-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-i (CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2or Z iswherein X is NH and R2 is (CH2-CH(CH3)2and R1 is the same as R2 or (CH2N)-Pro-NH2.

9. The method of claim 8, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2- CH(CH3)2)2.

10. The method of any one of claims 1-9, wherein the compound of Formula (I) is a compound of Formula (II)wherein C and P are as defined in any one of Claim 1 and 12-15, and wherein the chelating moiety C is complexed with a radionuclide M.

11. The method of any one of claims 1-10, wherein the radiopharmaceutical compound is M- NeoB of the following formula (III).(III), or pharmaceutically acceptable salts thereof, wherein M is a radionuclide, for example M is177Lu.

12. The method of any one of claims 1-11 , wherein said subject has ER positive, HER-2 negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer.

13. The method of any one of claims 1-12, wherein said subject has been selected from subjects experiencing progression after previous endocrine therapy in combination with a CDK4 / 6 inhibitor.

14. The method of treating breast cancer in a subject in need thereof according to claim 1 , said method comprising administering to said subject a therapeutically effective amount of a radiopharmaceutical compound, in combination with a 5-fluorouracil prodrug which is capecitabine, wherein said radiopharmaceutical compound is NeoB of the following formula (III).(HI), wherein M is177Lu, and wherein said subject has ER positive, HER-2 negative (ER+ / HER2-) and GRPR-positive (GRPR+) metastatic breast cancer and has been selected from subjects experiencing progression after previous endocrine therapy in combination with a CDK4 / 6 inhibitor.

15. The method of any one of claims 13-14, wherein said endocrine therapy comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a non-steroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader.

16. The method of claim 15, wherein said endocrine therapy comprises administering a therapeutically effective amount of a selective ER degrader.

17. The method of claim 16, wherein said selective ER degrader is fulvestrant.

18. The method of any one of claims 13-17, wherein said CDK4 / 6 inhibitor is ribociclib and said endocrine therapy comprises administering a therapeutically effective amount of fulvestrant.

19. The method of any one of claims 1-18, wherein said radiopharmaceutical compound is administered 3 to 12 times, 4 to 10 times, 4 to 8 times, 6 times, 10 times, or 12 times.

20. The method of claim 19, wherein said radiopharmaceutical compound comprises an administration interval of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 or 4 weeks, or 4 weeks.

21. The method of any one of Claims 1-20, wherein said radiopharmaceutical compound is administered at a dose ranging from 0.925 GBq (25mCi) to 29.6GBq (800 mCi), from 1.48 GBq (40 mCi) to 18.5 GBq (500mCi), from 1.85 GBq (50mCi) to 14.8 GBq (400mCi), from 3.7 GBq (100mCi) to 11.1 GBq(300mCi), about 3.7 GBq (100mCi), about 5.55 GBq (150mCi), about 7.4 GBq (200mCi), about 9.25GBq (250mCi), or about 11.1 GBq (300mCi).

22. The method of any one of claims 1-21 , wherein said 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, is administered orally at a daily dose of 1000-2500 mg / m2, e.g. about 2000 mg / m2, e.g. in cycles of a period of 15 to 28 days, e.g. each cycle including about 14 days of daily administration followed by a period of about 7 days off treatment, and is administered for at least as long as the radiopharmaceutical is administered, and optionally administration of said fluoruracil or fluoruracil prodrug continues until disease progression.

23. The method of claim 22, wherein said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously every 14-56 days, for 1 to 12 cycles, for example 6 to 12 cycles, at a dose ranging from 3.7 GBq (100mCi) to 11.1 GBq(300mCi), e.g. about 100 mCi, about 150 mCi, or about 200mCi, in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2, for 7 to 21 days per cycle.

24. The method of claim 22, wherein said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously about every 14-28 days, e.g. about every 21 days, for 1 to 12 cycles, for example 6 to 12 cycles, at a dose of about 3.7 GBq (100mCi) or about 5.55 GBq (150 mCi) in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2 for 7-21 days per cycle, e.g. about 14 days per cycle.

25. The method of claim 22, wherein said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously about every 35-50 days, e.g. about every 42 days, on odd numbered cycles only of 14-28 day cycles, e.g. about 21 day cycles, for 1 to 12 cycles, for example 6 to 12 cycles, at a dose of about 5.55 GBq (150mCi), in combination with 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2 for 7-21 days per cycle, e.g. about 14 days per cycle.

26. The method of claim 22, wherein said radiopharmaceutical compound is [177Lu]Lu-NeoB and is administered intravenously about every 35-50 days, e.g. about every 42 days, on odd numbered cycles only of 14-28 day cycles, e.g. about 21 day cycles for 1 to 12 cycles, for example 6 to 12 cycles, at a dose of about 7.4 GBq (200mCi), in combination with 5-fluorouracil or 5- fluorouracil prodrug, e.g. capecitabine, administered orally at a daily dose of about 2000 mg / m2 for 7-21 days per cycle, e.g. about 14 days per cycle.

27. The method of any one of Claims 1-26, wherein said subject is a post-menopausal woman with metastatic breast cancer.

28. The method of any one of Claims 1-27, wherein said subject is a pre-menopausal or peri- menopausal woman with metastatic breast cancer.

29. The method of any one of claims 1-28, wherein said subject has been selected by PET / CT or PET / MRI imaging with the same radiopharmaceutical compound as defined for the treatment, but with an alternate radionuclide suitable for imaging, for example 68-Gallium, 67-Gallium or 64- Copper, e.g. 68-Gallium, based on detection of said radionuclide in the imaging scan at the tumor region, for example, two weeks prior to start of said treatment.

30. The method of any one of claims 1-29, wherein said subject has HR positive, HER-2 negative (HR+ / HER2-) and GRPR-positive (GRPR+) breast cancer and is experiencing progression after previous endocrine therapy in combination with a CDK4 / 6 inhibitor, wherein said radiopharmaceutical compound is administered to said subject in combination with 5-fluorouracilor 5-fluorouracil prodrug, e.g. capecitabine, wherein a first dose of said radiopharmaceutical compound is administered the within 3 days, e.g., the same day, as the first dose of 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine,.

31. The method of claim 30, wherein 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, is administered orally at a daily dose of about 2000 mg / m2, for example in cycles of a period of about 21 days, each cycle for example including about 14 days of administration followed by a period of about 7 days off treatment, wherein the radiopharmaceutical compound is administered for 4-10 cycles, and 5-fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, is administered for at least as long as the radiopharmaceutical is administered, and optionally administration of 5- fluorouracil or 5-fluorouracil prodrug, e.g. capecitabine, continues until disease progression.

32. The method of Claim 30 or 31 , wherein said radiopharmaceutical compound is M-NeoB of the following formula:wherein M is177Lu.

33. The method of any one of claims 1-32, wherein said radiopharmaceutical compound is M-NeoB of the following formula:wherein M is177Lu, and said radiopharmaceutical compound is administered by intravenous infusion at a concentration of 370MBq / mL.

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