Methods for treating glioblastoma

Abstract

The present disclosure relates to a method of treating glioblastoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical compound having a GRPR antagonist moiety, preferably [177Lu] 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 methods for treating glioblastoma in a subject in need thereof, wherein a therapeutically effective amount of a radiopharmaceutical compound comprising a GRPR antagonist moiety, such as [ 177 Lu]Lu-NeoB in combination with radiation therapy and optionally other adjuvant therapies. Background Art

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

[0003] The overall age-adjusted incidence of glioblastoma in the United States is 3.22 per 100,000 people, with the highest incidence between the ages of 75 and 79. The incidence is higher in men and increases with age at diagnosis. Glioblastoma contributes disproportionately to morbidity and mortality, with an overall 5-year relative survival rate of only 6.8%, which varies by age at diagnosis and sex (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 among malignant brain tumors (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, the median overall survival (OS) is estimated to be in the range of 3.5-6 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 consists of the alkylating agent temozolomide in combination with radiotherapy, which was approved in 2005 based on the results of a large randomized phase III trial comparing radiotherapy with radiotherapy followed by daily temozolomide followed by maintenance temozolomide alone. The results showed a statistically significant improvement in both progression-free survival (PFS) and overall survival (OS), with a median PFS of 6.9 months in the radiotherapy plus temozolomide group and 5 months in the radiotherapy group (P<0.001), and a median OS of 14.6 months and 12.1 months, respectively (P<0.001) (Stupp et al. 2005, N Engl J Med; 352(10):987-96).

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

[0007] Trials combining immunotherapy with standard of care therapy are underway in the newly diagnosed setting, with radiotherapy in patients with newly diagnosed glioblastoma who have unmethylated MGMT promoter status (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 methylated MGMT promoter status (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 [Phase 3 trial of chemoradiotherapy combined with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma targeting the methylated MGMT promoter]. NeuroOncol [Neuro-Oncology]) A phase 3 clinical trial with the PD-1 inhibitor nivolumab (NIVO) combined with standard of care radiation therapy and temozolomide (relative to SoC) failed to show an improvement in overall survival. CheckMate-498 showed that the median OS (mOS) was 13.4 months for patients treated with NIVO+RT and 14.9 months for patients in the temozolomide+RT group (HR, 1.31; P = .0037). Patients with methylated MGMT promoter status included in CheckMate-548 showed an mOS of 28.9 months and 32.1 months in the NIVO+radiotherapy+temozolomide group and in the placebo+RT+temozolomide group, respectively (HR, 1.1).

[0008] Based on the results of a phase 3 trial, the United States and several EU countries have approved the use of alternating electric fields (TTF, tumor treating fields) as an adjunct to temozolomide maintenance in newly diagnosed glioblastoma, in which median OS and PFS were significantly prolonged. The median overall survival was 20.9 months in the TTField-temozolomide group, compared with 16.0 months in the temozolomide alone group (HR, 0.63; P < .001) (Stupp et al., JAMA [Journal of the American Medical Association], 2017; 318(23): 2306-2316). Despite the positive phase 3 results, the use of TTF remains controversial and is not widely used in Europe (Lassman et al. 2020, Current usage of tumor treating fields for glioblastoma [Current usage of tumor treating fields for glioblastoma]. Neurooncol Adv [Progress in Neuro-Oncology]; 2(1): vdaa069).

[0009] Current guidelines still recommend RT and concomitant temozolomide for newly diagnosed glioblastoma, followed by maintenance temozolomide (Nabors et al. 2020, J Natl Compr Canc Netw [Journal of the National Comprehensive Cancer Network]; 18(11):1537-1570; Weller et al. 2021, Nat Rev Clin Oncol [Nature Reviews - Clinical Oncology]; 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 in a variety of cancers, including gliomas / glioblastomas (Flores et al. 2010, Brain Res Bull; 82(1-2):95-8).

[0012] NeoB peptides are new generation bombesin analogs that bind to GRPR with high affinity (half maximal inhibitory concentration (IC50) 1-2 nM, Nock et al. J. Nucl. Med. 2017;58(1):75-80) and show low internalization, consistent with the antagonistic behavior of the peptide. NeoB peptides contain a DOTA metal chelator in their structure, which allows radiolabeling with different radionuclides, including gallium-68 (for PET imaging), lutetium-177 (for radionuclide therapy), and other related radionuclides, which enables the therapeutic diagnostic use of NeoB without affecting receptor affinity, internalization properties, or biodistribution. In nonclinical models, [ 68 Ga]Ga-NeoB and [ 177 Lu]-Lu NeoB has been shown to have high affinity for GRPR overexpressed in breast tumors, prostate tumors, gastrointestinal stromal tumors (GISTs) and gliomas (including glioblastomas) (Flores et al. 2010, supra, Morgat et al., J. Nucl. Med. 2017;58(9):1401-1407) and low internalization after binding to specific receptors.

[0013] The ability of radiolabeled compounds to target GRPR-expressing tumors has been demonstrated in in vivo imaging and biodistribution studies in tumor models.[ 177 Lu]Lu-NeoB is rapidly cleared from the blood and is quickly eliminated by the renal system without retention in the kidneys. Background radioactivity was observed in GRPR-expressing tissues (mainly the pancreas), but this background radioactivity decreased over time, consistent with the GRPR antagonist spectrum. On the contrary, tumor remanence was continuous, and uptake values ​​could be detected within 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-47DCells and Tumor-Bearing Mice [NeoBOMB1, a GRPR antagonist for breast cancer therapy and diagnosis: [ 67[Ga] Preliminary results of preclinical studies of 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 is a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0015] CSP(I)

[0016] in:

[0017] C is the chelating moiety,

[0018] P is the GRP receptor antagonist part,

[0019] S is an optional spacer that covalently links C and P,

[0020] And wherein the radiopharmaceutical compound is labeled with a radionuclide M.

[0021] This disclosure provides for various aspects as outlined below:

[0022] 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 is a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0023] CSP(I)

[0024] in:

[0025] C is the chelating moiety,

[0026] P is the GRP receptor antagonist part,

[0027] S is an optional spacer that covalently links C and P,

[0028] And wherein the radiopharmaceutical compound is labeled with a radionuclide M.

[0029] 2. The method of embodiment 1, wherein the method further comprises administering a therapeutically effective amount of an alkylating agent.

[0030] 3. The method of embodiment 2, wherein the alkylating agent is temozolomide.

[0031] 4. The method of embodiment 2 or 3, wherein the alkylating agent, preferably temozolomide, is administered daily at a dose of 50 to 100 mg / m2 during the induction phase. 2 / day, preferably about 75 mg / m 2 A dose of 100 mg / day is administered concomitantly with radiation therapy, typically for a period of 4 to 8 weeks, preferably 6 weeks.

[0032] 5. The method of embodiment 4, wherein the alkylating agent, preferably temozolomide, is administered after radiotherapy at a dose of 50 to 400 mg / m2 per day during the maintenance period following the induction period. 2 / day, preferably 75 to 300 mg / m 2 / day, more preferably 150 to 200 mg / m 2 The dosage is administered daily for 5 consecutive days, followed by a 2-day rest, every 28 days for a period of 20 to 28 weeks, preferably 24 weeks.

[0033] 6. The method of any one of embodiments 2-5, wherein the radiation therapy and the alkylating agent, preferably temozolomide, are both started on the same day, for example 7 to 10 days after the first administration of the radiopharmaceutical compound.

[0034] 7. The method of any one of embodiments 2-6, wherein the alkylating agent, preferably temozolomide, is administered concomitantly with the radiation therapy during the induction phase without interruption.

[0035] 8. The method of any one of embodiments 2-7, wherein the alkylating agent, preferably temozolomide, is administered in a first dose daily during concomitant administration with the radiation therapy, eg, for a period of 6 consecutive weeks.

[0036] 9. The method of any one of embodiments 1-8, wherein the radionuclide M is selected from 90 Y. 131 I. 121 Sn, 186 Re、 188 Re、 64 Cu, 67 Cu, 59 Fe, 89 Sr. 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Such as 149 Tb, 161 Tb, 213 Bi, 166Ho, 165 Second, 169 Second, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At 67 Cu, 186 Re、 188 Re、 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As、 111 Ag and 47 Sc.

[0037] 10. The method of embodiment 9, wherein M is 177 Lu.

[0038] 11. The method of any one of embodiments 1-10, wherein C is obtained by grafting to S or P, and C is a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Titan), Tritan, 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-1,4,7,10-tetra ... Heterocyclododecane-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, such as AAZTA5).

[0039] 12. The method of embodiment 11, wherein C has the formula,

[0040]

[0041] 13. The method of any one of embodiments 1-12, wherein P has the formula

[0042] DPhe-Gln-Trp-Ala-Val-Gly-His-Z

[0043] wherein Z is selected from Leu-ψ(CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2

[0044] Or Z is

[0045]

[0046] wherein X is NH(amide) and R2 is (CH2-CH(CH3)2, and R1 and R2 are the same or are (CH2N)-Pro-NH2.

[0047] 14. The method of embodiment 13, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2.

[0048] 15. The method of any one of embodiments 1-14, wherein the compound of formula (I) is a compound of formula (II)

[0049]

[0050] wherein C and P are as defined in any one of claims 1 and 11-14, and wherein the chelating moiety C is complexed with the radionuclide M.

[0051] 16. The method of any one of embodiments 1-15, wherein the radiopharmaceutical compound is M-NeoB having the following formula (III):

[0052] (III),

[0053] or a pharmaceutically acceptable salt thereof,

[0054] wherein M is a radionuclide, preferably M is 177 Lu.

[0055] 17. The method of any one of embodiments 1-16, wherein the radiopharmaceutical compound is administered 1 to 10 times / treatment, preferably 4 to 10 times / treatment, more preferably 6 to 8 times / treatment.

[0056] 18. The method of embodiment 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 or 4 weeks, more preferably once every 4 weeks.

[0057] 19. The method of any one of embodiments 1-18, wherein the radiopharmaceutical compound is administered to the subject in multiple treatments, preferably 2-3 treatments, with a 2-12 month pause between treatments.

[0058] 20. The method of any one of embodiments 1-19, wherein the radiopharmaceutical compound is administered at a dose within 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.

[0059] 21. The method of any one of embodiments 1-20, wherein the radiation therapy comprises irradiating the subject with a total dose of 40-80 Gy, eg, 60 Gy.

[0060] 22. The method of any one of embodiments 1-21, wherein the radiation therapy is performed at a dose of 1 Gy to 4 Gy / day, preferably about 2 Gy / day, during a period of 3 to 7 days, preferably about 5 days per week, over a period of 4 to 8 weeks, preferably 6 weeks.

[0061] 23. The method of any one of embodiments 1-22, wherein the radiation therapy begins 7-10 days after the first administration of the radiopharmaceutical compound.

[0062] 24. The method of any one of embodiments 1-23, wherein the subject is newly diagnosed with glioblastoma.

[0063] 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.

[0064] 26. The method of any one of embodiments 1-25, wherein the radiation therapy is whole brain irradiation.

[0065] 27. The method of any one of embodiments 1-26, wherein the subject has been imaged by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI prior to any surgery, e.g., two weeks prior to the start of the treatment, using the same radiopharmaceutical compound as defined for the treatment, but using an alternative radionuclide or contrast agent suitable for imaging, preferably 68-gallium, 67-gallium or 64-copper, more preferably 68-gallium, selected based on detection of the radionuclide in imaging scans of the tumor area.

[0066] 28. The method of embodiment 27, wherein the subject is selected from subjects who have demonstrated the presence of alternative radionuclide or contrast agent enhancement, such as gadolinium enhancement, on a PET / MRI scan of the tumor area prior to any surgery.

[0067] 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, wherein the radiopharmaceutical compound is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide, wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days prior to the start of radiation therapy.

[0068] 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, wherein the radiopharmaceutical compound is administered to the subject at least 6 times in combination with radiation therapy and further in combination with temozolomide, and wherein the administration interval between two administrations of the radiopharmaceutical compound is 4 weeks, and wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy and temozolomide.

[0069] 31. The method of embodiment 29 or 30, wherein the radiopharmaceutical compound is M-NeoB having the formula:

[0070]

[0071] where M is 177 Lu.

