Methods for treating glioblastoma

Abstract

The present disclosure provides a method of treating glioblastoma in a subject in need thereof, comprising administering a therapeutically effective amount of a GRPR antagonist moiety, preferably 177 [0013] The present invention relates to a method for treating a rheumatoid arthritis (RA) comprising administering to said subject a radiopharmaceutical compound having the formula [0014] Lu-NeoB in combination with radiation therapy and, optionally, a therapeutically effective amount of an alkylating agent, preferably temozolomide.

Description

[Technical Field]

[0001] The present invention relates to a method for treating glioblastoma in a subject in need thereof, comprising administering a therapeutically effective amount of a radiopharmaceutical compound comprising a GRPR antagonist moiety, e.g., 177 Lu]Lu-NeoB is administered to the subject in combination with radiation therapy and optionally other adjuvant therapies. [Background technology]

[0002] Glioblastoma (GBM) is the most common aggressive type of primary brain tumor and is associated with a high mortality rate despite extensive efforts to develop new treatment options.

[0003] The overall age-adjusted incidence rate of glioblastoma in the United States is 3.22 cases / 100,000, with the highest incidence occurring between the ages of 75 and 79 years. It is higher in men and increases with age at diagnosis. Glioblastoma contributes disproportionately to morbidity and mortality, with a 5-year overall relative survival rate of only 6.8%, which varies by age at diagnosis and gender (Wen et al. 2020, Neuro Oncol;22(8):1073-1113).

[0004] Survival rates for patients diagnosed with glioblastoma remain low, with a median overall survival of approximately 15-18 months. Glioblastoma has one of the lowest long-term survival rates of any malignant brain tumor (Ostrom QT, Cioffi G, Gittleman H, et al (2019) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016. Neuro Oncol;12(S5):1-10). Once glioblastoma recurs, median overall survival (OS) is estimated to range from 3.5 to 6 months (Wen PY, Weller M, Lee EQ, et al (2020) Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol;22(8):1073-113).

[0005] The current standard of care (SoC) for newly diagnosed glioblastoma involves the combination of the alkylating agent temozolomide with radiotherapy, approved and established since 2005 based on the results of a large, randomized phase III trial comparing radiotherapy with concurrent daily temozolomide followed by temozolomide maintenance alone. Results showed statistically significant improvements in both progression-free survival (PFS) and overall survival (OS), with a median PFS of 6.9 months in the radiotherapy plus temozolomide arm versus 5 months in the radiotherapy arm (P<0.001), and a median OS of 14.6 months versus 12.1 months, respectively (P<0.001) (Stupp et al. 2005, N Engl J Med;352(10):987-96).

[0006] Several trials have been conducted to improve the standard treatment regimen of using radiation therapy with temozolomide. A phase 3 trial of the VEGF inhibitor bevacizumab in newly diagnosed glioblastoma demonstrated an improvement in PFS, but there was no corresponding improvement in OS, and on this basis, bevacizumab was not approved for the treatment of patients with newly diagnosed glioblastoma (Iwamoto et al 2009, Neurology;73(15):1200-6).

[0007] Trials incorporating immunotherapy into standard of care regimens are being conducted in the newly diagnosed setting. Phase 3 clinical trials using the PD-1 inhibitor nivolumab (NIVO) failed to demonstrate an improvement in overall survival in patients with newly diagnosed glioblastoma with an unmethylated MGMT promoter status in combination with radiotherapy (CheckMate-498) (Omuro et al. 2022, Radiotherapy Combined With Nivolumab or Temozolomide for Newly Diagnosed Glioblastoma With Unmethylated MGMT Promoter: An International Randomized Phase 3 Trial. Neuro Oncol), and in patients with a methylated MGMT promoter status in combination with standard of care radiotherapy and temozolomide (vs. SoC) (CheckMate-548) (Lim et al. 2022, Phase 3 Trial of Chemoradiotherapy With Temozolomide Plus Nivolumab or Placebo for Newly Diagnosed Glioblastoma With Methylated MGMT Promoter. Neuro Oncol). CheckMate-498 showed that median OS (mOS) was 13.4 months for patients treated with NIVO plus RT and 14.9 months for patients in the temozolomide plus RT arm (HR, 1.31; P = .0037). Patients with methylated MGMT promoter status included in CheckMate-548 showed mOS of 28.9 months in the NIVO plus radiotherapy plus temozolomide arm versus 32.1 months in the placebo plus RT plus temozolomide arm (HR, 1.1).

[0008] The use of alternating current electric fields (TTF, tumor treating fields) as an adjunct to temozolomide maintenance therapy in newly diagnosed glioblastoma has been approved in the United States and several EU countries based on the results of a phase 3 trial that significantly extended median OS and PFS. Median overall survival was 20.9 months in the TTF-temozolomide group versus 16.0 months in the temozolomide-alone group (HR, 0.63; P < .001) (Stupp et al., JAMA, 2017;318(23):2306-2316). Despite the positive phase 3 results, the use of TTF remains controversial, and TTF is not widely used in Europe (Lassman et al., 2020, Current usage of tumor treating fields for glioblastoma. Neurooncol Adv;2(1):vdaa069).

[0009] Current guidelines continue to recommend treatment of newly diagnosed glioblastoma with RT and concomitant temozolomide followed by maintenance temozolomide (Nabors et al. 2020, J Natl Compr Canc Netw;18(11):1537-1570; Weller et al. 2021, Nat Rev Clin Oncol;18(3):170-186).

[0010] Therefore, there remains a need to provide improved clinical treatments for glioblastoma.

[0011] Gastrin-releasing peptide (GRP) is a mammalian bombesin-like peptide that regulates many biological responses, primarily in the central and enteric nervous systems (Flores et al. 2010, Brain Res Bull;82(1-2):95-8). GRP acts through specific membrane G-protein coupled receptors (GRPRs) that are overexpressed by various cancers, including gliomas / glioblastomas (Flores et al. 2010, Brain Res Bull;82(1-2):95-8).

[0012] The NeoB peptide is a new generation bombesin analogue that binds to GRPR with high affinity (half-maximal inhibitory concentration (IC50) of 1-2 nM, Nock et al. J. Nucl. Med. 2017;58(1):75-80) and exhibits low internalization, consistent with the peptide's antagonist behavior. The NeoB peptide contains a DOTA metal chelator within its structure, allowing radiolabeling with different radionuclides, including gallium-68 (for PET imaging), lutetium-177 (for radionuclide therapy), and other related radionuclides, enabling the theranostic use of NeoB without affecting receptor affinity, internalization properties, or biodistribution. In preclinical models, [ 68 Ga]Ga-NeoB and [ 177 Lu]-Lu NeoB exhibits high affinity for GRPR, which is overexpressed in breast, prostate, gastrointestinal stromal tumors (GIST), and gliomas (glioblastomas) (Flores et al. 2010, supra; Morgat et al. J. Nucl. Med. 2017;58(9):1401-1407), and low internalization upon binding to specific receptors.

[0013] The ability of radiolabeled compounds to target GRPR-expressing tumors has been confirmed in in vivo imaging and biodistribution studies in tumor models. 177[Lu]Lu-NeoB is rapidly cleared from the blood, rapidly eliminated through the renal system, and not retained in the kidney. Consistent with a GRPR antagonist profile, background radioactivity is observed in GRPR-expressing tissues (mostly the pancreas) but decreases over time. In contrast, tumor retention is persistent, with detectable uptake levels up to 7 days after injection. (Kaloudi A, Lymperis E, Giarika A, Dalm S, Orlandi F, Barbato D, Tedesco M, Maina T, de Jong M, Nock BA. NeoBOMB1, a GRPR-Antagonist for Breast Cancer Theragnostics: First Results of a Preclinical Study with [ 67 Ga]NeoBOMB1 in T-47D Cells and Tumor-Bearing Mice.Molecules.2017 Nov 11;22(11):1950.doi:10.3390 / molecules22111950.PMID:29137110;PMCID:PMC6150197). Summary of the Invention

[0014] The present disclosure provides a method for treating glioblastoma in a subject in need thereof by administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with radiation therapy, and optionally temozolomide, wherein the radiopharmaceutical compound has Formula (I): CSP(I) (In the formula, C is a chelating moiety; P is a GRP receptor antagonist moiety; S is an optional spacer that covalently links C and P or a pharmaceutically acceptable salt thereof, and labeled with a radionuclide M.

