Combination Therapy with Radionuclide Complexes

Abstract

The present disclosure is directed to a method of treating glioblastoma in a subject in need of treatment comprising administering to the subject in need of treatment an effective amount of a radiopharmaceutical compound. The present disclosure is also directed to a method of treating glioblastoma in a subject in need of treatment comprising administering to the subject in need of treatment an effective amount of a radiopharmaceutical compound, in combination with irradiating the subject with an effective dose of ionizing radiation, and optionally with a therapeutically effective amount of an alkylating agent, preferably temozolomide.

Description

[Technical field]

[0001] The present invention relates to a method of treating glioblastoma in a subject in need thereof, wherein a therapeutically effective amount of said radiopharmaceutical compound is administered to said subject in combination with radiation therapy. [Background technology]

[0002] Glioblastoma (GB) is the most commonly occurring malignant central nervous system (CNS) tumor, accounting for 14.6% of all 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):1-100). It is an aggressive primary brain tumor with a high mortality rate despite extensive efforts to develop new treatments. Currently, there are no curative treatment options for glioblastoma, and despite rigorous therapeutic research, survival rates for patients diagnosed with glioblastoma remain low. The median overall survival (OS) is approximately 15 months, with a 5-year survival rate of less than 10% (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). Glioblastoma is one of the malignant brain tumors with the lowest long-term survival rates, with a 5-year overall relative survival rate of only 6.8% (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): 1-100).

[0003] The overall age-adjusted incidence rate of glioblastoma in the United States is 3.22 / 100,000, with a male predominance and an increase with older age at diagnosis (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). Standard treatment for newly diagnosed patients with glioblastoma begins with surgery intended to perform maximal safe tumor removal (Nabors LB, Portnow J, Ahluwalia M, et al (2020) Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw p. 1537-1570). Glioblastoma is a radiosensitive tumor, and radiation therapy (RT) has been considered the most important treatment modality for glioblastoma after surgery since the 1980s.

[0004] The current standard of care in newly diagnosed patients is the combination of temozolomide (TMZ) (an oral alkylating agent) and radiation therapy (RT), which was approved based on the results of a large randomized phase III trial comparing radiotherapy (60 Gy for 6 weeks) with radiotherapy plus daily concomitant temozolomide 75 mg / m2 / day followed by maintenance temozolomide 150-200 mg / m2 / day for 5 consecutive days every 28-day cycle for up to 6 cycles (Stupp R, Mason WP, van den Bent MJ, et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblatoma. N Engl J Med; 352: 987-96). The addition of temozolomide to radiotherapy extended median overall survival from 12.1 to 14.6 months.

[0005] Methylation of the promoter of the O-6-methylguanine-DNA methyltransferase (MGMT) gene in glioblastoma is both a prognostic and predictive marker for response to treatment with alkylating agents. In a study involving 206 newly diagnosed glioblastoma patients, the overall survival of patients with MGMT promoter methylation was highly significant compared to patients whose tumors did not have a methylated MGMT promoter (P<0.001; hazard ratio for death, 0.45). The study also showed that in patients with a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiation therapy, with a median survival of 21.7 months compared to 15.3 months in patients treated with radiation therapy alone (P=0.007). In contrast, in patients whose tumors were not methylated at the MGMT promoter, the difference in overall survival was not significant, with a median survival of 12.7 months in patients treated with temozolomide and radiotherapy and 11.8 months in patients treated with radiotherapy alone (P=0.06) (Hegi ME, Diserens AC, Gorlia T, et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med; 352: 997-1003). Other studies have also shown that the presence of MGMT promoter methylation results in approximately 50% longer median survival for glioblastoma patients treated with temozolomide and in patients lacking MGMT promoter methylation. In this regard, the use of temozolomide has no clinical benefit in this patient group and results in undesirable toxicity.Thus, withholding temozolomide from glioblastomas lacking MGMT promoter methylation has become acceptable, especially with regard to clinical trials conducted in recent years (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).

[0006] Inevitably, nearly all patients will experience disease recurrence, with a median progression-free survival (PFS) of approximately 6-10 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). Available treatment options for recurrent disease have limited survival benefit, and there is no established set of therapies for recurrent glioblastoma. Treatment of recurrent glioblastoma is challenging due to the limited efficacy of available options and the lack of established treatment options. Treatment guidelines recommend clinical trials as the preferred option for eligible patients (Nabors LB, Portnow J, Ahluwalia M, et al (2020) Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw p.1537-1570; 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). Surgery may have a role for symptomatic and / or large disease. However, only patients who undergo complete or near-total resection have any survival benefit (Nam JY, de Groot JF (2017) Treatment of Glioblastoma. J Oncol Pract; 13 (10): 629-39).Other treatment options include systemic therapy, such as temozolomide rechallenge, nitrosoureas, bevacizumab, re-irradiation, and tumor field therapy, which have not been shown to extend survival in randomized trials in this setting or in palliative care for patients with poor performance status. Single-agent nitrosoureas (carmustine, lomustine, and fotemustine) have been evaluated in recurrent glioblastoma. In a recent study, 437 patients were randomized 2:1 between lomustine as a single agent and lomustine in combination with bevacizumab. Patients in the lomustine arm had a median PFS of 1.5 months and an OS of 8.6 months. The addition of bevacizumab to lomustine showed an improved median PFS of 1.5 months in the lomustine arm versus 4.2 months in the combination arm (P<0.001); however, the difference in median OS did not confer a survival difference of 8.6 months in the lomustine arm versus 9.1 months in the combination arm (Wick W, Gorlia T, Bendszus M, et al(2017)Lomustine and Bevacizumab in Progressive Glioblastoma.N Engl J Med;377:1954-1963).

[0007] Pilot studies are evaluating the activity of radiolabeled DOTA peptides in patients with glioblastoma. Heute et al. reported the use of 90Y-DOTATOC in three patients with grade IV recurrent glioblastoma (Heute D, Kostron H, von Guggenberg E, et al (2010) Response of recurrent high-grade glioma to treatment with (90)Y-DOTATOC. J Nucl Med; 51: 397-400). Nemati et al. reported the use of 177Lu-DOTATATE in high-grade glioma (HGG) (Nemati R, Shooli H, Rekabpour SJ, et al (2021) Feasibility and Therapeutic Potential of Peptide Receptor Radionuclide Therapy for High-Grade Gliomas. Clin Nucl Med; 46 (5): 389-95).

[0008] There remains a need to provide improved clinical treatments for glioblastoma. Summary of the Invention

[0009] The present disclosure relates to a method of treating glioblastoma in a subject in need of such treatment by administering to said subject a therapeutically effective amount of a radiopharmaceutical compound in combination with radiation therapy, and optionally temozolomide.

[0010] The present disclosure is provided in various aspects, as outlined below: 1. A radiopharmaceutical compound for use in the treatment of glioblastoma in a subject in need of such treatment, wherein a therapeutically effective amount of said radiopharmaceutical compound is administered to said subject, preferably in combination with radiation therapy.

[0011] 2. The radiopharmaceutical compound has the formula: MCSP (in the formula, M is a radionuclide; C is a chelating agent capable of chelating said radionuclide; S is an optional spacer covalently linking C and P; P is a somatostatin receptor binding peptide covalently linked directly to C or indirectly via S. The radiopharmaceutical compound for use according to embodiment 1, which is a compound of

[0012] 3. M. 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 Sc, preferably 177 The radiopharmaceutical compound for use according to any one of the preceding claims, wherein the compound is Lu.

[0013] 4. A radiopharmaceutical compound for use according to embodiments 1 to 3, wherein C is selected from DOTA (tetrazoxetan), trizoxetan, DOTAGA, DTPA, NTA, EDTA, DO3A, TETA, NOTA, NOTAGA, NODAGA, NODAPA, and AAZTA (e.g. AAZTA5) chelators, preferably a DOTA, DOTAGA, NOTA or DTPA chelator, more preferably a DOTA chelator.

[0014] 5. A radiopharmaceutical compound for use according to embodiments 1 to 4, wherein P is selected from octreotide, octreotate, satreotide, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate.

[0015] 6. A radiopharmaceutical compound for use according to embodiments 1 to 5, selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), satreotide tetraxetane, DOTA-LAN and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

[0016] 7. [ 177 Lu]Lu-DOTA-TOC( 177 Lu-Edotreotide) or [ 177 Lu]Lu-DOTA-TATE( 177 Lu-oxodotreotide), more preferably [ 177 Lu]Lu-DOTA-TATE( 177 The radiopharmaceutical compound for use in embodiments 1 to 6, which is Lu-oxodotreotide.

[0017] 8. The radiopharmaceutical compound for use according to embodiments 1 to 7, wherein the radiopharmaceutical compound is administered to said subject in combination with radiation therapy and with a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0018] 9. The alkylating agent, preferably temozolomide, is administered at 50-100 mg / m each day for an initial period of 4-8 weeks, preferably 5-7 weeks, more preferably 6 weeks (during the induction period). 2 / day, preferably about 75 mg / m 2 The radiopharmaceutical compound for use according to embodiment 8, administered at a dose of 100 mg / day.

[0019] 10. The radiopharmaceutical compound for use according to embodiment 8 or 9, wherein both the radiation therapy and the administration of the alkylating agent, preferably temozolomide, are started on the same day.

[0020] 11. The radiopharmaceutical compound for use according to embodiments 8 to 10, wherein said alkylating agent, preferably temozolomide, is administered concomitantly with radiotherapy without interruption (from the first day to the last day of radiotherapy).