[0072] 32. The method of any one of embodiments 1-30, wherein the radiopharmaceutical compound is M-NeoB having the formula:

[0073]

[0074] where M is 177Lu, and the radiopharmaceutical compound was administered by intravenous infusion at a concentration of 370 MBq / mL.

[0075] 33. A radiopharmaceutical compound for use in a method of treating glioblastoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the radiopharmaceutical compound in combination with radiation therapy, wherein the radiopharmaceutical compound is a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0076] CSP(I)

[0077] in:

[0078] C is the chelating moiety,

[0079] P is the GRP receptor antagonist part,

[0080] S is an optional spacer that covalently links C and P,

[0081] And wherein the radiopharmaceutical compound is labeled with a radionuclide M.

[0082] 34. A radiopharmaceutical compound for use as described in embodiment 33, wherein the method further comprises administering a therapeutically effective amount of an alkylating agent.

[0083] 35. A radiopharmaceutical compound for use as described in embodiment 34, wherein the alkylating agent is temozolomide.

[0084] 36. A radiopharmaceutical compound for use as described in embodiment 34 or 35, wherein the alkylating agent, preferably temozolomide, is administered daily at a dose of 50 to 100 mg / m2 during the induction phase. 2 / day, preferably about 75 mg / m 2 The dosage is administered daily, typically for a period of 4 to 8 weeks, preferably 6 weeks.

[0085] 37. A radiopharmaceutical compound for use as described in Example 36, wherein the alkylating agent, preferably temozolomide, is administered daily at a dose of 50 to 400 mg / m2 during the maintenance period following the induction period. 2 / day, preferably 75 to 300 mg / m 2 / day, more preferably 150 to 200 mg / m 2 The dosage is administered daily for 5 consecutive days, followed by a 2-day rest, every 28 days for a period of 20 to 28 weeks, preferably 24 weeks.

[0086] 38. A radiopharmaceutical compound for use as described in any one of embodiments 34-37, wherein the radiotherapy and the alkylating agent, preferably temozolomide, are both started on the same day, for example 7 to 10 days after the first administration of the radiopharmaceutical compound.

[0087] 39. A radiopharmaceutical compound for use as described in any one of embodiments 34-38, wherein the alkylating agent, preferably temozolomide, is administered concomitantly with the radiotherapy during the induction phase without interruption.

[0088] 40. A radiopharmaceutical compound for use as described in any one of embodiments 34-39, wherein the alkylating agent, preferably temozolomide, is administered in a first dose daily during concomitant administration with the radiotherapy, eg for a period of 6 consecutive weeks.

[0089] 41. A radiopharmaceutical compound for use as described in any one of embodiments 33-40, wherein the radionuclide M is selected from 90 Y. 131 I. 121 Sn, 186 Re、 188 Re、 64 Cu, 67 Cu, 59 Fe, 89 Sr. 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Such as 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Second, 169 Second, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At 67 Cu, 186 Re、 188 Re、 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr,143 Pr, 76 As、 111 Ag and 47 Sc.

[0090] 42. A radiopharmaceutical compound for use as described in Example 41, wherein M is 177 Lu.

[0091] 43. A radiopharmaceutical compound for use as described in any one of embodiments 33-42, wherein C is obtained by grafting to S or P, and C is a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Titan), Tritan, 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-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, such as AAZTA5).

[0092] 44. A radiopharmaceutical compound for use as described in Example 43, wherein C has the formula:

[0093]

[0094] 45. A radiopharmaceutical compound for use as described in any one of embodiments 33-44, wherein P has the general formula

[0095] DPhe-Gln-Trp-Ala-Val-Gly-His-Z

[0096] wherein Z is selected from Leu-ψ(CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2

[0097] Or Z is

[0098]

[0099] wherein X is NH(amide) and R2 is (CH2-CH(CH3)2, and R1 and R2 are the same or are (CH2N)-Pro-NH2.

[0100] 46. ​​A radiopharmaceutical compound for use as described in embodiment 45, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2.

[0101] 47. A radiopharmaceutical compound for use as described in any one of embodiments 33-46, wherein the compound of formula (I) is a compound of formula (II)

[0102]

[0103] wherein C and P are as defined in claim 1, and wherein the chelating moiety C is complexed with the radionuclide M.

[0104] 48. A radiopharmaceutical compound for use as described in any one of embodiments 33-47, wherein the radiopharmaceutical compound is M-NeoB having the following formula (III):

[0105] (III),

[0106] or a pharmaceutically acceptable salt thereof,

[0107] wherein M is a radionuclide, preferably M is 177 Lu.

[0108] 49. A radiopharmaceutical compound for use as described in any one of embodiments 33-48, wherein the radiopharmaceutical compound is administered 1 to 10 times / treatment, preferably 4 to 10 times / treatment, more preferably 6 to 8 times / treatment.

[0109] 50. A radiopharmaceutical compound for use as described in embodiment 49, 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 or 4 weeks, more preferably once every 4 weeks.

[0110] 51. A radiopharmaceutical compound for use as described in any one of embodiments 33-50, wherein the radiopharmaceutical compound is administered to the subject in multiple treatments, preferably 2-3 treatments, with a 2-12 month pause between treatments.

[0111] 52. A radiopharmaceutical compound for use as described in any one of embodiments 33-51, 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.

[0112] 53. A radiopharmaceutical compound for use as described in any one of embodiments 33-52, wherein the radiation therapy comprises irradiating the subject with a total dose of 40-80 Gy, such as 60 Gy.

[0113] 54. A radiopharmaceutical compound for use as described in any one of embodiments 33-53, wherein the radiotherapy is performed at a dose of 1 Gy to 4 Gy / day, preferably about 2 Gy / day, during a period of 3 to 7 days, preferably about 5 days per week, over a period of 4 to 8 weeks, preferably 6 weeks.

[0114] 55. A radiopharmaceutical compound for use as described in any one of embodiments 33-54, wherein the radiation therapy is started 7-10 days after the first administration of the radiopharmaceutical compound.

[0115] 56. A radiopharmaceutical compound for use as described in any one of embodiments 33-55, wherein the subject is newly diagnosed with glioblastoma.

[0116] 57. A radiopharmaceutical compound for use as described in any one of embodiments 33-56, wherein the subject is selected from subjects with a positive methylated O-6-methylguanine-DNA methyltransferase promoter status.

[0117] 58. A radiopharmaceutical compound for use as described in any one of embodiments 33-57, wherein the radiation therapy is whole brain irradiation.

[0118] 59. A radiopharmaceutical compound for use as described in any one of embodiments 33-58, wherein the subject has been imaged by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI prior to any surgery, e.g., two weeks before the start of the treatment, using the same radiopharmaceutical compound as defined for the treatment but using an alternative radionuclide or contrast agent suitable for imaging, preferably 68-gallium, 67-gallium or 64-copper, more preferably 68-gallium, selected based on detection of the radionuclide in the imaging scan of the tumor area.

[0119] 60. A radiopharmaceutical compound for use as described in embodiment 59, wherein the subject is selected from subjects who have demonstrated the presence of an alternative radionuclide or contrast agent enhancement, such as gadolinium enhancement, on a PET / MRI scan of the tumor area prior to any surgery.

[0120] 61. A radiopharmaceutical compound for use as described in any one of embodiments 33-60, wherein the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, wherein the radiopharmaceutical compound is administered to the subject in combination with radiotherapy and an alkylating agent, preferably temozolomide, wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before starting radiotherapy.

[0121] 62. A radiopharmaceutical compound for use as described in any one of embodiments 33-60, wherein the subject is newly diagnosed with glioblastoma and has a negative methylated O-6-methylguanine-DNA methyltransferase promoter status, wherein the radiopharmaceutical compound is administered to the subject at least 6 times in combination with radiation therapy and further in combination with temozolomide, and wherein the administration interval between two administrations of the radiopharmaceutical compound is 4 weeks, and wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy and temozolomide.

[0122] 63. A radiopharmaceutical compound for use as described in embodiment 61 or 62, wherein the radiopharmaceutical compound is M-NeoB having the formula:

[0123]

[0124] where M is 177 Lu.

[0125] 64. A radiopharmaceutical compound for use as described in any one of embodiments 1-62, wherein the radiopharmaceutical compound is M-NeoB having the formula:

[0126]

[0127] where M is 177 Lu, and the radiopharmaceutical compound was administered by intravenous infusion at a concentration of 370 MBq / mL.

[0128] 65. Use of a radiopharmaceutical compound in the manufacture of a medicament for use in a method of treating glioblastoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the radiopharmaceutical compound in combination with radiation therapy, wherein the radiopharmaceutical compound is a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0129] CSP(I)

[0130] in:

[0131] C is the chelating moiety,

[0132] P is the GRP receptor antagonist part,

[0133] S is an optional spacer that covalently links C and P,

[0134] And wherein the radiopharmaceutical compound is labeled with a radionuclide M.

[0135] 66. The use of embodiment 65, wherein the method further comprises administering a therapeutically effective amount of an alkylating agent.

[0136] 67. The use of embodiment 66, wherein the alkylating agent is temozolomide.

[0137] 68. The use according to embodiment 66 or 67, wherein the alkylating agent, preferably temozolomide, is administered daily at a dose of 50 to 100 mg / m2 during the induction phase. 2 / day, preferably about 75 mg / m 2 The dosage is administered daily, typically for a period of 4 to 8 weeks, preferably 6 weeks.

[0138] 69. The use according to embodiment 68, wherein the alkylating agent, preferably temozolomide, is administered daily at a dose of 50 to 400 mg / m2 during the maintenance phase following the induction phase. 2 / day, preferably 75 to 300 mg / m 2 / day, more preferably 150 to 200 mg / m 2 The dosage is administered daily for 5 consecutive days, followed by a 2-day rest, every 28 days for a period of 20 to 28 weeks, preferably 24 weeks.

[0139] 70. The use of any one of embodiments 66-69, wherein both the radiotherapy and the alkylating agent, preferably temozolomide, are started on the same day, eg, 7 to 10 days after the first administration of the radiopharmaceutical compound.

[0140] 71. The use according to any one of embodiments 66-70, wherein the alkylating agent, preferably temozolomide, is administered concomitantly with the radiotherapy during the induction phase without interruption.

[0141] 72. The use of any one of embodiments 66-71, wherein the alkylating agent, preferably temozolomide, is administered in a first dose daily during concomitant administration with the radiotherapy, eg, for a period of 6 consecutive weeks.

[0142] 73. The use of any one of embodiments 65-72, wherein the radionuclide M is selected from 90 Y. 131 I. 121 Sn, 186 Re、 188 Re、 64 Cu, 67 Cu, 59 Fe, 89 Sr. 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Such as 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Second, 169 Second, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At 67 Cu, 186 Re、 188 Re、 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As、111 Ag and 47 Sc.

[0143] 74. The use of embodiment 73, wherein M is 177 Lu.

[0144] 75. The use of any one of embodiments 65-73, wherein C is obtained by grafting to S or P, and C is a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Titan), Tritan, 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-1,4,7,10-tetra ... Heterocyclododecane-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, such as AAZTA5).

[0145] 76. The use of embodiment 75, wherein C has the formula,

[0146]

[0147] 77. The use of any one of embodiments 65-76, wherein P has the formula

[0148] DPhe-Gln-Trp-Ala-Val-Gly-His-Z

[0149] wherein Z is selected from Leu-ψ(CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2

[0150] Or Z is

[0151]

[0152] wherein X is NH(amide) and R2 is (CH2-CH(CH3)2, and R1 and R2 are the same or are (CH2N)-Pro-NH2.

[0153] 78. The use of embodiment 77, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2.

[0154] 79. The use of any one of embodiments 65-78, wherein the compound of formula (I) is a compound of formula (II)

[0155]

[0156] wherein C and P are as defined in any one of claims 65 and 75-78, and wherein the chelating moiety C is complexed with the radionuclide M.

[0157] 80. The use of any one of embodiments 65-79, wherein the radiopharmaceutical is M-NeoB having the following formula (III):

[0158] (III),

[0159] or a pharmaceutically acceptable salt thereof,

[0160] wherein M is a radionuclide, preferably M is 177 Lu.

[0161] 81. The use of any one of embodiments 65-80, wherein the radiopharmaceutical compound is administered 1 to 10 times / treatment, preferably 4 to 10 times / treatment, more preferably 6 to 8 times / treatment.

[0162] 82. The use of embodiment 81, wherein the 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 or 4 weeks, more preferably once every 4 weeks.

