Methods for treating breast cancer

Abstract

The present disclosure relates to methods of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound having a GRPR antagonist moiety, such as [177Lu] Lu-NeoB, in combination with a CDK4 / 6 inhibitor, such as ribociclib, and a therapeutically effective amount of an endocrine therapy, such as fulvestrant.

Description

Technical Field

[0001] This invention relates to a method for treating breast cancer in a subject of need, wherein the subject is administered a therapeutically effective amount of a radiopharmaceutical compound comprising a GRPR binding moiety, such as […]. 177 Lu]Lu-NeoB in combination with CDK4 / 6 inhibitors and endocrine therapy. Background Technology

[0002] Breast cancer is the most common cancer among women worldwide and a leading cause of cancer death. The global incidence rate is 85.8 to 91.6 per 100,000 people, while the mortality rate ranges from 17.4 to 20.1 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 advancements in new treatments, there is still a need to provide improved clinical care for breast cancer. Summary of the Invention

[0004] This disclosure relates to a method for treating breast cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor such as ribociclib and an endocrine therapy such as fulvestrant, wherein the radiopharmaceutical compound is a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0005] CSP (I)

[0006] in:

[0007] C is the chelate portion.

[0008] P is the GRP receptor binding site.

[0009] S is an optional spacer that covalently connects C and P.

[0010] Furthermore, the radiopharmaceutical compound is labeled with the radionuclide M.

[0011] This disclosure is provided in the various aspects outlined below:

[0012] 1. A method for treating breast cancer in a subject in need, 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, wherein the radiopharmaceutical compound is a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0013] CSP (I)

[0014] in:

[0015] C is the chelate portion.

[0016] P is the GRP receptor antagonist moiety.

[0017] S is an optional spacer that covalently connects C and P.

[0018] Furthermore, the radiopharmaceutical compound is labeled with the radionuclide M.

[0019] 2. The method as described in Example 1, wherein the CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abemaciclib.

[0020] 3. The method as described in Example 2, wherein the CDK4 / 6 inhibitor is ribociclib.

[0021] 4. The method as described in any one of Examples 1-3, wherein 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.

[0022] 5. The method as described in any one of Examples 1-4, wherein the endocrine therapy comprises administering a therapeutically effective amount of a selective ER degrader.

[0023] 6. The method as described in Example 5, wherein the selective ER degrading agent is fulvestrant.

[0024] 7. The method as described in Example 5 or 6, wherein a therapeutically effective amount of the selective ER degrader is administered, for example, every 14 to 56 days, such as 28 days, starting from the same day as the administration of the radiopharmaceutical compound, and the administration continues for at least the same duration as the administration of the radiopharmaceutical, and optionally the administration of the ER degrader continues until disease progression.

[0025] 8. The method as described in any one of Examples 1-7, wherein the CDK4 / 6 inhibitor is ribociclib, and the endocrine therapy comprises administering a therapeutically effective amount of fulvestrant.

[0026] 9. The method as described in Example 8, wherein the CDK4 / 6 inhibitor, preferably ribociclib, is administered concurrently with fulvestrant.

[0027] 10. The method as described in any one of Examples 1-9, wherein M is selected from... 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 Sc.

[0028] 11. The method as described in any one of Examples 1-10, wherein M is 177 Lu.

[0029] 12. The method as described in any one of Examples 1-11, wherein C is obtained by being linked to S or P, and C is a chelating agent selected from: 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), aminotriacetic 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-diazacycloheptatriene (AAZTA, e.g., AAZTA5).

[0030] 13. The method as described in Example 12, wherein C has the following formula:

[0031] .

[0032] 14. The method as described in any one of Examples 1-13, wherein the peptide P has the following general formula:

[0033] DPhe-Gln-Trp-Ala-Val-Gly-His-Z

[0034] Z is selected from Leu-ψ(CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2

[0035] Or Z is

[0036]

[0037] Where X is NH (amide) and R2 is (CH2-CH(CH3)2, and R1 is the same as R2 or (CH2N)-Pro-NH2.

[0038] 15. The method as described in Example 14, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2.

[0039] 16. The method as described in any one of Examples 1-15, wherein the compound having formula (I) is a compound having formula (II).

[0040] (II)

[0041] Wherein C and P are as defined in claim 1.

[0042] 17. The method as described in any one of Examples 1-16, wherein the radiopharmaceutical is M-NeoB having the following formula (III):

[0043]

[0044] (III),

[0045] Or its pharmaceutically acceptable salt.

[0046] Where M is a radioactive nuclide, for example, M is 177 Lu.

[0047] 18. The method as described in any one of Examples 1-17, wherein the radiopharmaceutical compound is administered 3 to 12 times, 4 to 10 times, 4 to 8 times, 6 times, or 10 times.

[0048] 19. The method as described in Example 18, wherein the radiopharmaceutical compound comprises an administration interval of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 or 4 weeks, or 4 weeks.

[0049] 20. The method of any one of Examples 1-19, wherein the radiopharmaceutical compound is administered in doses ranging from 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), from 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), from 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), from 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).

[0050] 21. The method as described in any one of Examples 1-20, wherein the CDK4 / 6 inhibitor, such as ribociclib, is administered orally at a daily dose of 400 to 800 mg, for example about 600 mg, for one to six cycles over a period of 15 to 28 days, each cycle comprising, for example, 21 days of daily administration, followed by a 7-day period of treatment cessation.

[0051] 22. The method as described in Example 21, wherein the radiopharmaceutical compound is 177Lu-NeoB and is combined with ribociclib administered orally at a daily dose of 600 mg for 15 to 21 days per cycle, wherein the radiopharmaceutical compound is administered intravenously at a dose ranging from 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi) or from 3.7 GBq (100 mCi) to 9.25 GBq (250 mCi), for example, 250 mCi or 150 mCi every 28 days for 3 to 12 cycles, for example, 6 cycles.

[0052] 23. The method as described in any one of Examples 1-22, wherein the endocrine therapy, such as fulvestrant, is administered via intramuscular administration at a dose of 250 to 700 mg, for example using a long-acting formulation.

[0053] 24. The method as described in any one of Examples 1-23, wherein the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer.

[0054] 25. The method of any one of Examples 1-24, wherein the subject has been selected from subjects who have experienced early relapse after neoadjuvant or adjuvant prior endocrine therapy, or subjects who have experienced progression while receiving prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor.

[0055] 26. The method as described in any one of Examples 1-25, wherein the subject is a postmenopausal woman with advanced metastatic breast cancer.

[0056] 27. The method as described in any one of Examples 1-26, wherein the subject is a premenopausal or perimenopausal woman with advanced metastatic breast cancer.

[0057] 28. The method of any one of claims 1-27, wherein the subject has been selected from subjects who have experienced early relapse after neoadjuvant or adjuvant prior endocrine therapy.

[0058] 29. The method of any one of claims 1-27, wherein the subject has been selected from subjects who have experienced progression while receiving prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor.

[0059] 30. The method as described in Example 29, wherein the prior CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abeciclib, for example, ribociclib.

[0060] 31. The method of any one of Examples 25-30, wherein the prior 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. 32. The method of any one of Examples 1-31, wherein the endocrine therapy further comprises, for example, subcutaneous administration of a synthetic analogue of gonadotropin-releasing hormone, such as goserelin, at a dose of approximately 3.6 mg every 28 days.

[0061] 33. The method of any one of Examples 1-32, wherein the subject has been subjected to SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging prior to any surgery, for example, two weeks prior to the start of the treatment, using the same radiopharmaceutical compound as defined for the treatment but using an alternative radionuclide suitable for imaging, such as 68-gallium, 67-gallium, or 64-copper. For example, 68-gallium is selected based on the detection of the alternative radionuclide in an imaging scan of the tumor region.

[0062] 34. The method as described in Example 33, wherein the subject is selected from subjects whose PET / MRI scans of the tumor region prior to any surgery showed enhancement of radioactive metals, such as gadolinium enhancement.

[0063] 35. The method of any one of Examples 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, wherein the radiopharmaceutical compound is administered to the subject in combination with ribociclib and fulvestrant, wherein a first dose of the radiopharmaceutical compound is administered on the same day as a first dose of ribociclib.

[0064] 36. The method as described in Example 35, wherein ribociclib is administered orally at a daily dose of about 600 mg, for example, in cycles of 28 days, each cycle comprising, for example, 21 days of administration followed by a 7-day treatment-free period, wherein the radiopharmaceutical compound is administered for 4-10 cycles, and ribociclib administration is continued for at least as long as the administration of the radiopharmaceutical, and optionally, administration of the CDK4 / 6 inhibitor continues until disease progression.

[0065] 37. The method as described in Example 35 or 36, wherein the radiopharmaceutical compound is M-NeoB having the following formula:

[0066]

[0067] Where M is 177-Lu.

[0068] 38. The method of any one of Examples 1-37, wherein the radiopharmaceutical compound is M-NeoB having the following formula:

[0069]

[0070] Wherein M is 177-Lu, and the radiopharmaceutical compound is administered via intravenous infusion at a concentration of 370 MBq / mL.

[0071] 39. A radiopharmaceutical compound for use in a method of treating breast cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of the radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor and endocrine therapy, wherein the radiopharmaceutical compound is a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0072] CSP (I)

[0073] in:

[0074] C is the chelate portion.

[0075] P is the GRP receptor antagonist moiety.

[0076] S is an optional spacer that covalently connects C and P.

[0077] Furthermore, the radiopharmaceutical compound is labeled with the radionuclide M.

[0078] 40. The radiopharmaceutical compound for use as described in Example 39, wherein the CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abeciclib.

[0079] 41. The radiopharmaceutical compound for use as described in Example 40, wherein the CDK4 / 6 inhibitor is ribociclib.

[0080] 42. The radiopharmaceutical compound for use as described in Examples 39-41, wherein 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.

[0081] 43. The radiopharmaceutical compound for use as described in Examples 39-42, wherein the endocrine therapy comprises administering a therapeutically effective amount of a selective ER degrader.

[0082] 44. The radiopharmaceutical compound for use as described in Example 43, wherein the selective ER degrader is fulvestrant.

[0083] 45. The radiopharmaceutical compound for use as described in Examples 43 or 44, wherein a therapeutically effective amount of the selective ER degrader is administered, for example, every 14 to 56 days, such as 28 days, starting from the same day as the administration of the radiopharmaceutical compound, and the administration continues for at least the same duration as the administration of the radiopharmaceutical, and optionally the administration of the ER degrader continues until disease progression.

[0084] 46. ​​The radiopharmaceutical compound for use as described in Examples 39-45, wherein the CDK4 / 6 inhibitor is ribociclib, and the endocrine therapy comprises administering a therapeutically effective amount of fulvestrant.

[0085] 47. The radiopharmaceutical compound for use as described in Example 46, wherein the CDK4 / 6 inhibitor, preferably ribociclib, is administered concurrently with fulvestrant.

[0086] 48. A radiopharmaceutical compound for use as described in Examples 39-47, wherein M is selected from... 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 Sc.

[0087] 49. A radiopharmaceutical compound for use as described in Examples 38-47, wherein M is 177 Lu.

[0088] 50. A radiopharmaceutical compound for use as described in Examples 39-49, wherein C is obtained by being linked to S or P, and C is a chelating agent selected from: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Titan), drytan, 1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), aminotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraacetic acid... The chelate moieties include azircyclic dodecane-1,4,7-triacetic acid (DO3A), triethylenetetramine (TETA), 1,4,7-triazacyclic nonane-1,4,7-triacetic acid (NOTA), NOTAGA, 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclic nonane (NODAGA), NODASA, NODAPA, and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazacyclic heptatriene (AAZTA, e.g., AAZTA5).

[0089] 51. A radiopharmaceutical compound for use as described in Example 50, wherein C has the following formula:

[0090] .

[0091] 52. The radiopharmaceutical compound for use as described in Examples 39-51, wherein the peptide P has the following general formula:

[0092] DPhe-Gln-Trp-Ala-Val-Gly-His-Z

[0093] Z is selected from Leu-ψ(CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2

[0094] Or Z is

[0095]

[0096] Where X is NH (amide) and R2 is (CH2-CH(CH3)2, and R1 is the same as R2 or (CH2N)-Pro-NH2.

[0097] 53. The radiopharmaceutical compound for use as described in Example 52, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2.

[0098] 54. A radiopharmaceutical compound for use as described in any one of Examples 39-53, wherein the compound having formula (I) is a compound having formula (II).

[0099] (II)

[0100] Wherein C and P are as defined in claim 1.

[0101] 55. A radiopharmaceutical compound for use as described in any one of Examples 39-54, wherein the radiopharmaceutical compound is M-NeoB having the following formula (III):

[0102]

[0103] (III),

[0104] Or its pharmaceutically acceptable salt.

[0105] Where M is a radioactive nuclide, for example, M is 177 Lu.

[0106] 56. A radiopharmaceutical compound for use as described in any one of Examples 39-55, wherein the radiopharmaceutical compound is applied 3 to 12 times, 4 to 10 times, 4 to 8 times, 6 times, or 10 times.

[0107] 57. A radiopharmaceutical compound for use as described in Example 56, wherein the radiopharmaceutical compound comprises an administration interval of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 or 4 weeks, or 4 weeks.

[0108] 58. A radiopharmaceutical compound for use as described in any one of Examples 39-57, wherein the radiopharmaceutical compound is administered in doses ranging from 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), from 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), from 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), from 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).

[0109] 59. A radiopharmaceutical compound for use as described in any of Examples 39-58, wherein the CDK4 / 6 inhibitor, such as ribociclib, is administered orally at a daily dose of 400 to 800 mg, for example, about 600 mg, for one to six cycles over a period of 15 to 28 days, each cycle comprising, for example, 21 days of daily administration, followed by a 7-day period of treatment cessation.

[0110] 60. A radiopharmaceutical compound for use as described in Example 59, wherein the radiopharmaceutical compound is [ 177 Lu]Lu-NeoB, and in combination with ribociclib administered orally at a daily dose of 600 mg for 15 to 21 days per cycle, the radiopharmaceutical compound is administered intravenously at doses ranging from 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi) or from 3.7 GBq (100 mCi) to 9.25 GBq (250 mCi), for example 250 mCi or 150 mCi every 28 days for 3 to 12 cycles, for example 6 cycles.

[0111] 61. The radiopharmaceutical compound for use as described in any of Examples 39-60, wherein the 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.

[0112] 62. The radiopharmaceutical compound for use as described in any of Examples 39-61, wherein the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer.

[0113] 63. The radiopharmaceutical compound for use as described in any of Examples 39-62, wherein the subject has been selected from subjects who have experienced early relapse after neoadjuvant or adjuvant prior endocrine therapy, or subjects who have experienced progression while receiving prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor.

[0114] 64. The radiopharmaceutical compound for use as described in any one of Examples 39-63, wherein the subject is a postmenopausal woman with advanced metastatic breast cancer.

[0115] 65. The radiopharmaceutical compound for use as described in any one of Examples 39-63, wherein the subject is a premenopausal or perimenopausal woman with advanced metastatic breast cancer.

[0116] 66. The method as described in any one of Examples 39-65, wherein the subject has been selected from subjects who have experienced early relapse after neoadjuvant or adjuvant prior endocrine therapy.

[0117] 67. The method of any one of Examples 39-65, wherein the subject has been selected from subjects who have experienced progression while receiving prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor.

[0118] 68. The method as described in Example 67, wherein the prior CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abeciclib, for example, ribociclib.

[0119] 69. The method of any one of Examples 63-68, wherein the prior 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.

[0120] 70. The radiopharmaceutical compound for use as described in any one of Examples 1-69, wherein the endocrine therapy further comprises, for example, a synthetic analogue of gonadotropin-releasing hormone, such as goserelin, administered subcutaneously at a dose of about 3.6 mg every 28 days.

[0121] 71. A radiopharmaceutical compound for use as described in any of Examples 39-70, wherein the subject has been subjected to SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging prior to any surgery, for example, two weeks prior to the start of the treatment, using the same radiopharmaceutical compound as defined for the treatment but using an alternative radionuclide suitable for imaging, such as 68-gallium, 67-gallium, or 64-copper. For example, 68-gallium is selected based on detection of the alternative radionuclide in an imaging scan of the tumor region.

[0122] 72. The radiopharmaceutical compound for use as described in Example 71, wherein the subject is selected from subjects whose PET / MRI scan of the tumor area prior to any surgery showed radioactive metal enhancement, such as gadolinium enhancement.

[0123] 73. A radiopharmaceutical compound for use as described in any of Examples 39-72, 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, wherein the radiopharmaceutical compound is administered to the subject in combination with ribociclib and fulvestrant, wherein a first dose of the radiopharmaceutical compound is administered on the same day as a first dose of ribociclib.

[0124] 74. The radiopharmaceutical compound for use as described in Example 73, wherein ribociclib is administered orally at a daily dose of about 600 mg, for example, in cycles of 28 days, each cycle comprising, for example, 21 days of administration followed by a 7-day treatment break, wherein the radiopharmaceutical compound is administered for 4-10 cycles, and ribociclib administration is continued for at least as long as the administration of the radiopharmaceutical, and optionally, administration of the CDK4 / 6 inhibitor continues until disease progression.

