Methods for treating breast cancer

Abstract

The present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a radiopharmaceutical compound having a GRPR antagonist moiety, e.g., 177 [0013] The present invention relates to a method comprising administering to the subject [0014] Lu]Lu-NeoB in combination with a CDK4 / 6 inhibitor, e.g., ribocicilib, and a therapeutically effective amount of an endocrine therapy, e.g., fulvestrant.

Description

[Technical Field]

[0001] The present invention provides a method for treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a radiopharmaceutical compound comprising a GRPR binding moiety, e.g., 177

[0033] Lu-NeoB is administered to the subject in combination with a CDK4 / 6 inhibitor and endocrine therapy. [Background technology]

[0002] Breast cancer is the most common cancer and the leading cause of cancer death for women worldwide. Global incidence is 85.8-91.6 cases per 100,000 people, while mortality rates range from 17.4-20.1 deaths per 100,000 people (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).

[0003] Despite advances in new therapeutic approaches, there remains a need to provide improved clinical treatments for breast cancer. Summary of the Invention

[0004] The present disclosure provides a method for treating breast cancer in a subject in need thereof by administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor, such as ribocicilib, and an endocrine treatment, such as fulvestrant, wherein the radiopharmaceutical compound has Formula (I): CSP(I) (In the formula, C is a chelating moiety; P is a GRP receptor binding moiety; S is an optional spacer that covalently links C and P or a pharmaceutically acceptable salt thereof, and labeled with a radionuclide M.

[0005] The present disclosure is provided in various aspects, as outlined below: 1. A method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor and endocrine therapy, wherein the radiopharmaceutical compound has Formula (I): CSP(I) (In the formula, C is a chelating moiety; P is a GRP receptor antagonist moiety; S is an optional spacer that covalently links C and P or a pharmaceutically acceptable salt thereof, and is labeled with a radionuclide M. 2. The method of embodiment 1, wherein said CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abemaciclib. 3. The method of embodiment 2, wherein said CDK4 / 6 inhibitor is ribociclib. 4. The method of any one of embodiments 1-3, wherein said endocrine therapy comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader. 5. The method of any one of embodiments 1-4, wherein said endocrine treatment comprises administering a therapeutically effective amount of a selective ER degrader. 6. The method of embodiment 5, wherein said selective ER degrader is fulvestrant. 7. The method of embodiment 5 or 6, wherein a therapeutically effective amount of said selective ER degrading agent is administered, e.g., starting on the same day as administration of said radiopharmaceutical compound, and once every 14 to 56 days, e.g., 28 days, for at least the period that the radiopharmaceutical compound is administered, and optionally, administration of the ER degrading agent continues until disease progression. 8. The method of any one of embodiments 1-7, wherein said CDK4 / 6 inhibitor is ribociclib and said endocrine treatment comprises administering a therapeutically effective amount of fulvestrant. 9. The method of embodiment 8, wherein said CDK4 / 6 inhibitor, preferably ribociclib, is administered simultaneously with fulvestrant. 10. M, 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At,67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 10. The method of any one of embodiments 1-9, wherein Sc is selected from: 11. M, 177 The method of any one of embodiments 1-10, wherein Lu is 12.C is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetrazoxetan), trizoxetan, 1,4,7,10-tetraazacyclododecane, 1(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramine (T 12. The method of any one of embodiments 1-11, wherein the compound is obtained by linking to S or P a chelating agent selected from 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA, e.g., AAZTA5), 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). 13.C is a compound of the formula [ka] 13. The method of embodiment 12, wherein 14. The peptide P has the general formula DPhe-Gln-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-ψ(CHN)-Pro-NH and NH—CH(CH—CH(CH)) or or Z is [ka] where X is NH (amide), R2 is (CH2-CH(CH3)2, and R1 is the same as R2 or (CH2N)-Pro-NH2). 14. The method of any one of embodiments 1 to 13, wherein 15. The method of embodiment 14, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2. 16. The compound of formula (I) is represented by the formula (II) [ka] (wherein C and P are as defined in claim 1). 16. The method of any one of embodiments 1-15, wherein the compound is 17. The radiopharmaceutical compound is represented by the following formula (III): [ka] wherein M is a radionuclide, for example, M is 177 Lu) or a pharmaceutically acceptable salt thereof. 18. The method of any one of embodiments 1-17, wherein said radiopharmaceutical compound is administered 3 to 12 times, 4 to 10 times, 4 to 8 times, 6 times, or 10 times. 19. The method of embodiment 18, wherein said radiopharmaceutical compound comprises an administration interval of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 weeks, or 4 weeks, or 4 weeks. 20. The method of any one of embodiments 1-19, wherein said radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), about 3.7 GBq (100 mCi), about 5.55 GBq (150 mCi), about 7.4 GBq (200 mCi), about 9.25 GBq (250 mCi), or about 11.1 GBq (300 mCi). 21. The method of any one of embodiments 1-20, wherein the CDK4 / 6 inhibitor, e.g., ribociclib, is administered orally in a daily dose of 400 to 800 mg, e.g., about 600 mg, for example, 1 to 6 cycles of 15 to 28 days duration, each cycle comprising, e.g., 21 days of daily administration followed by 7 days of rest from treatment. 22. The radiopharmaceutical compound is administered orally in a daily dose of 600 mg for 15 to 21 days per cycle in combination with ribociclib; 177 22. The method of embodiment 21, wherein the compound is Lu-NeoB and is administered intravenously every 28 days for 3 to 12 cycles, for example 6 cycles, at a dose in the range of 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), or 3.7 GBq (100 mCi) to 9.25 GBq (250 mCi), for example 250 mCi, for example 150 mCi. 23. The method of any one of embodiments 1-22, wherein the endocrine therapy, e.g., fulvestrant, is administered via intramuscular administration, e.g., using a long-acting formulation, at a dose of 250-700 mg. 24. The method of any one of embodiments 1-23, wherein said subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer. 25. The method of any one of embodiments 1-24, wherein the subject is selected from subjects who have experienced early relapse after prior neoadjuvant or adjuvant endocrine therapy, or subjects who have experienced progression on prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor. 26. The method of any one of embodiments 1-25, wherein the subject is a postmenopausal woman with advanced metastatic breast cancer. 27. The method of any one of embodiments 1-26, wherein said subject is a pre- or peri-menopausal woman with advanced metastatic breast cancer. 28. The method of any one of embodiments 1-27, wherein said subject is selected from subjects experiencing early relapse after prior neoadjuvant or adjuvant endocrine therapy. 29. The method of any one of embodiments 1-27, wherein said subject is selected from subjects who have experienced progression to a prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor. 30. The method of embodiment 29, wherein said preceding CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abemaciclib, e.g., ribociclib. 31. The method of any one of embodiments 25-30, wherein said prior endocrine treatment comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader. 32. The method of any one of embodiments 1-31, wherein said endocrine therapy further comprises concurrently administering, e.g., via subcutaneous administration, a synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, e.g., at a dose of about 3.6 mg every 28 days. 33. The method of any one of embodiments 1-32, wherein the subject is treated with the same radiopharmaceutical compound as defined for treatment, but prior to any surgery, for example 2 weeks prior to the start of treatment, an alternative radionuclide suitable for imaging, for example 68-gallium, 67-gallium or 64-copper, for example 68-gallium, is selected by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging, based on detection of said alternative radionuclide in an imaging scan in the tumor area. 34. The method of embodiment 33, wherein said subject is selected from among subjects who show the presence of radiometal enhancement, such as gadolinium enhancement, in any pre-operative PET / MRI scan in the tumor area. 35. The method of any one of embodiments 1-34, wherein the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer and is experiencing early recurrence from neoadjuvant or adjuvant therapy, and wherein the radiopharmaceutical compound is administered to the subject in combination with ribociclib and fulvestrant, and wherein the first dose of the radiopharmaceutical compound is administered on the same day as the first dose of ribociclib. 36. The method of embodiment 35, wherein ribociclib is administered orally in a daily dose of about 600 mg, e.g., in 28-day cycles, each cycle comprising, e.g., 21 days of administration followed by 7 days of treatment rest, wherein the radiopharmaceutical compound is administered for 4 to 10 cycles, ribociclib is administered for at least the period during which the radiopharmaceutical is administered, and optionally, administration of the CDK4 / 6 inhibitor continues until disease progression. 37. The radiopharmaceutical compound has the following formula: [ka] (Wherein M is 177 37. The method of embodiment 35 or 36, wherein M-NeoB is M-NeoB of formula (I). 38. The radiopharmaceutical compound has the following formula: [ka] (Wherein M is 177 Lu) and is administered by intravenous infusion at a concentration of 370 MBq / mL. 39. A radiopharmaceutical compound for use in a method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor and endocrine therapy, the radiopharmaceutical compound comprising the formula (I): CSP(I) (In the formula, C is a chelating moiety; P is a GRP receptor antagonist moiety; S is an optional spacer that covalently links C and P or a pharmaceutically acceptable salt thereof, and labeled with a radionuclide M. 40. The radiopharmaceutical compound for use according to embodiment 39, wherein said CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abemaciclib. 41. The radiopharmaceutical compound for use according to embodiment 40, wherein said CDK4 / 6 inhibitor is ribociclib. 42. The radiopharmaceutical compound for use in embodiments 39-41, wherein said endocrine treatment comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader. 43. The radiopharmaceutical compound for use according to embodiments 39-42, wherein said endocrine treatment comprises administering a therapeutically effective amount of a selective ER degrader. 44. The radiopharmaceutical compound for use according to embodiment 43, wherein said selective ER degrader is fulvestrant. 45. The radiopharmaceutical compound for use according to embodiment 43 or 44, wherein a therapeutically effective amount of said selective ER degrader is administered, e.g., starting on the same day as administration of said radiopharmaceutical compound, and once every 14 to 56 days, e.g., 28 days, and for at least the period during which the radiopharmaceutical is administered, and optionally, administration of the ER degrader continues until disease progression. 46. ​​The radiopharmaceutical compound for use according to embodiments 39-45, wherein said CDK4 / 6 inhibitor is ribociclib and said endocrine treatment comprises administering a therapeutically effective amount of fulvestrant. 47. The radiopharmaceutical compound for use according to embodiment 46, wherein said CDK4 / 6 inhibitor, preferably ribociclib, is administered concomitantly with fulvestrant. 48. M, 90 Y, 131 I, 121 Sn, 186 Re,188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 48. The radiopharmaceutical compound for use according to embodiments 39 to 47, wherein the radiopharmaceutical compound is selected from Sc. 49. M, 177 The radiopharmaceutical compound for use according to any one of embodiments 38 to 47, wherein the compound is Lu. 50.C is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1,4,7,10-tetraazacyclododecane, 1(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramine (TETA), 1,4,7-triazacyclono 50. The radiopharmaceutical compound for use in embodiments 39 to 49, obtained by linking to S or P a chelating agent selected from nan-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) chelating moieties. 51.C is a compound of the formula: [ka] 51. The radiopharmaceutical compound for use according to embodiment 50, wherein 52. The peptide P has the general formula DPhe-Gln-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-ψ(CHN)-Pro-NH and NH—CH(CH—CH(CH)) or or Z is [ka] where X is NH (amide), R2 is (CH2-CH(CH3)2, and R1 is the same as R2 or (CH2N)-Pro-NH2). 52. The radiopharmaceutical compound for use according to embodiments 39 to 51, wherein 53. The radiopharmaceutical compound for use in embodiment 52, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2. 54. The compound of formula (I) is a compound of formula (II) [ka] (wherein C and P are as defined in claim 1). 54. The radiopharmaceutical compound for use according to any one of embodiments 39 to 53, which is a compound of the formula: 55. The compound of formula (III) [ka] wherein M is a radionuclide, for example, M is 177 Lu) 55. The radiopharmaceutical compound for use according to any one of embodiments 39 to 54, which is M-NeoB of the formula: 56. The radiopharmaceutical compound for use according to any one of embodiments 39 to 55, wherein the compound is administered 3 to 12 times, 4 to 10 times, 4 to 8 times, 6 times, or 10 times. 57. The radiopharmaceutical compound for use of embodiment 56, comprising an administration interval of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 weeks or 4 weeks, or 4 weeks. 58. The radiopharmaceutical compound for use according to any one of embodiments 39 to 57, wherein the radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), about 3.7 GBq (100 mCi), about 5.55 GBq (150 mCi), about 7.4 GBq (200 mCi), about 9.25 GBq (250 mCi), or about 11.1 GBq (300 mCi). 59. The radiopharmaceutical compound for use according to any one of embodiments 39 to 58, wherein the CDK4 / 6 inhibitor, e.g. ribociclib, is administered orally in a daily dose of 400 to 800 mg, e.g. about 600 mg, for example, over 1 to 6 cycles of 15 to 28 days, each cycle comprising, e.g., 21 days of daily administration followed by 7 days of rest from treatment. 60.[ 177 59. The radiopharmaceutical compound for use in embodiment 59 is [Lu]Lu-NeoB administered intravenously every 28 days for 3 to 12 cycles, for example 6 cycles, at a dose in the range of 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), or 3.7 GBq (100 mCi) to 9.25 GBq (250 mCi), for example 250 mCi, for example 150 mCi, in combination with ribociclib administered orally at a daily dose of 600 mg for 15 to 21 days per cycle. 61. The radiopharmaceutical compound for use according to any one of embodiments 39 to 60, wherein said endocrine therapy, such as fulvestrant, is administered via intramuscular administration, for example using a long-acting formulation, at a dose of 250 to 700 mg. 62. The radiopharmaceutical compound for use according to any one of embodiments 39 to 61, wherein said subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer. 63. The radiopharmaceutical compound for use according to any one of embodiments 39 to 62, wherein said subject is selected from subjects who have experienced early relapse after prior neoadjuvant or adjuvant endocrine therapy, or subjects who have experienced progression on prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor. 64. The radiopharmaceutical compound for use according to any one of embodiments 39 to 63, wherein said subject is a postmenopausal woman with advanced metastatic breast cancer. 65. The radiopharmaceutical compound for use according to any one of embodiments 39 to 63, wherein said subject is a pre- or peri-menopausal woman with advanced metastatic breast cancer. 66. The method of any one of embodiments 39-65, wherein said subject is selected from subjects experiencing early relapse after prior neoadjuvant or adjuvant endocrine therapy. 67. The method of any one of embodiments 39-65, wherein said subject is selected from subjects who have experienced progression to a prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor. 68. The method of embodiment 67, wherein said preceding CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abemaciclib, e.g., ribociclib. 69. The method of any one of embodiments 63-68, wherein said prior endocrine treatment comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader. 70. The radiopharmaceutical compound for use of any one of embodiments 1-69, wherein said endocrine therapy further comprises concurrent administration of a synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, e.g., via subcutaneous administration, every 28 days at a dose of about 3.6 mg. 71. The radiopharmaceutical compound for use according to any one of embodiments 39 to 70, wherein said subject is treated with the same radiopharmaceutical compound as defined for treatment, but prior to any surgery, for example 2 weeks before the start of said treatment, an alternative radionuclide suitable for imaging, for example 68-gallium, 67-gallium or 64-copper, for example 68-gallium, is selected by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging, based on detection of said alternative radionuclide in an imaging scan in the tumor area. 72. The radiopharmaceutical compound for use in embodiment 71, wherein said subject is selected from among subjects who show the presence of radiometal enhancement, such as gadolinium enhancement, in any pre-operative PET / MRI scan in the tumor area. 73. The radiopharmaceutical compound for use according to any one of embodiments 39 to 72, wherein the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer and is experiencing early recurrence from neoadjuvant or adjuvant therapy, and wherein the radiopharmaceutical compound is administered to the subject in combination with ribociclib and fulvestrant, and wherein the first dose of the radiopharmaceutical compound is administered on the same day as the first dose of ribociclib. 74. The radiopharmaceutical compound for use of embodiment 73, wherein ribociclib is administered orally in a daily dose of about 600 mg, for example, in 28-day cycles, each cycle comprising, for example, 21 days of administration followed by 7 days of treatment rest, wherein the radiopharmaceutical compound is administered over 4 to 10 cycles, ribociclib is administered for at least the period during which the radiopharmaceutical is administered, and optionally, administration of the CDK4 / 6 inhibitor continues until disease progression. 75. The following formula: [ka] (Wherein M is 177 75. The radiopharmaceutical compound for use in embodiment 73 or 74, wherein M-NeoB is M-NeoB (wherein M-NeoB is M-NeoB). 76. The following formula: [ka] (Wherein M is 177 736. The radiopharmaceutical compound for use in any one of embodiments 39-735, wherein the radiopharmaceutical compound is M-NeoB of formula (I) and is administered by intravenous infusion at a concentration of 370 MBq / mL. 77. A radiopharmaceutical compound of formula (I): in the manufacture of a medicament for use in a method of treating breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor and endocrine therapy. CSP(I) (In the formula, C is a chelating moiety; P is a GRP receptor antagonist moiety; S is an optional spacer that covalently links C and P or a pharmaceutically acceptable salt thereof and labeled with a radionuclide M. 78. The use of embodiment 77, wherein said CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abemaciclib. 79. The use of embodiment 78, wherein the CDK4 / 6 inhibitor is ribociclib. 80. The use of embodiments 77-79, wherein said endocrine treatment comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader. 81. The use of embodiments 77-80, wherein said endocrine treatment comprises administering a therapeutically effective amount of a selective ER degrader. 82. The use of embodiment 81, wherein said selective ER degrader is fulvestrant. 83. The use of embodiment 81 or 82, wherein a therapeutically effective amount of said selective ER degrader is administered, e.g., starting on the same day as administration of said radiopharmaceutical compound, and once every 14 to 56 days, e.g., 28 days, and for at least the period that the radiopharmaceutical is administered, and optionally, administration of the ER degrader continues until disease progression. 84. The use of embodiments 77 to 83, wherein the CDK4 / 6 inhibitor is ribociclib and the endocrine treatment comprises administering a therapeutically effective amount of fulvestrant. 85. The use of embodiment 84, wherein said CDK4 / 6 inhibitor, preferably ribociclib, is administered simultaneously with fulvestrant. 86.M, 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 86. The use of embodiments 77 to 85, wherein Sc is selected from: 87.M, 177 Use of embodiments 77 to 86, wherein Lu is 88.C is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1,4,7,10-tetraazacyclododecane, 1(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramine (TETA), 1,4, Use according to embodiments 77 to 87, obtained by linking to S or P a chelating agent selected from 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). 89.C is a compound of the formula: [ka] Use of embodiment 88, wherein 90. The peptide P has the general formula DPhe-Gln-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-ψ(CHN)-Pro-NH and NH—CH(CH—CH(CH)) or or Z is [ka] where X is NH (amide), R2 is (CH2-CH(CH3)2, and R1 is the same as R2 or (CH2N)-Pro-NH2). Use of embodiments 77 to 89, wherein 91. The use of embodiment 90, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His BR>|NH—CH(CH2—CH(CH3)2)2. 92. The compound of formula (I) is a compound of formula (II) [ka] (wherein C and P are as defined in claim 1). The use of any one of embodiments 77 to 91, wherein the compound is 93. The radiopharmaceutical compound has the following formula (III): [ka] wherein M is a radionuclide, for example, M is 177 Lu) The use of any one of embodiments 77 to 92, wherein the compound is M-NeoB of the formula: or a pharmaceutically acceptable salt thereof. 94. The use of any one of embodiments 77-93, wherein the radiopharmaceutical compound is administered 3 to 12 times, 4 to 10 times, 4 to 8 times, 6 times, or 10 times. 95. The use of embodiment 94, wherein said radiopharmaceutical compound comprises an administration interval of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 weeks or 4 weeks, or 4 weeks. 96. The use of any one of embodiments 77-95, wherein said radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), about 3.7 GBq (100 mCi), about 5.55 GBq (150 mCi), about 7.4 GBq (200 mCi), about 9.25 GBq (250 mCi), or about 11.1 GBq (300 mCi). 97. The use of any one of embodiments 77 to 96, wherein the CDK4 / 6 inhibitor, such as ribociclib, is administered orally in a daily dose of 400 to 800 mg, such as about 600 mg, for example, over 1 to 6 cycles of 15 to 28 days duration, each cycle comprising, for example, 21 days of daily administration followed by 7 days of treatment rest. 98. The radiopharmaceutical compound is 17798. The use of embodiment 97, wherein the medicament is ribociclib administered intravenously every 28 days for 3 to 12 cycles, for example 6 cycles, at a dose in the range of 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), or 3.7 GBq (100 mCi) to 9.25 GBq (250 mCi), for example 250 mCi, for example 150 mCi, in combination with ribociclib administered orally at a daily dose of 600 mg for 15 to 21 days per cycle. 99. The use of embodiments 77 to 98, wherein the endocrine therapy, preferably fulvestrant, is administered via intramuscular administration, for example, using a long-acting formulation, at a dose of 250 to 700 mg. 100. The use of any one of embodiments 77 to 99, wherein the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer. 101. The use of any one of embodiments 77 to 100, wherein the subject is selected from subjects who have experienced early relapse after prior neoadjuvant or adjuvant endocrine therapy, or subjects who have experienced progression to prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor. 102. The use of any one of embodiments 77 to 101, wherein the subject is a postmenopausal woman with advanced metastatic breast cancer. 103. The use of any one of embodiments 77-101, wherein the subject is a pre- or peri-menopausal woman with advanced metastatic breast cancer. 104. The method of any one of embodiments 77-103, wherein the subject is selected from subjects experiencing early relapse after prior neoadjuvant or adjuvant endocrine therapy. 105. The method of any one of embodiments 77-104, wherein said subject is selected from subjects who have experienced progression to a prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor. 106. The method of embodiment 105, wherein said preceding CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abemaciclib, e.g., ribociclib. 107. The method of any one of embodiments 107-106, wherein said prior endocrine treatment comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader. 108. The use of any one of embodiments 77 to 107, wherein the endocrine therapy further comprises concurrent administration, e.g., via subcutaneous administration, of a synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, at a dose of about 3.6 mg every 28 days. 109. The use of any one of embodiments 77 to 108, wherein the subject is treated with the same radiopharmaceutical compound as defined for treatment, but before any surgery, for example 2 weeks before the start of treatment, a radiometal suitable for imaging, for example 68-gallium, 67-gallium or 64-copper, for example 68-gallium, is selected by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging, based on detection of said radiometal in an imaging scan in the tumor area. 110. The use of embodiment 109, wherein the subject is selected from among subjects who show the presence of radiometal enhancement, such as gadolinium enhancement, in any pre-operative PET / MRI scan in the tumor area. 111. The use of any one of embodiments 77-110, wherein the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer and is experiencing early recurrence from neoadjuvant or adjuvant therapy, and wherein the radiopharmaceutical compound is administered to the subject in combination with ribociclib and fulvestrant, and wherein the first dose of the radiopharmaceutical compound is administered on the same day as the first dose of ribociclib. 112. The use of embodiment 111, wherein ribociclib is administered orally in a daily dose of about 600 mg, for example, in 28-day cycles, each cycle comprising, for example, 21 days of administration followed by 7 days of treatment rest, wherein the radiopharmaceutical compound is administered for 4 to 10 cycles, ribociclib is administered for at least the period during which the radiopharmaceutical is administered, and optionally, administration of the CDK4 / 6 inhibitor continues until disease progression. 113. The radiopharmaceutical compound has the following formula: [ka] (Wherein M is 177 113. The use of embodiment 111 or 112, wherein M-NeoB is M-NeoB. 114. The radiopharmaceutical compound has the following formula: [ka] (Wherein M is 177 Lu) and is administered by intravenous infusion at a concentration of 370 MBq / mL.