[0163] 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 2-12 month pause between treatments.

[0164] 84. The use of any one of embodiments 65-83, wherein the radiopharmaceutical compound is administered at a dose within 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.

[0165] 85. The use of any one of embodiments 65-84, wherein the radiation therapy comprises irradiating the subject with a total dose of 40-80 Gy, eg, 60 Gy.

[0166] 86. The use of any one of embodiments 65-85, wherein the radiotherapy is performed at a dose of 1 Gy to 4 Gy / day, preferably about 2 Gy / day, during a period of 3 to 7 days, preferably about 5 days per week, over a period of 4 to 8 weeks, preferably 6 weeks.

[0167] 87. The use of any one of embodiments 65-86, wherein the radiation therapy is initiated 7-10 days after the first administration of the radiopharmaceutical compound.

[0168] 88. The method of any one of embodiments 65-87, wherein the subject is newly diagnosed with glioblastoma.

[0169] 89. The use of any one of embodiments 65-88, wherein the subject is selected from subjects with a positive methylated O-6-methylguanine-DNA methyltransferase promoter status.

[0170] 90. The use of any one of embodiments 65-89, wherein the radiation therapy is whole brain irradiation.

[0171] 91. The use of any one of embodiments 65-90, wherein the subject has been imaged by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI prior to any surgery, e.g., two weeks prior to the start of the treatment, using the same radiopharmaceutical compound as defined for the treatment, but using an alternative radionuclide or contrast agent suitable for imaging, preferably 68-gallium, 67-gallium or 64-copper, more preferably 68-gallium, selected based on detection of the radionuclide in imaging scans of the tumor area.

[0172] 92. The use of embodiment 91, wherein the subject is selected from subjects who have shown the presence of alternative radionuclide or contrast agent enhancement, such as gadolinium enhancement, in a PET / MRI scan of the tumor area prior to any surgery.

[0173] 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, wherein the radiopharmaceutical compound is administered to the subject in combination with radiotherapy and an alkylating agent, preferably temozolomide, wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before starting radiotherapy.

[0174] 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, wherein the radiopharmaceutical compound is administered to the subject at least 6 times in combination with radiotherapy and further in combination with temozolomide, and wherein the administration interval between the two administrations of the radiopharmaceutical compound is 4 weeks, and wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiotherapy and temozolomide.

[0175] 95. The use of embodiment 93 or 94, wherein the radiopharmaceutical compound is M-NeoB having the formula:

[0176]

[0177] where M is 177 Lu.

[0178] 96. The use of any one of embodiments 1-94, wherein the radiopharmaceutical compound is M-NeoB having the formula:

[0179]

[0180] where M is 177 Lu, and the radiopharmaceutical compound was administered by intravenous infusion at a concentration of 370 MBq / mL.

[0181] According to one aspect of the present disclosure, it has been found that the combination of radiopharmaceuticals, radiation therapy, and optionally in combination with other treatments, such as alkylating agents, eg, temozolomide, is at least additive or preferably synergistic in the treatment methods of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0182] Figure 1 Indicates the treatment regimen proposed for the clinical study. DETAILED DESCRIPTION

[0183] The present disclosure relates to a method for treating glioblastoma in a subject by administering to the subject in need thereof a therapeutically effective amount of a radiopharmaceutical compound in combination with radiation therapy and optionally an alkylating agent, preferably temozolomide.

[0184] General Definition

[0185] Unless otherwise indicated herein or clearly contradicted by context, the use of the articles "a" and "an" and "the" in the specification and claims should be construed to include both the singular and the plural. Unless otherwise indicated, the terms "comprising," "having," "being of," "including," and "containing" should be construed as open-ended terms (i.e., meaning "including but not limited to"), unless otherwise indicated. In addition, whenever "comprising" or another open-ended term is used in connection with an embodiment, it should be understood that the intervening term "consisting essentially of" or the closing term "consisting of" may be used to more narrowly claim the same embodiment.

[0186] The term "about" or "approximately" in this context means that the following value may vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, even more preferably ±1%.

[0187] As used herein, the term "treating" or "treatment" includes treatment that alleviates, reduces or relieves at least one symptom of a subject or delays the progression of a disease. For example, treatment can be a reduction in one or more symptoms of a disorder or a complete eradication of a disorder (such as cancer). Within the meaning of the present disclosure, the term "treating" also means preventing the disease, delaying the onset of the disease (i.e., the time period before the clinical manifestation of the disease), and / or reducing the risk of the disease developing or worsening. As used herein, in the context of the disclosed combination therapies, the term "treatment" encompasses the administration of a radiopharmaceutical compound, optionally in combination with radiotherapy and / or an alkylating agent. Such treatment can include one or more administrations of the radiopharmaceutical compound over a determined time period.

[0188] As used herein, "glioblastoma" refers to an aggressive brain tumor that is a grade IV astrocytoma brain tumor. The term glioblastoma also includes its variants, gliosarcoma, giant cell glioblastoma, and small cell glioblastoma. Because the cells in this tumor vary in size and shape, i.e., they are pleomorphic, glioblastoma is also called glioblastoma multiforme (GBM).

[0189] As used herein, the term "radiopharmaceutical" or "radiopharmaceutical compound" refers to a pharmaceutical compound labeled with a radionuclide element, typically of metallic nature. Such radiopharmaceutical compounds have binding affinity to specific markers on target cells, such as receptors or tumor antigens, and therefore include target ligands (or target binding moieties). Radiopharmaceutical compounds can be used 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).

[0190] In accordance with the International System of Units, "MBq" is the abbreviation of "megabecquerel", a unit of radioactivity.

[0191] As used herein, "PET" stands for positron emission tomography.

[0192] As used herein, "SPECT" stands for single photon emission computed tomography.

[0193] As used herein, "MRI" stands for magnetic resonance imaging.

[0194] As used herein, "CT" stands for computed tomography.

[0195] The terms "tumor" and "cancer" are used interchangeably herein, e.g., these two terms encompass solid and liquid tumors, e.g., diffuse or circulating tumors. As used herein, the terms "cancer" or "tumor" include pre-malignant and malignant cancers and tumors, as well as benign cancers. The term "cancer" as used herein includes primary malignant cells or tumors (e.g., those whose cells have not migrated to a site other than the original malignant tumor or tumor site in the subject's body) and secondary malignant cells or tumors (e.g., those caused by metastasis (malignant cells or tumor cells migrate to a second site different from the original tumor site)).

[0196] As used herein, the phrase "therapeutically effective amount" of a compound refers to that amount of a compound that will elicit a desired therapeutic response in at least a subpopulation of subjects, e.g., ameliorate symptoms, alleviate symptoms, slow or delay disease progression, or prevent disease, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0197] As used herein, the term "subject" or "patient" is intended to include animals that are capable of having or suffering from cancer or any disorder directly or indirectly related to 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 one embodiment, the subject is a human, such as a human who has cancer, is at risk of developing cancer, or may be susceptible to cancer.

[0198] "Combination therapy" refers to a therapy that includes administration of a fixed combination in a dosage unit form, or a therapy in which a radiopharmaceutical compound as disclosed herein and a combination partner, e.g., another drug as explained below, such as an alkylating agent and / or radiotherapy, can be administered simultaneously or separately, i.e., separately at time intervals, especially when these time intervals allow the combination partner and / or the combination radiotherapy to exhibit a cooperative effect (e.g., synergistic effect) with the radiopharmaceutical compound. The individual components can be packaged in a kit or packaged separately. One or both components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration.

[0199] As used herein, the terms "co-administration" or "combined administration" and the like are also intended to encompass 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 are intended to include treatment regimens in which these agents are not necessarily administered by the same route of administration or administered simultaneously.

[0200] In chemical formulas, the wavy line Indicates the point of attachment to the part.

[0201] Radiopharmaceutical compounds for use in the combination therapies of the present disclosure

[0202] The radiopharmaceutical compound for use in the methods of the present disclosure is a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0203] CSP(I)

[0204] in:

[0205] C is a chelating moiety;

[0206] S is an optional spacer that covalently links C and P;

[0207] P is a GRP receptor binding moiety covalently linked to C directly or indirectly via S,

[0208] The compound is labeled with a radioactive nuclide M.

[0209] M is selected from radioactive isotopes that can be used in nuclear medicine. Examples of such radioactive isotopes 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 Such as 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Second, 169 Second, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At 67 Cu, 186 Re、 188 Re、 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As、 111 Ag and 47 Sc. Preferably, M is 177 Lu.

[0210] In particular embodiments, M is complexed with a chelating moiety.

[0211] 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.

[0212] In a preferred embodiment, P is a GRP receptor antagonist moiety having the general formula:

[0213] Xaa1-Xaa2—Xaa3—Xaa4—Xaa5—Xaa6—Xaa7—Z; where

[0214] Xaa1 is absent or selected from the group consisting of the following amino acid residues: Asn, Thr, Phe, 3-(2-thienyl)alanine (Thi), 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodotyrosine (oI-Tyr), Trp and pentafluorophenylalanine (5-F-Phe) (all L-isomers or D-isomers); preferably D-Phe,

[0215] Xaa2 is Gln, Asn or His; preferably Gln,

[0216] Xaa3 is Trp or 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi); preferably Trp,

[0217] Xaa4 is Ala, Ser or Val; preferably Ala,

[0218] Xaa5 is Val, Ser or Thr; preferably Val,

[0219] Xaa6 is Gly, sarcosine (Sar), D-Ala, or β-Ala; preferably Gly,

[0220] Xaa7 is His or (3-methyl)histidine (3-Me)His; preferably His,

[0221] Z is selected from -NHOH, -NHNH2, -NH-alkyl, -N(alkyl)2, and -O-alkyl,

[0222] Or Z is

[0223]

[0224] wherein X is NH (amide) or O (ester), and R1 and R2 are the same or different and are selected from a proton, optionally substituted alkyl, optionally substituted alkyl ether, aryl, aryl ether or alkyl-, halogen, hydroxy, hydroxyalkyl, amine, amino, amido or amide-substituted aryl or heteroaryl group.

[0225] According to an embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-His-Z; wherein Z is as defined above.

[0226] According to an embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-His-Z, wherein Z is selected from Leu-ψ(CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2

[0227] Or Z is

[0228]

[0229] wherein X is NH(amide) and R2 is CH(CH2-CH(CH3)2, and R1 and R2 are the same or different (CH2N)-Pro-NH2.

[0230] As used herein, the term "chelating moiety" refers to an organic moiety comprising a functional group capable of forming a non-covalent bond with a radionuclide M, thereby forming a stable radionuclide complex.

[0231] In the context of the present disclosure, the chelating moiety can be obtained by grafting a chelating agent to S or P, the chelating agent being selected from the following list: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Titan), Tritan, 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-1,4,7,10-tetra ... Cyclododecane-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, such as AAZTA5).

[0232] In certain embodiments, the chelating moiety C has the formula,

[0233]

[0234] The wavy bond represents the attachment point of the chelator to the spacer S or to the GRP receptor antagonist P.

[0235] This chelating moiety is directly linked to the GRP receptor antagonist moiety or is linked via a linker molecule or also referred to herein as a spacer S. The one or more connecting bonds are covalent or non-covalent bonds between the GRP receptor antagonist (and spacer) and the chelating moiety, preferably the one or more bonds are covalent bonds.

[0236] The chelating moiety C is typically bonded to the N-terminus of the peptide derivative formula disclosed above, optionally via a spacer S, such as DPhe-Gln-Trp-Ala-Val-Gly-His-Z.

[0237] In certain embodiments, the spacer S is selected from the group consisting of:

[0238] a) an aryl group containing a residue having any of the formula:

[0239]

[0240] b) a dicarboxylic acid, ω-aminocarboxylic acid, ω-diaminocarboxylic acid or diamine derivative having any of the following formulae:

[0241]

[0242] wherein each n independently represents an integer from 0 to 12, for example, n=0, 1, 2, 3 or 4;

[0243] c) PEG spacers of various chain lengths, in particular PEG spacers selected from any of the following formulae:

[0244]

[0245] wherein m is an integer from 1 to 36, for example m=1, 2, 3 or 4, and

[0246] p is an integer from 0 to 5, for example, p=0 or 1;

[0247] d) β-amino acid residues, either as a single chain or as a homologous chain of varying chain lengths or as a heterologous chain of varying chain lengths, in particular:

[0248] and / or

[0249] e) Any combination of one or more of a, b, c and / or d.