[0015] The present disclosure is provided in various aspects, as outlined below: 1. A method of treating glioblastoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with radiation therapy, wherein the radiopharmaceutical compound has Formula (I): CSP(I) (In the formula, C is a chelating moiety; P is a GRP receptor antagonist moiety; S is an optional spacer that covalently links C and P or a pharmaceutically acceptable salt thereof, and is labeled with a radionuclide M. 2. The method of embodiment 1, further comprising administering a therapeutically effective amount of an alkylating agent. 3. The method of embodiment 2, wherein said alkylating agent is temozolomide. 4. The alkylating agent, preferably temozolomide, is administered at a dose of 50-100 mg / m daily during the induction period, concurrently with radiation therapy. 2 / day, preferably about 75 mg / m 2 4. The method of embodiment 2 or 3, wherein the dose is administered at a dose of 100 mg / day for a period typically of 4 to 8 weeks, preferably 6 weeks. 5. The alkylating agent, preferably temozolomide, is administered at a dose of 50 to 400 mg / m daily during the maintenance phase following the induction phase after radiation therapy. 2 / day, preferably 75-300 mg / m 2 / day, more preferably 150-200 mg / m 2 5. The method of embodiment 4, wherein the medicament is administered at a dose of 100 mg / day for 5 consecutive days followed by 2 days of rest every 28 days for a period of 20 to 28 weeks, preferably 24 weeks. 6. The method of any one of embodiments 2-5, wherein both the radiation therapy and the alkylating agent, preferably temozolomide, are initiated on the same day, e.g., 7-10 days after the first administration of the radiopharmaceutical compound. 7. The method of any one of embodiments 2-6, wherein said alkylating agent, preferably temozolomide, is administered concomitantly with radiation therapy without interruption during the induction phase. 8. The method of any one of embodiments 2-7, wherein said alkylating agent, preferably temozolomide, is administered daily at the initial dose, for example, for a period of 6 consecutive weeks, during co-administration with radiation therapy. 9. The radionuclide M is 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 9. The method of any one of embodiments 1-8, wherein Sc is selected from: 10. M, 177 10. The method of embodiment 9, wherein Lu is 11.C is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1,4,7,10-tetraazacyclododecane, 1(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramine (T 11. The method of any one of embodiments 1-10, wherein the compound is obtained by grafting onto S or P a chelating agent selected from 1,4,7-triazacyclononane-1,4,7-triacetic acid (ETA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), NOTAGA, 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane (NODAGA), NODASA, NODAPA, and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA, e.g., AAZTA5). 12.C is the following formula [ka] 12. The method of embodiment 11, wherein 13.P is a compound of the general formula DPhe-Gln-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-ψ(CHN)-Pro-NH and NH—CH(CH—CH(CH)) or or Z is [ka] where X is NH (amide), R2 is (CH2-CH(CH3)2, and R1 is the same as R2 or (CH2N)-Pro-NH2). 13. The method of any one of embodiments 1 to 12, wherein 14. The method of embodiment 13, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2. 15. The compound of formula (I) is represented by the following formula (II): [ka] wherein C and P are as defined in claim 1 and any one of claims 11 to 14, and the chelating moiety C is complexed with a radionuclide M. 15. The method of any one of embodiments 1-14, wherein the compound is 16. The radiopharmaceutical compound is represented by the following formula (III): [ka] wherein M is a radionuclide, preferably M is 177 Lu) or a pharmaceutically acceptable salt thereof. 17. The method of any one of embodiments 1-16, wherein said radiopharmaceutical compound is administered 1-10 times per treatment, preferably 4-10 times per treatment, more preferably 6-8 times per treatment. 18. The method of embodiment 17, wherein said treatment with the radiopharmaceutical compound comprises an administration interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 weeks or 4 weeks, more preferably every 4 weeks. 19. The method of any one of embodiments 1-18, wherein said radiopharmaceutical compound is administered to the subject in multiple treatments, preferably 2-3 treatments, with a rest of 2-12 months between treatments. 20. The method of any one of embodiments 1-19, wherein said radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), preferably 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), preferably 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), more preferably 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), even more preferably 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) per administration. 21. The method of any one of embodiments 1-20, wherein said radiation therapy comprises irradiating said subject with a total dose of 40-80 Gy, for example 60 Gy. 22. The method of any one of embodiments 1-21, wherein said radiation therapy is administered at a dose of 1 Gy to 4 Gy / day, preferably about 2 Gy / day, for a period of 3 to 7 days per week, preferably about 5 days per week, over a period of 4 to 8 weeks, preferably 6 weeks. 23. The method of any one of embodiments 1-22, wherein said radiation therapy is initiated 7-10 days after the first administration of said radiopharmaceutical compound. 24. The method of any one of embodiments 1-23, wherein said subject is newly diagnosed with glioblastoma. 25. The method of any one of embodiments 1-24, wherein the subject is selected from subjects with a positive methylated O-6-methylguanine-DNA methyltransferase promoter status. 26. The method of any one of embodiments 1-25, wherein said radiation therapy is whole brain radiation therapy. 27. The method of any one of embodiments 1-26, wherein said subject is treated with the same radiopharmaceutical compound as defined for treatment, but prior to any surgery, for example 2 weeks prior to the start of said treatment, an alternative radionuclide or contrast agent suitable for imaging, preferably 68-gallium, 67-gallium or 64-copper, more preferably 68-gallium, is selected by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging, based on detection of said radionuclide in an imaging scan in the tumor area. 28. The method of embodiment 27, wherein the subject is selected from subjects who show the presence of alternative radionuclide or contrast agent enhancement, such as gadolinium enhancement, in any pre-operative PET / MRI scan in the tumor region. 29. The method of any one of embodiments 1-28, wherein the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and wherein the radiopharmaceutical compound is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide, and the first dose of the radiopharmaceutical compound is preferably administered 7-10 days before the start of radiation therapy. 30. The method of any one of embodiments 1-28, wherein the subject is newly diagnosed with glioblastoma and has a negative methylated O-6-methylguanine-DNA methyltransferase promoter status, and wherein the radiopharmaceutical compound is administered to the subject at least six times in combination with radiation therapy, and further in combination with temozolomide, wherein the administration interval between two administrations of the radiopharmaceutical compound is four weeks, and the first administration of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy and temozolomide. 31. The radiopharmaceutical compound has the following formula: [ka] (Wherein M is 177 31. The method of embodiment 29 or 30, wherein M-NeoB is M-NeoB of formula (I). 32. The radiopharmaceutical compound has the following formula: [ka] (Wherein M is 177 Lu) and is administered by intravenous infusion at a concentration of 370 MBq / mL. 33. A radiopharmaceutical compound for use in a method for treating glioblastoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with radiation therapy, the radiopharmaceutical compound comprising a compound of formula (I): CSP(I) (In the formula, C is a chelating moiety; P is a GRP receptor antagonist moiety; S is an optional spacer that covalently links C and P or a pharmaceutically acceptable salt thereof, which is labeled with a radionuclide M. 34. The radiopharmaceutical compound for use in embodiment 33, wherein said method further comprises administering a therapeutically effective amount of an alkylating agent. 35. The radiopharmaceutical compound for use according to embodiment 34, wherein said alkylating agent is temozolomide. 36. The alkylating agent, preferably temozolomide, is administered at a dose of 50 to 100 mg / m daily during the induction period. 2 / day, preferably about 75 mg / m 2 36. The radiopharmaceutical compound for use according to embodiment 34 or 35, wherein the radiopharmaceutical compound is administered at a dose of 0.1 mg / day for a period of typically 4 to 8 weeks, preferably 6 weeks. 37. The alkylating agent, preferably temozolomide, After radiation therapy , 50–400 mg / m daily during the maintenance phase following the induction phase 2 / day, preferably 75-300 mg / m 2 / day, more preferably 150-200 mg / m 237. The radiopharmaceutical compound for use according to embodiment 36, wherein the radiopharmaceutical compound is administered at a dose of 100 mg / day for 5 consecutive days followed by 2 days rest every 28 days for a period of 20 to 28 weeks, preferably 24 weeks. 38. The radiopharmaceutical compound for use according to any one of embodiments 34 to 37, wherein both the radiotherapy and the alkylating agent, preferably temozolomide, are started on the same day, e.g., 7 to 10 days after the first administration of the radiopharmaceutical compound. 39. The radiopharmaceutical compound for use according to any one of embodiments 34 to 38, wherein said alkylating agent, preferably temozolomide, is administered simultaneously with radiation therapy, without interruption, during the induction phase. 40. The radiopharmaceutical compound for use according to any one of embodiments 34 to 39, wherein said alkylating agent, preferably temozolomide, is administered initially, for example daily for a period of 6 consecutive weeks, during co-administration with radiation therapy. 41. The radionuclide M is 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, 199Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 The radiopharmaceutical compound for use according to any one of embodiments 33 to 40, wherein the radiopharmaceutical compound is selected from Sc. 42. M, 177 The radiopharmaceutical compound for use according to embodiment 41, wherein the compound is Lu. 43.C is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1,4,7,10-tetraazacyclododecane, 1(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramine (TETA), 1,4,7-triazacyclono 43. The radiopharmaceutical compound for use according to any one of embodiments 33 to 42, obtained by grafting onto S or P a chelator selected from nan-1,4,7-triacetic acid (NOTA), NOTAGA, 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane (NODAGA), NODASA, NODAPA, and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA, e.g., AAZTA5). 44.C is a compound of the formula: [ka] 44. The radiopharmaceutical compound for use according to embodiment 43, wherein 45.P is a compound of the general formula DPhe-Gln-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-ψ(CHN)-Pro-NH and NH—CH(CH—CH(CH)) or or Z is [ka] where X is NH (amide), R2 is (CH2-CH(CH3)2, and R1 is the same as R2 or (CH2N)-Pro-NH2). The radiopharmaceutical compound for use according to any one of embodiments 33 to 44, wherein 46. ​​The radiopharmaceutical compound for use in embodiment 45, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2). 47. The compound of formula (I) is the following compound of formula (II): [ka] wherein C and P are as defined in claim 1 and the chelating moiety C is complexed with a radionuclide M. The radiopharmaceutical compound for use according to any one of embodiments 33 to 46, wherein 48. A radiopharmaceutical compound having the following formula (III): [ka] wherein M is a radionuclide, preferably M is 177 Lu) 48. The radiopharmaceutical compound for use according to any one of embodiments 33 to 47, which is M-NeoB of the formula: 49. The radiopharmaceutical compound for use according to any one of embodiments 33 to 48, wherein said radiopharmaceutical compound is administered 1 to 10 times per treatment, preferably 4 to 10 times per treatment, more preferably 6 to 8 times per treatment. 50. The radiopharmaceutical compound for use of embodiment 49, wherein treatment with said radiopharmaceutical compound comprises an administration interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 weeks or 4 weeks, more preferably every 4 weeks. 51. The radiopharmaceutical compound for use according to any one of embodiments 33 to 50, wherein said radiopharmaceutical compound is administered to the subject in multiple treatments, preferably 2 to 3 treatments, with a break of 2 to 12 months between treatments. 52. The radiopharmaceutical compound for use according to any one of embodiments 33 to 51, wherein said radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), preferably 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), preferably 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), more preferably 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), even more preferably 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), per administration. 53. The radiopharmaceutical compound for use according to any one of embodiments 33 to 52, wherein said radiotherapy comprises irradiating said subject with a total dose of 40 to 80 Gy, such as 60 Gy. 54. The radiopharmaceutical compound for use according to any one of embodiments 33 to 53, wherein said radiotherapy is administered at a dose of 1 Gy to 4 Gy / day, preferably about 2 Gy / day, for a period of 3 to 7 days per week, preferably about 5 days, over a period of 4 to 8 weeks, preferably 6 weeks. 55. The radiopharmaceutical compound for use according to any one of embodiments 33 to 54, wherein said radiotherapy is initiated 7 to 10 days after the first administration of said radiopharmaceutical compound. 56. The radiopharmaceutical compound for use according to any one of embodiments 33 to 55, wherein said subject is newly diagnosed with glioblastoma. 57. The radiopharmaceutical compound for use according to any one of embodiments 33 to 56, wherein said subject is selected from subjects with a positive methylated O-6-methylguanine-DNA methyltransferase promoter status. 58. The radiopharmaceutical compound for use according to any one of embodiments 33 to 57, wherein said radiotherapy is whole brain irradiation. 59. The radiopharmaceutical compound for use according to any one of embodiments 33 to 58, wherein said subject is treated with the same radiopharmaceutical compound as defined for treatment, but prior to any surgery, for example 2 weeks before the start of said treatment, an alternative radionuclide or contrast agent suitable for imaging, preferably 68-gallium, 67-gallium or 64-copper, more preferably 68-gallium, is selected by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging, based on detection of said radionuclide in an imaging scan in the tumor area. 60. The radiopharmaceutical compound for use in embodiment 59, wherein said subject is selected from subjects who show the presence of alternative radionuclide or contrast agent enhancement, such as gadolinium enhancement, in any pre-operative PET / MRI scan in the tumor area. 61. The radiopharmaceutical compound for use according to any one of embodiments 33 to 60, wherein the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and wherein the radiopharmaceutical compound is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide, and the first administration of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy. 62. The radiopharmaceutical compound for use according to any one of embodiments 33 to 60, wherein the subject is newly diagnosed with glioblastoma and has a negative methylated O-6-methylguanine-DNA methyltransferase promoter status, and wherein the radiopharmaceutical compound is administered to the subject at least six times in combination with radiation therapy, and further in combination with temozolomide, wherein the administration interval between two administrations of the radiopharmaceutical compound is 4 weeks, and the first administration of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy and temozolomide. 63. The radiopharmaceutical compound has the following formula: [ka] (Wherein M is 17763. The radiopharmaceutical compound for use in embodiment 61 or 62, wherein M-NeoB is M-NeoB (wherein M-NeoB is M-NeoB). 64. The radiopharmaceutical compound has the following formula: [ka] (Wherein M is 177 63. The radiopharmaceutical compound for use in any one of embodiments 1-62, wherein the radiopharmaceutical compound is M-NeoB of formula (I) and is administered by intravenous infusion at a concentration of 370 MBq / mL. 65. A radiopharmaceutical compound of formula (I): in the manufacture of a medicament for use in a method for treating glioblastoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of said radiopharmaceutical compound in combination with radiation therapy. CSP(I) (In the formula, C is a chelating moiety; P is a GRP receptor antagonist moiety; S is an optional spacer that covalently links C and P or a pharmaceutically acceptable salt thereof, which is labeled with a radionuclide M. 66. The use of embodiment 65, wherein the method further comprises administering a therapeutically effective amount of an alkylating agent. 67. The use of embodiment 66, wherein said alkylating agent is temozolomide. 68. The alkylating agent, preferably temozolomide, is administered at a dose of 50 to 100 mg / m daily during the induction period. 2 / day, preferably about 75 mg / m 2 68. The use of embodiment 66 or 67, wherein the dose is administered at a dose of 100 mg / day for a period of typically 4 to 8 weeks, preferably 6 weeks. 69. The alkylating agent, preferably temozolomide, is administered at a dose of 50 to 400 mg / m daily during the maintenance phase following the induction phase. 2 / day, preferably 75-300 mg / m 2 / day, more preferably 150-200 mg / m 269. The use of embodiment 68, wherein the medicament is administered at a dose of 100 mg / day for 5 consecutive days followed by 2 days of rest every 28 days for a period of 20 to 28 weeks, preferably 24 weeks. 70. The use of any one of embodiments 66-69, wherein both radiotherapy and the alkylating agent, preferably temozolomide, are started on the same day, e.g., 7-10 days after the first administration of the radiopharmaceutical compound. 71. The use of any one of embodiments 66 to 70, wherein the alkylating agent, preferably temozolomide, is administered simultaneously with radiation therapy, without interruption, during the induction phase. 72. The use of any one of embodiments 66-71, wherein said alkylating agent, preferably temozolomide, is administered at the first dose, for example daily, for a period of 6 consecutive weeks during co-administration with radiation therapy. 73. The radionuclide M is 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, 151Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 The use of any one of embodiments 65 to 72, wherein Sc is selected from. 74. M, 177 Use of embodiment 73, wherein Lu is 75.C is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1,4,7,10-tetraazacyclododecane, 1(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramine (TETA), 1,4,7-triacetic acid (T ... The use of any one of embodiments 65 to 73, obtained by grafting onto S or P a chelating agent selected from azacyclononane-1,4,7-triacetic acid (NOTA), NOTAGA, 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane (NODAGA), NODASA, NODAPA, and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA, e.g., AAZTA5). 76.C is a compound of the formula [ka] Use of embodiment 75, wherein 77.P is a compound of the general formula DPhe-Gln-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-ψ(CHN)-Pro-NH and NH—CH(CH—CH(CH)) or Z is [ka] where X is NH (amide), R2 is (CH2-CH(CH3)2, and R1 is the same as R2 or (CH2N)-Pro-NH2). Use according to any one of embodiments 65 to 76, wherein 78. The use of embodiment 77, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2. 79. The compound of formula (I) is represented by the following formula (II): [ka] wherein C and P are as defined in any one of claims 65 and 75-78, and the chelating moiety C is complexed to a radionuclide M. The use of any one of embodiments 65 to 78, wherein the compound is 80. A radiopharmaceutical having the following formula (III): [ka] wherein M is a radionuclide, preferably M is 177 Lu) 80. The use of any one of embodiments 65 to 79, wherein the compound is M-NeoB of the formula: or a pharmaceutically acceptable salt thereof. 81. The use of any one of embodiments 65-80, wherein said radiopharmaceutical compound is administered 1-10 times per treatment, preferably 4-10 times per treatment, more preferably 6-8 times per treatment. 82. The use of embodiment 81, wherein the treatment with said radiopharmaceutical compound comprises an administration interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 weeks or 4 weeks, more preferably every 4 weeks. 83. The use of any one of embodiments 65-82, wherein the radiopharmaceutical compound is administered to the subject in multiple treatments, preferably 2-3 treatments, with a break of 2-12 months between treatments. 84. The use of any one of embodiments 65-83, wherein said radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), preferably 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), preferably 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), more preferably 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), even more preferably 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) per administration. 85. The use of any one of embodiments 65-84, wherein said radiation therapy comprises irradiating said subject with a total dose of 40-80 Gy, such as 60 Gy. 86. The use of any one of embodiments 65 to 85, wherein the radiation therapy is administered at a dose of 1 Gy to 4 Gy / day, preferably about 2 Gy / day, for a period of 4 to 8 weeks, preferably 6 weeks, for a period of 3 to 7 days per week, preferably about 5 days per week. 87. The use of any one of embodiments 65-86, wherein said radiotherapy is initiated 7-10 days after the first administration of said radiopharmaceutical compound. 88. The use of any one of embodiments 65-87, wherein the subject is newly diagnosed with glioblastoma. 89. The use of any one of embodiments 65 to 88, wherein the subject is selected from subjects with a positive methylated O-6-methylguanine-DNA methyltransferase promoter status. 90. The use of any one of embodiments 65 to 89, wherein said radiation therapy is whole brain irradiation. 91. The use of any one of embodiments 65 to 90, wherein the subject is treated with the same radiopharmaceutical compound as defined for treatment, but prior to any surgery, for example 2 weeks before the start of said treatment, an alternative radionuclide or contrast agent suitable for imaging, preferably 68-gallium, 67-gallium or 64-copper, more preferably 68-gallium, is selected by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging, based on detection of said radionuclide in an imaging scan in the tumor area. 92. The use of embodiment 91, wherein the subject is selected from subjects who show the presence of alternative radionuclide or contrast agent enhancement, such as gadolinium enhancement, in any pre-operative PET / MRI scan in the tumor area. 93. The use of any one of embodiments 65-92, wherein the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and wherein the radiopharmaceutical compound is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide, and the first dose of the radiopharmaceutical compound is preferably administered 7-10 days before the start of radiation therapy. 94. The use of any one of embodiments 65-92, wherein the subject is newly diagnosed with glioblastoma and has a negative methylated O-6-methylguanine-DNA methyltransferase promoter status, and wherein the radiopharmaceutical compound is administered to the subject at least six times in combination with radiation therapy, and further in combination with temozolomide, wherein the administration interval between two administrations of the radiopharmaceutical compound is 4 weeks, and the first administration of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy and temozolomide. 95. The radiopharmaceutical compound has the following formula: [ka] (Wherein M is 177 Use of embodiment 93 or 94, wherein M-NeoB is M-NeoB (wherein M-NeoB is M-NeoB). 96. The radiopharmaceutical compound has the following formula: [ka] (Wherein M is 177 95. The use of any one of embodiments 1-94, wherein the M-NeoB is M-NeoB of formula (I) and is administered by intravenous infusion at a concentration of 370 MBq / mL.