[0006] In some embodiments, there is provided a method of use, use, or use in the manufacture of a medicament for treating breast cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor and endocrine therapy, wherein said radiopharmaceutical compound has the following formula: [ka] (Wherein M is 177 Lu) M-NeoB; the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer; and The subject is selected from subjects who have experienced early relapse after prior neoadjuvant or adjuvant endocrine therapy, or subjects who have experienced progression on prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor. Methods, uses, or uses in the manufacture of medicaments are provided. [Brief explanation of the drawings]

[0007] [Figure 1] 1 shows the treatment scheme for the dose-escalation part of the clinical trial. [Figure 2] This shows the treatment scheme for the dose-expansion part of the clinical trial. [Figure 3] 1 depicts a decision tree for the escalation or backfill part of a clinical trial. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present disclosure relates to methods 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 a CDK4 / 6 inhibitor and endocrine therapy.

[0009] Gastrin-releasing peptide (GRP) is a mammalian bombesin-like peptide that regulates many biological responses, primarily in the central and enteric nervous systems (Flores et al. 2010, Brain Res Bull;82(1-2):95-8). GRP acts through specific membrane G-protein coupled receptors (GRPRs) that are overexpressed by various cancers, including gliomas and breast cancers (Flores et al. 2010, Brain Res Bull;82(1-2):95-8).

[0010] NeoB compounds are new-generation bombesin analogs that bind to GRPR with high affinity (half-maximal inhibitory concentration (IC50) of 1-2 nM, Nock et al. J. Nucl. Med. 2017;58(1):75-80) and exhibit low internalization, consistent with the peptide's antagonist behavior. NeoB compounds contain a DOTA metal chelator within their structure, which allows for radiolabeling with different radionuclides, including gallium-68 (for PET imaging), lutetium-177 (for radionuclide therapy), and other related radionuclides, enabling the theranostic use of NeoB without affecting receptor affinity, internalization properties, or biodistribution. In nonclinical models, [ 68 Ga]Ga-NeoB and [ 177 Lu]-Lu NeoB exhibits high affinity for GRPR, which is overexpressed in breast, prostate, gastrointestinal stromal tumors (GIST), and gliomas (including glioblastoma) (Flores et al. 2010, supra; Morgat et al, J. Nucl. Med. 2017;58(9):1401-1407), and low internalization upon binding to specific receptors.

[0011] The ability of radiolabeled compounds to target GRPR-expressing tumors has been confirmed in in vivo imaging and biodistribution studies in tumor models. 177 [Lu]Lu-NeoB is rapidly cleared from the blood, rapidly eliminated through the renal system, and not retained in the kidney. Consistent with its GRPR antagonist profile, background radioactivity is observed in GRPR-expressing tissues (mostly the pancreas) but diminishes over time. In contrast, tumor radioactivity is persistent, with detectable uptake levels up to 7 days after injection.

[0012] Given that ER is the primary oncogenic driver in ER+ breast cancer, treatment can incorporate endocrine therapy (ET) that targets ER either through direct inhibition with selective estrogen receptor modulators (SERMs), estrogen deprivation with selective nonsteroidal aromatase inhibitors (NSAIs) and steroidal aromatase inhibitors (SAIs), or promotion of ER degradation via selective ER degraders (SERDs).

[0013] In the past few years, the advent of CDK4 / 6 inhibitors (palbociclib, abemaciclib, and ribociclib) in combination with ET has dramatically improved progression-free survival (PFS) and quality of life compared with ET alone, slowing the emergence of endocrine resistance in the treatment of advanced / metastatic HR+ / HER2- breast cancer (Chen et al. (2019) Latest Overview of the Cyclin-Dependent Kinases 4 / 6 Inhibitors in Breast Cancer: The Past, the Present, and the Future. J Cancer;10(26):6608-6617; (2020) 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC5). Ann Oncol;31(12):1623-1649).

[0014] CDK4 / 6i can be combined with fulvestrant during adjuvant AI therapy or in first-line therapy in patients who have relapsed within 12 months of discontinuing adjuvant AI (Gennari et al. 2021, NCCN Guideline Breast Cancer Version 4.2022). Results from Monarch-2 have been updated (Sledge et al. (2020) The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol;6(1):116-124).

[0015] general definition The use of the articles "a," "an," and "the" in both the description and the claims should be construed to encompass both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "being of," "including," and "containing" should 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 should be understood that the same embodiment could be more narrowly claimed using the intermediate term "consisting essentially of" or the closed term "consisting of."

[0016] The term "about" or "ca.," as used herein, means that the value that follows can vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, and even more preferably ±1%.

[0017] The terms "treating" or "treatment," as used herein, include treatment that alleviates, reduces, or relieves at least one symptom in a subject, or causes a delay in the progression of a disease. For example, treatment can be a decrease in one or several symptoms of a disorder, such as cancer, or a complete eradication of the disorder. Also, within the meaning of the present disclosure, the term "treat" refers to arresting, delaying the onset (i.e., the period before clinical manifestations of the disease), and / or reducing the risk of developing or worsening a disease. When used herein in connection with the disclosed combination therapies, the term "treatment" encompasses the administration of a radiopharmaceutical compound, optionally in combination with a CDK4 / 6 inhibitor and / or endocrine therapy. Such treatment may include one or more administrations of a radiopharmaceutical compound over a determined period of time.

[0018] 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 ER and progesterone receptor (PgR), and the expression and amplification of HER2: HR positive (HR+; ER+, PgR+ and HER2-), HER2 positive (HER2+) and triple negative (TN; ER-, PR- and HER2-).

[0019] As used herein, the term "radiopharmaceutical" or "radiopharmaceutical compound" refers to a pharmaceutical compound that is labeled with a radionuclide agent, typically a metallic one. Such radiopharmaceutical compounds have binding affinity for a specific marker on a target cell, such as a receptor or tumor antigen, and therefore comprise a targeting ligand (or target-binding moiety). Radiopharmaceutical compounds are useful as contrast agents in imaging techniques such as PET scans or MRI scans, or as therapeutic agents in nuclear medicine, also known as radioligand therapy (RLT) or PRRT (peptide receptor radionuclide therapy).

[0020] As used herein, "prior endocrine treatment" refers to an endocrine treatment, as defined herein, that precedes treatment with a radiopharmaceutical compound. Methods that use an "endocrine treatment" that is not "prior" refer to the use of an endocrine treatment in combination with a radiopharmaceutical compound. The compound used in the "prior endocrine treatment" may be the same as or different from the compound used in the endocrine treatment in combination with the radiopharmaceutical compound.

[0021] In some embodiments, the subject is selected from those who have experienced early relapse after prior endocrine therapy in combination with a CDK4 / 6 inhibitor, hi some embodiments, the CDK4 / 6 inhibitor is palbociclib, ribociclib, or abemaciclib.

[0022] As used herein, "early recurrence" refers to recurrence during neoadjuvant or adjuvant endocrine therapy or within 12 months after completion of neoadjuvant or adjuvant endocrine therapy. "Recurrence" in the case of cancer refers to a return to progressive disease after a period of static or regressive disease. Progressive disease, e.g., an increase in the number or size of tumors or cancerous lesions, can be measured by any method deemed appropriate for the cancer in question.

[0023] In some embodiments, "endocrine therapy" comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader. In some embodiments, the endocrine therapy comprises administering a therapeutically effective amount of a selective ER degrader. In some embodiments, the endocrine therapy comprises administering a therapeutically effective amount of fulvestrant or an aromatase inhibitor.

[0024] "Neoadjuvant therapy" is a therapy administered before another therapy. "Adjuvant therapy" is a therapy administered after another therapy. For example, if an aromatase inhibitor is administered 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 administered 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.

[0025] In accordance with the International System of Units, "MBq" is an abbreviation for the unit of radioactivity "megabecquerel."

[0026] As used herein, "PET" stands for positron emission tomography.

[0027] As used herein, "SPECT" stands for Single Photon Emission Computed Tomography.

[0028] As used herein, "MRI" stands for magnetic resonance imaging.

[0029] As used herein, "CT" stands for computed tomography.

[0030] 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 pre-malignant cancers and pre-malignant tumors, as well as malignant cancers and malignant tumors and benign cancers. The term "cancer," as used herein, includes primary malignant cells or tumors (e.g., where cells have not migrated to a site within a subject's body other than the site of the original malignant tumor or tumor) and secondary malignant cells or tumors (e.g., where they arise from metastasis, the migration of malignant cells or tumor cells to a secondary site different from the site of the original tumor).

[0031] As used herein, the phrase "therapeutically effective amount" of a compound refers to that amount of the compound that will induce a desired therapeutic response, e.g., ameliorate symptoms, reduce pathology, slow or delay disease progression, or prevent disease, in at least a subpopulation of subjects, at a reasonable benefit-risk ratio applicable to any medical treatment.

[0032] The terms "subject" or "patient," as used herein, are intended to include animals that can be directly or indirectly afflicted with or afflicted by cancer or any disorder, including cancer. Examples of subjects include mammals, such as humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the subject is a human, such as a human suffering from, at risk of suffering from, or potentially suffering from cancer.

[0033] "Combination therapy" refers to either a therapy involving the administration of a fixed combination in one dosage unit form, or a therapy in which the radiopharmaceutical compounds disclosed herein and a combination partner, e.g., another agent as described below, e.g., a CDK4 / 6 inhibitor, and / or an endocrine therapy, may be administered simultaneously or serarately, i.e., separately within time intervals, particularly when these time intervals allow the combination partner and / or combined radiotherapy to exhibit a cooperative effect, e.g., a synergistic effect, with the radiopharmaceutical compound. The single components can be packaged in a kit or separately. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose before administration.

[0034] Additionally, "co-administration" or "administration in combination" or the like, as used herein, is meant to encompass the administration of selected combination partners, e.g., a radiopharmaceutical compound and a CDK4 / 6 inhibitor, to a single subject (e.g., a patient) in need thereof, and is intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0035] In chemical formulas, wavy lines [ka] represents the attachment point of the part.

[0036] Radiopharmaceutical compounds for use in combination therapy of the present disclosure The radiopharmaceutical compounds for use in the methods of the present disclosure have the formula (I): CSP(I) (In the formula, C is a chelating moiety; S is an optional spacer covalently linking C and P; P is a GRP receptor binding moiety covalently linked to C directly or indirectly via S. or a pharmaceutically acceptable salt thereof, and is labeled with a radionuclide M.

[0037] M is selected from among radioisotopes useful in nuclear medicine. Examples of such radioisotopes include, but are not limited to: 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 Preferably, M is 177 This is Lu.

[0038] In specific embodiments, M is conjugated to a chelating moiety.

[0039] Preferred GRP receptor binding compounds are GRP receptor antagonist compounds. Examples of GRP receptor antagonist compounds include RM2, SB3, RM26, BAY-864367, CB-TE2A-AE06, or Pro-BOMB1.

[0040] In a preferred embodiment, P has the general formula: Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z (in the formula, Xaa1 is absent or selected from the group consisting of the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Thi), 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo-tyrosine (oI-Tyr), Trp and pentafluorophenylalanine (5-F-Phe) (when all are L- or D-isomers); preferably D-Phe; Xaa2 is Gln, Asn or His; preferably Gln; Xaa3 is Trp or 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi); preferably Trp; Xaa4 is Ala, Ser or Val; preferably Ala, Xaa5 is Val, Ser or Thr; preferably Val, Xaa6 is Gly, sarcosine (Sar), D-Ala, or β-Ala; preferably Gly; Xaa7 is His or (3-methyl)histidine (3-Me)His; preferably His; Z is selected from -NHOH, -NHNH, -NH-alkyl, -N(alkyl), and -O-alkyl; or Z is [ka] wherein X is NH (amide) or O (ester), and R1 and R2 are the same or different and are selected from a proton, an optionally substituted alkyl, an optionally substituted alkyl ether, an aryl, an aryl ether or alkyl group, a halogen group, a hydroxyl group, a hydroxyalkyl group, an amine group, an amino group, an amido group, or an amido-substituted aryl or heteroaryl group.