[0250] According to a preferred embodiment, the radiopharmaceutical compound for use in the therapeutic methods of the present disclosure is selected from the group consisting of radiolabeled compounds having the formula:

[0251]

[0252] wherein C and P are as defined above, and M is a radioisotope complexed with a chelating moiety, preferably M is selected from 177 Lu.

[0253] Preferably, the radiopharmaceutical compound used according to the present disclosure is a compound having formula (II)

[0254]

[0255] wherein C and P are as defined above, and C is complexed with the radionuclide M.

[0256] According to a particularly preferred embodiment, the radiopharmaceutical compound for use in a method of treatment is M-NeoB having the formula (III):

[0257]

[0258] wherein M is as defined above, preferably M is 177 Lu.

[0259] Radiopharmaceutical compounds[ 177 Lu]Lu-NeoB refers to a compound having formula (III), wherein M is 177 Lu.

[0260] According to an embodiment, the radiopharmaceutical compound is radiolabeled NeoB2 having the formula (IV):

[0261]

[0262] wherein M is as defined above, preferably 177 Lu.

[0263] According to another specific embodiment, the radiopharmaceutical compound used in accordance with the present disclosure is a compound having formula (I), which is ProBOMB1 having the following formula (V):

[0264]

[0265] It uses M, preferably 177 Lu radiolabeled.

[0266] Many embodiments of the present disclosure encompass the preferred use of [ 177 Lu]Lu-NeoB as a radiopharmaceutical compound for combination therapy.

[0267] The radiopharmaceutical compound is used to treat glioblastoma in a subject in need thereof, wherein a therapeutically effective amount of the radiopharmaceutical compound is administered to the subject.

[0268] The individual components or their precursors, typically unlabeled NeoB, can be packaged in a kit or individually. One or both components (eg, powder or liquid) can be reconstituted or diluted to the desired dose prior to administration.

[0269] In certain embodiments, the radiopharmaceutical compounds for use in the disclosed combination therapies can be formulated as previously described, for example, in WO 2021 / 052960.

[0270] Typically, combination therapy involves administering a pharmaceutical composition consisting of:

[0271] (a) A complex formed by

[0272] (ai) radionuclide 177 Lutetium ( 177 Lu), and

[0273] (aii) NeoB having formula (III):

[0274] as well as;

[0275] (b) gentisic acid or a salt thereof and ascorbic acid or a salt thereof;

[0276] (c) optionally, polyethylene glycol 15 hydroxystearate;

[0277] (d) acetate buffer;

[0278] (e) water for injection, and

[0279] (f) at least one other pharmaceutically acceptable excipient, for example a chelating agent such as DTPA.

[0280] Synthesis of compounds of formula (I), (II), (III), (IV) and (V)

[0281] Compounds of formula (I), (II), (III), (IV) and (V) can be synthesized using the methods disclosed in the following reference: “Positron Emission Tomography Imaging of the Gastrin-Releasing Peptide Receptor with a Novel Bombesin Analogue” ACS Omega 2019, 4, 1470 1478.

[0282] Further information on the synthesis of compounds of formula (V) can be found in WO 2021 / 0608051.

[0283] Radiation therapy as used in combination therapy

[0284] In one embodiment, a method of treating glioblastoma in a subject in need thereof comprises the step of irradiating the subject with an effective dose of ionizing radiation (ie, radiation therapy).

[0285] As used herein, the term "radiotherapy" is used to treat neoplastic diseases using ionizing radiation. The energy deposited by the ionizing radiation damages or destroys cells in the treated area (target tissue) by destroying their genetic material, rendering them unable to continue growing.

[0286] In certain embodiments, the methods of the present disclosure include exposing the tumor to be treated to an effective dose of ionizing radiation, wherein the ionizing radiation is photons, such as X-rays. Depending on the amount of energy they have, the rays can be used to destroy cancer cells on the surface of the body or deeper in the body. The higher the energy of the X-ray beam, the deeper the X-rays can penetrate into the target tissue. Linear accelerators and betatrons produce X-rays with increasing energy. Using a machine to focus radiation (such as X-rays) on the cancer site is called external beam radiation therapy.

[0287] In an alternative embodiment of a treatment method according to the present disclosure, gamma rays are used. Gamma rays are produced spontaneously when certain elements (such as radium, uranium, and cobalt-60) release radiation as they decompose or decay.

[0288] The ionizing radiation is typically 2 keV to 25000 keV, in particular 2 keV to 6000 keV (ie 6 MeV) or 2 keV to 1500 keV (such as a Cobalt 60 source).

[0289] Those skilled in the art of radiotherapy know how to determine appropriate dosing and administration schedules based on the nature of the disease and the patient's constitution. In particular, they know how to assess dose-limiting toxicity (DLT) and how to determine the maximum tolerated dose (MTD) accordingly.

[0290] 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. Typical total doses for solid tumors range from 20 to 120 Gy for cure. Radiation oncologists consider many other factors when selecting a dose, including whether the patient is receiving chemotherapy, the patient's comorbidities, whether radiation therapy is given before or after surgery, and how successful the surgery was.

[0291] The total dose is typically fractionated (spread out over time). The amount and schedule (ionizing radiation, fractionated doses, fractionated delivery regimen, planning and delivery of the total dose alone or in combination with other anticancer agents, etc.) are defined for any disease / anatomical site / disease stage patient background / age and constitute the standard of care for any particular situation.

[0292] A typical conventional fractionation schedule for the methods of the present disclosure for adults can be 1 Gy to 4 Gy / day, preferably about 2 Gy / day, over a period of 3 to 7 days, preferably about 5 days per week, for a period of 4 to 8 weeks, preferably 6 weeks. In a specific embodiment, the radiation therapy consists of exposing the subject to a total dose of 50 to 70 Gy, for example 60 Gy, of ionizing radiation.

[0293] In other specific embodiments, the subject is exposed to a dose of about 2 to 12 Gy of ionizing radiation per fraction, and the total dose is preferably administered in a maximum of 6 fractions. In other words, the radiation therapy is performed for 5 consecutive days, followed by 2 days of rest, for 6 consecutive weeks.

[0294] Preferably, the subject will be exposed to a combination of standard of care for treating glioblastoma patients and temozolomide. This clinical standard includes subjecting the subject to a dose of 2 Gy / day for 5 days, followed by 2 days of rest, for 6 consecutive weeks, for a total dose of 60 Gy.

[0295] In certain embodiments where the subject has glioblastoma, the radiation therapy employed in the methods disclosed herein is whole brain radiation therapy (WBRT).

[0296] Alkylating agents as used in combination therapy

[0297] The method of treating glioblastoma in a subject in need thereof optionally comprises administering to the subject a radiopharmaceutical compound in combination with radiation therapy and a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0298] Alkylating agents are divided into different categories, including:

[0299] 1. Nitrogen mustards: such as dichloromethyl diethylamine (nitrogen mustard), chlorambucil, cyclophosphamide ifosfamide and melphalan;

[0300] 2. Nitrosoureas: such as streptozotocin, carmustine (BCNU) and lomustine;

[0301] 3. Alkyl sulfonates: busulfan;

[0302] 4. Triazines: dacarbazine (DTIC) and temozolomide as well as

[0303] 5. Ethylenimines: Thiotepa and hexamethylmelamine (hexamethylmelamine).

[0304] As used herein, "temozolomide" refers to a triazine alkylating agent, and more particularly refers to a compound having the formula 3,4-dihydro-3-methyl-4-oxoimidazolo[5,1-d][1,2,3,5]tetrazine-8-carboxamide and its pharmaceutically acceptable salts (CAS No. 85622-93-1). Alkylating agents directly damage DNA (the genetic material in each cell) to prevent cell reproduction. These drugs 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 cancer, breast cancer and ovarian cancer.

[0305] In one embodiment, the alkylating agent, preferably temozolomide, is administered daily at a dose of 50 to 100 mg / m 2 / day, preferably about 75 mg / m 2 The dosage is administered daily for a period of 4 to 8 weeks, preferably 6 weeks.

[0306] As used herein, "induction period" refers to the period of time during which the alkylating agent, preferably temozolomide, is administered to a subject concomitantly with radiotherapy. The induction period may have a duration of up to 11 weeks, for example, from day 1 of week 1 to day 7 of week 11.

[0307] Treatment of glioblastoma with temozolomide concomitantly with radiation therapy is the standard of care, and temozolomide can be administered according to the prescribing information for the combination therapy of the present disclosure.

[0308] In one embodiment, the radiotherapy and the alkylating agent, preferably temozolomide, are both started on the same day. In a certain aspect, the alkylating agent, preferably temozolomide, is administered daily with the radiotherapy without interruption. In a more specific embodiment, the radiotherapy and the alkylating agent, preferably temozolomide, are both started on the same day, 7 to 10 days after the first administration of the radiopharmaceutical compound.

[0309] For example, temozolomide is first administered in week 2 and continues until the end of week 7 at a dose of 75 mg / m2 / day from the first to the last day of radiotherapy (external beam radiotherapy).

[0310] In certain embodiments, the alkylating agent, preferably temozolomide, is administered daily at a first dosing schedule during concomitant administration with radiation therapy (induction phase), e.g., for a period of 6 weeks, and at a second dosing schedule during a maintenance phase following concomitant administration with radiation therapy, e.g., for a period of up to 24 weeks.

[0311] As used herein, "maintenance phase" refers to the period of time beginning after the induction phase or concomitant administration of radiation therapy, with the dose increased compared to the dose during the induction phase, for example, on Day 1 of Week 12, and lasting up to 25 weeks.

[0312] In certain embodiments, during the maintenance period, the alkylating agent, preferably temozolomide, may be administered daily at a dose of 50 to 400 mg / m 2 / day, preferably 75 to 300 mg / m 2 / day, more preferably 150 to 200 mg / m 2 The dosage is administered daily for 5 consecutive days, followed by a 2-day rest, every 28 days for a period of 20 to 28 weeks, preferably 24 weeks.

[0313] In a specific embodiment, the dosage of temozolomide in patients treated with temozolomide will be increased during the maintenance treatment period. For the same patient, if 150 mg / m2 temozolomide treatment is well tolerated, the dosage of temozolomide will be 150 mg / m2 for 5 days at week 12 and 200 mg / m2 for 5 days at weeks 16, 20, 24, 28, and 32, respectively. More generally, one can follow the approved prescribing information.

[0314] Combination therapy

[0315] In a particular embodiment, a method of treating glioblastoma in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a radiopharmaceutical compound as described above, preferably [ 177 Combination of Lu]Lu-NeoB and radiotherapy.

[0316] In another embodiment, the present disclosure relates to a method of treating glioblastoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the radiopharmaceutical compound as described above, preferably [ 177 The invention relates to a method for treating a catalytically induced inflammatory bowel disease (TAD) in combination with Lu]Lu-NeoB and radiotherapy and further with a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0317] The present disclosure also relates to the use of a radiopharmaceutical compound in the preparation of a medicament for treating glioblastoma in a subject in need thereof, wherein a therapeutically effective amount of the radiopharmaceutical compound is administered to the subject simultaneously, separately or sequentially, e.g. 177 The invention relates to a combination of Lu]Lu-NeoB and radiotherapy and optionally a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0318] In various embodiments of the present disclosure, the combination therapy comprises jointly (i) administering to a subject in need thereof a therapeutically effective amount of a compound comprising a radiopharmaceutical compound (e.g., [ 177 and (ii) irradiating the subject with a therapeutically effective dose of ionizing radiation, and (iii) administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an alkylating agent, preferably temozolomide.

[0319] As used herein, the term "in combination" means that the therapeutic agent and the ionizing radiation can be administered separately within time intervals (e.g., in a time-staggered manner, especially in a specific order within such time intervals) to show a (preferably synergistic) interaction (i.e., a combined therapeutic effect).

[0320] In various embodiments of the present disclosure, a combination is administered wherein the radiopharmaceutical compound (e.g., 177 Lu-NeoB) and radiation therapy are administered simultaneously or separately within time intervals, especially if these time intervals allow the combination partners to exhibit a cooperative (eg, synergistic) effect.

[0321] In one embodiment, the 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.

[0322] Administration of the radiopharmaceutical compound may include an administration interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 or 4 weeks, more preferably once every 4 weeks.