[0125] 75. A radiopharmaceutical compound for use as described in Examples 73 or 74, wherein the radiopharmaceutical compound is M-NeoB having the following formula:

[0126]

[0127] Where M is 177-Lu.

[0128] 76. A radiopharmaceutical compound for use as described in any one of Examples 39-735, wherein the radiopharmaceutical compound is M-NeoB having the following formula:

[0129]

[0130] Wherein M is 177-Lu, and the radiopharmaceutical compound is administered via intravenous infusion at a concentration of 370 MBq / mL.

[0131] 77. Use of a radiopharmaceutical compound in a pharmaceutical agent for use in a method of treating breast cancer in a subject of need, said method comprising administering to said subject a therapeutically effective amount of the radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor and endocrine therapy, wherein said radiopharmaceutical compound is a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0132] CSP (I)

[0133] in:

[0134] C is the chelate portion.

[0135] P is the GRP receptor antagonist moiety.

[0136] S is an optional spacer that covalently connects C and P.

[0137] Furthermore, the radiopharmaceutical compound is labeled with the radionuclide M.

[0138] 78. The use as described in Example 77, wherein the CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abeciclib.

[0139] 79. The use as described in Example 78, wherein the CDK4 / 6 inhibitor is ribociclib.

[0140] 80. Use as described in Examples 77-79, wherein 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.

[0141] 81. The use as described in Examples 77-80, wherein the endocrine therapy comprises administering a therapeutically effective amount of a selective ER degrader.

[0142] 82. The use as described in Example 81, wherein the selective ER degrader is fulvestrant.

[0143] 83. The use as described in Examples 81 or 82, wherein a therapeutically effective amount of the selective ER degrader is administered, for example, every 14 to 56 days, such as 28 days, starting from the same day as the administration of the radiopharmaceutical compound, and the administration continues for at least the same duration as the administration of the radiopharmaceutical, and optionally the administration of the ER degrader continues until disease progression.

[0144] 84. The use as described in Examples 77-83, wherein the CDK4 / 6 inhibitor is ribociclib, and the endocrine therapy comprises administering a therapeutically effective amount of fulvestrant.

[0145] 85. Use as described in Example 84, wherein the CDK4 / 6 inhibitor, preferably ribociclib, is administered concomitantly with fulvestrant.

[0146] 86. The use as described in Examples 77-85, wherein M is selected from... 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 Sc.

[0147] 87. The use as described in Examples 77-86, wherein M is 177 Lu.

[0148] 88. The use as described in Examples 77-87, wherein C is obtained by being linked to S or P, and C is a chelating agent selected from: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Titan), drytan, 1,4,7,10-tetraazacyclododecane, 1(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), aminotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane, ... Dodecane-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-diazacycloheptatriene (AAZTA, e.g., AAZTA5).

[0149] 89. The use as described in Example 88, wherein C has the following formula:

[0150] .

[0151] 90. The use as described in Examples 77-89, wherein the peptide P has the following general formula:

[0152] DPhe-Gln-Trp-Ala-Val-Gly-His-Z

[0153] Z is selected from Leu-ψ(CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2

[0154] Or Z is

[0155]

[0156] Where X is NH (amide) and R2 is (CH2-CH(CH3)2, and R1 is the same as R2 or (CH2N)-Pro-NH2.

[0157] 91. The use as described in Example 90, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2.

[0158] 92. Use as described in any one of Examples 77-91, wherein the compound having formula (I) is a compound having formula (II).

[0159] (II)

[0160] Wherein C and P are as defined in claim 1.

[0161] 93. Use as described in any one of Examples 77-92, wherein the radiopharmaceutical compound is M-NeoB having the following formula (III):

[0162]

[0163] (III),

[0164] Or its pharmaceutically acceptable salt.

[0165] Where M is a radioactive nuclide, for example, M is 177 Lu.

[0166] 94. Use as described in any one of Examples 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.

[0167] 95. Use as described in Example 94, wherein the radiopharmaceutical compound comprises an administration interval of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 or 4 weeks, or 4 weeks.

[0168] 96. The use as described in any one of Examples 77-95, wherein the radiopharmaceutical compound is administered in doses ranging from 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), from 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), preferably from 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), from 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).

[0169] 97. Use as described in any one of Examples 77-96, wherein the CDK4 / 6 inhibitor, such as ribociclib, is administered orally at a daily dose of 400 to 800 mg, for example about 600 mg, for one to six cycles over a period of 15 to 28 days, each cycle comprising, for example, 21 days of daily administration followed by a 7-day period of treatment cessation.

[0170] 98. The use as described in Example 97, wherein the radiopharmaceutical compound is [ 177 Lu]Lu-NeoB, and in combination with ribociclib administered orally at a daily dose of 600 mg for 15 to 21 days per cycle, the radiopharmaceutical compound is administered intravenously at doses ranging from 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi) or from 3.7 GBq (100 mCi) to 9.25 GBq (250 mCi), for example 250 mCi or 150 mCi every 28 days for 3 to 12 cycles, for example 6 cycles.

[0171] 99. Use as described in Examples 77-98, wherein the endocrine therapy, preferably fulvestrant, is administered intramuscularly at a dose of 250 to 700 mg, for example using a long-acting formulation.

[0172] 100. Use as described in any one of Examples 77-99, wherein the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer.

[0173] 101. Use as described in any one of Examples 77-100, wherein the subject has been selected from subjects who have experienced early relapse after neoadjuvant or adjuvant prior endocrine therapy, or subjects who have experienced progression while receiving prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor.

[0174] 102. The use as described in any one of Examples 77-101, wherein the subject is a postmenopausal woman with advanced metastatic breast cancer.

[0175] 103. The use as described in any one of Examples 77-101, wherein the subject is a premenopausal or perimenopausal woman with advanced metastatic breast cancer.

[0176] 104. The method as described in any one of Examples 77-103, wherein the subject has been selected from subjects who have experienced early relapse after neoadjuvant or adjuvant prior endocrine therapy.

[0177] 105. The method as described in any one of Examples 77-104, wherein the subject has been selected from subjects who have experienced progression while receiving prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor.

[0178] 106. The method as described in Example 105, wherein the prior CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abeciclib, for example, ribociclib.

[0179] 107. The method of any one of Examples 107-106, wherein the prior 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. 108. The use of any one of Examples 77-107, wherein the endocrine therapy further comprises, for example, administering subcutaneously at a dose of about 3.6 mg every 28 days, concomitantly with the administration of a synthetic analogue of gonadotropin-releasing hormone, such as goserelin.

[0180] 109. The use as described in any one of Examples 77-108, wherein the subject has been subjected to SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging prior to any surgery, for example, two weeks prior to the start of the treatment, using the same radiopharmaceutical compound as defined for the treatment but using a radioactive metal suitable for imaging, such as 68-gallium, 67-gallium, or 64-copper. For example, 68-gallium is selected based on the detection of said radioactive metal in an imaging scan of the tumor region.

[0181] 110. The use as described in Example 109, wherein the subject is selected from subjects whose PET / MRI scans of the tumor area prior to any surgery show radioactive metal enhancement, such as gadolinium enhancement.

[0182] 111. The use as described in any one of Examples 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, wherein the radiopharmaceutical compound is administered to the subject in combination with ribociclib and fulvestrant, wherein a first dose of the radiopharmaceutical compound is administered on the same day as a first dose of ribociclib.

[0183] 112. The use as described in Example 111, wherein ribociclib is administered orally at a daily dose of about 600 mg, for example, in cycles of 28 days, each cycle comprising, for example, 21 days of administration followed by a 7-day treatment break, wherein the radiopharmaceutical compound is administered for 4-10 cycles, and ribociclib administration is continued for at least as long as the administration of the radiopharmaceutical, and optionally, administration of the CDK4 / 6 inhibitor continues until disease progression.

[0184] 113. The use as described in Examples 111 or 112, wherein the radiopharmaceutical compound is M-NeoB having the following formula:

[0185]

[0186] Where M is 177-Lu.

[0187] 114. The use as described in any one of Examples 77-113, wherein the radiopharmaceutical compound is M-NeoB having the following formula:

[0188]

[0189] Wherein M is 177-Lu, and the radiopharmaceutical compound is administered via intravenous infusion at a concentration of 370 MBq / mL.

[0190] In some embodiments, methods for treating breast cancer in a subject of need using a radiopharmaceutical compound, the use of a radiopharmaceutical compound for treating breast cancer in a subject of need, or the use of a radiopharmaceutical compound in the manufacture of an agent for treating breast cancer in a subject of need are provided, said methods, uses, or uses in the manufacture of an agent comprising administering to the subject a therapeutically effective amount of the radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor and endocrine therapy, said radiopharmaceutical compound being M-NeoB having the following formula:

[0191]

[0192] Where M is 177-Lu;

[0193] The subjects had ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer; and

[0194] The subjects were selected from those who experienced early relapse after neoadjuvant or adjuvant prior endocrine therapy, or those who experienced progression while receiving prior endocrine therapy, optionally in combination with a prior CDK4 / 6 inhibitor. Attached Figure Description

[0195] Figure 1 The treatment regimen for the dose escalation portion of the clinical study is shown.

[0196] Figure 2 The treatment regimen from the dose extension portion of the clinical study is presented.

[0197] Figure 3 A decision tree illustrating the incremental or backfill portion of a clinical study. Detailed Implementation

[0198] This disclosure relates to a method for treating breast cancer in a subject of need, which involves administering a therapeutically effective amount of a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor and endocrine therapy to the subject.

[0199] Gastrin-releasing peptide (GRP) is a mammalian bufotin-like peptide that primarily regulates many biological responses in the central and enteric nervous systems (Flores et al. 2010, Brain Res Bull; 82(1-2):95-8). GRP functions through specific membrane G protein-coupled receptors (GRPRs), which are overexpressed in a variety of cancers, including gliomas and breast cancer (Flores et al. 2010, Brain Res Bull; 82(1-2):95-8).

[0200] NeoB compounds are a new generation of bufotin analogues that bind with high affinity to GRPR (half-maximal inhibitory concentration (IC50) 1–2 nM, Nok et al. J. Nucl. Med. [Journal of Nuclear Medicine] 2017; 58(1):75–80) and exhibit low internalization, consistent with the antagonistic behavior of the peptide. NeoB compounds contain a DOTA metal chelator in their structure, which allows for radiolabeling with various radionuclides, including gallium-68 (for PET imaging), lutetium-177 (for radionuclide therapy), and other relevant radionuclides. This enables the therapeutic and diagnostic use of NeoB without affecting receptor affinity, internalization properties, or biodistribution. In non-clinical models, [ 68Ga]Ga-NeoB and [ 177 Lu-Lu NeoB has shown high affinity for GRPR overexpressed in breast tumors, prostate tumors, gastrointestinal stromal tumors (GIST), and gliomas (including glioblastoma) (Flores et al. 2010, ibid., Morgat et al., J. Nucl. Med. [Journal of Nuclear Medicine] 2017;58(9):1401-1407) and low internalization after binding to specific receptors.

[0201] The ability of radiolabeled compounds to target tumors expressing GRPR has been demonstrated in in vivo imaging and biodistribution studies in tumor models. 177 Lu-NeoB is rapidly cleared from the blood and eliminated quickly via the renal system without retention in the kidneys. Background radioactivity was observed in GRPR-expressing tissues (primarily the pancreas), however, it decreased over time, consistent with the GRPR antagonist spectrum. In contrast, tumor radioactivity was persistent, with detectable uptake values ​​up to 7 days post-injection.

[0202] Given that ER is the main oncogenic driver of ER+ breast cancer, treatment can be combined with endocrine therapy (ET), which targets ER by directly inhibiting it with selective estrogen receptor modulators (SERMs), depriving it of estrogen with selective nonsteroidal aromatase inhibitors (NSAIs) and steroidal aromatase inhibitors (SAIs), or promoting ER degradation via selective ER degraders (SERDs).

[0203] In recent years, the combination of CDK4 / 6i (palbociclib, abeciclib, and ribociclib) with ET has significantly improved progression-free survival (PFS) and quality of life compared with ET alone, and has delayed 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 (ABC 5) [Ann Oncol]; 31(12):1623-1649).

[0204] In patients who relapse during adjuvant AI therapy or within 12 months of stopping adjuvant AI therapy, CDK4 / 6i can be combined with fulvestrant in first-line therapy (Gennari et al. 2021, NCCN Guideline Breast Cancer Version 4 [NCCN Breast Cancer Guideline 4]. 2022). Updated results from Monarch-2 (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 [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 [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 Oncology]; 6(1):116-124)

[0205] General definition

[0206] Unless otherwise indicated herein or clearly contradicted by the context, the use of the articles “a,” “an,” and “the” in the specification and claims shall be construed as including both the singular and plural. Unless otherwise stated, the terms “comprising,” “having,” “being of,” “including,” and “containing” shall be construed as open-ended terms (i.e., meaning “including but not limited to”). Furthermore, whenever “comprising” or another open-ended term is used in an embodiment, it should be understood that the same embodiment may be claimed more narrowly using the intermediate term “consistently comprising” or the closed term “consisting of.”

[0207] The term “about” or “approximately” in this document means that the following value may vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, even more preferably ±1%.

[0208] As used herein, the term "treating" or "treatment" includes treatment that reduces, diminishes, or alleviates at least one symptom in a subject or delays disease progression. For example, treatment may be the reduction of one or more symptoms of a disorder or the complete eradication of a disorder (such as cancer). Within the meaning of this disclosure, the term "treatment" also means preventing disease, delaying disease onset (i.e., the period prior to clinical manifestations of disease), and / or reducing the risk of disease development or worsening. As used herein in the context of 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 the administration of a radiopharmaceutical compound once or multiple times over a defined period of time.

[0209] As used in this article, breast cancer refers to the most common cancer among women worldwide and a leading cause of cancer death. The term breast cancer also includes the following subtypes based on the presence or absence of the 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-).

[0210] As used herein, the term "radiopharmaceutical" or "radiopharmaceutical compound" refers to a pharmaceutical compound labeled with a radioactive nuclide element (typically having metallic properties). Such a radiopharmaceutical compound has a binding affinity for specific markers on target cells (e.g., receptors or tumor antigens), and therefore includes a target ligand (or target-binding moiety). Radiopharmaceutical compounds can be used as contrast agents in imaging techniques such as PET or MRI scans, or as therapeutic agents in nuclear medicine, also known as radioligand therapy (RLT) or PRRT (peptide receptor radionuclide therapy).

[0211] As used herein, “previous endocrine therapy” refers to endocrine therapy as defined herein that precedes treatment with a radiopharmaceutical compound. The use of a non-“previous” “endocrine therapy” approach refers to the use of a combination of endocrine therapy and a radiopharmaceutical compound. The compound used in “previous endocrine therapy” may be the same as or different from the compound used in the combination of endocrine therapy and a radiopharmaceutical compound.

[0212] In some embodiments, the subjects have been selected from those who have experienced early relapse following a combination of prior endocrine therapy and a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib, ribociclib, or abeciclib.

[0213] As used in this article, “early relapse” refers to a relapse during or within 12 months of completing neoadjuvant or adjuvant endocrine therapy. In the case of cancer, “relapse” refers to a return to disease progression after a period of quiescence or regression. Disease progression can be measured in ways appropriate to the cancer discussed, such as an increase in the number or size of tumors or cancerous lesions.

[0214] In some embodiments, "endocrine therapy" includes administering a therapeutically effective amount of a selective estrogen receptor modulator, a nonsteroidal aromatase inhibitor, a steroidal aromatase inhibitor, or a selective ER-degrading agent. In some embodiments, the endocrine therapy includes administering a therapeutically effective amount of a selective ER-degrading agent. In some embodiments, the endocrine therapy includes administering a therapeutically effective amount of fulvestrant or an aromatase inhibitor.

[0215] "Neoadjuvant therapy" is a therapy given before another therapy. "Adjuvant therapy" is a therapy given after another therapy. For example, if an aromatase inhibitor is given to a breast cancer patient before surgical removal of a breast cancer tumor, the aromatase inhibitor is administered as neoadjuvant therapy for the surgery. As another example, if an aromatase inhibitor is given to a breast cancer patient after surgical removal of a breast cancer tumor, the aromatase inhibitor is administered as adjuvant therapy for the surgery.

[0216] Consistent with the International System of Units (SI), "MBq" is an abbreviation for "megabecquerel," a radioactive unit.

[0217] As used in this article, "PET" stands for positron emission tomography.

[0218] As used in this article, "SPECT" stands for Single Photon Emission Computed Tomography.

[0219] As used in this article, "MRI" stands for magnetic resonance imaging.

[0220] As used in this article, "CT" stands for computed tomography.

[0221] The terms “tumor” and “cancer” are used interchangeably herein; for example, both terms cover solid and liquid tumors, such as diffuse or circulating tumors. As used herein, the terms “cancer” or “tumor” include pre-malignant cancers and tumors as well as benign cancers. The term “cancer” as used herein includes primary malignant cells or tumors (e.g., those whose cells have not migrated to sites other than the original malignant tumor or tumor site) and secondary malignant cells or tumors (e.g., those caused by metastasis (malignant cells or tumor cells migrating to a second site different from the original tumor site)).