[0021] 12. The alkylating agent, preferably temozolomide, is administered in a first daily dose (preferably 50-100 mg / m 2 ) for a period of, for example, 6 weeks (± 1 week) during co-administration with radiation therapy. 2 / day, more preferably 75 mg / m 2 12. The radiopharmaceutical compound for use in embodiments 8-11, wherein the compound is administered daily at a dose of 100 mg / day (100 mg / day) and during a maintenance phase following administration in combination with radiation therapy, for example for a period of up to 24 weeks, a second dose is administered, said second daily dose being at least twice the first daily dose, and preferably said second dose being administered on each of days 1-5 of a 28 day cycle.

[0022] 13. The alkylating agent, preferably temozolomide, is administered at a dose of 50 to 400 mg / m2 on each of days 1 to 5 of a 28-day cycle during the maintenance phase for 4 to 8 cycles, preferably 5 to 7 cycles, more preferably 6 cycles. 2 / day, preferably 75-300 mg / m 2 / day, more preferably 150-200 mg / m 2 The radiopharmaceutical compound for use according to embodiments 8 to 12, administered at a dose of 100 mg / day.

[0023] 14. The radiopharmaceutical compound for use according to embodiments 8 to 13, wherein said subject is selected from subjects having a positive methylated O-6-methylguanine-DNA methyltransferase promoter status.

[0024] 15. A radiopharmaceutical compound for use according to any one of the preceding embodiments, 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), 5.55 GBq (150 mCi), 7.4 GBq (200 mCi) or 9.25 GBq (250 mCi).

[0025] 16. The radiopharmaceutical compound for use according to any one of the preceding embodiments, wherein the compound is administered 1 to 8 times, preferably 2 to 7 times, more preferably 4 to 6 times, with a treatment interval between every two administrations of said radiopharmaceutical compound.

[0026] 17. A radiopharmaceutical compound for use according to embodiments 1 to 16, wherein the administration of said radiopharmaceutical compound comprises a treatment interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 and / or 4 weeks, more preferably every 3 weeks.

[0027] 18. The radiopharmaceutical compound for use according to embodiments 1 to 17, wherein the first dose of said radiopharmaceutical compound is administered 1 to 20 days, preferably 3 to 15 days, more preferably 7 to 10 days, before the start of radiation therapy.

[0028] 19. A radiopharmaceutical compound for use according to embodiments 1 to 18, wherein said radiotherapy induction is carried out at a dose of 1 Gy to 4 Gy / day, preferably about 2 Gy / day, for a period of 3 to 7 days, preferably about 5 days, per week, for a period of 4 to 8 weeks, preferably 6 weeks.

[0029] 20. The radiopharmaceutical compound for use according to embodiments 1 to 19, wherein said radiotherapy is administered for 5 consecutive days followed by 2 days of rest for 6 consecutive weeks.

[0030] 21. The radiopharmaceutical compound for use according to embodiments 1 to 20, wherein said radiotherapy is whole brain radiotherapy.

[0031] 22. The subject is a subject, wherein M is a radioactive metal suitable for imaging, preferably 68 Ga, 67 Ga or 64 Cu, more preferably 68 The radiopharmaceutical compound for use in embodiments 1 to 21 selected for treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with the same radiopharmaceutical compound as defined for treatment, except that Ga.

[0032] 23. The radiopharmaceutical compound for use according to embodiments 1 to 22, wherein said subject is newly diagnosed with glioblastoma or suffers from recurrent glioblastoma.

[0033] 24. The radiopharmaceutical compound for use according to embodiments 1 to 23, wherein the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide, and a first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days prior to the start of radiation therapy.

[0034] 25. The radiopharmaceutical compound for use of embodiments 1-24, wherein the subject is newly diagnosed with glioblastoma and has a negative methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound is administered to the subject in combination with radiation therapy, but not in combination with other chemotherapeutic agents, such as temozolomide; the treatment interval between two doses of the radiopharmaceutical compound is 4 weeks for the first two intervals and 3 weeks for the third and any subsequent intervals; and the first dose of the radiopharmaceutical compound is preferably administered 7-10 days before the start of radiation therapy.

[0035] 26. A method of treating glioblastoma in a subject in need of treatment comprising administering to the subject an efficient amount of a radiopharmaceutical compound, preferably in combination with irradiating the subject with an efficient dose of ionizing radiation.

[0036] 27. The radiopharmaceutical compound has the formula: MCSP (in the formula, M is a radionuclide; C is a chelating agent capable of chelating said radionuclide; S is an optional spacer covalently linking C and P; P is a somatostatin receptor binding peptide covalently linked directly to C or indirectly via S. 27. The method of embodiment 26, wherein the compound is

[0037] 28. M. 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb,161 Tb, 213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 Sc, preferably 177 28. The method of embodiment 26 or 27, wherein Lu is

[0038] 29. The method of any one of embodiments 26 to 28, wherein C is selected from DOTA (tetrazoxetan), trizoxetan, DOTAGA, DTPA, NTA, EDTA, DO3A, TETA, NOTA, NOTAGA, NODAGA, NODASA, NODAPA, and AAZTA (e.g., AAZTA5) chelators, preferably a DOTA, DOTAGA, NOTA or DTPA chelator, more preferably a DOTA chelator.

[0039] 30. The method of embodiments 26-29, wherein P is selected from octreotide, octreotate, satreotide, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

[0040] 31. The method of embodiments 26-30, wherein the radiopharmaceutical compound is selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), satreotide tetraxetane, DOTA-LAN, and DOTA-VAP, preferably DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

[0041] 32. A radiopharmaceutical compound is 177 Lu]Lu-DOTA-TOC( 177 Lu-Edotreotide) or [ 177 Lu]Lu-DOTA-TATE (177Lu-oxodotreotide), more preferably [ 177 Lu]Lu-DOTA-TATE( 177 32. The method of embodiments 26-31, wherein the agonist is acetylcholinesterase (Ala-Tyr-2-oxodotreotide).

[0042] 33. The method of embodiments 26-32, further comprising administering a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0043] 34. The alkylating agent, preferably temozolomide, is administered at 50-100 mg / m each day for an initial period of 4-8 weeks, preferably 5-7 weeks, more preferably 6 weeks (during the induction period). 2 / day, preferably about 75 mg / m 2 The method of embodiment 33, wherein the dose is administered in a dose of 100 mg / day.

[0044] 35. The method of embodiment 33 or 34, wherein both the radiation and the administration of the alkylating agent, preferably temozolomide, are started on the same day.

[0045] 36. The method of embodiments 33-35, wherein the alkylating agent, preferably temozolomide, is administered concomitantly with radiation (e.g., from the first day to the last day of radiation) without interruption.

[0046] 37. The alkylating agent, preferably temozolomide, is administered in a first daily dose (preferably 50-100 mg / m 2 ) for a period of, for example, 6 weeks (± 1 week) during co-administration with radiation therapy. 2 / day, more preferably 75 mg / m 2 37. The method of embodiments 33-36, wherein the first daily dose is administered daily at a dose of 100 mg / day (i.e., 100 mg / day) and during a maintenance phase following administration in combination with radiation therapy, for example for a period of up to 24 weeks, a second daily dose is administered, said second daily dose being at least twice the first daily dose, and preferably said second dose being administered on each of days 1-5 of a 28 day cycle.

[0047] 38. The alkylating agent, preferably temozolomide, is administered at a dose of 50 to 400 mg / m2 on each of days 1 to 5 of a 28-day cycle during the maintenance phase for 4 to 8 cycles, preferably 5 to 7 cycles, more preferably 6 cycles. 2 / day, preferably 75-300 mg / m 2 / day, more preferably 150-200 mg / m 2 The method of embodiments 33-37, wherein the dose is administered in a dose range of 10-15 mg / day.

[0048] 39. The method of embodiments 33 to 38, wherein the subject is selected from subjects having a positive methylated O-6-methylguanine-DNA methyltransferase promoter status.

[0049] 40. The method of any one of embodiments 26 to 39, wherein said radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), preferably 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), preferably 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), more preferably 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), even more preferably about 3.7 GBq (100 mCi), 5.55 GBq (150 mCi), 7.4 GBq (200 mCi) or 9.25 GBq (250 mCi).

[0050] 41. The method of embodiments 26-40, wherein the radiopharmaceutical compound is administered 1 to 8 times, preferably 2 to 7 times, more preferably 4 to 6 times, and there is a treatment interval between every two administrations of the radiopharmaceutical compound.

[0051] 42. The method of embodiments 26-41, wherein said radiopharmaceutical compound comprises a treatment interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 and / or 4 weeks, more preferably every 3 weeks.

[0052] 43. The method of embodiments 26-42, wherein the first dose of said radiopharmaceutical compound is administered 1 to 20 days, preferably 3 to 15 days, more preferably 7 to 10 days, before the start of radiation exposure.

[0053] 44. The method of embodiments 26-33, wherein the radiation induction is carried out at a dose of 1 Gy-4 Gy / day, preferably about 2 Gy / day, for a period of 3-7 days, preferably about 5 days, per week, for a period of 4-8 weeks, preferably 6 weeks.

[0054] 45. The method of any one of embodiments 26 to 44, wherein said radiation is administered for 5 consecutive days followed by 2 days of rest for 6 consecutive weeks.

[0055] 46. ​​The method of embodiments 26-45, wherein said radiation is whole brain radiation.