[0323] In certain embodiments, the radiopharmaceutical compound (e.g., [ 177 Lu]Lu-NeoB) is administered to the subject at least 6 times in combination with radiotherapy and further in combination with temozolomide, and wherein the administration interval between two administrations of the radiopharmaceutical compound is 4 weeks, and wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiotherapy and temozolomide.

[0324] In certain embodiments, the radiopharmaceutical compound (e.g., [ 177Lu]Lu-NeoB) is administered at a dose within 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), for example about 5.55 GBq (150 mCi) to about 9.25 GBq (250 mCi), at each administration.

[0325] In certain embodiments, the radiopharmaceutical compound (e.g., [ 177 Lu]Lu-NeoB) is administered 1 to 10 times / treatment, preferably 4 to 10 times / treatment, more preferably 6 to 8 times / treatment. For example, the radiopharmaceutical compound (e.g., [ 177 Lu]Lu-NeoB) is preferably administered 6 to 10 times every 4 weeks at a dose ranging from 5.55 GBq (150 mCi) to 9.25 GBq (250 mCi).

[0326] A particularly preferred treatment regimen for combination therapy is Figure 1 Shown in.

[0327] Advantageously, in certain embodiments, the radiopharmaceutical compound (e.g., [ 177 The combined effect of Lu]Lu-NeoB) treatment and radiation therapy and optionally an alkylating agent such as temozolomide increases the overall survival rate of the subject to at least 10%, 20%, 30%, 40% or at least 50%.

[0328] "Overall survival" (OS) is defined herein as the time from the date of the first dose to the date of death of a participant in the clinical study due to any cause, such as disclosed in Example 1. If a participant is not known to have died, overall survival is censored at the latest date the participant is known to be alive (on or before the cutoff date). The Kaplan-Meier method will be used to estimate the OS distribution.

[0329] In certain embodiments, the radiopharmaceutical compound (e.g., [ 177The combined effect of Lu]Lu-NeoB) treatment and radiation therapy and optionally an alkylating agent such as temozolomide also increases progression-free survival to at least 10%, 20%, 30%, 40% or at least 50%.

[0330] As used herein, the term "progression-free survival" (PFS) is defined as the time from the date of the first dose to the date of confirmed progression or death from any cause according to a modified RANO. If no PFS event is observed, PFS is censored at the data cutoff date and the date of the last adequate tumor assessment before the start of the new anti-tumor therapy (whichever comes first). PFS distribution is estimated using the Kaplan-Meier method.

[0331] In certain aspects, a subject eligible for such treatment is administered a drug comprising a radiopharmaceutical compound (e.g., [ 177 Lu]Lu-NeoB) compositions can inhibit, delay and / or reduce tumor growth in subjects. In some aspects, compared with untreated control subjects, tumor growth is delayed by at least 50%, 60%, 70% or 80%. In some aspects, compared with untreated control subjects, tumor growth is delayed by at least 80%. In some aspects, compared with the predicted growth of a tumor without treatment, tumor growth is delayed by at least 50%, 60%, 70% or 80%. In some aspects, compared with the predicted growth of a tumor without treatment, tumor growth is delayed by at least 80%. The assessment of tumor volume in glioblastoma can be determined by using the modified neuro-oncology response assessment (mRANO) standard, which uses, for example, an international brain tumor imaging protocol to allow two-dimensional and volumetric measurements of enhanced tumors in clinical trials. For additional details, 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).

[0332] In certain aspects, a subject eligible for such treatment is administered a drug comprising a radiopharmaceutical compound (e.g., [ 177In some aspects, the increase in survival rate is compared with the predicted survival length of the subject receiving standard of care treatment. In some aspects, the increase in survival period is compared with the predicted survival length of the subject receiving standard of care treatment. In some aspects, the survival length is increased by at least 3 times, 4 times or 5 times the length compared with the control subjects of untreated control subjects or the control subjects receiving standard of care treatment (such as the combination of radiotherapy and temozolomide for the patient newly diagnosed with glioblastoma). In some aspects, the survival length 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 with the control subjects receiving standard of care treatment (such as the combination of radiotherapy and temozolomide for the patient newly diagnosed with glioblastoma). In certain aspects, the length of survival is increased by at least one month, two months, or three months compared to the predicted length of survival for subjects receiving standard of care treatment, such as a combination of radiation therapy and temozolomide for patients newly diagnosed with glioblastoma.

[0333] Methods for selecting subjects for combination therapy

[0334] In certain embodiments of the present disclosure, the glioblastoma is a GRPR-positive disease.

[0335] In certain embodiments, the subject is selected for treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with the same compounds as defined for such treatment, but wherein M is an alternative radioactive metal or contrast agent suitable for imaging, i.e., an imaging radiopharmaceutical compound, based on the detection of said radionuclide in imaging scans of the tumor area post-operatively.

[0336] Typical radiometals suitable for use as contrast agents in imaging include the following: 111 In, 133m In, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 72 As、 97 Such as 203 Pb, 62 Cu, 64 Cu, 61 Cu, 177 Lu, 86 Y. 51 Cr, 52mMn, 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.

[0337] According to a preferred embodiment, the radioactive metal suitable for imaging is 67 Ga, 68 Ga or 64 Cu, preferably 68 Ga.

[0338] In one embodiment, the tumor is assessed by PET / CT or PET / MRI scanning in the tumor region (e.g., the entire brain). 68 The subjects were selected based on Ga-NeoB uptake.

[0339] In certain embodiments, the subject eligible for combination therapy is selected from subjects who demonstrate the presence of alternative radionuclide or contrast agent enhancement, such as gadolinium enhancement, on a post-operative PET / MRI scan of the tumor area.

[0340] Typically, a radiopharmaceutical compound labeled with a radiometal suitable for imaging (e.g., [ 68 PET scans were performed using a PET scanner using a PET scanner using a PET scanner.

[0341] Thus, the present disclosure also relates to a method for determining whether a human subject having glioblastoma can be selected for a combination therapy as disclosed herein, the method comprising the steps of:

[0342] 1. administering an effective amount of an imaging radiopharmaceutical compound as a contrast agent to image the uptake of said radiopharmaceutical compound,

[0343] 2. Obtaining an image scan via PET / MRI or PET / CT of the patient, and

[0344] 3. Compare with the control image scan.

[0345] The purpose of the above selection method is to select patients with GRPR-positive tumors, i.e., which patients 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 the imaging radiopharmaceutical compound as a contrast agent.

[0346] As used herein, a good responder is a patient selected from a patient population that shows a statistically better response to treatment than a random patient population (i.e., a population not selected by the selection step of the method of the invention) and / or that shows fewer side effects of treatment than a random patient population (i.e., a population not selected by the selection step of the method of the invention).

[0347] In one respect, 68 Ga]Ga-NeoB is provided in a kit. The kit can be composed of 2 sterile vials as a single-dose product:

[0348] Vial 1: NeoB (active ingredient), 50 μg, powder for solution for injection to be reconstituted with a solution of gallium-68 chloride (68GaCl3) in HCl eluted from a 68Ge / 68Ga generator;

[0349] Vial 2: Reaction Buffer. Add Vial 2 to the reconstituted Vial 1.

[0350] Examples of such kits are disclosed in WO 2021053040.

[0351] Based on the current activity provided by the generator and the physical decay of the radionuclide (half-life = 68 min), the injection dose corresponding to the radioactivity to be administered is calculated according to the estimated injection time. 68 The volume of Ga]Ga-NeoB solution.

[0352] In one embodiment, selection of the subject occurs 10 to 18 days, preferably about 14 days, prior to the first administration of the radiopharmaceutical compound.

[0353] In certain embodiments, the imaging radiopharmaceutical is administered as a single intravenous dose of 150 to 250 MBq (4.1-6.8 mCi).

[0354] Images of the subject's body are then acquired by PET / MRI or PET / CT imaging, and the images are compared to control images to identify whether lesions identified by conventional imaging (e.g., by MRI, CT, SPECT, or PET) are also uptaken by the imaging radiopharmaceutical compound (i.e., [ 68Typically, PET / MRI or PET / CT imaging is performed 30 to 120 minutes, preferably 60 to 90 minutes, after intravenous administration of the imaging radiopharmaceutical compound to the subject.

[0355] In a particular embodiment of this method, the subject selected for the combination therapy of the present disclosure satisfies the following criteria: at least 10%, preferably more than 20%, preferably more than 30%, preferably more than 40%, preferably more than 50%, preferably more than 60%, preferably more than 70%, preferably more than 80% of the lesions detected by conventional imaging of the subject (e.g., by MRI, CT, SPECT or PET) are also uptaken by the imaging radiopharmaceutical compound (e.g., [ 68 Ga]Ga-NeoB uptake) is identified as determined by PET / MRI or PET / CT imaging in the subject.

[0356] In certain embodiments, the term "lesion" refers to a measurable tumor lesion according to the modified 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.

[0357] Pathological conditions, including brain tumors such as glioblastoma, as well as chemical or physical stimuli such as surgery, radiation therapy, or certain chemotherapeutic agents, may increase blood-brain barrier (BBB) ​​permeability, thereby disrupting its integrity (Chen et al., Front. Pharmacol. 2019; 10:86; Deeken ... Clin. Cancer Res [Clinical Cancer Research]., 2007; 13(6): 1663-74). Thus, in one aspect, the subject is selected from a subject newly diagnosed with glioblastoma and exhibiting blood-brain barrier (BBB) ​​disruption, such as determined by conventional gadolinium contrast enhancement of magnetic resonance imaging (MRI).

[0358] In a certain aspect, the subject is newly diagnosed with glioblastoma or has recurrent glioblastoma.

[0359] Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been widely studied as a prediction and prognostic biomarker for glioblastoma. Methylation of the MGMT promoter leads to the loss of MGMT protein expression, which reduces the DNA repair activity of glioma cells, followed by sensitivity to alkylating agents (such as TMZ) (Hegi et al. 2005, NEngl J Med [New England Journal of Medicine]; 352 (10): 997-1003, Nabors et al. 2020, J Natl Compr CancNetw [National Comprehensive Cancer Network Journal]; 18 (11): 1537-1570). Interestingly, in the absence of adjuvant alkylating chemotherapy, MGMT promoter methylation is also shown to be associated with the improved outcome of radiotherapy in glioblastoma (Rivera et al. 2010, Neuro Oncol [Neuro-Oncology]; 12 (2): 116-21).

[0360] Therefore, in a particular embodiment, the subject is further selected by assessing its methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Typically, the subject receiving an alkylating agent, preferably temozolomide and a combination therapy as disclosed herein can be advantageously selected from a subject with a positive MGMT promoter status. The method for determining the MGMT promoter status of a subject is, for example, disclosed in Mansouri, Alireza et al. ("MGMT promotermethylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges [MGMT promoter methylation status testing for guiding glioblastoma treatment: based on new evidence and current challenges to improve methods]." Neuro-oncology [Neuro-oncology] Vol. 21, 2(2019): 167-178.doi:10.1093 / neuonc / noy132)

[0361] In certain aspects, in these selected subjects with a methylated MGMT promoter, a radiopharmaceutical compound (e.g., [ 177 The Lu]Lu-NeoB) is administered in combination with concomitant radiation therapy and an alkylating agent, preferably temozolomide, followed by administration of the radiopharmaceutical complex in combination with an alkylating agent, preferably temozolomide, during a maintenance period.

[0362] For example, in certain embodiments, the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound, preferably [ 177 Lu]Lu-NeoB is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide.

[0363] In a specific embodiment, the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, wherein the radiopharmaceutical compound is administered to the subject at least 6 times in combination with radiation therapy and further in combination with temozolomide, and wherein the administration interval between two administrations of the radiopharmaceutical compound is 4 weeks, and wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy and temozolomide.

[0364] In certain embodiments, the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, wherein the radiopharmaceutical compound is administered to the subject at least 6 times in combination with radiation therapy and further in combination with temozolomide, and wherein the administration interval between two administrations of the radiopharmaceutical compound is 4 weeks, and wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy and temozolomide, and

[0365] wherein the alkylating agent, preferably temozolomide, is administered daily at a first dosing schedule during concomitant administration with radiotherapy (induction phase), e.g., for a period of 6 weeks, and at a second dosing schedule during a maintenance phase after concomitant administration with radiotherapy, e.g., for a period of up to 24 weeks.

[0366] Preferably, during the maintenance treatment period, temozolomide is administered prior to administration of the radiopharmaceutical compound (typically [ 177 Lu]Lu-NeoB) was administered one week before.