[0222] As used herein, the phrase "therapeutic effective amount" of a compound refers to the amount of the compound that will elicit a desired therapeutic response in at least one subgroup of subjects, such as improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease with a reasonable benefit / risk ratio applicable to any medical treatment.

[0223] As used herein, the terms “subject” or “patient” are intended to include animals capable of developing or suffering from cancer or any disorder directly or indirectly related to cancer. Examples of subjects include mammals such as humans, apes, monkeys, dogs, cattle, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and genetically modified non-human animals. In one embodiment, a subject is a human being, such as someone who has cancer, is at risk of developing cancer, or is likely to develop cancer.

[0224] "Combination therapy" refers to a therapy comprising the administration of a fixed combination in the form of a single dose unit, or a therapy in which a radiopharmaceutical compound, as disclosed herein, and a combination partner (e.g., another drug as explained below, such as a CDK4 / 6 inhibitor and / or endocrine therapy) can be administered in parallel or alone, i.e., alone at time intervals, particularly where these time intervals allow the combination partner and / or combination radiotherapy to exhibit a synergistic effect (e.g., a co-existing effect) with the radiopharmaceutical compound. Single components may be packaged in a kit or individually. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration.

[0225] The terms “co-administration” or “combined administration” as used herein are also intended to cover the administration of selected combination partners (e.g., radiopharmaceutical compounds and CDK4 / 6 inhibitors) to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which these agents are not necessarily administered via the same route of administration or administered simultaneously.

[0226] In chemical formulas, wavy lines This indicates the attachment point to this part.

[0227] Radiopharmaceutical compounds used in the combination therapies disclosed herein

[0228] The radiopharmaceutical compound used in the methods disclosed herein is a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0229] CSP (I)

[0230] in:

[0231] C is the chelate portion;

[0232] S is an optional spacer that covalently connects C and P;

[0233] P is the GRP receptor binding site that is directly or indirectly covalently linked to C via S.

[0234] The compound is labeled with the radionuclide M.

[0235] M is selected from radioactive isotopes that can be used in nuclear medicine. Examples of such radioactive isotopes include, but are not limited to, those that can be used in nuclear medicine. 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 Sc. Preferably, M is 177 Lu.

[0236] In a particular embodiment, M is complexed with the chelating portion.

[0237] 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.

[0238] In a preferred embodiment, P is a GRP receptor antagonist portion having the following general formula:

[0239] Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z; where

[0240] Xaa1 is absent or selected from the group consisting of the following 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-tetrahydronorhalman-3-carboxylic acid (Tpi), Tyr, 3-iodotyrosine (oI-Tyr), Trp, and pentafluorophenylalanine (5-F-Phe) (all L-isomers or D-isomers); D-Phe is preferred.

[0241] Xaa2 is Gln, Asn, or His; Gln is preferred.

[0242] Xaa3 is Trp or 1,2,3,4-tetrahydrodemethylhalman-3-carboxylic acid (Tpi); Trp is preferred.

[0243] Xaa4 is Ala, Ser, or Val; Ala is preferred.

[0244] Xaa5 is Val, Ser, or Thr; Val is preferred.

[0245] Xaa6 is Gly, sarcosine (Sar), D-Ala, or β-Ala; preferably Gly.

[0246] Xaa7 is His or (3-methyl)histidine (3-Me)His; preferably His.

[0247] Z is selected from -NHOH, -NHNH2, -NH-alkyl, -N(alkyl)2 and -O-alkyl.

[0248] Or Z is

[0249]

[0250] Wherein X is NH (amide) or O (ester), and R1 and R2 are the same or different and are selected from proton, optionally substituted alkyl, optionally substituted alkyl ether, aryl, aryl ether or alkyl-, halogen, hydroxyl, hydroxyalkyl, amine, amino, amide or amide-substituted aryl or heteroaryl groups.

[0251] According to one embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-His-Z; where Z is as defined above.

[0252] According to one embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-His-Z, where Z is selected from Leu-ψ(CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2.

[0253] Or Z is

[0254]

[0255] Where X is NH (amide), and R2 is CH(CH2-CH(CH3)2, and R1 is the same as or different from R2 (CH2N)-Pro-NH2.

[0256] As used herein, the term "chelate moiety" refers to an organic moiety containing a functional group capable of forming a non-covalent bond with radionuclide M, thereby forming a stable radionuclide complex.

[0257] In the context of this disclosure, the chelating portion can be obtained by grafting a chelating agent onto S or P, said chelating agent being selected from the following list (which is not limiting): 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Titan), drytan, 1,4,7,10-tetraazacyclododecane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), aminotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,1-tetraazacyclododecane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), aminotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,1-tetraazacyclododecane,1-(glutaric acid)-4,7,1-triacetic acid (DOTAGA ... 1,4,7,1-tetraazacyclododecane,1-(glutaric acid)-4,7,1-triacetic acid (DOTAGA), 1,4,7,1-tetraazacyclododecane,1-(glutaric acid)- 0-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-diazacycloheptatriene (AAZTA, e.g., AAZTA5).

[0258] In a particular embodiment, the chelating portion C has the following formula:

[0259] ,

[0260] The wavy bond represents the attachment point between the chelating agent and the spacer S or the GRP receptor antagonist P.

[0261] Such chelating moieties are directly connected to the GRP receptor antagonist moieties or via a linker molecule (or, as referred to herein, spacer S). One or more linking bonds are one or more covalent or non-covalent bonds from the GRP receptor antagonist (and spacer) and the chelating moieties, preferably the one or more bonds being covalent.

[0262] The chelate C is typically optionally bonded via spacer S to the N-terminus of the peptide derivative formula disclosed above (such as DPhe-Gln-Trp-Ala-Val-Gly-His-Z).

[0263] In a particular embodiment, the spacer S is selected from the group consisting of:

[0264] a) Having any of the following aryl residues:

[0265] ;

[0266] b) Dicarboxylic acids, ω-aminocarboxylic acids, ω-diaminocarboxylic acids, or diamine derivatives having any of the following formulas:

[0267]

[0268] Each n independently represents an integer from 0 to 12, for example, n = 0, 1, 2, 3 or 4;

[0269] c) PEG spacers with various chain lengths, especially PEG spacers selected from any of the following formulas:

[0270]

[0271] Where m is an integer from 1 to 36, for example, m = 1, 2, 3 or 4, and

[0272] p is an integer from 0 to 5, for example, p = 0 or 1;

[0273] d) β-amino acid residues, either a single chain or a homologous chain of various chain lengths or a heterologous chain of various chain lengths, especially:

[0274] ; and / or,

[0275] e) Any combination of one or more of a, b, c and / or d.

[0276] In some embodiments, the radiopharmaceutical compounds used in the treatment methods disclosed herein are selected from the group consisting of compounds having a radiolabeled shape with the following formula:

[0277]

[0278] Wherein C and P are as defined above, and M is a radioactive isotope complexed with the chelate moiety; in some embodiments, M is selected from... 177 Lu.

[0279] In some embodiments, the radiopharmaceutical compound for use according to this disclosure is a compound having formula (II):

[0280] (II)

[0281] C and P are as defined above, and C is complexed with the radionuclide M.

[0282] In some embodiments, the radiopharmaceutical compound used in the treatment method is M-NeoB having formula (III):

[0283] (III),

[0284] Where M is as defined above, and in some embodiments, M is... 177 Lu.

[0285] Radiopharmaceutical compounds [ 177 Lu]Lu-NeoB refers to a compound having formula (III), where M is 177 Lu.

[0286] According to one embodiment, the radiopharmaceutical compound is a radiolabeled NeoB2 having formula (IV):

[0287] (IV),

[0288] Where M is as defined above, preferred 177 Lu.

[0289] According to another specific embodiment, the radiopharmaceutical compound for use according to this disclosure is a compound having formula (I), specifically ProBOMB1 having the following formula (V):

[0290] (V)

[0291] It is radiolabeled with M, and in some embodiments, M is... 177 Lu.

[0292] Some embodiments disclosed herein cover the use of [ 177 Lu]Lu-NeoB as a combination therapy of radiopharmaceutical compounds.

[0293] A radiopharmaceutical compound is used to treat breast cancer in a subject in need, wherein a therapeutically effective amount of the radiopharmaceutical compound is administered to the subject.

[0294] A single component or its precursor (typically unlabeled NeoB) may be packaged in a kit or individually. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration.

[0295] In certain embodiments, the radiopharmaceutical compound for use in the disclosed combination therapy may be formulated as previously described, for example, as described in WO 2021 / 052960.

[0296] In some embodiments, combination therapy includes administration of a pharmaceutical composition comprising:

[0297] (a) Complexes formed from the following:

[0298] (ai) radioactive nuclide 177 Lu ( 177 Lu), and

[0299] (aii) NeoB with equation (III):

[0300] (III); and;

[0301] (b) Gentianic acid or its salts and ascorbic acid or its salts;

[0302] (c) Optionally, Macrogol 15-hydroxystearate;

[0303] (d) Acetate buffer;

[0304] (e) Water for injection, and

[0305] (f) At least one other pharmaceutically acceptable excipient, such as a chelating agent, like DTPA.

[0306] Synthesis of compounds having formulas (I), (II), (III), (IV) and (V)

[0307] Compounds having formulas (I), (II), (III), (IV), and (V) can be synthesized using the method disclosed in the following reference: "Positron Emission Tomography Imaging of the Gastrin-Releasing Peptide Receptor with a Novel Bombesin Analogue" ACS Omega 2019, 4, 1470-1478.

[0308] Further information on the synthesis of compounds having formula (V) can be found in WO 2021 / 0608051.

[0309] Such as CDK4 / 6 inhibitors used in combination therapy

[0310] Methods for treating breast cancer in subjects in need include administering a combination of a radiopharmaceutical compound and a CDK4 / 6 inhibitor (e.g., ribociclib) and endocrine therapy (e.g., fulvestrant) to the subject.

[0311] As used herein, the term "CDK4 / 6 inhibitor" refers to cyclin-dependent kinase 4 / 6 inhibitors and is used to treat tumor-related diseases by affecting cell cycle progression and inducing apoptosis. Indeed, CDK4 / 6 proteins have been found in both healthy and cancer cells and control the rate of cell growth and division. In breast cancer, these proteins can become overactive, leading to uncontrolled cell growth and division. CDK4 / 6 inhibitors disrupt these proteins to slow or even halt cancer cell growth.

[0312] In some embodiments, the method disclosed herein includes exposing a 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 abeciclib (Verzenio). Preferably, the CDK4 / 6 inhibitor is ribociclib.

[0313] As used herein, “rebociclib” refers to a cyclin-dependent kinase 4 / 6 inhibitor, and more specifically to a compound having the following formula: 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide, and its pharmaceutically acceptable salt (CAS No. 1211441-98-3).

[0314] In one embodiment, the CDK4 / 6 inhibitor, preferably ribociclib, is administered orally at a therapeutically effective daily dose of 400 to 800 mg, preferably 500 to 700 mg, more preferably 550 to 650 mg, or even more preferably about 600 mg.

[0315] In one embodiment, the CDK4 / 6 inhibitor (e.g., ribociclib) is administered orally at a daily dose of about 600 mg for one to six cycles over a period of 15 to 28 days, for example, each cycle consisting of, for example, 21 days of daily administration followed by a 7-day period of treatment cessation.

[0316] In some embodiments, the CDK4 / 6 inhibitor (e.g., ribociclib) is administered orally at a daily dose of about 600 mg for 1 to 6 cycles over a period of 28 days, for example, each cycle comprising, for example, 21 days of administration followed by a 7-day period of treatment cessation, wherein the radiopharmaceutical compound is administered for 3 to 12 cycles.

[0317] Endocrine therapy, such as that used in combination therapy

[0318] Methods for treating breast cancer in subjects in need include administering a combination of a radiopharmaceutical compound and a CDK4 / 6 inhibitor and a therapeutically effective dose of endocrine therapy (e.g., fulvestrant) to the subject.

[0319] As used in this article, the terms "endocrine therapy," "hormonal therapy," "hormone therapy," or "hormone treatment" 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.

[0320] The following strategies are used to treat hormone-sensitive breast cancer, including:

[0321] 1. Blocking ovarian function can be achieved through surgery, radiation therapy, or treatment with gonadotropin-releasing hormone (GnRH) agonists (also known as luteinizing hormone-releasing hormone (LHRH) agonists). Examples of ovarian suppression drugs are leuprorelin (Lupron), or synthetic analogues of gonadotropin-releasing hormone such as goserelin (Zoladex).

[0322] 2. Blocking estrogen production can be achieved through treatment with steroidal or nonsteroidal aromatase inhibitors such as anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin);

[0323] 3. Blocking the effects of estrogen can be achieved through treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen (Nolvadex) and toremifene (Fareston) or selective ER degraders such as fulvestrant (Faslodex).

[0324] In some embodiments, the endocrine therapy includes 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 includes administering a therapeutically effective amount of a selective ER degrader.

[0325] In some embodiments, the selective ER degrading agent is fulvestrant.

[0326] As used herein, “fulvestrant” refers to a steroidal anti-estrogen, and more specifically to a compound having 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-decahydrocyclopentadien[a]phenanthrene-3,17-diol, and its pharmaceutically acceptable salt (CAS No. 129453-61-8).

[0327] In some embodiments, the selective ER degrader (e.g., fulvestrant) is administered, for example, every 14 to 56 days (e.g., 28 days) starting from the same day as the administration of the radiopharmaceutical compound, and the administration continues for at least the same duration as the administration of the radiopharmaceutical, and optionally the administration of the ER degrader continues until disease progression.

[0328] In one embodiment, the endocrine therapy (e.g., the selective ER degrader, such as fulvestrant) is administered concomitantly with the CDK4 / 6 inhibitor (e.g., ribociclib).

[0329] In one embodiment, the endocrine therapy (e.g., fulvestrant) is administered via intramuscularly at a dose of 250 to 700 mg, for example using a long-acting formulation.

[0330] In some embodiments, both the CDK4 / 6 inhibitor and endocrine therapy (e.g., fulvestrant) are started on the same day. In some embodiments, the CDK4 / 6 inhibitor (e.g., ribociclib) is administered concurrently with endocrine therapy (e.g., fulvestrant).

[0331] In some embodiments, the endocrine therapy further comprises, for example, administration of a synthetic analogue of gonadotropin-releasing hormone, such as goserelin, via subcutaneous administration at a dose of about 3.6 mg every 28 days. In some embodiments, a CDK4 / 6 inhibitor (e.g., ribociclib), endocrine therapy (e.g., fulvestrant), and a synthetic analogue of gonadotropin-releasing hormone (e.g., goserelin) are initiated on the same day. In some embodiments, the synthetic analogue of gonadotropin-releasing hormone (e.g., goserelin) is preferably administered every 28 days starting from the same day as the administration of the radiopharmaceutical compound, and the administration continues for at least the same duration as the administration of the radiopharmaceutical, and optionally, the ER degrading agent is continued until disease progression.

[0332] Combination therapy

[0333] In some embodiments, a method of treating breast cancer in a subject in need includes administering to the subject a therapeutically effective amount of a radiopharmaceutical compound as described above, preferably […]. 177Lu]Lu-NeoB in combination with CDK4 / 6 inhibitors and endocrine therapy.

[0334] In some embodiments, this disclosure relates to methods for treating breast cancer in a subject in need, methods comprising administering to the subject a therapeutically effective amount of the 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 endocrine therapy (e.g., fulvestrant).

[0335] This disclosure also relates to the use of a radiopharmaceutical compound in the preparation of a medicament for use in the treatment of breast cancer in a subject of need, wherein a therapeutically effective amount of the radiopharmaceutical compound is administered to the subject simultaneously, alone, or sequentially (e.g., […]). 177 Lu]Lu-NeoB) in combination with CDK4 / 6 inhibitors (e.g., ribociclib) and a therapeutically effective dose of endocrine therapy (e.g., fulvestrant).

[0336] In various embodiments disclosed herein, the combination therapy includes, in combination (i) administering to a subject in need a therapeutically effective amount of a radiopharmaceutical compound (e.g., […]). 177 (ii) administering a therapeutically effective amount of a pharmaceutical composition comprising a CDK4 / 6 inhibitor (e.g., ribociclib) to a subject in need, and (iii) administering a therapeutically effective amount of a pharmaceutical composition comprising endocrine therapy (e.g., fulvestrant) to a subject in need.

[0337] As used herein, the term “combined” means that the therapeutic agent can be administered individually over time intervals (e.g., in an interleaved manner, especially in a particular order within such time intervals) to demonstrate (preferably synergistic) interactions (i.e., combined therapeutic effects).

[0338] In various embodiments disclosed herein, combined administration is performed, wherein a radiopharmaceutical compound (e.g., 177 Lu-NeoB and CDK4 / 6 inhibitors can be administered simultaneously or separately at time intervals, especially where these time intervals allow the combined couple to exhibit synergistic (e.g., co-existing) effects.

[0339] In some embodiments, a radiopharmaceutical compound (e.g., [ 177 Lu]Lu-NeoB) was administered on the same day as a CDK4 / 6 inhibitor.

[0340] The administration of radiopharmaceutical compounds may include administration intervals of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 3 or 4 weeks, or 4 weeks.