[0041] According to one embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-His-Z; wherein Z is as defined above.

[0042] According to one embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-ψ(CHN)-Pro-NH and NH-CH(CH-CH(CH)). or Z is [ka] wherein X is NH (amide), R2 is CH(CH2-CH(CH3)2, and R1 is (CH2N)-Pro-NH2, which is the same as or different from R2.

[0043] As used herein, the term "chelating moiety" refers to an organic moiety that contains a functional group that is capable of forming a non-covalent bond with a radionuclide M, thereby forming a stable radionuclide complex.

[0044] A chelating moiety in the context of the present disclosure can be obtained by grafting one chelating agent onto S or P, said chelating agent can be selected from the following list (but is not limited to): 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetraxetane), trizoxetane, 1,4,7,10-tetraazacyclododecane, 1(glutarate)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic 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).

[0045] In specific embodiments, the chelating moiety C has the formula: [ka] where the wavy bond represents the point of attachment of the chelator to the spacer S or GRP receptor antagonist P.

[0046] Such a chelating moiety is either directly linked to the GRP receptor antagonist moiety or linked via a linker molecule or what is also referred to herein as a spacer S. The linking bond is either a covalent or non-covalent bond between the GRP receptor antagonist (and spacer) and the chelating moiety, preferably the bond is a covalent bond.

[0047] The chelating moiety C is typically attached to the N-terminus of the peptide derivative formula disclosed above, such as DPhe-Gln-Trp-Ala-Val-Gly-His-Z, optionally via a spacer S.

[0048] In specific embodiments, the spacer S is a) an aryl-containing residue of any formula: [ka] b) a dicarboxylic acid, ω-aminocarboxylic acid, ω-diaminocarboxylic acid or diamine derivative of any of the following formulas: [ka] (wherein each n independently represents an integer of 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 of the following formulas: [ka] (wherein m is an integer of 1 to 36, for example, m=1, 2, 3, or 4, and p is an integer of 0 to 5, for example, p=0 or 1). d) β-amino acid residues in single or homologous chains of various lengths or heterologous chains of various lengths, in particular [ka] and / or e) any combination of one or more of a, b, c and / or d is selected from the group consisting of:

[0049] In some embodiments, the radiopharmaceutical compound for use in the treatment methods of the present disclosure has the following chemical formula: [ka] wherein C and P are as defined above, M is a radioisotope conjugated to a chelating moiety, and in some embodiments, M is 177 Lu) The radiolabeled compound is selected from the group consisting of:

[0050] In some embodiments, the radiopharmaceutical compound for use in accordance with the present disclosure is of the following formula (II): [ka] where C and P are as defined above and C is complexed to a radionuclide M. is a compound of

[0051] In some embodiments, the radiopharmaceutical compound for use in the method of treatment has formula (III): [ka] wherein M is as defined above, and in some embodiments, M is 177 Lu) This is M-NeoB.

[0052] Radiopharmaceutical compounds [ 177 Lu]Lu-NeoB is 177 Lu refers to a compound of formula (III).

[0053] According to one embodiment, the radiopharmaceutical compound has formula (IV): [ka] wherein M is as defined above, preferably 177 Lu) Radiolabeled NeoB2.

[0054] According to another specific embodiment, the radiopharmaceutical compound for use in accordance with the present disclosure has the following formula (V): [ka] and is radiolabeled with M, and in some embodiments, M is 177 This is Lu.

[0055] Some embodiments of the present disclosure provide a radiopharmaceutical compound 177 Lu]Lu-NeoB.

[0056] The radiopharmaceutical compound is for use in the treatment of breast cancer in a subject in need thereof, wherein a therapeutically effective amount of said radiopharmaceutical compound is administered to said subject.

[0057] The single components or their precursors, typically unlabeled NeoB, can be packaged in a kit or separately. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration.

[0058] In specific embodiments, the radiopharmaceutical compounds for use in the disclosed combination therapies can be formulated as described above, for example, in WO 2021 / 052960.

[0059] In some embodiments, the combination therapy comprises: (a)(ai) Radionuclides 177 lutetium( 177 Lu), and (aii) Formula (III): [ka] NeoB The complex formed by; and; (b) gentisic acid or its salts and ascorbic acid or its salts; (c) optionally, macrogol 15 hydroxystearate; (d) acetate buffer; (e) Water for injection, and (f) at least one other pharmaceutically acceptable excipient, e.g., a sequestering agent such as DTPA and administering a pharmaceutical composition comprising:

[0060] Synthesis of Compounds of Formulas (I), (II), (III), (IV) and (V) The compounds of formula (I), (II), (III), (IV) and (V) can be synthesized using the method 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.

[0061] CDK4 / 6 inhibitors used in combination therapy A method of treating breast cancer in a subject in need thereof comprises administering to said subject a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor, such as ribocicilib, and an endocrine therapy, such as fulvestrant.

[0062] As used herein, the term "CDK4 / 6 inhibitor" refers to a cyclin-dependent kinase 4 / 6 inhibitor, which is used to treat diseases of an oncological nature by affecting cell cycle progression and causing cell apoptosis. Naturally, CDK4 / 6 proteins are found in both healthy and cancer cells and control how cells rapidly grow and divide. In breast cancer, these proteins can become overactivated, causing uncontrolled cell growth and division. CDK4 / 6 inhibitors block these proteins, slowing and even stopping the growth of cancer cells.

[0063] In some embodiments, the methods of the present disclosure include exposing the tumor to be treated to a therapeutically effective amount of a CDK4 / 6 inhibitor. The CDK4 / 6 inhibitor may be selected from the group consisting of ribociclib (Kisqali), palbociclib (Ibrance), and abemaciclib (Verzenio). Preferably, the CDK4 / 6 inhibitor is ribociclib.

[0064] As used herein, "ribociclib" refers to a cyclin-dependent kinase 4 / 6 inhibitor, and more specifically to the compound of formula: 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide and pharmaceutically acceptable salts thereof (CAS Number: 1211441-98-3).

[0065] In one embodiment, the CDK4 / 6 inhibitor, preferably ribociclib, is orally administered in a daily therapeutically effective amount of 400-800 mg, preferably 500-700 mg, more preferably 550-650 mg, and even more preferably about 600 mg.

[0066] In one embodiment, the CDK4 / 6 inhibitor, e.g., ribociclib, is administered orally at a daily dose of about 600 mg, e.g., for 1 to 6 cycles of 15 to 28 days in duration, each cycle comprising, e.g., 21 days of daily administration followed by 7 days of rest from treatment.

[0067] In some embodiments, the CDK4 / 6 inhibitor, e.g., ribociclib, is administered orally at a daily dose of about 600 mg, e.g., for 1 to 6 cycles of 28 days duration, each cycle comprising, e.g., 21 days of administration followed by 7 days of rest, and wherein the radiopharmaceutical compound is administered for 3 to 12 cycles.

[0068] Endocrine treatments used in combination therapy A method of treating breast cancer in a subject in need thereof comprises administering to said subject a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor and a therapeutically effective amount of an endocrine therapy, such as fulvestrant.

[0069] As used herein, the terms "endocrine therapy," "hormonal therapy," "hormone therapy," or "hormone therapy" refer to treatments that slow or stop the growth of hormone-sensitive tumors by blocking the body's ability to produce hormones or by interfering with the effects of hormones on breast cancer cells.

[0070] Several strategies are used to treat hormone-sensitive breast cancer, including: 1. Blockade of ovarian function, which can be performed surgically, by radiation therapy, or by treatment with gonadotropin-releasing hormone (GnRH) agonists, also known as luteinizing hormone-releasing hormone (LHRH) agonists. Examples of ovarian suppression drugs are synthetic analogs of gonadotropin-releasing hormone, such as leuprolide (Lupron) or gosereline (Zoladex); 2. Blockade of estrogen production, which can be achieved by treatment with steroidal or non-steroidal aromatase inhibitors such as anastrozole (Arimidex), letrozole (Femara) or exemestane (Aromasin); 3. Blockade of the effects of estrogen, which can be achieved by treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen (Nolvadex) and toremifene (Fareston), or with selective ER degraders such as fulvestrant (Faslodex).

[0071] In some embodiments, the endocrine therapy comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader, hi some embodiments, the endocrine therapy comprises administering a therapeutically effective amount of a selective ER degrader.

[0072] In some embodiments, the selective ER degrader is fulvestrant.

[0073] As used herein, "fulvestrant" refers to a steroidal anti-estrogen, and more specifically to the compound of the formula (7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol and pharmaceutically acceptable salts thereof (CAS Number 129453-61-8).

[0074] In some embodiments, the selective ER degrading agent, e.g., fulvestrant, is administered once every 14 to 56 days, e.g., 28 days, e.g., starting on the same day as administration of the radiopharmaceutical compound, for at least the period that the radiopharmaceutical compound is administered, and optionally, administration of the ER degrading agent continues until disease progression.

[0075] In one embodiment, the endocrine therapy, eg, the selective ER degrader, eg, fulvestrant, is administered simultaneously with the CDK4 / 6 inhibitor, eg, ribociclib.

[0076] In one embodiment, the endocrine treatment, eg, fulvestrant, is administered via intramuscular administration, eg, using a long-acting formulation, at a dose of 250-700 mg.

[0077] In some embodiments, both the CDK4 / 6 inhibitor and the endocrine therapy, e.g., fulvestrant, are started on the same day. In some embodiments, the CDK4 / 6 inhibitor, e.g., ribociclib, is administered simultaneously with the endocrine therapy, e.g., fulvestrant.

[0078] In some embodiments, the endocrine therapy further comprises concurrently administering a synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, at a dose of about 3.6 mg every 28 days, e.g., via subcutaneous administration. In some embodiments, the CDK4 / 6 inhibitor, e.g., ribociclib, endocrine therapy, e.g., fulvestrant, and the synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, are initiated on the same day. In some embodiments, the synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, preferably begins on the same day as administration of the radiopharmaceutical compound and is administered once every 28 days for at least the period that the radiopharmaceutical is administered, and optionally, administration of the ER degrader continues until disease progression.

[0079] Combination therapy In some embodiments, the method of treating breast cancer in a subject in need thereof comprises administering a therapeutically effective amount of a radiopharmaceutical compound as described above, preferably 177 The method includes administering to the subject [Lu]Lu-NeoB in combination with a CDK4 / 6 inhibitor and endocrine therapy.

[0080] In some embodiments, the present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of said radiopharmaceutical compound as described above, preferably 177 Lu]Lu-NeoB in combination with a CDK4 / 6 inhibitor, e.g., ribociclib, and further in combination with a therapeutically effective amount of an endocrine therapy, e.g., fulvestrant, to the subject.

[0081] The present disclosure also provides the use of a radiopharmaceutical compound in the preparation of a medicament for use in treating breast cancer in a subject in need thereof, wherein a therapeutically effective amount of said radiopharmaceutical compound, e.g., 177 Lu]Lu-NeoB is administered to said subject in combination simultaneously, separately or sequentially with a CDK4 / 6 inhibitor, such as ribociclib, and a therapeutically effective amount of an endocrine therapy, such as fulvestrant.

[0082] In various embodiments of the present disclosure, the combination therapy comprises (i) a therapeutically effective amount of a radiopharmaceutical compound (e.g., 177 and (ii) administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a CDK4 / 6 inhibitor, e.g., ribocicillib, and (iii) administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an endocrine therapy, e.g., fulvestrant.

[0083] As used herein, the term "synergistically" means that therapeutic agents can be administered separately within a time interval (e.g., in a time-staggered manner, particularly in a sequence-specific manner within such a time interval) to exhibit a (preferably synergistic) interaction (i.e., a joint therapeutic effect).

[0084] In various embodiments of the present disclosure, the combined administration includes a radiopharmaceutical compound (e.g., 177 Lu-NeoB) and a CDK4 / 6 inhibitor when administered simultaneously and independently or separately within a time interval, particularly when these time intervals allow the combination partners to exhibit a cooperative effect, e.g., a synergistic effect.

[0085] In some embodiments, a radiopharmaceutical compound, e.g., 177 Lu]Lu-NeoB is administered on the same day as the CDK4 / 6 inhibitor.

[0086] Administration of the radiopharmaceutical compound may comprise dosing intervals of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 weeks or 4 weeks, or 4 weeks.

[0087] In some embodiments, the radiopharmaceutical compound, e.g., 177 Lu]Lu-NeoB is administered to the subject at least six times in combination with a CDK4 / 6 inhibitor and further in combination with endocrine therapy, wherein the administration interval between two administrations of the radiopharmaceutical compound is four weeks, and the first administration of the radiopharmaceutical compound is administered on the same day as the CDK4 / 6 inhibitor, e.g., ribociclib, and the endocrine therapy, e.g., fulvestrant.

[0088] In some embodiments, the radiopharmaceutical compound, e.g., 177 Lu]Lu-NeoB was administered at each dose, with the following concentrations: 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), and 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi). i), about 3.7 GBq (100 mCi), about 5.55 GBq (150 mCi), about 7.4 GBq (200 mCi), about 9.25 GBq (250 mCi), or about 11.1 GBq (300 mCi), for example, about 3.7 GBq (100 mCi) to about 7.4 GBq (200 mCi).

[0089] In some embodiments, the radiopharmaceutical compound, e.g., 177 [Lu]Lu-NeoB is administered intravenously every 28 days for 3 to 12 cycles, for example, 4 to 10 cycles, for example, 6 cycles. 177

[0033] Lu]Lu-NeoB is administered, for example, at a dose in the range of 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), for example 150 mCi, every 4 weeks for 3 to 12 cycles, for example 4 to 10 cycles, for example 6 cycles, in combination with said CDK4 / 6 inhibitor, for example ribociclib, administered orally at a daily dose of 400 to 800 mg, for example about 600 mg, for 15 to 21 days per cycle, and in combination with said endocrine treatment, for example fulvestrant, administered via intramuscular administration at a dose of 250 to 700 mg, for example using a long-acting formulation, once every 14 or 28 days for 4 to 6 cycles.

[0090] An embodiment of a treatment scheme for combination therapy is shown in FIG.

[0091] In some embodiments, the endocrine therapy further comprises concurrent administration of a synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, at a dose of about 3.6 mg once every 28 days, typically via subcutaneous administration. In some embodiments, the CDK4 / 6 inhibitor, e.g., ribociclib, endocrine therapy, e.g., fulvestrant, and the synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, are initiated on the same day. In some embodiments, the synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, is administered once every 28 days for 4 to 10 cycles, or for at least the duration of the radiopharmaceutical administration, e.g., beginning on the same day as administration of the radiopharmaceutical compound, and optionally continuing until disease progression. In some embodiments, the administration of the synthetic analog of gonadotropin-releasing hormone, e.g., 177 [Lu]Lu-NeoB is administered intravenously every 28 days for 3 to 12 cycles, for example, 4 to 10 cycles, for example, 6 cycles. 177

[0033] Lu]Lu-NeoB may be administered in combination with the CDK4 / 6 inhibitor, preferably ribociclib, administered orally at a daily dose of 600 mg for 15 to 21 days per cycle, and in combination with the endocrine treatment, such as fulvestrant, administered via intramuscular administration at least once every 14 or 28 days for the duration of the radiopharmaceutical administration, for example, at a dose ranging from 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), for example, 150 mCi, every 4 weeks for 3 to 12 cycles. and optionally, the administration of the endocrine therapy is continued until disease progression, e.g., over 4 to 10 cycles, e.g., 6 cycles, and optionally, the administration of the endocrine therapy is continued at a dose of 250 to 700 mg, e.g., using a long-acting formulation, and further comprises a synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, administered at a dose of about 3.6 mg once every 28 days for at least the period that the radiopharmaceutical is administered, and optionally, the administration of the synthetic analog of gonadotropin-releasing hormone is continued until disease progression.

[0092] A second embodiment of a treatment scheme for combination therapy is shown in FIG.

[0093] In some embodiments, a radiopharmaceutical compound (e.g., 177 The combined effect of [Lu]Lu-NeoB) therapy and the CDK4 / 6 inhibitor, e.g., ribociclib, and endocrine therapy, e.g., fulvestrant and / or goserelin, increases overall survival in the subject by at least 10%, 20%, 30%, 40%, or at least 50% compared to a single CDK4 / 6 inhibitor, e.g., ribociclib, or combination therapy of a CDK4 / 6 inhibitor, e.g., ribociclib, and endocrine therapy, e.g., fulvestrant and / or goserelin.

[0094] "Overall survival" (OS) is defined herein as the period from the date of first administration to the date of death from any cause in a clinical trial participant, as disclosed, for example, in Example 1. If the participant is not known to have died, overall survival is censored at the most recent date the participant was known to be alive (at or before the cutoff date). OS distributions are estimated using the Kaplan-Meier method.

[0095] Also, in some embodiments, radiopharmaceutical compounds (e.g., 177 The combined effect of [Lu]Lu-NeoB) therapy and a CDK4 / 6 inhibitor, and endocrine therapy increases progression-free survival by at least 10%, 20%, 30%, 40%, or at least 50% compared to a single CDK4 / 6 inhibitor, e.g., ribociclib, or combination therapy of a CDK4 / 6 inhibitor, e.g., ribociclib, with endocrine therapy, e.g., fulvestrant and / or goserelin.