[0016] According to one aspect of the present disclosure, the combination of radiopharmaceutical radiation therapy, and optionally other treatments, such as alkylating agents, such as temozolomide, in the treatment methods of the present disclosure has been found to be at least additive, and preferably synergistic. [Brief explanation of the drawings]

[0017] [Figure 1] 1 represents the proposed treatment scheme for clinical trials. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present disclosure relates to methods for treating glioblastoma in a subject in need thereof by administering to said subject a therapeutically effective amount of a radiopharmaceutical compound in combination with radiation therapy and optionally an alkylating agent, preferably temozolomide.

[0019] general definition The use of the articles "a," "an," and "the" in both the description and the claims should be construed to encompass both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. "Comprising," "having," "being of," "including," and "containing" should be construed as open terms (i.e., meaning "including, but not limited to") unless otherwise noted. Additionally, whenever "comprising" or another open-ended term is used in an embodiment, it should be understood that the same embodiment could be more narrowly claimed using the intermediate term "consisting essentially of" or the closed term "consisting of."

[0020] The term "about" or "ca.," as used herein, means that the value that follows can vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, and even more preferably ±1%.

[0021] The terms "treating" or "treatment," as used herein, include treatment that alleviates, reduces, or relieves at least one symptom in a subject, or causes a delay in the progression of a disease. For example, treatment can be a decrease in one or several symptoms of a disorder, such as cancer, or a complete eradication of the disorder. Also, within the meaning of the present disclosure, the term "treat" refers to arresting, delaying the onset (i.e., the period before clinical manifestations of the disease), and / or reducing the risk of developing or worsening a disease. When used herein in connection with the disclosed combination therapies, the term "treatment" encompasses the administration of a radiopharmaceutical compound, optionally in combination with radiation therapy and / or an alkylating agent. Such treatment may include one or more administrations of a radiopharmaceutical compound over a determined period of time.

[0022] As used herein, "glioblastoma" refers to an aggressive brain tumor that belongs to the grade IV astrocytoma brain tumor category. The term glioblastoma also includes its variants, gliosarcoma, giant cell glioblastoma, and small cell glioblastoma. Because the size and shape of the cells in this tumor vary, i.e., they are pleomorphic, glioblastoma is also called glioblastoma multiforme (GBM).

[0023] As used herein, the term "radiopharmaceutical" or "radiopharmaceutical compound" refers to a pharmaceutical compound that is labeled with a radionuclide agent, typically a metallic one. Such radiopharmaceutical compounds have binding affinity for a specific marker on a target cell, such as a receptor or tumor antigen, and therefore comprise a targeting ligand (or target-binding moiety). Radiopharmaceutical compounds are useful as contrast agents in imaging techniques such as PET scans or MRI scans, or as therapeutic agents in nuclear medicine, also known as radioligand therapy (RLT) or PRRT (peptide receptor radionuclide therapy).

[0024] In accordance with the International System of Units, "MBq" is an abbreviation for the unit of radioactivity "megabecquerel."

[0025] As used herein, "PET" stands for positron emission tomography.

[0026] As used herein, "SPECT" stands for Single Photon Emission Computed Tomography.

[0027] As used herein, "MRI" stands for magnetic resonance imaging.

[0028] As used herein, "CT" stands for computed tomography.

[0029] The terms "tumor" and "cancer" are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating tumors. As used herein, the term "cancer" or "tumor" includes pre-malignant cancers and pre-malignant tumors, as well as malignant cancers and malignant tumors and benign cancers. The term "cancer," as used herein, includes primary malignant cells or tumors (e.g., where cells have not migrated to a site within a subject's body other than the site of the original malignant tumor or tumor) and secondary malignant cells or tumors (e.g., where they arise from metastasis, the migration of malignant cells or tumor cells to a secondary site different from the site of the original tumor).

[0030] As used herein, the phrase "therapeutically effective amount" of a compound refers to that amount of the compound that will induce a desired therapeutic response, e.g., ameliorate symptoms, reduce pathology, slow or delay disease progression, or prevent disease, in at least a subpopulation of subjects, at a reasonable benefit-risk ratio applicable to any medical treatment.

[0031] The terms "subject" or "patient," as used herein, are intended to include animals that can be directly or indirectly afflicted with or afflicted by cancer or any disorder, including cancer. Examples of subjects include mammals, such as humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the subject is a human, such as a human suffering from, at risk of suffering from, or potentially suffering from cancer.

[0032] "Combination therapy" refers to either a therapy involving the administration of a fixed combination in one dosage unit form, or a therapy in which the radiopharmaceutical compounds disclosed herein and a combination partner, e.g., another agent as described below, e.g., an alkylating agent, and / or radiation therapy, may be administered simultaneously or serarately, i.e., separately within a time interval, particularly when these time intervals allow the combination partner and / or combined radiation therapy to exhibit a cooperative, e.g., synergistic, effect with the radiopharmaceutical compound. The single components can be packaged in a kit or separately. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose before administration.

[0033] Also, "co-administration" or "administration in combination" or the like, as used herein, is meant to encompass the administration of selected combination partners, e.g., a radiopharmaceutical compound and an alkylating agent, to a single subject (e.g., a patient) in need thereof, and is intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0034] In chemical formulas, wavy lines [ka] represents the attachment point of the part.

[0035] Radiopharmaceutical compounds for use in combination therapy of the present disclosure The radiopharmaceutical compounds for use in the methods of the present disclosure have the formula (I): CSP(I) (In the formula, C is a chelating moiety; S is an optional spacer covalently linking C and P; P is a GRP receptor binding moiety covalently linked to C directly or indirectly via S. or a pharmaceutically acceptable salt thereof, which is labeled with a radionuclide M.

[0036] M is selected from among radioisotopes useful in nuclear medicine. Examples of such radioisotopes include, but are not limited to: 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 Preferably, M is 177 This is Lu.

[0037] In specific embodiments, M is conjugated to a chelating moiety.

[0038] 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.

[0039] In a preferred embodiment, P has the general formula: Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z (in the formula, Xaa1 is absent or selected from the group consisting of the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Thi), 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo-tyrosine (oI-Tyr), Trp and pentafluorophenylalanine (5-F-Phe) (when all are L- or D-isomers); preferably D-Phe; Xaa2 is Gln, Asn or His; preferably Gln; Xaa3 is Trp or 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi); preferably Trp; Xaa4 is Ala, Ser or Val; preferably Ala, Xaa5 is Val, Ser or Thr; preferably Val, Xaa6 is Gly, sarcosine (Sar), D-Ala, or β-Ala; preferably Gly; Xaa7 is His or (3-methyl)histidine (3-Me)His; preferably His; Z is selected from -NHOH, -NHNH, -NH-alkyl, -N(alkyl), and -O-alkyl; or Z is [ka] wherein X is NH (amide) or O (ester), and R1 and R2 are the same or different and are selected from a proton, an optionally substituted alkyl, an optionally substituted alkyl ether, an aryl, an aryl ether or alkyl group, a halogen group, a hydroxyl group, a hydroxyalkyl group, an amine group, an amino group, an amido group, or an amido-substituted aryl or heteroaryl group.

[0040] According to one embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-His-Z; wherein Z is as defined above.

[0041] According to one embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-ψ(CHN)-Pro-NH and NH-CH(CH-CH(CH)). or Z is [ka] wherein X is NH (amide), R2 is (CH2-CH(CH3)2, and R1 is (CH2N)-Pro-NH2, which is the same as or different from R2. is.

[0042] As used herein, the term "chelating moiety" refers to an organic moiety that contains a functional group that is capable of forming a non-covalent bond with a radionuclide M, thereby forming a stable radionuclide complex.

[0043] A chelating moiety in the context of the present disclosure can be obtained by grafting one chelating agent onto S or P, said chelating agent can be selected from the following list: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1,4,7,10-tetraazacyclododecane, 1(glutarate)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA ), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramine (TETA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), NOTAGA, 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane (NODAGA), NODASA, NODAPA, and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA, e.g., AAZTA5).

[0044] In specific embodiments, the chelating moiety C has the formula: [ka] where the wavy bond represents the point of attachment of the chelator to the spacer S or GRP receptor antagonist P.

[0045] Such a chelating moiety is either directly linked to the GRP receptor antagonist moiety or linked via a linker molecule or what is also referred to herein as a spacer S. The linking bond is either a covalent or non-covalent bond between the GRP receptor antagonist (and spacer) and the chelating moiety, preferably the bond is a covalent bond.

[0046] The chelating moiety C is typically attached to the N-terminus of the peptide derivative formula disclosed above, such as DPhe-Gln-Trp-Ala-Val-Gly-His-Z, optionally via a spacer S.

[0047] In specific embodiments, the spacer S is a) an aryl-containing residue of any formula: [ka] b) a dicarboxylic acid, ω-aminocarboxylic acid, ω-diaminocarboxylic acid or diamine derivative of any of the following formulas: [ka] (wherein each n independently represents an integer of 0 to 12, for example, n=0, 1, 2, 3, or 4). c) PEG spacers of various chain lengths, in particular PEG spacers selected from any of the following formulas: [ka] (wherein m is an integer of 1 to 36, for example, m=1, 2, 3, or 4, and p is an integer of 0 to 5, for example, p=0 or 1). d) β-amino acid residues, in single or homologous chains of various lengths or heterologous chains of various lengths, in particular [ka] and / or e) any combination of one or more of a, b, c and / or d is selected from the group consisting of:

[0048] According to a preferred embodiment, the radiopharmaceutical compound for use in the therapeutic methods of the present disclosure has the following chemical formula: [ka] wherein C and P are as defined above and M is a radioisotope conjugated to a chelating moiety, preferably M is 177 Lu) The radiolabeled compound is selected from the group consisting of:

[0049] Preferably, the radiopharmaceutical compound for use in accordance with the present disclosure has the following formula (II): [ka] where C and P are as defined above and C is complexed to a radionuclide M. is a compound of

[0050] According to a particularly preferred embodiment, the radiopharmaceutical compound for use in the method of treatment has the formula (III): [ka] wherein M is as defined above, and preferably M is 177 Lu) This is M-NeoB.

[0051] Radiopharmaceutical compounds [ 177 Lu]Lu-NeoB is 177 Lu refers to a compound of formula (III).

[0052] According to one embodiment, the radiopharmaceutical compound has formula (IV): [ka] wherein M is as defined above, preferably 177 Lu) Radiolabeled NeoB2.