[0341] In some embodiments, the radiopharmaceutical compound (e.g., [ 177 The radiopharmaceutical compound (Lu]Lu-NeoB) was administered to the subject in combination with a CDK4 / 6 inhibitor and further in combination with endocrine therapy at least 6 times, wherein the interval between two administrations of the radiopharmaceutical compound was 4 weeks, and wherein the first dose of the radiopharmaceutical compound was administered on the same day as the CDK4 / 6 inhibitor (e.g., ribociclib) and the endocrine therapy (e.g., fulvestrant).

[0342] In some embodiments, the radiopharmaceutical compound (e.g., [ 177 Lu-NeoB is administered at each dose in the following ranges: from 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), from 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), from 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), from 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), for example, from about 3.7 GBq (100 mCi) to about 7.4 GBq (200 mCi).

[0343] In some embodiments, the radiopharmaceutical compound (e.g., [ 177 Lu-NeoB) is administered intravenously every 28 days for 3-12 cycles, for example 4-10 cycles, for example 6 cycles. For example, the radiopharmaceutical compound (e.g., [ 177 Lu]Lu-NeoB) is administered, for example, at a dose ranging from 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi) (e.g., 150 mCi) every 4 weeks for 3-12 cycles, such as 4-10 cycles, such as 6 cycles, in combination with the CDK4 / 6 inhibitor (e.g., ribociclib) administered orally at a daily dose of 400 to 800 mg (e.g., about 600 mg) for 15 to 21 days per cycle, and in combination with the endocrine therapy (e.g., fulvestrant) administered intramuscularly at a dose of 250 to 700 mg, for example, using a long-acting formulation, every 14 or 28 days for 4-6 cycles.

[0344] Examples of combination therapy treatment regimens are shown in Figure 1 middle.

[0345] In some embodiments, the endocrine therapy further comprises, typically, subcutaneous administration of a synthetic analogue of gonadotropin-releasing hormone, such as goserelin, every 28 days at a dose of about 3.6 mg. In some embodiments, a CDK4 / 6 inhibitor (e.g., ribociclib), endocrine therapy (e.g., fulvestrant), and a synthetic analogue of gonadotropin-releasing hormone (e.g., goserelin) are initiated on the same day. In some embodiments, the synthetic analogue of gonadotropin-releasing hormone (e.g., goserelin) is administered, for example, every 28 days from the same day as the administration of the radiopharmaceutical compound for 4 to 10 cycles, or for at least the same duration as the administration of the radiopharmaceutical compound, and optionally, the synthetic analogue of gonadotropin-releasing hormone is continued until disease progression. In some embodiments, the radiopharmaceutical compound (e.g., […]) is administered… 177 Lu-NeoB) is administered intravenously every 28 days for 3-12 cycles, for example 4-10 cycles, for example 6 cycles. For example, the radiopharmaceutical compound (e.g., [ 177 Lu-NeoB, for example, is administered at a dose ranging from 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi) (e.g., 150 mCi) every 4 weeks for 3-12 cycles, such as 4-10 cycles, such as 6 cycles, 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 therapy (e.g., fulvestrant) administered intramuscularly at a dose of 250 to 700 mg, for example using a long-acting formulation, every 14 or 28 days for at least the same duration as the administration of a radiopharmaceutical and optionally continuing endocrine therapy until disease progression, and further includes the synthetic analogue of gonadotropin-releasing hormone (e.g., goserelin) administered at a dose of about 3.6 mg every 28 days for at least the same duration as the administration of a radiopharmaceutical and optionally continuing until disease progression.

[0346] A second embodiment of the combination therapy treatment regimen is shown in Figure 2 middle.

[0347] In some embodiments, compared with a single CDK4 / 6 inhibitor (e.g., ribociclib) or a combination therapy of a CDK4 / 6 inhibitor (e.g., ribociclib) and endocrine therapy (e.g., fulvestrant and / or goserelin), radiopharmaceutical compounds (e.g., […]) are less effective than combination therapy of a single CDK4 / 6 inhibitor (e.g., ribociclib) and endocrine therapy (e.g., fulvestrant and / or goserelin).177 The combined effect of Lu-NeoB treatment with the CDK4 / 6 inhibitor (e.g., ribociclib) and endocrine therapy (e.g., fulvestrant and / or goserelin) increased the overall survival of subjects by at least 10%, 20%, 30%, 40%, or at least 50%.

[0348] Overall survival (OS) is defined in this paper as the time from the date of the first dose to the date on which a participant in the clinical study dies for any cause, such as as disclosed in Example 1. If it is unknown whether a participant has died, overall survival is censored on the latest date on which it is known that a participant is still alive (on or before the cutoff date). The Kaplan-Mayer method will be used to estimate the OS distribution.

[0349] In some embodiments, compared with a single CDK4 / 6 inhibitor (e.g., ribociclib) or a combination therapy of a CDK4 / 6 inhibitor (e.g., ribociclib) and endocrine therapy (e.g., fulvestrant and / or goserelin), radiopharmaceutical compounds (e.g., […]) are less effective than combination therapy of a single CDK4 / 6 inhibitor (e.g., ribociclib) and endocrine therapy (e.g., fulvestrant and / or goserelin). 177 The combination of Lu-NeoB therapy with CDK4 / 6 inhibitors and endocrine therapy also increased progression-free survival by at least 10%, 20%, 30%, 40%, or at least 50%.

[0350] As used herein, the term “progression-free survival” (PFS) is defined as the time from the date of the first dose to the date on which progression or death from any cause is confirmed according to the modified RANO. If no PFS event is observed, PFS is censored to the date of the last adequate oncology assessment prior to the data cutoff date and the start of a new anti-tumor therapy (whichever comes first). The distribution of PFS was estimated using the Kaplan-Mayer method.

[0351] In some respects, administering a radiopharmaceutical compound (e.g., […]) to a subject qualified for the treatment. 177The composition of Lu-NeoB can inhibit, delay, and / or reduce tumor growth in subjects. In some aspects, tumor growth is delayed by at least 50%, 60%, 70%, or 80% compared to untreated control subjects. In some aspects, tumor growth is delayed by at least 80% compared to untreated control subjects. In some aspects, tumor growth is delayed by at least 50%, 60%, 70%, or 80% compared to the predicted growth of untreated tumors. In some aspects, tumor growth is delayed by at least 80% compared to the predicted growth of untreated tumors. The assessment of tumor volume in breast cancer can be performed using RECIST tumor response criteria (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. JNatl 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.) to determine.

[0352] In some respects, administering a radiopharmaceutical compound (e.g., […]) to a subject qualified for the treatment. 177Compositions of Lu-NeoB can increase the survival length of subjects. In some respects, the increase in survival is compared to treatment-naïve control subjects or control subjects receiving standard care (such as a combination of a CDK4 / 6 inhibitor (e.g., ribociclib) and endocrine therapy (e.g., fulvestrant and / or goserelin) for patients newly diagnosed with breast cancer). In some respects, the increase in survival is compared to the predicted survival length of subjects receiving standard care. In some respects, the survival length is increased by at least 3, 4, or 5 times compared to treatment-naïve control subjects or control subjects receiving standard care (such as a combination of a CDK4 / 6 inhibitor (e.g., ribociclib) and endocrine therapy (e.g., fulvestrant and / or goserelin) for patients newly diagnosed with breast cancer). In some respects, survival was extended by at least one week, two weeks, one month, two months, three months, six months, one year, two years, or three years compared to control subjects receiving standard care (such as a combination of CDK4 / 6 inhibitors (e.g., ribociclib) and endocrine therapy (e.g., fulvestrant and / or goserelin) for newly diagnosed breast cancer patients).

[0353] In some embodiments, the combined therapeutic effects of radiopharmaceuticals, ER degrading agents, and endocrine therapy show synergistic effects.

[0354] Methods for selecting subjects for combination therapy

[0355] In some embodiments disclosed herein, the breast cancer is a GRPR-positive disease.

[0356] In a particular embodiment, subjects are selected for treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging, using the same compound as defined for the treatment, but where M is an alternative radionuclide suitable for imaging, i.e., an imaging radiopharmaceutical compound, based on the detection of said radionuclide in postoperative imaging scans of the tumor region.

[0357] Typical alternative radionuclides suitable for use as contrast agents in imaging include the following: 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.

[0358] In some embodiments, the radionuclide suitable for imaging is 67 Ga、 68 Ga or 64 Cu, preferred 68 Ga.

[0359] In some embodiments, evaluation is performed by PET / CT or PET / MRI scans in the tumor region (e.g., the breast region). 68 Subjects were selected based on their Ga]Ga-NeoB intake.

[0360] In some embodiments, the subjects eligible for combination therapy are selected from those who show radionuclide enhancement (e.g., gadolinium enhancement) on a postoperative PET / MRI scan of the tumor area.

[0361] In some embodiments, a radiopharmaceutical compound labeled with an imaging-suitable radiometal may be used 42 days to 1 day prior to the first administration of the radiopharmaceutical compound for combination therapy (e.g., […]). 68 PET scans were performed using Ga]Ga-NeoB.

[0362] Therefore, this disclosure also relates to a method for determining whether a human subject with breast cancer can be selected for the combination therapy as disclosed herein, the method comprising the following steps:

[0363] 1. An effective amount of an imaging radiopharmaceutical compound is administered as a contrast agent to image the uptake of the radiopharmaceutical compound.

[0364] 2. Acquire images of the patient via PET / MRI or PET / CT, and

[0365] 3. Compare with control image scans.

[0366] The purpose of the above selection method is to select patients with GRPR-positive tumors, i.e., those patients who are better responders to the combination therapy disclosed herein. GRPR-positive tumors can be advantageously detected by evaluating the uptake of the imaging radiopharmaceutical compound by PET / MRI or PET / CT imaging after injection of the imaging radiopharmaceutical compound as a contrast agent.

[0367] As used herein, a good responder is a patient group selected from those who, compared to a randomized patient group (i.e., a group not selected by the selection steps of the method of the present invention), show a statistically better response to treatment and / or show fewer treatment side effects compared to a randomized patient group (i.e., a group not selected by the selection steps of the method of the present invention).

[0368] In one respect, [ 68 Ga-NeoB is provided in the kit. The kit can consist of two sterile vials as single-dose products:

[0369] Vial 1: NeoB (active ingredient), 50 μg, powder for injection solution, ready for reconstitution of gallium chloride-68 (68GaCl3) eluted from 68Ge / 68Ga generator in HCl;

[0370] Vial 2: Reaction buffer. Add vial 2 to the reconstructed vial 1.

[0371] Examples of such kits are disclosed in WO 2021053040.

[0372] Based on the current activity and physical decay of the radionuclide (half-life = 68 min) provided by the generator, the injection dose corresponding to the radioactive dose to be administered is calculated according to the estimated injection time. 68 The volume of the Ga]Ga-NeoB solution.

[0373] In some embodiments, subject selection is performed 10 to 18 days, preferably about 14 days, before the first administration of the radiopharmaceutical compound.

[0374] In some embodiments, the imaging radiopharmaceutical is administered in a single intravenous dose of 150 to 250 MBq (4.1-6.8 mCi).

[0375] Then, images of the subject's body are acquired via PET / MRI or PET / CT imaging, and these images are compared with control images to determine whether lesions identified by conventional imaging (e.g., MRI, CT, SPECT, or PET) are also taken up by the imaging radiopharmaceutical compound (i.e., […]). 68 Ga]Ga-NeoB uptake was identified. In some embodiments, PET / MRI or PET / CT imaging was performed 30 to 120 minutes (e.g., 60 to 90 minutes) after intravenous administration of the imaging radiopharmaceutical compound to the subject.

[0376] In some embodiments of this method, subjects selected for the combination therapy disclosed herein meet the following criteria: 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., by MRI, CT, SPECT, or PET) of the subject are also taken up by imaging radiopharmaceutical compounds (e.g., […]). 68 Ga]Ga-NeoB uptake was identified, as determined by PET / MRI or PET / CT imaging of the subjects.

[0377] In some embodiments, the term "lesion" refers to a measurable tumor lesion according to the RECIST 1.1 criteria as defined above.

[0378] In some embodiments, the subject is newly diagnosed with breast cancer or has recurrent breast cancer.

[0379] As used in this article, "recurrent" means that the patient has relapsed after at least one treatment.

[0380] In some embodiments, the subject has ER-positive, HER-2-negative (ER+ / HER2-) and GRPR-positive (GRPR+) breast cancer.

[0381] In some embodiments, the subjects have been selected from those who have experienced early relapse after neoadjuvant or adjuvant endocrine therapy.

[0382] As used in this article, “early relapse” refers to a relapse during or within 12 months of completing neoadjuvant or adjuvant endocrine therapy.

[0383] As used in this article, “neoadjuvant endocrine therapy” refers to aromatase inhibitors, such as letrozole.

[0384] In some embodiments, the subject is a postmenopausal woman with advanced metastatic breast cancer.

[0385] In some embodiments, the subject is a premenopausal or perimenopausal woman with advanced metastatic breast cancer. In such specific embodiments, endocrine therapy may further comprise, typically via subcutaneous administration of a synthetic analogue of gonadotropin-releasing hormone, such as goserelin, at a dose of about 3.6 mg every 28 days.

[0386] In the following description, other aspects of the combination therapies disclosed herein are described in more detail and specifically with reference to examples, however these examples are not intended to limit the invention.

[0387] Example

[0388] Example 1: Clinical study I for treating breast cancer subjects

[0389] This article provides an example of a phase Ib dose-exploration study protocol that evaluated the safety and activity of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant in subjects with ER-positive, HER-2-negative, and GRPR-positive breast cancer who had experienced early recurrence from (neo)adjuvant endocrine therapy.

[0390] summary

[0391]

[0392] Experimental Design:

[0393] This is a phase Ib, single-arm, multicenter, open-label, dose-exploration study of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant in adult female participants who had recurrent ER+ / HER2-, GRPR+ advanced / metastatic breast cancer during or within 12 months of prior (neo)adjuvant ET. The study includes a dose-escalation phase followed by a dose-expansion phase. The dose-expansion phase will also include premenopausal / perimenopausal women who will receive [177Lu]Lu-NeoB in combination with ribociclib, fulvestrant, and goserelin.

[0394] Brief overview:

[0395] Metastatic breast cancer (MBC) is an incurable disease with a 5-year overall survival (OS) rate of approximately 22% (National Cancer Institute, 2021). In recent years, the addition of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (CDK4 / 6i) to adjuvant therapy (ET) has significantly improved the prognosis of patients with hormone receptor-positive (HR+) / HER2- advanced / metastatic breast cancer. However, the OS benefit remains limited for a subset of patients who relapsed within 12 months of (neo)adjuvant therapy (early recurrence) compared to a subset of patients who developed new disease or relapsed >12 months after (neo)adjuvant ET (38.8 months vs. 67.6 months, respectively) (undisclosed data from Novartis, Neven et al., 2022). These patients represent an unmet medical need for novel therapies.

[0396] The addition of [177Lu]Lu-NeoB (a radionuclide therapy targeting GRPR overexpressed in breast cancer cells) to the currently recommended and approved combination of ET and CDK4 / 6i is expected to be a safe and effective first-line treatment option for HR+ / HER2- MBC patients with early recurrence after (neo)adjuvant ET.

[0397] The aim of this phase 1b, single-arm, multicenter, open-label, dose-exploration study was to estimate the recurrent disease (RD) in adult female participants with ER+, HER2-, GRPR+ advanced / metastatic breast cancer who had relapsed within 12 months of prior (neo)adjuvant ET (incremental portion). Additionally, this study aimed to characterize the safety and tolerability of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant in postmenopausal participants, and the safety and tolerability of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant in premenopausal / perimenopause participants (extended portion).

[0398] The study consists of a dose-escalation phase followed by a dose-expansion phase. The dose-escalation phase will estimate the RD (reactive protein) in the combination of [177Lu]Lu-NeoB with ribociclib and fulvestrant; four provisional dose levels are planned to be tested in cohorts of 3 to 6 participants: 100 mCi (initial dose), 150 mCi, 200 mCi, and 250 mCi. After each cohort of 3 to 6 participants is enrolled, the incidence of DLT (diminished toxicity) will be compared to a predefined toxicity rate boundary to determine whether the next cohort will receive a lower, higher, or the same dose, or whether the trial will be terminated. The expansion phase will evaluate the safety, tolerability, and antitumor activity of the RD dose of [177Lu]Lu-NeoB (as determined in the dose-escalation phase) with ribociclib and fulvestrant in both postmenopausal and premenopausal / perimenopause participants (who will also receive goserelin). A total of 15 participants will be enrolled in the expansion phase.

[0399] During the screening period, study participants will receive the study imaging agent [68Ga]Ga-NeoB. A further administration of [68Ga]Ga-NeoB will be performed 2–8 weeks after the last administration of [177Lu]Lu-NeoB for PET / CT or PET / MRI.

[0400] The study treatment will consist of [177Lu]Lu-NeoB for six cycles, starting on day 1 (+ ≤ 3) of each 28-day cycle, followed by ribociclib (once daily; days 1 to 21 of each 28-day cycle) and fulvestrant (C1D1, C1D15, C2D1, and every 28 days thereafter), until disease progression. Premenopausal and perimenopausal participants in the extended portion will additionally receive goserelin on day 1 of each cycle.