[0056] 47. The object is: 177 Instead of Lu, a radioactive metal suitable for imaging, preferably 68 Ga, 67 Ga or 6 4 Cu, more preferably 68 The method of any one of embodiments 26 to 46, selected for treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with the same radiopharmaceutical compound as defined for treatment, except that Ga is used, by evaluating the uptake of said radiopharmaceutical compound suitable for imaging in said subject.

[0057] 48. The method of embodiments 26-47, wherein the subject is newly diagnosed with glioblastoma or suffers from recurrent glioblastoma.

[0058] 49. The method of embodiments 26-48, wherein the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide, and a first dose of the radiopharmaceutical compound is preferably administered 7-10 days prior to the start of radiation.

[0059] 50. The method of embodiments 26-49, wherein the subject is newly diagnosed with glioblastoma and has a negative methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound is administered to the subject in combination with radiation therapy, but not in combination with other chemotherapeutic agents, such as temozolomide; the treatment interval between two doses of the radiopharmaceutical compound is 4 weeks for the first two intervals, and 3 weeks for the third and any subsequent intervals; and the first dose of the radiopharmaceutical compound is preferably administered 7-10 days before the start of radiation.

[0060] 51. Use of a radiopharmaceutical compound in the preparation of a medicament for use in the treatment of glioblastoma in a subject in need of such treatment, wherein a therapeutically effective amount of said radiopharmaceutical compound is administered to said subject, preferably in combination with radiation therapy.

[0061] 52. The radiopharmaceutical compound has the formula: MCSP (in the formula, M is a radionuclide; C is a chelating agent capable of chelating said radionuclide; S is an optional spacer covalently linking C and P; P is a somatostatin receptor binding peptide covalently linked directly to C or indirectly via S. The use of embodiment 51, wherein the compound is

[0062] 53. M. 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 Sc, preferably 177 The use of embodiment 51 or 52, wherein Lu is

[0063] 54. Use of embodiments 51 to 53, wherein C is selected from DOTA (tetrazoxetan), trizoxetan, DOTAGA, DTPA, NTA, EDTA, DO3A, TETA, NOTA, NOTAGA, NODAGA, NODASA, NODAPA, and AAZTA (e.g., AAZTA5) chelators, preferably a DOTA, DOTAGA, NOTA or DTPA chelator, more preferably a DOTA chelator.

[0064] 55. The use of embodiments 51 to 54, wherein P is selected from octreotide, octreotate, satreotide, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

[0065] 56. The use of embodiments 51 to 55, wherein the radiopharmaceutical compound is selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), satreotide tetraxetane, DOTA-LAN, and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

[0066] 57. A radiopharmaceutical compound is 177 Lu]Lu-DOTA-TOC( 177 Lu-Edotreotide) or [ 177 Lu]Lu-DOTA-TATE( 177 Lu-oxodotreotide), more preferably [ 177 Lu]Lu-DOTA-TATE( 177 The use of embodiments 51 to 56, wherein the agonist is benzodiazepine (Zinc phosphate phosphate), benzodiazepine (Zinc phosphate phosphate), benzodiazepine (Zinc phosphate), benzotriazolidine ...

[0067] 58. The use of embodiments 51-57, wherein said radiopharmaceutical compound is administered to said subject in combination with radiation therapy and with a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0068] 59. The alkylating agent, preferably temozolomide, is administered at 50-100 mg / m2 daily for an initial period of 4-8 weeks, preferably 5-7 weeks, more preferably 6 weeks (during the induction period). 2 / day, preferably about 75 mg / m 2 The use of embodiment 58, wherein the dose is administered in a dose of 100 / day.

[0069] 60. The use of embodiment 58 or 59, wherein both radiation therapy and administration of an alkylating agent, preferably temozolomide, are started on the same day.

[0070] 61. The use of embodiments 58-60, wherein the alkylating agent, preferably temozolomide, is administered concomitantly with radiation therapy without interruption (e.g., from the first day to the last day of radiation therapy).

[0071] 62. The alkylating agent, preferably temozolomide, is administered in a first daily dose (preferably 50-100 mg / m 2 ) for a period of, for example, 6 weeks (± 1 week) during co-administration with radiation therapy. 2 / day, more preferably 75 mg / m 2 / day) and during a maintenance phase following administration in combination with radiation therapy, for example for a period of up to 24 weeks, a second daily dose is administered, said second daily dose being at least twice the first daily dose, preferably said second dose being administered on each of days 1-5 of a 28 day cycle.

[0072] 63. The alkylating agent, preferably temozolomide, is administered at a dose of 50 to 400 mg / m2 on each of days 1 to 5 of a 28-day cycle during the maintenance phase for 4 to 8 cycles, preferably 5 to 7 cycles, more preferably 6 cycles. 2 / day, preferably 75-300 mg / m 2 / day, more preferably 150-200 mg / m 2 The use of embodiments 58 to 62, wherein the dose is administered in a dose of 100 mg / day.

[0073] 64. The use of embodiments 58 to 63, wherein the subject is selected from subjects with a positive methylated O-6-methylguanine-DNA methyltransferase promoter status.

[0074] 65. The use of embodiments 51-64, wherein said radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), preferably 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), preferably 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), more preferably 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), even more preferably about 3.7 GBq (100 mCi), 5.55 GBq (150 mCi), 7.4 GBq (200 mCi) or 9.25 GBq (250 mCi).

[0075] 66. The use of embodiments 51-65, wherein the radiopharmaceutical compound is administered 1-8 times, preferably 2-7 times, more preferably 4-6 times, and there is a treatment interval between every two administrations of the radiopharmaceutical compound.

[0076] 67. The use of embodiments 51-66, wherein the administration of said radiopharmaceutical compound comprises a treatment interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 and / or 4 weeks, more preferably every 3 weeks.

[0077] 68. The use of embodiments 51-67, wherein the first dose of said radiopharmaceutical compound is administered 1 to 20 days, preferably 3 to 15 days, more preferably 7 to 10 days, before the start of radiation therapy.

[0078] 69. The use of embodiments 51-68, wherein the radiotherapy induction is carried out at a dose of 1 Gy-4 Gy / day, preferably about 2 Gy / day, for a period of 3-7 days, preferably about 5 days, per week, for a period of 4-8 weeks, preferably 6 weeks.

[0079] 70. The use of embodiments 51-69, wherein said radiation therapy is administered for 5 consecutive days followed by 2 days of rest for 6 consecutive weeks.

[0080] 71. The use of embodiments 51 to 70, wherein said radiotherapy is whole brain radiotherapy.

[0081] 72. The subject is a subject, wherein M is a radioactive metal suitable for imaging, preferably 68 Ga, 67 Ga or 64 Cu, more preferably 68 The use of embodiments 51 to 71, selected for treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with the same radiopharmaceutical compound as defined for treatment, but with a radiometal suitable for imaging, but with the same radiopharmaceutical compound as defined for treatment, but with Ga.

[0082] 73. The use of embodiments 51-72, wherein the subject is newly diagnosed with glioblastoma or suffers from recurrent glioblastoma.

[0083] 74. The use of embodiments 51-73, wherein the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide, and a first dose of the radiopharmaceutical compound is preferably administered 7-10 days prior to the start of radiation therapy.

[0084] 75. The use of embodiments 51-74, wherein the subject is newly diagnosed with glioblastoma and has a negative methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound is administered to the subject in combination with radiation therapy, but not in combination with other chemotherapeutic agents, such as temozolomide; the treatment interval between two doses of the radiopharmaceutical compound is 4 weeks for the first two intervals, and 3 weeks for the third and any subsequent intervals; and the first dose of the radiopharmaceutical compound is preferably administered 7-10 days before the start of radiation therapy.

[0085] 76. A method of treating glioblastoma in a subject in need of treatment comprising administering to the subject in need of treatment an effective amount of a radiopharmaceutical compound having the formula: MCSP (in the formula, M is a radionuclide; C is a chelating agent capable of chelating said radionuclide; S is an optional spacer covalently linking C and P; P is a somatostatin receptor binding peptide covalently linked directly to C or indirectly via S. is a compound of The method does not include the concomitant step of irradiating the subject with an efficient dose of ionizing radiation.

[0086] 77. M. 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb, 213 Bi, 166 Ho,165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 Sc, preferably 177 The method of embodiment 76, wherein Lu is

[0087] 78. The method of embodiment 76 or 77, wherein C is selected from DOTA (tetrazoxetan), trizoxetan, DTPA, NTA, EDTA, DO3A, TETA, NOTA, NOTAGA, NODOGA, NODASA, NODAPA, and AAZTA (e.g., AAZTA5) chelators, preferably a DOTA, NOTA or DTPA chelator, more preferably a DOTA chelator.

[0088] 79. The method of embodiments 76-78, wherein P is selected from octreotide, octreotate, satreotide, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

[0089] 80. The method of embodiments 76-79, wherein the radiopharmaceutical compound is selected from DOTA-OC, DOTA-TOC (edotreotide), satreotide tetraxetane, DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP, preferably DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

[0090] 81. A radiopharmaceutical compound is 177 Lu]Lu-DOTA-TOC( 177 Lu-Edotreotide) or [ 177 Lu]Lu-DOTA-TATE( 177 Lu-oxodotreotide), more preferably [ 177 Lu]Lu-DOTA-TATE( 177 82. The method of embodiments 76-81, wherein the agonist is acetylcholinesterase (Ala-Tyr-2-oxodotreotide).