[0053] According to another specific embodiment, the radiopharmaceutical compound for use in accordance with the present disclosure comprises M, preferably 177 Radiolabeled with Lu, of the following formula (V): [ka] is a compound of formula (I) which is ProBOMB1.

[0054] Many embodiments of the present disclosure preferably involve the use of [ 177 Lu]Lu-NeoB.

[0055] The radiopharmaceutical compound is for use in treating glioblastoma in a subject in need thereof, wherein a therapeutically effective amount of said radiopharmaceutical compound is administered to said subject.

[0056] The single components or their precursors, typically unlabeled NeoB, can be packaged in a kit or separately. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration.

[0057] In specific embodiments, the radiopharmaceutical compounds for use in the disclosed combination therapies can be formulated as described above, for example, in WO 2021 / 052960.

[0058] Typically, the combination therapy includes: (a)(ai) Radionuclides 177 lutetium( 177 Lu), and (aii) Formula (III): [ka] NeoB The complex formed by; and; (b) gentisic acid or its salts and ascorbic acid or its salts; (c) optionally, macrogol 15 hydroxystearate; (d) acetate buffer; (e) Water for injection, and (f) at least one other pharmaceutically acceptable excipient, e.g., a sequestering agent such as DTPA and administering a pharmaceutical composition comprising:

[0059] Synthesis of Compounds of Formulas (I), (II), (III), (IV) and (V) The compounds of formula (I), (II), (III), (IV) and (V) can be synthesized using the method disclosed in the reference "Positron Emission Tomography Imaging of the Gastrin-Releasing Peptide Receptor with a Novel Bombesin Analogue" ACS Omega 2019, 4, 1470-1478.

[0060] Further information on the synthesis of compounds of formula (V) can be found in WO 2021 / 0608051.

[0061] Radiation therapy used in combination therapy In certain embodiments, a method of treating glioblastoma in a subject in need thereof comprises administering to the subject an effective dose of ionizing radiation, i.e., radiotherapy.

[0062] As used herein, the term "radiotherapy" refers to the treatment of diseases of an oncological nature by irradiation with ionizing radiation, which deposits energy that injures or destroys cells in the area being treated (target tissue) by damaging their genetic material and making it impossible for these cells to continue to multiply.

[0063] In specific embodiments, the disclosed method involves exposing the tumor to be treated to an effective dose of ionizing radiation, where the ionizing radiation is photons, e.g., X-rays. Depending on the amount of energy they possess, the rays can be used to destroy cancer cells on the surface of the body or deep within the body. As the energy of the X-ray beam increases, the X-rays can travel deeper into the target tissue. Linear accelerators and betatrons produce X-rays with progressively greater energy. The use of a machine to deliver radiation (such as X-rays) to the cancer site is called external beam radiation therapy.

[0064] An alternative embodiment of a treatment method according to the present disclosure uses gamma rays, which are spontaneously produced when certain elements (such as radium, uranium, and Conalt-60) emit radiation as they decompose or decay.

[0065] The ionizing radiation is typically between 2 keV and 25000 keV, in particular between 2 keV and 6000 keV (ie 6 MeV) or between 2 keV and 1500 keV (such as a Cobalt-60 source).

[0066] Those skilled in the art of radiotherapy know how to determine the appropriate dosage and application schedule depending on the nature of the disease and the patient's profile, and therefore, in particular, how to assess dose-limiting toxicities (DLTs) and how to determine the maximum tolerated dose (MTD).

[0067] The amount of radiation used in radiation therapy is measured in grays (Gy) and varies depending on the type and stage of the cancer being treated. For therapeutic cases, typical total doses for solid tumors range from 20 to 120 Gy. When selecting a dose, radiation oncologists consider many other factors, including whether the patient has received chemotherapy, the patient's comorbidities, whether radiation therapy is being administered before or after surgery, and the success of the surgery.

[0068] The total dose is typically fractionated (spread over time). The amount and schedule (planning and delivery of ionizing radiation, fractionated dose, fractionated delivery scheme, total dose alone or in combination with other anti-cancer drugs, etc.) are defined for any disease / anatomical site / disease stage, patient setting / age, and constitute the standard of care for any particular situation.

[0069] A typical conventional fractionation schedule for an adult for the methods of the present disclosure can be 1-4 Gy / day, preferably about 2 Gy / day, for 3-7 days, preferably about 5 days per week, for a period of 4-8 weeks, preferably 6 weeks. In a specific embodiment, the radiation therapy consists of exposing the subject to a total dose of ionizing radiation of 50-70 Gy, e.g., 60 Gy.

[0070] In another specific embodiment, the subject is exposed to a dose per fraction of about 2-12 Gy of ionizing radiation, with the total dose preferably administered in up to 6 fractions, i.e., 5 consecutive days followed by 2 days of rest, for 6 consecutive weeks.

[0071] Preferably, the subject will be exposed to standard of care for treating patients with glioblastoma in combination with temozolomide, which clinical standard comprises administering to the subject a dose of 2 Gy / day for 5 days, followed by 2 days of rest, for a total dose of 60 Gy over 6 consecutive weeks.

[0072] In a specific embodiment where the subject is afflicted with glioblastoma, the radiation therapy applied in the methods disclosed herein is whole brain radiation therapy (WBRT).

[0073] Alkylating Agents Used in Combination Therapy A method of treating glioblastoma in a subject in need thereof comprises administering to said subject a radiopharmaceutical compound, optionally in combination with radiation therapy and a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0074] Alkylating agents are divided into different classes, including: 1. Nitrogen mustards: such as mechlorethamine (nitrogen mustard), chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan; 2. Nitrosoureas: such as streptozocin, carmustine (BCNU), and lomustine; 3. Alkyl sulfonates: Busulfan; 4. Triazines: dacarbazine (DTIC) and temozolomide (Temodar®); and 5. Ethylenimines: Thiotepa and Altretamine (Hexamethylmelamine)

[0075] As used herein, "temozolomide" refers to a triazine-type alkylating agent, and more specifically, the compound of formula 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide and its pharmaceutically acceptable salts (CAS number 85622-93-1). Alkylating agents directly damage DNA (the genetic material within each cell), preventing the cell from reproducing. These agents act at all stages of the cell cycle and are used to treat many different cancers, including glioblastoma, leukemia, lymphoma, Hodgkin's disease, multiple myeloma, and sarcoma, as well as lung, breast, and ovarian cancers.

[0076] In one embodiment, the alkylating agent, preferably temozolomide, is administered at a dose of 50-100 mg / m daily during the induction phase. 2 / day, preferably about 75 mg / m 2 / day for a period of 4 to 8 weeks, preferably 6 weeks.

[0077] As used herein, "induction period" refers to the period during which the alkylating agent, preferably temozolomide, is administered to a subject simultaneously with radiation therapy.The induction period can have a duration of up to 11 weeks, for example, from week 1, day 1 to the end of week 11, day 7.

[0078] Treatment of glioblastoma with temozolomide concurrent with radiation therapy is the standard of care, and temozolomide may be administered according to the prescribing information for the combination therapy according to the present disclosure.

[0079] In some embodiments, both radiation therapy and the alkylating agent, preferably temozolomide, are initiated on the same day. In particular aspects, the alkylating agent, preferably temozolomide, is administered daily without interruption, concurrently with radiation therapy. In more specific embodiments, both radiation therapy and the alkylating agent, preferably temozolomide, are initiated on the same day, 7-10 days after the first administration of the radiopharmaceutical compound.

[0080] For example, temozolomide is administered at a dose of 75 mg / m from the first day to the last day of radiation therapy (external beam radiation therapy). 2 / day, initially administered in week 2 and continued until the end of week 7.

[0081] In certain embodiments, the alkylating agent, preferably temozolomide, is administered daily during co-administration with radiation therapy (induction phase), e.g., in an initial dosing regimen over a period of 6 weeks, and during the maintenance phase after co-administration with radiation therapy, e.g., in a two-dose regimen over a period of up to 24 weeks.

[0082] As used herein, "maintenance phase" refers to a period beginning after the induction phase or co-administration with radiation therapy at an increased dose compared to the dose in the induction phase, e.g., starting on day 1 of week 12 for a duration of up to 25 weeks.

[0083] In a specific embodiment, during this maintenance phase, the alkylating agent, preferably temozolomide, is administered at a dose of 50 to 400 mg / m daily. 2 / day, preferably 75-300 mg / m 2 / day, more preferably 150-200 mg / m 2 / day for 5 consecutive days followed by 2 days of rest every 28 days for a period of 20 to 28 weeks, preferably 24 weeks.

[0084] In a specific embodiment, intrapatient dose escalation of temozolomide treatment is performed during the maintenance treatment period. For the same patient, if 150 mg / m temozolomide treatment is well tolerated, the dose of temozolomide is 150 mg / m for 5 days during week 12 and 200 mg / m for 5 days each during weeks 16, 20, 24, 28, and 32. More generally, approved prescribing information can be followed.

[0085] Combination therapy In a specific embodiment, the method of treating glioblastoma in a subject in need thereof comprises administering a therapeutically effective amount of a radiopharmaceutical compound, preferably 177 The method comprises administering to said subject [Lu]Lu-NeoB in combination with radiation therapy.

[0086] In another embodiment, the present disclosure provides a method of treating glioblastoma in a subject in need thereof, comprising administering a therapeutically effective amount of said radiopharmaceutical compound, preferably 177

[0013] The present invention is directed to a method comprising administering to said subject

[0014] Lu]Lu-NeoB in combination with radiotheray, and further in combination with a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0087] The present disclosure also relates to the use of a radiopharmaceutical compound in the preparation of a medicament for use in treating glioblastoma in a subject in need thereof, wherein a therapeutically effective amount of said radiopharmaceutical compound, e.g., 177 Lu]Lu-NeoB is administered to the subject simultaneously, separately or sequentially in combination with radiation therapy and, optionally, a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0088] In various embodiments of the present disclosure, the combination therapy comprises (i) a therapeutically effective amount of a radiopharmaceutical compound (e.g., 177and (ii) irradiating the subject with a therapeutically effective dose of ionizing radiation; and (iii) administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0089] As used herein, the term "synergistically" means that a therapeutic agent and ionizing radiation can be administered separately within a time interval (e.g., in a time-staggered manner, particularly in a sequence-specific manner within such time interval) to exhibit a (preferably synergistic) interaction (i.e., a joint therapeutic effect).

[0090] In various embodiments of the present disclosure, the combined administration includes a radiopharmaceutical compound (e.g., 177 Lu-NeoB) and radiotherapy are administered simultaneously and independently or separately within a time interval, particularly when these time intervals allow the combination partners to exhibit a cooperative effect, e.g., a synergistic effect.

[0091] In certain embodiments, a radiopharmaceutical compound, e.g., 177 Lu]Lu-NeoB is administered 1 to 20 days, preferably 3 to 15 days, more preferably 7 to 10 days before the start of radiotherapy.

[0092] Administration of the radiopharmaceutical compound may comprise dosing intervals of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 weeks or 4 weeks, more preferably every 4 weeks.

[0093] In a specific embodiment, the radiopharmaceutical compound, e.g., 177 Lu]Lu-NeoB is administered to the subject at least six times in combination with radiation therapy, and further in combination with temozolomide, wherein the administration interval between two administrations of the radiopharmaceutical compound is four weeks, and the first administration of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy and temozolomide.

[0094] In a specific embodiment, the radiopharmaceutical compound, e.g., 177 [Lu]Lu-NeoB is administered at a dose of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), preferably 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), preferably 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), more preferably 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi). mCi), even more preferably about 3.7 GBq (100 mCi), about 5.55 GBq (150 mCi), about 7.4 GBq (200 mCi), about 9.25 GBq (250 mCi), or about 11.1 GBq (300 mCi), for example, about 5.55 GBq (150 mCi) to about 9.25 GBq (250 mCi).

[0095] In a specific embodiment, the radiopharmaceutical compound, e.g., 177 [Lu]Lu-NeoB is administered 1-10 times per treatment, preferably 4-10 times per treatment, more preferably 6-8 times per treatment. For example, the radiopharmaceutical compound, e.g., [ 177 Lu]Lu-NeoB is administered 6 to 10 times every 4 weeks, preferably at a dose ranging from 5.55 GBq (150 mCi) to 9.25 GBq (250 mCi).

[0096] A particularly preferred treatment scheme for combination therapy is shown in FIG.

[0097] Advantageously, in specific embodiments, a radiopharmaceutical compound (e.g., 177 The combined effect of [Lu]Lu-NeoB) therapy with radiation therapy, and optionally an alkylating agent such as temozolomide, increases overall survival in a subject by at least 10%, 20%, 30%, 40%, or at least 50% compared to single radiation therapy or combination therapy with radiation therapy and an alkylating agent, e.g., temozolomide.

[0098] "Overall survival" (OS) is defined herein as the period from the date of first administration to the date of death from any cause in a clinical trial participant, as disclosed, for example, in Example 1. If the participant is not known to have died, overall survival is censored at the most recent date the participant was known to be alive (at or before the cutoff date). OS distributions are estimated using the Kaplan-Meier method.