[0401] During the treatment period, participants will be required to attend a field visit approximately every 28 days, on the first day of each cycle (and on C1D2, C1D3, C1D8, C1D15, C2D15, C3D3, and C5D3) for study treatment administration, dosing, and safety assessment. Tumor assessment will be conducted every 8 weeks until month 18, every 12 weeks until month 36, and thereafter as clinically indicated until disease progression. After study treatment is discontinued, participants will be followed for 8 weeks following the last administration of study treatment. Following the initial 8-week safety follow-up, all participants will be followed every 12 weeks until month 36, and then every 24 weeks until month 60 (according to Section 1.3 SoA) for a total of 5 years from the date of enrollment, or until death, loss to follow-up, or Worc.

[0402] Study completion is defined as the date of the last visit, planned procedure, or follow-up of the last participant in the global study (or the date of death, WoC, or loss to follow-up, whichever occurs first), as shown in Section 1.3 SoA, or 5 years from the date of enrollment of the last participant, whichever occurs earlier.

[0403] Purpose of treatment

[0404] This study included [68Ga]Ga-NeoB as an imaging agent, and [177Lu]Lu-NeoB, ribociclib, fulvestrant, and goserelin (in the extended section, only for premenopausal / perimenopausal women) as study treatments.

[0405] NeoB is a next-generation bufotin (BN) analogue, a GRPR antagonist with superior pharmacokinetic and toxicological properties compared to agonist analogues. It binds to GRPR with high affinity and exhibits low internalization, consistent with its antagonistic behavior (Nock et al. 2017). Its structure contains a DOTA metal chelator, which allows for radiolabeling with various radionuclides, including gallium-68 (for positron emission tomography (PET) imaging) and lutetium-177 (for radionuclide therapy), without affecting receptor affinity, internalization properties, or biodistribution.

[0406] [68Ga]Ga-NeoB will be used as an imaging agent and is intended as a tool of choice for [177Lu]Lu-NeoB treatment in patients with tumors that overexpress GRPR, including subjects affected by breast cancer (Flores et al. 2010, Morgat et al. 2017). [68Ga]Ga-NeoB has shown favorable technical and diagnostic performance in both preclinical and clinical studies for identifying GRPR-expressing malignancies, with good image quality that allows for easy interpretation.

[0407] [177Lu]Lu-NeoB has demonstrated a 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. [177Lu]Lu-NeoB is rapidly cleared from the bloodstream and eliminated quickly via the renal system without retention in the kidneys. Background radioactivity was observed in GRPR-expressing tissues (primarily the pancreas), however, it decreased over time, consistent with the GRPR antagonist spectrum. In contrast, tumor residual is persistent, with uptake values ​​detectable up to 7 days post-injection. These characteristics make [177Lu]-Lu NeoB an ideal candidate for peptide receptor radionuclide therapy (PRRT). A Phase I / IIa, open-label, multicenter study of [177Lu]Lu-NeoB as a single agent is currently being evaluated to assess the safety, tolerability, systemic distribution, radiation dosimetry, and antitumor activity of [177Lu]Lu-NeoB administered in patients with advanced solid tumors known to overexpress GRPR, where no other treatment options are available. Data show that [177Lu]Lu-NeoB has demonstrated good tolerability and safety profile, as well as favorable biodistribution and low uptake, in organs considered at risk due to GRPR expression (such as the pancreas) or due to radioligand therapy (RLT) (such as red bone marrow) and excretion pathways (such as the kidneys).

[0408] In this study, participants will receive a combination of [177Lu]Lu-NeoB with ribociclib and fulvestrant (and goserelin, where applicable, only in the extended portion).

[0409] Number of participants:

[0410] Up to 27 participants will be enrolled in the dose escalation portion of the study: 3–6 participants in 4 cohorts for 4 dose levels; and another 3–6 participants, for a total of up to 9 participants, can be enrolled at specific dose levels. Once the RD has been estimated, approximately 15 participants will be enrolled in the dose extension portion.

[0411] Key inclusion criteria:

[0412] • The informed consent was given by an adult female aged 18 or older.

[0413] • Participants were postmenopausal (incremental portion) at the start of the study treatment.

[0414] • Participants were in premenopause / perimenopause or postmenopause at the start of the study treatment (extended section).

[0415] • Estrogen receptor-positive breast cancer with ER > 10% (excluding PgR expression) confirmed histologically and / or cytologically by local laboratory testing (based on the most recently analyzed tissue sample).

[0416] • HER2-negative breast cancer is defined as a negative in situ hybridization test or an immunohistochemical (IHC) status of 0, 1+, or 2+. If IHC is 2+, a negative in situ hybridization test (e.g., FISH, CISH, or SISH) performed by a local laboratory (based on the most recently analyzed tissue sample) is required.

[0417] • Disease relapse within ≤ 12 months after completion of (neo)adjuvant ET or (neo)adjuvant ET (which may already include CDK4 / 6 inhibitors).

[0418] • Patients with advanced [localized recurrence, unsuitable for curative therapies (e.g., surgery and / or RT)] or metastatic disease

[0419] • Having measurable disease, meaning having at least one measurable lesion according to RECIST 1.1. (If there are clear signs of progression since irradiation, a lesion at a previously irradiated site can only be counted as a target lesion), or if only osteolytic lesions are present, at least one lesion must have a soft tissue component that can be evaluated by CT or MRI and meet the definition of measurability according to RECIST criterion 1.1 (if there is documented evidence of disease progression in the osteolytic lesion after irradiation, only one participant with a previously irradiated major osteolytic lesion qualifies).

[0420] • Participants had at least one target lesion (RECIST 1.1) with [68Ga]Ga-NeoB uptake on PET / CT or PET / MRI based on baseline independent computed tomography (CT) / magnetic resonance imaging (MRI). The same identified measurable lesion showed [68Ga]Ga-NeoB uptake on PET / CT or PET / MRI based on a visual rating scale.

[0421] • Sufficient bone marrow and organ function

[0422] • There are standard 12-lead ECG values, defined as the average of three ECGs, and evaluated by a central laboratory.

[0423] • The QT interval (QTcF) corrected for Fridricia formula was < 450 msec during screening.

[0424] • Average resting heart rate is 50-90 bpm (determined from ECG).

[0425] • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

[0426] Key Exclusion Criteria

[0427] • Previously treated in advanced / metastatic cases

[0428] • Based on the researcher's best judgment, participants with symptomatic visceral diseases or any disease burden that disqualifies them from receiving ribocinica endocrine therapy may be excluded.

[0429] • CNS involvement is present unless the following two criteria are met: 1) At least 4 weeks have passed between the completion of previous therapy (including radiation and / or surgery) and the start of study treatment. 2) The CNS tumor is clinically stable at the time of screening and the patient has not received steroids and / or enzyme-induced antiepileptic drugs for brain metastases.

[0430] • Currently receiving warfarin or other coumarin-derived anticoagulants for treatment, prophylaxis, or other purposes. Treatment with heparin, low molecular weight heparin, or fondaparinux is permitted.

[0431] • Diagnosed with inflammatory breast cancer during screening.

[0432] •Child Pugh's score is B or C

[0433] • A history of or current diagnosis of impaired cardiac function, clinically significant heart disease, or ECG abnormalities that indicate a significant safety risk to the participant.

[0434] • Known or anticipated hypersensitivity to any investigational drug or any of its excipients

[0435] • Previous administration of radiopharmaceuticals, unless 10 or more half-lives have passed before the injection of [68Ga]Ga-NeoB.

[0436] • Participants had received extended-field RT ≤ 4 weeks or limited-field RT ≤ 2 weeks prior to starting treatment and had not recovered from grade 1 or better from side effects associated with this therapy (other than hair loss or other toxicities not considered a safety risk to the participant in the investigator's judgment) and / or from previous EBRT-related side effects affecting more than 25% of the bone marrow.

[0437] • The patient is currently receiving or has received systemic corticosteroids within ≤ 2 weeks prior to starting the study treatment, or the patient has not yet fully recovered from the side effects of such treatment. Note: The following corticosteroids are permitted: single-dose topical application (e.g., for a rash), inhaled spray (e.g., for obstructive airway disease), eye drops, or local injections (e.g., intra-articular injections).

[0438] • Participants with a history of acute pancreatitis or persistent acute pancreatitis within one year of screening.

[0439] • Participants are currently receiving any of the following substances and cannot discontinue them 7 days prior to starting the study treatment:

[0440] • Accompanying drugs, herbal supplements, and / or fruits (e.g., grapefruit, pomelo, star fruit, lime) and their juices that are strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4 / 5).

[0441] • Drugs with a narrow therapeutic window and primarily metabolized by CYP3A4 / 5

[0442] • One or more concomitant medications with a known risk of prolonging the QT interval and / or known to cause TdP that cannot be discontinued or replaced by a safe alternative (e.g., within 5 half-lives or 7 days prior to the start of study treatment).

[0443] Treatment group:

[0444] • Following the 42-day screening period is the treatment period, which continues until disease progression, or until the study treatment is discontinued for any other reason (such as unacceptable toxicity, worsening symptoms, withdrawal of consent (WoC), loss to follow-up, investigator's decision, or death), whichever occurs first. Post-treatment follow-up includes an 8-week safety follow-up period after treatment discontinuation and a long-term follow-up period of up to 5 years from the date of participant enrollment.

[0445] • During the screening period, each participant will receive [68Ga]Ga-NeoB for PET / CT or PET / MRI imaging. [68Ga]Ga-NeoB will be administered in a single intravenous dose with an activity in the range of 150-250 MBq (4.1-6.8 mCi).

[0446] • In the dose escalation phase, each participant in a specific cohort will receive 3.7 GBq (100 mCi) + / - 10% of the starting dose of [177Lu]Lu-NeoB (intravenous infusion every 28 days for 6 cycles) in combination with ribociclib (tablets, 600 mg daily for 21 consecutive days, followed by a 7-day treatment break) and fulvestrant (intramuscular injection, 500 mg on day 1 of the 28-day cycle plus an additional single dose administered on day 15 of cycle 1). Four dose levels of [177Lu]Lu-NeoB (100, 150, 200, or 250 mCi) are planned to be explored during the escalation phase to estimate RD.

[0447] • In the extended phase, each participant will receive a combination of [177Lu]Lu-NeoB (intravenous infusion, RD, every 28 days for 6 cycles) with ribociclib (tablets, 600 mg daily for 21 consecutive days, followed by a 7-day treatment break) and fulvestrant (intramuscular injection, 500 mg on day 1 of the 28-day cycle plus an additional single dose administered on day 15 of cycle 1). Additionally, premenopausal / perimenopausal women will receive goserelin (3.6 mg on day 1 of the 28-day cycle).

[0448] • If the initial dose of the incremental portion of [177Lu]Lu-NeoB is not tolerated, lower doses will not be tested, and the study will be terminated.

[0449] • Within 2–8 weeks after the last administration of [177Lu]Lu-NeoB, an additional administration of the research imaging agent [68Ga]Ga-NeoB will be performed to assess the difference between baseline [68Ga]Ga-NeoB PET scans and those following the administration of the last dose of [177Lu]Lu-NeoB.

[0450] Example 2: Clinical Study II for the treatment of breast cancer patients, compared to the regimen from Clinical Study I of Example 1. renew

[0451] Changes relative to Example 1:

[0452] Changes in research design

[0453] The study design has been updated from a “dose escalation followed by a dose extension” to a dose escalation followed by parallel backfilling at lower and previously cleared dose levels. The dose extension portion has been removed. The purpose of this design change is to allow for the generation of robust and effective data at all tested dose levels, which will help determine recommended doses for future studies and to understand future dose optimization based on the overall data.

[0454] Key changes to qualification standards

[0455] • This study will include patients with HR+, HER2- advanced breast cancer who have progressed while receiving first-line treatment for advanced disease (ET + CDK4 / 6 inhibitors). The clinical situation of patients following CDK4 / 6i is challenging because they may have more aggressive disease compared to patients in the endocrine failure-only scenario. Furthermore, the selection of subsequent therapies is challenging and often based on clinical experience, as no guidelines are available to determine the optimal treatment sequence, highlighting the unmet medical need for novel therapies in this population.

[0456] • Male patients will be allowed in the study.

[0457] • Throughout the study, female participants will be allowed to participate regardless of their menopausal status in order to coordinate patient groups across all dose levels.

[0458] • The selection criteria have been updated following the updated research design. 177 Participants treated with Lu-NeoB 68 Ga]Ga-NeoB uptake thresholds. While two different thresholds based on a visual uptake rating scale were previously applied to each part of the study (dose escalation and dose extension), the current design selects only one set of criteria requiring higher uptake. The required score corresponds to the score previously set for the escalation part of the study, and is based on enriching a more homogeneous population to maximize efficacy.

[0459] • New exclusion criteria related to the use of NEP inhibitors at the time of study entry have been introduced. This is because [ 177 Potential risks of drug-drug interactions between Lu]Lu-NeoB and neprilysin (NEP) inhibitors.

[0460] Other changes

[0461] •[ 177 The clinical experience with Lu]Lu-NeoB has been updated, with the latest data supporting the identification of RP2D in the ongoing first-in-human study CAAA603A12101 (NeoRay).

[0462] • Statistical considerations have been updated to reflect the new study design, including endpoint definition and sample size. (For use in […]) 68 The diagnostic set for Ga-NeoB correlation analysis has been divided into the following two analysis sets: 68 Ga]Ga-NeoB security analysis set and [ 68 Ga]Ga-NeoB evaluable set.

[0463] • The biomarker strategy has been updated to allow for paired pre- and post-treatment tumor biopsy collection when medically feasible. Additionally, provisions for […] have been added. 68 A new assessment of Ga]Ga-NeoB was conducted to examine GRPR expression in tissue biopsies collected at C3D1 and in PET at C2D15. 68 The relationship between Ga]Ga-NeoB uptake.

[0464] • After HA feedback, the last applied [ 177 The time between Lu-NeoB dose and subsequent PET scan has changed from 2-8 weeks to 4-8 weeks.

[0465] • Information and specifications regarding concomitant use and potential DDI of NEP inhibitors (e.g., Entresto, racecadotril) have been added.

[0466] •exist Section 7.5 In the criteria for stopping or suspending the study, the number of participants who would trigger a coordinated safety review has been updated, given that all participants will undergo DLT evaluation (according to the new study design). Furthermore, based on HA feedback and local regulations, the HA notification and recruitment restart process has been clarified.

[0467] • "Clinical Outcome Assessment (COA)" has been removed. Section 8.5 Further exploratory evaluations will be conducted because, in the new design, there will no longer be a dedicated extension section with a single recommended dose for expansion. Instead, a backfill section will be used to understand the initial benefit-risk assessment of different doses. This type of clinical outcome assessment will be implemented in future development steps at the planning level.

[0468] title:

[0469] Evaluate[ 177 A phase Ib dose-finding study of the safety and activity of Lu]Lu-NeoB in combination with ribociclib and fulvestrant in participants with ER+, HER2- and GRPR+ advanced breast cancer who had relapsed early from (neo)adjuvant endocrine therapy or progressed while receiving endocrine therapy in combination with a CDK4 / 6 inhibitor.

[0470] Purpose:

[0471] In order to estimate [ 177The recommended dose (RD) of Lu]Lu-NeoB 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 experienced early relapse from (neo)adjuvant endocrine therapy or progressed while receiving endocrine therapy for advanced disease in combination with a CDK4 / 6 inhibitor.

[0472] Experimental Design:

[0473] This study was conducted in adult female and male participants with ER+ / HER2-, GRPR+ advanced breast cancer who experienced early relapse from (neo)adjuvant endocrine therapy or progressed while receiving endocrine therapy for advanced disease in combination with a CDK4 / 6 inhibitor. 177 A Phase Ib, single-arm, multicenter, open-label, dose-exploration study of Lu]Lu-NeoB in combination with ribociclib and fulvestrant (+ / - goserelin). The study includes a dose-escalation phase and a concurrent backfilling phase. The backfilling phase will allow enrollment at previously cleared dose levels (during the escalation phase) to obtain additional safety and tolerability data.

[0474] The study comprises a dose escalation phase and a parallel backfill phase. The backfill phase will allow enrollment at previously cleared dose levels (during the escalation phase) to obtain additional safety, tolerability, and preliminary efficacy data. The following four provisional dose levels are planned to be tested in cohorts of 3 to 6 participants: 100 mCi (initial dose), 150 mCi, 200 mCi, and 250 mCi. After each cohort of 3 to 6 participants is enrolled, the incidence of DLT will be compared to a predefined toxicity rate boundary to determine whether the next cohort will receive a lower, higher, or the same dose, or whether the trial will be terminated. During the backfill phase, the cumulative incidence of DLT will also be compared to a predefined toxicity rate boundary to determine whether escalation should restart from a lower dose level.

[0475] During the screening period, study participants will receive a study imaging agent. 68 Ga]Ga-NeoB. [ 68 The additional application of Ga-NeoB will be in the last application. 177 The study will be conducted within 4–8 weeks after Lu-NeoB treatment for positron emission tomography (PET) / computed tomography (CT) or PET / magnetic resonance imaging (MRI). The study treatment will include day 1 (+≤ day 3) of each 28-day cycle. 177Lu]Lu-NeoB was administered for 6 cycles, along with ribociclib (once daily; days 1 to 21 of a 28-day cycle) and fulvestrant (C1D1, C1D15, C2D1, and every 28 days thereafter) until disease progression. Premenopausal and perimenopausal participants received goserelin additionally on day 1 of each cycle.