[0091] 82. The method of embodiments 76-81, wherein said radiopharmaceutical compound is administered at a dose in the range of 0.925 GBq (25 mCi) to 29.6 GBq (800 mCi), preferably 1.48 GBq (40 mCi) to 18.5 GBq (500 mCi), preferably 1.85 GBq (50 mCi) to 14.8 GBq (400 mCi), more preferably 3.7 GBq (100 mCi) to 11.1 GBq (300 mCi), even more preferably about 3.7 GBq (100 mCi), 5.55 GBq (150 mCi), 7.4 GBq (200 mCi) or 9.25 GBq (250 mCi).

[0092] 83. The method of embodiments 76-82, wherein the radiopharmaceutical compound is administered 1 to 8 times, preferably 2 to 7 times, more preferably 4 to 6 times, and there is a treatment interval between every two administrations of the radiopharmaceutical compound.

[0093] 84. The method of embodiments 76-83, wherein the administration of the radiopharmaceutical compound comprises 2 to 7 cycles of treatment with treatment intervals of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably every 3 weeks.

[0094] 85. The object is: 177 Instead of Lu, a radioactive metal suitable for imaging, preferably 68 Ga, 67 Ga or 64 Cu, more preferably 68 The method of any one of embodiments 76 to 84, wherein the subject is selected for treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with the same radiopharmaceutical compound as defined for treatment, except that Ga is used, by evaluating the uptake of said radiopharmaceutical compound suitable for imaging in said subject.

[0095] 86. The method of embodiments 76-85, wherein the subject is newly diagnosed with glioblastoma or suffers from recurrent glioblastoma, in particular the subject suffers from recurrent glioblastoma.

[0096] 87. The method of any one of embodiments 76 to 86, wherein the subject is afflicted with recurrent glioblastoma and does not include a concomitant step of administering an alkylating agent, such as temozolomide.

[0097] 88. The method of any one of embodiments 76 to 87, wherein the subject suffers from recurrent glioblastoma, does not include a concomitant step of irradiating the subject with an effective dose of ionizing radiation, does not include a concomitant step of administering an alkylating agent, e.g., temozolomide, and comprises 2 to 7 cycles of treatment with the radiopharmaceutical, and the treatment interval between two administrations of the radiopharmaceutical compound is 3 weeks.

[0098] Embodiments 76-88 may alternatively be expressed in the following format: A radiopharmaceutical compound for use in the treatment of glioblastoma in a subject in need of such treatment, wherein a therapeutically effective amount of said radiopharmaceutical compound is administered to said subject.

[0099] Such as use of a radiopharmaceutical compound in the preparation of a medicament for use in treating glioblastoma in a subject in need of such treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0100] The present disclosure relates to a method of treating glioblastoma in a subject in need of treatment for glioblastoma by administering to the subject in need of treatment a therapeutically effective amount of a radiopharmaceutical compound in combination with radiation therapy, and optionally an alkylating agent, preferably temozolomide.

[0101] general definition The use of the articles "a," "an," and "the" in both the detailed description and the claims should be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "of," "including," and "containing," such as in a complex of "a cellular receptor-binding organic moiety linked to a radionuclide and a chelator," should be construed as open terms (i.e., "including but not limited to") unless otherwise noted. Furthermore, whenever "comprising" or another open-ended term is used in an embodiment, it should be understood that the same embodiment may be narrowly claimed using the intermediate term "consisting essentially of" or the closed term "consisting of."

[0102] The terms "about" or "approximately" are used herein to mean that the subsequent value may vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, and even more preferably ±1%.

[0103] Unless otherwise defined, "%" herein has the meaning of weight percent (wt%), also referred to as weight percent (w / w%).

[0104] A "total concentration" refers to the sum of one or more individual concentrations.

[0105] "Aqueous solution" refers to a solution of one or more solutes in water.

[0106] The phrases "treatment of" and "treating" include the amelioration or cessation of a disease, disorder, or a symptom thereof. In particular, with respect to the treatment of tumors, the term "treatment" can refer to the inhibition of tumor growth or the reduction in tumor size.

[0107] As used herein, "glioblastoma" refers to aggressive brain tumors that belong to grade IV astrocytoma brain tumors.The term glioblastoma also includes its subtypes 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).

[0108] In agreement with the International System of Units, "MBq" is the abbreviation for the unit of radioactivity "megabecquerel".

[0109] As used herein, "PET" means positron emission tomography.

[0110] As used herein, "SPECT" means single photon emission computed tomography.

[0111] As used herein, "MRI" means magnetic resonance imaging.

[0112] As used herein, "CT" means computed tomography.

[0113] As used herein, the term "effective amount" or "therapeutically effective amount" of a compound refers to an amount of a compound that elicits a biological or medical response in a subject, e.g., ameliorates symptoms, alleviates a pathology, slows or delays the progression of a disease, or prevents a disease.

[0114] The terms "patient" and "subject," used interchangeably, refer to humans and include, for example, subjects with cancer.

[0115] "For commercial use" refers to a drug product, e.g., an aqueous pharmaceutical solution, that may obtain (preferably has obtained) market approval by a health authority, e.g., US-FDA or EMA, by complying with all drug product quality and stability requirements required by such health authority, that may be manufactured (preferably is manufactured) on a commercial scale from or at a pharmaceutical production site, that may then undergo quality control testing procedures, and that the drug product may be supplied (preferably is supplied) to an end user, e.g., a hospital or a patient, at a remote location.

[0116] "Combination" refers to either a fixed combination in one dosage unit form, or a combination administration in which the compound of the present disclosure and a combination partner (e.g., another drug described below, also referred to as a "therapeutic agent" or "co-agent") can be administered independently at the same time or separately within a time interval, particularly where these time intervals allow the combination partners to exhibit a coordinated, e.g., synergistic, effect. The single components can be packaged in a kit or separately. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose before administration. The terms "co-administration" or "combination administration" and the like, as used herein, are meant to encompass administration of selected combination partners to a single subject (e.g., patient) where administration is required, and are intended to include treatment regimes in which the agents are not necessarily administered by the same route of administration or at the same time.

[0117] The term "pharmaceutical combination" as used herein means a product resulting from the mixing or combination of two or more therapeutic agents, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that both therapeutic agents, such as radiolabeled somatostatin binding receptor compounds and combination partners, such as alkylating agents, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that both therapeutic agents, such as radiolabeled somatostatin binding receptor compounds and combination partners, such as alkylating agents, are administered to a patient simultaneously, concomitantly or sequentially as separate entities without a defined time limit, and such administration provides the patient with a therapeutically effective level of the two compounds. Non-fixed combination also applies to cocktail therapy, such as the administration of three or more therapeutic agents.

[0118] Radiopharmaceutical Compounds in the Treatment Methods of the Disclosure As used herein, the term "radiopharmaceutical" refers to a pharmaceutical compound that is typically labeled with a metallic radionuclide element. Thus, a radiopharmaceutical compound is an SSTR binding compound that contains a radionuclide and has specific binding affinity for an SSTR, for example, at least the SSTR2 receptor.

[0119] Thus, a radiolabeled somatostatin receptor binding compound is a compound that contains a radionuclide and has specific binding affinity to a somatostatin receptor. In some embodiments of the present disclosure, said radiolabeled somatostatin receptor binding compound has specific binding affinity to at least the SSTR2 receptor.

[0120] In these and other embodiments of the present disclosure, the radiopharmaceutical compound has the formula MCSP (in the formula, M is a radionuclide; C is a chelating agent capable of chelating said radionuclide; S is an optional spacer covalently linking C and P; P is a somatostatin receptor-binding peptide that is covalently linked, e.g., via its N-terminus, directly to C or indirectly via S). It is a compound of the formula:

[0121] Such radiopharmaceutical compounds may be selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

[0122] In some embodiments of the present disclosure, the radionuclide M is a selected radionuclide isotope suitable for PRRT.

[0123] Examples of such suitable radionuclides M include, but are not limited to: 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm,142 Pr, 143 Pr, 76 As, 111 Ag and 47 Sc, preferably 177 This is Lu.

[0124] As used herein, the term "chelating agent" refers to an organic moiety that contains a functional group that can form a non-covalent bond with a radionuclide, thereby forming a stable radionuclide complex. The chelating agent of the present disclosure can be 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramineTETA, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). In many embodiments of the present disclosure, the chelating agent is DOTA.

[0125] Such chelators are linked directly to the somatostatin receptor binding peptide or are connected via a linker molecule, preferably it is directly linked. The linking bond(s) is / are a covalent or non-covalent bond(s) between the cell receptor binding organic moiety (and linker) and the chelator, preferably the bond(s) is / are a covalent bond.

[0126] As used herein, the term "somatostatin receptor binding peptide" refers to a peptidic moiety having specific binding affinity to a somatostatin receptor. Such somatostatin receptor binding peptides may be selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, and preferably selected from octreotide and octreotate.

[0127] According to many embodiments of the disclosed methods, the somatostatin receptor binding peptide linked to the chelator is selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP. In many of these embodiments, the somatostatin receptor binding peptide is DOTA-TOC or DOTA-TATE. In many such embodiments, the somatostatin receptor binding peptide is DOTA-TATE.

[0128] In one embodiment, the radiopharmaceutical compound of the present disclosure comprises: 177 Lu-DOTA-TOC( 177 Lu-Edotreotide) or 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide), more preferably 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide).

[0129] Many embodiments of the present disclosure include combination therapy with the radiopharmaceutical compounds.