[0099] Also, in specific embodiments, radiopharmaceutical compounds (e.g., [ 177 The combined effect of [Lu]Lu-NeoB) therapy and radiation therapy, optionally with an alkylating agent such as temozolomide, increases progression-free survival by at least 10%, 20%, 30%, 40%, or at least 50% compared to single radiation therapy or combination therapy of radiation therapy with an alkylating agent such as temozolomide.

[0100] The term "progression-free survival" (PFS), as used herein, is defined as the time from the date of first dose to the date of confirmed progression, according to modified RANO or death from any cause. If no PFS event is observed, PFS is censored at the earlier of the date of the last adequate tumor assessment before the data cutoff date or the date of initiation of new antineoplastic therapy. PFS distributions are estimated using the Kaplan-Meier method.

[0101] In certain embodiments, radiopharmaceutical compounds (e.g., 177Administration of a composition comprising [Lu]Lu-NeoB) to a subject eligible for such treatment can inhibit, delay, and / or reduce tumor growth in the subject. In certain embodiments, tumor growth is delayed by at least 50%, 60%, 70%, or 80% compared to an untreated control subject. In certain embodiments, tumor growth is delayed by at least 80% compared to an untreated control subject. In certain embodiments, tumor growth is delayed by at least 50%, 60%, 70%, or 80% compared to the expected growth of the tumor without treatment. In certain embodiments, tumor growth is delayed by at least 80% compared to the expected growth of the tumor without treatment. Assessment of tumor volume in glioblastoma can be determined, for example, by using the modified Response Assessment in Neuro-Oncology (mRANO) criteria, which uses an international brain tumor imaging protocol that allows for both dimensional and volumetric measurements of tumor enhancement in clinical trials. For further details, please refer to the mRANO criteria (Ellingson BM, Wen PY, Cloughesy TF. Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials. Neurotherapeutics. 2017 Apr;14(2):307-320. doi:10.1007 / s13311-016-0507-6. PMID:28108885; PMCID:PMC5398984).

[0102] In certain embodiments, a radiopharmaceutical compound (e.g., 177Administration of a composition comprising [Lu]Lu-NeoB) to a subject eligible for such treatment can increase the subject's survival. In certain embodiments, the increase in survival is compared to untreated control subjects or control subjects receiving standard treatment, such as radiation therapy in combination with temozolomide, for newly diagnosed patients with glioblastoma. In certain embodiments, the increase in survival is compared to the expected survival of a subject receiving standard treatment. In certain embodiments, survival is increased by at least 3-fold, 4-fold, or 5-fold compared to untreated control subjects or control subjects receiving standard treatment, such as radiation therapy in combination with temozolomide, for newly diagnosed patients with glioblastoma. In certain embodiments, survival is increased by at least 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 3 years compared to control subjects receiving standard treatment, such as radiation therapy in combination with temozolomide, for newly diagnosed patients with glioblastoma. In certain aspects, survival is increased by at least 1 month, 2 months, or 3 months as compared to the predicted survival of subjects receiving standard treatment for newly diagnosed glioblastoma, such as a combination of radiation therapy and temozolomide.

[0103] Methods for selecting subjects for combination therapy In certain embodiments of the present disclosure, the glioblastoma is a GRPR-positive disease.

[0104] In a specific embodiment, the subject is selected for treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with the same compound as defined for this treatment, but where M is an alternative radiometal or contrast agent suitable for imaging, i.e., imaging of the radiopharmaceutical compound, based on detection of said radionuclide in an imaging scan in the tumor area after surgery.

[0105] Typical radiometals suitable for use as contrast agents in imaging include: 111 In, 133m In, 99m Tc, 94mTc, 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.

[0106] According to a preferred embodiment, the radiometal suitable for imaging is: 67 Ga, 68 Ga or 64 Cu, preferably 68 It's Ga.

[0107] In one embodiment, the subject is screened for tumor area, e.g., by whole brain PET / CT or PET / MRI scan. 68 Select by assessing Ga-NeoB uptake.

[0108] In a specific embodiment, the subject eligible for combination therapy is selected from subjects who, after surgery, demonstrate the presence of alternative radionuclide or contrast agent enhancement, e.g., gadolinium enhancement, on PET / MRI scans in the tumor region.

[0109] Typically, radiopharmaceutical compounds labeled with radioactive metals suitable for imaging, e.g. 68A PET scan with ]Ga]Ga-NeoB may be performed at least 3 days before the first administration of the radiopharmaceutical compound for combination therapy.

[0110] Accordingly, the present disclosure also provides a method for determining whether a human subject having glioblastoma can be selected for combination therapy as disclosed herein, comprising: 1. administering an effective amount of an imaging radiopharmaceutical compound as an imaging contrast agent for imaging uptake of said radiopharmaceutical compound; 2. obtaining a PET / MRI or PET / CT image scan of the patient; and 3. Comparison with Control Image Scan The present invention relates to a method comprising:

[0111] The purpose of the above selection method is to select patients with GRPR-positive tumors, i.e., patients who are better responders to the combination therapy of the present disclosure. GRPR-positive tumors can be advantageously detected by assessing the uptake of the imaging radiopharmaceutical compound by PET / MRI or PET / CT imaging after injection of said imaging radiopharmaceutical compound as a contrast agent.

[0112] As used herein, a good responder is a patient selected from a patient population who exhibits a statistically better response to treatment compared to a randomized patient population (i.e., not selected by the selection step of the method) and / or who exhibits fewer side effects to treatment compared to a randomized patient population (i.e., not selected by the selection step of the method).

[0113] In certain embodiments, 68 [Ga]Ga-NeoB is provided in a kit. The kit may consist of two sterile vials as a single-dose product: Vial 1: NeoB (active ingredient), 50 μg, powder for solution for injection, reconstituted with a solution of gallium-68 chloride (68GaCl3) in HCl eluted from a 68Ge / 68Ga generator; Vial 2: Reaction buffer. Vial 2 will be added to reconstituted vial 1.

[0114] An example of such a kit is disclosed in WO2021053040.

[0115] corresponding to the radiation dose to be administered, 68 The volume of the [Ga]Ga-NeoB injection solution is calculated according to the estimated injection time based on the current activity provided by the generator and the physical decay of the radionuclide (half-life = 68 min).

[0116] In one embodiment, subject selection is performed 10-18 days, preferably about 14 days, prior to the first administration of the radiopharmaceutical compound.

[0117] In certain embodiments, the imaging radiopharmaeutical is administered in a single intravenous dose of 150-250 MBq (4.1-6.8 mCi).

[0118] Images of the subject's body are then acquired by PET / MRI or PET / CT imaging, and the images are compared with control images to determine whether the lesions identified by conventional imaging, e.g., MRI, CT, SPECT, or PET, have increased uptake of the imaging radiopharmaceutical compound, i.e., [ 68 The PET / MRI or PET / CT imaging is typically performed 30 to 120 minutes, preferably 60 to 90 minutes, after intravenous administration of the imaging radiopharmaceutical compound to a subject.

[0119] In specific embodiments of the method, a subject is selected for the combination therapy of the present disclosure that meets the following criteria: and at least 10%, preferably more than 20%, preferably more than 30%, preferably more than 40%, preferably more than 50%, preferably more than 60%, preferably more than 70%, preferably more than 80% of lesions detected by conventional imaging, e.g., MRI, CT, SPECT or PET, in said subject have imaging radiopharmaceutical compound uptake, e.g., [ 68 β-NeoB incorporation.

[0120] In specific embodiments, the term "lesion" refers to a measurable tumor lesion according to the revised RANO criteria as defined in Ellingson BM, Wen PY, Cloughesy TF. Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials. Neurotherapeutics. 2017 Apr;14(2):307-320. doi:10.1007 / s13311-016-0507-6. PMID:28108885; PMCID:PMC5398984.

[0121] Pathological conditions, including brain tumors such as glioblastoma, and chemical or physical stimuli such as surgery, radiation therapy, or some chemotherapeutic agents, can increase blood-brain barrier (BBB) ​​permeability and disrupt its integrity (Chen et al., Front. Pharmacol. 2019;10:86; Deeken and Loescher, Clin. Cancer Res., 2007;13(6):1663-74). Thus, in certain embodiments, the subject is selected from among subjects newly diagnosed with glioblastoma and exhibiting blood-brain barrier (BBB) ​​disruption, as determined, for example, by conventional gadolinium contrast enhancement by magnetic resonance imaging (MRI).

[0122] In certain embodiments, the subject is newly diagnosed with glioblastoma or suffers from recurrent glioblastoma.

[0123] O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been extensively studied as a predictive and prognostic biomarker in glioblastoma. MGMT promoter methylation leads to decreased MGMT protein expression, which reduces DNA repair activity in glioma cells and subsequently leads to sensitivity to alkylating agents such as TMZ (Hegi et al., 2005, N Engl J Med;352(10):997-1003; Nabors et al., 2020, J Natl Compr Canc Netw;18(11):1537-1570). Interestingly, MGMT promoter methylation has also been shown to be associated with improved outcomes to radiation therapy in glioblastoma in the absence of adjuvant alkylating chemotherapy (Rivera et al., 2010, Neuro Oncol;12(2):116-21).

[0124] Therefore, in a specific embodiment, the subject is further selected by assessing the methylation status of its methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Typically, subjects receiving an alkylating agent, preferably temozolomide, along with the combination therapy as disclosed herein can be advantageously selected from subjects with a positive MGMT promoter status. Methods for determining the MGMT promoter status in a subject are disclosed, for example, in Mansouri, Alireza et al. ("MGMT promoter methylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges." Neuro-oncology vol. 21, 2 (2019): 167-178. doi: 10.1093 / neuonc / noy132).

[0125] In certain embodiments, in subjects with these selected methylated MGMT promoters, during the induction period, a radiopharmaceutical compound, e.g., 177 Lu]Lu-NeoB can be administered in combination with concomitant radiation therapy and an alkylating agent, preferably temozolomide, followed by a maintenance phase in which a radiopharmaceutical compound in combination with an alkylating agent, preferably temozolomide, is administered.

[0126] For example, in a specific embodiment, the subject is newly diagnosed with glioblastoma, has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and is administered the radiopharmaceutical compound, preferably 177 Lu]Lu-NeoB is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide.

[0127] In a specific embodiment, the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound is administered to the subject at least six times in combination with radiation therapy, and further in combination with temozolomide, wherein the administration interval between two administrations of the radiopharmaceutical compound is four weeks, and the first administration of the radiopharmaceutical compound is preferably administered 7-10 days before the start of radiation therapy and temozolomide.

[0128] In a specific embodiment, the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound is administered to the subject at least six times in combination with radiation therapy, and further in combination with temozolomide, wherein the administration interval between two administrations of the radiopharmaceutical compound is four weeks, and the first administration of the radiopharmaceutical compound is preferably administered 7-10 days before the start of radiation therapy and temozolomide; wherein the alkylating agent, preferably temozolomide, is administered daily during co-administration with radiotherapy, e.g., in an initial dosing regimen (induction phase) for a period of 6 weeks, and in a two-dose regimen during the maintenance phase after co-administration with radiotherapy, e.g., for a period of up to 24 weeks.

[0129] Preferably, during the maintenance treatment period, temozolomide is administered in combination with a radiopharmaceutical compound, typically 177 Lu] administered the week before administration of Lu-NeoB.

[0130] Suitable dosing regimens for alkylating agents, and temozolomide in particular, during the induction and maintenance phases are disclosed, for example, in the previous section on alkylating agents used in combination therapy.

[0131] Further aspects of the combination therapy of the present disclosure are described in more detail and specificity hereinafter with reference to examples, which are not intended to limit the invention. [Example]

[0132] Example 1: Clinical Trial to Treat Subjects with Glioblastoma Provided herein are studies of treatment with MGMT in combination with radiation therapy and temozolomide in subjects with newly diagnosed glioblastoma with MGMT methylated or unmethylated promoter status. 177

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

[0133] overview

[0134] [Table 1]

[0135] [Table 2]

[0136] Study Design: 1. Single-arm, Phase Ib, multicenter, dose-finding expansion study 2. Newly diagnosed glioblastoma 3. Open label 4. Dose Escalation and Expansion Cohort Allocation 5. Review Group: Dose Escalation Committee and Trial Steering Committee

[0137] overview: Glioblastoma (GBM) is the most common aggressive type of primary brain tumor with a high mortality rate. The current standard of care (SoC) in newly diagnosed GBM involves the alkylating agent temozolomide (TMZ) in combination with radiation therapy (RT). The hypothesis of this study is to compare the current standard of care with radioligand therapy [ 177 The goal of this study is to improve patient outcomes by combining [Lu]Lu-NeoB with [Lu]Lu-NeoB. Patients enrolled in this study will receive [Lu]Lu-NeoB every 4 weeks. 177 In exceptional cases, patients are treated with the standard regimen of TMZ and RT in combination with [Lu]Lu-NeoB for up to 32 weeks. 177 If patients tolerate and benefit from [Lu]Lu-NeoB, they may receive up to 10 doses, resulting in a treatment duration of up to 37 weeks. During this period, regular safety and efficacy assessments are planned on a weekly basis. The primary objective of this study is to evaluate the efficacy of [Lu]Lu-NeoB in combination with TMZ and RT in participants with newly diagnosed GBM. 177 The objectives of this study are to estimate the recommended dose of [Lu]Lu-NeoB and characterize the safety and tolerability of this treatment. For these reasons, patients will be enrolled and treated in cohorts of increasing dose levels, and the totality of available data will be used to define the recommended dose. In expansion cohorts, additional patients will be treated to further characterize safety and tolerability, and preliminary efficacy data will be collected from this cohort. Contrast-enhanced MRI assessments are recommended to be repeated every 8 weeks, and patient-reported outcome (PRO) questionnaires will be used to evaluate the effect of the study treatment on patient-reported symptoms and tolerability. After treatment, all patients will be followed for up to an additional 5 years for safety, disease progression, and survival.