[0476] During the treatment period, participants will be required to attend a field visit approximately every 28 days, on the first day of each cycle (and on C1D2, C1D3, C1D8, C1D15, C2D15, C3D3, and C5D3) for study treatment administration, dosing, and safety assessment. Tumor assessment will be conducted every 8 weeks until month 18, every 12 weeks until month 36, and thereafter as clinically indicated until disease progression. After study treatment is discontinued, participants will be followed for 8 weeks following the last administration of study treatment. Following the initial 8-week safety follow-up, all participants will be followed every 12 weeks until month 36, and then every 24 weeks until month 60, for a total of 5 years from enrollment, or until death, loss to follow-up, or withdrawal of consent (WoC), whichever occurs first.

[0477] Study completion is defined as the date of the last visit, planned procedure, or follow-up of the last participant in the global 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 earlier.

[0478] Treatment phase

[0479] The study comprises a dose escalation phase and a parallel backfill phase. The backfill phase will allow enrollment at previously cleared dose levels (during the escalation phase) to obtain additional safety, tolerability, and preliminary efficacy data. The following four provisional dose levels are planned to be tested in cohorts of 3 to 6 participants: 100 mCi (initial dose), 150 mCi, 200 mCi, and 250 mCi. After each cohort of 3 to 6 participants is enrolled, the incidence of DLT will be compared to a predefined toxicity rate boundary to determine whether the next cohort will receive a lower, higher, or the same dose, or whether the trial will be terminated. During the backfill phase, the cumulative incidence of DLT will also be compared to a predefined toxicity rate boundary to determine whether escalation should restart from a lower dose level.

[0480] During the screening period, study participants will receive a study imaging agent. 68 Ga]Ga-NeoB. [ 68 The additional application of Ga-NeoB will be in the last application. 177The study will be conducted within 4–8 weeks after Lu-NeoB treatment for positron emission tomography (PET) / computed tomography (CT) or PET / magnetic resonance imaging (MRI). The study treatment will include day 1 (+≤ day 3) of each 28-day cycle. 177 Lu]Lu-NeoB was administered for 6 cycles, along with ribociclib (once daily; days 1 to 21 of a 28-day cycle) and fulvestrant (C1D1, C1D15, C2D1, and every 28 days thereafter) until disease progression. Premenopausal and perimenopausal participants received goserelin additionally on day 1 of each cycle.

[0481] During the treatment period, participants will be required to attend a field visit approximately every 28 days, on the first day of each cycle (and on C1D2, C1D3, C1D8, C1D15, C2D15, C3D3, and C5D3) for study treatment administration, dosing, and safety assessments. Tumor assessments will be conducted every 8 weeks until month 18, every 12 weeks until month 36, and thereafter as clinically indicated until disease progression. Following discontinuation of study treatment, participants will be followed for 8 weeks following the last administration of study treatment. After the initial 8-week safety follow-up, all participants will be followed every 12 weeks until month 36, and then every 24 weeks until month 60 (based on clinical indications). Section 1.3 The SoA (So-A) period is defined as a total of 5 years from the date the participant is enrolled in the study, or until death, loss to follow-up, or withdrawal of consent (WoC), whichever occurs first.

[0482] Study completion is defined as the date of the last visit, planned procedure, or follow-up of the last participant in the global study (or the date of death, WoC, or loss to follow-up, whichever occurs first). Section 1.3 The SoA is indicated by either the date of enrollment of the last participant or five years from the date of enrollment of the last participant, whichever occurs earlier.

[0483] Number of participants

[0484] Up to approximately 48 participants are expected to receive treatment at four dose levels. A cohort of 3 to 6 evaluable participants will be enrolled in the dose escalation phase. Additional participants will be backfilled at each dose level, up to approximately 12 participants in total (including those enrolled during the escalation phase at that dose level).

[0485] Key inclusion criteria

[0486] • The informed consent was given by an adult female or male aged 18 or older.

[0487] • Breast cancer that is histologically and / or cytologically confirmed by local laboratory testing (based on recently analyzed tissue samples) as estrogen receptor-positive with an ER > 10% (excluding progesterone receptor (PgR) expression).

[0488] • HER2-negative breast cancer is defined as a negative in situ hybridization test or an immunohistochemical (IHC) status of 0, 1+, or 2+. If the IHC is 2+, a negative in situ hybridization test (e.g., fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), or silver in situ hybridization (SISH)) performed by a local laboratory (based on the most recently analyzed tissue sample) is required.

[0489] Participants had advanced (localized recurrence, unsuitable for curative therapies (e.g., surgery and / or radiation therapy), or metastatic breast cancer.

[0490] Participants can:

[0491] a. Relapse (documented evidence of relapse) during or within 12 months of receiving (neo)adjuvant endocrine therapy (+ / - CDK4 / 6 inhibitor) without receiving treatment for advanced disease, or

[0492] b. Relapse more than 12 months after completion of (neo)adjuvant endocrine therapy (documented evidence of relapse), followed by progression after a subsequent line of endocrine therapy (other than fulvestrant) (+ / - CDK4 / 6 inhibitor) for advanced disease (documented evidence of progression), or

[0493] c. Advanced breast cancer at diagnosis, which progressed after a line of endocrine therapy (other than fulvestrant) (+ / - CDK4 / 6 inhibitor) (documented evidence of progression).

[0494] Note: Participants who relapsed (documented evidence of relapse) during or within 12 months of receiving (neo)adjuvant endocrine therapy, and then progressed (documented evidence of progression) after a subsequent line of endocrine therapy for advanced disease (with anti-estrogens or aromatase inhibitors), will not be included in the study. Based on a visual rating scale, participants must have at least one target lesion (i.e., a measurable lesion according to RECIST 1.1) on baseline independent CT or MRI, which shows a score of 2 or higher on PET / CT or PET / MRI. 68 Ga]Ga-NeoB uptake (see Section 8.5.2).

[0495] • Sufficient bone marrow and organ function.

[0496] • There are standard 12-lead ECG values, defined as the average of three ECGs, and evaluated locally:

[0497] • The QT interval (QTcF) corrected for Fridricia formula was < 450 msec during screening.

[0498] • Average resting heart rate is 50-90 bpm (determined from ECG).

[0499] • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

[0500] Key Exclusion Criteria

[0501] • Previous treatment with more than one line of therapy in advanced / metastatic cases. Participants should not have previously received fulvestrant treatment.

[0502] • In adjunctive situations or for use in advanced disease, there is documented prior evidence of dose reduction for ribociclib for safety reasons.

[0503] • In adjuvant or for advanced disease, relapse or disease progression within 6 months of receiving CDK4 / 6 inhibitor therapy. Subject to investigator's best judgment, symptomatic visceral disease, or any disease burden that disqualifies the participant from receiving ribocinic acid plus endocrine therapy.

[0504] • Central nervous system (CNS) involvement is present unless the following two criteria are met: 1) At least 4 weeks have passed between the completion of previous therapy (including radiation and / or surgery) and the start of study treatment. 2) The CNS tumor is clinically stable at the time of screening and the patient has not received steroids and / or enzyme-induced antiepileptic drugs for brain metastases.

[0505] • Currently receiving warfarin or other clomiphene-derived anticoagulants for treatment, prophylaxis, or other purposes. Treatment with heparin, low molecular weight heparin, or fondaparin is permitted.

[0506] • Diagnosed with inflammatory breast cancer during screening.

[0507] •Child Pugh's score is B or C

[0508] • A history of impaired cardiac function, clinically significant heart disease, or ECG abnormalities that indicate a significant safety risk to the participant, or a current diagnosis of impaired cardiac function, clinically significant heart disease, or ECG abnormalities.

[0509] • Known or anticipated hypersensitivity to any investigational drug or any of its excipients.

[0510] • Previous administration of radioactive drugs, unless during injection [ 68 Ga]Ga-NeoB or [ 177 Lu-NeoB has already passed 10 or more half-lives.

[0511] • Participants had received extended-field RT ≤ 4 weeks or limited-field RT ≤ 2 weeks prior to starting treatment and had not recovered from grade 1 or better from side effects associated with this therapy (other than hair loss or other toxicities not considered a safety risk to the participant in the investigator's judgment) and / or from previous external beam radiation therapy (EBRT) affecting more than 25% of the bone marrow.

[0512] • Participants are currently receiving or have received systemic corticosteroids within ≤ 2 weeks prior to starting the study treatment, or participants have not yet fully recovered from side effects of such treatment. Note: The following corticosteroids are permitted: single-dose topical application (e.g., for a rash), inhaled spray (e.g., for obstructive airway disease), eye drops, or local injections (e.g., intra-articular injections).

[0513] • Participants have a history of acute pancreatitis or have had persistent acute pancreatitis within 1 year of screening.

[0514] • Participants are currently receiving any of the following substances and cannot discontinue them 7 days prior to starting the study treatment:

[0515] • Accompanying drugs, herbal supplements, and / or fruits (e.g., grapefruit, pomelo, star fruit, lime) and their juices that are strong inducers or inhibitors of cytochrome P450 (CYP) 3A4.

[0516] • Drugs with a narrow therapeutic window and primarily metabolized by CYP3A4 / 5

[0517] • One or more concomitant medications that have a known risk of prolonging the QT interval and / or are known to cause torsion of the tip (TdP) and cannot be discontinued or replaced by a safe alternative (e.g., within 5 half-lives or 7 days prior to the start of study treatment).

[0518] • The participant is currently receiving a NEP inhibitor (e.g., Entresto®, racecadotril) and images of this participant for dose determination assessment are unavailable.

[0519] Backfill section

[0520] Once a dose level is declared safe during the dose escalation phase, additional participants will be allowed to backfill to the previously cleared dose level (during the dose escalation phase) to obtain additional data. Participants enrolled in the backfill phase will also be evaluated for dose-limiting toxicities. Any new DLTs observed in backfill participants at a given dose level will trigger a review of the cumulative DLT rate for the dose level under consideration relative to the boundary defined by BOIN. If BOIN recommends dose reduction or maintaining the dose level, participating investigators and sponsors will meet and agree on the next dose to be tested. The recommended dose (RD) will be determined considering all available data from both the escalation and backfill phases. Only one escalation cohort and one backfill cohort can be open for recruitment in parallel. Participant allocation in the escalation or backfill cohort will be based on the following principles and decision tree ( Figure 3 (This serves as a guide.)

[0521] • Incremental queues will always be given priority.

[0522] • If more than one dose level is declared safe (during the escalation phase), backfilling to the lowest dose level for open enrollment will be permitted until that dose level has reached the maximum required number of participants. Afterward, backfilling to the next safe dose level will be permitted.

[0523] For the decision tree regarding participant allocation in the incremental queue or backfill section, see [link to relevant documentation]. picture 3.

[0524] Example 3: Principles of the Research

[0525] Non-clinical biodistribution and DMPK

[0526] In non-clinical models, [68Ga]Ga-NeoB and [177Lu]Lu-NeoB have shown high affinity for GRPR overexpressed in breast tumors, prostate tumors, GISTs, and gliomas (including glioblastoma) (Flores et al. 2010, Morgat et al. 2017).

[0527] The ability of radiolabeled peptides to target tumors expressing GRPR has been demonstrated in in vivo imaging and biodistribution studies in healthy mice and tumor models. [177Lu]Lu-NeoB is rapidly cleared from the bloodstream and eliminated quickly via the renal system without retention in the kidneys. Indeed, at 4 hours post-injection, uptake remained relatively high only in GRPR-expressing tissues (primarily the pancreas), however, it decreased over time, consistent with the GRPR antagonist spectrum. In contrast, tumor residue was persistent, with uptake values ​​detectable up to 7 days post-injection. These characteristics make [177Lu]-Lu NeoB an ideal candidate for PRRT. For more information, refer to the [177Lu]Lu-NeoB Investigator's Brochure (IB).

[0528] [177Lu]Lu-NeoB primarily induces cell damage through the formation of free radicals in GRPR-positive tumors and adjacent cells.

[0529] Based on the results of in vitro drug-drug interaction (DDI) studies, [177Lu]Lu-NeoB is not considered to have the potential for CYP or transporter-mediated DDI.

[0530] Preclinical cardiac safety studies in vivo indicated that the electrophysiological risks of [177Lu]Lu-NeoB were negligible. No significant effects on cardiac electrophysiological function or hemodynamics were observed, as measured by telemetry at 55–85 times margin of the administered peptide dose of NeoB at doses of 200–300 µg in awake miniature pigs. Since [177Lu]Lu-NeoB also appears to be metabolized, maternal concentrations are expected to be even lower. Furthermore, [177Lu]Lu-NeoB exhibits very low radiation uptake in the heart. Therefore, the overall cardiac risk can be considered very low.

[0531] toxicology

[0532] Non-clinical studies were conducted using a non-radioactive alternative, [175Lu]Lu-NeoB formulation, and these studies support the safety of NeoB peptide administration in patients. No adverse effects were observed in the safety pharmacology studies. Similarly, no signs of toxicity were reported after acute or repeated administration of [175Lu]Lu-NeoB, confirming the safety of the non-radioactive molecule.

[0533] [177Lu] Clinical experience with Lu-NeoB

[0534] NeoRay (EUDRACT No. 2018-004727-37) is an ongoing Phase I / IIa, open-label, multicenter study to evaluate the safety, tolerability, systemic distribution, radiation dosimetry, and antitumor activity of [177Lu]Lu-NeoB in patients with advanced solid tumors known to overexpress GRPR.

[0535] As of October 11, 2022, [177Lu]Lu-NeoB had been administered to 11 patients. Patients included in the first cohort received a first dose (cycle 1) of 1.85 GBq (50 mCi) of [177Lu]Lu-NeoB. Based on clinical dosimetry from cycle 1, the intra-patient dose was escalated to 150 mCi of [177Lu]Lu-NeoB from cycle 2 onwards.

[0536] Dose level 1 (50 mCi in cycle 1 and 150 mCi in subsequent cycles) has been evaluated in 3 patients with breast cancer, prostate cancer, and GIST cancer. Two patients received 2 cycles and one patient received 6 cycles. Overall, treatment was well tolerated, and no DLT or SAE was reported.

[0537] Dose level 2 evaluated 300 mCi per cycle and enrolled 4 patients: 2 with prostate cancer and 2 with GIST. Two patients received 1 cycle, 1 received 2 cycles, and 1 received 3 cycles. Two of the 4 enrolled patients experienced DLT (both had grade 3 anemia and one had grade 3 encephalopathy). All of these events were resolved. One of the grade 3 anemia events occurred in a prostate cancer patient who had extensive bone metastases and persistent grade 2 anemia at screening (for which the subject also received a red blood cell transfusion before starting treatment); the patient developed grade 3 anemia on day 36 post-infusion, followed by grade 4 thrombocytopenia, while in disease progression (PD); the patient discontinued treatment, and with supportive care, the anemia temporarily improved to grade 2, but died with grade 4 thrombocytopenia due to PD. Two other DLTs (grade 3 anemia and grade 3 encephalopathy) in patients affected by GIST were documented, occurring within one week of administration of the first treatment dose. The patient presented with extensive pelvic bone metastases and grade 1 anemia at baseline. Left-sided facial paralysis and altered mental status were noted, accompanied by grade 2 vomiting and grade 3 hyponatremia; brain MRI ruled out stroke and brain metastases. Three days later, the patient also developed seizures. The patient was being treated with a very high dose of diazepam, which was interrupted a few days after the [177Lu]Lu-NeoB infusion, raising suspicion that withdrawal syndrome was a confounding factor. No other significant toxicities were reported.

[0538] DLT was observed at dose level 2, and the dose was reduced to 250 mCi (dose level 3) according to the protocol. Dose level 3 was evaluated in 4 patients (2 affected by GIST, 1 affected by prostate cancer, and 1 affected by glioblastoma). The glioblastoma patient received 3 cycles of [177Lu]Lu-NeoB, and one of the GIST patients received 2 cycles. Both patients discontinued treatment due to disease progression, while the other 2 patients (GIST and prostate cancer) have each received 2 cycles and treatment is ongoing. Overall, treatment was well tolerated, with most reported AEs being mild / moderate, and no DLT or SAEs were reported.

[0539] At the assessed dose levels, two prolonged periods of disease stability were observed: approximately one year for GIST patients and approximately five months for prostate cancer patients.

[0540] Of the 11 patients treated in the study, three completed treatment, two discontinued treatment due to adverse events (AEs), three discontinued treatment due to progressive diseases (PDs), one decided to stop treatment, and two are currently receiving treatment.

[0541] Preliminary blood radioactive PK of [177Lu]Lu-NeoB from NeoRay showed rapid elimination from systemic circulation, with a geometrical 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 revealed metabolism in systemic circulation and urine (likely pharmacologically inactive metabolites that cannot bind to receptors), but cumulative excretion of activity suggests that radioactivity is still primarily (mean ≥ 80%) excreted via the kidneys over 24–48 hours. The enzymes involved in the metabolism of [177Lu]Lu-NeoB are currently unknown.