[0367] Suitable dosage regimens for alkylating agents, in particular temozolomide, during the induction and maintenance phases are disclosed, for example, in the previous section related to alkylating agents for use in combination therapy.

[0368] Hereinafter, other aspects of the disclosed combination therapy are described in more detail and with specific reference to examples, which however are not intended to limit the invention.

[0369] Examples

[0370] Example 1: Clinical study for the treatment of glioblastoma subjects

[0371] This article provides an example of a protocol that describes the evaluation [ 177 A Phase Ib Dose-Finding Study of the Safety and Activity of Lu]Lu-NeoB in Combination with Radiation Therapy and Temozolomide in Subjects with Newly Diagnosed Glioblastoma with Methylated or Unmethylated MGMT Promoter Status

[0372] summary

[0373]

[0374] Experimental Design:

[0375] 1. Single-arm, Phase Ib, multicenter, dose-finding study in the expansion phase

[0376] 2. Newly diagnosed glioblastoma

[0377] 3. Open Label

[0378] 4. Allocation to dose escalation and expansion cohorts

[0379] 5. Review Group: Dose Escalation Committee and Study Steering Committee

[0380] Brief Overview:

[0381] Glioblastoma (GBM) is the most common and aggressive type of primary brain tumor with a high mortality rate. The current standard of care (SoC) for newly diagnosed GBM consists of the alkylating agent temozolomide (TMZ) in combination with radiotherapy (RT). The hypothesis of this study was to compare the current standard of care with radioligand therapy [ 177 Patients included in this trial will receive standard regimens of TMZ and RT in combination with [ 177 Lu]Lu-NeoB combination therapy, up to 32 weeks, once every 4 weeks. In special cases, if the patient tolerates [ 177 If patients benefit from Lu]Lu-NeoB, they can receive up to 10 doses, resulting in a treatment duration of up to 37 weeks. During this period, regular weekly safety and efficacy assessments are planned. The primary goal of this trial is to estimate [ 177The recommended dose of Lu]Lu-NeoB in combination with TMZ and RT in participants newly diagnosed with GBM and characterizes the safety and tolerability of this treatment. Therefore, patients will be included in cohorts with increasing dose levels and treated, and all available data will be used to determine the recommended dose. In the expansion cohort, additional patients will be treated to further characterize safety and tolerability, and preliminary efficacy data will be collected from this cohort. It is recommended to repeat contrast-enhanced MRI assessments every 8 weeks, and the patient-reported outcome (PRO) questionnaire will be used to assess the effect of the study treatment on patient-reported symptoms and tolerability. After treatment, all patients will be followed up for up to an additional 5 years for safety, disease progression, and survival.

[0382] Study treatments and treatment modalities:

[0383] In this study, the term "study drug" refers to [ 68 Ga]Ga-NeoB, as a radioligand imaging compound, was used to explore the expression of GRPR, and [ 177 Lu]Lu-NeoB, used as radioligand therapy. The term "study therapy" means [ 177 Combination of Lu]Lu-NeoB, temozolomide (TMZ) and radiotherapy (RT).

[0384] Study Duration: Participants will be monitored for safety during the 60-month follow-up period (starting from the last dose of study treatment) (last dose of [ 177 Efficacy was monitored by contrast-enhanced MRI every 8 weeks until disease progression was confirmed (8 weeks after the initiation of Lu]Lu-NeoB and 4 weeks after the last dose of TMZ). Survival was monitored every 12 weeks thereafter.

[0385] Duration of treatment: 177 Lu]Lu-NeoB is given every 4 weeks, starting on day 1 of week 1, for a maximum of 6 doses. In special cases, if the patient tolerates [ 177 If they received Lu]Lu-NeoB and benefited from it, they could receive up to four additional doses.

[0386] Treatment of Interest: The term "study drug" means [ 68 Ga]Ga-NeoB, as a radioligand imaging compound, was used to explore the expression of GRPR, and [ 177 Lu]Lu-NeoB, used as radioligand therapy. The term "study therapy" means [ 177 A combination of Lu]Lu-NeoB, radiotherapy (RT) and temozolomide (TMS).

[0387] Number of Participants: Approximately 42 participants will be enrolled, with up to 21 participants in the dose-escalation phase and approximately 15 participants in the dose-expansion phase.

[0388] Key inclusion criteria:

[0389] 1. Must provide signed informed consent before participating in the study

[0390] 2. Histologically confirmed glioblastoma according to the WHO classification established after surgical resection or biopsy

[0391] 3. Adequate bone marrow and organ function, as defined by the following laboratory values ​​obtained ≤14 days prior to receiving study treatment

[0392] 4. Gadolinium enhancement in the tumor area on preoperative MRI

[0393] 5. Karnofsky physical condition ≥ 60%

[0394] Key exclusion criteria

[0395] 6. Additional, concomitant, or active therapy for glioblastoma outside of this study

[0396] 7. In the case of injection 68 The radiopharmaceutical was administered with therapeutic intent within 10 half-lives of the previously used radionuclide Ga]Ga-NeoB

[0397] 8. History or current diagnosis of impaired cardiac function

[0398] 9. History of another active malignant tumor within 3 years before study enrollment

[0399] 10. Known hypersensitivity to any study treatment, its excipients, or dacarbazine

[0400] Treatment Group:

[0401] [ 177 Lu]Lu-NeoB was administered once every 4 weeks, starting on day 1 of week 1, for a maximum of 6 doses. 177 Participants who benefit from Lu]Lu-NeoB may receive up to 10 doses. TMZ and RT will be administered after the first dose of [ 177 Lu]Lu-NeoB starts 7 to 10 days after.

[0402] TMZ will be administered orally at a dose of 75 mg / m2 / day during the concomitant period of RT according to the approved prescribing information. RT will be delivered at a dose of 2 Gy / day, 5 days per week (followed by 2 days of rest) for 6 consecutive weeks.

[0403] Example 2: Rationale for the study

[0404] Nonclinical biodistribution, drug metabolism, and pharmacokinetics

[0405] [ 177 The biodistribution of Lu]Lu-NeoB was evaluated in vivo in healthy mice and tumor-bearing models. NeoB was rapidly cleared from the blood and eliminated through the renal system without retention in the body. Background radioactivity observed in GRPR-expressing tissues (primarily the pancreas) decreased over time, as expected for an antagonist. In contrast, tumor uptake remained high at all evaluated time points, resulting in an increase in the tumor / background ratio.

[0406] Pathological conditions, including brain tumors (i.e., glioblastoma) and chemical or physical stimuli such as surgery, RT, and certain chemotherapeutic agents, may increase blood-brain barrier (BBB) ​​permeability, thereby disrupting its integrity (Chen et al. 2019 supra, Deeken and 2007 supra). In brain tumors, BBB dysfunction has been detected on conventional gadolinium contrast-enhanced magnetic resonance imaging (MRI) (Sarkaria et al., Neuro. Oncol., 2018 Jan 22;20(2):184-191). In this study, participants who show contrast enhancement on MRI will be selected to ensure that the BBB is disrupted, and the study agent [ 177 Lu]Lu-NeoB can penetrate through. In addition, [ 177 Lu]Lu-NeoB will be administered concomitantly with chemoradiotherapy.

[0407] [ 177 Lu]Lu-NeoB induces cell damage primarily through free radical formation in GRPR-positive tumor and adjacent cells.

[0408] Based on the results of in vitro drug-drug interaction (DDI) studies, [ 177 Lu]Lu-NeoB is not considered to have the potential for CYP- or transporter-mediated drug-drug interactions.

[0409] toxicology

[0410] Use of non-radioactive alternatives [ 175 Nonclinical studies have been conducted on the Lu]Lu-NeoB formulation and support the absence of pharmacological activity of the NeoB peptide. No adverse effects were observed in safety pharmacology studies. Similarly, acute or repeated administration of [ 175 No signs of toxicity were subsequently reported for Lu]Lu-NeoB, confirming the safety of the non-radioactive molecule.

[0411] [ 177Clinical experience with Lu]Lu-NeoB

[0412] NeoRay (EUDRACT No. 2018-004727-37) is an ongoing Phase I / IIa, open-label, multicenter study evaluating [ 177 Safety, tolerability, systemic distribution, radiation dosimetry, and antitumor activity of Lu]Lu-NeoB.

[0413] In the NeoRay study, as of October 11, 2022, 11 patients had been administered [ 177 Lu]Lu-NeoB. Patients included in the first cohort received 1.85 GBq (50 millicuries (mCi)) of [ 177 Based on the clinical dosimetry of cycle 1, the dose in patients was escalated to 150 mCi[ 177 Lu]Lu-NeoB. Each treatment cycle had a duration of 6 weeks.

[0414] Dose level 1 (50 mCi in the first cycle and 150 mCi in subsequent cycles) was evaluated in three patients with breast cancer, prostate cancer, and GIST cancer, respectively. 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.

[0415] Dose level 2 evaluated 300mCi per cycle and enrolled 4 patients, 2 of whom had prostate cancer and 2 had GIST. 2 patients received 1 cycle, 1 patient received 2 cycles, and 1 patient received 3 cycles. 2 of the 4 enrolled patients experienced DLT (both patients had grade 3 anemia and 1 patient had grade 3 encephalopathy). All of these events have resolved. One of the grade 3 anemia events occurred in a patient with prostate cancer who had extensive bone metastases and persistent grade 2 anemia at screening (for which the subject also received red blood cell transfusions before starting treatment); the patient developed grade 3 anemia on day 36 after the transfusion and subsequently developed grade 4 thrombocytopenia while in progressive disease; the patient discontinued treatment, and with supportive care, the anemia temporarily improved to grade 2, but the patient still had grade 4 thrombocytopenia at the time of death, which was due to progressive disease. Two DLTs (grade 3 anemia and grade 3 encephalopathy) were recorded for one patient affected by GIST, with onset within one week of the first therapeutic dose of treatment. The patient had extensive pelvic bone metastases and grade 1 anemia at baseline. The patient was noted to have left-sided facial palsy and mental changes, with grade 2 vomiting and grade 3 hyponatremia; a brain MRI ruled out stroke and brain metastases. Three days later, the patient also developed a seizure. The patient was being treated with very high doses of diazepam, which was not effective at [ 177 Lu]Lu-NeoB infusion was interrupted for several days, raising suspicion of withdrawal syndrome as a confounding factor. No other significant toxicities were reported, and the patient received only one [ 177 Lu]Lu-NeoB infusion.

[0416] A DLT was observed at dose level 2, and the dose was reduced to 250 mCi (dose level 3) according to the protocol. Dose level 3 was evaluated in 4 patients (2 affected by GIST, 1 affected by prostate cancer, and 1 affected by glioblastoma). The glioblastoma patient received 3 cycles, one GIST patient received 2 cycles, and both patients discontinued treatment due to disease progression, while the other 2 patients (GIST and prostate cancer) each received 2 cycles and treatment is ongoing. Overall, treatment was well tolerated, with most reported AEs being mild / moderate, and no DLTs or SAEs reported.

[0417] Across the dose levels evaluated, two prolonged disease stabilizations were observed: approximately one year in patients with GIST and five months in patients with prostate cancer.

[0418] Of the 11 treated patients in the study, 3 patients completed treatment, 2 patients discontinued treatment due to AEs, 3 discontinued treatment due to progressive disease (PD), 1 patient decided to stop treatment, and 2 patients are ongoing.

[0419] From NeoRay 177 Preliminary blood radioactivity PK of Lu]Lu-NeoB showed 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. Radio-HPLC data showed evidence of metabolism in the systemic circulation and urine (possibly pharmacologically inactive metabolites unable to bind to receptors), however, cumulative excretion of activity indicated that the radioactivity was primarily (average ≥80%) excreted via the kidneys within 24-48 hours.

[0420] Preliminary dosimetric results demonstrate favorable biodistribution and low uptake in organs considered at risk due to GRPR expression (such as the pancreas) or due to RLT (such as red bone marrow) and excretion pathways (such as the kidney). The dose-normalized mean absorbed dose (rounded to 2 significant figures) (± SD, n = 10) across all dose levels studied was 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).

[0421] Based on the safety and biodistribution profile at 250 mCi, a protocol-based decision was made to re-escalate to 300 mCi. This study is ongoing and enrolling patients to receive the 300 mCi dose level per cycle.