[0096] 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 modified RANO or death from any cause. If no PFS event is observed, PFS is censored at the earlier of the date of the last adequate tumor assessment before the data cutoff date or the date of initiation of new antineoplastic therapy. PFS distributions are estimated using the Kaplan-Meier method.

[0097] In certain embodiments, radiopharmaceutical compounds (e.g., 177Administration of a composition comprising [Lu]Lu-NeoB) to a subject eligible for such treatment can inhibit, slow, and / or reduce tumor growth in the subject. In certain embodiments, tumor growth is slowed by at least 50%, 60%, 70%, or 80% compared to an untreated control subject. In certain embodiments, tumor growth is slowed by at least 80% compared to an untreated control subject. In certain embodiments, tumor growth is slowed by at least 50%, 60%, 70%, or 80% compared to the expected growth of the tumor without treatment. In certain embodiments, tumor growth is slowed by at least 80% compared to the expected growth of the tumor without treatment. Tumor volume assessment in breast cancer can be determined using the RECIST criteria for tumor response (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 tumors: revised RECIST guideline (version 1.1). Eur J Cancer; 45(2): 228-47).

[0098] In certain embodiments, a radiopharmaceutical compound (e.g., 177Administration of a composition comprising [Lu]Lu-NeoB) to a subject eligible for such treatment can increase the subject's survival. In certain embodiments, the increase in survival is compared to untreated control subjects or control subjects receiving standard of care for newly diagnosed breast cancer patients, such as a combination of a CDK4 / 6 inhibitor, e.g., ribociclib, and endocrine therapy, e.g., fulvestrant and / or gosereline. In certain embodiments, the increase in survival is compared to the expected survival of a subject receiving standard of care. In certain embodiments, survival is increased by at least three-fold, four-fold, or five-fold compared to untreated control subjects or control subjects receiving standard of care for newly diagnosed breast cancer patients, such as a combination of a CDK4 / 6 inhibitor, e.g., ribociclib, and endocrine therapy, e.g., fulvestrant and / or gosereline. In certain embodiments, survival is increased by at least 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 3 years compared to a control subject receiving standard of care for newly diagnosed breast cancer patients, such as a combination of a CDK4 / 6 inhibitor, e.g., ribociclib, and endocrine therapy, e.g., fulvestrant and / or goserelin. In certain embodiments, survival is increased by at least 1 month, 2 months, or 3 months compared to the expected survival of a subject receiving standard of care for newly diagnosed breast cancer patients, such as a combination of a CDK4 / 6 inhibitor, e.g., ribociclib, and endocrine therapy, e.g., fulvestrant and / or goserelin.

[0099] In some embodiments, the combined therapeutic effect of the radiopharmaceutical, ER degrader and endocrine therapy is synergistic.

[0100] Methods for selecting subjects for combination therapy In certain embodiments of the present disclosure, the breast cancer is a GRPR-positive disease.

[0101] In a specific embodiment, the subject is selected for treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with the same compound as defined for this treatment, but where M is an alternative radionuclide suitable for imaging, i.e., imaging of the radiopharmaceutical compound, based on detection of said radionuclide in an imaging scan in the tumor area after surgery.

[0102] Typical alternative radionuclides suitable for use as contrast agents in imaging include: 111 In, 133m In, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 72 As, 97 Ru, 203 Pb, 62 Cu, 64 Cu, 61 Cu 177 Lu, 86 Y, 51 Cr, 52m Mn, 157 Gd, 169 Yb, 172 Tm, 117m Sn, 123 I, 124 I, 125 I, 18 F, Al 18 F, 152 Tb, 155 Tb, 82 Rb, 89 Zr, 43 Sc, 44 Sc.

[0103] In some embodiments, the radionuclide suitable for imaging is 67 Ga, 68 Ga or 64 Cu, preferably 68 It's Ga.

[0104] In some embodiments, the subject is diagnosed with a tumor by PET / CT or PET / MRI scan in the tumor region, e.g., the breast region. 68 Select by assessing Ga-NeoB uptake.

[0105] In some embodiments, the subjects eligible for combination therapy are selected from those who, after surgery, demonstrate the presence of radionuclide enhancement, such as gadolinium enhancement, on a PET / MRI scan in the tumor region.

[0106] In some embodiments, radiopharmaceutical compounds labeled with radioactive metals suitable for imaging, e.g., 68 A PET scan with [Ga]Ga-NeoB may be performed 1 day to 42 days before the first administration of the radiopharmaceutical compound for combination therapy.

[0107] Thus, the present disclosure also provides a method for determining whether a human subject with breast cancer can be selected for combination therapy as disclosed herein, comprising: 1. administering an effective amount of an imaging radiopharmaceutical compound as an imaging contrast agent for imaging uptake of said radiopharmaceutical compound; 2. obtaining a PET / MRI or PET / CT image scan of the patient; and 3. Comparison with Control Image Scans The present invention relates to a method comprising:

[0108] The purpose of the above selection method is to select patients with GRPR-positive tumors, i.e., patients who are better responders to the combination therapy of the present disclosure. GRPR-positive tumors can be advantageously detected by assessing the uptake of the imaging radiopharmaceutical compound by PET / MRI or PET / CT imaging after injection of said imaging radiopharmaceutical compound as a contrast agent.

[0109] As used herein, a good responder is a patient selected from a patient population who exhibits a statistically better response to treatment compared to a randomized patient population (i.e., not selected by the selection step of the method) and / or who exhibits fewer side effects to treatment compared to a randomized patient population (i.e., not selected by the selection step of the method).

[0110] In certain embodiments, 68 [Ga]Ga-NeoB is provided in a kit. The kit may consist of two sterile vials as a single-dose product: Vial 1: NeoB (active ingredient), 50 μg, powder for solution for injection, 68Ge / 68 Gallium-68 chloride in HCl eluted from a Ga generator ( 68 Reconstituted in a solution of GaCl3); Vial 2: Reaction buffer. Vial 2 will be added to reconstituted vial 1.

[0111] An example of such a kit is disclosed in WO2021053040.

[0112] corresponding to the radiation dose to be administered, 68 The volume of the [Ga]Ga-NeoB injection solution is calculated according to the estimated injection time based on the current activity provided by the generator and the physical decay of the radionuclide (half-life = 68 min).

[0113] In some embodiments, subject selection is performed 10-18 days, preferably about 14 days, prior to the first administration of the radiopharmaceutical compound.

[0114] In some embodiments, the imaging radiopharmaeutical is administered in a single intravenous dose of 150-250 MBq (4.1-6.8 mCi).

[0115] Images of the subject's body are then acquired by PET / MRI or PET / CT imaging, and the images are compared with control images to determine whether the lesions identified by conventional imaging, e.g., MRI, CT, SPECT, or PET, have increased uptake of the imaging radiopharmaceutical compound, i.e., [ 68 In some embodiments, PET / MRI or PET / CT imaging is performed 30-120 minutes, preferably 60-90 minutes, after intravenous administration of the imaging radiopharmaceutical compound to a subject.

[0116] In some embodiments of the method, a subject is selected for the combination therapy of the present disclosure that meets the following criteria: and at least 10%, preferably more than 20%, preferably more than 30%, preferably more than 40%, preferably more than 50%, preferably more than 60%, preferably more than 70%, preferably more than 80% of lesions detected by conventional imaging, e.g., MRI, CT, SPECT or PET, in said subject have imaging radiopharmaceutical compound uptake, e.g., [ 68 β-NeoB incorporation.

[0117] In some embodiments, the term "lesion" refers to a measurable tumor lesion according to RECIST 1.1 criteria as defined above.

[0118] In some embodiments, the subject is newly diagnosed with breast cancer or suffers from recurrent breast cancer.

[0119] As used herein, "recurrent" refers to a patient who has relapsed after at least one treatment.

[0120] In some embodiments, the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer.

[0121] In some embodiments, the subject is selected from those experiencing early relapse after neoadjuvant or adjuvant endocrine therapy.

[0122] As used herein, "early recurrence" refers to a recurrence during neoadjuvant or adjuvant endocrine therapy or within 12 months after completion of neoadjuvant or adjuvant endocrine therapy.

[0123] As used herein, "neoadjuvant endocrine therapy" refers to aromatase inhibitors, such as letrozole.

[0124] In some embodiments, the subject is a postmenopausal woman with advanced metastatic breast cancer.

[0125] In some embodiments, the subject is a pre- or peri-menopausal woman with advanced metastatic breast cancer. In certain such embodiments, the endocrine treatment may further comprise concurrent administration of a synthetic analog of gonadotropin-releasing hormone, e.g., goserelin, at a dose of about 3.6 mg every 28 days, typically via subcutaneous administration.

[0126] Further aspects of the combination therapy of the present disclosure are described in more detail and specificity hereinafter with reference to examples, which are not intended to limit the invention. [Example]

[0127] Example 1: Clinical Trial to Treat Subjects with Breast Cancer Provided herein is the use of ribociclib in combination with fulvestrant in subjects with ER-positive, HER-2-negative and GRPR-positive breast cancer who have experienced early recurrence from (neo)adjuvant endocrine therapy. 177

[0033] Figure 1 is an example protocol describing a Phase Ib dose-finding study evaluating the safety and activity of [Lu]Lu-NeoB.

[0128] [Table 1]

[0129] [Table 2]

[0130] Study Design: This was in combination with ribociclib and fulvestrant in adult female participants with ER+ / HER2-, GRPR+ advanced / metastatic breast cancer that had relapsed during or within 12 months of the completion of prior (neo)adjuvant ET [ 177 This is a Phase 1b, single-arm, multicenter, open-label, dose-finding study of [Lu]Lu-NeoB. The study includes a dose-escalation part followed by a dose-expansion part. The dose-expansion part also includes [Lu]Lu-NeoB in combination with ribociclib, fulvestrant, and goserelin. 177 Lu]Include premenopausal / perimenopausal women undergoing Lu-NeoB.

[0131] overview: Metastatic breast cancer (MBC) is an incurable disease with a 5-year OS rate of approximately 22% (National Cancer Institute, 2021). Over the past few years, the addition of cyclin-dependent kinase 4 / 6 (CDK4 / 6i) inhibitors (CDK4 / 6i) to ET has dramatically improved the prognosis of patients with hormone receptor-positive (HR+) / HER2- advanced / metastatic breast cancer. However, the OS benefit remains limited in the subset of patients who relapse during or within 12 months of completing neoadjuvant therapy (early recurrent), compared with patients with new disease or recurrence >12 months after completion of neoadjuvant ET (38.8 vs. 67.6 months, respectively; unpublished data from Novartis, Neven et al., 2022). These patients represent an unmet medical need for novel therapies.

[0132] This is a radionuclide therapy that targets GRPR, which is overexpressed in breast cancer cells. 177The addition of Lu]Lu-NeoB to currently recommended and approved ET and CD4 / 6i combinations is expected to be a safe and effective treatment option as first-line treatment for patients with HR+ / HER2- MBC who have early relapse after (neo)adjuvant ET.

[0133] The objective of this phase 1b, single-arm, multicenter, open-label, dose-finding study was to evaluate the efficacy and safety of ribociclib in combination with fulvestrant in adult female participants with ER+, HER2-, GRPR+ advanced or metastatic breast cancer that has recurred during or within 12 months of the completion of prior (neo)adjuvant ET. 177 The objective of this study is to estimate the RD of [Lu]Lu-NeoB (titration part). In addition, this study aims to evaluate the efficacy and safety of [Lu]Lu-NeoB in combination with ribociclib and fulvestrant in postmenopausal participants, and in combination with ribociclib, fulvestrant, and goserelin in premenopausal / perimenopausal participants. 177 The aim of this study was to characterize the safety and tolerability of [Lu]Lu-NeoB (extended part).

[0134] The study includes a dose-escalation part followed by a dose-expansion part. In the dose-escalation part, ribociclib was combined with fulvestrant. 177 The RD of [Lu]Lu-NeoB will be estimated; four interim dose levels will be studied: 100 mCi (initial dose), 150 mCi, 200 mCi, and 250 mCi in cohorts of 3 to 6 participants. After enrollment in each cohort of 3 to 6 participants, the incidence of DLTs will be compared with predefined toxicity rate boundaries to determine whether the next cohort will receive a lower, higher, or the same dose, or whether the study will be terminated. The expansion part will evaluate the efficacy of [Lu]Lu-NeoB in combination with ribociclib and fulvestrant (and also receive goserelin) in both postmenopausal and premenopausal / perimenopausal participants, as established in the dose-escalation part. 177 The safety, tolerability, and antitumor activity of RD dose of [Lu]Lu-NeoB will be evaluated. A total of 15 participants will be enrolled in the expansion part.

[0135] During screening, study participants were not given any investigational imaging agent [ 68 Administer Ga]Ga-NeoB. 68 Additional administration of Ga]Ga-NeoB is necessary for PET / CT or PET / MRI. 177 This is performed within 2 to 8 weeks after the last dose of ]Lu-NeoB.

[0136] The study treatment was administered on day 1 (+ ≤ 3 days) of each 28-day cycle for 6 cycles. 177 The study includes [Lu]Lu-NeoB, ribociclib (once daily; days 1-21 of a 28-day cycle), and fulvestrant (C1D1, C1D15, C2D1, and every 28 days thereafter) until disease progression. Premenopausal and perimenopausal participants in the expansion part will additionally receive goserelin on day 1 of every cycle.

[0137] During the treatment period, participants will be required to attend site visits approximately every 28 days on the first day of each cycle (as well as on C1D2, C1D3, C1D8, C1D15, C2D15, C3D3, and C5D3) for study treatment administration, dosimetry, and safety assessments. Tumor assessments will be performed every 8 weeks until 18 months, every 12 weeks until 36 months, and thereafter as clinically indicated until disease progression. After discontinuation of study treatment, participants will be followed for safety for 8 weeks after their last study treatment dose. After the initial 8 weeks of safety follow-up, all participants will be followed according to the SoA in Section 1.3, every 12 weeks until 36 months, and then every 24 weeks until 60 months, for a total of 5 years from the participant's enrollment in the study, or until death, loss to follow-up, or WoC.

[0138] End of study will be defined as the date of the last visit, scheduled procedure, or follow-up of the last participant in the study, inclusively, as indicated in the SoA in Section 1.3 (or the date of death, WoC, or loss to follow-up, whichever occurs first), or 5 years from the date of enrollment of the last participant, whichever occurs first.

[0139] Targeted treatment This test uses [ 68 Ga]Ga-NeoB, and as an experimental therapeutic agent, [ 177 Lu]Lu-NeoB, ribociclib, fulvestrant, and goserelin (in the expansion part for pre- / peri-menopausal women only).

[0140] The NeoB peptide is a new-generation bombesin (BN) analogue that is a GRPR antagonist with superior pharmacokinetic and toxicological properties compared to agonist analogues. It binds to the GRPR with high affinity and exhibits low internalization, consistent with antagonist behavior (Nock et al., 2017). Its structure contains a DOTA metal chelator, which allows radiolabeling with different radionuclides, including gallium-68 (for positron emission tomography (PET) imaging) and lutetium-177 (for radionuclide therapy), without affecting receptor affinity, internalization properties, or biodistribution.

[0141] [ 68 [Ga]Ga-NeoB has been used as an imaging agent to detect and treat GRPR-overexpressing tumors in patients with GRPR-overexpressing tumors, including subjects with breast cancer. 177 Lu]Lu-NeoB is intended as a tool of choice for treatment (Flores et al. 2010, Morgat et al. 2017). 68 [Ga]Ga-NeoB has shown favorable technical and diagnostic performance for identifying GRPR-expressing malignancies in both preclinical and clinical studies, with good image quality allowing for easy interpretation.

[0142] [ 177 Lu]Lu-NeoB exhibits high affinity for GRPR, and its ability to target GRPR-expressing tumors has been confirmed in in vivo imaging and biodistribution studies in tumor models. 177[Lu]Lu-NeoB is rapidly cleared from the blood, rapidly eliminated through the renal system, and not retained in the kidney. Consistent with its GRPR antagonist profile, background radioactivity is observed in GRPR-expressing tissues (mostly the pancreas), but it diminishes over time. In contrast, tumor retention is persistent, with detectable uptake levels up to 7 days after injection. These characteristics allow for the development of [Lu]Lu-NeoB. 177 Lu]-Lu NeoB would be an ideal candidate for peptide receptor radionuclide therapy (PRRT). 177 Lu]Lu-NeoB will be administered to patients with advanced solid tumors known to overexpress GRPR who have no available options for treatment[ 177 [Lu]Lu-NeoB is currently being evaluated as a single agent in an ongoing Phase I / IIa, open-label, multicenter study to assess its safety, tolerability, systemic distribution, radiation dosimetry, and antitumor activity. 177 We show that [Lu]Lu-NeoB exhibits a good tolerability and safety profile and favorable biodistribution, with low uptake in organs considered at risk due to GRPR expression, such as the pancreas, or in organs considered at risk due to radioligand therapy (RLT), such as the red bone marrow, and in organs considered at risk due to excretion pathways, such as the kidney.

[0143] In this study, participants received ribociclib in combination with fulvestrant (and goserelin, if applicable, in the expansion part only). 177 Lu]Lu-NeoB is administered.

[0144] Number of participants: Up to 27 participants will be enrolled in the dose-escalation part of the study: four cohorts of 3 to 6 participants for each of the four dose levels, and an additional 3 to 6 participants, for a total of up to 9 participants, will be enrolled at a particular dose level. Once RD has been assessed, approximately 15 participants will be enrolled in the dose-expansion part.