[0542] Preliminary dosimetry results demonstrated favorable biodistribution and low uptake in organs considered at risk due to GRPR expression (such as the pancreas) or RLT (such as red bone marrow) and excretion pathways (such as the kidneys). The dose-normalized mean absorbed dose (rounded to two significant figures) (±SD, n = 10) at all study dose levels in Gy / GBq 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).

[0543] Given the safety and biodistribution profile at 250 mCi, the NeoRay study protocol decided to increase the limit back to 300 mCi.

[0544] As of June 7, 2023, in the CAAA603A12101 study, 17 patients received [treatment / treatment] at 5 cohorts and 3 dose levels. 177 Lu]Lu-NeoB treatment.

[0545] Table 1. Patients enrolled in the cohort of study CAAA603A12101

[0546]

[0547] Subsequently, based on the overall favorable safety profile at dose level 3, the dose was escalated back to 300 mCi according to protocol. Considering that some patients treated at 300 mCi experienced DLT, the dose was reduced to 250 mCi (DL 3) in cohort 5 according to protocol.

[0548] In cohort 5, as of June 7, 2023, five (5) patients received a 250 mCi dose (dose level 3). 177 Lu]Lu-NeoB. None of these 5 patients experienced any DLT or SAE. Most reported AEs were mild or moderate in severity. Laboratory abnormalities ≥ grade 2 were not clinically significant.

[0549] The generated Phase I dose measurement data showed favorable […]. 177 The Lu]Lu-NeoB organ dosimetry spectrum offers a greater safety margin even at high cumulative activity compared to the EBRT threshold. Therefore, based on comprehensive data including dosimetry at the test dose level, observed safety (including DLT data), and tolerability data, Novartis and the participating investigators announce an RP2D of 250 mCi. This dose will be further tested in the Phase IIa portion of the study.

[0550] about[ 68 Ga]Ga-NeoB Background

[0551] [68Ga]Ga-NeoB will be used in this study; it is used for PET and is intended as a tool of choice for [177Lu]Lu-NeoB treatment in patients with tumors that overexpress GRPR, including MBC patients. [68Ga]Ga-NeoB has demonstrated advantageous technical and diagnostic performance in both preclinical and clinical studies for identifying GRPR-expressing malignancies, with good image quality that allows for easy interpretation. Its diagnostic performance has been evaluated in the following two completed clinical trials:

[0552] • MITIGATE (EudraCT No. 2016-002053-38) was a Phase I / IIa clinical trial evaluating the safety, biodistribution, dosimetry, and preliminary diagnostic performance of [68Ga]Ga-NeoB in subjects with advanced tyrosine kinase inhibitor pretreatment for GIST. [68Ga]Ga-NeoB was well tolerated in all nine participants with a favorable safety profile (radioactive doses ranging from 127 to 214 MBq). Radiation exposure was low due to rapid renal and blood clearance. Biodistribution showed high uptake of [68Ga]Ga-NeoB in the pancreas, followed by the kidneys and liver. Rapid, visually moderate to high tumor-specific uptake was identified in lesions expressing GRPR.

[0553] • NeoFIND (EudraCT No. 2017-0003432-37) (as mentioned in Section 2.2.3), a phase II clinical trial evaluating the preliminary diagnostic performance of [68Ga]Ga-NeoB 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). The safety profile of [68Ga]Ga-NeoB was confirmed in this study. Results showed variable uptake of [68Ga]Ga-NeoB in tumor lesions, with the highest number of lesions exhibiting visually intermediate to high uptake in breast cancer patients.

[0554] • [68Ga]Ga-NeoB is currently being used in the ongoing Phase I / IIa NeoRay study (EudraCT number 2018-004727-37) as an imaging agent for patients selected for treatment with [177Lu]Lu-NeoB. As of October 11, 2022, 41 patients have received [68Ga]Ga-NeoB, and no safety issues related to [68Ga]Ga-NeoB have been reported, with doses ranging from 150 to 250 MBq administered.

[0555] Background information about Rebocini

[0556] Ribociclib is an orally bioavailable and 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.

[0557] Following oral administration, the time to reach maximum plasma concentration (Tmax) is 1 to 4 hours, with 70% binding to human plasma proteins in vitro. Elimination of ribociclib is primarily driven by oxidative metabolism via CYP3A4, with a minimal contribution from flavin-containing monooxygenase 3. Co-administration of drugs that inhibit or induce CYP3A4 may affect ribociclib elimination (KISQALI® US Prescribing Information).

[0558] Ribociclib is indicated for the treatment of adult patients with HR+ / HER2- advanced / metastatic breast cancer at a daily oral dose of 600 mg (according to US prescribing information), in combination with the following:

[0559] • AI, as an initial endocrine-based therapy; or

[0560] • Fulvestrant, as an initial endocrine-based therapy or after disease progression during ET treatment, in postmenopausal women or men.

[0561] The combination of ribociclib and ET (letrozole or fulvestrant) has been investigated in postmenopausal women with HR+ / HER2- advanced / metastatic breast cancer in two randomized studies (Monaleesa-2 and Monaleesa-3, respectively), and the combination has consistently shown a significant survival benefit compared with the matched placebo group.

[0562] In Monaleesa-2, the combination of ribociclib and letrozole showed a median overall survival (OS) of 63.9 months at a median follow-up of 79.7 months, compared to 51.4 months in the matched placebo group (HR, 0.76; 95% CI, 0.63–0.93; P = .004). The estimated 6-year OS rate for ribociclib + letrozole was 44.2%, compared to 32.0% for letrozole alone (Hortobagyi et al. 2022).

[0563] In Monaleesa-3, the combination of ribociclib and fulvestrant showed a median overall survival (OS) of 67.6 months at a median follow-up of 70.8 months, compared to 51.8 months in the matched placebo group (HR 0.67; 95% CI, 0.50–0.90). In the case of first-line transfer, the 5-year OS of ribociclib + fulvestrant was 56.5 months, compared to 42.1 months for fulvestrant alone (Neven et al. 2022).

[0564] The combination of ribociclib with ET (the LHRH analog goserelin and NSAI or tamoxifen) was also investigated in another phase 3 randomized study (Monaleesa-7) that enrolled only premenopausal / perimenopausal women with HR+ / HER2- advanced / metastatic breast cancer, and at 42 months, the combination also showed a significantly longer overall survival (OS) than ET alone (70.2% vs. 46%) (Im et al. 2019).

[0565] Based on the above results, regardless of endocrine partner, line of therapy, and menopausal status, ribociclib remains the only CDK4 / 6i therapy in the three phase 3 trials to demonstrate statistically significant OS benefit.

[0566] Clinical safety of ribociclib

[0567] In the Monaleesa-3 study, the most common adverse events (reported at a frequency of ≥20%) in the combination group (ribociclib + fulvestrant) were neutropenia, infection, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. Most adverse events (AEs) were mild to moderate in severity. The most common grade 3 / 4 adverse events (reported at a frequency of ≥5%) were neutropenia, leukopenia, infection, and abnormal liver function tests (LFT). Neutropenia was generally uncomplicated, and torsion of the tip (TdP) was not observed. AE-related treatment discontinuation was rare, further supporting the manageable safety profile of ribociclib-based combinations. The adverse events (AEs) that led to discontinuation of fulvestrant plus ribociclib (compared to fulvestrant plus placebo) were elevated alanine aminotransferase (ALT) (5% vs. 0%), elevated AST (3% vs. 0.6%), and vomiting (1% vs. 0%) (KISQALI® US Prescribing Information).

[0568] For additional information regarding ribociclib and the management of ribociclib-related adverse events, please refer to your local prescribing information.

[0569] Background information on fulvestrant

[0570] Fulvestrant is an ER downregulator without known agonist activity (Addo et al. 2002). It binds to, blocks, and degrades ER, completely inhibiting ER signaling. As a result, ER is less likely to be activated by alternative pathways believed to cause resistance (e.g., growth factor-mediated mechanisms) (Nicholson et al. 2007).

[0571] Following intramuscular administration of 500 mg (long-acting formulation), fulvestrant is slowly absorbed. Exposure is approximately dose-proportional within the dose range of 50 to 500 mg after intramuscular administration. Maximum plasma concentrations are reached after approximately 5 days. If an additional dose is administered 2 weeks after the initial dose, steady state is reached within the first month of administration. At steady state, there is a difference of more than 2-fold between the mean Cmax and Cmin. Fulvestrant is widely and rapidly distributed and is primarily eliminated through metabolism. The main route of excretion is via feces, with less than 1% excreted in urine. It has a high clearance rate, indicating that it is a drug with a high extraction rate. The terminal half-life after intramuscular administration is determined by the rate of absorption and is estimated to be 40–50 days. Increased fulvestrant exposure has been observed in patients with moderate hepatic impairment (Child-Pugh Class B). It has not been administered to patients with severe hepatic impairment (Child-Pugh Class C) (FASLODEX® Prescribing Information). Therefore, patients with Child-Pugh class B and C will not be enrolled in this study.

[0572] Based on data from the CONFIRM study, fulvestrant is the first endocrine agent of its kind approved for the treatment of postmenopausal women with HR+ advanced / metastatic breast cancer who have failed prior anti-estrogenic therapy (Di Leo et al. 2010, Di Leo et al. 2014). Further randomized studies (Mehta et al. 2012, Ellis et al. 2015) have demonstrated the superiority of fulvestrant as a first-line therapy (compared to or in combination with anastrozole). The combination of fulvestrant and CDK4 / 6i is a recommended treatment for subjects who have relapsed during adjuvant ET or within 12 months of discontinuing adjuvant therapy (Gennari et al. 2021).

[0573] Clinical safety of fulvestrant

[0574] Fulvestrant has a manageable safety profile; the most common clinically significant adverse reactions occurring in ≥ 5% of patients as monotherapy are as follows: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, limb pain, hot flashes, vomiting, anorexia, weakness, musculoskeletal pain, cough, dyspnea, and constipation. Elevated liver enzymes (ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP)) occurred in > 15% of patients treated with fulvestrant, and this was not dose-dependent.

[0575] In subjects with bleeding tendencies, thrombocytopenia, or those using anticoagulants, fulvestrant should be used with caution (FASLODEX® prescribing information).

[0576] Background information about Gosherelin

[0577] Goserelin will be used in combination with [177Lu]Lu-NeoB, ribociclib, and fulvestrant in an extended portion of the study in premenopausal / perimenopausal women only.

[0578] Goserelin is a synthetic decapeptide analog of gonadotropin-releasing hormone (GnRH) and is indicated for prostate cancer, endometriosis, thinning of the endometrium, 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), the Tmax (total gestational age) is 12–15 days after administration, and 8–22 days after administration in women. Goserelin is not CYP-mediated; rather, it is metabolized via the hydrolysis of C-terminal amino acids. Over 90% of the radiolabeled dose is excreted in the urine, with approximately 20% of the dose remaining unchanged in the urine (Zoladex® US Prescribing Information).

[0579] Clinical safety of goserelin

[0580] In the treatment of HR+ / HER2- premenopausal / perimenopause patients, goserelin has been associated with different types of ET and has shown a manageable and well-tolerated safety profile (Jakesz 2006, Kim et al. 2018).

[0581] In the Paloma-3 study, goserelin was used in combination with palbociclib and fulvestrant to treat premenopausal / perimenopausal women, and the safety profile of the triple combination was not different from that of the palbociclib and fulvestrant combination (Turner et al. 2018). In the Monaleesa-7 study, goserelin was also used in combination with ribociclib and tamoxifen or an AI without showing any new safety signals (Im et al. 2019).

[0582] Advanced adverse events (AEs) occurring in >20% of women treated with goserelin for breast cancer, dysfunctional uterine bleeding, and endometriosis include hot flashes, headaches, sweating, acne, mood swings, depression, decreased libido, vaginitis, breast atrophy, seborrhea, and peripheral edema (according to US Prescribing Information).

[0583] For further information regarding goserelin and the management of goserelin-related adverse events, please refer to your local prescribing information.

[0584] filter

[0585] Informed consent forms (ICF) for research must be signed and dated before any research-specific screening procedure is performed, except for evaluations conducted as part of standard care.

[0586] During the 42-day screening period, participant eligibility will be determined according to predefined inclusion and exclusion criteria. All screening assessments should be conducted according to the SoA (Social Application). Each participant will receive administration of [68Ga]Ga-NeoB during the screening period to confirm eligibility for treatment with [177Lu]Lu-NeoB. All participants will be called 3 (+ / - 1) days after administration of [68Ga]Ga-NeoB for safety follow-up.

[0587] Participants who meet all eligibility criteria during the screening process can be enrolled in the study.

[0588] Treatment period

[0589] 1 - Dosage escalation portion

[0590] like Figure 1 The dose escalation portion will estimate the RD (reactive protein) of the combination of [177Lu]Lu-NeoB with ribociclib and fulvestrant. The BOIN method (Yuan et al. 2015, Yuan et al. 2016) will be used to determine the dose escalation or de-escalation requirements. After each cohort with 3 to 6 participants, the incidence of DLT will be compared to a predefined toxicity rate boundary to determine whether the next cohort will receive a lower, higher, or the same dose, or whether the trial will be terminated.

[0591] The initial dose of [177Lu]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 a 7-day break) and fulvestrant (500 mg on day 1 of the 28-day cycle plus an additional single dose administered on day 15 of cycle 1). Provisional dose levels have been established within the protocol to guide dose selection. Based on risk-benefit considerations, and if participants tolerate treatment and demonstrate benefit, [177Lu]Lu-NeoB may continue until completion of 6 cycles (or more than 10 cycles, at the investigator's discretion), subject to agreement with the sponsor. Participants will continue treatment with ribociclib and fulvestrant until disease progression (according to RECIST 1.1, as assessed by the investigator) or until study treatment is discontinued for any other reason, such as unacceptable toxicity, worsening symptoms, WoC, loss to follow-up, investigator's decision, or death, whichever occurs first. Then, where applicable, participants will enter a post-treatment follow-up period regardless of the reason for treatment discontinuation.

[0592] At the end of the DLT reporting period for the last participant in each dose cohort, the investigator and sponsor will make a dose escalation / decrease decision, guided by the DLT rate, biodistribution (dosimetry) data of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant from evaluable participants, all AEs of CTCAE > 2 reported during the DLT reporting period, and cumulative safety data (which may include other dose levels) collected from previously treated participants.

[0593] 2 - Dosage Extension Section

[0594] like Figure 2 The dose extension portion will evaluate in postmenopausal participants a combination of RD-controlled [177Lu]Lu-NeoB (every 28 days, for 6 cycles) (as determined in the dose escalation portion) with ribociclib (600 mg daily for 21 consecutive days, followed by a 7-day treatment break) and fulvestrant (500 mg on day 1 of the 28-day cycle plus an additional single dose administered on day 15 of cycle 1). Premenopausal / perimenopausal participants will be included in the extension portion and will receive goserelin (3.6 mg on day 1 of the 28-day cycle) in addition to the treatments mentioned above. Based on risk-benefit, and if participants tolerate the treatment and demonstrate benefit, [177Lu]Lu-NeoB may continue until 6 cycles are completed (or up to 10 cycles, as determined by the investigator), subject to agreement with the sponsor. Participants will continue study treatment with ribociclib, fulvestrant, and goserelin (premenopausal / perimenopause women only) until disease progression (according to RECIST 1.1, as assessed by the investigator) or until study treatment is discontinued for any other reason, such as unacceptable toxicity, worsening symptoms, Worsening of the disease (WoC), loss to follow-up, investigator's decision, or death, whichever occurs first. Participants will then, where applicable, enter a post-treatment follow-up period regardless of the reason for treatment discontinuation.

[0595] A total of 15 participants will be enrolled in the extended portion to further evaluate the safety, tolerability, and antitumor activity of [177Lu]Lu-NeoB in RD. Approximately one-third of the cohort will include premenopausal / perimenopause participants.

[0596] Scientific Principles of Research Design

[0597] This is a phase Ib, single-arm, dose-exploratory study of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant (and goserelin, in the extended section for premenopausal / perimenopausal women) in adult female participants with HR+ / HER2-, GRPR+ advanced / metastatic breast cancer that relapsed during or within 12 months after (neo)adjuvant ET.

[0598] Patients with early recurrence from adjuvant therapy represent a poorer prognostic subset of patients requiring better treatment. Given that recommended treatments for HR+ / HER2- advanced / metastatic breast cancer are generally similar in premenopausal and postmenopausal women (Azim and Partridge 2014, Gennari et al. 2021, NCCN Guideline Breast Cancer Version 4 [NCCN Breast Cancer Guideline 4th Edition]. 2022), this study will enroll both premenopausal and postmenopausal participants, except for the addition of LHRH to premenopausal / perimenopause women in the extended phase mentioned above (Rugo et al. 2016, Bardia and Hurvitz 2018). Although no difference in the expected safety profile is expected, due to the lack of data on this treatment combination, the study will begin with a more conservative approach, investigating three treatments ([177Lu]Lu-NeoB, ribociclib, fulvestrant) in postmenopausal women in the escalating phase, and then adding goserelin to premenopausal / perimenopause women in the extended phase.