[0422] Research update as of June 7, 2023

[0423] As of June 7, 2023, [177Lu]Lu-NeoB has been administered to 17 patients according to Table 1. Patients included in the first cohort received a first dose of 50 mCi (1.85 GBq) of [177Lu]Lu-NeoB (Cycle 1). In dose level (DL) 1, based on clinical dosimetry in Cycle 1, the patient dose was escalated to 150 mCi [177Lu]Lu-NeoB.

[0424] Table 1. Patients included in the NeoRay cohort

[0425]

[0426] DL1 (50 mCi in the first cycle and 150 mCi in subsequent cycles) did not result in any significant toxicity (no serious adverse events (SAEs)). The breast cancer patient included in this cohort was a 54-year-old female who was first diagnosed with stage IV HR+ / HER2+ invasive ductal carcinoma with multiple bone metastases in May 2018. The patient received prior mastectomy, radiotherapy, and multiple lines of therapy (including palbociclib + ET, trastuzumab, pertuzumab, fulvestrant, capecitabine, and everolimus + exemestane) before inclusion in the study. Due to disease progression, the patient received 2 doses of [ 177 Study treatment was discontinued after administration of Lu]Lu-NeoB.

[0427] In the second cohort of patients who received dose level 2 (300 mCi), two of the 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 resolved.

[0428] A DLT was observed at dose level 2, and the dose was reduced to 250 mCi (dose level 3) according to the protocol.

[0429] Dose level 3 was initially evaluated in 4 patients at 250 mCi, and treatment was generally well tolerated, with most reported AEs being mild / moderate, and no DLTs or SAEs reported.

[0430] Given the overall favorable safety profile of DL3, the decision was made to re-escalate the dose to 300 mCi in Cohort 4. Only one GBM patient was enrolled and experienced moderate (grade 2) nausea, severe (grade 3) vomiting, and 'neurological decline' (grade 3) (preferred term: neurologic disorder) 5 days after the first dose of study treatment, leading to hospitalization the next day. All events were considered serious by the investigator and possibly related to [ 177 Lu]Lu-NeoB related. Neurological decline met the definition of DLT. Twelve days after the first dose of study treatment, new grade 2 nausea and grade 3 vomiting events were experienced, while the AE of neurological disorder worsened to grade 4. Although the nausea and vomiting events resolved quickly on the second day, the neurological disorder events further worsened to grade 4 despite increased dexamethasone therapy, leading to treatment discontinuation and continuing at the time of the patient's death due to active euthanasia. Considering that the first patient treated in this new cohort experienced a DLT (neurological decline) at 300mCi, and considering that the other 2 patients in the previous cohort experienced DLT (anemia and encephalopathy) at 300mCi (DL2), the dose was reduced to 250mCi (DL3) according to the protocol, and recruitment of the 5th cohort was opened.

[0431] As of June 7, 2023, a total of five patients were enrolled in the fifth cohort at the 250 mCi dose (DL3), four of whom had GIST and one had a prostate cancer indication. No patients in the fifth cohort experienced any DLTs or SAEs. Reported AEs were mild or moderate in severity. Laboratory abnormalities ≥ Grade 2 were not clinically significant.

[0432] Among the dose levels evaluated, two prolonged disease stabilizations (approximately one year for GIST patients and five months for prostate cancer patients) were observed in Cohort 1 (50 mCi and 150 mCi).

[0433] Of the 17 treated patients in the study, 4 patients completed treatment, 2 patients discontinued treatment due to AEs, 7 discontinued treatment due to PD, 3 patients discontinued treatment due to investigator / patient decision, and 1 patient is ongoing treatment.

[0434] From NeoRay 177 Preliminary blood radiopharmacokinetics of Lu]Lu-NeoB showed 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. Radio-HPLC data showed evidence of metabolism in the systemic circulation and urine (possibly pharmacologically inactive metabolites unable to bind to receptors), and cumulative excretion of activity indicated that radioactivity was still primarily (average ≥80%) excreted via the kidneys within 24-48 hours. Metabolites in plasma will be investigated.

[0435] Preliminary dosimetric results demonstrate favorable biodistribution and low uptake in organs considered at risk due to GRPR expression (such as the pancreas) or due to RLT (such as red bone marrow) and excretion pathways (such as the kidney). The observed dose-normalized mean absorbed dose (rounded to 2 significant figures) (± SD, n = 13) from all cohorts was 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.

[0436] Given the overall favorable safety profile of DL3, the decision was made to re-escalate the dose to 300 mCi in cohort 4. Only one GBM patient was enrolled and experienced moderate (grade 2) nausea, severe (grade 3) vomiting, and 'neurological decline' (grade 3) (PT: neurologic disorder) 5 days after the first dose of study treatment, leading to hospitalization the next day. All events were considered serious by the investigator and possibly related to [177 [177Lu]Lu-NeoB is associated with GIST. Neurological decline met the definition of a DLT. Given that the first patient treated in this new cohort experienced a DLT (neurological decline) at 300 mCi, and given that two other patients in the previous cohort experienced DLTs (anemia and encephalopathy) at 300 mCi (DL2), the dose was reduced to 250 mCi (DL3) per protocol. As of January 29, 2023, enrollment in cohort 5 at 250 mCi is ongoing, and two additional patients affected by GIST (total of six) have received one cycle of [177Lu]Lu-NeoB at this DL with no reported DLTs.

[0437] The generated Phase I dosimetry data showed favorable [ 177 The organ dosimetry spectrum of Lu-Lu-NeoB provides a large safety margin compared to EBRT thresholds, even at high cumulative activity. Therefore, based on safety and tolerability data observed at the tested dose levels, the MTD was established as 250 mCi every 6 weeks. Novartis AG and participating investigators announced a recommended Phase II dose (RP2D) of 250 mCi, which will be further tested in the Phase IIa portion of the FIH study CAAA603A12101.

[0438] [ 68 Clinical experience with Ga]Ga-NeoB

[0439] [ 68 Ga]Ga-NeoB has demonstrated favorable technical and diagnostic performance in both preclinical and clinical studies to identify GRPR-expressing malignancies, with good image quality and ease of 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:

[0440] A phase I / IIa clinical trial (MITIGATE; EudraCT number 2016-002053-38) was designed to evaluate [ 68 Safety, biodistribution, dosimetry, and preliminary diagnostic performance of Ga]Ga-NeoB in patients with advanced GIST pretreated with tyrosine kinase inhibitors. 68 Ga]Ga-NeoB was well tolerated in all 9 participants, with no reported side effects. 68 Adverse events associated with Ga]Ga-NeoB. Radiation exposure is low due to rapid clearance from the kidneys and blood. Biodistribution showed [ 68[Ga]Ga-NeoB uptake was higher in the kidney and liver, followed by rapid, visually moderate to high tumor-specific uptake in GRPR-expressing lesions.

[0441] A phase II clinical trial (NeoFIND; EudraCT number 2017-003432-37) evaluated [ 68 The preliminary diagnostic performance of Ga]Ga-NeoB 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) was confirmed in this study. 68 The safety profile of Ga]Ga-NeoB. The results indicate that there are variable [ 68 Ga]Ga-NeoB uptake, with the highest number of lesions in breast cancer patients showing visually moderate to high uptake.

[0442] [ 68 Ga]Ga-NeoB is currently used in the ongoing Phase I / IIa NeoRay study (EudraCT number 2018-004727-37) in selected patients receiving [ 177 Lu] Lu-NeoB imaging agent for treatment. As of October 11, 2022, 41 patients have received [ 68 Ga]Ga-NeoB, and no reports have been made with [ 68 Ga]Ga-NeoB-related safety issues, the administered dose is 150-250MBq.

[0443] In this study, [ 68 Ga]Ga-NeoB will be explored as a positron emission tomography (PET) agent for use in [ 177 Tumor areas were imaged before Lu]Lu-NeoB treatment and during disease progression.

[0444] Rationale for targeting GRPR in glioblastoma

[0445] The presence of GRPR has been confirmed in various glioma cell lines (Sharif et al., Mol. Cell Endocrinol [Molecular and Cellular Endocrinology]., 1997; 130: 119-130; Farias CB et al., Oncology [Oncology], 2008; 75 (1-2): 27-31). Immunohistochemistry (IHC) staining studies evaluated the expression of GRPR in gliomas of different WHO grades and normal human brain (34 samples from glioma patients (24 of which were glioblastoma multiforme) and 9 samples of normal brain tissue from 9 autopsies were selected). GRPR was detected in 100% of the samples analyzed. High GRPR expression was also observed in tumor endothelial cells. GRPR was not detected in glial cells of normal brain tissue samples; 10%–50% of neuronal cells showed varying intensities of GRPR expression (Flores et al., 2010, Brain Res Bull; 82(1-2):95-8).

[0446] In patients with a high suspicion of recurrent glioma [ 68 Ga]Ga-bombesin analogues[ 68 Ga]Ga-BZH3 dynamic PET imaging studies were performed. All three cases of WHO grade IV astrocytomas showed visible [ 68 Ga]Ga-BZH3 uptake was increased (Dimitrakopoulou-Strauss et al., Clin. Nucl. Med., 2011 Feb;36(2):101-8). Another imaging study used GRPR-targeted, 68 Ga-labeled bombesin (BBN) peptide derivative PET tracer NOTA-Aca-BBN (expressed as [ 68 Ga]Ga-BBN) was used to evaluate the receptor expression level in glioma patients. Twelve patients diagnosed with glioma by contrast-enhanced MRI were injected with [ 68 Ga]Ga-BBN was followed by PET / CT. Within one week, the tumors were surgically resected and tumor samples were stained for GRPR by IHC and correlated with the PET / CT results. In 12 glioma patients (glioblastoma multiforme, n=2), all MRI-identified lesions were in the [ 68Ga]Ga-BBN showed high signal intensity on PET / CT. With normal brain tissue as the background, the tumor-to-background ratios based on the maximum SUV and the average SUV were 24.0±8.85 and 13.4±4.54, respectively. IHC staining confirmed that SUV was positively correlated with 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).

[0447] In conclusion, IHC staining showed that GRPR was highly expressed in glioblastoma multiforme samples. 68 Imaging studies of Ga-labeled BBN analogs have shown strong uptake in patients with high-grade gliomas, including GBM. For radiosensitive tumors (such as glioblastoma), delivering radiation via targeting specific receptors (such as GRPR) overexpressed in glioblastoma cancer cells in combination with current SoCs (RT and TMZ) may improve treatment outcomes for subjects newly diagnosed with glioblastoma and therefore warrant further study. The ultimate goal of treatment for this patient population is to prolong survival, but current treatment alternatives offer limited benefits.

[0448] In some embodiments, the combination of the GRPR radiopharmaceuticals of the present disclosure with radiation and optionally other agents provides a synergistic effect for treating glioblastoma.

[0449] Justification of dosage

[0450] The starting dose in the dose escalation phase was 100 mCi (3.7 GBq) of [ 177 Lu]Lu-NeoB, once every 4 weeks (Q4W). Based on data from NeoRay 50mCi (1st cycle) + 150mCi, [ 177 Lu]Lu-NeoB Q6W was well tolerated as a monotherapy, with no DLTs and G3 / 4 adverse events. The absorbed radiation dose to critical organs (kidneys, pancreas, red bone marrow, testes, ovaries) was low, indicating a low risk of radiation-related toxicity from a single administration.

[0451] GBM is an aggressive and rapidly growing tumor with a high mortality rate and poor long-term survival, with rapid disease progression (ie, less than 7 months in newly diagnosed patients). Therefore, compared with the Q6W schedule in the NeoRay first-in-human study, [ 177 Lu]Lu-NeoB will be administered at a shorter interval of Q4 W. Shorter intervals will allow for administration of sufficient cycles of radioligand therapy to achieve a potentially effective cumulative dose within an appropriate timeframe.

[0452] Although[ 177 The contribution of Lu]Lu-NeoB frequency to safety has not been fully investigated, but [ 177 Safety review of blood laboratory parameters over time after Lu]Lu-NeoB administration showed no trend toward decrease or worsening of hematological parameters. Therefore, a recovery period between administrations is not necessary, and there are no data to suggest that more frequent administration will enhance the safety of a single administration, especially since [ 177 Lu]Lu-NeoB-related radioactivity is rapidly cleared from the body. Therefore, Q4W is considered to be [ 177 Acceptable administration frequency of Lu]Lu-NeoB.