[0145] Key inclusion criteria: Adult females ≥ 18 years of age at the time of informed consent Participants are postmenopausal at the time of starting study treatment (titration part). Participants are pre- / peri-menopausal or post-menopausal at the time of initiation of study treatment (expansion part). Histologically and / or cytologically confirmed estrogen receptor-positive breast cancer with ER>10% (irrespective of PgR expression) according to local laboratory testing (based on the most recently analyzed tissue sample) HER2-negative breast cancer is defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+, or 2+. If the IHC is 2+, a negative in situ hybridization (e.g., FISH, CISH, or SISH) test is required by local clinical testing (based on the most recently analyzed tissue sample). Disease recurrence during (neo)adjuvant ET or ≤12 months after completion of (neo)adjuvant ET (which may include a CDK4 / 6 inhibitor) Progressive [locoregionally recurrent, not amenable to definitive treatment (e.g., surgery and / or RT)] or metastatic disease Measurable disease, i.e., at least one measurable lesion according to RECIST 1.1. (Lesions in previously irradiated sites may be counted as target lesions only if there is clear evidence of progression since irradiation) or if only lytic bone lesions are present, at least one lesion must have a soft tissue component assessable by CT or MRI, meeting the definition of measurable according to RECIST 1.1. (Participants with only one previously irradiated, primarily lytic bone lesion are eligible if there is documented evidence of disease progression in the bone lesion after irradiation). Participants had at least one target lesion (based on RECIST 1.1, baseline standalone computed tomography (CT) / magnetic resonance imaging (MRI) [ 68 The same identified measurable lesions were scored by PET / CT or PET / MRI based on a visual scoring scale, with uptake of [Ga]Ga-NeoB.68 1 shows the uptake of Ga]Ga-NeoB. Adequate bone marrow and organ function Standard 12-lead ECG values, defined as the mean of triplicate ECGs and assessed by a central laboratory QT interval corrected by the Fridericia formula (QTcF) <450 ms at screening Average resting heart rate 50-90 bpm (determined from ECG) Eastern Cooperative Oncology Group (ECOG) activity status 0 or 1

[0146] Key exclusion criteria Upfront treatment in the advanced / metastatic setting Symptomatic visceral disease or any disease burden that, according to the investigator's best judgment, would make the participant ineligible for ribociclib plus endocrine therapy Presence of CNS involvement unless both of the following criteria are met: 1) at least 4 weeks between the completion of prior therapy (including radiation and / or surgery) and the start of study treatment; 2) clinically stable CNS tumor not receiving steroid and / or enzyme-inducing antiepileptic medication for brain metastases at the time of screening. Currently receiving warfarin or other Coumadin-derived anticoagulants for treatment, prophylaxis, or other reasons. Treatment with heparin, low-molecular-weight heparin, or fondaparinux is permitted. Diagnosis of inflammatory breast cancer during screening Child-Pugh classification B or C History or current diagnosis of cardiac dysfunction, clinically significant cardiac disease, or ECG abnormalities that present a significant safety risk for the participant Known or suspected hypersensitivity to any of the study drugs or any of their excipients ·[ 68 Prior administration of radiopharmaceuticals if at least 10 half-lives have not elapsed prior to injection of [Ga]Ga-NeoB Participant received extensive RT ≤ 4 weeks or limited-field RT ≤ 2 weeks prior to treatment initiation and has not recovered to Grade 1 or greater from side effects related to such therapy and / or from side effects related to prior EBRT to more than 25% of the bone marrow (excluding alopecia or other toxicities not considered a safety risk to the participant at the investigator's discretion). Patients are currently receiving systemic corticosteroids or have received them within 2 weeks prior to starting the study treatment, or patients have not fully recovered from the side effects of such treatment. Note: The following uses of corticosteroids are permitted: single dose, topical application (e.g., for rashes), inhaled spray (e.g., for obstructive airway disease), eye drops, or local injection (e.g., intra-articular). Participants have a history of acute pancreatitis within one year of screening or have ongoing acute pancreatitis. Participant is currently receiving any of the following substances and cannot discontinue them within 7 days prior to starting the study treatment: Concomitant medications, herbal supplements, and / or fruits (e.g., grapefruit, pomelo, starfruit, Seville orange) and their juices that are strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4 / 5) Medications with narrow therapeutic windows that are primarily metabolized via CYP3A4 / 5 Concomitant medications that have a known risk of prolonging the QT interval and / or are known to cause TdP that cannot be discontinued or replaced by a safe alternative (e.g., within 5 half-lives or 7 days before starting the study treatment).

[0147] Treatment group: After the 42-day screening period, the treatment period continues until discontinuation of study medication due to disease progression, any other reason, e.g., unacceptable toxicity, symptomatic deterioration, withdrawal of consent (WoC), loss to follow-up, investigator decision, or death (whichever occurs first). The post-treatment follow-up period includes a safety follow-up period of 8 weeks after treatment discontinuation and long-term follow-up for up to 5 years from the participant's date of enrollment. During screening, each participant will be required to undergo a PET / CT or PET / MRI imaging 68 Administer Ga]Ga-NeoB. 68 [Ga]Ga-NeoB is administered as a single intravenous dose of activity in the range of 150-250 MBq (4.1-6.8 mCi). In the dose-escalation part, each participant within a specific cohort will receive ribociclib (tablets, 600 mg daily for 21 consecutive days followed by 7 days off treatment) in combination with fulvestrant (500 mg on day 1, intramuscular injection in a 28-day cycle + an additional single dose administered on day 15 of cycle 1). 177 Lu]Lu-NeoB will be administered at a starting dose of 3.7 GBq (100 mCi) + / - 10% (intravenous infusion, every 28 days for 6 cycles). During the titration part, [ 177 Four dose levels (100, 150, 200, or 250 mCi) of Lu]Lu-NeoB are planned to be explored. In the expansion part, each participant will receive ribociclib (tablets, 600 mg daily for 21 consecutive days followed by 7 days off treatment) in combination with fulvestrant (500 mg on day 1, intramuscular injection in a 28-day cycle + an additional single dose administered on day 15 of cycle 1). 177 Lu]Lu-NeoB will be administered by RD (intravenous infusion, RD, every 28 days for 6 cycles). In addition, pre- / peri-menopausal women will receive goserelin (3.6 mg on day 1 of a 28-day cycle). In the gradual increase part 177 If the starting dose of [Lu]Lu-NeoB is not tolerated, lower doses will not be tested and the study will be terminated. ·[ 177 Within 2 to 8 weeks after the final dose of the investigational imaging agent [ 68 Additional administration of Ga]Ga-NeoB was performed to improve the baseline [ 68 Ga]Ga-NeoB PET scan and [ 177 The difference between the administration of the final dose of [Lu]Lu-NeoB and the post-administration dose of [Lu]Lu-NeoB is assessed.

[0148] Example 2: Clinical Trial II for Treating Breast Cancer Subjects, Update to the Protocol of Clinical Trial I from Example 1 Changes from Example 1: Changes in study design The study design has been updated from "dose escalation followed by a dose expansion part" to dose escalation at lower, previously excluded dose levels and simultaneous backfilling. The dose expansion part has been eliminated. The purpose of this design change is to enable robust and efficient data generation at all tested dose levels that will facilitate dose recommendations for future studies and inform future dose optimization based on the totality of the data.

[0149] Major changes in eligibility criteria Patients with HR+, HER2- advanced breast cancer who have progressed on first-line therapy (ET+CDK4 / 6 inhibitors) for advanced disease are accepted into the study. Patients in the CDK4 / 6i setting may have more aggressive disease compared to patients in the endocrine-only failure setting, presenting a challenging clinical scenario. Furthermore, the selection of subsequent treatments is challenging and often empirically based, as no guidelines identifying optimal treatment sequencing are available and there is significant unmet medical need for novel therapies in this population. Male patients are allowed in the study. To match patient populations across all dose levels, female participants will be allowed throughout the study regardless of their menopausal status. ·[ 177 Lu] to select participants for treatment with Lu-NeoB [ 68The uptake threshold for [Ga]Ga-NeoB has been updated in accordance with the updated study design. While two different thresholds based on visual uptake scoring scales were previously applied to each part of the study (dose escalation and dose expansion), a set of criteria requiring exclusively higher uptake has been selected in the current design. The required scores correspond to those previously established for the escalation part of the study and are based on the goal of maximizing efficacy and enriching a more homogeneous population. At the time of study enrollment, new exclusion criteria related to the use of NEP inhibitors were introduced. 177 This is due to the potential risk of drug-drug interactions between [Lu]Lu-NeoB and neprilysin (NEP) inhibitors.

[0150] Other changes ·[ 177 Clinical experience with [Lu]Lu-NeoB is updated with recent data supporting the determination of the RP2D in the ongoing phase 1 in human trial CAAA603A12101 (NeoRay). Statistical considerations have been updated according to the new study design, including endpoint definitions and sample size. 68 The diagnostic set used for the Ga]Ga-NeoB association analysis is divided into two analysis sets: 68 Ga]Ga-NeoB safety analysis set and [ 68 Ga]Ga-NeoB evaluable set. Updated biomarker methods to allow for the collection of paired pre- and post-treatment tumor biopsies, where medically feasible. 68 With the addition of a new evaluation of [Ga]Ga-NeoB, GRPR expression in tissue biopsies obtained at C3D1 and PET at C2D15 was significantly increased. 68 We are checking the relationship with Ga]Ga-NeoB uptake. ·[ 177 The time course between the final administration of [Lu]Lu-NeoB and the subsequent PET scan has been changed from 2–8 weeks to 4–8 weeks according to HA feedback. Added information and specifications regarding co-administration with NEP inhibitors (e.g., Entresto, Racecadotril) and potential DDIs. In Section 7.5 (Criteria for Stopping or Pausing a Trial), the number of participants that would trigger a coordinated safety review, assuming all participants undergo DLT assessment (according to the new trial design), has been updated. Additionally, following HA feedback, clarification has been added to the process for HA notification and resumption of mobilization based on local regulations. Further exploratory evaluation of Clinical Outcome Assessments (COA) (Section 8.5) is eliminated because the new design no longer has a centralized expansion part with one single recommended dose for expansion. Instead, the backfill part will inform a preliminary benefit-risk assessment of different doses. This type of clinical outcome assessment will be performed in future program-level development phases.

[0151] title: In combination with ribociclib and fulvestrant in participants with ER+, HER2- and GRPR+ advanced breast cancer who have early relapsed from (neo)adjuvant endocrine therapy or progressed on endocrine therapy in combination with a CDK4 / 6 inhibitor [ 177 A Phase Ib dose-finding study evaluating the safety and activity of ]Lu-NeoB.

[0152] the purpose: In combination with ribociclib and fulvestrant in participants with estrogen receptor (ER)-positive (ER+), human epidermal growth factor receptor-2 (HER2)-negative (HER2-) and gastrin-releasing peptide receptor (GRPR)-positive (GRPR+) advanced breast cancer who have experienced early relapse from (neo)adjuvant endocrine therapy or have progressed on endocrine therapy in combination with a CDK4 / 6 inhibitor for advanced disease [ 177 To estimate the recommended dose (RD) of Lu]Lu-NeoB

[0153] Study Design: This was in combination with ribociclib and fulvestrant (+ / - goserelin) in adult female and male participants with ER+ / HER2-, GRPR+ advanced breast cancer who had experienced early relapse from (neo)adjuvant endocrine therapy or had progressed on endocrine therapy in combination with a CDK4 / 6 inhibitor for advanced disease. 177 This is a Phase 1b, single-arm, multicenter, open-label, dose-finding study of [Lu]Lu-NeoB. The study includes a dose-escalation portion and a parallel backfill portion. The backfill portion will allow enrollment at previously excluded dose levels (during the escalation portion) to obtain additional safety and tolerability data.

[0154] The study will include a dose escalation portion and a parallel backfill portion. The backfill portion will allow for enrollment at previously excluded dose levels (during the escalation portion) to obtain further safety, tolerability, and preliminary efficacy data. Four interim dose levels are planned: 100 millicuries (mCi) (initial dose), 150 mCi, 200 mCi, and 250 mCi in cohorts of 3 to 6 participants. After enrollment of 3 to 6 participants in each cohort, the incidence of DLTs will be compared with predefined toxicity rate boundaries to determine whether the next cohort will receive a lower, higher, or the same dose, or whether the study will be terminated. Also, during the backfill portion, the cumulative incidence of DLTs will be compared with predefined toxicity rate boundaries to determine whether escalation should resume at a lower dose level.

[0155] During screening, study participants were not given any investigational imaging agent [ 68 Administer Ga]Ga-NeoB. 68 Additional administration of ]Ga-NeoB is recommended for positron emission tomography (PET) / computed tomography (CT) or PET / magnetic resonance imaging (MRI). 177 The study treatment will be administered within 4-8 weeks after the last dose of [Lu]Lu-NeoB. The study treatment will be administered on day 1 (+ ≤ 3 days) of each 28-day cycle for 6 cycles. 177The study included [Lu]Lu-NeoB, ribociclib (once daily; days 1-21 of a 28-day cycle), and fulvestrant (C1D1, C1D15, C2D1, and every 28 days thereafter) until disease progression. In addition, premenopausal and perimenopausal participants received goserelin on day 1 of each cycle.

[0156] During treatment, participants will be required to attend site visits approximately every 28 days on the first day of each cycle (as well as on C1D2, C1D3, C1D8, C1D15, C2D15, C3D3, and C5D3) for study treatment administration, dosimetry, and safety assessments. Tumor assessments will be performed every 8 weeks until 18 months, every 12 weeks until 36 months, and then as clinically indicated until disease progression. After discontinuation of study treatment, participants will be followed for safety for 8 weeks after their last study treatment dose. After the initial 8 weeks of safety follow-up, all participants will be followed every 12 weeks until 36 months, and then every 24 weeks until 60 months, for a total of 5 years from the participant's enrollment in the study or until death, loss to follow-up, or withdrawal of consent (WoC), whichever occurs first.

[0157] The end of the study will be defined comprehensively as the date of the last visit, scheduled procedure, or follow-up of the last participant in the study (or the date of death, WoC, or loss to follow-up, whichever occurs first), or 5 years from the date of enrollment of the last participant, whichever occurs first.

[0158] treatment period The study will include a dose escalation portion and a parallel backfill portion. The backfill portion will allow for enrollment at previously excluded dose levels (during the escalation portion) to obtain further safety, tolerability, and preliminary efficacy data. Four interim dose levels are planned: 100 millicuries (mCi) (initial dose), 150 mCi, 200 mCi, and 250 mCi in cohorts of 3 to 6 participants. After enrollment of 3 to 6 participants in each cohort, the incidence of DLTs will be compared with predefined toxicity rate boundaries to determine whether the next cohort will receive a lower, higher, or the same dose, or whether the study will be terminated. Also, during the backfill portion, the cumulative incidence of DLTs will be compared with predefined toxicity rate boundaries to determine whether escalation should resume at a lower dose level.

[0159] During screening, study participants were not given any investigational imaging agent [ 68 Administer Ga]Ga-NeoB. 68 Additional administration of ]Ga-NeoB is recommended for positron emission tomography (PET) / computed tomography (CT) or PET / magnetic resonance imaging (MRI). 177 The study treatment will be administered within 4-8 weeks after the last dose of [Lu]Lu-NeoB. The study treatment will be administered on day 1 (+ ≤ 3 days) of each 28-day cycle for 6 cycles. 177 The study included [Lu]Lu-NeoB, ribociclib (once daily; days 1-21 of a 28-day cycle), and fulvestrant (C1D1, C1D15, C2D1, and every 28 days thereafter) until disease progression. In addition, premenopausal and perimenopausal participants received goserelin on day 1 of each cycle.

[0160] During the treatment period, participants will be required to attend site visits approximately every 28 days on the first day of each cycle (as well as on C1D2, C1D3, C1D8, C1D15, C2D15, C3D3, and C5D3) for study treatment administration, dosimetry, and safety assessments. Tumor assessments will be performed every 8 weeks until 18 months, every 12 weeks until 36 months, and then as clinically indicated until disease progression. After discontinuation of study treatment, participants will be followed for safety for 8 weeks after their last study treatment dose. After the initial 8 weeks of safety follow-up, all participants will be followed according to the Schedule of Activities (SoA) in Section 1.3 every 12 weeks until 36 months, and then every 24 weeks until 60 months, for a total of 5 years from the participant's enrollment in the study or until death, loss to follow-up, or withdrawal of consent (WoC), whichever occurs first.

[0161] End of study will be defined as the date of the last visit, scheduled procedure, or follow-up of the last participant in the study, inclusively, as outlined in the SoA in Section 1.3 (or the date of death, WoC, or loss to follow-up, whichever occurs first), or 5 years from the date of enrollment of the last participant, whichever occurs first.

[0162] Number of participants A maximum of approximately 48 participants are expected to be treated at four dose levels. Cohorts of 3-6 evaluable participants will be enrolled in the dose escalation portion. Additional participants will be backfilled at each dose level (including participants enrolled during the escalation portion at that dose level), up to a total of approximately 12 participants.

[0163] Key inclusion criteria Adult female or male ≥ 18 years of age at the time of informed consent Histologically and / or cytologically confirmed estrogen receptor-positive breast cancer with ER>10% (irrespective of progesterone receptor (PgR) expression) according to local laboratory testing (based on the most recently analyzed tissue sample) HER2-negative breast cancer is defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+, or 2+. If the IHC is 2+, a negative in situ hybridization (e.g., fluorescent in situ hybridization (FISH), chromogenic in situ hybridization (CISH), or silver in situ hybridization (SISH)) test is required by local clinical testing (based on the most recently analyzed tissue sample).