[0130] The radiopharmaceutical compound is for use in the treatment of glioblastoma in a subject in need of such treatment, wherein a therapeutically effective amount of said radiopharmaceutical compound is administered to said subject.

[0131] In one embodiment, 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), 5.55 GBq (150 mCi), 7.4 GBq (200 mCi) or 9.25 GBq (250 mCi).

[0132] In another embodiment, the radiopharmaceutical compound for use is administered 1 to 8 times per treatment during the induction phase, preferably 2 to 7 times per treatment, more preferably 4 to 6 times per treatment. Administration of the radiopharmaceutical compound for use may include treatment intervals of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 or 4 weeks, more preferably every 3 weeks.

[0133] Thus, the cell receptor binding moiety and the chelator may be a molecule such as: DOTA-OC: [DOTA 0 ,D-Phe 1 ]Octreotide, The following formula: [ka] DOTA-TOC represented by: [DOTA 0 ,D-Phe 1 ,Tyr 3 ]Octreotide, edotreotide (INN), DOTA-NOC: [DOTA 0 , D-Phe 1 ,1-Nal 3 ]Octreotide, The following formula: [ka] DOTA-TATE represented by: [DOTA 0 ,D-Phe 1 ,Tyr 3 ]Octreotate, DOTA-Tyr 3 -Octreotate, DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (cyclo 2,7), oxodotreotide (INN) DOTA-LAN: [DOTA 0 ,D-β-Nal 1 ]Lanreotide, DOTA-VAP: [DOTA 0 ,D-Phe 1 ,Tyr 3 ]vapreotide, Satreotide Trizoxetan [ka] Satreotide Tetraxetan [ka] can be formed together.

[0134] Common "cell receptor binding moiety linked to a chelator" molecules of the present disclosure for use in combination therapy are DOTA-TOC, DOTA-TATE, and satreotide tetraxetane, more preferably the molecule is DOTA-TATE.

[0135] More specifically, in many embodiments of the present disclosure, the complex formed by the cell receptor binding moiety linked to a radionuclide and a chelator according to the present invention comprises 177 Lu-DOTA-TATE, which is lutetium (177Lu) oxodotreotide (INN), i.e., hydrogen [N-{[4,7,10-tris(carboxylato-κO-methyl)-1,4,7,10-tetraazacyclododecan-1-yl-κ 4 N 1 ,N 4 ,N 7 ,N 10 ]acetyl-κO}-D-phenylalanyl-L-cysteinyl-tyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threoninatocyclic (2→7)-disulfide(4-)](177Lu) lutetate(1-), The following formula: [ka] It is expressed by:

[0136] The radiolabeled somatostatin receptor binding compound is typically formulated for administration in a therapeutically effective amount in a subject in need thereof.

[0137] The radiolabeled somatostatin receptor binding compound may be present at a concentration that provides a volumetric activity of 100 MBq / mL or greater. In many embodiments of the present disclosure, the volumetric activity is 250 MBq / mL or greater.

[0138] In many embodiments of the present disclosure, the radiolabeled somatostatin receptor binding compound may be present in a concentration that provides a volumetric activity of from 100 MBq / mL to 1000 MBq / mL, including from 250 MBq / mL to 500 MBq / mL, for example, at a concentration of about 370 MBq / mL (10 mCi / mL).

[0139] Pharmaceutically acceptable excipients can be any of those commonly used and are limited only by physicochemical considerations, such as solubility and lack of reactivity with the active compound(s).

[0140] In particular, the one or more pharma- ceutically acceptable excipients may be selected from a number of different classes of such pharma-ceutically acceptable excipients, examples of which include radiation decomposition stabilizers, buffers, sequestering agents, and mixtures thereof.

[0141] As used herein, "radiolysis stabilizers" refers to stabilizers that protect organic molecules against radiolysis, for example, when gamma rays emitted from a radionuclide are cleaving bonds between atoms of organic molecules and radicals are formed, which are then eliminated by stabilizers that prevent the radicals from undergoing any other chemical reactions that may result in undesired potentially ineffective or even toxic molecules. Therefore, these stabilizers are also called "free radical scavengers" or "radical scavengers" for short. Other alternative terms for these stabilizers are "radiostability enhancers", "radiolysis stabilizers", or simply "quenchers".

[0142] As used herein, "sequestering agent" refers to a chelating agent suitable for complexing free radionuclide metal ions in the formulation (that are not complexed with the radiolabeled peptide).

[0143] Buffers include acetate buffers, citrate buffers and phosphate buffers.

[0144] According to many embodiments of the present disclosure, the pharmaceutical composition is an aqueous solution, e.g., an injection formulation. According to certain embodiments, the pharmaceutical composition is an infusion solution.

[0145] The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of skill in the art (see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., 238-250 (1982), and SHP Handbook on Injectable Drugs, Trissel, 15th ed., 622-630 (2009)).

[0146] The following paragraphs refer to various embodiments of suitable aqueous pharmaceutical solutions for use in the combination methods of the present disclosure. The following paragraphs are provided as non-limiting.

[0147] 82.(a) (ai) Radionuclides, and (aii) a cell receptor-binding organic moiety linked to a chelator. A complex formed by (b) at least one stabilizer against radiolysis 1. An aqueous pharmaceutical solution comprising: The aqueous pharmaceutical solution in which the radionuclide is present in a concentration which provides a volumetric activity of at least 100 MBq / mL, preferably at least 250 MBq / mL.

[0148] 83. The aqueous pharmaceutical solution according to embodiment 82, wherein the stabilizer, component (b), is present in a total concentration of at least 0.2 mg / mL, preferably at least 0.5 mg / mL, more preferably at least 1.0 mg / mL, even more preferably at least 2.7 mg / mL.

[0149] 84. An aqueous pharmaceutical solution according to any one of the previous embodiments, wherein the radionuclide is present in a concentration such that it provides a volumetric radioactivity of 100-1000 MBq / mL, preferably 250-500 MBq / mL.

[0150] 85. The aqueous pharmaceutical solution according to any one of the above embodiments, wherein the stabilizer is present in a total concentration of 0.2 to 20.0 mg / mL, preferably 0.5 to 10.0 mg / mL, more preferably 1.0 to 5.0 mg / mL, and even more preferably 2.7 to 4.1 mg / mL.

[0151] 86. The aqueous pharmaceutical solution according to any one of the previous embodiments, wherein component (b) is only one stabilizer against radiolysis, i.e. only the first stabilizer.

[0152] 87. The aqueous pharmaceutical solution according to any one of the previous embodiments, wherein component (b) comprises at least two stabilizers against radiolysis, i.e. at least a first and a second stabilizer, preferably only two stabilizers, i.e. only a first and a second stabilizer.

[0153] 88. The aqueous pharmaceutical solution according to any one of embodiments 86 to 87, wherein the first stabilizer is present in a concentration of 0.2 to 5 mg / mL, preferably 0.5 to 5 mg / mL, more preferably 0.5 to 2 mg / mL, even more preferably 0.5 to 1 mg / mL, and even more preferably 0.5 to 0.7 mg / mL.

[0154] 89. The aqueous pharmaceutical solution of embodiment 87 or 88, wherein the second stabilizer is present in a concentration of 0.5 to 10 mg / mL, more preferably 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, even more preferably 2.2 to 3.4 mg / mL.

[0155] 90. The aqueous pharmaceutical solution of any one of the above embodiments, wherein the stabilizer is selected from gentisic acid (2,5-dihydroxybenzoic acid) or a salt thereof, ascorbic acid (L-ascorbic acid, vitamin C) or a salt thereof (e.g., sodium ascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine, preferably selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof.

[0156] 97. The aqueous pharmaceutical solution of any one of the previous embodiments, which is free of ethanol.

[0157] 98. The aqueous pharmaceutical solution according to any one of embodiments 86-90, wherein the first stabilizer is selected from gentisic acid and ascorbic acid, preferably, the first stabilizer is gentisic acid.

[0158] 99. The aqueous pharmaceutical solution according to any one of embodiments 87-91, wherein the second stabilizer is selected from gentisic acid and ascorbic acid, preferably, the second stabilizer is ascorbic acid.

[0159] 100. The pharmaceutical aqueous solution according to any one of embodiments 87 to 89, wherein the first stabilizer is gentisic acid or a salt thereof, the second stabilizer is ascorbic acid or a salt thereof, and the ratio of the concentration (mg / mL) of the first stabilizer to the concentration (mg / mL) of the second stabilizer is 1:3 to 1:7, preferably 1:4 to 1:5.

[0160] 101. Radioactive nuclides are 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb,213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag and 47 Sc, preferably 177 3. The aqueous pharmaceutical solution of claim 1, wherein

[0161] 102. The aqueous pharmaceutical solution according to any one of the previous embodiments, wherein the cell receptor binding moiety is a somatostatin receptor binding peptide, preferably said somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate.

[0162] 103. The aqueous pharmaceutical solution according to any one of the previous embodiments, wherein the chelating agent is selected from DOTA, DTPA, NTA, EDTA, DO3A, TETA and NOTA, preferably DOTA.

[0163] 104. The aqueous pharmaceutical solution of any one of the above embodiments, wherein the cell receptor binding moiety and the chelating agent are selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP, preferably, together form a molecule selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

[0164] 105. A complex comprising a radionuclide, a cell receptor binding moiety and a chelating agent. 177 Lu-DOTA-TOC( 177 Lu-Edotreotide) or 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide), preferably 177 The aqueous pharmaceutical solution of any one of the above embodiments, which together form Lu-DOTA-TATE.