[0453] Based on the above information and in view of [ 177 Lu]Lu-NeoB will be used in combination with RT and TMZ, with dosing frequency reduced to Q4 / day compared to Q6 / day in monotherapy (NeoRay study), and the study will begin with a dose of 100 mCi.

[0454] In this study, [ 177 Lu]Lu-NeoB 6 times. Based on the currently available dosimetric data for the three investigated dose levels (150 mCi, 250 mCi, and 300 mCi) in the FIH study, the mean cumulative absorbed doses in the kidneys, pancreas, red bone marrow, testes, and ovaries were significantly below the external beam radiotherapy (EBRT) threshold. 11.1 GBq (300 mCi) [ 177 The margin for 6 cycles of Lu]Lu-NeoB (the highest radiation dose studied to date) is approximately 9-10 times that of the pancreas (40Gy EBRT threshold; ICRP118 et al. 2012), approximately 1.6 times that of the red bone marrow (2Gy EBRT threshold; Howard et al. 2017), 1.3-2 times that of the testes and ovaries (1Gy and 3Gy EBRT thresholds; De Felice et al., 2019; Husseinzadeh et al., 1994; Chambers SK), and 3 times that of the kidneys (23Gy EBRT threshold; Emami et al. 1991, Emami 2013, ICRP2012). The calculations are based on the average absorbed doses cited in Section 2.2 and the EBRT thresholds mentioned above. The lower the starting dose, the higher the margin.

[0455] However, these EBRT limitations may be overly conservative in their application to RLT due to the inherent differences between external beam radiotherapy and radionuclide therapy. These include different dose rates and fractionation schedules, non-uniform absorbed dose distributions, and potentially different radiobiological mechanisms of cytotoxicity leading to 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, there is growing evidence that a biologically effective dose (BED) of approximately 40 Gy is safe for the kidneys in the case of 177Lu-labeled RLT, with a conversion factor of 1.09 for converting absorbed dose to BED (Bodei, 2008, Eur J Nucl Med Mol Imaging; 35(10):1847-56; 2022, Extensive 177Lu-PSMA Radioligand Therapy Can Lead to Radiation Nephropathy with a Renal Thrombotic Microangiopathy-like Picture [Eur Urol]. Therefore, even beyond 6 cycles, there may be minimal concern about radiation-induced toxicity because organs may be able to tolerate higher radiation doses.

[0456] Based on the above evidence, there is scope for administration of more than 6 cycles. Therefore, in this study, it can be considered to administer more than 6 cycles [ 177 Lu]Lu-NeoB was administered up to four additional doses based on individual benefit-risk assessment by the treating physician and in agreement with the study participant; based on treatment tolerability, clinical benefit, and the participant's continued use of [ 177 Lu]Lu-NeoB's wishes and reached an agreement with the sponsor.

[0457] To give 4 additional doses beyond the 6 doses [ 177 For each Lu]Lu-NeoB administration, the investigator should determine:

[0458] Whether the participant showed evidence of stable disease or response (i.e., radiographic or clinical assessment),

[0459] Whether the participant shows no signs or symptoms of clinical worsening

[0460] Participants' 177 Whether Lu]Lu-NeoB treatment showed good tolerance was not documented in the next [ 177 Lu]Lu-NeoB dose that was not previously addressed and led to treatment interruption 177 Lu]Lu-NeoB-related SAE.

[0461] If the patient meets all the above criteria and agrees to continue using [ 177 Lu]Lu-NeoB for further treatment, the investigator may administer up to an additional 4 times (i.e., up to a total of 10 times) in consultation with the sponsor. 177 Lu]Lu-NeoB administration.

[0462] Study Treatment

[0463] In this clinical study, the term "study drug" refers to [ 68 Ga]Ga-NeoB, as a radioligand imaging compound, was used to explore the expression of GRPR, and [ 177 Lu]Lu-NeoB, used as radioligand therapy.

[0464] The term "study treatment" means [ 177 Combination of Lu]Lu-NeoB, temozolomide (TMZ) and radiotherapy (RT).

[0465]

[0466] [ 177 Lu]Lu-NeoB

[0467] [ 177 Lu]Lu-NeoB is a sterile radiopharmaceutical supplied as a ready-to-use solution for infusion containing [ 177 Lu]Lu-NeoB, with a volumetric activity of 370 megabecquerels (MBq) / mL at a reference date and time (calibration time (tc)). 177 The starting dose level of Lu]Lu-NeoB was 100 mCi.

[0468] [ 177 Lu]Lu-NeoB is given every 4 weeks, starting on day 1 of week 1, for a maximum of 6 doses. In special cases, if the patient tolerates [ 177If they benefit from Lu]Lu-NeoB, they can receive up to 10 doses, with additional details outlined in Section 4.3. 177 Lu]Lu-NeoB does not allow for in vivo dose escalation in patients.

[0469] TMZ and RT will be administered during the first [ 177 Lu]Lu-NeoB starts 7 to 10 days after.

[0470] TMZ will be administered orally at a dose of 75 mg / m2 / day during the concomitant period of RT according to the approved prescribing information.

[0471] RT will be delivered at a dose of 2 Gy / day, 5 days per week (followed by 2 days of rest), for 6 consecutive weeks, for a total dose of 60 Gy (without interruption).

[0472] During the maintenance treatment period, the TMZ dose will be escalated. For the same patient, if 150 mg / m2 of TMZ is well tolerated, the TMZ dose will be increased to 150 mg / m2 for 5 days at week 12 and 200 mg / m2 for 5 days each at weeks 16, 20, 24, 28, and 32. For additional information, please refer to the approved prescribing information.

[0473] [ 68 Ga]Ga-NeoB

[0474] For [ 68 The kit for preparing the radiopharmaceutical of Ga]Ga-NeoB contains 50 μg of NeoB. In this study, [ 68 Ga]Ga-NeoB as an imaging agent for PET / CT or PET / MRI.

[0475] After radiolabeling with Ga-68, [ 68 Ga]Ga-NeoB will be used in positron emission tomography (PET) to localize GRPR-positive tumors.

[0476] [ 68 Ga]Ga-NeoB will be administered as a single intravenous (iv) dose with an activity of 150 to 250 MBq (4.1-6.8 mCi).

[0477] After reconstruction, [ 68 [Ga]Ga-NeoB will be administered by slow intravenous injection. Images should be acquired 120±30 min after intravenous administration.

[0478] Eligibility screening

[0479] Participants will be evaluated for study inclusion and exclusion criteria and safety assessments. If values ​​outside the normal range are observed in screening laboratory results, repeat laboratory evaluations will be permitted. If repeat laboratory results fall within the normal laboratory range, they will be used for enrollment eligibility testing.

[0480] During the screening period, images and results of a gadolinium-enhanced MRI performed during routine preoperative workup will be collected in the clinical database for eligibility assessment. In addition, results of the postoperative MRI will be collected.

[0481] During the screening period, the study drug must be administered 2 weeks after surgery / biopsy. 177 Lu]Lu-NeoB at least 3 days before [ 68 Ga]Ga-NeoB PET / CT (or PET / MRI). [ 68 Ga]Ga-NeoB PET / CT will not be used for eligibility assessment but for exploratory purposes.

[0482] [ 68 Ga]Ga-NeoB PET scan

[0483] The patients were randomly assigned to receive the test at baseline, at least 2 weeks after surgery / biopsy of the tumor lesion, and [ 177 At least 3 days before the first dose of Lu]Lu-NeoB 68 Ga]Ga-NeoB PET / CT or PET / MRI. In cases of disease progression, PET / CT or PET / MRI will be performed to assess GRPR expression in the tumor.

[0484] PET / CT or PET / MRI will be brain-dedicated acquisitions 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 whenever possible.

[0485] will be 68 The uptake of Ga]Ga-NeoB in the tumor area (guided by the postoperative MRI results when baseline and guided by the MRI results confirming disease progression in the PET scan obtained when progressive disease) is visually and semi-quantitatively assessed. Visual assessment will record the pattern (focal or diffuse, uniform or heterogeneous) and the degree of uptake (mild, moderate or high). Semi-quantitative evaluation will include SUV maximum, SUV mean value and uptake background ratio (UBR). Background activity will be considered as uptake in healthy brain parenchyma areas (e.g., contralateral hemisphere, if retained).

Claims

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 is a compound having formula (I) or a pharmaceutically acceptable salt thereof: CSP(I) in: C is the chelating moiety, P is the GRP receptor antagonist part, S is an optional spacer that covalently links C and P, And wherein the radiopharmaceutical compound is labeled with a radionuclide M.

2. The method of claim 1, wherein the method further comprises administering a therapeutically effective amount of an alkylating agent.

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

4. The method of claim 2 or 3, wherein the alkylating agent, preferably temozolomide, is administered daily at a dose of 50 to 100 mg / m2 during the induction phase. 2 / day, preferably about 75 mg / m 2 A dose of 100 mg / day is administered concomitantly with radiation therapy, typically for a period of 4 to 8 weeks, preferably 6 weeks.

5. The method of claim 4, wherein the alkylating agent, preferably temozolomide, is administered daily at a dose of 50 to 400 mg / m2 during a maintenance period following the induction period, following radiotherapy. 2 / day, preferably 75 to 300 mg / m 2 / day, more preferably 150 to 200 mg / m 2 The dosage is administered daily 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 claims 2 to 5, wherein both radiotherapy and the alkylating agent, preferably temozolomide, are started on the same day, for example 7 to 10 days after the first administration of the radiopharmaceutical compound.

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

8. The method of any one of claims 2 to 7, wherein the alkylating agent, preferably temozolomide, is administered in a first dose daily during concomitant administration with the radiotherapy, eg for a period of 6 consecutive weeks.

9. The method of any one of claims 1 to 8, wherein the radionuclide M is selected from 90 Y. 131 I. 121 Sn, 186 Re、 188 Re、 64 Cu, 67 Cu, 59 Fe, 89 Sr. 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Such as 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Second, 169 Second, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At 67 Cu, 186 Re、 188 Re、 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As、 111 Ag and 47 Sc.

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

11. The method of any one of claims 1 to 10, wherein C is obtained by grafting to S or P, and C is a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Titan), Tritan, 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-1,4,7,10-tetra ... Heterocyclododecane-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, such as AAZTA5).

12. The method of claim 11, wherein C has the formula, 13. The method of any one of claims 1 to 12, wherein P has the general formula DPhe-Gln-Trp-Ala-Val-Gly-His-Z wherein Z is selected from Leu-ψ(CH2N)-Pro-NH2 and NH-CH(CH2-CH(CH3)2)2 Or Z is wherein X is NH(amide) and R2 is (CH2-CH(CH3)2, and R1 and R2 are the same or are (CH2N)-Pro-NH2.

14. The method of claim 13, wherein P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2.

15. The method of any one of claims 1 to 14, wherein the compound of formula (I) is a compound of formula (II) wherein C and P are as defined in any one of claims 1 and 11-14, and wherein the chelating moiety C is complexed with the radionuclide M.

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

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

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 or 4 weeks, more preferably once every 4 weeks.

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

20. The method of any one of claims 1 to 19, wherein the radiopharmaceutical compound is administered at a dose within 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 claims 1-20, wherein the radiation therapy comprises irradiating the subject with a total dose of 40-80 Gy, such as 60 Gy.

22. The method of any one of claims 1-21, wherein the radiation therapy is performed at a dose of 1 Gy to 4 Gy / day, preferably about 2 Gy / day, during 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. The method of any one of claims 1-22, wherein the radiation therapy begins 7-10 days after the first administration of the radiopharmaceutical compound.

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

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

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

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

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, wherein the radiopharmaceutical compound is administered to the subject in combination with radiotherapy and an alkylating agent, preferably temozolomide, wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before starting radiotherapy.

30. 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, wherein the radiopharmaceutical compound is administered to the subject at least 6 times in combination with radiation therapy and further in combination with temozolomide, and wherein the administration interval between two administrations of the radiopharmaceutical compound is 4 weeks, and wherein the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy and temozolomide.

31. The method of claim 29 or 30, wherein the radiopharmaceutical compound is M-NeoB having the formula: where M is 177 Lu.

32. The method of any one of claims 1-30, wherein the radiopharmaceutical compound is M-NeoB having the formula: where M is 177 Lu, and the radiopharmaceutical compound was administered by intravenous infusion at a concentration of 370 MBq / mL.

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