[0138] Study medication and treatment modality: In this study, the term "investigational drug" refers to a radioligand imaging compound used to explore GRPR expression. 68 Ga]Ga-NeoB, and used as radioligand therapy [ 177 The term "investigative drug" refers to [ 177 Lu]Lu-NeoB, refers to the combination of temozolomide (TMZ) and radiation therapy (RT).

[0139] Study Duration: Participants will be monitored for safety during the 60-month follow-up period (from the last dose of study medication) 177 Patients will be monitored for efficacy every 8 weeks by contrast-enhanced MRI until disease progression is confirmed. Survival follow-up will be every 12 weeks thereafter.

[0140] Treatment duration:[ 177 Lu]Lu-NeoB will be administered every 4 weeks for up to 6 doses, starting on week 1, day 1. In exceptional cases, patients may 177 If they tolerate and benefit from [Lu]Lu-NeoB, they may receive up to four additional doses.

[0141] Therapeutic Purpose: The term "investigational drug" refers to a radioligand imaging compound used to explore GRPR expression. 68 Ga]Ga-NeoB, and used as radioligand therapy [ 177 The term "investigative drug" refers to [ 177 Lu]Lu-NeoB, which refers to the combination of radiation therapy (RT) and temozolomide (TMS).

[0142] Number of Participants: Approximately 42 participants will be enrolled, with a maximum of 21 participants in the dose escalation phase and approximately 15 participants in the dose expansion phase.

[0143] Key inclusion criteria: 1. Signed informed consent must be obtained prior to participation in the study 2. Histologically confirmed glioblastoma according to the WHO classification established after either surgical resection or biopsy 3. Adequate bone marrow and organ function as defined by the following laboratory values ​​obtained ≤14 days prior to administration of study treatment: 4. Presence of gadolinium enhancement in the tumor area on preoperative MRI 5. Karnofsky Performance Status ≥ 60%

[0144] Key exclusion criteria 6. Additional, concurrent, or active treatment for glioblastoma other than this study 7. 68 Administration of radiopharmaceuticals with therapeutic intent within a period corresponding to 10 half-lives of the radionuclide used prior to injection of [Ga]Ga-NeoB 8. History or current diagnosis of cardiac dysfunction 9. History of another active malignancy within the past 3 years prior to study enrollment 10. Known hypersensitivity to the study drug, its excipients, or dacarbazine

[0145] Treatment group: [ 177 Lu]Lu-NeoB will be administered every 4 weeks for up to 6 doses, starting on week 1, day 1. 177 Participants who tolerate and benefit from [Lu]Lu-NeoB may receive up to 10 doses. TMZ and RT administration will be 177 Lu] should be initiated 7 to 10 days after the first dose of Lu-NeoB.

[0146] TMZ should be administered at a dose of 75 mg / m during the concomitant use with RT, according to the approved prescribing information. 2RT will be delivered at a dose of 2 Gy / day, 5 days per week (followed by 2 rest days) for 6 consecutive weeks.

[0147] Example 2: Rationale for the study Non-clinical biodistribution and drug metabolism and pharmacokinetics [ 177 The biodistribution of [Lu]Lu-NeoB has been evaluated in vivo in healthy mice and tumor-bearing models. NeoB is rapidly cleared from the blood, eliminated through the renal system, and not retained in the body. The background radioactivity observed in GRPR-expressing tissues (mostly the pancreas) declines over time, as expected for an antagonist. In contrast, tumor uptake remains high at all time points evaluated, resulting in an increased tumor / background ratio.

[0148] Pathological conditions, including brain tumors (i.e., glioblastoma), and chemical or physical stimuli such as surgery, RT, and some chemotherapeutic agents, can increase blood-brain barrier (BBB) ​​permeability and disrupt its integrity (Chen et al. 2019 supra; Deeken and Loescher 2007 supra). In brain tumors, BBB dysfunction is detected by conventional gadolinium-contrast-enhanced magnetic resonance imaging (MRI) (Sarkaria et al., Neuro. Oncol., 2018 Jan 22;20(2):184-191). In this study, the BBB was disrupted, leading to the development of an investigational drug [ 177 To confirm the penetrability of [Lu]Lu-NeoB, participants who show contrast enhancement on MRI will be selected. 177 Lu]Lu-NeoB is administered simultaneously with chemoradiotherapy.

[0149] [ 177 Lu]Lu-NeoB induces cell damage primarily through free radical formation in GRPR-positive tumor and adjacent cells.

[0150] Based on the results of in vitro drug-drug interaction (DDI) studies, 177Lu]Lu-NeoB is not believed to be capable of CYP or transporter-mediated drug-drug interactions.

[0151] toxicology Nonclinical studies have been performed using alternative nonradioactive [175Lu]Lu-NeoB formulations, which support the absence of pharmacological activity of the NeoB peptide. No adverse effects have been observed in safety pharmacology studies. Similarly, no signs of toxicity have been reported after either acute or repeated administration of [175Lu]Lu-NeoB, confirming the safety of the nonradioactive molecule.

[0152] [ 177 Clinical experience with Lu]Lu-NeoB NeoRay (EUDRACT No. 2018-004727-37) was administered to patients with advanced solid tumors known to overexpress GRPR. 177 This is an ongoing phase I / IIa, open-label, multicenter study to evaluate the safety, tolerability, systemic distribution, radiation dosimetry, and antitumor activity of ]Lu-NeoB.

[0153] In the NeoRay trial, as of October 11, 2022, [ 177 Eleven patients received 1.85 GBq (50 millicuries (mCi)) of [Lu]Lu-NeoB as their first dose (cycle 1). 177 Lu]Lu-NeoB was administered. 177 Intrapatient dose escalation to [Lu]Lu-NeoB was performed from cycle 2 onwards based on clinical dosimetry within cycle 1. Each treatment cycle has a duration of 6 weeks.

[0154] Dose level 1 (50 mCi in cycle 1 and 150 mCi in subsequent cycles) was evaluated in three patients each with breast cancer, prostate cancer, and GIST cancer. Two patients received two cycles and one patient received six cycles. Overall treatment was well tolerated, with no dose-limiting toxicities (DLTs) or SAEs reported.

[0155] Dose level 2 was assessed at 300 mCi / cycle and enrolled four patients, two with prostate cancer and two with GIST. Two patients received one cycle, one patient received two cycles, and one patient received three cycles. Two of the four enrolled patients experienced DLTs (grade 3 anemia in both patients and grade 3 encephalopathy in one patient). All of these events resolved. In a patient with prostate cancer and extensive bone metastases, one grade 3 anemia event occurred, and grade 2 anemia had progressed at screening (the subject also received a red blood cell transfusion before starting treatment). The patient developed grade 3 anemia 36 days after infusion and later grade 4 thrombocytopenia despite progressive disease. The patient discontinued treatment, and while anemia temporarily improved to grade 2 with supportive care, grade 4 thrombocytopenia was ongoing at the time of death due to progressive disease. Two DLTs were recorded in a patient with GIST that occurred within one week of administration of the first therapeutic dose (anemia grade 3 and encephalopathy grade 3). The patient had extensive pelvic bone metastases and anemia grade 1 at baseline. The patient was noted to have left-sided facial paralysis and altered mental changes, along with grade 2 vomiting and grade 3 hyponatremia; a brain MRI ruled out stroke and brain metastases. Three days later, the patient also developed seizures. The patient was being treated with very high doses of diazepam and [ 177 After several days of infusion of [Lu]Lu-NeoB, it was discontinued, raising the suspicion of withdrawal syndrome as a confounding factor. No other significant toxicities were reported, and the patient experienced one [ 177 Lu]Lu-NeoB infusion alone.

[0156] Following the occurrence of DLTs observed at dose level 2, a decision was made to de-escalate the dose to 250 mCi (dose level 3), consistent with the protocol. Dose level 3 was evaluated in four patients (two with GIST, one with prostate cancer, and one with glioblastoma). The glioblastoma patient received three cycles, one with GIST received two cycles, and both patients discontinued due to disease progression, while the other two patients (GIST and prostate cancer) received two cycles each and treatment is still ongoing. Overall treatment was very well tolerated, with the majority of reported AEs being mild / moderate, and no DLTs or SAEs were reported.

[0157] Stabilization of two chronic diseases was observed across the dose levels evaluated: approximately 1 year in GIST patients and 5 months in patients with prostate cancer.

[0158] Of the 11 treated patients in the study, 3 patients completed treatment, 2 patients discontinued due to AEs, 3 patients discontinued due to progressive disease (PD), 1 patient decided to discontinue treatment, and 2 patients are ongoing.

[0159] From NeoRay 177 Preliminary blood radioactivity PK of [Lu]Lu-NeoB indicated rapid elimination from the systemic circulation, with a geometric mean elimination half-life of approximately 60-80 hours and a mean effective half-life of approximately 48 hours. Radioactive HPLC data showed signs of metabolism in the systemic circulation and urine (as well as pharmacologically inactive metabolites unable to bind receptors); however, cumulative excretion of activity indicated that the radioactivity was primarily (on average ≥80%) excreted via the kidneys within 24-48 hours.

[0160] Preliminary dosimetry results indicate favorable biodistribution with low uptake in organs considered at risk due to GRPR expression, e.g., the pancreas, or RLT expression, e.g., the red bone marrow, and in organs considered at risk due to excretory pathways, e.g., the kidney. Across all dose levels studied, the dose-normalized mean absorbed doses (rounded to 2 significant figures) in Gy / GBq (±SD, n=10) were 0.11±0.059 (kidney), 0.019±0.0066 (red bone marrow), 0.063±0.038 (pancreas), 0.011±0.0034 (testis, n=7), 0.021±0.0077 (ovary, n=3), and 0.72±0.94 (all tumor lesions, n=18), respectively.

[0161] Given the safety and biodistribution characteristics of 250 mCi, a protocol re-escalation to 300 mCi was decided upon. The trial is ongoing and patients receiving dose levels of 300 mCi per cycle are being accrued.

[0162] Exam Updates as of June 7, 2023 As of June 7, 2023, [177Lu]Lu-NeoB has been administered to 17 patients according to Table 1. Patients in the first cohort received 50 mCi (1.85 GBq) of [177Lu]Lu-NeoB as the initial dose (cycle 1). In dose level (DL) 1, intrapatient dose escalation to 150 mCi of [177Lu]Lu-NeoB was performed based on clinical dosimetry in cycle 1.

[0163] [Table 3]

[0164] DL1 (50 mCi in cycle 1 and 150 mCi in subsequent cycles) did not cause any significant toxicity (no serious adverse events (SAEs)). The patient with breast cancer enrolled in this cohort was a 54-year-old woman with stage IV HR+ / HER2+ invasive ductal carcinoma with multiple bone metastases, first diagnosed in May 2018. Prior to enrollment in the study, the patient had received upfront mastectomy, radiation therapy, and multiple lines of treatment (including palbociclib + ET, trastuzumab, pertuzumab, fulvestrant, capecitabine, and everolimus + exemestane). The patient was discontinued due to disease progression. 177 After two doses of [Lu]Lu-NeoB, the study treatment was discontinued.

[0165] In the second cohort of patients receiving dose level 2 (300 mCi), two of four enrolled patients experienced dose-limiting toxicities (DLTs): grade 3 anemia in both patients and grade 3 encephalopathy in one patient. All of these events have resolved.

[0166] Following the occurrence of DLTs observed at dose level 2, a decision was made to de-escalate the dose to 250 mCi (dose level 3), consistent with the protocol.

[0167] Dose level 3 of 250 mCi was initially evaluated in four patients, and overall treatment was well tolerated, with the majority of reported AEs being mild / moderate, and no DLTs or SAEs reported.

[0168] Given the overall favorable safety profile of DL3, a dose re-escalation to 300 mCi for Cohort 4 was decided upon. Only one patient with GBM was enrolled, who experienced moderate (Grade 2) nausea, severe (Grade 3) vomiting 5 days after the first dose of study treatment, and "neurological depression" (Grade 3) (preferred term: nervous system disorder), leading to hospitalization the following day. All events were considered serious by the investigator and possibly [ 177Neurological deterioration met the definition of a DLT. Twelve days after the first dose of study treatment, new events occurred: grade 2 nausea and grade 3 vomiting, while the neurological AE worsened to grade 4. While the nausea and vomiting events rapidly resolved the next day, the neurological AE further worsened to grade 4 despite increased dexamethasone therapy, leading to treatment discontinuation and ongoing at the time of the patient's death by active euthanasia. Given that the very first patient treated in this new cohort at 300 mCi experienced a DLT (neurological deterioration), and given the two other patients in the preceding cohort at 300 mCi (DL2) who experienced DLTs (anemia and encephalopathy), the dose was tapered to 250 mCi (DL3) per protocol, and Cohort 5 was open for enrollment.