[0165] 106. The aqueous pharmaceutical solution according to any one of the above embodiments, further comprising a buffer solution, preferably an acetate buffer in an amount to provide a concentration of 0.3-0.7 mg / mL (preferably about 0.48 mg / mL) of acetic acid and 0.4-0.9 mg / mL (preferably about 0.66 mg / mL) of sodium acetate.

[0166] 107. The aqueous pharmaceutical solution of any one of the above embodiments, further comprising a sequestering agent, preferably said sequestering agent being diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount resulting in a concentration of 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL).

[0167] 108. The aqueous pharmaceutical solution according to any one of the above embodiments, having a shelf life of at least 24 hours (h) at ≦25°C, at least 48h at ≦25°C, at least 72h at ≦25°C, from 24h to 120h at ≦25°C, from 24h to 96h at ≦25°C, from 24h to 84h at ≦25°C, from 24h to 72h at ≦25°C, in particular having a shelf life of ≦72h at ≦25°C.

[0168] 109. The aqueous pharmaceutical solution according to any one of the previous embodiments, produced in a commercial scale manufacturing, in particular in a batch size of at least 20 GBq, at least 50 GBq, or at least 70 GBq.

[0169] 110. An aqueous pharmaceutical solution according to any one of the above embodiments, which is ready for use.

[0170] 111. The aqueous pharmaceutical solution of any one of the above embodiments, for commercial use.

[0171] 112.(a) (ai) The radionuclide 177-lutetium ( 177 Lu), and (aii) Chelator-linked somatostatin receptor binding organic moieties DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide) The complex formed by; (bi) gentisic acid or a salt thereof as a first stabilizer against radiolysis, present in a concentration of 0.5 to 1 mg / mL; (bii) ascorbic acid or a salt thereof as a second stabilizer against radiolysis, present in a concentration of 2.0 to 5.0 mg / mL; 13. A pharmaceutical aqueous solution comprising:

[0172] 113.(c) Diethylenetriaminepentaacetic acid (DTPA) or its salts at a concentration of 0.01 to 0.10 mg / mL 110. The aqueous pharmaceutical solution of embodiment 109, further comprising:

[0173] 114.(d) Acetic acid at a concentration of 0.3-0.7 mg / mL and sodium acetate at a concentration of 0.4-0.9 mg / mL 111. The aqueous pharmaceutical solution of embodiment 109 or 110, further comprising:

[0174] 115. An aqueous pharmaceutical solution according to any one of the previous embodiments, wherein a stabilizer is present in the solution during the complexation of components (ai) and (aii).

[0175] 116. The aqueous pharmaceutical solution according to any one of embodiments 86 to 115, wherein only the first stabilizer is present during the complexation of components (ai) and (aii), preferably in an amount resulting in a concentration in the final solution of 0.5 to 5 mg / mL, more preferably 0.5 to 2 mg / mL, even more preferably 0.5 to 1 mg / mL, even more preferably 0.5 to 0.7 mg / mL.

[0176] 117. The aqueous pharmaceutical solution according to any one of embodiments 86 to 116, wherein a portion of the amount of the second stabilizer is already present in the solution during the complexation of components (ai) and (aii), and another portion of the amount of the second stabilizer is added after the complexation of components (ai) and (aii).

[0177] 118. The aqueous pharmaceutical solution according to any one of embodiments 86 to 117, wherein the second stabilizer is added after the complexation of components (ai) and (aii).

[0178] 119. The aqueous pharmaceutical solution according to any one of embodiments 87 to 118, wherein the second stabilizer is added after complex formation of components (ai) and (aii) in an amount that results in a concentration in the final solution of 0.5 to 10 mg / mL, more preferably 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, even more preferably 2.2 to 3.4 mg / mL.

[0179] 120. An aqueous pharmaceutical solution according to any one of the above embodiments, further comprising a sequestering agent added after complexation of components (ai) and (aii) to remove any uncomplexed Lu, preferably said sequestering agent being diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount resulting in a concentration of 0.01-0.10 mg / mL (preferably about 0.05 mg / mL) in the final solution.

[0180] 177 Lu-DOTA-TATE or 177 An infusion solution of Lu-DOTA-TOC, for example, with a specific activity concentration of 370 MBq / mL (±5%) is often used in the combination methods of the present disclosure.

[0181] A particular method for producing the aqueous pharmaceutical solution defined in any one of the above embodiments comprises the following method steps: (1) (1.1) preparing an aqueous solution containing a radionuclide; (1.2) preparing an aqueous solution containing a chelator-linked cell receptor binding organic moiety, a first stabilizer, and optionally a second stabilizer; and (1.3) mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture; forming a complex of a radionuclide and a chelator-linked cell receptor binding organic moiety by: (2) (2.1) preparing an aqueous dilute solution, optionally including a second stabilizer; and (2.2.) Mixing the complex solution obtained in step (1) with the diluted solution obtained in step (2.1) Diluting the complex solution obtained in step (1) by may include.

[0182] Radiation therapy used in combination therapy In one embodiment, a method of treating glioblastoma in a subject in need of such treatment comprises irradiating the subject with an effective dose of ionizing radiation, i.e., radiation therapy.

[0183] As used herein, the term "radiotherapy" is used for the treatment of neoplastic diseases with irradiation corresponding to ionizing radiation, which deposits energy that damages or destroys cells in the area being treated (target tissue) by damaging their genetic material, making them unable to continue growing.

[0184] In a specific embodiment, the method of the present disclosure includes exposing the tumor to be treated to an effective dose of ionizing radiation, said ionizing radiation being photons, e.g., X-rays. Depending on the amount of energy it has, the light beam can be used to destroy cancer cells on the surface of the body or deeper inside 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 of increasingly greater energy. The use of machines to focus radiation (e.g., X-rays) on the cancer site is called external beam radiation therapy.

[0185] In an alternative embodiment of the method of treatment according to the present disclosure, gamma rays are used. Gamma rays are produced naturally as certain elements (e.g., radium, uranium, and cobalt-60) emit radiation upon their decomposition, or decay.

[0186] The ionizing radiation is typically from 2 keV to 25000 keV, in particular from 2 keV to 6000 keV (ie 6 MeV) or from 2 keV to 1500 keV (eg Cobalt 60 source).

[0187] Those skilled in the art of radiotherapy know how to determine appropriate dosing and application schedules depending on the nature of the disease and the patient profile, in particular how to assess dose-limiting toxicities (DLTs) and accordingly determine the maximum tolerated dose (MTD).

[0188] The amount of radiation used in radiation therapy is measured in grays (Gy) and varies depending on the type and stage of the cancer being treated. For curative cases, typical total doses for solid tumors range from 20 to 120 Gy. Many other factors are considered by the radiation oncologist when selecting the dose, including whether the patient has received chemotherapy, the patient's comorbidities, whether radiation therapy is administered pre- or post-operatively, and the degree of success of surgery.

[0189] The total dose is typically fractionated (spread over time). The amount and schedule (planning and delivery of ionizing radiation, fractionated doses, fractionated delivery schemes, total dose alone or in combination with other anticancer drugs, etc.) are defined for any disease / anatomical site / stage patient setting / age and constitute the standard of care for any specific situation.

[0190] A typical conventional fractionation schedule for adults for the methods of the present disclosure can be 1-4 Gy per day, preferably about 2 Gy / day, for 3-7 days, preferably about 5 days per week, for a period of 4-8 weeks, preferably 6 weeks. In a specific embodiment, the radiation therapy consists of exposing the subject to a total dose of ionizing radiation of 50-70 Gy, e.g., 60 Gy.

[0191] In another specific embodiment, the subject is exposed to ionizing radiation at a dose per fraction of about 2-12 Gy, with the total dose preferably being administered in up to 6 fractions, in other words, the radiation therapy is administered for 5 consecutive days followed by 2 days of rest for 6 consecutive weeks.

[0192] In a specific embodiment in which the subject is afflicted with glioblastoma, the radiation therapy applied in the methods disclosed herein is whole brain radiation therapy (WBRT).

[0193] Alkylating Agents Used in Combination Therapy A method of treating glioblastoma in a subject in need of such treatment comprises administering to said subject a radiopharmaceutical compound, optionally in combination with radiation therapy and with a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0194] The alkylating agent is - Nitrogen mustards: such as mechlorethamine (nitrogen mustard), chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan; - Nitrosoureas: e.g., streptozocin, carmustine (BCNU), and lomustine; - Alkyl sulfonates: busulfan; - triazines: dacarbazine (DTIC) and temozolomide (Temodar®); and - Ethylenimines: Thiotepa and Altretamine (Hexamethylmelamine) are divided into different classes including

[0195] As used herein, "temozolomide" refers to a triazine alkylating agent, more specifically a compound of formula 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide and its pharma- ceutically acceptable salts (CAS number 85622-93-1). Alkylating agents directly damage DNA (the genetic material in each cell) to prevent cell proliferation. These drugs function in all phases of the cell cycle and are used to treat many different cancers, including glioblastoma, leukemia, lymphoma, Hodgkin's disease, multiple myeloma, and sarcoma, as well as lung, breast, and ovarian cancers.

[0196] In one embodiment, the alkylating agent, preferably temozolomide, is administered at 50-100 mg / m each day for a period of 4-8 weeks, preferably 6 weeks, during the induction phase. 2 / day, preferably about 75 mg / m 2 It is administered at a dose of / day.