[0599] Evidence of high GRPR expression in breast cancer, the possibility of using [68Ga]Ga-NeoB as an imaging agent to select patients at a specific GRPR threshold, and the synergistic effect of ribociclib with RLT make the addition of [177Lu]Lu-NeoB a potentially effective therapy aimed at improving the prognosis of this patient population.

[0600] The study included a dose escalation portion, followed by a dose extension portion.

[0601] The BOIN design was used to evaluate four provisional dose levels in the dose escalation phase. The BOIN design was chosen because it does not require a fixed cohort size and allows decisions to be made at any time during the trial by comparing the observed DLT rate at the current dose with the escalation and deceleration boundaries. Another feature of the BOIN design is the determination of the sample size to achieve the ideal probability of correctly estimating the RD (Yuan et al. 2016). Furthermore, given the relatively small number of dose levels to be tested, the BOIN design is more suitable than more complex model-based designs.

[0602] An extension was added to further characterize the safety, tolerability, and preliminary antitumor activity of RD's [177Lu]Lu-NeoB. This does not preclude the need for further dose optimization in future studies.

[0603] Justification of dosage

[0604] The principle of dose selection and administration frequency of [177Lu]Lu-NeoB

[0605] The starting dose for the dose escalation portion will be 100 mCi (3.7 GBq) of [177Lu]Lu-NeoB every 28 days.

[0606] Based on data from the NeoRay study (as of June 15, 2022), [177Lu]Lu-NeoB administered every 42 days at an initial dose of 50 mCi (cycle 1) + 150 mCi (from cycle 2 onwards) was well tolerated as monotherapy, with no DLT or grade 3 / 4 adverse events experienced in this cohort. Low absorbed radiation doses in key organs (kidneys, pancreas, red bone marrow, testes, ovaries) suggest a low risk of radiation-related toxicity from a single administration.

[0607] A safety review of hematological parameters over time following [177Lu]Lu-NeoB administration showed no trend toward decreasing or worsening of hematological parameters. Based on data generated to date, a 28-day timetable for [177Lu]Lu-NeoB administration has been proposed, and the dose will be gradually evaluated as part of a dose exploration protocol. Furthermore, a 4-week timetable will be used to adapt to the 4-week cycles of ribociclib and fulvestrant, and to allow for concurrent administration with the other two therapies.

[0608] Based on the above information, and given that [177Lu]Lu-NeoB will be combined with ribociclib and fulvestrant and the administration frequency will be reduced to 28 days (from the 42-day cycle as a single agent in NeoRay), the study will begin with a dose of 100 mCi.

[0609] In this study, [177Lu]Lu-NeoB was administered six times every four weeks. Based on available dose determination data from three study dose levels (150 mCi, 250 mCi, and 300 mCi) in the FIH study, the mean cumulative absorbed dose in the kidneys, pancreas, red bone marrow, testes, and ovaries was significantly below the EBRT threshold. The margin for 11.1 GBq (300 mCi) [177Lu]Lu-NeoB (the highest studied radiation dose to date) over 6 cycles is approximately 9–10 times for the pancreas (40 Gy EBRT threshold; Stewart et al. 2012), approximately 1.6 times for red bone marrow (2 Gy EBRT threshold; Howard et al. 2017), 1.3–2 times for the testes and ovaries (1 Gy and 3 Gy EBRT thresholds; Chambers et al. 1991, De Felice et al. 2019), and 3 times for the kidneys (23 Gy EBRT threshold; Emami et al. 1991, Stewart et al. 2012).

[0610] However, these limitations on the application of EBRT in RLT may be overly conservative due to the inherent differences between external beam radiotherapy and radionuclide therapy. These include different dose rates and fractionation schemes, non-uniform absorbed dose distribution, and potentially different radiobiological mechanisms leading to cytotoxicity with varying biological effects (Wessels et al. 2008, Bergsma et al. 2016a, Bergsma et al. 2016b). Indeed, mounting evidence suggests that in the case of Lu-177-labeled RLT, a bioeffective dose (BED) of approximately 40 Gy is safe for the kidneys, with a conversion factor of 1.09 for the absorbed dose to the BED of 177Lu-based RLT (Bodei et al. 2008, Schäfer et al. 2022). Therefore, even beyond 6 cycles, radiation-induced toxicity issues are likely to be minimal, as organs may be able to tolerate higher radiation doses.

[0611] Based on the above evidence, there is leeway in administering more than 6 cycles. Therefore, based on the individual benefit-risk assessment, in this study, up to 4 additional administrations may be considered in addition to the planned 6 administrations of [177Lu]Lu-NeoB.

[0612] In order to perform each of the four additional administrations of [177Lu]Lu-NeoB, the researchers should determine:

[0613] • Whether the participant showed evidence of disease stability or response (i.e., underwent radiological or clinical evaluation).

[0614] • Did the participants not show any signs or symptoms of clinical deterioration?

[0615] • Whether participants have shown good tolerability to [177Lu]Lu-NeoB treatment, and whether there are any documented [177Lu]Lu-NeoB-related SAEs that were not resolved before the next NeoB dose and led to treatment interruption.

[0616] If a participant meets all of the above criteria and agrees to continue further treatment with [177Lu]Lu-NeoB, the investigator may administer up to four additional doses of [177Lu]Lu-NeoB (i.e., a maximum of 10 doses in total) upon agreement with the sponsor.

[0617] The principle of ribociclib dosage selection

[0618] Ribociclib will be administered at the recommended starting dose of 600 mg po (three 200 mg tablets), with or without food, once daily for 21 consecutive days, followed by a 7-day break. Dose interruption, reduction, and / or discontinuation may be necessary based on individual safety and tolerability.

[0619] The principle of fulvestrant dosage selection

[0620] On days 1, 15, and 29, fulvestrant will be administered intramuscularly at the approved dose of 500 mg, slowly (1-2 minutes per injection) into the buttock (gluteal region), in two 5 mL injections, once per buttock, thereafter monthly. For patients with moderate hepatic impairment, a dose of 250 mg is recommended on days 1, 15, and 29, administered intramuscularly at a dose of 5 mL, slowly (1-2 minutes per injection) into the buttock (gluteal region), thereafter monthly.

[0621] The principle of dose selection for goserelin (only applicable to premenopausal / perimenopausal women in the extended portion)

[0622] Goserelin will be administered subcutaneously at the approved dose of 3.6 mg on day 1 of the 28-day cycle.

[0623] Research on treatment

[0624] In this study, the term "investigation drug" refers to the radioligand imaging compound [68Ga]Ga-NeoB, used for participant selection during screening and for PET imaging following the final dose of [177Lu]Lu-NeoB to assess treatment-induced changes in PET scan patterns; and refers to [177Lu]Lu-NeoB for RLT. The term "investigation treatment" refers to the combination of [177Lu]Lu-NeoB, ribociclib, and fulvestrant (+ / - goserelin, if applicable, only in the extended section).

[0625] In the dose escalation and dose extension phases of the study, participants will receive [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant. Goserelin administration is only permitted for premenopausal / perimenopausal participants in the dose extension phase.

[0626] Kits for the preparation of [177Lu]Lu-NeoB and radiopharmaceuticals for [68Ga]Ga-NeoB will be centrally supplied by Novartis AG. Ribociclib, fulvestrant, and goserelin will be supplied locally by research centers, by Novartis AG subsidiaries or commissioned agencies, if commercially available, or centrally by Novartis AG in each participating country in accordance with local practices and regulations.

[0627] All doses prescribed and administered to participants during the study, and all dose changes, must be recorded on the dose administration record (eCRF).

[0628] The accompanying Pharmacy Manual outlines the requirements for the storage, administration, and administration of the investigational treatment, as well as details on participant numbering, prescription, and dispensing instructions.

[0629] Study drug and control drug

[0630]

[0631] 1 For use only in premenopausal and perimenopausal women in the extended portion.

[0632] [ 68 Ga]Ga-NeoB

[0633] In this study, after radiolabeling with Ga-68, [ 68 Ga]Ga-NeoB is used as a radioactive imaging compound for PET to localize GRPR-positive lesions.

[0634] [ 68 Ga]Ga-NeoB will be administered in a single intravenous dose, with activity in the range of 150-250 MBq (4.1-6.8 mCi).

[0635] [ 177 Lu]Lu-NeoB

[0636] Study participants will receive a dose of 3.7 GBq (100 mCi) + / - 10% of [ 177 Lu]Lu-NeoB will be applied once every 28 days (1 cycle) for 6 cycles.

[0637] Dosage and treatment regimen (incremental portion)

[0638]

[0639] Dosage and treatment regimen (extended section)

[0640]

[0641] The dose escalation will be administered on day 1 of every 28 days (+ ≤ day 3) with an initial dose of 100 mCi. 177 Lu]Lu-NeoB begins with 6 cycles, in combination with ribociclib (600 mg daily for 21 consecutive days, followed by a 7-day break) and fulvestrant (500 mg on day 1 of a 28-day cycle). During cycle 1, a single additional dose of fulvestrant will be administered on day 15 (C1D15).

[0642] Each evaluated dose level [ 177The first infusion of Lu]Lu-NeoB will be followed by the DLT period, defined as a total of 28 days / 4 weeks.

[0643] The dose extension will evaluate the RD dose in postmenopausal, premenopausal / perimenopause participants. 177 Lu]Lu-NeoB (on day 1 of every 28 days (+ ≤ 3 days), for 6 cycles) (as determined in the dose escalation section) in combination with ribociclib (600 mg daily for 21 consecutive days, followed by a 7-day treatment break) and fulvestrant (500 mg on day 1 of every 28-day cycle and a single additional dose of fulvestrant on day 15 (C1D15). Premenopausal / perimenopausal participants will also receive goserelin (3.6 mg) on ​​day 1 of every 28-day cycle.

[0644] On the same day, preferably in [ 177 Lu]Lu-NeoB was administered prior to the administration of ribociclib, fulvestrant, and goserelin (where applicable).

[0645] Qualification screening

[0646] Informed consent must be obtained before any study-specific procedures are performed, except for assessments conducted as part of standard care. All screening assessments will be completed within 42 days prior to study enrollment after the study ICF is signed.

[0647] During the screening period, imaging with [68Ga]Ga-NeoB should be performed as soon as possible to avoid delaying participant enrollment. All participants who received [68Ga]Ga-NeoB will be followed up for safety before leaving the imaging unit at screening, and a dedicated call will be made 3 + / - 1 day after administration to assess for the occurrence of adverse events (AEs).

[0648] Only participants who meet all eligibility criteria at screening will be enrolled in the study. The screening period must be shortened as much as possible. Participant enrollment and ordering of [177Lu]Lu-NeoB must be carried out immediately after all eligibility criteria have been verified and participants have been confirmed to be eligible, and at least 14 days before the planned administration of [177Lu]Lu-NeoB.

[0649] Once participants for screening have been identified, they will be registered in the IRT system. After registration in IRT for screening, participant eligibility will be checked once all screening procedures are completed. Eligibility checks are embedded within the IRT system. Please refer to and follow the detailed guidelines in the IRT manual.

[0650] [ 68 Ga-NeoB Imaging

[0651] [68Ga]Ga-NeoB PET scan as an inclusion standard

[0652] [68Ga]Ga-NeoB PET / CT or PET / MRI must be acquired 120 ± 30 minutes after intravenous injection of 4.1–6.8 mCi (150–250 MBq) of radiotracer, scanning from the top of the head to the proximal mid-thigh (including the trunk and head), with arms raised if possible.

[0653] PET / CT or PET / MRI will be read locally. According to the table below, a visual scale must be used to grade the [68Ga]Ga-NeoB uptake in the tumor lesion during PET / CT or PET / MRI.

[0654] [68Ga]Ga-NeoB Visual Intake Rating Scale

[0655]

[0656] Eligible participants must have at least one target lesion detected on baseline independent CT or MRI (according to RECIST 1.1 criteria). Participants in the ascending fraction must have a [68Ga]Ga-NeoB uptake score of 1 or higher on PET / CT or PET / MRI, and participants in the extended fraction must have a score of 2 or higher. The required score is based on the purpose of [68Ga]Ga-NeoB uptake in each fraction of the study: in the ascending fraction, low uptake (score 1) is acceptable for lesion identification; however, in the extended fraction, higher uptake (score 2) is required for enriched clusters and thus for the initial conception of efficacy.

[0657] [68Ga]Ga-NeoB PET scan following the final dose of [177Lu]Lu-NeoB.

[0658] For participants in the extended cohort, [68Ga]Ga-NeoB PET / CT or PET / MRI will be performed two weeks and eight weeks after the administration of the final dose of [177Lu]Lu-NeoB. The injected [68Ga]Ga-NeoB radiation dose and the acquisition characteristics of this PET scan should be the same as those used in the baseline PET / CT or PET / MRI.

[0659] This PET scan will assess changes in the number of target lesions (visual evaluation) and semi-quantitative parameters [SUVmax, SUV mean, and TBR] compared to baseline PET / CT or PET / MRI.

[0660] TBR is defined as the ratio between the maximum SUV of a tumor lesion and the average SUV of healthy tissue (Rogasch et al. 2015). For TBR calculation, background activity is considered to be the uptake of [68Ga]Ga-NeoB within a spherical target volume (VOI) of approximately 3 cm in diameter (Wahl et al. 2009). In each PET scan, two TBR values ​​are retrieved: one with spleen as background activity and the other with liver as background activity.

Claims

1. A method of treating breast cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with a CDK4 / 6 inhibitor such as ribociclib and an endocrine therapy such as fulvestrant, wherein the radiopharmaceutical compound is a compound having formula (I) or a pharmaceutically acceptable salt thereof: CSP (I) in: C is the chelate portion. S is an optional spacer that covalently connects C and P. P is the GRP receptor antagonist moiety. Furthermore, the radiopharmaceutical compound is labeled with the radionuclide M.

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

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

4. The method of any one of claims 1-3, wherein 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.

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

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

7. The method of claim 5 or 6, wherein a therapeutically effective amount of the selective ER degrader is administered, for example, every 14 to 56 days, such as 28 days, starting from the same day as the administration of the radiopharmaceutical compound, and the administration continues for at least the same duration as the administration of the radiopharmaceutical, and optionally the administration of the ER degrader continues until disease progression.

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

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

10. The method of any one of claims 1-9, wherein M is selected from... 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 Sc.

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

12. The method of any one of claims 1-11, wherein C is obtained by linking to S or P, and C is a chelating agent selected from: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Titan), drytan, 1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), aminotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra ... Heterocyclic dodecane-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-diazacycloheptatriene (AAZTA, e.g., AAZTA5).

13. The method of claim 12, wherein C has the following formula: 。 14. The method according to any one of claims 1-13, wherein P has the following general formula: DPhe-Gln-Trp-Ala-Val-Gly-His-Z Z is selected from Leu-ψ(CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2 Or Z is Where X is NH (amide) and R2 is (CH2-CH(CH3)2, and R1 is the same as R2 or (CH2N)-Pro-NH2.

15. The method of claim 14, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2.

16. The method according to any one of claims 1-15, wherein the compound having formula (I) is a compound having formula (II). (II) Wherein C and P are as defined in any one of claims 1 and 12-15, and wherein the chelated portion C is complexed with the radionuclide M.

17. The method of any one of claims 1-16, wherein the radiopharmaceutical compound is M-NeoB having the following formula (III): (III), Or its pharmaceutically acceptable salt. Where M is a radioactive nuclide, for example, M is 177 Lu.

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

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

20. The method of any one of claims 1-19, wherein the radiopharmaceutical compound is administered in doses ranging from 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), from 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), from 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), from 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 claims 1-20, wherein the CDK4 / 6 inhibitor, such as ribociclib, is administered orally at a daily dose of 400 to 800 mg, for example 600 mg, in cycles of 15 to 28 days, each cycle comprising, for example, 21 days of daily administration followed by a 7-day treatment break, and administration continues for at least as long as the administration of the radiopharmaceutical, and optionally, administration of the CDK4 / 6 inhibitor continues until disease progression.

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

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

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

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

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

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

28. The method of any one of claims 1-27, wherein the subject has been selected from subjects who have experienced early relapse after neoadjuvant or adjuvant prior endocrine therapy.

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

30. The method of claim 29, wherein the prior CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, palbociclib, and abeciclib, for example, ribociclib.

31. The method of any one of claims 25-30, wherein the prior 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.

32. The method of any one of claims 1-31, wherein the endocrine therapy further comprises, for example, subcutaneous administration of a synthetic analogue of gonadotropin-releasing hormone, such as goserelin, at a dose of about 3.6 mg every 28 days.

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

34. The method of claim 33, wherein the subject is selected from subjects whose PET / MRI scans of the tumor region prior to any surgery show enhancement of alternative radionuclides, such as gadolinium enhancement.

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, wherein the radiopharmaceutical compound is administered to the subject in combination with ribociclib and fulvestrant, wherein a first dose of the radiopharmaceutical compound is administered on the same day as a first dose of ribociclib.

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

37. The method of claim 35 or 36, wherein the radiopharmaceutical compound is M-NeoB having the following formula: Where M is 177-Lu.

38. The method of any one of claims 1-37, wherein the radiopharmaceutical compound is M-NeoB having the following formula: Wherein M is 177-Lu, and the radiopharmaceutical compound is administered via intravenous infusion at a concentration of 370 MBq / mL.

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