[0164] Participants have advanced (locoregionally recurrent, or metastatic, not amenable to definitive treatment (eg, surgery and / or radiation therapy)) breast cancer.

[0165] Participants can be: a. Relapsed without treatment for progressive disease with documented evidence of recurrence at or within 12 months of completion of (neo)adjuvant endocrine therapy (+ / - CDK4 / 6 inhibitor), OR b. Relapsed with documented evidence of recurrence more than 12 months after completion of (neo)adjuvant endocrine therapy, and subsequently progressed with documented evidence of progression after first-line endocrine therapy (excluding fulvestrant) (+ / - CDK4 / 6 inhibitors) for progressive disease, or c. Advanced breast cancer at diagnosis that has progressed after first-line endocrine therapy (excluding fulvestrant) (+ / - CDK4 / 6 inhibitors) with documented evidence of progression

[0166] Note: Participants who relapse with documented evidence of recurrence during or within 12 months of completion of (neo)adjuvant endocrine therapy and then subsequently progress with documented evidence of progression after first-line endocrine therapy (with either antiestrogen or aromatase inhibitors) for progressive disease will not be included in the study. At least one target lesion (i.e., a measurable lesion according to RECIST 1.1) on the baseline stand-alone CT or MRI must be present on a visual scoring scale (see section 8.5.2) with a PET / CT or PET / MRI scoring of 2 or greater. 68 1 shows the uptake of Ga]Ga-NeoB. Adequate bone marrow and organ function Standard 12-lead ECG values, defined as the mean of triplicate ECGs and assessed locally: QT interval corrected by the Fridericia formula (QTcF) <450 msec at screening Average resting heart rate 50-90 bpm (determined from ECG) Eastern Cooperative Oncology Group (ECOG) activity status 0 or 1

[0167] Key exclusion criteria Prior second-line or higher therapy in the advanced / metastatic setting. Participants are not required to have received prior fulvestrant treatment. Documented evidence of upfront ribociclib dose reduction for safety reasons, either in the adjuvant setting or in the setting of progressive disease Relapse or disease progression within 6 months of receiving CDK4 / 6 inhibitor therapy in either the adjuvant setting or progressive disease. Symptomatic visceral disease or any disease burden that would make the participant ineligible for ribociclib plus endocrine therapy, according to the investigator's best judgment. Presence of central nervous system (CNS) involvement unless both of the following criteria are met: 1) at least 4 weeks between the completion of prior therapy (including radiation and / or surgery) and the start of study treatment, and 2) clinically stable CNS tumors not receiving steroid and / or enzyme-inducing antiepileptic medication for brain metastases at the time of screening. Currently receiving warfarin or other Coumadin-derived anticoagulants for treatment, prophylaxis, or other reasons. Treatment with heparin, low-molecular-weight heparin, or fondaparinux is acceptable. Diagnosis of inflammatory breast cancer during screening Child-Pugh classification B or C History or current diagnosis of cardiac dysfunction, clinically significant cardiac disease or ECG abnormalities that present a significant safety risk for the participant. Known or suspected hypersensitivity to any of the study drugs or any of their excipients ·[ 68 Radiopharmaceuticals or [Ga]Ga-NeoB if 10 half-lives or more have not elapsed prior to injection 177 Preceding administration of [Lu]Lu-NeoB Participant received extensive RT ≤ 4 weeks or limited-field RT ≤ 2 weeks prior to treatment initiation and has not recovered from Grade 1 or greater side effects related to such therapy (excluding alopecia or other toxicities not considered a safety risk to the participant at the investigator's discretion) and / or from side effects related to upfront external beam radiation therapy (EBRT) to more than 25% of the bone marrow. Participants are currently receiving systemic corticosteroids or have received them within 2 weeks prior to starting the study treatment, or participants have not fully recovered from the side effects of such treatment. Note: The following uses of corticosteroids are permitted: single dose, topical application (e.g., for rashes), inhaled spray (e.g., for obstructive airway disease), eye drops, or local injection (e.g., intra-articular). Participants have a history of acute pancreatitis within one year of screening or have ongoing acute pancreatitis. Participant is currently receiving any of the following substances and cannot discontinue them within 7 days prior to starting the study treatment: Concomitant medications, herbal supplements, and / or fruits (e.g., grapefruit, pomelo, starfruit, Seville orange) and their juices that are strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 Medications with narrow therapeutic windows that are primarily metabolized via CYP3A4 / 5 Concomitant medications that have a known risk of prolonging the QT interval and / or are known to cause polymorphic ventricular tachycardia (TdP) that cannot be interrupted or replaced by a safe alternative (e.g., within 5 half-lives or 7 days before starting the study treatment). The participant is currently receiving an NEP inhibitor (e.g., Entresto®, racecadotril), and images for dosimetry assessment cannot be obtained for this participant.

[0168] Backfill Part Once a dose level is declared safe during the dose escalation part, additional participants are allowed to backfill that previously excluded dose level (during the dose escalation part) to obtain further data. Participants enrolled in the backfill part are also evaluated for dose-limiting toxicity. Any new DLT observed for a given dose level in a backfill participant triggers a review of the cumulative DLT rate for the considered dose level against the boundaries defined by the BOIN. If the BOIN suggests tapering or maintaining that dose level, the participating investigators and sponsor will be satisfied and agree on the next dose to be tested. The recommended dose (RD) is determined taking into account all available data from the escalation and backfill parts. Only one escalation cohort and one backfill cohort may be open to simultaneous mobilization. The allocation of participants to either the escalation or backfill cohort is guided by the following principles and decision tree (Figure 3). Priority will always be given to the incremental cohort. If two or more dose levels are declared safe (during the titration part), backfilling will be allowed at the lowest dose level that is open to enrollment until that dose level reaches the required maximum number of participants. Then backfilling will be allowed at the next safe dose level.

[0169] See Figure 3 for the decision tree for participant allocation in the escalation cohort or backfill part.

[0170] Example 3: Rationale for the study Nonclinical biodistribution and DMPK In non-clinical models, [ 68 Ga]Ga-NeoB and [ 177 Lu]Lu-NeoB shows high affinity for GRPR, which is overexpressed in breast, prostate, GIST, and gliomas (including glioblastoma) (Flores et al., 2010, Morgat et al., 2017).

[0171] The ability of the radiolabeled peptide to target GRPR-expressing tumors has been confirmed in in vivo imaging and biodistribution studies in healthy mice and tumor models. 177 [Lu]Lu-NeoB is rapidly cleared from the blood, rapidly eliminated through the renal system, and not retained in the kidney. Indeed, 4 hours after injection, uptake remains relatively high only in GRPR-expressing tissues (mostly the pancreas), but declines over time, consistent with a GRPR antagonist profile. In contrast, tumor retention is persistent, with detectable uptake levels up to 7 days after injection. These characteristics allow [Lu]Lu-NeoB to be rapidly cleared from the blood and rapidly eliminated through the renal system, without retention in the kidney. Indeed, 4 hours after injection, uptake remains relatively high only in GRPR-expressing tissues (mostly the pancreas), but declines over time, consistent with a GRPR antagonist profile. In contrast, tumor retention is persistent, with detectable uptake levels up to 7 days after injection. 177 Lu]-Lu NeoB is an ideal candidate for PRRT. For more information, see [ 177 Please see the Investigator Brochure (IB) for Lu-NeoB.

[0172] [ 177 Lu]Lu-NeoB induces cell damage primarily through free radical formation in GRPR-positive tumor and adjacent cells.

[0173] Based on the results of in vitro drug-drug interaction (DDI) studies, 177 Lu]Lu-NeoB is not believed to have the potential for CYP- or transporter-mediated DDIs.

[0174] In vivo preclinical cardiac safety studies showed that 177 This indicates that the risk of electrophysiological effects from [Lu]Lu-NeoB is negligible. No significant effects on cardiac electrophysiological function or hemodynamics were observed as measured by telemetry in conscious minipigs with a 55- to 85-fold margin for mass doses of 200-300 μg of administered NeoB peptide. 177 Since [Lu]Lu-NeoB has been shown to be metabolized, the parent concentration is projected to be even lower. 177 [Lu]Lu-NeoB showed very low radioactive uptake in the heart, therefore the overall cardiac risk can be considered very low.

[0175] toxicology Nonclinical studies have been conducted using a nonradioactive alternative [175Lu]Lu-NeoB formulation, which supports the safety of administering the NeoB peptide to patients. No adverse effects have been observed in safety pharmacology studies. Similarly, no signs of toxicity have been reported after either acute or repeated administration of [175Lu]Lu-NeoB, confirming the safety of the nonradioactive molecule.

[0176] [ 177 Clinical experience with Lu]Lu-NeoB NeoRay (EUDRACT no. 2018-004727-37) was administered in patients with advanced solid tumors known to overexpress GRPR [ 177 This is an ongoing phase I / IIa, open-label, multicenter study to evaluate the safety, tolerability, systemic distribution, radiation dosimetry, and antitumor activity of ]Lu-NeoB.

[0177] As of October 11, 2022, [ 177 Eleven patients received 1.85 GBq (50 mCi) of [Lu]Lu-NeoB as the initial dose (cycle 1). 177 Lu]Lu-NeoB was administered. 177 Intrapatient dose escalation to [Lu]Lu-NeoB was performed from cycle 2 onwards based on clinical dosimetry in cycle 1.

[0178] Dose level 1 (50 mCi in cycle 1 and 150 mCi in subsequent cycles) was evaluated in three patients with breast, prostate, and GIST cancer. Two patients received two cycles and one patient received six cycles. Overall treatment was well tolerated, with no DLTs or SAEs reported.

[0179] Dose level 2 was assessed at 300 mCi / cycle and enrolled four patients, two with prostate cancer and two with GIST. Two patients received one cycle, one patient received two cycles, and one patient received three cycles. Two of the four enrolled patients experienced DLTs (grade 3 anemia in both patients and grade 3 encephalopathy in one patient). All of these events resolved. In a patient with prostate cancer and extensive bone metastases, one grade 3 anemia event occurred, and grade 2 anemia had progressed at screening (the subject also received a red blood cell transfusion before starting treatment). The patient developed grade 3 anemia 36 days after infusion and later grade 4 thrombocytopenia despite progressive disease. The patient discontinued treatment, and while anemia temporarily improved to grade 2 with supportive care, grade 4 thrombocytopenia was ongoing at the time of death due to PD. Two other DLTs were recorded in a patient with GIST that occurred within one week of receiving the first therapeutic dose (anemia grade 3 and encephalopathy grade 3). The patient had extensive pelvic bone metastases and anemia grade 1 at baseline. The patient was noted to have left-sided facial paralysis and altered mental changes, along with grade 2 vomiting and grade 3 hyponatremia; a brain MRI ruled out stroke and brain metastases. Three days later, the patient also developed seizures. The patient was being treated with very high doses of diazepam. 177 The infusion of [Lu]Lu-NeoB was discontinued after several days, raising the suspicion of withdrawal syndrome as a confounding factor. No other significant toxicities were reported.

[0180] Following the occurrence of DLT observed at dose level 2, a dose de-escalation to 250 mCi (dose level 3) was decided, consistent with the protocol. Dose level 3 was evaluated in four patients (two with GIST, one with prostate cancer, and one with glioblastoma). The glioblastoma patient received three cycles of [ 177One patient with GIST received [Lu]Lu-NeoB and one patient with GIST received two cycles. Both patients discontinued due to disease progression, while the other two patients (GIST and prostate cancer) have each received two cycles and treatment is still ongoing. Overall treatment was very well tolerated, with the majority of reported AEs being mild / moderate, and no DLTs or SAEs were reported.

[0181] Stabilization of two chronic diseases was observed across the dose levels evaluated: approximately 1 year in GIST patients and 5 months in prostate cancer patients.

[0182] Of the 11 treated patients in the study, 3 patients completed treatment, 2 patients discontinued due to AEs, 3 patients discontinued due to PD, 1 patient decided to discontinue treatment, and 2 patients are ongoing.

[0183] From NeoRay 177 Preliminary blood radioactivity PK of [Lu]Lu-NeoB indicated rapid elimination from the systemic circulation, with a geometric mean elimination half-life of approximately 60-80 hours and a mean effective half-life of approximately 48 hours. Radioactive high-performance liquid chromatography (HPLC) data indicated metabolism in the systemic circulation and urine (as well as pharmacologically inactive metabolites unable to bind receptors), but cumulative excretion of activity indicates that radioactivity is still primarily (on average ≥80%) excreted via the kidneys within 24-48 hours. 177 The enzymes involved in the metabolism of [Lu]Lu-NeoB are currently unknown.

[0184] Preliminary dosimetry results indicate favorable biodistribution with low uptake in organs considered at risk due to GRPR expression, e.g., the pancreas, or RLT expression, e.g., the red bone marrow, and in organs considered at risk due to excretory pathways, e.g., the kidney. Across all dose levels studied, the dose-normalized mean absorbed doses (rounded to 2 significant figures) in Gy / GBq (±SD, n=10) were 0.11±0.059 (kidney), 0.019±0.0066 (red bone marrow), 0.063±0.038 (pancreas), 0.011±0.0034 (testis, n=7), 0.021±0.0077 (ovary, n=3), and 0.72±0.94 (all tumor lesions, n=18), respectively.

[0185] Given the safety and biodistribution profile at 250 mCi, a decision was made to re-escalate to 300 mCi per the NeoRay study protocol.

[0186] As of June 7, 2023, 17 patients across five cohorts and three dose levels in study CAAA603A12101 have 177 Lu] Lu-NeoB treatment.

[0187] [Table 3]

[0188] A decision was subsequently made to re-escalate the dose to 300 mCi, consistent with protocol, based on the overall favorable safety profile of dose level 3. Given that some patients treated with the 300 mCi dose experienced DLTs, the dose was de-escalated to 250 mCi (DL3) in cohort 5, per protocol.

[0189] In Cohort 5 as of June 7, 2023, five patients will receive a 250 mCi dose (dose level 3) [ 177Lu]Lu-NeoB was administered. None of these five patients experienced either DLTs or SAEs. The majority of reported AEs were mild or moderate in severity. No grade 2 or higher laboratory abnormalities were clinically significant.

[0190] The generated Phase I dosimetry data are favorable, with a large safety margin compared to the EBRT threshold, even at high cumulative activity. 177 The organ dosimetry profile of [Lu]Lu-NeoB was demonstrated. Consequently, based on the overall data, including dosimetry, observed safety (including DLT data), and tolerability data at the dose levels tested, Novartis, along with the participating investigators, announced the RP2D as 250 mCi. This dose will be further tested in the Phase IIa part of the study.

[0191] [ 68 Background on Ga]Ga-NeoB [ 68 [Ga]Ga-NeoB is used in the study; it is used for PET and [Ga]Ga-NeoB in patients with tumors that overexpress GRPR, including MBC patients. 177 [Lu]Lu-NeoB is intended as a tool of choice for treatment. 68 In both preclinical and clinical trials, [Ga]Ga-NeoB has demonstrated favorable technical and diagnostic performance for identifying GRPR-expressing malignancies, with good image quality allowing for easy interpretation. Its diagnostic performance has been evaluated in two completed clinical trials: The Phase I / IIa clinical trial MITIGATE (EudraCT No. 2016-002053-38) demonstrated the efficacy of thrombomodulin in patients with GIST who had been previously treated with advanced tyrosine kinase inhibitors. 68 The safety, biodistribution, dosimetry, and preliminary diagnostic performance of [Ga]Ga-NeoB were evaluated. 68[Ga]Ga-NeoB was well tolerated in all nine participants with a favorable safety profile (radioactivity doses ranging from 127 to 214 MBq were administered). Radiation exposure was low due to rapid renal and blood clearance. Biodistribution was high in the pancreas, followed by the kidneys and liver. 68 We demonstrated the uptake of [Ga]Ga-NeoB. Rapid visually moderate to high tumor-specific uptake was identified in GRPR-expressing lesions. The Phase II clinical trial, NeoFIND (EudraCT number 2017-003432-37), mentioned in section 2.2.3, in 19 subjects with breast cancer (n=5), prostate cancer (n=5), colorectal cancer (n=5), non-small cell lung cancer (n=3), and small cell lung cancer (n=1) 68 The preliminary diagnostic performance of [Ga]Ga-NeoB was evaluated. 68 The safety profile of [Ga]Ga-NeoB was confirmed in this study. Results showed variable [ 68 Uptake of [Ga]Ga-NeoB is shown, where the highest number of lesions show visually moderate to high uptake in breast cancer patients. ·[ 68 Ga]Ga-NeoB has been shown to be effective in the ongoing Phase I / IIa NeoRay trial (EudraCT no. 2018-004727-37) 177 It is currently being used as an imaging agent to select patients for treatment with [Lu]Lu-NeoB. As of October 11, 2022, 41 patients have been treated with [ 68 Received 150-250MBq of Ga]Ga-NeoB and received 150-250MBq of Ga]Ga-NeoB. 68 No safety concerns have been reported regarding Ga]Ga-NeoB.

[0192] Background on Ribociclib Ribociclib is an orally bioavailable, highly selective small molecule inhibitor of the CDK4 / cyclin-D1 and CDK6 / cyclin-D3 enzyme complexes with IC50 values ​​of 0.01 and 0.039 μM, respectively, in biochemical assays.