[0197] As used herein, "induction phase" refers to the period during which the alkylating agent, preferably temozolomide, is first administered to a subject, which period has a duration of up to 11 weeks, e.g., from week 1, day 1 to the end of week 11, day 7.

[0198] In one embodiment, both radiation therapy and the alkylating agent, preferably temozolomide, are initiated on the same day. In some aspects, the alkylating agent, preferably temozolomide, is administered concomitantly with radiation therapy without interruption.

[0199] In one embodiment, the alkylating agent, preferably temozolomide, is administered daily at a first dose during co-administration with radiation therapy, e.g., for a period of 6 weeks, and at a second dose during a maintenance phase following co-administration with radiation therapy, e.g., for a period of up to 24 weeks, wherein the second dose is at least twice the first dose of the radiopharmaceutical compound.

[0200] As used herein, "maintenance phase" refers to a period beginning, for example, on day 1 of the 12th week after the induction phase or coadministration with radiation therapy, with a duration of up to 25 weeks, in which the dose is increased compared to the dose in the induction phase. In a specific embodiment, in this maintenance phase, the alkylating agent, preferably temozolomide, is administered at 50-400 mg / m each day for 5 consecutive days every 28 days for a period of 20-28 weeks, preferably 24 weeks. 2 / day, preferably 75-300 mg / m 2 / day, more preferably 150-200 mg / m 2 / day followed by 2 days off treatment.

[0201] In one embodiment, the alkylating agent, preferably temozolomide, is formulated for oral administration.

[0202] Combination therapy In a specific embodiment, the method of treating glioblastoma in a subject in need of such treatment comprises administering to said subject an effective amount of a radiopharmaceutical compound, preferably 177 Lu]Lu-DOTA-TATE( 177 Lu-oxodotreotide).

[0203] In another embodiment, the present disclosure is directed to a method of treating glioblastoma in a subject in need of treatment comprising administering to the subject an effective amount of a radiopharmaceutical compound in combination with irradiating the subject with an effective dose of ionizing radiation, and optionally with a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0204] Accordingly, the present disclosure relates to a radiopharmaceutical compound for use in the treatment of glioblastoma in a subject in need thereof, wherein a therapeutically effective amount of said radiopharmaceutical compound is administered to said subject in combination, simultaneously, separately or sequentially with radiation therapy, and optionally with a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0205] The present disclosure also relates to the use of a radiopharmaceutical compound in the preparation of a medicament for use in the treatment of glioblastoma in a subject in need thereof, wherein a therapeutically effective amount of said radiopharmaceutical compound is administered to said subject in combination, simultaneously, separately or sequentially with radiation therapy, and optionally with a therapeutically effective amount of an alkylating agent, preferably temozolomide.

[0206] In various embodiments of the present disclosure, the combination therapy comprises (i) administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a radiopharmaceutical compound; and (ii) irradiating the subject with an effective dose of ionizing radiation, and optionally, (iii) in combination with administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an alkylating agent, preferably temozolomide.

[0207] As used herein, the term "in conjunction" means that the therapeutic agents may be given separately (in a chronologically staggered manner, particularly in a sequence-specific manner) at time intervals such that they exhibit a (preferably synergistic) interaction (i.e., a synergistic therapeutic effect).

[0208] In various embodiments of the present disclosure, a radiopharmaceutical compound (e.g., 177

[0036] A combination administration in which the combination partners are administered simultaneously or separately within a time interval, particularly such that the time interval allows the combination partners to exhibit a coordinated, e.g., synergistic, effect.

[0209] In one embodiment, the radiopharmaceutical compound is first administered 1 to 20 days, preferably 3 to 15 days, more preferably 7 to 10 days prior to the initiation of radiation therapy.

[0210] Administration of the radiopharmaceutical compound may involve treatment intervals of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 or 4 weeks, more preferably every 3 weeks.

[0211] Advantageously, the combined effect of the radiopharmaceutical compound and radiation therapy treatment regimen increases the overall response rate by at least 10%, 20%, 30%, 40%, or at least 50% compared to radiation therapy alone.

[0212] The single components or their precursors, typically unlabeled DOTATE, can be packaged in the kit or separately. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration.

[0213] In certain embodiments, administration of a composition comprising a radiopharmaceutical compound to a subject eligible for said treatment may inhibit, delay and / or reduce tumor growth in the subject. In certain embodiments, tumor growth is delayed by at least 30%, 40%, 50% or 60% compared to an untreated control subject. In certain embodiments, tumor growth is delayed by at least 60% compared to an untreated control subject. In certain embodiments, tumor growth is delayed by at least 30%, 40%, 50% or 6% compared to the expected growth of the tumor without treatment. In certain embodiments, tumor growth is delayed by at least 60% compared to the expected growth of the tumor without treatment.

[0214] In some embodiments, administration of a composition comprising a radiopharmaceutical composition to a subject eligible for said treatment may increase the length of survival of the subject. In some embodiments, the increase in survival is compared to an untreated control subject. In some embodiments, the increase in survival is compared to the expected length of survival of a subject without treatment. In some embodiments, the length of survival is increased by at least 1.1-fold, 1.2-fold, 1.3-fold, or 1.4-fold compared to an untreated control subject. In some embodiments, the length of survival is increased by at least 1.2-fold compared to an untreated control subject. In some embodiments, the length of survival is increased by at least 1.1-fold, 1.2-fold, 1.3-fold, or 1.4-fold compared to the expected length of survival of a subject without treatment. In some embodiments, the length of survival is increased by at least 1.2-fold compared to the expected length of survival of a subject without treatment. In some embodiments, the length of survival is increased by at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months compared to an untreated control subject. In some embodiments, the length of survival is increased by at least 3 months or 4 months compared to untreated control subjects. In some embodiments, the length of survival is increased by at least 1 month, 2 months, 3 months, 4 months, or 6 months compared to the expected length of survival of a subject without treatment. In some embodiments, the length of survival is increased by at least 3 months or 4 months compared to the expected length of survival of a subject without treatment.

[0215] Methods for selecting subjects for combination treatment In one embodiment of the present disclosure, the glioblastoma is an SSTR positive disease. In one embodiment, the subject is selected for treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with the same radiopharmaceutical compound as defined for treatment, except that M is a radiometal suitable for imaging, i.e., imaging radiopharmaceutical compound. Exemplary 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 Ru, 203 Pb, 62 Cu, 64 Cu, 61 Cu 177 Lu, 86 Y, 51 Cr, 52m Mn, 157 Gd, 169 Yb, 172 Tm, 117m Sn, 123 I, 124 I, 125 I, 18 F, Al 18 F, 152 Tb, 155 Tb, 82 Rb, 89 Zr, 43 Sc, 44 Sc is an example.

[0216] According to a preferred embodiment, the radiometal suitable for imaging is 67 Ga, 68 Ga or 64 Cu, preferably 68 It's Ga.

[0217] In one embodiment, the subject is assessed for tumor area, e.g., by PET / CT or PET / MRI scan of the whole brain [ 68 The IL-16 receptor agonist (IL-16) is selected by assessing the uptake of [Ga]Ga-DOTA-TATE.

[0218] Thus, the present disclosure also provides a method for determining whether a human patient having glioblastoma may be selected for combination therapy, comprising: (i) administering an effective amount of an imaging radiopharmaceutical compound as an imaging agent for imaging uptake of said radiopharmaceutical compound; (ii) acquiring images by PET / MRI or PET / CT of the patient; and (iii) comparing with a control image The present invention relates to a method comprising the steps of:

[0219] The aim of the above method is to select patients with SSTR-positive tumors, i.e., good responders to treatment with the radiopharmaceutical compounds of the present disclosure. SSTR-positive tumors can be advantageously detected by evaluating the uptake of said imaging radiopharmaceutical compound by PET / MRI or PET / CT imaging after injection of said imaging radiopharmaceutical compound as a contrast agent.

[0220] As used herein, a good responder is a patient selected from a patient population that exhibits a statistically better response to the treatment compared to a randomized patient population (i.e., not selected by the selection step of the method) and / or exhibits fewer side effects to the treatment compared to a randomized patient population (i.e., not selected by the selection step of the method).

[0221] In one embodiment, 68 [Ga]Ga-DOTA-TATE is provided in a kit called NETSPOT® (Gallium Ga68 dotatate (USAN)). This kit has been approved in the United States (USA) (2016), Canada (2019) and Switzerland (2019) for the following indications: 68 For radiopharmaceutical formulation of Ga]Ga-DOTA-TATE:( 68 Ga) and then formulated for use in PET for the localization of SSTR-positive neuroendocrine tumors (NETSPOT® PI).

[0222] In one embodiment, subject selection is performed 10-18 days, preferably about 14 days, prior to the first administration of the radiopharmaceutical compound.

[0223] In one embodiment, the imaging radiopharmaceutical is administered at a dose of 1.5 MBq / kg (0.040 mCi / kg) to 2.5 MBq / kg (0.067 mCi / kg), preferably about 2 MBq / kg body weight (0.054 mCi / kg), with a minimum dose of 100 MBq (2.7 mCi) and a maximum dose of 200 MBq (5.4 mCi), typically by intravenous injection, preferably by slow intravenous injection.