[0169] As of June 7, 2023, a total of five patients had been enrolled in Cohort 5, with a dose of 250 mCi (DL3), including four patients with GIST and one patient with prostate cancer. None of the patients in Cohort 5 experienced DLTs or SAEs. Reported AEs were mild or moderate in severity. Grade ≥ 2 laboratory abnormalities were not clinically significant.

[0170] Across the dose levels evaluated, two chronic disease stabilizations were observed in Cohort 1 (50 mCi and 150 mCi) (approximately 1 year in GIST patients and 5 months in prostate cancer patients).

[0171] Of the 17 treated patients in the study, 4 patients completed treatment, 2 patients discontinued due to AE, 7 patients discontinued due to PD, 3 patients discontinued by investigator / patient decision, and 1 patient is ongoing.

[0172] From NeoRay 177Preliminary blood radiopharmacokinetics of [Lu]Lu-NeoB indicated rapid elimination from the systemic circulation, with a geometric mean elimination half-life of approximately 55-80 hours and a mean effective half-life of approximately 44 hours. Radioactive HPLC data showed metabolites in the systemic circulation and urine (as well as pharmacologically inactive metabolites unable to bind to receptors), and cumulative excretion of activity again indicated that radioactivity was primarily (on average ≥80%) excreted via the kidneys within 24-48 hours. Metabolites will be examined in plasma.

[0173] Preliminary dosimetry results indicate favorable biodistribution with low uptake in organs considered at risk due to GRPR expression, e.g., the pancreas, or RLT expression, e.g., the red bone marrow, and in organs considered at risk due to excretory pathways, e.g., the kidney. The dose-normalized observed mean absorbed doses (rounded to 2 significant figures) from all cohorts in Gy / GBq (±SD, n=13) were 0.10±0.056 (kidney), 0.018±0.0076 (red bone marrow), 0.056±0.038 (pancreas), 0.011±0.0041 (testis, n=10), 0.021±0.0094 (ovary, n=3), and 0.53±0.84 (all tumor lesions, n=28), respectively.

[0174] Given the overall favorable safety profile of DL3, a dose re-escalation to 300 mCi for Cohort 4 was decided upon. Only one patient with GBM was enrolled, who experienced moderate (grade 2) nausea, severe (grade 3) vomiting 5 days after the first dose of study treatment, and "neurological depression" (grade 3) (PT: Nervous system disorder), leading to hospitalization the following day. All events were considered serious by the investigator and possibly [ 177The neurological decline met the definition of a DLT. Given that the very first patient treated in this new cohort at 300 mCi experienced a DLT (neurological decline), and taking into account two other patients in the preceding cohort at 300 mCi (DL2) who experienced DLTs (anemia and encephalopathy), the dose was tapered to 250 mCi (DL3) per protocol. As of January 29, 2023, while patient accrual to Cohort 5 at 250 mCi was ongoing, two additional patients (for a total of six) with GIST had received one cycle of [177Lu]Lu-NeoB at this DL, with no reported DLTs.

[0175] The generated Phase I dosimetry data show favorable [ 177 The organ dosimetry profile of [Lu]Lu-NeoB was demonstrated. Consequently, based on the safety and tolerability data observed at the dose levels tested, the MTD was determined to be 250 mCi every 6 weeks. Novartis, with participating investigators, published the recommended phase II dose (RP2D) as 250 mCi, which will be further studied in the phase IIa portion of the FIH trial CAAA603A12101.

[0176] [ 68 Clinical experience with Ga]Ga-NeoB [ 68 [Ga]Ga-NeoB has shown favorable technical and diagnostic performance for identifying GRPR-expressing malignancies in both preclinical and clinical studies, with good image quality allowing for easy interpretation. 68 The [Ga]Ga-NeoB PET agent has been evaluated in two completed clinical trials and is currently being evaluated in one ongoing trial:

[0177] A phase I / IIa clinical trial (MITIGATE; EudraCT no. 2016-002053-38) demonstrated the efficacy of thrombin-1 in patients with GIST who had been previously treated with advanced tyrosine kinase inhibitors. 68The objective of this study was to evaluate the safety, biodistribution, dosimetry, and preliminary diagnostic performance of [Ga]Ga-NeoB. 68 Ga]Ga-NeoB was very well tolerated in all nine participants, and [ 68 No adverse events were reported with [Ga]Ga-NeoB. Radiation exposure was low due to rapid renal and blood clearance. Biodistribution was high in the pancreas, followed by the kidney and liver. 68 We demonstrated [Ga]Ga-NeoB uptake. Rapid visually moderate to high tumor-specific uptake was identified in GRPR-expressing lesions.

[0178] A phase II clinical trial (NeoFIND; EudraCT number 2017-003432-37) in 19 patients with breast cancer (n=5), prostate cancer (n=5), colorectal cancer (n=5), non-small cell lung cancer (n=3), and small cell lung cancer (n=1) [ 68 The preliminary diagnostic performance of [Ga]Ga-NeoB was evaluated. 68 The safety profile of [Ga]Ga-NeoB was confirmed in this study. Results showed variable [ 68 Ga]Ga-NeoB uptake is shown, where the highest number of lesions show visually moderate to high uptake in breast cancer patients.

[0179] [ 68 Ga]Ga-NeoB has been shown to be effective in the ongoing Phase I / IIa NeoRay trial (EudraCT no. 2018-004727-37) 177 It is currently being used as an imaging agent to select patients for treatment with [Lu]Lu-NeoB. As of October 11, 2022, 41 patients have been treated with [ 68 Received 150-250MBq of Ga]Ga-NeoB and received 150-250MBq of Ga]Ga-NeoB. 68 No safety concerns have been reported regarding Ga]Ga-NeoB.

[0180] In this exam, 68 Ga]Ga-NeoB is 177Lu]Lu-NeoB will be explored as a positron emission tomography (PET) agent for imaging of tumor areas before treatment and during disease progression.

[0181] Rationale for targeting GRPR in glioblastoma The presence of GRPR has been confirmed in various glioma cell lines (Sharif et al., Mol. Cell Endocrinol., 1997;130:119-130; Farias CB et al., Oncology, 2008;75(1-2):27-31). Immunohistochemical (IHC) staining studies evaluated GRPR expression in gliomas of different WHO grades and normal human brain tissues (34 samples from patients with gliomas, 24 of which were glioblastoma multiforme, and 9 normal brain tissue samples from 9 autopsies were selected). GRPR was detected in 100% of the gliomas analyzed. Furthermore, high levels of GRPR expression were observed in tumor endothelial cells. GRPR was not detected in glial cells in normal brain tissue samples; 10–50% of neurons showed GRPR expression at various intensities (Flores et al., 2010, Brain Res Bull;82(1-2):95-8).

[0182] [ 68 Ga]Ga-bombesin analogues[ 68 Dynamic PET imaging studies with [Ga]Ga-BZH3 were performed in patients with highly suspected recurrent glioma. In a total of three WHO grade IV astrocytomas, [ 68 Increased Ga]Ga-BZH3 uptake was visually demonstrated (Dimitrakopoulou-Strauss et al., Clin. Nucl. Med., 2011 Feb;36(2):101-8). In another imaging study, targeting GRPR, 68 PET tracer NOTA-Aca-BBN ([ 68The level of receptor expression in glioma patients was assessed using [Ga]Ga-BBN. Twelve patients with glioma diagnosed by contrast-enhanced MRI were 68 After the [Ga]Ga-BBN injection, patients underwent PET / CT. Within 1 week, the tumors were surgically removed, and IHC staining of tumor samples for GRPR was performed, which correlated with the PET / CT results. In 12 glioma patients (n=2 with glioblastoma multiforme), all MRI-identified lesions were [ 68 The tumors exhibited high signal intensity on PET / CT. Using normal brain tissue as the background, the tumor-to-background ratios based on SUVmax and SUVmean were 24.0 ± 8.85 and 13.4 ± 4.54, respectively. IHC staining confirmed a positive correlation between SUV and GRPR expression levels (r² = 0.71, P < 0.001). No significant differences in SUV were found between lesions of different WHO grades (Zhang et al., J. Nucl. Med., 2018 Jun;59(6):922-928).

[0183] In summary, GRPR has been shown to be highly expressed by IHC staining in glioblastoma multiforme samples. 68 Imaging studies using Ga-labeled BBN analogs have demonstrated robust uptake in patients with high-grade gliomas, including GBM. For radiation-sensitive tumors such as glioblastoma, radiation delivered via targeting specific receptors overexpressed in glioblastoma cancer cells, such as GRPR, in combination with current SoCs (RT and TMZ) may improve outcomes for subjects with newly diagnosed glioblastoma, warranting further investigation. The ultimate therapeutic goal for this patient population is extended survival, yet current treatment alternatives offer limited benefit.

[0184] In some embodiments, the combination of a GRPR radiopharmaceutical of the present disclosure with radiation and optionally other agents provides a synergistic effect for the treatment of glioblastoma.

[0185] Dose justification The starting dose for the dose escalation phase was 100 mCi (3.7 GBq) every 4 weeks (Q4W) [ 177 Based on the data from 50 mCi (cycle 1) + 150 mCi of NeoRay, [ 177 [Lu]Lu-NeoB Q6W was well tolerated as monotherapy, with no DLTs and no G3 / 4 adverse events. Absorbed radiation doses to major organs (kidneys, pancreas, red bone marrow, testes, and ovaries) were low, indicating a low risk of radiation-related toxicity from a single dose.

[0186] GBM is an aggressive, rapidly growing tumor with a high mortality rate, poor long-term survival, and rapid disease progression (i.e., less than 7 months in newly diagnosed patients). 177 [Lu]Lu-NeoB is administered at a shorter interval of Q4W compared to the Q6W schedule in the first NeoRay in human trials. The shorter interval allows for the administration of enough cycles of radioligand therapy to reach a potentially effective cumulative dose in an appropriate time frame.

[0187] [ 177 While the contribution of frequency to safety for Lu]Lu-NeoB has not yet been fully investigated, [ 177 A safety review of blood laboratory parameters over time following administration of [Lu]Lu-NeoB showed no trends for a decline or worsening of hematological parameters. As such, there is no need to allow for a specific recovery period between doses, particularly [ 177 There are no available data to suggest that a higher dosing frequency would compromise the safety of a single dose, as the radioactivity associated with [Lu]Lu-NeoB is rapidly cleared from the body. Therefore, Q4W is 177 This is considered an acceptable dosing frequency for Lu]Lu-NeoB.

[0188] Based on the above information, 177Assuming that Lu]Lu-NeoB is combined with RT and TMZ and the dosing frequency is reduced to Q4W days compared to Q6W in monotherapy (NeoRay trial), the trial will start with a dose of 100 mCi.

[0189] [ 177 Six doses of 11.1 GBq (300 mCi) of [Lu]Lu-NeoB every 4 weeks will be given in this study. Based on currently available dosimetry data from the three dose levels examined in the FIH study (150 mCi, 250 mCi, and 300 mCi), the mean cumulative absorbed doses in the kidneys, pancreas, red bone marrow, testes, and ovaries are significantly below the threshold for external beam radiotherapy (EBRT). To date, the highest examined radiation dose of 11.1 GBq (300 mCi) of [Lu]Lu-NeoB has been used. 177 The margins for six cycles of [Lu]Lu-NeoB were approximately 9-10 times for the pancreas (EBRT threshold of 40 Gy; ICRP et al., 2012), approximately 1.6 times for the red bone marrow (EBRT threshold of 2 Gy; Howard et al., 2017), 1.3-2 times for the testes and ovaries (EBRT thresholds of 1 Gy and 3 Gy; De Felice et al., 2019; Husseinzadeh et al., 1994; Chambers, SK), and 3 times for the kidneys (EBRT threshold of 23 Gy; Emami et al., 1991, Emami, 2013, ICRP, 2012). Calculations are based on the average absorbed doses referenced in Section 2.2 and the EBRT thresholds mentioned above. Margins are proportionally higher for lower starting doses.

[0190] However, applying these EBRT limitations to RLT is likely too conservative due to inherent differences between external beam radiation and radionuclide therapy, including different dose rates and fractionation schemes, heterogeneous absorbed dose distributions, and different radiobiological mechanisms of cytotoxicity potentially resulting in different biological effects (Wessels et al 2008, J Nucl Med;49(11):1884-99; Bergsma et al 2016 Eur J Nucl Med Mol Imaging;43(3):453-63; Bergsma et al 2016 Eur J Nucl Med Mol Imaging;43(10):1802-11). In fact, (Bodei, 2008, Eur J Nucl Med Mol Imaging;35(10):1847-56; Schaefer 2022, Extensive 177 Lu-PSMA Radioligand Therapy Can Lead to Radiation Nephropathy with a Renal Thrombotic Microangiopathy-like Picture. EurUrol), with a biologically effective dose (BED) of approximately 40 Gy, due to a conversion factor of 1.09 for converting absorbed dose to BED. 177 There is growing evidence that Lu-labeled RLT is safe for the kidney. Therefore, even with cycles greater than six, there may be minimal concern about radiation-induced toxicity, as the organ may be able to tolerate higher radiation doses.