[0193] After oral administration, the time to reach maximum plasma concentrations (Tmax) occurred between 1 and 4 hours, while in vitro binding to human plasma proteins was 70%. Elimination of ribociclib is primarily governed by oxidative metabolism via CYP3A4, with a minor contribution from flavin-containing monooxygenase 3. Elimination of ribociclib can be affected by coadministered medications that inhibit or induce CYP3A4 (KISQALI® US prescribing information).

[0194] Ribociclib is indicated for the treatment of adult patients with HR+ / HER2- advanced / metastatic breast cancer. AI as initial endocrine-based therapy; or Fulvestrant as initial endocrine-based therapy or after disease progression for ET in postmenopausal women or men In combination with , it is prescribed (according to the US prescribing information) at a daily dose of 600 mg p.o.

[0195] Ribociclib has been tested in combination with ET (letrozole or fulvestrant) in two randomized trials (Monaleesa-2 and Monaleesa-3, respectively) in postmenopausal women with HR+ / HER2- advanced / metastatic breast cancer, demonstrating a significant and durable survival benefit versus the matched placebo arm.

[0196] In Monaleesa-2, ribociclib in combination with letrozole at a median follow-up of 79.7 months demonstrated a median OS of 63.9 months versus 51.4 months in the matched placebo arm (HR, 0.76; 95% CI, 0.63-0.93; P = .004), with estimated 6-year OS rates of 44.2% for ribociclib plus letrozole and 32.0% for letrozole alone (Hortobagyi et al., 2022).

[0197] In Monaleesa-3, ribociclib in combination with fulvestrant at a median follow-up of 70.8 months showed a median OS of 67.6 months versus 51.8 months in the matched placebo arm (HR 0.67; 95% CI, 0.50-0.90), with an estimated 5-year OS of 56.5 months for ribociclib plus fulvestrant and 42.1 months for fulvestrant alone in the first-line metastatic setting (Neven et al., 2022).

[0198] Ribociclib has also been tested in combination with ET (the LHRH analogue goserelin and either an NSAI or tamoxifen) in another phase 3 randomized trial (Monaleesa-7) enrolling only pre- / peri-menopausal women with HR+ / HER2- advanced / metastatic breast cancer, and also demonstrated significantly longer OS than ET alone at 42 months (70.2% vs. 46%) (Im et al., 2019).

[0199] Based on these results, ribociclib remains the only CDK4 / 6i therapy, providing a statistically significant OS benefit across three phase 3 trials, regardless of endocrine partner, line of treatment, and menopausal status.

[0200] Clinical safety of ribociclib In the Monaleesa-3 trial, the most common adverse reactions (reported with a frequency of ≥20%) in the combination arm (ribociclib + fulvestrant) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. Most AEs were mild or moderate in severity. The most common grade 3 / 4 adverse reactions (reported with a frequency of ≥5%) were neutropenia, leukopenia, infections, and abnormal liver function tests (LFTs). Neutropenia was generally uncomplicated, and no incidences of polymorphic ventricular tachycardia (TdP) were observed. AE-related treatment discontinuations were rare, further supporting the manageable safety profile of the ribociclib-based combination. AEs leading to treatment discontinuation with fulvestrant plus ribociclib (compared to fulvestrant plus placebo) were elevated alanine transaminase (ALT) (5% vs. 0%), elevated AST (3% vs. 0.6%), and vomiting (1% vs. 0%) (KISQALI® US Prescribing Information).

[0201] Please refer to the local prescribing information for additional information regarding ribociclib and the management of ribociclib-related adverse events.

[0202] Background on Fulvestrant Fulvestrant is an ER downregulator with unknown agonistic effects (Addo et al., 2002). It binds to, blocks, and degrades ER, completely inhibiting ER signaling. As a result, the chances of ER activation by alternative pathways that may lead to resistance (e.g., growth factor-mediated mechanisms) are reduced (Nicholson et al., 2007).

[0203] Fulvestrant is absorbed slowly after a 500 mg intramuscular dose (long-acting formulation). After intramuscular administration, exposure is roughly dose-proportional within the 50-500 mg dose range. Maximum plasma concentrations are reached approximately 5 days later. If a booster dose is administered 2 weeks after the initial dose, steady state is achieved within the first month of administration. At steady state, a greater than two-fold difference occurs between mean Cmax and Cmin. Fulvestrant is distributed extensively and rapidly and is eliminated primarily by metabolism. The primary route of excretion is via the feces, with less than 1% excreted in urine. It has a high clearance rate, suggesting that it is a highly extractable drug. The terminal half-life after intramuscular administration is governed by the rate of absorption and estimated to be 40-50 days. Increased exposure to fulvestrant was observed in patients with moderate hepatic impairment (Child-Pugh class B). It is not administered to patients with severe hepatic impairment (Child-Pugh class C) (FASLODEX® prescribing information). Therefore, patients with Child-Pugh class B and Child-Pugh class C will not be enrolled in this study.

[0204] Fulvestrant is the first endocrine agent class approved for the treatment of postmenopausal women with HR+ advanced / metastatic breast cancer who have failed prior anti-estrogen therapy, based on data from the CONFIRM trial (Di Leo et al., 2010, Di Leo et al., 2014). Additional randomized trials (Mehta et al., 2012, Ellis et al., 2015) have demonstrated the superiority of fulvestrant as first-line therapy compared with or in conjunction with anastrozole. Fulvestrant in combination with a CDK4 / 6i is the recommended treatment for patients who have relapsed at the time of adjuvant ET or within 12 months of cessation of adjuvant therapy (Gennari et al., 2021).

[0205] Clinical safety of fulvestrant Fulvestrant has a manageable safety profile; the most common clinically significant adverse reactions occurring in ≥5% of patients in monotherapy are: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flashes, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation. Elevations of liver enzymes (ALT, aspartate transaminase (AST), alkaline phosphatase (ALP)) occurred in >15% of patients treated with fulvestrant and were not dose-related.

[0206] Fulvestrant should be used with caution in subjects with bleeding tendencies, thrombocytopenia, or anticoagulant use (FASLODEX® prescribing information).

[0207] Background on Goserelin Goserelin was shown to be effective in the expansion part of the study in pre- / peri-menopausal women only. 177 Lu]Lu-NeoB, in combination with ribociclib and fulvestrant.

[0208] Goserelin is a synthetic decapeptide analog of gonadotropin-releasing hormone (GNH) indicated for the treatment of prostate cancer, endometriosis, endometrial thinning, and advanced breast cancer. Goserelin is administered subcutaneously at a dose of 3.6 mg every 28 days. Following subcutaneous administration of goserelin (3.6 mg for 2 months), Tmax was 12-15 days post-dose in men and 8-22 days post-dose in women. Goserelin's metabolism is not CYP-mediated; rather, it is metabolized by hydrolysis of the C-terminal amino acid. More than 90% of the radiolabeled dose is excreted in urine, with approximately 20% of the urinary dose being accounted for by unchanged Goserelin (Zoladex® US Prescribing Information).

[0209] Clinical safety of goserelin Goserelin has been associated with different types of ET in the treatment of HR+ / HER2- pre- / peri-menopausal patients and has demonstrated a manageable and well-tolerated safety profile (Jakesz 2006, Kim et al. 2018).

[0210] In the Paloma-3 trial, goserelin was used in association with palbociclib and fulvestrant to treat pre- / peri-menopausal women, and the safety profile of the triple combination was not different from that of palbociclib and fulvestrant (Turner et al., 2018). Goserelin was also used in association with ribociclib and tamoxifen or AIs in the Monaleesa-7 trial, which did not show any new safety signals (Im et al., 2019).

[0211] AEs occurring in >20% of women treated with goserelin for breast cancer, dysfunctional uterine bleeding, and endometriosis include hot flashes, headache, sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast atrophy, seborrhea, and peripheral edema (per US prescribing information).

[0212] Please refer to the local prescribing information for additional information regarding goserelin and the management of goserelin-related adverse events.

[0213] screening The study informed consent form (ICF) must be signed and dated before any study-specific screening procedures are performed, except for assessments performed as part of standard care.

[0214] During the screening period of up to 42 days, participant eligibility will be determined according to the protocol's predefined inclusion and exclusion criteria. All screening assessments must be performed in accordance with the SoA. Each participant will be 177 During screening, to confirm eligibility for treatment with [Lu]Lu-NeoB, 68Received 100 mg Ga]Ga-NeoB. Safety follow-up calls were 68 This will be performed in all participants 3 (+ / - 1 day) after administration of [Ga]Ga-NeoB.

[0215] Participants who meet all eligibility criteria at screening may enroll in the study.

[0216] Treatment duration 1-Dose Escalation Part In the dose-escalation part described in Figure 1, ribociclib was combined with fulvestrant [ 177 The RD of [Lu]Lu-NeoB will be estimated. The BOIN approach (Yuan et al., 2015, Yuan et al., 2016) will be used to determine dose escalation or de-escalation requirements. After enrollment of 3–6 participants in each cohort, the incidence of DLTs will be compared with predefined toxicity rate boundaries to determine whether the next cohort will receive a lower, higher, or the same dose, or whether the study will be terminated.

[0217] [ 177 The initial dose of [Lu]Lu-NeoB will be 100 mCi (every 28 days for 6 cycles) in combination with ribociclib (600 mg daily for 21 consecutive days followed by 7 days off treatment) and fulvestrant (500 mg on day 1 of a 28-day cycle, plus an additional single dose on day 15 of cycle 1). Interim dose levels have been established within the protocol to guide dose selection. 177Based on a risk-benefit analysis and in agreement with the sponsor, Lu]Lu-NeoB may be continued until the completion of six cycles (or up to 10 cycles beyond, as determined by the investigator) if the participant develops tolerance to treatment and demonstrates benefit. Participants will continue treatment with ribociclib and fulvestrant until disease progression (as determined by the investigator according to RECIST 1.1) or discontinuation of study treatment for any other reason, such as unacceptable toxicity, symptomatic deterioration, WoC, loss to follow-up, investigator decision, or death, whichever occurs first. Participants will then enter a post-treatment follow-up period, if applicable, regardless of the reason for treatment discontinuation.

[0218] Dose escalation / de-escalation decisions were made by the investigator and sponsor at the end of the DLT reporting period for the last participant in each dosing cohort and in combination with ribociclib and fulvestrant from evaluable participants. 177 The DLT rate for [Lu]Lu-NeoB will be guided by biodistribution (dosimetry) data, where all AEs of CTCAE grade >2 were reported during the DLT reporting period, and cumulative safety data, possibly including other dose levels, were collected in previously treated participants.

[0219] 2-Dose Expansion Part In the dose-expansion part described in Figure 2, in postmenopausal participants, ribociclib (600 mg daily for 21 consecutive days followed by 7 days off treatment) and fulvestrant (500 mg on day 1 of a 28-day cycle, plus an additional single dose administered on D15 of cycle 1) were combined with [ 177 The RD dose of Lu]Lu-NeoB (every 28 days for 6 cycles) will be evaluated. Premenopausal / perimenopausal participants will be included in the expansion part and will also receive goserelin (3.6 mg on day 1 of a 28-day cycle) in addition to the treatments mentioned above. 177Lu]Lu-NeoB is based on a risk-benefit analysis and, if the participant tolerates or demonstrates benefit, may be continued until completion of six cycles (or up to 10 cycles beyond, as determined by the investigator), subject to agreement with the sponsor. Participants will continue study treatment with ribociclib, fulvestrant, and goserelin (pre- / peri-menopausal women only) until disease progression (as assessed by the investigator according to RECIST 1.1) or discontinuation of study treatment for any other reason, such as unacceptable toxicity, symptomatic deterioration, WoC, loss to follow-up, investigator decision, or death, whichever occurs first. Participants will then enter a post-treatment follow-up period, if applicable, regardless of the reason for treatment discontinuation.

[0220] [ 177 A total of 15 participants will be enrolled in the expansion part to further evaluate the safety, tolerability, and antitumor activity of RD of [Lu]Lu-NeoB. Approximately one-third of the cohort will consist of pre- / peri-menopausal participants.

[0221] Scientific basis for study design This was in combination with ribociclib and fulvestrant (and goserelin for pre- / peri-menopausal women in the expansion part) in adult female participants with HR+ / HER2-, GRPR+, advanced / metastatic breast cancer who had relapsed during or within 12 months of completing (neo)adjuvant ET. 177 This is a phase Ib, single-arm, dose-finding study of ]Lu-NeoB.

[0222] Patients who experience early relapse from adjuvant therapy represent a subset of patients with a poorer prognosis and in need of better treatment options. Assuming that treatment recommendations for HR+ / HER2- advanced / metastatic breast cancer in premenopausal and postmenopausal women will generally be similar in the expansion phase (Azim and Partridge 2014, Gennari et al. 2021, NCCN Guideline Breast Cancer Version 4.2022), with the exception of the aforementioned addition of LHRH in premenopausal / perimenopausal women (Rugo et al. 2016, Bardia and Hurvitz 2018), this study will enroll both premenopausal and postmenopausal participants. While differences in safety profiles are not anticipated due to the lack of data for this treatment combination, the study will begin with a more conservative approach before adding goserelin for premenopausal / perimenopausal women in the expansion portion and will include three treatments ([ 177 Lu]Lu-NeoB, ribocliclib, and fulvestrant will be considered.

[0223] Evidence for high expression of GRPR in breast cancer, as an imaging agent [ 68 The possibility of using Ga]Ga-NeoB to select patients with a specific GRPR threshold, and the synergistic effect of ribociclib with RLT, 177 The addition of [Lu]Lu-NeoB could potentially be an effective treatment aimed at improving the prognosis in this patient population.

[0224] The study consists of a dose escalation part followed by a dose expansion part.

[0225] The dose-escalation part will evaluate four interim dose levels using a BOIN design. The BOIN design was chosen because it does not require a fixed cohort size and allows for decision-making by comparing the DLT rate observed at the current dose with the escalation and deescalation boundaries at any time during the study. Another feature of the BOIN design is that the sample size is determined to obtain a desired probability of accurately estimating the RD (Yuan et al., 2016). Furthermore, the BOIN design is preferable to more complex model-based designs, given that lower dose levels will be tested.

[0226] [RD] 177 An extension part was added to further characterize the safety, tolerability, and preliminary antitumor activity of [Lu]Lu-NeoB, which does not preclude the need for further dose optimization in future studies.

[0227] Dose justification [ 177 Justification for dose selection and administration frequency of [Lu]Lu-NeoB The starting dose for the dose escalation part was 100 mCi (3.7 GBq) every 28 days [ 177 Lu]Lu-NeoB.

[0228] Based on data from the NeoRay trial (data cutoff June 15, 2022), it will be administered every 42 days. 177 A starting dose of 50 mCi (cycle 1) + 150 mCi (cycles 2 and beyond) of [Lu]Lu-NeoB was well tolerated as monotherapy in this cohort, with no DLTs or G3 / 4 adverse events. Absorbed radiation doses to major organs (kidneys, pancreas, red bone marrow, testes, and ovaries) were low, indicating a low risk of radiation-related toxicity from a single dose.

[0229] [ 177A safety review of blood laboratory parameters over time following administration of [Lu]Lu-NeoB showed no trends toward a decline or worsening of hematological parameters. Based on the data generated to date, the 28-day schedule is 177 The proposed dosing frequency for [Lu]Lu-NeoB is being evaluated over time as part of a dose-finding scheme. Furthermore, a 4-week schedule would accommodate the 4-week cycle of ribociclib and fulvestrant, allowing for coadministration with the other two therapies.

[0230] Based on the above information, 177 Assuming that Lu]Lu-NeoB will be combined with ribociclib and fulvestrant and the dosing frequency reduced to 28 days (from a 42-day cycle as a single agent in NeoRay), the trial will start with a dose of 100 mCi.

[0231] [ 177 Six doses of 11.1 GBq (300 mCi) of [Lu]Lu-NeoB every 4 weeks will be given in this study. Based on available dosimetry data from the three dose levels examined in the FIH study (150 mCi, 250 mCi, and 300 mCi), the mean cumulative absorbed doses in the kidneys, pancreas, red bone marrow, testes, and ovaries are significantly below the EBRT threshold. To date, the highest examined radiation dose of 11.1 GBq (300 mCi) of [Lu]Lu-NeoB has been used. 177 The margins for six cycles of [Lu]Lu-NeoB were approximately 9-10x for the pancreas (EBRT threshold of 40 Gy; Stewart et al., 2012), approximately 1.6x for the red bone marrow (EBRT threshold of 2 Gy; Howard et al., 2017), 1.3-2x for the testes and ovaries (EBRT thresholds of 1 Gy and 3 Gy; Chambers et al., 1991, De Felice et al., 2019), and 3x for the kidneys (EBRT threshold of 23 Gy; Emami et al., 1991, Stewart et al., 2012).

[0232] However, applying these EBRT limitations to RLT is likely too conservative due to inherent differences between external beam radiation and radionuclide therapy, including different dose rates and fractionation schemes, heterogeneous absorbed dose distributions, and potentially different radiobiological mechanisms of cytotoxicity that result in various biological effects (Wessels et al. 2008, Bergsma et al. 2016a, Bergsma et al. 2016b). In fact, a biologically effective dose (BED) of approximately 40 Gy is considered to be the absorbed dose of 177 With a conversion factor of 1.09 for conversion to BED in Lu-based RLT, there is growing evidence of kidney safety with Lu-177 labeled RLT (Bodei et al., 2008, Schaefer et al., 2022). Therefore, even with cycles greater than six, there may be minimal concern about radiation-induced toxicity, as the organ may be able to tolerate higher radiation doses.

[0233] Based on the above evidence, there is a margin for dosing for more than six cycles. 177 Up to four additional doses of ]Lu]Lu-NeoB beyond the planned six doses could be considered in this study based on individual benefit-risk assessment.