[0224] Images of the subject's body are then obtained by PET / MRI or PET / CT imaging and the images are compared to control images to determine whether lesions identified by conventional imaging, e.g., MRI, CT, SPECT or PET, have increased uptake of the imaging radiopharmaceutical compound, i.e., [ 68 The tumor is also identified by uptake of [Ga]Ga-DOTA-TATE. Typically, PET / MRI or PET / CT imaging is performed 30-120 minutes, preferably 60-90 minutes, after intravenous administration of the imaging radiopharmaceutical compound to the subject.

[0225] In a specific embodiment of the method, a subject is selected for the combination therapy of the present disclosure and meets the following conditions: 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 in said subject, e.g., by MRI, CT, SPECT or PET, have an uptake of the imaging radiopharmaceutical compound as determined by PET / MRI or PET / CT imaging in said subject, e.g., [ 68 They are also identified by the uptake of [Ga]Ga-DOTA-TATE.

[0226] In a specific embodiment, 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.

[0227] In certain embodiments, the subject is newly diagnosed with glioblastoma or suffers from recurrent glioblastoma.

[0228] In another embodiment, the subject is further selected by evaluating its methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.Typically, the subject to receive an alkylating agent, preferably temozolomide, is selected from the subjects with a positive MGMT promoter status.

[0229] Patients who carry methylation in the MGMT promoter in their tumors are the majority who benefit from alkylating agents, such as temozolomide. In some embodiments, in this patient group with methylated MGMT promoter, the radiopharmaceutical compound of the present disclosure can be evaluated in combination with concomitant radiation therapy and alkylating agents, preferably temozolomide, and then the radiopharmaceutical compound can be evaluated in combination with a maintenance alkylating agent, preferably temozolomide. EXAMPLES

[0230] Example 1: Clinical Trial to Treat Glioblastoma Subjects In combination with radiotherapy with or without temozolomide in newly diagnosed glioblastoma and as a single agent in recurrent glioblastoma 177An example protocol describing a prospective Phase Ib dose-finding study evaluating the safety and activity of [Lu]Lu-DOTA-TATE is provided herein.

[0231] [Table 1]

[0232] [Table 2]

[0233] [Table 3]

[0234] [Table 4]

[0235] [Table 5]

[0236] [Table 6]

[0237] [Table 7]

[0238] [Table 8]

[0239] [Table 9]

[0240] [Table 10]

[0241] [Table 11]

[0242] [Table 12]

[0243] [Table 13]

[0244] The study for each participant consisted of a screening period, a treatment period, and a 12-month follow-up period.

[0245] Eligible participants with newly diagnosed glioblastoma will be assigned to Arm 1 or Arm 2 according to MGMT promoter methylation status: Group 1: Combined radiation therapy and temozolomide 177 [Lu]Lu-DOTA-TATE and subsequent maintenance 177 Participants with newly diagnosed glioblastoma harboring a methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter treated with]Lu-DOTA-TATE and temozolomide. Group 2: Combined with radiation therapy 177 Lu]Lu-DOTA-TATE followed by [ 177 Participants with newly diagnosed glioblastoma harboring an unmethylated MGMT promoter treated with]Lu-DOTA-TATE alone.

[0246] Eligible participants with recurrent glioblastoma were assigned to Arm 3 and were randomized to receive 177 Receive [Lu]Lu-DOTA-TATE.

[0247] [Table 14]

[0248] The three arm clinical trial design is depicted below:

[0249] [Table 15]

[0250] [Table 16]

[0251] [Table 17]

Claims

1. 1. A pharmaceutical composition for use in a method of treating glioblastoma in a subject in need thereof, comprising administering to said subject an effective amount of a radiopharmaceutical compound in combination with irradiating said subject with an effective dose of ionizing radiation.

2. The radiopharmaceutical compound has the formula: M-C-S-P (In the formula, M is a radionuclide; C is a chelating agent capable of chelating said radionuclide; S is an optional spacer covalently linking C and P; P is a somatostatin receptor-binding peptide covalently linked to C directly or indirectly via S.

2. The pharmaceutical composition of claim 1, wherein the compound is

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

4. 2. The pharmaceutical composition of claim 1, wherein C is selected from DOTA (tetrazoxetan), trizoxetan, DTPA, NTA, EDTA, DO3A, TETA, NOTA, NOTAGA, NODOGA, NODASA, NODAPA, and AAZTA (e.g., AAZTA5) chelators, preferably a DOTA, NOTA, or DTPA chelator, more preferably a DOTA chelator.

5. 2. The pharmaceutical composition of claim 1, wherein P is selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably octreotide and octreotate.

6. 2. The pharmaceutical composition of claim 1, wherein the radiopharmaceutical compound is selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), satreotide tetraxetane, DOTA-LAN, and DOTA-VAP, preferably DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

7. The radiopharmaceutical compound is １７７ Lu】Lu-DOTA-TOC( １７７ Lu-edotreotide) or [ １７７ Lu】Lu-DOTA-TATE( １７７ Lu-oxodotreotide), more preferably １７７ Lu】Lu-DOTA-TATE( １７７ 2. The pharmaceutical composition of claim 1, wherein the compound is benzodiazepine (DHT-1), ...

8. The pharmaceutical composition of claim 1, wherein the method further comprises administering a therapeutically effective amount of an alkylating agent, preferably temozolomide.

9. The alkylating agent, preferably temozolomide, is administered at 50-100 mg / m each day for a period of 4-8 weeks, preferably 6 weeks, during the induction period. ２ / day, preferably about 75 mg / m ２ 10. The pharmaceutical composition of claim 1, wherein the composition is administered in a dose of 0.1 mg / day.

10. 2. The pharmaceutical composition of claim 1, wherein both the radiation and the alkylating agent, preferably temozolomide, are started on the same day.

11. 2. The pharmaceutical composition of claim 1, wherein the alkylating agent, preferably temozolomide, is administered in combination with radiation without interruption.

12. 2. The pharmaceutical composition of claim 1, wherein the alkylating agent, preferably temozolomide, is administered daily at a first dose during the combined administration with the radiotherapy, e.g., for a period of 6 weeks, and at a second dose during a maintenance phase following the combined administration with the radiotherapy, e.g., for a period of up to 24 weeks, wherein the second dose is at least twice the first dose.

13. The alkylating agent, preferably temozolomide, is administered at a dose of 50-400 mg / m 2 each day for 5 consecutive days every 28 days for a period of 20-28 weeks, preferably 24 weeks, during the maintenance phase. ２ / day, preferably 75 to 300 mg / m ２ / day, more preferably 150 to 200 mg / m ２ 10. The pharmaceutical composition of claim 1, wherein the composition is administered at a dose of 100 mg / day followed by a two-day rest period.

14. 2. The pharmaceutical composition of claim 1, wherein the subject is selected from subjects with a positive methylated O-6-methylguanine-DNA methyltransferase promoter status.

15. 2. The pharmaceutical composition of claim 1, 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), 5.55 GBq (150 mCi), 7.4 GBq (200 mCi) or 9.25 GBq (250 mCi).

16. 10. The pharmaceutical composition of claim 1, wherein said radiopharmaceutical compound is administered 1 to 8 times per treatment, preferably 2 to 7 times per treatment, more preferably 4 to 6 times per treatment during the induction phase.

17. 2. The pharmaceutical composition of claim 1, wherein the radiopharmaceutical compound comprises a treatment interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks or even 6 weeks, preferably 3 or 4 weeks, more preferably every 3 weeks.

18. 10. The pharmaceutical composition of claim 1, wherein the first dose of the radiopharmaceutical compound is administered 1 to 20 days, preferably 3 to 15 days, more preferably 7 to 10 days before the start of radiation.

19. 2. The pharmaceutical composition of claim 1, wherein the radiation induction is carried out at a dose of 1 Gy to 4 Gy / day, preferably about 2 Gy / day, for a period of 3 to 7 days, preferably about 5 days, per week for a period of 4 to 8 weeks, preferably 6 weeks.

20. 10. The pharmaceutical composition of claim 1, wherein the radiation is administered for 5 consecutive days followed by 2 days of rest for 6 consecutive weeks.

21. The pharmaceutical composition of claim 1 , wherein the radiation is whole brain radiation.

22. The object is １７７ Instead of Lu, a radiometal suitable for imaging, preferably ６８ Ga, ６７ Ga or ６４ Cu, more preferably ６８ 2. The pharmaceutical composition of claim 1, selected for said treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with the same radiopharmaceutical compound as defined for said treatment, except with Ga, by assessing the uptake of said radiopharmaceutical compound suitable for imaging in said subject.

23. 10. The pharmaceutical composition of claim 1, wherein the subject is newly diagnosed with glioblastoma or suffers from recurrent glioblastoma.

24. 24. The pharmaceutical composition of claim 23, wherein the subject is newly diagnosed with glioblastoma and has a positive methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound is administered to the subject in combination with radiation therapy and an alkylating agent, preferably temozolomide, and wherein a first dose of the radiopharmaceutical compound is administered preferably 7-10 days before the start of radiation therapy.

25. 24. The pharmaceutical composition of claim 23, wherein the subject is newly diagnosed with glioblastoma and has a negative methylated O-6-methylguanine-DNA methyltransferase promoter status, and the radiopharmaceutical compound is administered to the subject in combination with radiation therapy and not in combination with other chemotherapeutic agents, such as temozolomide; the treatment interval between two administrations of the radiopharmaceutical compound is 4 weeks for the first two intervals and 3 weeks for the third and any subsequent intervals; and the first dose of the radiopharmaceutical compound is preferably administered 7 to 10 days before the start of radiation therapy.