[0191] Based on the above evidence, there is a margin for dosing for more than six cycles. 177 Up to four additional doses of Lu]Lu-NeoB beyond the planned six doses may be administered in this study based on individual benefit-risk assessments performed by the treating physician and in agreement with the study participants; treatment tolerability, clinical benefit, and in agreement with the sponsor 177 This can be considered to be based on the participants' desire to continue with Lu]Lu-NeoB.

[0192] [177 To proceed with each of the four additional doses above six of [Lu]Lu-NeoB, the investigator must determine if: Participants demonstrate evidence of disease stabilization or response (i.e., radiologically or clinically assessed). Participants do not show any signs or symptoms of clinical deterioration Participants can click 177 Lu]Lu-NeoB treatment was well tolerated, and the following [ 177 Lu] not resolved before Lu-NeoB administration, leading to treatment interruption, 177 No SAEs have been recorded for Lu]Lu-NeoB.

[0193] If the patient meets all of the above criteria and 177 If the patient agrees to continue further treatment with Lu]Lu-NeoB, the investigator must, in agreement with the sponsor, 177 Up to four additional doses of [Lu]Lu-NeoB (ie, up to 10 doses total) can be administered.

[0194] experimental drug In this clinical trial, the term "investigational drug" refers to the radioligand imaging compound used to probe GRPR expression. 68 Ga]Ga-NeoB, and used as radioligand therapy [ 177 Lu] refers to Lu-NeoB.

[0195] The term "investigative drug" refers to 177 Lu]Lu-NeoB, refers to the combination of temozolomide (TMZ) and radiation therapy (RT).

[0196] [Table 4]

[0197] [ 177 Lu]Lu-NeoB [ 177Lu]Lu-NeoB has a volume activity of 370 megabecquerels (MBq) / mL at the reference day and time (calibration time (tc)) [ 177 It is a sterile radiopharmaceutical supplied as a ready-to-use solution for injection containing [Lu]Lu-NeoB. 177 The starting dose level of Lu]Lu-NeoB is 100 mCi.

[0198] [ 177 Lu]Lu-NeoB is administered every 4 weeks for up to 6 doses, starting on week 1, day 1. In exceptional cases, patients may 177 If patients tolerate and benefit from [Lu]Lu-NeoB, they may receive up to 10 doses; further details are outlined in Section 4.3. 177 Intrapatient dose escalation is not permitted for [Lu]Lu-NeoB.

[0199] TMZ and RT administration were 177 Lu] should be initiated 7 to 10 days after the first dose of Lu-NeoB.

[0200] TMZ should be administered at a dose of 75 mg / m during the concomitant use with RT, according to the approved prescribing information. 2 It is administered orally at a dose of 100 mg / day.

[0201] RT was delivered at a dose of 2 Gy / day, 5 days per week for 6 consecutive weeks (followed by 2 days of rest), for a total dose of 60 Gy (without interruptions).

[0202] During the maintenance treatment period, intrapatient dose escalation with TMZ treatment occurs. For the same patient, if 150 mg / m2 of TMZ treatment is well tolerated, the dose of TMZ is 150 mg / m2 for 5 days at week 12 and 200 mg / m2 for 5 days at weeks 16, 20, 24, 28, and 32. Please refer to the approved prescribing information for further details.

[0203] [ 68 Ga]Ga-NeoB [ 68The kit for radioactive preparation of [Ga]Ga-NeoB contains 50 μg of NeoB. In this study, [Ga]Ga-NeoB was used as an imaging agent for PET / CT or PET / MRI. 68 Ga]Ga-NeoB is used.

[0204] After radiolabeling with Ga-68, [ 68 [Ga]Ga-NeoB is used in positron emission tomography (PET) for the localization of GRPR-positive tumors.

[0205] [ 68 [Ga]Ga-NeoB is administered as a single intravenous (intravenous) dose with an activity of 150 and 250 MBq (4.1 to 6.8 mCi).

[0206] After reconfiguration, [ 68 [Ga]Ga-NeoB is administered by slow intravenous injection. Images should be acquired 120 ± 30 minutes after intravenous administration.

[0207] Eligibility Screening Participants will be assessed against study inclusion and exclusion criteria and safety assessments. If deviations from normal range values ​​are noted in screening laboratory results, repeat laboratory evaluations will be permitted. If the repeated laboratory results fall within the laboratory's normal range, they will be used to test for enrollment eligibility.

[0208] During the screening period, gadolinium-enhanced MRI images and findings performed during routine pre-operative workups are required for eligibility assessment and will be collected in a clinical database. In addition, post-operative MRI findings will also be collected.

[0209] During the screening period, 68 Ga]Ga-NeoB PET / CT (or PET / MRI) was performed 2 weeks after surgery / biopsy and at 1 week after the investigational drug [ 177 Lu] must be performed within a time interval beginning at least 3 days before administration of Lu-NeoB. 68Ga]Ga-NeoB PET / CT will not be used for eligibility assessment but will be used for exploratory purposes.

[0210] [ 68 Ga]Ga-NeoB PET scan [ 68 Ga]Ga-NeoB PET / CT or PET / MRI were performed at baseline, at least 2 weeks after surgery / biopsy of tumor lesions, and 177 In the event of disease progression, PET / CT or PET / MRI will be performed to assess GRPR expression in the tumor.

[0211] The PET / CT or PET / MRI will be a head-specific acquisition performed 120 ± 30 minutes after injection of 150–250 MBq (4.1–6.8 mCi) of radiotracer. PET scans will be read locally by the same local radiologist / nuclear medicine physician throughout the study, if possible.

[0212] in the tumor area (guided by postoperative MRI findings at baseline and MRI findings confirming disease progression for PET scans obtained with progressive disease) 68 [Ga]Ga-NeoB uptake will be assessed both visually and semiquantitatively. Visual assessment will record the pattern (focal or diffuse, homogeneous or heterogeneous) and degree of uptake (mild, moderate, or severe). Semiquantitative assessment will include SUVmax, SUVmean, and uptake-to-background ratio (UBR). Background activity will be considered as uptake within regions of healthy brain parenchyma (e.g., the contralateral hemisphere, if spared).

Claims

1. 1. A method of treating glioblastoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound in combination with radiation therapy, wherein the radiopharmaceutical compound has Formula (I): C-S-P (I) (In the formula, C is a chelating moiety; P is a GRP receptor antagonist moiety; S is an optional spacer that covalently links C and P. or a pharmaceutically acceptable salt thereof, which is labeled with a radionuclide M.

2. 10. The method of claim 1, further comprising administering a therapeutically effective amount of an alkylating agent.

3. 3. The method of claim 2, wherein the alkylating agent is temozolomide.

4. The alkylating agent, preferably temozolomide, is administered at 50-100 mg / m daily during the induction period, concurrently with radiation therapy. ２ / day, preferably about 75 mg / m ２ 4. The method according to claim 2 or 3, wherein the compound is administered at a dose of 0.1 mg / day for a period typically of 4 to 8 weeks, preferably 6 weeks.

5. The alkylating agent, preferably temozolomide, is administered at 50-400 mg / m daily during the maintenance phase following the induction phase after radiation therapy. ２ / day, preferably 75 to 300 mg / m ２ / day, more preferably 150-200 mg / m ２ / day for 5 consecutive days followed by 2 days rest every 28 days for a period of 20 to 28 weeks, preferably 24 weeks.

6. 6. The method of any one of claims 2 to 5, wherein both the radiotherapy and the alkylating agent, preferably temozolomide, are started on the same day, e.g., 7 to 10 days after the first administration of the radiopharmaceutical compound.

7. The method according to any one of claims 2 to 6, wherein the alkylating agent, preferably temozolomide, is administered simultaneously with the radiotherapy without interruption during the induction phase.

8. 8. The method of any one of claims 2 to 7, wherein the alkylating agent, preferably temozolomide, is administered initially daily for a period of, for example, 6 consecutive weeks during co-administration with the radiotherapy.

9. The radionuclide M is 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 9. The method of claim 1, wherein the hydroxybenzoates are selected from the group consisting of hydroxybenzoates, ...

10. M, １７７ 10. The method of claim 9, wherein Lu is

11. C is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetraxetan), trizoxetan, 1,4,7,10-tetraazacyclododecane, 1(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramine (TETA), 1,4,7-triaza 11. The method of any one of claims 1 to 10, obtained by grafting onto S or P a chelating agent selected from cyclononane-1,4,7-triacetic acid (NOTA), NOTAGA, 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane (NODAGA), NODASA, NODAPA, and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA, e.g., AAZTA5).

12. C is of the following formula: 【Chemistry 1】 The method of claim 11, wherein

13. P is a compound of the general formula DPhe-Gln-Trp-Ala-Val-Gly-His-Z (where Z is Leu−ψ(CH ２ N)-Pro-NH ２ and NH—CH(CH ２ -CH(CH ３ ) ２ ) ２ Is it selected from Or Z is 【Chemistry 2】 where X is NH (amide) and R2 is (CH ２ -CH(CH ３ ) ２ and R1 is the same as R2 or (CH ２ N)-Pro-NH ２ is) The method according to any one of claims 1 to 12, wherein

14. P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH ２ -CH(CH ３ ) ２ ) ２ The method of claim 13, wherein

15. The compound of formula (I) is the following compound of formula (II): 【Transformation 3】 wherein C and P are as defined in claim 1 and any one of claims 11 to 14, and said chelating moiety C is complexed with a radionuclide M. The method according to any one of claims 1 to 14, wherein

16. The radiopharmaceutical compound has the following formula (III): 【Chemistry 4】 wherein M is a radionuclide, preferably M is １７７ Lu) The method according to any one of claims 1 to 15, wherein the compound is M-NeoB or a pharmaceutically acceptable salt thereof.

17. The method of any one of claims 1 to 16, wherein the radiopharmaceutical compound is administered 1 to 10 times per treatment, preferably 4 to 10 times per treatment, more preferably 6 to 8 times per treatment.

18. 18. The method of claim 17, wherein treatment with the radiopharmaceutical compound comprises an administration interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 weeks or 4 weeks, more preferably every 4 weeks.

19. 19. The method of any one of claims 1 to 18, wherein the radiopharmaceutical compound is administered to the subject in multiple treatments, preferably 2 to 3 treatments, with a break of 2 to 12 months between treatments.

20. 20. The method of any one of claims 1 to 19, wherein the radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), preferably 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), preferably 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), more preferably 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), even more preferably 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) per administration.

21. 21. The method of any one of claims 1 to 20, wherein the radiotherapy comprises irradiating the subject with a total dose of 40 to 80 Gy, such as 60 Gy.

22. 22. The method according to any one of claims 1 to 21, wherein said radiotherapy is administered at a dose of 1 Gy to 4 Gy / day, preferably about 2 Gy / day, for a period of 3 to 7 days, preferably about 5 days per week, over a period of 4 to 8 weeks, preferably 6 weeks.

23. 23. The method of any one of claims 1 to 22, wherein the radiotherapy is initiated 7 to 10 days after the first administration of the radiopharmaceutical compound.

24. The method of any one of claims 1 to 23, wherein the subject is newly diagnosed with glioblastoma.

25. 25. The method of any one of claims 1 to 24, wherein the subject is selected from subjects with a positive methylated O-6-methylguanine-DNA methyltransferase promoter status.

26. The method of any one of claims 1 to 25, wherein the radiation therapy is whole brain irradiation.

27. 27. The method of any one of claims 1 to 26, wherein said subject has been selected by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging using the same radiopharmaceutical compound as defined for said treatment, but prior to any surgery, for example 2 weeks prior to the start of said treatment, with an alternative radionuclide or contrast agent suitable for imaging, preferably 68-gallium, 67-gallium or 64-copper, more preferably 68-gallium, based on detection of said radionuclide in an imaging scan in the area of ​​the tumor.

28. 28. The method of claim 27, wherein the subject is selected from subjects who, prior to any surgery, show the presence of alternative radionuclide or contrast agent enhancement, such as gadolinium enhancement, in a PET / MRI scan in the tumor region.

29. 29. The method of any one of claims 1 to 28, wherein the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and wherein the radiopharmaceutical compound is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide, and the first administration of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy.

30. 29. The method of any one of claims 1 to 28, wherein the subject is newly diagnosed with glioblastoma and has a negative methylated O-6-methylguanine-DNA methyltransferase promoter status, and wherein the radiopharmaceutical compound is administered to the subject at least six times in combination with radiation therapy and further in combination with temozolomide, wherein the administration interval between two administrations of the radiopharmaceutical compound is four weeks, and the first administration of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy and temozolomide.

31. The radiopharmaceutical compound has the following formula: 【Transformation 5】 (Wherein M is １７７ 31. The method of claim 29 or 30, wherein M-NeoB is M-NeoB of formula (I).

32. The radiopharmaceutical compound has the following formula: 【Transformation 6】 (Wherein M is １７７ 31. The method of any one of claims 1 to 30, wherein the M-NeoB is M-NeoB of 370 MBq / mL.

Images