[0234] [ 177 To proceed with each of the four additional doses of [Lu]Lu-NeoB, the investigator must determine if: Participants demonstrate evidence of disease stabilization or response (i.e., radiologically or clinically assessed). Participants do not show any signs or symptoms of clinical deterioration Participants can click 177 Lu]Lu-NeoB treatment was well tolerated and did not resolve before the next NeoB dose, leading to treatment discontinuation. 177 No SAEs were recorded for Lu]Lu-NeoB.

[0235] If the participant meets all of the above criteria, 177If the patient agrees to continue further treatment with Lu]Lu-NeoB, the investigator must, in agreement with the sponsor, 177 Up to four additional doses of [Lu]Lu-NeoB (ie, up to 10 doses total) can be administered.

[0236] Rationale for ribociclib dose selection Ribociclib is administered at a recommended starting dose of 600 mg p.o. (three 200 mg tablets) once daily with or without food for 21 consecutive days, followed by a 7-day rest period. Dose interruptions, reductions, and / or discontinuation may be required based on individual safety and tolerability.

[0237] Rationale for dose selection of fulvestrant Fulvestrant is administered intramuscularly (over 1 to 2 minutes per injection) in the buttocks (gluteal area) at the approved dose of 500 mg as two 5 mL injections, one in each buttock on days 1, 15, and 29, and then monthly. A 250 mg dose is recommended for patients with moderate hepatic impairment, to be administered intramuscularly (over 1 to 2 minutes) in the buttocks (gluteal area) as one 5 mL injection on days 1, 15, and 29, and then monthly.

[0238] Rationale for dose selection of goserelin (applicable only to premenopausal / perimenopausal women in the expansion section) Goserelin is administered subcutaneously at the approved dose of 3.6 mg on day 1 of a 28-day cycle.

[0239] experimental drug In this study, the term "investigational drug" is used for the purpose of participant selection during screening and for assessing treatment-induced changes in PET scan patterns. 177 A radioligand imaging compound [Lu]Lu-NeoB was used for PET imaging after the final dose. 68 Used as Ga]Ga-NeoB and RLT [ 177The term "investigative drug" refers to [ 177 Lu] refers to the combination of Lu-NeoB, ribociclib, and fulvestrant (+ / - goserelin, if applicable in the expansion part only).

[0240] Participants received ribociclib in combination with fulvestrant in the dose-escalation and dose-expansion portions of the study. 177 Goserelin administration is available only to premenopausal / perimenopausal participants in the dose expansion part.

[0241] [ 177 Lu]Lu-NeoB and [ 68 Kits for radiopharmaceutical preparation of [Ga]Ga-NeoB will be provided centrally by Novartis. Ribociclib, fulvestrant, and goserelin will be provided commercially or centrally by Novartis locally by testing facilities, by Novartis subsidiaries or designees, in accordance with local practices and regulations in each participating country.

[0242] All doses prescribed and dispensed to participants and all dose changes during the study must be recorded in the Dosage Administration Record eCRF.

[0243] Details regarding requirements for storage, management and administration of study medication, instructions for participant numbering, prescribing and dispensing are outlined in the accompanying Pharmacy Practices Manual.

[0244] [Table 4]

[0245] [ 68 Ga]Ga-NeoB In this study, after radiolabeling with Ga-68, 68[Ga]Ga-NeoB serves as a radioactive imaging compound to be used in PET for the localization of GRPR-positive lesions.

[0246] [ 68 [Ga]Ga-NeoB is administered as a single intravenous dose of activity in the range of 150-250 MBq (4.1-6.8 mCi).

[0247] [ 177 Lu]Lu-NeoB Study participants will receive 3.7 GBq (100 mCi) + / - 10% [ 177 Lu]Lu-NeoB was administered.

[0248] [Table 5]

[0249] [Table 6]

[0250] The dose-escalation part will be administered in combination with ribociclib (600 mg daily for 21 consecutive days followed by 7 days off treatment) and fulvestrant (500 mg on day 1 of a 28-day cycle) on day 1 (+ ≤ 3 days) of every 28 days for 6 cycles. 177 Starting with 100 mCi as the initial dose of ]Lu-NeoB. In cycle 1, a single boost dose of fulvestrant is administered on D15 (C1D15).

[0251] For each evaluation dose level [ 177 The initial infusion of Lu]Lu-NeoB will be followed by a DLT period defined as 28 days / 4 weeks overall.

[0252] The dose-expansion part will evaluate the efficacy and safety of ribociclib (600 mg daily for 21 consecutive days followed by 7 days off treatment) in combination with fulvestrant (500 mg single dose fulvestrant added on Day 1 and Day 15 (C1D15) of a 28-day cycle) in postmenopausal and premenopausal / perimenopausal participants, as established in the dose-escalation part (Day 1 (+ ≤ 3 days) of every 28 days for 6 cycles). Wataru) [ 177 The RD dose of [Lu]Lu-NeoB will be evaluated. Premenopausal / perimenopausal participants will also receive goserelin (3.6 mg) on ​​day 1 of every 28-day cycle.

[0253] Ribociclib, fulvestrant, and goserelin (where applicable) 177 Lu]Lu-NeoB is administered on the same day as, and preferably before, Lu-NeoB.

[0254] Eligibility Screening Informed consent must be obtained before any study-specific procedures are performed, except for evaluations performed as part of standard care. After signing the study ICF, all screening evaluations will occur within 42 days prior to study enrollment.

[0255] During the screening period, 68 Imaging with [Ga]Ga-NeoB should be performed as soon as possible to avoid delaying participant enrollment. 68 All participants receiving Ga]Ga-NeoB will be followed for safety by person-to-person call 3 days + / - 1 day after dosing to assess for the occurrence of AEs before being discharged from the imaging department at screening.

[0256] Only participants who meet all eligibility criteria at the time of screening may be enrolled in the study. The screening period should be as short as possible. Participant Enrollment and 177 Lu] Lu-NeoB orders will be placed as soon as all eligibility criteria have been verified and the participant has been confirmed as eligible, and [ 177The procedure must be performed at least 14 days before the planned administration of [Lu]Lu-NeoB.

[0257] Once participants are identified for screening, they will be enrolled in the IRT system. After enrolling in the IRT for screening, participants' eligibility will be checked once all screening procedures are completed. The eligibility check is included in the IRT system. Please refer to and follow the detailed guidelines in the IRT manual.

[0258] [ 68 Ga]Ga-NeoB imaging Inclusion criteria 68 Ga]Ga-NeoB PET scan [ 68 The [Ga]Ga-NeoB PET / CT or PET / MRI should be acquired 120 ± 30 minutes after intravenous injection of 4.1–6.8 mCi (150–250 MBq) of radiotracer, always scanning from the crown to the proximal mid-thigh (including the torso and head) with the arms elevated as much as possible.

[0259] PET / CT or PET / MRI is read locally. 68 Uptake of [Ga]Ga-NeoB should be graded on PET / CT or PET / MRI using a visual scale according to the table below.

[0260] [Table 7]

[0261] Eligible participants must have at least one target lesion (per RECIST 1.1 criteria), detected on baseline stand-alone CT or MRI. 68Uptake of [Ga]Ga-NeoB is a PET / CT or PET / MRI score of ≥1 for participants in the titration part and a score of ≥2 for participants in the expansion part. The required scores are 68 Based on the objective of uptake of [Ga]Ga-NeoB: in the titration part, the objective is to identify lesions and mild uptake (score 1) is acceptable; however, in the expansion part, more advanced uptake (moderate, score 2) is required to enrich the population and thus obtain a preliminary idea of ​​efficacy.

[0262] [ 177 Lu] after the final administration of Lu-NeoB [ 68 Ga]Ga-NeoB PET scan For participants in the extended part, 68 Ga]Ga-NeoB PET / CT or PET / MRI 177 This will be performed 2 and 8 weeks after the last dose of Lu]Lu-NeoB. 68 The radioactivity dose of [Ga]Ga-NeoB and acquisition characteristics of this PET scan should be the same as those used in the baseline PET / CT or PET / MRI.

[0263] This PET scan will evaluate changes in the number of target lesions (visual assessment) and semi-quantitative parameters (SUVmax, SUVmean, and TBR) compared to baseline PET / CT or PET / MRI.

[0264] TBR is defined as the ratio of SUVmax of tumor lesions to SUVmean of healthy tissues (Rogasch et al., 2015). For the calculation of TBR, background activity is defined as the [[SUVmax of tumor lesions] within a spherical volume of interest (VOI) with a diameter of approximately 3 cm. 68 The uptake of [Ga]Ga-NeoB is considered to be the uptake of [Ga]Ga-NeoB (Wahl et al 2009). For each PET scan, two TBR values ​​are collected: one interpreting the spleen as background activity and the other interpreting the liver as background activity.

Claims

1. 1. A method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor, e.g., ribociclib, and an endocrine therapy, e.g., fulvestrant, wherein the radiopharmaceutical compound has Formula (I): C-S-P (I) (In the formula, C is a chelating moiety; S is an optional spacer covalently linking C and P; P is a GRP receptor antagonist moiety. or a pharmaceutically acceptable salt thereof, and said radiopharmaceutical compound is labeled with a radionuclide M.

2. 2. The method of claim 1, wherein the CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abemaciclib.

3. 3. The method of claim 2, wherein the CDK4 / 6 inhibitor is ribociclib.

4. 4. The method of any one of claims 1 to 3, wherein the endocrine treatment comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader.

5. The method of any one of claims 1 to 4, wherein the endocrine therapy comprises administering a therapeutically effective amount of a selective ER degrader.

6. 6. The method of claim 5, wherein the selective ER degrader is fulvestrant.

7. 7. The method of claim 5 or 6, wherein a therapeutically effective amount of the selective ER degrading agent is administered, e.g., starting on the same day as the administration of the radiopharmaceutical compound, and once every 14 to 56 days, e.g., 28 days, for at least the period that the radiopharmaceutical compound is administered, and optionally, administration of the ER degrading agent is continued until disease progression.

8. 8. The method of any one of claims 1 to 7, wherein the CDK4 / 6 inhibitor is ribociclib and the endocrine treatment comprises administering a therapeutically effective amount of fulvestrant.

9. 9. The method of claim 8, wherein the CDK4 / 6 inhibitor, preferably ribociclib, is administered simultaneously with fulvestrant.

10. M, ９０ Y. １３１ I, １２１ Sn, １８６ Re, １８８ Re, ６４ Cu, ６７ Cu, ５９ Fe, ８９ Sr, １９８ Au, ２０３ Hg, ２１２ Pb, １６５ Dy, １０３ Ru, １４９ Tb, １６１ Tb, ２１３ Bi, １６６ Ho, １６５ Er, １６９ Er, １５３ Sm, １７７ Lu, ２１３ Bi, ２２３ Ra, ２２５ Ac, ２２７ Ac, ２２７ Th, ２１１ At, ６７ Cu, １８６ Re, １８８ Re, １６１ Tb, １７５ Yb, １０５ Rh, １６６ Dy, １９９ Au, ４４ Sc, １４９ Pm, １５１ Pm, １４２ Pr, １４３ Pr, ７６ As, １１１ Ag and ４７ 10. The method of claim 1, wherein the hydroxybenzoates are selected from the group consisting of hydroxybenzoates, ...

11. M, １７７ The method according to any one of claims 1 to 10, wherein Lu is

12. C is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1,4,7,10-tetraazacyclododecane, 1(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramine (TET 12. The method of any one of claims 1 to 11, wherein the chelating agent is obtained by linking S or P to a chelating agent selected from 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).

13. C is of the following formula: 【Chemistry 1】 The method of claim 12, wherein

14. P is a compound of the general formula DPhe-Gln-Trp-Ala-Val-Gly-His-Z (where Z is Leu−ψ(CH ２ N)-Pro-NH ２ and NH-CH(CH ２ -CH(CH ３ ) ２ ) ２ Selected from or Or Z is 【Chemistry 2】 where X is NH (amide) and R2 is (CH ２ -CH(CH ３ ) ２ and R1 is the same as R2 or (CH ２ N)-Pro-NH ２ is) The method according to any one of claims 1 to 13, wherein

15. P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH ２ -CH(CH ３ ) ２ ) ２ The method of claim 14, wherein

16. The compound of formula (I) is a compound of formula (II) 【Transformation 3】 wherein C and P are as defined in any one of claims 1 and 12 to 15. and said chelating moiety C is complexed to a radionuclide M.

17. The radiopharmaceutical compound has the following formula (III): 【Chemistry 4】 wherein M is a radionuclide, for example, M is １７７ Lu) The method according to any one of claims 1 to 16, wherein the compound is M-NeoB or a pharmaceutically acceptable salt thereof.

18. 18. The method of any one of claims 1 to 17, wherein the radiopharmaceutical compound is administered 3 to 12 times, 4 to 10 times, 4 to 8 times, 6 times, or 10 times.

19. 19. The method of claim 18, wherein the radiopharmaceutical compound comprises a dosing interval of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 weeks, or 4 weeks, or 4 weeks.

20. 20. The method of any one of claims 1 to 19, wherein the radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), about 3.7 GBq (100 mCi), about 5.55 GBq (150 mCi), about 7.4 GBq (200 mCi), about 9.25 GBq (250 mCi), or about 11.1 GBq (300 mCi).

21. 21. The method of any one of claims 1 to 20, wherein the CDK4 / 6 inhibitor, e.g. ribociclib, is administered orally in a daily dose of 400 to 800 mg, e.g. about 600 mg, in cycles of e.g. 15 to 28 days duration, each cycle comprising e.g. 21 days of daily administration followed by 7 days off treatment, and administered for at least the period during which the radiopharmaceutical is administered, and optionally administration of the CDK4 / 6 inhibitor continues until disease progression.

22. The radiopharmaceutical compound is １７７ 22. The method of claim 21 , wherein the medicament is ribociclib [Lu]Lu-NeoB administered intravenously every 28 days for 3 to 12 cycles, for example 6 cycles, at a dose in the range of 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), or 3.7 GBq (100 mCi) to 9.25 GBq (250 mCi), for example 250 mCi, for example 150 mCi, in combination with ribociclib administered orally at a daily dose of 600 mg for 15 to 21 days per cycle.

23. 23. The method according to any one of claims 1 to 22, wherein the endocrine therapy, preferably fulvestrant, is administered via intramuscular administration, for example using a long-acting formulation, at a dose of 250 to 700 mg.

24. 24. The method of any one of claims 1 to 23, wherein the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer.

25. 25. The method of any one of claims 1 to 24, wherein the subject is selected from subjects who have experienced early relapse after prior neoadjuvant or adjuvant endocrine therapy, or subjects who have experienced progression on prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor.

26. The method of any one of claims 1 to 25, wherein the subject is a postmenopausal woman with advanced metastatic breast cancer.

27. 27. The method of any one of claims 1 to 26, wherein the subject is a pre- or peri-menopausal woman with advanced metastatic breast cancer.

28. 28. The method of any one of claims 1 to 27, wherein the subject is selected from subjects experiencing early relapse after prior neoadjuvant or adjuvant endocrine therapy.

29. 28. The method of any one of claims 1 to 27, wherein the subject is selected from subjects who have experienced a progression to a prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor.

30. 30. The method of claim 29, wherein the preceding CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abemaciclib, e.g., ribociclib.

31. 31. The method of any one of claims 25-30, wherein the prior endocrine treatment comprises administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER degrader.

32. 32. The method of any one of claims 1 to 31, wherein the endocrine treatment further comprises the simultaneous administration, e.g., via subcutaneous administration, of a synthetic analogue of gonadotropin-releasing hormone, e.g., goserelin, e.g., at a dose of about 3.6 mg every 28 days.

33. 33. The method of any one of claims 1 to 32, wherein the subject has been treated with the same radiopharmaceutical compound as defined for said treatment, but prior to any surgery, for example 2 weeks prior to the start of said treatment, an alternative radionuclide suitable for imaging, for example 68-gallium, 67-gallium or 64-copper, for example 68-gallium, is selected by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging based on detection of said radionuclide in the imaging scan in the region of the tumor.

34. 34. The method of claim 33, wherein the subject is selected from among subjects who, prior to any surgery, show the presence of alternative radionuclide enhancement, e.g., gadolinium enhancement, in a PET / MRI scan in the tumor region.

35. 35. The method of any one of claims 1-34, wherein the subject has ER positive, HER-2 negative (ER+ / HER2-) and GRPR positive (GRPR+) breast cancer and is experiencing early recurrence from neoadjuvant or adjuvant therapy, and wherein the radiopharmaceutical compound is administered to the subject in combination with ribociclib and fulvestrant, and wherein a first dose of the radiopharmaceutical compound is administered on the same day as a first dose of ribociclib.

36. 36. The method of claim 35, wherein ribociclib is administered orally at a daily dose of about 600 mg, e.g., in 28-day cycles, e.g., each cycle comprising, e.g., 21 days of administration followed by 7 days of rest from treatment, wherein the radiopharmaceutical compound is administered for 4 to 10 cycles, and ribociclib is administered for at least the period during which the radiopharmaceutical is administered, and optionally, administration of the CDK4 / 6 inhibitor continues until disease progression.

37. The radiopharmaceutical compound has the following formula: 【Transformation 5】 (Wherein M is １７７ Lu), 37. The method of claim 35 or 36.

38. The radiopharmaceutical compound has the following formula: 【Transformation 6】 (Wherein M is １７７ 38. The method of any one of claims 1 to 37, wherein the radiopharmaceutical compound is M-NeoB of 370 MBq / mL.

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